TYK2 INHIBITORS AND USES THEREOF

INHIBITEURS DE TYK2 ET LEURS UTILISATIONS

English Abstract

Described herein are compounds that are TYK2 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of TYK2 activity.

French Abstract

L'invention concerne des composés qui sont des inhibiteurs de TYK2, des procédés de fabrication de tels composés, des compositions pharmaceutiques et des médicaments comprenant de tels composés et des procédés d'utilisation de tels composés dans le traitement d'états pathologiques, de maladies ou de troubles qui pourraient bénéficier de la modulation de l'activité de TYK2.

Claims

111
CLAIMS
What is claimed is:
1. A compound of Formula (I):
Image
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
Ring A is an unsubstituted or substituted 6-membered heterocyclic ring wherein
Al and
A2 are independently N or C, wherein if Ring A is substituted then Ring A is
substituted with p instances of le;
each R8 is independently hydrogen, halogen, unsubstituted or substituted C1-C6
alkyl,
unsubstituted or substituted Cl-C6 deuteroalkyl, unsubstituted or substituted
C2 -
Ch alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or
substituted Ci-C 6 fluoroalkyl, unsubstituted or substituted Cr-C6
heteroalkyl,
unsubstituted or substituted carbocycle, unsubstituted or substituted
heterocycle, -
CN, -OH, -OR'', -C(=0)R1 6, -CO2R16, -C(=0)N(R16)2, -N(R' 6)2, -NR'6C(=0)R'7,
-SR'', -S(=0)R1 7, -S02R1 7, or -SO2N(Rl6)2, wherein if R8 is attached to a
nitrogen atom, then R8 is hydrogen, unsubstituted or substituted Ci-C6 alkyl,
unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted
C2 -
C 6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or
substituted Cr-C 6 fluoroalkyl, unsubstituted or substituted Cr-C6
heteroalkyl,
unsubstituted or substituted carbocycle, unsubstituted or substituted
heterocycle, -
C(-0)R16, -CO2Rl6, -C(=0)N(R1-6)2, -S(-0)R17, -502R17, or -SO2N(R16)2, or two
R8 attached to the same carbon atom are taken together to form =0, =S, or
=1\11-1;
z is _moo-, _0_, _S-, -S(=0)-, or -S02-;
Itm is hydrogen, Cr-C6 alkyl, Cr-C6 deuteroalkyl, Ci-C6 fluoroalkyl, C3-C6
cycloalkyl, or monocyclic heterocycle,
X', X2, and X' are each independently CRH or N;
each R11 is independently hydrogen, halogen, unsubstituted or substituted C1-
C6
alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or
substituted C2-
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112
C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or
substituted C1-C 6 heteroalkyl, un substituted or substituted carbocycle,
unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=c)R16, -CO2R16,
-
C(=0)N(R16)2, N(R16)2, NR16C(_0)R17, SR16, s(_0)R17, 502R17, or -
SO2N(R16)2;
B1 is N or CR12a;
B2 is N or CR1 2b,
R and Ri2b are each independently hydrogen, halogen,
unsubstituted or substituted
C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or
substituted C2-C6 alkynyl, unsubstituted or substituted CI-C6 fluoroalkyl,
unsubstituted or substituted Cl-C6 heteroalkyl, unsubstituted or substituted
carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -
C(=0)R16, -CO2R16, -C(=0)N(R16)2, -NR16)2,
0)R17, -SR16, -S(=0)R17,
-SO2R17, or -SO2N(R16)2;
R1 is hydrogen, Ci-C6 alkyl, or Ci-C6 fluoroalkyl;
R2 is a Ring B that is an unsubstituted or substituted heterocycle or
unsubstituted or
substituted carbocycle, wherein if Ring B is substituted then Ring B is
substituted
with q instances of R'1;
each R13 is independently halogen, unsubstituted or substituted Ci-C6 alkyl,
unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6

alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or
substituted Cl-C6 heteroalkyl, unsubstituted or substituted carbocycle,
unsubstituted or substituted heterocycle, -CN, -OH,
-C(=0)R'6, -CO2R'6, -
C(=0)N(R16)2, _N(R16)2, _NR16C(_0)R17, _SR16, _s(_0)R17,502R17, or -
SO2N(R16)2;
or two R13 groups on adjacent atoms of Ring B are taken together with the
intervening atoms to which they are attached to form an unsubstituted or
substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or
substituted 5- or 6-membered monocyclic heterocycle;
or R2 is -C(=0)R14, _C(_(D)NR14R15, or -C(=0)0R14;
RIA is hydrogen, unsubstituted or substituted Cl-C6 alkyl, Ci-C6 deuteroalkyl
unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6

alkynyl, unsubstituted or substituted Ci-C6 heteroalkyl, unsubstituted or
substituted monocyclic carbocycle, unsubstituted or substituted bicyclic
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carbocycle, unsubstituted or substituted monocyclic heterocycle, or
unsubstituted
or sub stituted bi cycl i c heterocycl e;
R15 is hydrogen, C1-C6 alkyl, or CI -C6 fluoroalkyl;
or R14 and R15 are taken together with the intervening atoms to which they are

attached to form an unsubstituted or substituted 4- to 6-membered monocyclic
heterocycle;
or R' and R' 5 are taken together with the intervening atoms to which they are
attached to form an unsubstituted or substituted 5- or 6-membered monocyclic
heterocycle;
W is -NR3- or -0-;
R3 i s hydrogen, Cl-C6 alkyl, Ci-C6 deuteroalkyl, C1-C6 fluoroalkyl, C 3-C6
cycloalkyl, or
monocyclic heterocycle;
i s hydrogen, C1-C6 alkyl, CI-C6 deuteroalkyl, CI-C6 fluoroalkyl, C 3-C6
cycloalkyl, or
monocyclic heterocycle;
or R3 and R4 are taken together with the N atom to which they are attached to
form a
substituted or unsubstituted N-containing heterocycle;
or R3 and R12a are taken together with the intervening atoms to which they are
attached to
form a substituted or un substituted 5- or 6-membered heterocycl e;
R5 is hydrogen, Ci -C6 alkyl, C1 -C6 fluoroalkyl, C3-C6 cycloalkyl, or
monocyclic
heterocycle;
each R6 and R7 is independently hydrogen, deuterium, halogen, Ci-C6 alkyl, Ci-
C6
deuteroalkyl, Cl-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle, -
CN, -
OH, -OR', -C(=0)R'6, -0O2R16, -C(=0)N(R'6)2, -N(R'6)2, -
NR 16C(_c)Rt7, _SRt6,
S(=0)R17, -S021117, or -SO2N(R16)2;
or one R6 and one R7 attached to the same carbon atom are taken together with
the
carbon atom to which they are attached to form C=0 or C3-C4 cycloalkyl;
each R16 is independently hydrogen, substituted or unsubstituted Ci-C6 alkyl,
substituted
or unsubstituted Ci-C6 fluoroalkyl, substituted or unsubstituted Ci-C6
heteroalkyl,
substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted
monocyclic 3- to 8-membered hacrocycloalkyl, substituted or unsubstitutcd
phenyl,
or substituted or unsubstituted monocyclic heteroaryl;
or two R16 on the same N atom are taken together with the N atom to which they
are
attached to form a substituted or unsubstituted N-containing heterocycle; and
each R17 is independently substituted or unsubstituted Cl-C6 alkyl,
substituted or
unsubstituted CI-C6 fluoroalkyl, substituted or unsubstituted CI-C6
heteroalkyl,
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substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted
monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted
phenyl,
or substituted or unsubstituted monocyclic heteroaryl;
wherein each substituted alkyl, substituted fluoroalkyl, substituted
deuteroalkyl,
substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl,
substituted
carbocycle, and substituted heterocycle is substituted with one or more Rs
groups
independently selected from the group consisting of deuterium, halogen, Cl-C6
alkyl,
monocyclic carbocycle, monocyclic heterocycle, -CN, -CH7CN, -OR", -CH20108, -
CO2R18, -CH2CO2R18, -C(-0)N(R18)2, -CH2C(=0)N(R18)2, -N(R18)2, -CH2N(R18)2, -
NR"C(=0)R18, -CH2NR18C(=0)R", -NR"SO2R19, -CH2NR18S02R19, -SR", -
CH2SR18, -S(=0)109, -CH2S(=0)109, -SO2R1-9, -CH2S02R1-9, -SO2N(R18)2, or -
CH2S02N(R")2;
each R" is independently selected from hydrogen, CI-C6 alkyl, CI-C6
fluoroalkyl,
Ci-C6 heteroalkyl, G3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-

membered heteroaryl and 6-membered heteroaryl;
or two R18 groups are taken together with the N atom to which they are
attached to
form a N-containing heterocycle;
each R" is independently selected from Ci-C6 alkyl, Cl-C6 heteroalkyl, C3-C6
cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and

6-membered heteroaryl;
n is 1, 2, or 3;
p is 0, 1, 2, 3, or 4; and
q is 0, 1, 2, 3, or 4.
2. The compound of claim 1, or a pharmaceutically acceptable salt,
tautomer, or solvate
thereof, wherein R1 is hydrogen or Cl-C4 alkyl.
3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable
salt, tautomer, or
solvate thereof, wherein R5 is hydrogen or Cl-C4 alkyl.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable
salt, tautomer,
or solvate thereof, wherein R5 is hydrogen.
5. The compound of any onc of claims 1-4, or a pharmaceutically acceptable
salt, tautomer,
or solvate thereof, wherein W is -NR3-.
6. The compound of claim 5, or a pharmaceutically acceptable salt,
tautomer, or solvate
thereof, wherein re is hydrogen, C i-C4 alkyl, or CI-C4 deuteroalkyl.
7. The compound of claim 5 or claim 6, or a pharmaceutically acceptable
salt, tautomer, or
solvate thereof, wherein 1 is hydrogen.
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8. The compound of any one of claims 1-7, or a pharmaceutically acceptable
salt, tautomer,
or solvate thereof, wherein ie is hydrogen, C1-C24 alkyl, or C i-C4
deuteroalkyl.
9. The compound of claim 1 having a structure of Formula (II):
Image
or a pharmaceutically acceptable salt, tautomer, or solvate thereof
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable
salt, tautomer,
or solvate thereof, wherein:
X1 is CR", X2 is CR", and X3 is CR";
or is CR", X2 is CR", and X3 is N;
or X' is CR", X2 is N, and X3 is CR";
or Xl is CR", X2 is N, and X3 is N;
or X1 is N, X2 is CR", and X3 is CR";
or XI is N, X2 is CR11, and X3 is N;
or X' is N, X2 is N, and X3 is CR11.
11. The compound of any one of claims 1-10, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein:
XI is CR", X2 is CR", and X3 is CR";
or X1 is CR", X2 is CR", and X3 is N;
or Xl is CR", X2 is N, and X3 is CR";
or Xl is N, X2 is CR11, and X3 is CR".
12. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein:
Xl is CR", X2 is CR", and X3 is CR".
13. The compound of any one of claims 1-12, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein each R" is independently hydrogen,
halogen, Cl-C6
alkyl, Ci-C6 fluoroalkyl, -CN, -OH, -0R1-7, or -N(R16)2.
14. The compound of any one of claims 1-13, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein each RH is independently hydrogen or
fluoro.
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15. The compound of claim 1 having a structure of Formula (IV).
Image
or a phaunaceutically acceptable salt, tautomet, or solvate thereof.
16. The compound of any one of claims 1-15, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein Ring A is an unsubstituted or
substituted 6-
membered heteroaryl ring wherein A' and A' are independently N or C, wherein
if Ring
A is substituted then Ring A is substituted with p instances of R8.
17. The compound of any one of claims 1-16, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein Ring A is an unsubstituted or
substituted pyridine,
unsubstituted or substituted pyridazine, unsubstituted or substituted
pyrimidine,
unsubstituted or substituted pyrazine, unsubstituted or substituted triazine,
or
unsubstituted or substituted pyridone, wherein if Ring A is substituted then
Ring A is
substituted with p instances of
18. The compound of any one of claims 1-17, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein Ring A is an unsubstituted or
substituted pyridine,
unsubstituted or substituted pyrimidine, unsubstituted or substituted
pyrazine, or
unsubstituted or substituted pyridone, wherein if Ring A is substituted then
Ring A is
substituted with p instances of R8.
19. The compound of any one of claims 1-18, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein Ring A is an un substituted or
substituted pyri done;
wherein if Ring A is substituted then Ring A is substituted with p instances
of R8.
20. The compound of any one of claims 1-18, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein Ring A is an unsubstituted or
substituted pyridine,
or unsubstituted or substituted pyrimidine, wherein if Ring A is substituted
then Ring A
i s substituted with p instances of 118
21. The compound of claim 1 having a structure of Formula (VI):
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Image
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
(i) A' and A2 are each C; and A6, A7, Ag, and A9 are each independently Cle or
N;
(ii) i s N; A2 i s C; A6, A7, and Ag are each independently Clr or N; and
A9 is C(=0);
(iii) Al is C; A2 is N; A6 is C(-0); and A7, A8, and A9are each independently
CR8 or N;
or
(iv) Al and A2 are each C; one of A6, A7, A8, and A9is NR8, wherein A6, A7,
Ag, or A9
adjacent to the NR8 is C(-0) and the remaining members of A6, A7, Ag, and
A9are
each independently CR8 or N.
22. The compound of claim 21, or a pharmaceutically acceptable
salt, tautomer, or solvate
thereof, wherein:
A' is C; A2 is C; A6 is N; A7 is CRg; Ag is CRg; and A9 is CRg;
or Al is C; A2 is C; A6 i s CR8; A7 is N; Ag is CRg; and A9 is CRg;
or A' is C; A2 is C; A6 is CR8; A7 is CR8; g is N; and A9 is CR8;
or Al is C; A2 is C; A6 is CR8; A7 is CR8; Ag is CRg; and A9 is N;
or Al is N; A2 is C; A6 is CRg; A7 is CRg; Ag is CRg; and A9 is C(=0);
or Al is C; A2 is N; A6 is C(-0); A7 is CR8; A8 is CR8; and A9 is CRg;
or Al is C; A2 is C; A6 is Nits; A7 is C(=0); A8 is CR8; and A9 is CRg;
or Al is C; A2 is C; A6 is C(=0); A7 is NR8; A8 is CR8; and A9 is CRg;
or Al is C; A2 is C; A6 is CR8; A7 is NR8; A8 is C(-0); and A9 is CR8;
or Al is C; A2 is C; A6 is CR8; A7 is C(-0); A8 is NR8; and A9 is CR8;
or Al is C; A2 is C; A6 is CRg; A7 is CRg; Ag is NR8; and A9 is C(=0);
or Al is C; A2 is C; A6 is CRg; A7 is CRg; Ag is C(=0); and A9 is NRg;
or Al is C; A2 is C; A6 i s N; A7 is N; A8 is CR8; and A9 is CR8;
or Al is C; A2 is C; A6 is N; A7 is CR8; A8 is N; and A9 is CR8;
or Al is C; A2 is C; A6 is N; A7 is CR8; A8 is CR8; and A9 is N;
or Al is C; A2 is C; A6 i s CR8; A7 is N; A8 is N; and A9 is CR8;
or Al is C; A2 is C; A6 is CRg; A7 is N; A8 is CRg; and A9 is N;
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or A-1 is C, A2 is C; A6 is Cle; A7 is Cle; A8 is N; and A9 is N.
23. The compound of claim 21, or a pharmaceutically acceptable salt,
tautomer, or solvate
thereof, wherein:
Al is C; A2 is C; A6 is N; A7 is CR8: Ag is CR8; and A9 is CR8;
or Al is C; A2 is C; A6 is N; A7 is CR8; A8 is N; and A9 is CR8;
or Al is C, A2 is C; A6 is N; A7 is Cle; A8 is Cle; and A9 is N;
or A' is C; A2 is C; A6 is C(=0); A7 is Nle; A8 is CR8; and A9 is CR8
24. The compound of claim 21 having a structure of Formula (V1a):
Image
or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein
A8 is Cle or
N.
25. The compound of claim 21 having a structure of Formula (VIb) or Formula
(VIc):
Image
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
26. The compound of any one of claims 1-25, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein each R8 is independently hydrogen,
halogen,
unsubstituted or substituted Ci-C6 alkyl, unsubstituted or substituted C1-C6
deuteroalkyl,
unsubstituted or substituted CI-C6 fluoroalkyl, unsubstituted or substituted
carbocycle,
n substituted or substituted heterocycle, -CN, -OH, -0R17, -C(=0)R -CO2R16, or
-
C (=0)N(R16)2; wherein if R8 is attached to a nitrogen atom, then R8 is
hydrogen,
unsubstituted or substituted Ci-C6 alkyl, unsubstituted or substituted C1-C6
deuteroalkyl,

119
unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted
carbocycle,
unsubstituted or substituted heterocycle, -C(=0)R16, -CO2R1-6, or -C(=0)N(RI-
6)2.
27. The compound of any one of claims 1-26, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein each R8 is independently hydrogen, -C1, -
F, methyl,
ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CN, -
OH, -
CO2H, or -CO2CH3; wherein if R8 is attached to a nitrogen atom, then R8 is
hydrogen,
methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl,
azetidinyl, -CO2H,
or -CO2CH3.
28. The compound of any one of claims 1-27, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein each R8 is independently hydrogen,
methyl, -CD3, -
OH, -CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3; wherein if R8 is attached to a
nitrogen
atom, then R8 is hydrogen, methyl, -CD3, -CH2OH, oxetanyl, or -CO2CH3.
29. The compound of any one of claims 1-28, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein each R6 and R7 is independently
hydrogen,
deuterium, halogen, CI-C4 alkyl, or CI-C4 deuteroalkyl.
30. The compound of any one of claims 1-29, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein each R6 and R7 is independently
hydrogen,
deuterium, F, or m ethyl
3 1 . The compound of any one of claims 1-30, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein Z is -NR1 -, -0-, or -802-.
32. The compound of any one of claims 1-31, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein Z is -NR1 - or -0-.
33. The compound of any one of claims 1-32, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein Z is -NR1 -.
34. The compound of any one of claims 1-33, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein Rm is hydrogen, C1-C4 alkyl, CI-CI
deuteroalkyl, or
cyclopropyl.
35. The compound of any one of claims 1-32, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein Z is -0-.
36. The compound of any onc of claims 1-35, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein R2 is a Ring B that is an unsubstituted
or
substituted heterocycle or unsubstituted or substituted carbocycle, wherein if
Ring B is
substituted then Ring B is substituted with q instances of RE.
37. The compound of any one of claims 1-36, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein:

120
R2 is a Ring B that is an unsubstituted or substituted monocy clic carbocycle,

unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted

monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle,
wherein
if Ring B is substituted then Ring B is substituted with q instances of R1-3.
38. The compound of any one of claims 1-37, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein:
R2 is a Ring B that is an unsubstituted or substituted phenyl, unsubstituted
or substituted
monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-

membered heteroaryl, wherein if Ring B is substituted then Ring B is
substituted
with q instances of R13.
39. The compound of any one of claims 1-38, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein:
R2 is a Ring B that is an unsubstituted or substituted phenyl or unsubstituted
or
substituted monocyclic 6-membered heteroaryl, wherein if Ring B is substituted
then
Ring B is substituted with q instances of R13.
40. The compound of any one of claims 1-39, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein:
R2 i s a Ring B that i s an unsubstituted or substituted phenyl, unsubstituted
or substituted
pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or
substituted
pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein if Ring B i s
substituted then Ring B is substituted with q instances of R13.
41. The compound of any one of claims 1-40, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein:
R2 is a Ring B that is an unsubstituted or substituted pyridinyl or
unsubstituted or
substituted pyrimidinyl, wherein if Ring B is substituted then Ring B is
substituted
with q instances of R1'.
42. The compound of any one of claims 1-41, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein:
R2 is a Ring B that is an unsubstituted or substituted pyridinyl, wherein if
Ring B is
substituted thcn Ring B is substituted with q instances of R13.
43. The compound of any one of claims 1-39, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein:
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121
Image
R2 i s
and q is 0, 1,
2, 3, or 4.
44. The compound of any one of claims 1-39, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein:
Image
Ring B is , and q is 0, 1, 2, 3, or 4.
45. The compound of claim 1 having a structure of Formula (VIII):
Image
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
V is N, CH, or CR13;
q is 1, 2, 3, or 4;
Al and A' are each C; and
A6, A7, A8, and A9 are each independently CR8 or N.
46. The compound of claim 45 having a structure of Formula (Villa):
Image
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein
A8 is CR8 or
N.
47. The compound of any one of claims 45-46, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein V is N.
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48. The compound of any one of claims 45-46, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein V is CH or CR13.
49. The compound of any one of claims 1-48, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein each R13 is independently halogen,
unsubstituted or
substituted Cl-C6 alkyl, unsubstituted or substituted Cl-C6 fluoroalkyl,
unsubstituted or
substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -
OR', -
C(=0)R16, -CO2R' 6, -C(=0)N(R1 6)2, -N(R16)2, _N-R16C(=c)R17, _SO2R1 7, or -
SO2N(R16)2.
50. The compound of any one of claims 1-49, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein each R13 is independently -F, -C1, -CH3,
or -CF3.
1 . The compound of any one of claims 1-35, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein R2 is -C(=0)R14, -C(_0)NRI4R1.5, or -
C(=0)0R14.
52. The compound of claim 51, or a pharmaceutically acceptable salt,
tautomer, or solvate
thereof, wherein R2 is -C(=0)R14.
53. The compound of claim 51, having a structure of Formula (IX):
Image
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
A1 and A2 are each C; and
each of A6, A7, A8, and A9 are independently CR8 or N.
54. The compound of claim 53, having a structure of Formula (IXa):
Image

123
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein
A' is Cle or
N.
55. The compound of any one of claims 51-54, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein R14 is unsubstituted or substituted C1-
C6 alkyl,
unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted
4-membered
heterocycloalkyl; wherein the substituted alkyl, substituted heteroalkyl,
substituted
cycloalkyl, or substituted heterocycloalkyl is substituted with one or more RS
groups
independently selected from the group consisting of deuterium, halogen, -CN, -
NH2, -
OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHE', and -0CF3.
56. The compound of any one of claims 1-55, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein:
B1 is CR12a; and B2 is CR121);
or B1 is N; and B2 is CR12b;
or B1 is CR12a; and B2 is N;
or B1 is N; and B2 is N.
57. The compound of any one of claims 1-56, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein:
TV is CR'', and 112 is CR12h;
or B1 is N; and B2 is CR12b.
58. The compound of any one of claims 1-57, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein R12a and R121' are each independently
hydrogen,
halogen, Cl-C4 alkyl, Ci-C4 fluoroalkyl, or -CN.
59. The compound of any one of claims 1-58, or a pharmaceutically
acceptable salt,
tautomer, or solvate thereof, wherein R12a and R121' are each hydrogen.
60. A compound selected from:
1: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-06-methy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide;
2: 6-((5-fluoropyridin-2-yl)amino)-N-(methyl-d3)-4-06-methyl-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide; and
3: 6-(cyclopropanccarboxamido)-N-(methyl-d3)-4-06-methyl-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)nicotinamide;
4: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-446-methy1-5,6-
dihydropyrimido[5,4-
c]quinolin-7-yl)amino)nicotinamide;
5: 6-(cy cl opropanecarboxami do)-443 -fluoro-6-m ethyl -5, 6-
dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)nicotinamide;
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124
6: 6-(cy c1opropanecarboxamido)-N-(m ethy1-d3)-4-((6-m ethy1-5,6-dihy
dropyrimido[5,4-
c] quinolin-7-yl)amino)pyri dazine-3 -carboxami de;
7: 6-(cy clopropanecarb oxami do)-4-((3 -fluoro-6-methy1-5, 6-
dihydrob enzo [h] [1,6]naphthyri di n-7-yl)amino)-N-(m ethyl-d3)pyri dazine-3-
carb oxamide;
8: 6-(cy clopropanecarb oxami do)-N-(m ethyl -d3)-4-06-m ethy1-5,6-dihy
dropyrazino [2,3 -
c] quinolin-7-yl)amino)nicotinamide;
9: 6-(cy clopropanecarb oxami do)-44(2,6-dimethy1-1- oxo-1,2,5, 6-
tetrahydrobenzo[c] [2, 6]naphthyridin-7-y1)amino)-N-(methy1-d3)nicotinami de;
10: 6-(cyclopropanecarboxamido)-N-(m ethyl-d3)-4-((6 -methy1-5,6- di hy
dropyrazino [2,3 -
c] quinolin-7-yl)amino)pyridazine-3 -carboxamide;
11: 6-(cyclopropanecarboxamido)-4-((2,6-dimethyl-1-oxo-1,2,5,6-
tetrahydrobenzo[c] [2, 6]naphthyridin-7-y1)ami no)-N-(methy1 -d3)pyridazine-3 -

carb oxamide;
12: 4-((3-cyano-6-methy1-5,6-dihydrobenzo [h] [1, 6]naphthyridin-7-yl)amin o)-
6-
(cycloprop anecarb oxami do)-N-(methyl-d3)nicotinamide;
13: 4-((3-cyano-6-methy1-5,6-dihydrobenzo [h] [1, 6]naphthyridin-7-yl)amin o)-
6-
(cycl oprop a n ecarboxam i do)-N-(ni ethyl -d3)pyri dazi ne-3-carboxam i de;
14: 6-(cyclopropanecarboxamido)-N-(m ethyl-d3)-4-((6 -methy1-5,6- di hy
dropyrazino [2,3 -
c] [1,7]naphthyridin-7-yeamino)nicotinamide;
15: 6-(cyclopropanecarboxamido)-N-methy1-4-((6-methy1-5,6-
dihydrob enzo[h] [1,6]naphthyri di n-7-yl)amino)ni cotinamide;
16: 6-(cyclopropanecarboxamido)-N-(m ethyl-d3)-4-((6 -methy1-5,6- di hy
dropyrazino [2,3 -
c] quinolin-7-yl)amino)pyridazine-3 -carboxamide;
17: 6-(cyclopropanecarboxamido)-N-(m ethyl-d3)-4-((6-(methyl-d3)-5,6-
dihydropyrazino [2,3 -c]quinolin-7-yl)amino)nicotinamide;
18: 6-(cy cl opropanecarb oxami do)-N-(m ethyl-d3)-4-((6-(methyl-d3)-5,6-
dihydropyrazino [2,3 -c]quinolin-7-yl)amino)pyridazine-3 -carboxamide,
19: 6-(cyclopropanecarboxamido)-N-(m ethyl-d3)-4-((6 -methy1-5,6- di hy
dropyrido [3 ,4-
h] [1, 6]naphthyridin-7-yl)amino)nicotinamide;
20: 6-(cy cl opropanecarb oxami do)-N-(m ethyl-d3)-4-((6-methy1-5,6-
dihydrob enzo [h] [1,6]naphthyri di n-7-y1-5,5-d2)amino)nicotinamide;
21: 6-(cy cl opropanecarb oxami do)-443-fluoro-6-methy1-5,6-
di hydrob enzo[h] [1,6]naphthyri di n-7-y1-5,5-d2)amino)-N-(m ethyl -d3)pyri
dazin e-3 -
carb oxamide;
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125
22: 6-(cy clopropanecarboxamido)-443-fluoro-6-methy1-5,6-
di hydrob enzo[h] [1,6]naphthyri di n-7-yl -5,5-d2)ami no)-N-(m ethyl -d3)ni
coti n am i de;
23: 6-(cyclopropanecarboxamido)-4-((2,6-dimethy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-y1-5,5-d2)amino)-N-(methyl-d3)pyridazine-3-
carboxamide;
24: 6-(cyclopropanecarboxamido)-4-((2,6-dimethy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-y1-5,5-d2)amino)-N-(methyl-d3)nicotinamide;
25: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-44(6-methy1-2-(trifluoromethyl)-
5,6-
dihydrobenzo[h][1,6]naphthyridin-7-y1-5,5-d2)amino)nicotinamide;
26: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-44(6-methy1-2-(trifluoromethyl)-
5,6-
dihydrobenzo[h][1,6]naphthyridin-7-y1-5,5-d2)amino)pyridazine-3-carboxamide;
27: 6-(cyclopropanecarboxamido)-4-((2,6-dimethyl-1-oxo-1,2,5,6-
tetrahydropyridazino[4,5-c]quinolin-7-yl)amino)-N-(methyl-d3)pyridazine-3-
carboxamide;
28: 6-(cyclopropanecarboxamido)-4-((2,6-dimethyl-1-oxo-1,2,5,6-
tetrahydropyridazino[4,5-c]quinolin-7-yl)amino)-N-(methyl-d3)nicotinamide;
29: 6-(cyclopropanecarboxamido)-N-methy1-4-((6-methy1-5,6-
di hydrob en zo[li ] [1,6]naplithyri di n-7-y1 )am i no)pyri clazi n e-3-
carboxami de;
30: 6-(cyclopropanecarboxamido)-N-methy1-4-((6-methy1-5,6-dihydropyrazino[2,3-
c]quinolin-7-y1)amino)nicotinamide;
31: 6-(cyclopropanecarboxamido)-4410-fluoro-5-methy1-5,6-dihydrophenanthridin-
4-
yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide;
32: (R)-6-(cyclopropanecarboxamido)-445,6-dimethy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-
carboxamide; and
33: (S)-6-(cyclopropanecarboxamido)-4-((5,6-dimethy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-
carboxamide;
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
61. A pharmaceutical composition comprising the compound of any onc of
claims 1-60, or a
pharmaceutically acceptable salt, tautomer, or solvate thereof, and a
pharmaceutically
acceptable excipient.
62. A method of treating a TYK2-mediated disease or condition in a patient
in need thereof,
comprising administering to the patient a therapeutically effective amount of
a
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126
compound of any one of claims 1-60, or a pharmaceutically acceptable salt,
tautomer, or
solvate thereof
63. A method of treating an inflammatory disease or condition or autoimmune
disease or
condition in a patient in need thereof, comprising administering to the
patient a
therapeutically effective amount of a compound of any one of claims 1-60, or a

pharmaceutically acceptable salt, tautomer, or solvate thereof
64. The method of claim 62 or claim 63, wherein the disease or condition is
selected from
rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis,
lupus, systemic
lupus erythematosus, Sj Ogren's syndrome, ankylosing spondylitis, vitiligo,
atopic
dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye,
intestinal
bowel disease, Crohn's disease, ulcerative colitis, celiac disease, Bechet's
disease, type 1
diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.
65 The method of any one of claims 62-64, wherein the compound
is administered topically.
66. The method of claim 65, wherein the compound is provided in a gel,
cream, ointment,
liquid, or transdermal patch.
67. The method of any one of claims 62-64, wherein the compound is
administered by
ophthalmic administration.
6g The method of claim 67, wherein the compound is provided in a
li quid solution,
suspension, gel, depot, or other preparation that can be administered to the
eye or
surrounding tissue (e.g., eye drops).
69. A compound selected from:
3: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methy1-5,
dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)nicotinamide;
15: 6-(cyclopropanecarboxamido)-N-methy1-4-((6-methy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-y1)amino)nicotinamide;
34: 6-(cyclopropanecarboxamido)-4-((2,5-dimethy1-4,5-dihydro-2H-pyrazolo[4,3-
c]quinolin-6-yl)amino)-N-methylpyridazine-3-carboxamide;
35: 4-((2,5-dimethy1-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-645-
fluoropyridin-2-yDamino)-N-methylnicotinamide;
36: 44(2,5-dimethy1-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((2,6-

dimethylpyrimidin-4-y1)amino)-N-methylnicotinamide;
37: 6-(cyclopropanecarboxamido)-442,5-dimethy1-4,5-dihydro-2H-
[1,2,3]triazolo[4,5-
c]quinolin-6-yl)amino)-N-methylnicotinamide; and
38: 6-(cycl opropanecarboxami do)-4-((2,5-dim ethyl -4,5-di hydropyrazol o
[1,5-
a]quinoxalin-6-yl)amino)-N-methylpyridazine-3-carboxamide;
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127
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
70. A pharmaceutical composition comprising the compound of claim 69, or a
pharmaceutically acceptable salt, tautomer, or solvate thereof, and a
pharmaceutically
acceptable excipient.
71. A method of treating a TYK2-mediated disease or condition in a patient
in need thereof,
comprising administering to the patient a therapeutically effective amount of
a
compound of claim 69, or a pharmaceutically acceptable salt, tautomer, or
solvate
thereof.
72. A method of treating an inflammatory disease or condition or autoimmune
disease or
condition in a patient in need thereof, comprising administering to the
patient a
therapeutically effective amount of a compound of claim 69, or a
pharmaceutically
acceptable salt, tautomer, or solvate thereof
73. The method of claim 71 or claim 72, wherein the disease or condition is
selected from
rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis,
lupus, systemic
lupus erythematosus, SjOgren's syndrome, ankylosing spondylitis, vitiligo,
atopic
dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye,
intestinal
bowel disease, Crohn's disease, ulcerative colitis, celiac disease, Bechet's
disease, type 1
di abetes, systerni c scl erosi s, and i di opathi c pul m on ary fibrosi s
74. The method of any one of claims 71-73, wherein the compound is
administered topically.
75. The method of claim 74, wherein the compound is provided in a gel,
cream, ointment,
liquid, or transdermal patch.
76. The method of any one of claims 71-73, wherein the compound is
administered by
ophthalmic administration.
77. The method of claim 76, wherein the compound is provided in a liquid
solution,
suspension, gel, depot, or other preparation that can be administered to the
eye or
surrounding tissue (e.g., eye drops).
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Description

WO 2022/175746 PCT/1B2022/000062
1
TYK2 INHIBITORS AND USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
100011 This application claims the benefit of US Provisional Application No.
63/151,287 filed
on February 19, 2021 and US Provisional Application No. 63/193,514 filed on
May 26, 2021,
each of which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to compounds that bind to the
pseudokinase domain
(JH2) of the non-receptor tyrosine-protein kinase 2 (TYK2). Compounds of the
present
disclosure may inhibit certain cytokine signaling, for example IL-12, IL-23,
and IFNct signaling
Additional aspects of the invention include pharmaceutical compositions
comprising the
compounds described herein, methods of using the compounds to treat certain
diseases, and
intermediates and processes useful in the synthesis of the compounds.
[0003] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase
(JAKs) family of
protein kinases. The mammalian JAK family consists of four members, TYK2,
JAK1, JAK2,
and JAK3. JAK proteins, including TYK2, are integral to cytokine signaling.
TYK2 associates
with the cytoplasmic domain of type I and type II cytokine receptors, as well
as interferon types
I and III receptors, and is activated by those receptors upon cytokine
binding. Cytokines
implicated in TYK2 activation include interferons (e.g. IFN-a, IFN-I3, IFN-K,
IFN-6, IFN-e,
IFN-T, IFN-co, and IFN-c (also known as limitin), and interleukins (e.g. IL-4,
IL-6, IL-10, IL-1
1, IL-12, IL-13, IL-22, IL-23, IL-27, LL-31, oncostatin M, ciliary
neurotrophic factor,
cardiotrophin 1, cardiotrophin-like cytokine, and LIF). The activated TYK2
then goes on to
phosphorylate further signaling proteins such as members of the STAT family,
including
STAT1, STAT2, STAT4, and STAT6.
SUMMARY OF THE INVENTION
[0004] Compounds described herein are modulators of the JAK family of kinases.
More
specifically, the compounds of the present disclosure are inhibitors of TYK2.
In some
embodiments, compounds are selective for TYK2 over other JAKs. For example,
compounds
may bind specifically to the pscudokinasc domain (JH2) of TYK2 thereby
enhancing selectivity
over JAK family members. In some embodiments, a compound of the present
disclosure may be
an all osteric modulator or noncompetitive inhibitor of TYK2. In additional
embodiments, a
compound described herein may be useful in the treatment of TYK2 mediated
diseases or
disorders.
100051 In one aspect, described herein is a compound of Formula (1):
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WO 2022/175746
PCT/IB2022/000062
2
W, R4
E31
CSR
N B2- N rt
n IR7)"} Z X3
Al X2
CA): Xi
A
(R8)p
Formula (I),
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
Ring A is an unsubstituted or substituted 6-membered heterocyclic ring wherein
A1 and
A2 are independently N or C, wherein if Ring A is substituted then Ring A is
substituted with p instances of R8;
each R8 is independently hydrogen, halogen, unsubstituted or substituted Cl-C6
alkyl,
unsubstituted or substituted Cl-C6 deuteroalkyl, unsubstituted or substituted
C2-
C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or
substituted Ci-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl,

unsubstituted or substituted carbocycle, unsubstituted or substituted
heterocycle, -
CN, -OH, -OR'', -C(=0)R16, -CO2R16, -C(=0)N(R16)2, -N(R16)2, -NR16C(=0)R',
_sR16, _s(_0)R17, -SO2R17, or -SO2N(R16)2; wherein if R8 is attached to a
nitrogen atom, then R8 is hydrogen, unsubstituted or substituted CI-C6 alkyl,
unsubstituted or substituted Cl-C6 deuteroalkyl, unsubstituted or substituted
C2-
C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or
substituted Ci-C 6 fluoroalkyl, unsubstituted or substituted Ci-C6
heteroalkyl,
unsubstituted or substituted carbocycle, unsubstituted or substituted
heterocycle, -
C(=0)R16, -CO2R16, -C(=0)N(R16)2, -S(=0)R17, -SO2R17, or -SO2N(R16)2, or two
R8 attached to the same carbon atom are taken together to form =0, =S, or =NH;
Z is -NR' -, -0-, -S-, -S(=0)-, or -SO2-;
¨
_K is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, CI-Co fluoroalkyl, C3-C6
cycloalkyl, or monocyclic heterocycle;
X1, X2, and X' are each independently CR11 or N;
each R11 is independently hydrogen, halogen, unsubstituted or substituted Cl-
C6
alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or
substituted C2-
C6 alkynyl, unsubstituted or substituted Cl-C6 fluoroalkyl, unsubstituted or
substituted Ci-C6 heteroalkyl, unsubstituted or substituted carbocycle,
unsubstituted or substituted heterocycle, -CN, -OH, -0R17, -C(=0)R16, -CO2R16,
-
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WO 2022/175746 PCT/IB2022/000062
3
CI=011\T(R16)2, -N(R16)2, _NRI6c(_0)R17, _SR16, -S(=0)R1', -SO2R17, or -
SO2N(R16)2;
B1 is N or CR12a;
B2 is N or CR12b;
R12 and R12b are each independently hydrogen, halogen, unsubstituted or
substituted
Cl-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or
substituted C2-C6 alkynyl, unsubstituted or substituted Ci-C 6 tluoroalkyl,
unsubstituted or substituted Ci-C6 heteroalkyl, unsubstituted or substituted
carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -0R17, -
C(=0)R16, -CO2R16, -C(=0)N(R16)2, -1,f(R16)2, "NR16c(_c)Rt7, -SR16, -S(=0)R17,

-SO2R17, or -SO2N(R16)2;
R1 is hydrogen, Ci-C6 alkyl, or Cl-C6 fluoroalkyl;
R2 is a Ring B that is an unsubstituted or substituted heterocycle or
unsubstituted or
substituted carbocycle, wherein if Ring B is substituted then Ring B is
substituted
with q instances of R13;
each R13 is independently halogen, unsubstituted or substituted Ci-C6 alkyl,
unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6

alkynyl, un substituted or substituted Ci-C6 fluoroalkyl, unsubstituted or
substituted Ci-C6 heteroalkyl, unsubstituted or substituted carbocycle,
unsubstituted or substituted heterocycle, -CN, -OH, -OR'', -C(=0)R16, -CO2R16,
-
C(=0)N(R16)2, -/.õ1-(R16)2, _NR16c(_0)R17, _sR16, _s(_0)R17,
3021..17, or -
SO2N(R16)2;
or two R1.1 groups on adjacent atoms of Ring B are taken together with the
intervening atoms to which they are attached to form an unsubstituted or
substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or
substituted 5- or 6-membered monocyclic heterocycle;
or R2 is -C(=0)R14, _c(=o)N-Ri4R15, or
R14 is hydrogen, unsubstituted or substituted Ci-C6 alkyl, C,-C6 deuteroalkyl,

unsubstituted or substituted C7-C6 alkenyl, unsubstituted or substituted C2-C6

alkynyl, unsubstituted or substituted Ci-C6 hetcroalkyl, unsubstituted or
substituted monocyclic carbocycle, unsubstituted or substituted bicyclic
carbocycle, unsubstituted or substituted monocyclic heterocycle, or
unsubstituted
or substituted bicyclic heterocycle;
R15 is hydrogen, Ci-C6 alkyl, or Ci-C6 fluoroalkyl;
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WO 2022/175746
PCT/IB2022/000062
4
or R14 and R15 are taken together with the intervening atoms to which they are

attached to form an unsubstituted or substituted 4- to 6-membered monocyclic
heterocycle;
or R1 and R15 are taken together with the intervening atoms to which they are
attached to form an unsubstituted or substituted 5- or 6-membered monocyclic
heterocycle;
W is -NR3- or -0-;
R3 is hydrogen, C1-C6 alkyl, Ci-C6 deuteroalkyl, CI-Co fluoroalkyl, C3-C6
cycloalkyl, or
monocyclic heterocycle;
R4 is hydrogen, Ci-C6 alkyl, Cl-Co deuteroalkyl, Cl-Co fluoroalkyl, C3-C6
cycloalkyl, or
monocyclic heterocycle;
or R3 and R4 are taken together with the N atom to which they are attached to
form a
substituted or unsubstituted N-containing heterocycle;
or R3 and Rua are taken together with the intervening atoms to which they are
attached to
form a substituted or unsubstituted 5- or 6-membered heterocycle;
R5 is hydrogen, Ci-C6 alkyl, C,-C6 fluoroalkyl, C3-C6 cycloalkyl, or
monocyclic
heterocycle;
each Re' and R7 is independently hydrogen, deuterium, halogen, Cl-C6 alkyl, Ct-
C6
deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle, -
CN, -
OH, -0R17, -C(=0)R16, -CO2R16, -C(=0)N(R16)2, -
1..õ,f(R16)2, _N-Ri6c(=o)R17, _sR16, _
S(=0)R17, -SO2R17, or -SO2N(R16)2;
or one R6 and one R7 attached to the same carbon atom are taken together with
the
carbon atom to which they are attached to form C=0 or C3-C4 cycloalkyl;
each R16 is independently hydrogen, substituted or unsubstituted Ci-C6 alkyl,
substituted
or unsubstituted CI-Co fluoroalkyl, substituted or unsubstituted CI-Co
heteroalkyl,
substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted
monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted
phenyl,
or substituted or unsubstituted monocyclic heteroaryl;
or two R16 on the same 1\ atom are taken together with the N atom to which
they are
attached to form a substituted or unsubstitutcd N-containing heterocycle; and
each R17 is independently substituted or unsubstituted Ci-C6 alkyl,
substituted or
unsubstituted CI-C6 fluoroalkyl, substituted or unsubstituted Cl-C6
heteroalkyl,
substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted
monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted
phenyl,
or substituted or unsubstituted monocyclic heteroaryl;
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WO 2022/175746 PCT/IB2022/000062
wherein each substituted alkyl, substituted fluoroalkyl, substituted
deuteroalkyl,
substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl,
substituted
carbocycle, and substituted heterocycle is substituted with one or more Rs
groups
independently selected from the group consisting of deuterium. halogen, Ci-C6
alkyl,
monocyclic carbocycle, monocyclic heterocycle, -CN,
-0R18, -CH2OR18, -
CO2R18, -CH2CO2R", -C(=0)N(R18)2, -CH2C(=0)N(R18)2, -N(R18)2, -CH2N(R18)2, -
NR' 8C(=0)R' -CH2NR1 8C(=0)R1 -NR' SO2R19, -CH2NR1 8S02R19, -

CH2SR18, -S(=0)R19, -CH2S(=0)R19, -S02R19, -CH2S02R19, -SO2N(R18)2, or -
CH2S02N(R18)2;
each R18 is independently selected from hydrogen, C1-Co alkyl, C1-C6
fluoroalkyl,
Cl-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-

membered heteroaryl and 6-membered heteroaryl;
or two R" groups are taken together with the N atom to which they are attached
to
form a N-containing heterocycle;
each R19 is independently selected from CI-C6 alkyl, CI-Co heteroalkyl, C3-C6
cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and

6-membered heteroaryl;
n is 1, 2, or 3;
p is 0, 1, 2, 3, or 4; and
q is 0, 1, 2, 3, or 4.
100061 In some embodiments, the compound is a compound of Formula (II):
R4
'NH
131
4:)X
HN 13: NH
R6
n R7V Z r-LX3 R2
Al `, X2
A0: X1
(R8)p
Formula (II),
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[0007] In some embodiments, the compound is a compound of Formula (IV):
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R4
-NH
13N
HN B2-'L-NH
R;õ). z
R2
( R7
Al lieh
A NA2
(R8)p
Formula (IV),
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[0008] In some embodiments, the compound is a compound of Formula (VI).
R4,N H
,
HN N H
( R;) z
R2
R7
A9Al, 14111
-ik-
A1 0 AI 6
AT
Formula (VI),
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
(i) A' and A2 are each C; and A6, A7, A8, and A9 are each independently CR8 or
N;
(ii) A" is N; A2 is C; A6, A7, and A8 are each independently CR8 or N; and A9
is C(=0);
(iii) A" is C; A2 is N; A6 is C(=0); and A7, A8, and A9 are each independently
CR8 or N;
or
(iv) Al and A2 are each C; one of A6, A7, A8, and A9 is NR8, wherein A6, A7,
A8, or A9
adjacent to the Nit' is C(=0) and the remaining members of A6, A7, A8, and A9
are
each independently CR8 or N.
100091 In some embodiments, the compound is a compound of Formula (VIa):
R4, NH
N
I
H N B2- NH
/ R6 dõ
r, 1:t7 Z
R8)
P A8 N
Formula (VIa),
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or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein
A' is Cle or
N.
[0010] In some embodiments, the compound is a compound of Formula (VIb) or
Formula
(Vic):
R4, NH WINN
0 N 0-A1131-N
H B2-1' NH HN B2 NH
R6 7
R2 ( z
R2
kR7 n R
(R8) (R8)
p N N
Formula (VIb) Formula (Vic)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[0011] In some embodiments, the compound is a compound of Formula (VIII):
R4
'NH
0 N
HN
( R6 7
Nr-LI
Al j411134
A9 -'A2
0
Formula (VIII)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
V is N, CH, or CR13;
q is 1, 2, 3, 0r4;
Al and A2 are each C; and
A', A', A', and A' are each independently Cle or N.
[0012] In some embodiments, the compound is a compound of Formula (Villa):
NH
1
C3(13 N
HN B2 NH
(R7 Z
4R13)q
(R8)
P A8 N
Formula (Villa)
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or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein
A8 is Cle or
N.
100131 In some embodiments, the compound is a compound of Formula (IX):
R4.,NH
Bl,
N
H N B2 N R1
R7 in
o
R"
A- -A-
' '
A 80 A6
Foimula (IX),
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
A' and A2 are each C; and
each of A6, A7, A8, and A9 are independently CR8 or N.
[0014] In some embodiments, the compound is a compound of Formula (IXa):
R4,NH
0 N
H N B21-1..N R1
Re z
n R7 0 R A
(R8)P¨

A N
Formula (IXa)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein
A8 is CR8 or
N.
[0015] Any combination of the groups described above for the various variables
is
contemplated herein. Throughout the specification, groups and substituents
thereof are chosen
by one skilled in the field to provide stable moieties and compounds.
[0016] Also described herein are pharmaceutical compositions comprising a
compound
described herein, or a pharmaceutically acceptable salt, tautomer, or solvate
thereof, and a
pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical
composition is
formulated for administration to a mammal by intravenous administration,
subcutaneous
ad1111nist1aL10n, oral administration, inhalation, nasal adiniiiistiatioii,
dermal administration, 01
ophthalmic administration. In some embodiments, the pharmaceutical composition
is formulated
for administration to a mammal by oral administration. In some embodiments,
the
pharmaceutical composition is in the form of a tablet, a pill, a capsule, a
liquid, a suspension, a
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gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some
embodiments, the
pharmaceutical composition is in the form of a tablet, a pill, or a capsule.
In some embodiments,
the pharmaceutical composition in the form of an ointment, a lotion, a cream,
an oil, a gel, a
transdermal patch, or other topical formulation. In additional embodiments,
the pharmaceutical
composition is in the form of a liquid solution, suspension, gel, depot, or
other preparation that
can be administered to the eye or surrounding tissue (e.g., eye drops).
[0017] Described herein are compounds of Formula (Al), or a pharmaceutically
acceptable
salt, tautomer, or solvate thereof useful in the treatment of TYK2-mediated
disorders Described
herein are compounds of Formula (Al), or a pharmaceutically acceptable salt,
tautomer, or
solvate thereof, useful in the treatment of an inflammatory or autoimmune
disease. In some
embodiments, the disease is selected from rheumatoid arthritis, multiple
sclerosis, psoriasis,
psoriatic arthritis, lupus, systemic lupus erythematosus, Sjogren's syndrome,
ankylosing
spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis
suppurativa, uveitis,
dry eye, intestinal bowel disease, Crohn's disease, ulcerative colitis, celiac
disease, Bechet's
disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary
fibrosis. In some
embodiments, the disease is selected from psoriasis, psoriatic arthritis,
vitiligo, atopic dermatitis,
alopecia, and hidradenitis suppurativa. In some embodiments, the disease is
selected from
i nterferonopathi es such as, by way of example, Al cardi-Goutieres syndrome
[0018] In any of the aforementioned aspects are further embodiments in which
the effective
amount of the compound of Formula (I), or a pharmaceutically acceptable salt,
or solvate
thereof, is: (a) systemically administered to the mammal; and/or (b)
administered orally to the
mammal; and/or (c) intravenously administered to the mammal; and/or (d)
administered by
inhalation; and/or (e) administered by nasal administration; or and/or (f)
administered by
injection to the mammal; and/or (g) administered topically to the mammal;
and/or (h)
administered by ophthalmic administration; and/or (i) administered rectally to
the mammal;
and/or (j) administered non-systemically or locally to the mammal.
[0019] In any of the aforementioned aspects are further embodiments comprising
single
administrations of the effective amount of the compound, including further
embodiments in
which the compound is administered once a day to the mammal or the compound is

administered to the mammal multiple times over the span of one day. In some
embodiments, the
compound is administered on a continuous dosing schedule. In some embodiments,
the
compound is administered on a continuous daily dosing schedule.
[0020] In any of the embodiments disclosed herein, the mammal is a human.
[0021] In some embodiments, compounds provided herein are topically
administered to a
human.
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[0022] Articles of manufacture, which include packaging material, a compound
described
herein, or a pharmaceutically acceptable salt thereof, within the packaging
material, and a label
that indicates that the compound or composition, or pharmaceutically
acceptable salt, tautomers,
pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,
pharmaceutically
acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used
for modulating
TYK2, or for the treatment, prevention or amelioration of one or more symptoms
of a disease or
condition that would benefit from modulating TYK2, are provided.
[0023] Other objects, features and advantages of the compounds, methods and
compositions
described herein will become apparent from the following detailed description.
It should be
understood, however, that the detailed description and the specific examples,
while indicating
specific embodiments, are given by way of illustration only, since various
changes and
modifications within the spirit and scope of the instant disclosure will
become apparent to those
skilled in the art from this detailed description
DETAILED DESCRIPTION OF THE INVENTION
[0024] TYK2 activation has been linked to many diseases and disorders,
including
inflammatory diseases and disorders, autoimmune diseases and disorders,
respiratory diseases
and disorders, and cancer.
[0025] In particular, IL-23 activation of TYK2 is associated with inflammatory
diseases such
as inflammatory bowel disease (fl3D), Crohn's disease, celiac disease, and
ulcerative colitis. As
the downstream effector of IL-23, TYK2 also plays a role in psoriasis,
ankylosing spondylitis,
and Behcet's disease. TYK2 has also been associated with diseases and
conditions of the skin,
such as psoriasis, vitiligo, atopic dermatitis, hidradenitis suppurativa,
scleroderma; or diseases
and conditions of the eye, such as Sjogren's syndrome, uveitis, and dry eye.
[0026] TYK2 is associated with respiratory diseases and conditions such as
asthma, chronic
obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet
cell hyperplasia
(GCH) and mucous hypersecretion is mediated by IL-13-induced activation of the

TYK2/STAT6 pathway.
[0027] TYK2 is also associated with autoimmune diseases and conditions, such
as multiple
sclerosis (MS), lupus, and systemic lupus erythematosus (SLE). Loss of
function mutation in
TYK2, leads to decreased demyelination and increased remyelination of neurons,
further
suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS
demyelination
disorders_ Various type I IFN signaling pathways dependent on TYK2 signaling
have implicated
TYK2 in SLE and other autoimmune diseases and conditions.
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[0028] TYK2 is associated with arthritis, including psoriatic arthritis and
rheumatoid arthritis.
Decreased TYK2 activity leads to protection of joints from collagen antibody-
induced arthritis, a
model of human rheumatoid arthritis.
[0029] TYK2 has also been shown to play an important role in maintaining tumor
surveillance
and TYK2 knockout mice showed compromised cytotoxic T cell response, and
accelerated
tumor development. These effects are largely due to the efficient suppression
of natural killer
(NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are highly
suitable for the
treatment of autoimmune disorders or transplant rejection. Although other JA_K
family members
such as JAK3 have similar roles in the immune system, TYK2 is a superior
target because of its
involvement in fewer and more closely related signaling pathways, leading to
fewer off-target
effects. However, studies in T-cell acute lymphoblastic leukemia (T-ALL)
indicate that T-ALL
is highly dependent on IL-10 via TYK2/STAT1 signaling to maintain cancer cell
survival
through upregulation of anti-apoptotic protein BCL2. Knockdown of TYK2, but
not other TAX
family members, reduced cell growth. Thus, selective inhibition of TYK2 has
been suggested as
a suitable target for patients with IL-10 and/or BCL2-addicted tumors, such as
70% of adult T-
cell leukemia cases.
[0030] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal
cell death
caused by amyl oid-f3 (AP) peptide Decreased TYK2 phosphorylation of STAT3
following AP
administration lead to decreased neuronal cell death, and increased
phosphorylation of STAT3
has been observed in postmortem brains of Alzheimer's patients.
100311 Inhibition of JAK-STAT signaling pathways is also implicated in hair
growth, and the
reversal of the hair loss associated with alopecia areata.
[0032] Even though some TYK2 inhibitors are known, there is a continuing need
to provide
novel inhibitors having more effective or advantageous pharmaceutically
relevant properties.
For example, compounds with increased activity or increased selectivity over
other JAK kinases
(especially JAK2). In some embodiments provided herein, the present invention
provides
inhibitors of TYK2 which show selectivity over JAK I, JAK2, and/or JAK3. In
some
embodiments, compounds with this selectivity (particularly over JAK2) deliver
a
pharmacological response that favorably treats one or more of the diseases or
conditions
described herein without the side-effects associated with the inhibition of
JAK2.
[0033] In some embodiments, the TYK2 inhibitors described herein are used in
the treatment
of a disease or condition in a mammal.
Comnounds
[0034] Compounds described herein, including pharmaceutically acceptable
salts, tautomers,
and solvates thereof, are inhibitors of TYK2. In some embodiments, compounds
described
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herein are selective for TYK2 over other JAKs. In some embodiments, compounds
described
herein bind selectively/specifically to the pseudokinase domain (1I-12) of
TYK2. In some
embodiments, a compound described herein binds to an allosteric site of TYK2.
In additional
embodiments, a compound described herein may be useful in the treatment of
TYK2 mediated
diseases or disorders.
[0035] In one aspect, provided herein is a compound of Formula (I):
IN_ R4
B'
R5, R
N B2 N
R6
n R7i} Z X3 R2
Al X2
CiA),2, X1
A
(R8)p
Formula (I),
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
Ring A is an unsubstituted or substituted 6-membered heterocyclic ring wherein
A1 and
A2 are independently N or C, wherein if Ring A is substituted then Ring A is
substituted with p instances of R8;
each R8 is independently hydrogen, halogen, unsubstituted or substituted Ci-C6
alkyl,
unsubstituted or substituted Cl-C6 deuteroalkyl, unsubstituted or substituted
C2-
C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or
substituted Cl-C6 fluoroalkyl, unsubstituted or substituted CI-C6 heteroalkyl,

unsubstituted or substituted carbocycle, unsubstituted or substituted
heterocycle, -
CN, -OH, -OR'', -C(=0)R16, -CO2R16, -C(=0)N(R16)2, -N(R16)2, -NRi6c(_0)R17,
-SR16, -S(=0)R17, -SO2R17, or -SO2N(R16)2; wherein if R8 is attached to a
nitrogen atom, then R8 is hydrogen, unsubstituted or substituted Ci-C6 alkyl,
unsubstituted or substituted Cl-C6 deuteroalkyl, unsubstituted or substituted
C2-
C6 alkenyl, unsubstituted or substituted C7-C6 alkynyl, unsubstituted or
substituted Ci-C6 fluoroalkyl, unsubstituted or substituted CI-C6 heteroalkyl,

unsubstituted or substituted carbocycle, unsubstituted or substituted
heterocycle, -
C(=0)R16, -CO2R16, -C(=0)N(R16)2, -S(=0)R17, -SO2R17, or -SO2N(R16)2, or two
Rg attached to the same carbon atom are taken together to form =0, =S, or =NH;
Z is -NR1 -, -0-, -S-, -S(=0)-, or -SO2-;
R1 is hydrogen, Cl-C6 alkyl, Cl-C6 deuteroalkyl, Ci-C6 fluoroalkyl, C3-C6
cycloalkyl, or monocyclic heterocycle;
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XI, X2, and X' are each independently CR11 or N;
each R11 is independently hydrogen, halogen, unsubstituted or substituted Ci-
C6
alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or
substituted C2-
C6 alkynyl, unsubstituted or substituted Ci-C6 fluoroalkyl, unsubstituted or
substituted Cl-C6 heteroalkyl, unsubstituted or substituted carbocycle,
unsubstituted or substituted heterocycle, -CN, -OH, -C(=0)R16, -
CO2R', -
C(=0)N(R'6)2, -N(R'6)2, -NR'6C(=0)R", -SR16, -S(=0)R17, -SO2R", or -
SO2N(R16)2;
B1 is N or CR12a;
B2 is N or CR12b;
Rila and Rub are each independently hydrogen, halogen, unsubstituted or
substituted
Cl-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or
substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl,
unsubstituted or substituted Ci-C6 heteroalkyl, unsubstituted or substituted
carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -0R17, -
C(=0)R16, -CO2R16, -C(=0)N(R16)2, -N(t16)2, _NR16(_0)Rt7, -SR16, -S(=0)R17,
-S021C, or -SO2N(R16)2;
-121 is hydrogen, C1-C6 alkyl, or C,-C6 fluoroalkyl;
R2 is a Ring B that is an unsubstituted or substituted heterocycle or
unsubstituted or
substituted carbocycle, wherein if Ring B is substituted then Ring B is
substituted
with q instances of R13;
each R13 is independently halogen, unsubstituted or substituted Cl-C6 alkyl,
unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6

alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or
substituted Cl-C6 heteroalkyl, unsubstituted or substituted carbocycle,
unsubstituted or substituted heterocycle, -CN, -OH, -0R17, -C(=0)R16, -CO2R16,
-
C(=0)N(R16)2, -N(t16)2, _NR16c(_c)R17, _sR16, _s(_c)R17, _S02R17, or -
SO2N(R16)2;
or two R13 groups on adjacent atoms of Ring B are taken together with the
intervening atoms to which they are attached to form an unsubstituted or
substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or
substituted 5- or 6-membered monocyclic heterocycle;
or R2 is -C(=0)R14, -C(_o)\TR14R15, or -C(=0)0R14;
K is hydrogen, unsubstituted or substituted Cl-C6 alkyl, Cl-C6 deuteroalkyl,
unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6
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alkynyl, unsubstituted or substituted Cl-C6 heteroalkyl, unsubstituted or
substituted monocyclic carbocycle, unsubstituted or substituted bicyclic
carbocycle, unsubstituted or substituted monocyclic heterocycle, or
unsubstituted
or substituted bicyclic heterocycle;
R15 is hydrogen, C4-C6 alkyl, or Ci-C6 fluoroalkyl;
or Rm and R15 are taken together with the intervening atoms to which they are
attached to form an unsubstituted or substituted 5- or 6-membered monocyclic
heterocycle;
or R1 and R15 are taken together with the intervening atoms to which they are
attached to form an unsubstituted or substituted 5- or 6-membered monocyclic
heterocycle;
W is -NR3- or -0-;
R3 is hydrogen, CI-C6 alkyl, C1-C6 deuteroalkyl, CI-C6 fluoroalkyl, C3-C6
cycloalkyl, or
monocyclic heterocycle;
R4 is hydrogen, CI-C6 alkyl, CI-C6 deuteroalkyl, C
fluoroalkyl, C3-C6 cycloalkyl, or
monocyclic heterocycle;
or R3 and R4 are taken together with the N atom to which they are attached to
form a
substituted or un sub sti tilted N-containing heterocycle;
or R3 and Rua are taken together with the intervening atoms to which they are
attached to
form a substituted or unsubstituted 5- or 6-membered heterocycle;
R5 is hydrogen, Ci-C6 alkyl, Ci-C6 fluoroalkyl, C3-C6 cycloalkyl, or
monocyclic
heterocycle;
each 116 and 127 is independently hydrogen, deuterium, halogen, Ci-C6 alkyl,
C,-C6
deuteroalkyl, Ci-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle, -
CN, -
OH, -0107, -C(=0)R16, -CO2R16, -C(=0)N(R16)2, -N(R16)2, -NR16C(=0)R17, -SR16, -

S(=0)R17, -SO2R17, or -SO2N(R16)2;
or one R6 and one R7 attached to the same carbon atom are taken together with
the
carbon atom to which they are attached to form C=0 or C3-C4 cycloalkyl;
each 1116 is independently hydrogen, substituted or unsubstituted CI-C6 alkyl,
substituted
or unsubstituted CI-Co fluoroalkyl, substituted or unsubstituted CI-C6
hctcroalkyl,
substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted
monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted
phenyl,
or substituted or unsubstituted monocyclic heteroaryl;
or two R16 on the same -I\ atom are taken together with the N atom to which
they are
attached to form a substituted or unsubstituted N-containing heterocycle; and
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each RI' is independently substituted or unsubstituted Ci-C6 alkyl,
substituted or
unsubstituted CI-C6 fluoroalkyl, substituted or unsubstituted Ci-C6
heteroalkyl,
substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted
monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted
phenyl,
or substituted or unsubstituted monocyclic heteroaryl;
wherein each substituted alkyl, substituted fluoroalkyl, substituted
deuteroalkyl,
substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl,
substituted
carbocycle, and substituted heterocycle is substituted with one or more Rs
groups
independently selected from the group consisting of deuterium, halogen, Cl-C6
alkyl,
monocyclic carbocycle, monocyclic heterocycle, -CN, -CH7CN, -0R18, -CH2OR18, -

CO2R18, -CH2CO2R", -C(=0)N(R18)2, -CH2C(=0)N(R18)2, -N(R18)2, -CH2N(R18)2, -
NR"C(=0)R18, -CH2NR"C(=0)R1s, -NR"S021e-9, -CH2NlesSO2R19, -SR', -
CH2SR", -S(=0)R19, -CH2S(=0)109, -SO2R19, -CH2S02R1-9, -SO2N(R18)2, or -
CH2S02N(R18)2;
each R18 is independently selected from hydrogen, C1-C6 alkyl, CI-C6
fluoroalkyl,
Ci-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-

membered heteroaryl and 6-membered heteroaryl;
or two R18 groups are taken together with the N atom to which they are
attached to
form a N-containing heterocycle;
each R19 is independently selected from CI-Co alkyl, Ci-C6 heteroalkyl, C3-C6
cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and

6-membered heteroaryl;
n is 1, 2, or 3;
p is 1, 2, 3, or 4; and
q is 1,2, 3, or 4.
100361 For any and all of the embodiments, substituents are selected from
among a subset of
the listed alternatives. For example, in some embodiments, RI is hydrogen, C1-
C6 alkyl, or Ci-C6
fluoroalkyl. In some embodiments, le is hydrogen, CI-Ca alkyl, or Ci-Ca
fluoroalkyl. In some
embodiments, RI- is hydrogen or CI-C6 alkyl. In some embodiments, fe is
hydrogen or CI-Ca
alkyl. In some embodiments, R1 is hydrogen, methyl, ethyl, propyl, isopropyl,
or butyl. In some
embodiments, R1 is hydrogen or methyl. In some embodiments, RI- is hydrogen.
In some
embodiments, R1 is methyl.
[0037] In some embodiments, R5 is hydrogen, CI-C6 alkyl, or C1-C6 fluoroalkyl.
In some
embodiments, R5 is hydrogen, Ci-Ca alkyl, or Ci-C4 fluoroalkyl. In some
embodiments, R5 is
hydrogen or C1-C6 alkyl. In some embodiments, R5 is hydrogen or C1-C4 alkyl.
In some
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embodiments, R5 is hydrogen, methyl, ethyl, propyl, isopropyl, or butyl. In
some embodiments,
R5 is hydrogen or methyl. In some embodiments, R5 is hydrogen. In some
embodiments, R5 is
methyl.
[0038] In some embodiments, W is -0-.
100391 In some embodiments, W is -NR3-.
[0040] In some embodiments, the compound is a compound of Formula (la) or
Formula (lb):
N,R4 R4
B1
0-11 N
R5, R5,
N B2 N N B2 N
( R6, 7 ( R6 s z
n X3 R2
n R7 R2Y
A v2 A le2
`)N2 -.")(1 CA12: x1
A A
- (R8)13
Formula (Ia) Formula (Ib),
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[0041] In some embodiments, the compound is a compound of Formula (la), or a
pharmaceutically acceptable salt, tautomer, or solvate thereof. In some
embodiments, the
compound is a compound of Formula (lb), or a pharmaceutically acceptable salt,
tautomer, or
solvate thereof.
100421 In some embodiments, R4 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl,
or Ci-C 6
fluoroalkyl. In some embodiments, le is hydrogen, Cl-C6 alkyl, or Ci-C6
deuteroalkyl. In other
embodiments, le is hydrogen, C1-C4 alkyl, Ct-Ca deuteroalkyl, or Ct-C4
fluoroalkyl. In some
embodiments, R4 is hydrogen, CI-Ca alkyl, or CI-C4 deuteroalkyl. In some
embodiments, R4 is
hydrogen, C1-C2 alkyl, or Ci-C2 deuteroalkyl. In some embodiments, R4 is
hydrogen, -CH3, -
CH2D, -CHD2, or -CD3. In some embodiments, R4 is hydrogen. In some
embodiments, R4 is -
CH3. In some embodiments, R4 is -CD3.
[0043] In some embodiments when W is -0-, R4 is hydrogen, Cl-C6 alkyl, Cl-C6
deuteroalkyl,
or C1-C6 fluoroalkyl. In some embodiments, R4 is hydrogen, Ci-C6 alkyl, or C1-
C6 deuteroalkyl.
In other embodiments, R4 is hydrogen, Ci-C4 alkyl, Ci-C4 deuteroalkyl, or Ci-
C4 fluoroalkyl. In
some embodiments, R4 is hydrogen, CI-Ca alkyl, or C1-C4 deuteroalkyl. In some
embodiments,
R4 is hydrogen, CI-C2 alkyl, or C1-C2 deuteroalkyl. In some embodiments, R4 is
hydrogen, -CH3,
-CH2D, -CHD,, or -CD3. In some embodiments, R4 is hydrogen. In some
embodiments, R4 is -
CH3. In some embodiments, R4 is -CD3.
[0044] In some embodiments when W is -NR3-, It3 is hydrogen, Ci-C6 alkyl, Cl-
C6
deuteroalkyl, or Ci-C6 fluoroalkyl. In some embodiments, R3 is hydrogen, Ci-C6
alkyl, or Ci-C6
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deuteroalkyl. In other embodiments, Te is hydrogen, Ci-C4 alkyl, Ci-C4
deuteroalkyl, or Ci-C4
fluoroalkyl. In some embodiments, R3 is hydrogen, Ci-C4 alkyl, or Ci-C4
deuteroalkyl. In some
embodiments, R3 is hydrogen, Ci-C, alkyl, or C1-C2 deuteroalkyl. In some
embodiments, R3 is
hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R3 is hydrogen. In
some
embodiments, R3 is -CH3. In some embodiments, R3 is -CD3.
[0045] In some embodiments when W is -NR3-, R3 is hydrogen, Ci-C6 alkyl, Ci-C6

deuteroalkyl, or Ci-C6 fluoroalkyl. In some embodiments, R4 is hydrogen, Ci-C6
alkyl, or Ci-C6
deuteroalkyl. In other embodiments, R4 is hydrogen, Ci-C4 alkyl, Cl-C4
deuteroalkyl, or Ci-C4
fluoroalkyl. In some embodiments, R4 is hydrogen, Ci-C4 alkyl, or Ci-C4
deuteroalkyl. In some
embodiments, Te is hydrogen, CI-C2 alkyl, or CI-C2 deuteroalkyl. In some
embodiments, R4 is
hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R4 is hydrogen. In
some
embodiments, R4 is -CH3. In some embodiments, R4 is -CD3.
[0046] In some embodiments when W is -NR3-, R3 and le are each independently
hydrogen,
Ci-C6 alkyl, C1-C6 deuteroalkyl, or Ci-C6 fluoroalkyl. In some embodiments, R3
and R4 are each
independently hydrogen, Ci-C6 alkyl, or Ci-C6 deuteroalkyl. In other
embodiments, R3 and R4
are each independently hydrogen, Ci-C4 alkyl, Ci-C4 deuteroalkyl, or Ci-C4
fluoroalkyl. In some
embodiments, R3 and R4 are each independently hydrogen, Ci-C4 alkyl, or Ci-C4
deuteroalkyl.
In some embodiments, R3 and R4 are each independently hydrogen, Ci-C, alkyl,
or Ci-C?
deuteroalkyl. In some embodiments, R3 and R4 are each independently hydrogen, -
CH3, -CH2D,
-CHD2. or -CD3. In some embodiments, R3 is hydrogen. In some embodiments, R3
is hydrogen;
and R4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments,
R3 is hydrogen;
and R4 is hydrogen, Ci-C2 alkyl, or Ci-C2 deuteroalkyl. In some embodiments,
R3 is hydrogen;
and R4 is hydrogen, -CH3, -CHD2, or -CD3. In some embodiments, R3
is hydrogen; and
R4 is hydrogen. In some embodiments, R3 is hydrogen; and R4 is Ci-C4 alkyl, or
C1-C4
deuteroalkyl. In some embodiments, R3 is hydrogen; and R4 is Ci-C2 alkyl, or
Ci-C2
deuteroalkyl. In some embodiments, R3 is hydrogen; and R4 is -CH3, -CH2D, -
CHD2, or -CD3. In
some embodiments, R3 is hydrogen; and R4 is -CH3. In some embodiments, R3 is
hydrogen; and
R4 is -CD3.
[0047] In some embodiments when W is -NR3-, R3 and R4 are taken together with
the N atom
to which they arc attached to form a substituted or unsubstituted N-containing
heterocycle. In
some embodiments, R3 and R4 are taken together with the N atom to which they
are attached to
form a substituted or unsubstituted N-containing heterocycloalkyl. In some
embodiments, R3
and R4 are taken together with the N atom to which they are attached to form a
substituted or
unsubstituted monocyclic N-containing heterocycloalkyl. In some embodiments,
R3 and R4 are
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taken together with the N atom to which they are attached to form a
substituted or unsubstituted
3- to 6-membered N-containing heterocycloalkyl.
[0048] In some embodiments, the compound is a compound of Formula (II) or
Formula (III):
R4. R4,
NH 0
131,
(Dt1( 0 N
I 1,
HN 132- NH HNB2 NH
R;) R;)
R R
n R7 Z r- 2 LX3 n R7 Z X3 2
Al x2 Al X2
CA): XI CL2, X1
A A
(R8)p (R8)p
Formula (II) Formula (III),
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[0049] In some embodiments, the compound is a compound of Formula (II), or a
pharmaceutically acceptable salt, tautomer, or solvate thereof In some
embodiments, the
compound is a compound of Formula (III), or a pharmaceutically acceptable
salt, tautomer, or
solvate thereof
[0050] In some embodiments, R4 is hydrogen, CI-C6 alkyl, C,-C6 deuteroalkyl,
or Ca-C6
fluoroalkyl. In some embodiments, R4 is hydrogen, Ca-Co alkyl, or Cl-C6
deuteroalkyl. In other
embodiments, R4 is hydrogen, Ca-Ca alkyl, CI-Ca deuteroalkyl, or CI-C4
fluoroalkyl. In some
embodiments, R4 is hydrogen, Ca-C4 alkyl, or CI-Ca deuteroalkyl. In some
embodiments, R4 is
hydrogen, C,-C, alkyl, or CI-C2 deuteroalkyl. In some embodiments, R4 is
hydrogen, -C113, -
CH2D, -CHD2, or -CD,. In some embodiments, R4 is hydrogen. In some
embodiments, R4 is -
CH,. In some embodiments, R4 is -CD,.
[0051] In some embodiments, is cRll, x2 is c,-,K11,
and X3 is CR11; or X1 is CR11, X2 is
CR11, and X3 is N; or X" is CR11. X2 is N, and X3 is CR11; or X" is CR11, X2
is N, and X3 is N; or
X1 is N, X2 is CR11, and X3 is CR11; or X1 is N, X2 is CR11, and X3 is N; or
X1 is N, X2 is N, and
X3 is CR11 In some embodiments, X1 is cR11, x2 is call, and A -µ,3
is CR11. In some
embodiments, X1 is call, x2 is (2_1( ..11,
and X3 is N. In some embodiments, X1 is 0{11, x2 is N,
and X3 is CR11. In some embodiments, X' is it,
lc X2 is N, and X3 is N. In
some embodiments,
X1 is N, X2 is CR11, and X3 is CR11. In some embodiments, X1 is N, X2 is CR11,
and X3 is N. In
some embodiments, X1 is N, X2 is N, and X3 is CR11.
[0052] In some embodiments, X1 is cRll, x2 is c:-.11,
tc and X3 is CR11; or X1 is
CR11, X2 is
CR11, and X' is N; or X1 is CRII. X2 is N, and X' is CR11; or X1 is N, X2 is
CR11, and X' is CR11.
100531 In some embodiments, each 1211 is independently hydrogen, halogen, Ca-
C6 alkyl, Ca-
C6 fluoroalkyl, -CN, -OH, -OR", -CO2R16, -C(-0)N(R16)2, 2
4,4R16µ), _ SO2R17, or -SO2N(R16)2.
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In some embodiments, each R" is independently hydrogen, halogen, CI-C6 alkyl,
Cl-C6
fluoroalkyl, -CN, -OH, -C(=0)N(R15)2, -N(R16)2, or -SO2N(R16)2. In
some embodiments,
each R11 is independently hydrogen, halogen, Ci-C6 alkyl, Ci-C6 fluoroalkyl, -
CN, -OH, -OR1-7,
or -N(R16)2. In some embodiments, each is independently hydrogen,
halogen, Ci-C4 alkyl,
Ci-C4 fluoroalkyl, -CN, -OH, -0R17, or -N(R16)2. In some embodiments, each R11
is
independently hydrogen, halogen, CI-C4 alkyl, Cl-C4 fluoroalkyl, or -CN. In
some
embodiments, each R11 is independently hydrogen, halogen, or -CN. In some
embodiments, each
101 is independently hydrogen or halogen. In some embodiments, each RI- is
independently
hydrogen, fluoro, or chloro. In some embodiments, each is independently
hydrogen or
fluoro. In some embodiments, each is hydrogen.
[0054] In some embodiments, X1, X2, and X3 are each independently CH, CF, or
N. In some
embodiments, X', X2, and X3 are each independently CH or N. In some
embodiments, X2 is CH
or CF, X2 is CH or CF, and X3 is CH or CF; or XI is CH or CF, X2 is CH or CF,
and X3 is N; or
is CH or CF, X2 is N, and X3 is CH or CF; or XI- is N, X2 is CH or CF, and X3
is CH or CF. In
some embodiments, XI is CH, X2 is CH, and X3 is CH; or X1 is CH, X2 is CH, and
X2 is N; or X1
is CH, X2 is N, and X3 is CH; or X1 is N, X2 is CH, and X3 is CH.
[0055] In some embodiments, X1- is CH, X2 is CH, CF, or N, and X3 is CH. In
some
embodiments, X' is CH, X2 is CF or N, and X is CH In some embodiments, X' is
CH, CF, or
N, X2 is CH, and X3 is CH. In some embodiments, X1 is CF, or N, X2 is CH, and
X3 is CH. In
some embodiments, XI is CH, X2 is CH, and X3 is CH, CF, or N. In some
embodiments, X2 is
CH, X2 is CH, and X3 is CF or N.
[0056] In some embodiments, the compound is a compound of Formula (IV) or
Formula (V):
Rt NH R4
'0
0 N
HN B2 NH HN---µ.-B2 NH
( R6\ 2
R6'
n R7Z R2 n R7Z 140 R
A1 A1
i5k2
(R5)p (R8)p
Formula (IV) Formula (V)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[0057] In some embodiments, the compound is a compound of Formula (IV), or a
pharmaceutically acceptable salt, tautomer, or solvate thereof In some
embodiments, the
compound is a compound of Formula (V), or a pharmaceutically acceptable salt,
tautomer, or
solvate thereof.
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[0058] In some embodiments, leis hydrogen, CI-C6 alkyl, CI-C6 deuteroalkyl, or
Ca-C6
fluoroalkyl. In some embodiments, R4 is hydrogen, Ca-C6 alkyl, or Ci-C6
deuteroalkyl. In other
embodiments, R4 is hydrogen, Ci -Ca alkyl, CI-Ca deuteroalkyl, or Ci-C4
fluoroalkyl. In some
embodiments, R4 is hydrogen, Ca-Ca alkyl, or Ci-C4 deuteroalkyl. In some
embodiments, R4 is
hydrogen, C1-C2 alkyl, or Ca-C2 deuteroalkyl. In some embodiments, R4 is
hydrogen, -CH3, -
CH2D, -CHD2, or -CD3. In some embodiments, R4 is hydrogen. In some
embodiments, R4 is -
CH3. In some embodiments, R4 is -CD3.
100591 In some embodiments, Ring A is an unsubstituted or substituted 6-
membered
heterocycloalkyl ring wherein A1 and A2 are independently N or C, wherein if
Ring A is
substituted then Ring A is substituted with p instances of R8.
[0060] In some embodiments, each le is independently hydrogen, halogen,
unsubstituted or
substituted Ci-C6 alkyl, unsubstituted or substituted Cl-C6 deuteroalkyl,
unsubstituted or
substituted C2-C6 alkenyl, unsubstituted or substituted C)-C6 alkynyl,
unsubstituted or
substituted C1-C6 fluoroalkyl, unsubstituted or substituted CI-C6 heteroalkyl,
unsubstituted or
substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -
0R17, -C(=0)R16, -
CO2R16, -C(=0)N(R16)2, _N(R16)2, _NR16c (=o)R17, _sR16, _s(_o)R17, _SO2R17, or
-SO2N(R16)2;
wherein if R8 is attached to a nitrogen atom, then R8 is hydrogen,
unsubstituted or substituted
Ca-C6 alkyl, unsubstituted or substituted Ca-C6 deuteroalkyl, unsubstituted or
substituted C2-C6
alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or
substituted C1-C6
fluoroalkyl, unsubstituted or substituted Ca-C6 heteroalkyl, unsubstituted or
substituted
carbocycle, unsubstituted or substituted heterocycle, -C(=0)R16, -CO2R16, -
C(=0)N(R16)2, -
S(=0)R12, -SO2R17, or -SO2N(W6)2; or two R8 attached to the same carbon atom
are taken
together to form =0, =S, or =NH. In some embodiments, each 12_8 is
independently hydrogen,
halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or
substituted Ci-C6
deuteroalkyl, unsubstituted or substituted Ca-C6 fluoroalkyl, unsubstituted or
substituted
carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -0R17, -
C(=0)R16, -0O2R16, or -
C(=0)N(R16)2; wherein if R8 is attached to a nitrogen atom, then 128 is
hydrogen, unsubstituted
or substituted Ci-C6 alkyl, unsubstituted or substituted Ca-C6 deuteroalkyl,
unsubstituted or
substituted Ci-C6 fluoroalkyl, unsubstituted or substituted carbocycle,
unsubstituted or
substituted heterocycle, -C(=0)R16, -0O2R16, or -C(=0)N(R16)2; or two R8
attached to the same
carbon atom are taken together to form =0, =S, or =NH. In some embodiments,
each R8 is
independently hydrogen, -Cl, -F, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3,
cyclopropyl,
oxetanyl, azetidinyl, -CN, -OH, -CO2H, or -CO2CH3; wherein if le is attached
to a nitrogen
atom, then R8 is hydrogen, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3,
cyclopropyl,
oxetanyl, azetidinyl, -CO2H, or -CO2CH3; or two R8 attached to the same carbon
atom are taken
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together to form =0. In some embodiments, each le is independently hydrogen,
methyl, -CD3, -
OH, -CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3; wherein if R8 is attached to a
nitrogen atom,
then R8 is hydrogen, methyl, -CD3, -CH2OH, oxetanyl, or -0O2CH3; or two R8
attached to the
same carbon atom are taken together to form =0.
100611 In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is
1, 2, 3, or 4. In
some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some
embodiments, p is
1. In some embodiments, p is 2. In some embodiments, p is 0; and Ring A is
therefore
unsubstituted.
[0062] In some embodiments, Ring A is an unsubstituted or substituted 6-
membered
heteroaryl ring wherein Al and A2 are independently N or C, wherein if Ring A
is substituted
then Ring A is substituted with p instances of R8. In some embodiments, Ring A
is an
unsubstituted or substituted pyridine, unsubstituted or substituted
pyridazine, unsubstituted or
substituted pyrimidine, unsubstituted or substituted pyrazine, unsubstituted
or substituted
triazine, or unsubstituted or substituted pyridone, wherein if Ring A is
substituted then Ring A is
substituted with p instances of R8. In some embodiments, Ring A is an
unsubstituted or
substituted pyridine, unsubstituted or substituted pyrimidine, unsubstituted
or substituted
pyrazine, or unsubstituted or substituted pyridone, wherein if Ring A is
substituted then Ring A
is substituted with p instances of 128 In some embodiments, Ring A is an
unsubstituted or
substituted pyridine, or unsubstituted or substituted pyrimidine, wherein if
Ring A is substituted
then Ring A is substituted with p instances of R8.
100631 In some embodiments, Ring A is an unsubstituted or substituted
pyridine, wherein if
Ring A is substituted then Ring A is substituted with p instances of R8. In
some embodiments,
Ring A is an unsubstituted or substituted pyridazine, wherein if Ring A is
substituted then Ring
A is substituted with p instances of R8. In some embodiments, Ring A is an
unsubstituted or
substituted pyrimidine, wherein if Ring A is substituted then Ring A is
substituted with p
instances of R8. In some embodiments, Ring A is an unsubstituted or
substituted pyrazine,
wherein if Ring A is substituted then Ring A is substituted with p instances
of R8. In some
embodiments, Ring A is an unsubstituted or substituted triazine, wherein if'
Ring A is substituted
then Ring A is substituted with p instances of R8. In some embodiments, Ring A
is an
unsubstituted or substituted pyridone, wherein if Ring A is substituted then
Ring A is substituted
with p instances of Ie.
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N Ai NT-AI
N,
(Ra)p (1:28)10
N (118)p
[0064] In some embodiments, Ring A is
N-Yµ NUiy\
,x,N,D81 N...< 8
(R-)P, or v- 113 . In some
embodiments, Ring A is (R )P . In some embodiments,
N
8
Ring A is (R8)P . In some embodiments, Ring A is (R )P . In
some embodiments, Ring
N,
A is NB (R)P In some embodiments, Ring A is IR-1
"P In some embodiments, Ring A is
(Ra)p
a a
cAl \ b Al A
A9c3A- b
A
(Ra)p All.
100651 In some embodiments, is A7 AB
; wherein
(i) Al and A2 are each C; and A6, A7, A8, and A9 are each independently CR8 or
N;
(ii) Al is N; A2 is C; A6, A7, and A8 are each independently CR8 or N; and A9
is C(=0);
(iii) Al is C; A2 is N; A6 is C(=0); and A7, A8, and A9 are each independently
CR8 or N;
OF
(iv) A' and A2 are each C; one of A6, A7, A8, and A9 is NR', wherein A6, A7,
A8, or A9
adjacent to the NIP.' is C(=0) and the remaining members of A6, A7, A8, and A9
are
each independently CR8 or N.
a a
Al 2\ Al \
b b
A
A8\-1A6
(1728)p ,
100661 In some embodiments, is A7 ; wherein A' and A2
are each C;
a
,
b
CAl\
and A6, A7, A8, and A9 are each independently Cle or N. In some embodiments,
(R8) i
p s
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b
A8 \--;A8
; wherein Al is N; A2 is C; A6, A7, and A8 arc each independently CR8 or N;
and A9
Al 2\ Al
b AA:
\b
A
is C(=0). In some embodiments, (R8)p s =-A7
; wherein A' is C; A2 is N; A6 is
C(=0); and A7, A8, and A9 are each independently CR8 or N. In some
embodiments,
a
Ai 2\ Ai ,
b b
A
(R8)P is A8"A7A6 ; wherein Al and A2 are each C; one of A6,
A7, As, and A9 is NRs,
wherein A6, A7, A8, or A9 adjacent to the Me is C(=0) and the remaining
members of A6, A7,
As, and A9 are each independently CR8 or N.
100671 In some embodiments, the compound is a compound of Formula (VI) or
Formula
(VII):
R4 R4
N H
0 N 0 N
HNB2NH HN B-
H
R6'
IR7)) Z (
2 RR7i)Z R2
n Al , Al 10
A- ,70c5,51.,2
0
A8 A8 A8, A8
=/2k. A'
Formula (VI) Formula (VII)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein
(i) Al and A2 are each C; and A6, A7, A8, and A9 are each independently CR8 or
N;
(ii) Al is N; A2 is C; A6, A7, and A8 are each independently CR8 or N; and A9
is C(=0);
(iii) A' is C; A2 is N; A6 is C(=0); and A7, A8, and A9 are each independently
CR8 or N;
or
(iv) Ai and A2 are each C; one of A6, A7, A8, and A9 is NR8, wherein A6, A7,
A8, or A9
adjacent to the NR8 is C(=0) and the remaining members of A6, A7, A8, and A9
are
each independently CR8 or N.
100681 In some embodiments, A' and A2 are each C; and A6, A7, A8, and A9 are
each
independently CR8 or N. In some embodiments, A' is N; A2 is C; A6, A7, and A8
are each
independently CR8 or N; and A9 is C(=0). In some embodiments, Ai is C; A2 is
N; A6 is C(=0);
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and A7, Ag, and A9 are each independently CR8 or N. In some embodiments, Al-
and A2 are each
C; one of A6, A7, A8, and A9 is NR', wherein A6, A2, A8, or A9 adjacent to the
NR' is C(=0) and
the remaining members of A6, A7, Ag, and A9 are each independently CR8 or N.
[0069] In some embodiments, the compound is a compound of Formula (VI), or a
pharmaceutically acceptable salt, tautomer, or solvate thereof. In some
embodiments, the
compound is a compound of Formula (VII), or a phaimaceutically acceptable
salt, tautomer, or
solvate thereof
[0070] In some embodiments, A1 is C; A2 is C; A6 is N; A7 is CR8 or N; A8 is
CR8 or N; and
A9 is CR8 or N. In some embodiments, Al is C; A2 is C; A6 is N; A7 is CRg; Ag
is CRg; and A9 is
CRg.
[0071] In some embodiments,
Al is C; A2 is C; A6 is N; A7 is Cle: A8 is CR8; and A9 is CR8;
or Al is C; A2 is C; _A6 is CR8; A7 is N; Ag is CR% and A9 is CR8;
or Al is C; A2 is C; A6 is CR8; A7 is CR8; A8 is N; and A9 is CR8;
or Al is C; A2 is C; A6 is CR8; A7 is CR8; A8 is CR8; and A9 is N.
[0072] In some embodiments,
Al is N; A2 is C; A6 is CRg; A7 is CR8; is CR8; and A9 is C(=0);
or A' is C; A2 is N; AO is C(=0); A7 is CR8; Ag is C128; and A9 is CR8;
or Al is C; A2 is C; A6 is NR'; A7 is C(=0); A8 is CR8; and A9 is CRg;
or Al is C; A2 is C; A6 is C(=0); A7 is NR'; A8 is CR8; and A9 is CR8;
or Al is C; A2 is C; A6 is CR8; A7 is NR8; Ag is C(=0); and A9 is CRg;
or Al is C; A2 is C; A6 is CR8; A7 is C(=0); Ag is Nle; and A9 is Cie;
or Al is C; A2 is C; A6 is CI18; A7 is CR8; A8 is NR8; and A9 is C(=0);
or Al is C; A2 is C; A6 is CR8; A7 is CR8; A8 is C(=0); and A9 is NR8.
[0073] In some embodiments,
Al is C; A2 is C; A6 is N; A7 is N; Ag is CRg; and A9 is CRg;
or Al is C; A2 is C; A6 is N; A7 is CR8; Ag is N; and A9 is CR8;
or Al is C; A2 is C; A6 is N; A7 is CR% A8 is CR8; and A9 is N;
or Al is C; A2 is C; A6 is CR8; A7 is N; A8 is N; and A9 is CR8;
or Al is C; A2 is C; A6 is CR8; A7 is N; A8 is CR8; and A9 is N;
or Al is C; A2 is C; A6 is CRg; A7 is CRg; Ag is N; and A9 is N.
100741 In some embodiments,
Al is C; A2 is C; A6 is CIV; A7 is N; A8 is N; and A9 is N;
or Al is C; A2 is C; A6 is N; A7 is CR8; A8 is N; and A9 is N;
or Al is C; A2 is C; A6 is N; A7 is N; A8 is CR8; and A9 is N;
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or Al is C; A2 is C; A6 is N; A7 is N; A8 is N; and A9 is CR8;
or A' is C; A2 is C; A6 is N; A7 is N; Ag is N; and A9 is N
[0075] In some embodiments,
Al is C; A2 is C; A6 is N; A7 is CR8: Ag is CR8; and A9 is CRg;
or Al is C; A2 is C; A6 is N; A7 is CR8; A8 is N; and A9 is CR8; or
or Al is C; A2 is C; A6 is N; A7 is CRg; A8 is CRg; and A9 is N;
or A' is C; A2 is C; A6 is C(=0); A7 is NR'; A' is CR8; and A9 is CR8
[0076] In some embodiments,
Al is C; A2 is C; A6 is N; A7 is CR8: Ag is CRg; and A9 is CRg;
or Al is C; A2 is C; A6 is N; A7 is CR8; A8 is N; and A9 is CRg.
a
am , b .--, .1::I
HO a
A1
A9r-A2 A b -..õ, NA
b
.= ...,\
b
6
A, 7 A (R8)
100771 In some embodiments, A is P OH
\-:(- - ,
a a a a 7.
Al \
b 17--"A b NI`---- A` b 9--A2 b P,1/4 , a&\ b
I
N N,.,., LI.,,.1..,___,,. AD 7 A6 --
, N
, , -A . In some
embodiments, ' is N ,
a ¨ a
b N ' b I
b N ...'= b N =--õ, b
......N
1 I I
N _. N it,..r.N N,N.=;-. 11..N-- N /
-....... , or
. In some embodiments,
a
a.,.,. a ¨
A1
A9rm'A2\ b b A98Al0--A2\ b N.
--"kõ-..-N, b
nAsi , 1
9-1 A6 A A6 ;01
'A7 is ''''''4.. - . In some
embodiments, 'A7 is .
[0078] In some embodiments, Ring A exists in a tautomeric form wherein both
tautomers are
a ..õ..r.¨

I b
-...,,,
considered within the scope of the present disclosure. For example,
may be in a
a ¨,
a
7-
oy,,i1),\
.,,
tautomeric form that is: b. In some embodiments, 0 exists in
the
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7
a
-1-
),
-.' N b A9 Al'A2 \ b 0
=¨,s....L A 7
A6 LI
tautomeric form that is: 0 . In some
embodiments, A is or
a ¨ a
-7 a
QA1 b A A
- siok- b N A b
0 . In some embodiments, P1/47 is 0 . In some embodiments,
a ¨
am +,
a -7
a -.7 a -.7
0 N....-\ ----N")µ b
''.
Al % Al \
A9rTh'-A2 , b 4:),N...,..õ.\\. A8n'A2 ' b I b
Al " AI 6 U b Al 8'---; ik6
...z.,,,...,....A...
io1/47 =
( R8)
( R8)
In some embodiments, s'A" is P P
,
a a a a
r(70µ b a b "T"Ai b nA 13 (R8441TA b \ R'-'s)o ¨ N µI
N,Ra
N '0 0."-P'µ N iRi3)
0 R8 , , R8 P 0 P R8 P
,
a a ¨ a
-71)µ b Y)µ 0
b ..j, "A b
R8 N If?R-i A \
R8õ1 R8 N 8)
0 P N .....R8) P , or "` iP _
[0079] In some embodiments, Ring A exists as an N-oxide. In some embodiments,
Ring A is a
a ¨
a -- a
Cy\I b
b
Ai N0_ b I ) = = " +
N +
- ,+ (I _
-0' N
pyridine N-oxide. In some embodiments, Ring A is I ,
,
a _
N '=-= b
or .
[0080] In some embodiments, A1 and A2 are each C. In some embodiments, A6, A7,
A8, and
A9 are each independently CR8 or N. In some embodiments, A6, A7, A8, and A9
are each
independently CR8. In some embodiments, one of A6, A7, A8, and A9 is N. In
some
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a -r,
Al
r:\ b
C A
(R8 =
embodiments, two of A6, A7, A8, and A9 are N. In some embodiments, )0 is
a
b
A8 A6
, and A6, A7, A8, and A9 are each independently CR8 or N.
a
a
Al
b
A A6 A6 =-= A6 7
100811 In some embodiments, 'A" is A,
In some embodiments, A', A7, A8,
and A9 are each independently CR8 or N.
[0082] In some embodiments,
A6 is N; A7 is CR8; Ag is CR8; and A9 is CR8;
or A6 is CR8; A7 is N; A8 is CR8; and A9 is CR8;
or A6 is CR8; A' is CR8; A8 is N; and A9 is CR8;
or A6 is CR8; A7 is CR8; A8 is CR8; and A9 is N.
[0083] In some embodiments,
A6 is N; A7 is N; A8 is CR8; and A9 is CR8;
or A6 is N; A7 is CR8; Ag is N; and A9 is CR8;
or A6 is N; A7 is Cie, As is CR8; and A9 is N;
or A6 is CR8; A7 is N; A8 is N; and A9 is CR8;
or A6 is CR8; A7 is N; A8 is CR8; and A9 is N;
or A6 is CR8; A7 is CR8; A8 is N; and A9 is N.
100841 In some embodiments, A6 is CR8 or N; A7 is CR8; A8 is CR8 or N; and A9
is CR8.
a a
ç.
Al
ABc-A2 b
[0085] In some embodiments, A "A7 A
is ABA6; where A6 is CR8 or N and A8 is CR8
or N. In some embodiments, A6 is N and A8 is CR8 or N. In some embodiments, A6
is N and A8
is CR8. In some embodiments, A6 is N and A8 is N.
[0086] In some embodiments, the compound is a compound of Formula (VIa) or
Formula
(Vila):
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R4 R4
-NH 0
t(13.`IN 0 OBN
I ,L
HN 132- NH
HN B2- NH
/ R6 R6
rJR7 Z rA2
= 7R2
(R8) (R8)
P A8 N P A8 N
Formula (Via) Formula (Vila)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein
Ag is CR8 or N.
[0087] In some embodiments, the compound is a compound of Formula (VIa), or a
pharmaceutically acceptable salt, tautomer, or solvate thereof. In some
embodiments, the
compound is a compound of Formula (VIIa), or a pharmaceutically acceptable
salt, tautomer, or
solvate thereof In some embodiments, A8 is CR8. In some embodiments, A8 is N.
[0088] In some embodiments, the compound is a compound of Formula (VIb) or
Formula
(VIIb):
R4 R4NH 0
0 0
BN
HN Bi- NH
HN B2.- NH
R6 R6
,kR7 rA2
= 7R2
(R8i (R8i
P P N
Formula (VIb) Formula (VIIb)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[0089] In some embodiments, the compound is a compound of Formula (VIb), or a
pharmaceutically acceptable salt, tautomer, or solvate thereof. In some
embodiments, the
compound is a compound of Formula (VIIb), or a pharmaceutically acceptable
salt, tautomer, or
solvate thereof
100901 In some embodiments, the compound is a compound of Formula (Vie) or
Formula
(VIIc):
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R4 R4
-NH 0
t(13.`IN 0 OBN
I ,L
HN 132- NH
HN B2- NH
rJR7 Z r-x2
7R2
(R8) (R8)
N N N N
Formula (Vic) Formula (Vile)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[0091] In some embodiments, the compound is a compound of Formula (VIb), or a
pharmaceutically acceptable salt, tautomer, or solvate thereof. In some
embodiments, the
compound is a compound of Formula (VIIb), or a pharmaceutically acceptable
salt, tautomer, or
solvate thereof
[0092] In some embodiments, the compound is a compound of Formula (VId) or
Formula
(VIId):
R4NH R4
0
0 0
BN
HN Bi- NH
HN B2-- NH
n kR7 rA2
7R2
N N
(R8
P 1p
Formula (VId) Formula (VIId)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[0093] In some embodiments, the compound is a compound of Formula (VId), or a
pharmaceutically acceptable salt, tautomer, or solvate thereof. In some
embodiments, the
compound is a compound of Formula (VIId), or a pharmaceutically acceptable
salt, tautomer, or
solvate thereof
[0094] In some embodiments, the compound is a compound of Formula (Vie) or
Formula
(Vile):
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R4
'NH 0
OBN 0
BN
I ,L
HN B2- NH HN B2- NH
R6 R2 Re R2
n \ R7 n kR7
(R8)¨ (R8)¨
p p
0 1;1 0
R8 R8
Formula (Vie) Formula (Vile)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[0095] In some embodiments, the compound is a compound of Formula (VIe), or a
pharmaceutically acceptable salt, tautomer, or solvate thereof. In some
embodiments, the
compound is a compound of Formula (Vile), or a pharmaceutically acceptable
salt, tautomer, or
solvate thereof.
[0096] In some embodiments, each RB is independently hydrogen, halogen,
unsubstituted or
substituted Ci-C6 alkyl, unsubstituted or substituted Cl-C6 deuteroalkyl,
unsubstituted or
substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl,
unsubstituted or
substituted Ci-C6 fluoroalkyl, unsubstituted or substituted CI-C6 heteroalkyl,
unsubstituted or
substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -
OR'', -C(=0)R16, -
CO2R16, -C(=0)N(R16)2, -N(R16)2, _NRi6c(=o)R17, _sR16,
-SO2Ru, or -SO2N(R16)2;
wherein if le is attached to a nitrogen atom, then RB is hydrogen,
unsubstituted or substituted
Ci-C6 alkyl, unsubstituted or substituted Cl-C6 deuteroalkyl, unsubstituted or
substituted C2-C6
alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or
substituted Ci-C6
fluoroalkyl, unsubstituted or substituted Ci-C6 heteroalkyl, unsubstituted or
substituted
carbocycle, unsubstituted or substituted heterocycle, -C(=0)R16, -CO2R16, -
C(=0)N(R16)2, -
S(=0)R17, -SO2R17, or -SO2N(R16)2.
[0097] In some embodiments, each RB is independently hydrogen, halogen,
unsubstituted or
substituted Ci-C 6 alkyl, unsubstituted or substituted C,-C6 deuteroalkyl,
unsubstituted or
substituted Ci-C6 fluoroalkyl, unsubstituted or substituted carbocycle,
unsubstituted or
substituted heterocycle, -CN, -OH,
-C(=0)R16, -CO2R16, or -C(=0)N(R16)2; wherein if Rs
is attached to a nitrogen atom, then le is hydrogen, unsubstituted or
substituted C1-C6 alkyl,
unsubstituted or substituted Cl-C6 deuteroalkyl, unsubstituted or substituted
Cl-C6 fluoroalkyl,
unsubstituted or substituted carbocycle, unsubstituted or substituted
heterocycle, -C(=0)R16, -
CO2R16, or -C(=0)N(R16)2.
100981 In some embodiments, each RB is independently hydrogen, halogen, Ci-C 6
alkyl, Cl-C6
deuteroalkyl, CI-C6 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered
heterocycloalkyl, -CN, -
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OH, -OR', -C(=0)R16, -CO2R16, or -C(=0)N(R16)2; wherein if le is attached to a
nitrogen atom,
then R8 is hydrogen, Cl-C6 alkyl, Cl-C6 deuteroalkyl, Ci-C6 fluoroalkyl, C3-C6
cycloalkyl, 4- to
6-membered heterocycloalkyl, -C(=0)R16, -CO2R16, or -C(=0)N(R16)2.
[0099] In some embodiments, each R8 is independently hydrogen, -Cl, -F,
methyl, ethyl,
isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, -
CO2H, or -
CO2CH3; wherein if R8 is attached to a nitrogen atom, then R8 is hydrogen,
methyl, ethyl,
isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CO2H, or -
CO2CH3.
[00100] In some embodiments, each R8 is independently hydrogen, methyl, -CD3, -
OH, -
CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3; wherein if R8 is attached to a
nitrogen atom, then R8
is hydrogen, methyl, -CD3, -CH2OH, oxetanyl, or -CO2CH3.
[00101] In some embodiments, each R8 is independently hydrogen, unsubstituted
or substituted
CI-Cs alkyl, unsubstituted or substituted Cl-C6 deuteroalkyl, unsubstituted or
substituted CI-C6
fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or
substituted heterocycle, -
C(=0)R16, -CO2R16, or -C(=0)N(R16)2. In some embodiments, each R8 is
independently
hydrogen, C,-C6 alkyl, Ci-C6 deuteroalkyl, CI-C6 fluoroalkyl, C3-C6
cycloalkyl, 4- to 6-
membered heterocycloalkyl, -C(=0)R16, -CO2R16, or -C(=0)N(R16)2. In some
embodiments,
each R8 is independently hydrogen, methyl, ethyl, isopropyl, -CD3, -CH2OH, -
CF3, cyclopropyl,
oxetanyl, azetidinyl, -CN, or -CO2CH3 In some embodiments, each -128
is independently
hydrogen, methyl, -CD3, -CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3. In some
embodiments,
each R8 is independently hydrogen, CI-C6 alkyl, CI-C6 deuteroalkyl, or Ci-C6
fluoroalkyl. In
some embodiments, each R8 is independently hydrogen, C1-C4 alkyl, Cl-C4
deuteroalkyl, or Cl-
fluoroalkyl. In some embodiments, each le is independently hydrogen, methyl,
ethyl,
isopropyl, -CD3, or -CF3. In some embodiments, each 11_8 is independently
hydrogen, methyl, -
CD3, or -CF3. In some embodiments, each R8 is independently hydrogen or
methyl.
[00102] In some embodiments, each R6 and R7 is independently hydrogen,
deuterium, halogen,
Ci-C6 alkyl, Cl-C6 deuteroalkyl, Ci-C6 fluoroalkyl, C3-C6 cycloalkyl, or
monocyclic heterocycle,
-CN, -OH, -C(=0)
N(Ri6)2, _N(R16)2, _NRi6c(_0)R17, _SO2R17, or -SO2N(R16)2. In some
embodiments, each R6 and R7 is independently hydrogen, halogen, Cl-C6 alkyl,
Ci-C6
fluoroalkyl, -CN, -OH, -0R17, and -N(R16)2. In some embodiments, each R6 and
R7 is
independently hydrogen, halogen, or C1-C6 alkyl. In some embodiments, each R6
and R7 is
independently hydrogen or Ci-C6 alkyl. In some embodiments, each R6 and It7 is
independently
hydrogen, deuterium, halogen, Ci-C4 alkyl, or Ci-C4 deuteroalkyl. In some
embodiments, each
R6 and R7 is independently hydrogen or Ci-C4 alkyl. In some embodiments, each
R6 and R7 is
independently hydrogen, deuterium, F, Cl, -CD3, or methyl. In some
embodiments, each R6 and
R7 is independently hydrogen, deuterium, F, or methyl. In some embodiments,
each R6 and R7 is
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independently hydrogen or methyl. In some embodiments, one R6 or R7 is methyl.
In some
embodiments, one R6 is methyl. In some embodiments, each R6 and R7 is
hydrogen. In some
embodiments, each R6 and R7 is deuterium. In some embodiments, each R6 and R7
is F.
[00103] In some embodiments, one R6 and one R7 attached to the same carbon
atom are taken
together with the carbon atom to which they are attached to form C=0 or C3-C4
cycloalkyl. In
some embodiments, one R6 and one R7 attached to the same carbon atom are taken
together with
the carbon atom to which they are attached to form C=0. In some embodiments,
one R6 and one
R7 attached to the same carbon atom are taken together with the carbon atom to
which they are
attached to form C3-C4 cycloalkyl.
[00104] In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some
embodiments,
n is 2. In some embodiments, n is 3.
[00105] In some embodiments, Z is -NR'6-, -0-, -S-, or -S02-. In some
embodiments, Z is
_0-, or -SO2-. In some embodiments, z is _NR1 _, _0-, or
In some embodiments, Z is
-NR16- or -0-.
[00106] In some embodiments, Z is -NR1 -. In some embodiments, R1 is
hydrogen, CI-C6
alkyl, Cl-C6 deuteroalkyl, Ci-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-
membered
heterocycloalkyl. In some embodiments, Rli) is hydrogen, Ci-C6 alkyl, Cl-C6
fluoroalkyl, C3-C6
cycloalkyl, or 4-to 6-membered heterocycloalkyl. In some embodiments, Wu is
hydrogen, Ci-C4
alkyl, Cl-C4 deuteroalkyl, Ci-C4 fluoroalkyl, C3-C4 cycloalkyl, or 4-membered
heterocycloalkyl.
In some embodiments, RI is hydrogen, Cl-C4 alkyl, Ci-C4 fluoroalkyl, C3-C4
cycloalkyl, or 4-
membered heterocycloalkyl. In some embodiments, R1 is hydrogen, CI-C4 alkyl,
Ci-C4
deuteroalkyl, cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl. In some
embodiments, RI is
hydrogen, C1-C4 alkyl, cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl. In
some embodiments,
R1- is hydrogen, Cl-C4 alkyl, CI-C4 deuteroalkyl, or cyclopropyl. In some
embodiments, R1 is
hydrogen, C1-C4 alkyl, or cyclopropyl. In some embodiments, R" is hydrogen, Ci-
C4 alkyl, or
Ci-C4 deuteroalkyl. In some embodiments, RI is hydrogen, -CH3, or -CD3. In
some
embodiments, RI- is Cl-C4 alkyl or Ci-C4 deuteroalkyl. In some embodiments,
RI is -CH3 or -
CD3. In some embodiments, Rm is -CH3. In some embodiments, Rm is -CD3.
[00107] In some embodiments, Z is NH, NCH3, or NCD3. In some embodiments, Z is
NCH3 or
NCD3. In some embodiments, Z is NCH3. In some embodiments, Z is NCD3.
[00108] In some embodiments, Z is -0-. In some embodiments, Z is -S-. In some
embodiments,
Z is -S(=0)-. In some embodiments, Z is -SO2-.
[00109] In some embodiments, R2 is a Ring B that is an unsubstituted or
substituted heterocycle
or unsubstituted or substituted carbocycle, wherein if' Ring B is substituted
then Ring B is
substituted with q instances of RI-3. In some embodiments, R2 is a Ring B that
is an unsubstituted
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or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic
carbocycle,
unsubstituted or substituted monocyclic heterocycle, unsubstituted or
substituted bicyclic
heterocycle, unsubstituted or substituted spirocyclic carbocycle,
unsubstituted or substituted
spirocyclic heterocycle, unsubstituted or substituted bridged carbocycle, or
unsubstituted or
substituted bridged heterocycle, wherein if Ring B is substituted then Ring B
is substituted with
q instances of Rn.
[00110] In some embodiments, R2 is a Ring B that is an unsubstituted or
substituted
monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle,
unsubstituted or
substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic
heterocycle, wherein
if Ring B is substituted then Ring B is substituted with q instances of R13.
[00111] In some embodiments, R2 is a Ring B that is an unsubstituted or
substituted phenyl,
unsubstituted or substituted naphthyl, unsubstituted or substituted monocyclic
6-membered
heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, or
unsubstituted or
substituted bicyclic heteroarylõ wherein if Ring B is substituted then Ring B
is substituted with
q instances of R1-3.
[00112] In some embodiments, R2 is a Ring B that is an unsubstituted or
substituted phenyl,
unsubstituted or substituted monocyclic 6-membered heteroaryl, or
unsubstituted or substituted
monocyclic 5-membered heteroaryl, wherein if Ring B is substituted then Ring B
is substituted
with q instances of R13.
[00113] In some embodiments, R2 is a Ring B that is an unsubstituted or
substituted
monocyclic 5-membered heteroaryl, wherein if Ring B is substituted then Ring B
is substituted
with q instances of RH. In some embodiments, R2 is a Ring B that is an
unsubstituted or
substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or
substituted thiophenyl,
unsubstituted or substituted pyrazolyl, unsubstituted or substituted
imidazolyl, unsubstituted or
substituted oxazolyl, unsubstituted or substituted isoxazolyl, unsubstituted
or substituted
thiazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or
substituted triazolyl,
unsubstituted or substituted oxadiazolyl, unsubstituted or substituted
thiadiazolyl, or
unsubstituted or substituted tetrazolyl, wherein if Ring B is substituted then
Ring B is substituted
with q instances of Rn. In some embodiments, R2 is a Ring B that is an
unsubstituted or
substituted pyrrolyl, unsubstitutcd or substituted imidazolyl, unsubstitutcd
or substituted
pyrazolyl, unsubstituted or substituted triazolyl, or unsubstituted or
substituted tetrazolyl,
wherein if Ring B is substituted then Ring B is substituted with q instances
of R1-3. In some
embodiments, R2 is a Ring B that is an unsubstituted or substituted pyrrolyl,
unsubstituted or
substituted imidazolyl, or unsubstituted or substituted pyrazolyl, wherein if
Ring B is substituted
then Ring B is substituted with q instances of R1-3.
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[00114] In some embodiments, R2 is a Ring B that is an unsubstituted or
substituted phenyl or
unsubstituted or substituted monocyclic 6-membered heteroaryl, wherein if Ring
B is substituted
then Ring B is substituted with q instances of R13
[00115] In some embodiments, R2 is a Ring B that is an unsubstituted or
substituted phenyl,
unsubstituted or substituted pyridinyl, unsubstituted or substituted
pyrimidinyl, unsubstituted or
substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein if
Ring B is
substituted then Ring B is substituted with q instances of R13.
[00116] In some embodiments, R2 is a Ring B that is an unsubstituted or
substituted
monocyclic 6-membered heteroaryl, wherein if Ring B is substituted then Ring B
is substituted
with q instances of R13. In some embodiments, R2 is a Ring B that is an
unsubstituted or
substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted
or substituted
pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein if Ring B is
substituted then Ring
B is substituted with q instances of R1-3. In some embodiments, R2 is a Ring B
that is an
unsubstituted or substituted pyridinyl or unsubstituted or substituted
pyrimidinyl, wherein if
Ring B is substituted then Ring B is substituted with q instances of R13. In
some embodiments,
R2 is a Ring B that is an unsubstituted or substituted pyridinyl, wherein if
Ring B is substituted
then Ring B is substituted with q instances of R13. In some embodiments, R2 is
a Ring B that is
an unsubstituted or substituted pyrimidinyl, wherein if Ring B is substituted
then Ring B is
substituted with q instances of R13.
R13)õ,, 513)q õ.,(R13)1
AR13)q
N
N
[00117] In some embodiments, R2 is
, or
r
_4R13)q _411113)(1
AR13)q
1_6" 1_1
17.
; and q is 0-4. In some embodiments, R2 is N
R13 AR13).
,JR13
)(1 )
kr¨A, N
or N ; and q is 0-4. In some embodiments, R2 is N
Of ; and q is 0-
4.
.1R13)q
14
[00118] In some embodiments, R2 is N.V, where V is CH, CR9, or N; and q is 0,
1, 2, 3
AT. 11R13),1
I
or 4. In some embodiments, R2 is NV
, where V is CH, CR9, or N; and q is 0, 1, 2, or 3.
[00119] In some embodiments, the compound is a compound of Formula (VIII):
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R4
'NH
0
I
HN---'-131
NH
( R6 z
,\R7r1 0110 TtRi3N
Al _
0
A8 A6
Formula (VIII)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein V
is N, CH, or CR13;
q is 1, 2, 3, or 4; and A1, Az, A6, A7, k 8,
A and A9 are as defined herein.
[00120] In some embodiments, V is N. In some embodiments, V is CH or CR13. In
some
embodiments, V is CH. In some embodiments, V is CR'3.
[00121] In some embodiments,
(i) A1 and A2 are each C; and A6, A7, A8, and A9 are each independently CR8 or
N;
(ii) Al is N; A2 is C; A6, A7, and A8 are each independently CR8 or N; and A9
is C(=0);
(iii) Al is C; A2 is N; A6 is C(=0); and A7, A8, and A9 are each independently
CR8 or N;
OF
(iv) A' and A2 are each C; one of A6, A7, A8, and A9 is NR8, wherein A6, A7,
A8, or A9
adjacent to the NR8 is C(=0) and the remaining members of A6, A7, A8, and A9
are
each independently CR8 or N.
[00122] In some embodiments, R4 is hydrogen, CI-C6 alkyl, CI-C6 deuteroalkyl,
or Ci-C6
fluoroalkyl. In some embodiments, it4 is hydrogen, Ci-C6 alkyl, or Ci-C6
deuteroalkyl. In other
embodiments, le is hydrogen, Ci-C4 alkyl, CI-Ca deuteroalkyl, or CI-C4
fluoroalkyl. In some
embodiments, R4 is hydrogen, CI-CI alkyl, or CI-CI deuteroalkyl. In some
embodiments, R4 is
hydrogen, CL-C2 alkyl, or Ci-C2 deuteroalkyl. In some embodiments, R4 is
hydrogen, -CH3, -
CH2D, -CHD2, or -CD3. In some embodiments, R4 is hydrogen. In some
embodiments, R4 is -
CH3. In some embodiments, R4 is -CD3.
[00123] In some embodiments, the compound of Formula (VIII) is a compound of
Formula
(Villa):
R4
'NH
HNB2NH
( Re
i
7R3A
P A8
Formula (Villa),
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36
or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein
A' is Cle or N. In
some embodiments, A8 is CR8 In some embodiments, A8 is N.
[00124] In some embodiments, the compound is a compound of Formula (VIIIb) or
Formula
(VIIIc):
R4 R4 R4,NH
1
0.1E3--1N 13
HN B-- NH
n E (R7R6 Z n ( R6
R7 R13)
,R13)ci
(R8) V (R8) V
P N
Formula (VIIIb) Formula (VIIIc)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[00125] In some embodiments, the compound is a compound of Formula (VIIIb), or
a
pharmaceutically acceptable salt, tautomer, or solvate thereof. In some
embodiments, the
compound is a compound of Formula (VIIIc), or a pharmaceutically acceptable
salt, tautomer, or
solvate thereof.
[00126] In some embodiments, the compound is a compound of Formula (VIIId):
R4
-NH
0 N
I
HN B2- NH
( R6
R7
(R8)1,
P
Formula (VIIld)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[00127] In some embodiments, the compound is a compound of Formula (Ville):
R4,NH
OtC13*-1N
I _L
HN B2- NH
,(R7R6 ZLJ L
-11(R13)
(R8)P
0
R8
Formula (Ville)
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or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[00128] In some embodiments, V is N. In some embodiments, V is CH or CR". In
some
embodiments, V is CH. In some embodiments, V is CR13.
[00129] In some embodiments, R4 is hydrogen, CI-C6 alkyl, CI-C6 deuteroalkyl,
or CI-Co
fluoroalkyl. In some embodiments, le is hydrogen, Cl-C6 alkyl, or Cl-C6
deuteroalkyl. In other
embodiments, R4 is hydrogen, C1-C4 alkyl, CI-Ca deuteroalkyl, or Ct-C4
fluoroalkyl. In some
embodiments, R4 is hydrogen, C1-C4 alkyl, or Ci-C4 deuteroalkyl. In some
embodiments, R4 is
hydrogen, Ct-C2 alkyl, or Cl-C2 deuteroalkyl. In some embodiments, R4 is
hydrogen, -CH3, -
CH2D, -CHD2, or -CD3. In some embodiments, R4 is hydrogen. In some
embodiments, R4 is -
CH3. In some embodiments, R4 is -CD3.
[00130] In some embodiments, each R" is independently halogen, unsubstituted
or substituted
C1-C6 alkyl, unsubstituted or substituted CI-Co fluoroalkyl, unsubstituted or
substituted
carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR', -
C(=0)R', -CO7R16, -
C(=0)N(t16)2, _N(tt6)2, _N-Rtoc(_0)R17, _SO2R17, or -SO2N(R16)2. In some
embodiments, each
R13 is independently halogen, unsubstituted or substituted CI-C6 alkyl,
unsubstituted or
substituted Ci-C6 fluoroalkyl, unsubstituted or substituted carbocycle,
unsubstituted or
substituted heterocycle, -C(=0)106, -CO2R'6, or -C(=0)N(R16)2. In some
embodiments, each R"
is independently halogen, Cl-C6 alkyl, Cl-C6 fluoroalkyl, C3-C6 cycloalkyl, 4-
to 6-membered
heterocycloalkyl, -C(=0)R16, _CO2R16, or -C(=0)N(R16)2. In some embodiments,
each R13 is
independently halogen, CI-Ca alkyl, or Ci-Cafluoroalkyl. In some embodiments,
each R13 is
independently -F, -Cl, -CH3, or -CF3.
[00131] In some embodiments, q is 0, 1, 2, 3, or 4. In some embodiments, q is
0, 1, 2, or 3. In
some embodiments, q is 1, 2, or 3. In some embodiments, q is 1 or 2. In some
embodiments, q is
1. In some embodiments, q is 2. In some embodiments, q is 0; and Ring B is
therefore
unsubstituted.
[00132] In some embodiments, R2 is -C(=0)R14, -Q=0)N-Ri4Ri5, or -C(=0)0R14.
[00133] In some embodiments, R2 is -C(=0)R14.
[00134] In some embodiments, R2 is -C(=0)NR14IC-rs 15 or -C(=0)01t44.
[00135] In some embodiments, the compound is a compound of Formula (IX),
Formula (X), or
Formula (XI):
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Fit Rt
NH NH
Bt
0
I _r Nlj
HN B- NR1 H N B2 N
(R7R)
0 R14 n (R7 0 NRi 4
n ;
A'
n Al /N- , A9 410 Alik2 R15
A80.' 0
A6 As A6
-71/47
Formula (IX) Formula (X)
N H
N
H N B2-1. N R1
( R6
n 0 0
A1 JR114
tek-
0
As As
Formula (XI)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein
A', Az, A6, A7, As,
and A9 are as defined herein.
[00136] In some embodiments,
(i) Al and A2 are each C; and A6, A', A8, and A9 are each independently CR8 or
N;
(ii) Al is N; A2 is C; A6, A7, and A8 are each independently CR8 or N; and A9
is C(-0);
(iii) Al is C; A2 is N; A6 is C(=0), and A7, A8, and A9 are each independently
CR8 or N,
or
(iv) A' and A2 are each C; one of A6, A7, PO, and A9 is NW, wherein A6, A7,
A8, or A9
adjacent to the Nits is C(=0) and the remaining members of A6, A7, A8, and A9
are
each independently CR8 or N.
[00137] In some embodiments, the compound is a compound of Formula (IX), or a
pharmaceutically acceptable salt, tautomer, or solvate thereof In some
embodiments, the
compound is a compound of Formula (X), or a pharmaceutically acceptable salt,
tautomer, or
solvate thereof. In some embodiments, the compound is a compound of Formula
(XI), or a
pharmaceutically acceptable salt, tautomer, or solvate thereof.
[00138] In some embodiments, the compound is a compound of Formula (IXa),
Formula (Xa),
or Formula (X1a):
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R4..NH N H
o , N 0 N
====.I R1 RI
HN 13- N HN 13- N
Re 7
-)"-- 0 R = = id (R7) R6
0 N
Z ,R
1 4
n
R15
(Re)p
A8 N A8 N
Formula (IXa) Formula (Xa)
R4,NH
0 N
-
HN 13- NR1
( Re
n \ R7 0 0
104
A8 N
Formula (XIa)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein
Ag is Cle or N.
[00139] In some embodiments, the compound is a compound of Formula (IXa), or a

pharmaceutically acceptable salt, tautomer, or solvate thereof, In some
embodiments, the
compound is a compound of Formula (Xa), or a pharmaceutically acceptable salt,
tautomer, or
solvate thereof In some embodiments, the compound is a compound of Formula
(XIa), or a
pharmaceutically acceptable salt, tautomer, or solvate thereof, In some
embodiments, Ag is CRg.
In some embodiments, Ag is N.
[00140] In some embodiments, the compound is a compound of Formula (IXb),
Formula (Xb),
or Formula (XIb):
R4 R4
'NH 'NH
B.
0 N 0 N
HN-1B2.LN- R1 HN
132-"L N-R1
f Re ( Re
,R14
r, kR7 0 R14 n 0 N
R15
(R5)p¨t Formula (IXb) Formula (Xb)
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R4
-NH
o , N
HN B2N R1
( Re
n R7
0 0
it14
(R8)
P N
Formula (XIb)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein
A8 is CR8 or N.
In some embodiments, the compound is a compound of Formula (IXb), or a
pharmaceutically
acceptable salt, tautomer, or solvate thereof. In some embodiments, the
compound is a
compound of Formula (Xb), or a pharmaceutically acceptable salt, tautomer, or
solvate thereof.
In some embodiments, the compound is a compound of Formula (Xfb), or a
pharmaceutically
acceptable salt, tautomer, or solvate thereof.
[00141] In some embodiments, the compound is a compound of Formula (IXc),
Formula (Xc),
or Formula (Mc):
R4
-NH N H
B 1, B 1,
0 N 0 N
H NI B2N,
H NI B2 N R1
( R6 ( R6
,R14
\ R7 0 R i . .d n R7 ON
R15
N N (R8)p N
Formula (IXe) Formula (Xc)
Fe NH
B
N
HNI N- R1
R6
n R7 0 o
R14
N N
Formula (XIc)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
In some embodiments, the compound is a compound of Formula (IXc), or a
pharmaceutically
acceptable salt, tautomer, or solvate thereof. In some embodiments, the
compound is a
compound of Formula (Xc), or a pharmaceutically acceptable salt, tautomer, or
solvate thereof.
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41
In some embodiments, the compound is a compound of Formula (XIc), or a
pharmaceutically
acceptable salt, tautomer, or solvate thereof.
[00142] In some embodiments, the compound is a compound of Formula (IXd),
Formula (Xd),
or Formula (XId):
Rt NH RtNH
0 N 0 N
HNB2N. R1 R
HN B2 N-
( / R6 R6 ,Ria
õ kR7 0 R14 õ N
115
8 N N
(R8) N
Formula (IXd) Formula (Xd)
R4,NH
B,
0.-1 -1N
HN B2--L,N,R1
( R6
\ R7 0 0
1414
N
(R8) __
P N
Formula (XId)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[00143] In some embodiments, the compound is a compound of Formula (IXd), or a

pharmaceutically acceptable salt, tautomer, or solvate thereof. Ti' some
embodiments, the
compound is a compound of Formula (Xd), or a pharmaceutically acceptable salt,
tautomer, or
solvate thereof In some embodiments, the compound is a compound of Formula
(XId), or a
pharmaceutically acceptable salt, tautomer, or solvate thereof.
[00144] In some embodiments, the compound is a compound of Formula (IXe),
Formula (Xe),
or Formula (XIe):
R4,NH Rt NH
Ot(13.`1=N 01131
N
HN BN-R1 ,R1
HN 13- N
R6 4 R6 ,
\ R7 0 R-1 r, (z R7 0 R14 N
415
(R8)__( (118)p __
N 0 N 0
Re R8
Formula (IXe) Formula (Xe)
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R4
-NH
o , N
HNBiN"R1
( R6
1117Z7 0 0R,14
(R8)p-t
N 0
R8
Formula (XIe)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[00145] In some embodiments, the compound is a compound of Formula (IXe), or a

pharmaceutically acceptable salt, tautomer, or solvate thereof. In some
embodiments, the
compound is a compound of Formula (Xe), or a pharmaceutically acceptable salt,
tautomer, or
solvate thereof. In some embodiments, the compound is a compound of Formula
(XIe), or a
pharmaceutically acceptable salt, tautomer, or solvate thereof.
[00146] In some embodiments, R4 is hydrogen, CI-C6 alkyl, CI-C6 deuteroalkyl,
or Ci-C6
fluoroalkyl. In some embodiments, le is hydrogen, Cl-C6 alkyl, or Ci-C6
deuteroalkyl. In other
embodiments, R4 is hydrogen, CI-Ca alkyl, Ct-Ca deuteroalkyl, or Ct-Ca
fluoroalkyl. In some
embodiments, R4 is hydrogen, Ci-C4 alkyl, or Ci-C4 deuteroalkyl. In some
embodiments, R4 is
hydrogen, C1-C2 alkyl, or Ci-C2 deuteroalkyl. In some embodiments, R4 is
hydrogen, -CH3, -
CH2D, -CHD2, or -CD3. In sonic embodiments, R4 is hydrogen. In some
embodiments, R4 is -
CH3. In some embodiments, R4 is -CD3.
[00147] In some embodiments, le is hydrogen, CI-C6 alkyl, or Cl-C6
fluoroalkyl. In some
embodiments, R1 is hydrogen, C1-C4 alkyl, or Ci-C4 fluoroalkyl. In some
embodiments, R1 is
hydrogen or CI-C6 alkyl. In some embodiments, R1 is hydrogen or Ci-C4 alkyl.
In some
embodiments, R' is hydrogen, methyl, ethyl, propyl, isopropyl, or butyl. In
some embodiments,
R1 is hydrogen or methyl. In some embodiments, TO is hydrogen. In some
embodiments, R1 is
methyl.
[00148] In some embodiments, R1 and R15 are taken together with the
intervening atoms to
which they are attached to form an unsubstituted or substituted 5- or 6-
membered monocyclic
heterocycle. In some embodiments, R1 and R15 are taken together with the
intervening atoms to
which they are attached to form an unsubstituted or substituted 5- or 6-
membered monocyclic
heterocycloalkyl. In some embodiments, R1 and R15 are taken together with the
intervening
atoms to which they are attached to form an unsubstituted or substituted 5-
membered
monocyclic heterocycle. In some embodiments, R1 and R15 are taken together
with the
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43
intervening atoms to which they are attached to form an unsubstituted or
substituted 5-
m emb ered m on ocy cl i c heterocycl oal kyl .
[00149] In some embodiments, le is hydrogen.
[00150] In some embodiments, R" is hydrogen, unsubstituted or substituted CI-
C6 alkyl, Ci-C6
deuteroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or
substituted C2-C6
alkynyl, unsubstituted or substituted Ci-C6 heteroalkyl, unsubstituted or
substituted monocyclic
carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or
substituted
monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle
In some
embodiments, R14 is unsubstituted or substituted Ci-C6 alkyl, Ci-C6
deuteroalkyl, unsubstituted
or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl,
unsubstituted or
substituted Ci-C6 heteroalkyl, unsubstituted or substituted monocyclic
carbocycle, unsubstituted
or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic
heterocycle, or
unsubstituted or substituted bicyclic heterocycle In some embodiments, R" is
unsubstituted or
substituted Cl-C6 alkyl, Cl-C6 deuteroalkyl, unsubstituted or substituted Cl-
C6 heteroalkyl,
unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted
4- to 6-membered
heterocycloalkyl.
[00151] In some embodiments, R" is hydrogen, unsubstituted or substituted CI-
C6 alkyl,
un substituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-
C6 alkynyl,
unsubstituted or substituted Cl-C6 heteroalkyl, unsubstituted or substituted
monocyclic
carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or
substituted
monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle.
In some
embodiments, it'4 is unsubstituted or substituted Ci-C6 alkyl, unsubstituted
or substituted C2-C6
alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or
substituted Ci-C6
heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted
or substituted
bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or
unsubstituted or
substituted bicyclic heterocycle. In some embodiments, R" is unsubstituted or
substituted CI-C6
alkyl, unsubstituted or substituted Ci-C6 heteroalkyl, unsubstituted or
substituted C3-C6
cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl.
[00152] In some embodiments, R1-4 is unsubstituted or substituted C1-C6 alkyl,
Ci-C6
dcutcroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted
or substituted 4- to
6-membered heterocycloalkyl; wherein the substituted alkyl, substituted
heteroalkyl, substituted
cycloalkyl, or substituted heterocycloalkyl is substituted with one or more Rs
groups. In some
embodiments, It'4 is unsubstituted or substituted C1-C6 alkyl, unsubstituted
or substituted C3-C6
cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl;
wherein the
substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or
substituted heterocycloalkyl
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is substituted with one or more Rs groups. In some embodiments, R" is
unsubstituted or
substituted Ci-C6 alkyl, Cl-C6 deuteroalkyl, unsubstituted or substituted C3-
C6 cycloalkyl, or
unsubstituted or substituted 4- to 6-membered heterocycloalkyl; wherein the
substituted alkyl,
substituted heteroalkyl, substituted cycloalkyl, or substituted
heterocycloalkyl is substituted with
one or more RS groups independently selected from the group consisting of
deuterium, halogen,
Ci-C6 alkyl, -CN, -OR', and -N(R')2. In some embodiments, R1/ is unsubstituted
or substituted
CI-Cs alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted
or substituted 4- to 6-
membered heterocycloalkyl; wherein the substituted alkyl, substituted
heteroalkyl, substituted
cycloalkyl, or substituted heterocycloalkyl is substituted with one or more Rs
groups
independently selected from the group consisting of deuterium, halogen, CI-C6
alkyl, -CN, -
0R18, and -N(R18)2. In some embodiments, R14 is unsubstituted or substituted
Ci-C6 alkyl,
unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted
4-membered
heterocycloalkyl; wherein the substituted alkyl, substituted heteroalkyl,
substituted cycloalkyl,
or substituted heterocycloalkyl is substituted with one or more R5 groups
independently selected
from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -
N(CH3)2, -CH3, -
CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -0CF3 In some embodiments, R" is
methyl, -CD3,
\1-1 /..4;
ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, /
f(v.,F As .0F /Icy/ F /(vsõF se,44 õ04,1<?H
V
N) CF3
. In some embodiments, R14 is methyl, -CD3, ethyl,
tk.iv0H Ary
isopropyl, t-butyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl,
sõF AvsoF F ./(v.õF F ##(,<C2H
, or if(t\N`== In some
embodiments, R14 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl,
azetidinyl, oxetanyl,
/4.,<DH iecc\N
, or
[00153] In some embodiments, when R2 is -C(-0)
Nitta¨

K
R14 and R' are taken together with
the intervening atoms to which they are attached to form an unsubstituted or
substituted 4- to 6-
membered monocyclic heterocycle. In some embodiments, R14 and R15 are taken
together with
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the intervening atoms to which they are attached to form an unsubstituted or
substituted 4- to 6-
membered monocyclic heterocycloalkyl.
[00154] In some embodiments, B1 is CR12a; and B2 is CR12b; or B1 is N; and B2
is CR12b; or B1
is CR12'; and B2 is N; or B1 is N; and B2 is N. In some embodiments, B1 is
CR12a; and B2 is
cRim. In some embodiments, B1 is N; and B2 is CR12b. In some embodiments, B1
is CR12a; and
B2 is N. In some embodiments, B1 is N; and B2 is N.
[00155] In some embodiments, B1 is CR12a; and B2 is CR' 2b; or Ti1 is N; and
B2 is CR12b.
[00156] In some embodiments, R12a and R121) are each independently hydrogen,
halogen,
unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6
alkenyl,
unsubstituted or substituted C2-Co alkynyl, unsubstituted or substituted CI-Co
fluoroalkyl,
unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted
carbocycle,
unsubstituted or substituted heterocycle, -CN, -OH, -OR', -C(=0)R', -CO2R', -
C(=0)N(R16)2,
-N(RI6)2, -NRi6c(_o)R17, _sRio, _s(_0)R17, _s02--rc17,
or -SO2N(R16)2
[00157] In some embodiments, R12 and R12b are each independently hydrogen,
halogen, Cl-C6
alkyl, C,-C6 fluoroalkyl, -CN, -OH, -0R17, -CO2R16, -C(=0)N(R16)2, -N(R16)2, -
SO2R17, or -
SO2N(R16)2. In some embodiments, R12a and R121' are each independently
hydrogen, halogen, Ci-
05 alkyl, C,-C6 fluoroalkyl, -CN, -OH, -C(=0)N(R16)2, -N 006)2,
or -SO2N(R16)2. In
some embodiments, and R12h are each independently hydrogen,
halogen, C,-C6 alkyl, C,-C6
fluoroalkyl, -CN, -OH, -0R17, or -N(R16)2. In some embodiments, R12a and R12b
are each
independently hydrogen, halogen, CI-C4 alkyl, Cl-C4 fluoroalkyl, -CN, -OH, -
0R17, or -N(R16)2.
In some embodiments, R12 and R12b are each independently hydrogen, halogen, Ci-
C4 alkyl, Cl-
C4 fluoroalkyl, or -CN. In some embodiments, R12a and R12" are each
independently hydrogen,
halogen, or -CN. In some embodiments, R123 and RITh are each independently
hydrogen or
halogen. In some embodiments, R12a and R12b are each independently hydrogen,
fluoro, or
chloro. In some embodiments, R12a and R12b are each independently hydrogen or
fluoro. In some
embodiments, RI-2a and Rilb are each hydrogen.
[00158] In some embodiments, B1 and B2 are each independently CH, CF, or N. In
some
embodiments, B1 and B2 are each independently CH or N.
[00159] In some embodiments, B1 is CH or CF; and B2 is CH or CF; or BI- is N;
and B2 is CH
or CF; or B1 is CH or CF; and B2 is N; or B1 is N; and B2 is N. In some
embodiments, BI is CH;
and B2 is CH; or B1 is N; and B2 is CH; or B1 is CH; and B2 is N; or B1 is N;
and B2 is N.
[00160] In some embodiments, R3 and R12' are taken together with the
intervening atoms to
which they are attached to form a substituted or unsubstituted 5- or 6-
membered heterocycle. In
some embodiments, R3 and R12a are taken together with the intervening atoms to
which they are
attached to form a substituted or unsubstituted 5-membered heterocycle. In
some embodiments,
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R3 and R1-2 are taken together with the intervening atoms to which they are
attached to form a
R4, ,R3 õ
N R
C31,L
B2' 7
substituted or unsubstituted pyrazolidinone ring. In some embodiments,
is
R4
R4 R3
sN¨NH N R
I N
I I
V-'62-- 7 B2- 7
. In some embodiments, is RIn some
R4
R4õR3
NR12 sN¨NH
0
ONI I
B1 7
embodiments, is
[00161] In some embodiments, the compound is a compound of Formula (XII):
R4
N¨NH
ON
R2
H
/ R6 N
r,
'Al ,
A
0
e e
Formula (XII)
or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein
Al, Az, A6, A7, A8,
and A9 are as defined herein.
[00162] In some embodiments,
(i) A' and A2 are each C; and A6, A', A8, and A9 are each independently CR8 or
N;
(ii) A" is N; A2 is C; A6, A7, and A8 are each independently CR8 or N; and A9
is C(=0);
(iii) is C; A2 is N; A6 is C(=0); and A7, A8, and A9 are each independently
CR8 or N;
or
(iv) A' and A2 are each C; one of A6, A7, V, and A9 is NR', wherein A6, A7,
A8, or A9
adjacent to the NR' is C(=0) and the remaining members of A6, A], A8, and A9
are
each independently CR8 or N.
[00163] In some embodiments, le is hydrogen, CI-C6 alkyl, CI-C6 deuteroalkyl,
or Ci-C6
fluoroalkyl. In some embodiments, Ie is hydrogen, Cl-C6 alkyl, or Cl-C6
deuteroalkyl. In other
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embodiments, R4 is hydrogen, Ci-C4 alkyl, Ct-C4 deuteroalkyl, or Ct-C4
fluoroalkyl. In some
embodiments, R4 is hydrogen, Ci-C4 alkyl, or Ci-C4 deuteroalkyl. In some
embodiments, 114 is
hydrogen, CI -C2 alkyl, or C1-C2 deuteroalkyl. In some embodiments, R4 is
hydrogen, -CII3, -
CH2D, -CHD2, or -CD3. In some embodiments, R4 is hydrogen. In some
embodiments, R4 is -
CH3. In some embodiments, R4 is -CD3.
[00164] In some embodiments, R2 is a Ring B that is an unsubstituted or
substituted heterocycle
or unsubstituted or substituted carbocycle, wherein if Ring B is substituted
then Ring B is
substituted with q instances of R13. In some embodiments, R2 is a Ring B that
is an unsubstituted
or substituted monocyclic 6-membered heteroaryl, wherein if Ring B is
substituted then Ring B
is substituted with q instances of R13. In some embodiments, R2 is a Ring B
that is an
unsubstituted or substituted pyridinyl or unsubstituted or substituted
pyrimidinyl, wherein if
Ring B is substituted then Ring B is substituted with q instances of Rn.
[00165] In some embodiments, R2 is -C(=0)Rm, -C(=0)
NRI4R15, or -C(=0)ORN. In some
embodiments, R2 is -C(=0)R14.
[00166] In some embodiments, each R16 is independently hydrogen, substituted
or
unsubstituted Ci-C6 alkyl, substituted or unsubstituted Ci-C6 fluoroalkyl,
substituted or
unsubstituted Ci-Cs heteroalkyl, substituted or unsubstituted C3-C7
cycloalkyl, or substituted or
unsubstituted monocyclic 3- to 8-membered heterocycloalkyl; or two R16 on the
same N atom
are taken together with the N atom to which they are attached to form a
substituted or
unsubstituted N-containing heterocycloalkyl. In some embodiments, each R16 is
independently
hydrogen, CI-C6 alkyl, C1-C6 fluoroalkyl, Cl-C6 heteroalkyl, C3-C7 cycloalkyl,
or monocyclic 3-
to 8-membered heterocycloalkyl; or two R15 on the same N atom are taken
together with the N
atom to which they are attached to form a 4- to 6-membered N-containing
heterocycloalkyl.
[00167] In some embodiments, each R'7 is independently substituted or
unsubstituted Ci-Cs
alkyl, substituted or unsubstituted Ci-C6 fluoroalkyl, substituted or
unsubstituted Ci-C6
heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or
unsubstituted
monocyclic 3- to 8-membered heterocycloalkyl. In some embodiments, each R17 is

independently Cl-C6 alkyl, CI-Cs fluoroalkyl, Ci-C6 heteroalkyl, C3-C7
cycloalkyl, or
monocyclic 3- to 8-membered heterocycloalkyl.
[00168] In some embodiments, compounds described herein have the following
structure:
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HN
o- 0
HN N õR2
R6 z
i=
A1
A Pat2
(R8))
[00169] In some embodiments, F1', R2, R4, Z, n, R6, R7, A4, A2, Ring A, le and
p are as
3 b
Al \
P2A2
described herein. In some embodiments, BI-, R2, R4, z, n, R6, R7,
and (R8) are
as
described herein. In some embodiments, BI-, R2, ¨4,
K Z, n, R6, R7, Al, A2, Ring A, Rg and p are as
a b
Al \
A
described in Table 1. In some embodiments, B4, R2, R4, ¨, n, R6, R7, and
(R8) are as
described in Table 1.
[00170] Any combination of the groups described above for the various
variables is
contemplated herein. Throughout the specification, groups and sub stituents
thereof are chosen
by one skilled in the field to provide stable moieties and compounds.
[00171] Exemplary compounds described herein include the compounds described
in the
following Tables:
Table 1:
,R4
HN
0 N
HN N ,R2
1R6'
Al 140
C2)A):
A
(R8)p
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a b
Cpd No. 13' R2 R4 Z
R6 R n
A
(R8)p
0 a¨

1 N -CD3 NCH3 H H 1
b
N
a
F
r Y
2 N -CD3 NCH3 H H 1
\ b
N
0
3 CH \--kv -CD3 NCH3 H H 1 a&\ b
N
0
4 CH \<-11--,v -CD3 NCH3 H H 1 a7Y\ b
N N
0
CH \-.11,õv -CD3 NCH3 H H 1 b
N
0
6 N -CD3 NCH3 H H 1 a
I b
N N
0
7 N -CD3 NCH3 H H 1 aZ;)µ b
N
0 a
8 CH \,-*,v -CD3 NCH3 H H 1
NTTA b
ftrµj
0
9 CH \J-1-,v. -CD3 NCH3 H H 1
b
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a¨^7 b
Cpd No. 13' R2 R4 Z
R6 127 n
A
(R8)p
a
0
10 N -CD3 NCH3 H H 1
N .""Ab
0
11 N -CD3 NCH3 H H 1 a b
N 0
a
0
12 CH -CD3 NCH3 H H 1
b
-41
NC
a ¨
0
13 N -CD3 NCH3 H H 1
N
NC
O a
14 CH vky -CD3 NCH3 H H 1
b
O a
15 CH Nc.)1,,,v -CH3 NCH3 H H 1
I b
O a
16 N -CD3 NCH3 _______________ H H 1
NTTA b
O a
17 CH viLv -CD3 NCD3 H H 1
NI-TA b
N
O a
18 N -CD3 NCD 3 H H 1
N b
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a -^7 b
Cpd No. 13' R2 R4 Z
R6 127 n
A
(R8)p
0 a ¨
19 CH -CD3 NCH3 H H 1
b
N
a _
0
20 CH -CD3 NCH3 D D 1
\b
N
0
:
21 N Nc.)-1. -CD3 NCH3 D D 1 &µ b
F N
0
a
22 CH \\,,,ILv -CD3 NCH3 D D 1 6) b
F N
a
0
23 N -CD3 NCH3 D D 1
a
0
24 CH \--11.,y - CD3
NCH3 D D 1 7Yµb
N
0 a
25 CH \icy - CD3 NCH3 D
D 1
N
CF3
a
0
26 N \icy. -CD3 NCH3 D D 1 I -
õI*N
CF3
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a bN,
Cpd No. 13' R2 R4 Z R6 127 n
A
(R8)p
0
27 N -CD3 NCH3 H H 1 a TIA b
N,N 0
0
28 CH \\):1, -CD3 NCH3 H H 1 a 7171A b
N,N 0
O a
29 N \-11, -CH3 NCH3 H H 1
I b
O a
30 CH \--11-"v -CH3 NCH3 H H 1 Nyi. b
a
0
31 N -CD3 NCH3 H H 1
O a
32 N -CD3 NCH3 (R)-CH3 H 1
µb
N
O a ¨
33 N -CD3 NCH3 (S)-CH3 H 1
b
1001721 Compounds in Table 1 are named:
1: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-y1)amino)pyridazine-3-carboxamide;
2: 6-((5-fluoropyridin-2-yl)amino)-N-(methyl-d3)-4-46-methyl-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide; and
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3: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4((6-methy1-5, 6-
dihydrobenzo[h] [1 ,6]naphthyri di n-7-y1 )amino)ni cotinami de;
4: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-44(6-methy1-5,6-
dihydropyrimido[5,4-
c]quinolin-7-yl)amino)nicotinamide;
5: 6-(cyclopropanecarboxamido)-4-((3 -fluoro-6-methyl-5 ,6-dihydrobenzo[h] 11
,6]naphthyri din-
7-yl)amino)-N-(methyl -d3 )nicotinamide;
6: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-44(6-methy1-5,6-
dihydropyrimido[5,4-
c]quinolin-7-yl)amino)pyridazine-3 -carboxamide;
7: 6-(cyclopropanecarboxamido)-4-((3 -fluoro-6-methyl-5 ,6-dihydrobenzo[h] [I
,6]naphthyri din-
7-yl)amino)-N-(methyl -d3 )pyri dazine-3-carboxamide;
8: 6-(cy clopropanecarb oxami do)-N-(m ethyl -d3)-44(6-methy1-5, 6-
dihydropyrazino[2,3-
c]quinolin-7-yl)amino)nicotinamide;
9: 6-(cyclopropanecarboxamido)-442,6-dimethy1-1-oxo-1,2,5,6-
tetrahydrobenzo[c][2,6]naphthyridin-7-yl)amino)-N-(methyl-d3)nicotinamide;
10: 6-(cy clopropanecarboxamido)-N-(methyl-d3 )-4((6-methy1-5,6-di
hydropyrazino [2,3 -
c]quinolin-7-yl)amino)pyridazine-3 -carboxamide;
11: 6-(cy clopropanecarboxamido)-4-42,6-dimethyl -1 -oxo-1,2,5,6-
tetrahydroben zo[c] [2,6]n aphthyri di n -7-y1 )ami no)-N-(m ethyl -d3)pyri
dazi ne-3 -carboxam i de;
12: 4-((3-cyano-6-methyl-5,6-dihydrobenzo[h][ 1, 6]naphthyridin-7-yl)amino)-6-
(cyclopropanecarb oxamido)-N-(methyl-d3)nicotinamide;
13: 4-((3-cyano-6-methyl-5,6-dihydrobenzo[h][ 1, 6]naphthyridin-7-yl)amino)-6-
(cyclopropanecarb oxami do)-N-(methyl-d3)pyridazi ne-3 -carboxamide;
14: 6-(cy clopropanecarboxamido)-N-(methyl-d3 )-4((6-methy1-5,6-di
hydropyrazino [2,3 -
c] [1, 7]naphthyridin-7-yl)amino)nicotinamide;
15: 6-(cy clopropanecarboxamido)-N-methy1-4-((6-methyl- 5,6-
dihydrobenzo[h] 11,61naphthyridin-7-yl)amino)nicotinamide;
16: 6-(cy clopropanecarboxamido)-N-(methyl-d3 )-4((6-methy1-5,6-di
hydropyrazino [2,3 -
c]quinolin-7-yl)amino)pyridazine-3 -carboxamide;
17: 6-(cy clopropanecarboxamido)-N-(methyl-d3 )-44(6-(m ethyl-d3)-5,6-dihy
dropyrazino 12,3 -
c]quinolin-7-yl)amino)nicotinamidc;
18: 6-(cy clopropanecarboxamido)-N-(methyl-d3)-4-((6-(methyl-d3)-5,6-dihy
dropyrazino [2,3 -
c]quinolin-7-yl)amino)pyridazine-3 -carboxamide;
19: 6-(cy clopropanecarboxamido)-N-(methyl-d3 )-4-((6-methyl-5,6-di
hydropyrido [3 ,4-
1-1] [1 ,6]naphthyri di n-7-y1 )amino)ni cotinami de;
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20: 6-(cy clopropanecarboxamido)-N-(methyl-d3)-4-((6-methy1-5,6-
dihydrobenzo[h] [1,6]naphthyri di n-7-y1-5,5-d2)am ino)ni cotinami de;
21: 6-(cyclopropanecarboxamido)-4-43-fluoro-6-methyl-5,6-
dihydrobenzo[h][1,6]naphthyridin-
7-y1-5,5-d2)amino)-N-(methyl-d3)pyridazine-3-carboxamide;
22: 6-(cyclopropanecarboxamido)-4-((3-fluoro-6-methy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-
7-y1-5,5-d2)amino)-N-(methyl-d3)nicotinamide;
23: 6-(cyclopropanecarboxamido)-4-((2,6-dimethy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-yl-
5,5 -d2)amino)-N -(methyl-d3)pyri dazine-3 -carboxami de;
24: 6-(cyclopropanecarboxamido)-4-((2,6-dimethy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-y1-
5,5-d2)amino)-N-(methyl-d3)nicotinamide;
25: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-44(6-methy1-2-(trifluoromethyl)-
5,6-
dihydrobenzo[h][1,6]naphthyridin-7-y1-5,5-d2)amino)nicotinamide;
26: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-44(6-methy1-2-(trifluoromethyl)-
5,6-
dihydrobenzo[h][1,6]naphthyridin-7-y1-5,5-d2)amino)pyridazine-3 -carboxamide;
27: 6-(cyclopropanecarboxamido)-4-((2,6-dimethyl-1-oxo-1,2,5,6-
tetrahydropyridazino[4,5-
c]quinolin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide;
28: 6-(cyclopropanecarboxamido)-4-42,6-dimethyl-l-oxo-1,2,5,6-
tetrahydropyridazino[4,5-
c]qui n ol n -7-y1 )am i no)-N-(ni ethyl -d3)ni coti nami de;
29: 6-(cyclopropanecarboxamido)-N-methyl-4-((6-methy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide;
30: 6-(cyclopropanecarboxamido)-N-methyl-4-((6-methy1-5,6-dihydropyrazino[2,3-
c]quinolin-
7-yl)amino)nicotinamide;
31: 6-(cyclopropanecarboxamido)-4-((10-fluoro-5-methy1-5,6-
dihydrophenanthridin-4-
yDamino)-N-(methyl-d3)pyridazine-3-carboxamide;
32: (R)-6-(cyclopropanecarboxamido)-445,6-dimethy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-
7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide;
33: (S)-6-(cyclopropanecarboxamido)-4-((5,6-dimethy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-
7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.
[00173] In some embodiments, provided herein is a pharmaceutically acceptable
salt of a
compound that is described in Table 1.
[00174] In another aspect of the invention, the compound is a compound
selected from:
3: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-y1)amino)nicotinamide;
15: 6-(cyclopropanecarboxamido)-N-methy1-4-((6-methy1-5,6-
dihydrobenzo[h][1,61naphthyridin-7-y1)amino)nicotinamide;
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34: 6-(cyclopropanecarboxamido)-4-((2,5-dimethy1-4,5-dihydro-2H-pyrazolo[4,3-
c]quinolin-6-
yl)ami no)-N-m ethyl pyri dazine-3 -carboxami de;
35: 442,5-dimethy1-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-645-
fluoropyridin-
2-yl)amino)-N-methylnicotinamide;
36: 442,5-dimethy1-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((2,6-
dimethylpyrimidin-4-y1)amino)-N-methylnicotinamide;
37: 6-(cyclopropanecarboxamido)-4-((2,5-dimethy1-4,5-dihydro-2H-
[1,2,3]triazolo[4,5-
c]quinolin-6-yl)amino)-N-methylnicotinamide; and
38: 6-(cyclopropanecarboxamido)-4-((2,5-dimethy1-4,5-dihydropyrazolo[1,5-
a]quinoxalin-6-
yl)amino)-N-methylpyridazine-3-carboxamide;
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
[00175] In some embodiments, the compound is 6-(cyclopropanecarboxamido)-N-
(methyl-d3)-
4-((6-methy1-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)nicotinamide
(Compound 3),
which has the following structure:
NI
0 HN
D3C,NA'-e'', 0
H
N N
[00176] In some embodiments, the compound is 6-(cyclopropanecarboxamido)-N-
methy1-4-
((6-methy1-5,6-dihydrobenzo[h][1,6]naphthyridin-7-y1)amino)nicotinamide
(Compound 15),
which has the following structure:
NI
0 HN
I
N 1.1-)Cv
[00177] In some embodiments, the compound is 6-(cyclopropanecarboxamido)-4-
((2,5-
dimethy1-4,5-dihydro-2H-pyrazolo [4,3 -c]quinolin-6-yl)amino)-N-
methylpyridazine-3 -
carboxami de (Compound 34), which has the following structure.
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O HN
0
NNN
[00178] In some embodiments, the compound is 4-((2,5-dimethy1-4,5-dihydro-2H-
pyrazolo[4,3-c]quinolin-6-yl)amino)-645-fluoropyridin-2-y1)amino)-N-
methylnicotinamide
(Compound 35), which has the following structure:
O HN
N
H
[00179] In some embodiments, the compound is 44(2,5-dimethy1-4,5-dihydro-2H-
pyrazolo[4,3-c]quinolin-6-yl)amino)-642,6-dimethylpyrimidin-4-y1)amino)-N-
methylnicotinamide (Compound 36), which has the following structure:
O HN
NN
N N
[00180] In some embodiments, the compound is 6-(cyclopropanecarboxamido)-4-
((2,5-
dimethy1-4,5-dihydro-2H41,2,3]triazolo[4,5-c]quinolin-6-yDamino)-N-
methylnicotinamide
(Compound 37), which has the following structure:
N-N
/
z
O HN
'-N-ItTC 0
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[00181] In some embodiments, the compound is 6-(cyclopropanecarboxamido)-4-
((2,5-
dim ethyl -4,5-di hydropyrazol o[1,5-a] qui n oxali n-6 -yl)am i no)-N-m
ethylpyri dazi ne-3-
carboxamide (Compound 38), which has the following structure:
rels1
0 HN
0
H
N N
[00182] In one aspect, compounds described herein are in the form of
pharmaceutically
acceptable salts. In addition, the compounds described herein can exist in
unsolvated as well as
solvated forms with pharmaceutically acceptable solvents such as water,
ethanol, and the like.
The solvated forms of the compounds presented herein are also considered to be
disclosed
herein.
[00183] "Pharmaceutically acceptable," as used herein, refers a material, such
as a carrier or
diluent, which does not abrogate the biological activity or properties of the
compound, and is
relatively nontoxic at the concentration or amount used, i.e., the material is
administered to an
individual without causing undesirable biological effects or interacting in a
deleterious manner
with any of the components of the composition in which it is contained.
[00184] The term "pharmaceutically acceptable salt" refers to a form of a
therapeutically active
agent that consists of a cationic form of the therapeutically active agent in
combination with a
suitable anion, or in alternative embodiments, an anionic form of the
therapeutically active agent
in combination with a suitable cation. Handbook of Pharmaceutical Salts:
Properties, Selection
and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002.
S.M. Berge,
L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and
C. G. Wermuth,
editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use,
WeinheimiZurich:Wiley-VCH/VHCA, 2002. Pharmaceutical salts typically are more
soluble
and more rapidly soluble in stomach and intestinal juices than non-ionic
species and so are
useful in solid dosage forms. Furthermore, because their solubility often is a
function of pH,
selective dissolution in one or another part of the digestive tract is
possible and this capability
can be manipulated as one aspect of delayed and sustained release behaviors.
Also, because the
salt-forming molecule can be in equilibrium with a neutral form, passage
through biological
membranes can be adjusted.
[00185] In some embodiments, pharmaceutically acceptable salts are obtained by
reacting a
compound of Formula (I) with an acid. In some embodiments, the compound of
Formula (I) (i.e.
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free base form) is basic and is reacted with an organic acid or an inorganic
acid. Inorganic acids
include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric
acid, phosphoric
acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not
limited to, 1-
hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic
acid; 2-oxoglutaric
acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic
acid; ascorbic acid (L);
aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+);
camphor-10-sulfonic
acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic
acid (octanoic acid);
carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric
acid; ethane-1,2-
disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric
acid; gentisic acid;
glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid;
glutaric acid;
glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic
acid (DL);
lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid;
mandelic acid (DL);
methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic
acid; nicotinic
acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid;
proprionic acid;
pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic
acid; sulfuric acid;
tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and
undecylenic acid.
[00186] In some embodiments, a compound of Formula (I) is prepared as a
chloride salt, sulfate
salt, bromide salt, rn esyl ate salt, maleate salt, citrate salt or phosphate
salt
[00187] In some embodiments, pharmaceutically acceptable salts are obtained by
reacting a
compound of Formula (I) with a base. In some embodiments, the compound of
Formula (I) is
acidic and is reacted with a base. In such situations, an acidic proton of the
compound of
Formula (I) is replaced by a metal ion, e.g., lithium, sodium, potassium,
magnesium, calcium, or
an aluminum ion. In some cases, compounds described herein coordinate with an
organic base,
such as, but not limited to, ethanolamine, diethanolamine, triethanolamine,
tromethamine,
meglumine, N-methylglucamine, dicyclohexylamine,
tris(hydroxymethyl)methylamine. In other
cases, compounds described herein form salts with amino acids such as, but not
limited to,
arginine, lysine, and the like. Acceptable inorganic bases used to form salts
with compounds that
include an acidic proton, include, but are not limited to, aluminum hydroxide,
calcium
hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium
hydroxide,
lithium hydroxide, and the like. In some embodiments, the compounds provided
herein are
prepared as a sodium salt, calcium salt, potassium salt, magnesium salt,
meglumine salt, N-
methylglucamine salt or ammonium salt.
[00188] It should be understood that a reference to a pharmaceutically
acceptable salt includes
the solvent addition forms. In some embodiments, solvates contain either
stoichiometric or non-
stoichiometric amounts of a solvent, and are formed during the process of
crystallization with
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pharmaceutically acceptable solvents such as water, ethanol, and the like.
Hydrates are formed
when the solvent is water, or al coholates are formed when the solvent is
alcohol Solvates of
compounds described herein are conveniently prepared or formed during the
processes described
herein. In addition, the compounds provided herein optionally exist in
unsolvated as well as
solvated forms.
[00189] The methods and formulations described herein include the use of N-
oxides (if
appropriate), or pharmaceutically acceptable salts of compounds having the
structure of Formula
(I), as well as active metabolites of these compounds having the same type of
activity.
[00190] In some embodiments, sites on the organic radicals (e.g. alkyl groups,
aromatic rings)
of compounds of Formula (I) are susceptible to various metabolic reactions.
Incorporation of
appropriate substituents on the organic radicals will reduce, minimize or
eliminate this metabolic
pathway. In specific embodiments, the appropriate substituent to decrease or
eliminate the
susceptibility of the aromatic ring to metabolic reactions is, by way of
example only, a halogen,
deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
[00191] In another embodiment, the compounds described herein are labeled
isotopically (e.g.
with a radioisotope) or by another other means, including, but not limited to,
the use of
chromophores or fluorescent moieties, bioluminescent labels, or
chemiluminescent labels.
[00192] Compounds described herein include i sotopically-labeled compounds,
which are
identical to those recited in the various formulae and structures presented
herein, but for the fact
that one or more atoms are replaced by an atom having an atomic mass or mass
number different
from the atomic mass or mass number usually found in nature. Examples of
isotopes that can be
incorporated into the present compounds include isotopes of hydrogen, carbon,
nitrogen,
oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example,
2H, 3H, 13C, 14C, '5N,
180, 170, 35s, 18F, 36C1, 1231, 1241, 1251, 1311, 32F and 33P. In one aspect,
isotopically-labeled
compounds described herein, for example those into which radioactive isotopes
such as 3H and
14C are incorporated, are useful in drug and/or substrate tissue distribution
assays. In one aspect,
substitution with isotopes such as deuterium affords certain therapeutic
advantages resulting
from greater metabolic stability, such as, for example, increased in vivo half-
life or reduced
dosage requirements.
[00193] In some embodiments, the compounds of Formula (I) posscss one or more
stereocenters and each stereocenter exists independently in either the R or S
configuration. In
some embodiments, the compound of Formula (I) exists in the R configuration.
In some
embodiments, the compound of Formula (I) exists in the S configuration. The
compounds
presented herein include all di astereomeric, individual enantiorners,
atropisomers, and epimeric
forms as well as the appropriate mixtures thereof. The compounds and methods
provided herein
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include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as
well as the
appropriate mixtures thereof.
1001941 Individual stereoisomers are obtained, if desired, by methods such as,
stereoselective
synthesis and/or the separation of stereoisomers by chiral chromatographic
columns or the
separation of diastereomers by either non-chiral or chiral chromatographic
columns or
crystallization and recrystallization in a proper solvent or a mixture of
solvents. In certain
embodiments, compounds of Formula (I) are prepared as their individual
stereoisomers by
reacting a racemie mixture of the compound with an optically active resolving
agent to form a
pair of diastereoisomeric compounds/salts, separating the diastereomers and
recovering the
optically pure individual enantiomers. In some embodiments, resolution of
individual
enantiomers is carried out using covalent diastereomeric derivatives of the
compounds described
herein. In another embodiment, diastereomers are separated by
separation/resolution techniques
based upon differences in solubility. In other embodiments, separation of
stereoisomers is
performed by chromatography or by the forming diastereomeric salts and
separation by
recrystallization, or chromatography, or any combination thereof. Jean
Jacques, Andre Collet,
Samuel H. Wilen, "Enantiomers, Racemates and Resolutions-, John Wiley And
Sons, Inc.,
1981. In some embodiments, stereoisomers are obtained by stereoselective
synthesis.
[00195] In some embodiments, compounds described herein are prepared as
prodnigs A
-prodrug" refers to an agent that is converted into the parent drug in vivo.
Prodrugs are often
useful because, in some situations, they are easier to administer than the
parent drug. They are,
for instance, bioavailable by oral administration whereas the parent is not.
Further or
alternatively, the prodrug also has improved solubility in pharmaceutical
compositions over the
parent drug In some embodiments, the design of a prodnig increases the
effective water
solubility. An example, without limitation, of a prodrug is a compound
described herein, which
is administered as an ester (the "prodrug") but then is metabolically
hydrolyzed to provide the
active entity. A further example of a prodrug is a short peptide
(polyaminoacid) bonded to an
acid group where the peptide is metabolized to reveal the active moiety. In
certain embodiments,
upon in vivo administration, a prodrug is chemically converted to the
biologically,
pharmaceutically or therapeutically active form of the compound. In certain
embodiments, a
prodrug is enzymatically metabolized by one or more steps or processes to the
biologically,
pharmaceutically or therapeutically active form of the compound.
1001961 Prodrugs of the compounds described herein include, but are not
limited to, esters,
ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl
derivatives, N-
alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich
bases, Schiff
bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for
example Design of
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61
Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder,
K. et al.,
Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and
Application of Prodrugs"
in A Textbook of Drug Design and Development, Krosgaard-Larsen and H.
Bundgaard, Ed.,
1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review,
1992, 8, 1-
38, each of which is incorporated herein by reference. In some embodiments, a
hydroxyl group
in the compounds disclosed herein is used to form a prodrug, wherein the
hydroxyl group is
incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl
ester, aryl ester,
phosphate ester, sugar ester, ether, and the like. In some embodiments, a
hydroxyl group in the
compounds disclosed herein is a prodrug wherein the hydroxyl is then
metabolized in vivo to
provide a carboxylic acid group. In some embodiments, a carboxyl group is used
to provide an
ester or amide (i.e. the prodrug), which is then metabolized in vivo to
provide a carboxylic acid
group. In some embodiments, compounds described herein are prepared as alkyl
ester prodrugs.
[00197] Prodrug forms of the herein described compounds, wherein the prodrug
is metabolized
in vivo to produce a compound of Formula (I) as set forth herein are included
within the scope of
the claims. In some cases, some of the herein-described compounds is a prodrug
for another
derivative or active compound.
[00198] In some embodiments, any one of the hydroxyl group(s), amino group(s)
and/or
carboxylic acid group(s) are function alized in a suitable manner to provide a
prodmg moiety. In
some embodiments, the prodrug moiety is as described above.
[00199] In additional or further embodiments, the compounds described herein
are metabolized
upon administration to an organism in need to produce a metabolite that is
then used to produce
a desired effect, including a desired therapeutic effect.
[00200] A "metabolite" of a compound disclosed herein is a derivative of that
compound that is
formed when the compound is metabolized. The term "active metabolite" refers
to a biologically
active derivative of a compound that is formed when the compound is
metabolized. The term
"metabolized," as used herein, refers to the sum of the processes (including,
but not limited to,
hydrolysis reactions and reactions catalyzed by enzymes) by which a particular
substance is
changed by an organism. Thus, enzymes may produce specific structural
alterations to a
compound. For example, cytochrome P450 catalyzes a variety of oxidative and
reductive
reactions while uridinc diphosphatc glucuronyltransfcrascs catalyze the
transfer of an activated
glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic
acids, amines and
free sulfhydryl groups. Metabolites of the compounds disclosed herein are
optionally identified
either by administration of compounds to a host and analysis of tissue samples
from the host, or
by incubation of compounds with hepatic cells in vitro and analysis of the
resulting compounds.
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[00201] In some instances, heterocyclic rings may exist in tautomeric forms.
In such situations,
it is understood that the structures of said compounds are illustrated or
named in one tautomeric
form but could be illustrated or named in the alternative tautomeric foim. The
alternative
tautomeric forms are expressly included in this disclosure, such as, for
example, the structures
illustrated below. For example, pyridones could exist in the following
tautomeric forms:
OH 0 0 0+ 0" 0
NH N = N+
, and =
; all of which
are encapsulated within the group, "substituted pyridines." Similarly,
triazolones could exist in
the following tautomeric forms, which include zwitterionic forms:
-7--
N-N N-N N-N e N-N
,¨OH ¨ )-0 = ¨
HOH
N
, and
; all of which are encapsulated within the group, "substituted 5-membered
heteroaryl."
Similarly, pyrazoles, triazoles, pyrimidines, and the like are known to
tautomerize; for the
purpose of this disclosure, all tautomeric forms (including charged and
zwitterionic tautomers)
are considered within the scope of the present disclosure.
Synthesis of Compounds
[00202] Compounds of Formula (I) described herein are synthesized using
standard synthetic
techniques or using methods known in the art in combination with methods
described herein.
[00203] Unless otherwise indicated, conventional methods of mass spectroscopy,
NMR, HPLC
are employed.
[00204] Compounds are prepared using standard organic chemistry techniques
such as those
described in, for example, March's Advanced Organic Chemistry, 6th Edition,
John Wiley and
Sons, Inc. Alternative reaction conditions for the synthetic transformations
described herein may
be employed such as variation of solvent, reaction temperature, reaction time,
as well as
different chemical reagents and other reaction conditions.
[00205] In some embodiments, compounds described herein are prepared as
described in
Scheme A.
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63
Scheme A:
NH R4 Rt
NH NH
R1 31
A
CI B2 CI >
_IL R2
H2
HN R2-N H2 HN B2 N-
a or b Z
k n Z
n
A
N
A A
Variables are as defined in Formula (I).
[00206] In some embodiments, nucleophilic substitution of one chloro group of
intermediate A
with the free amino group of B affords intermediate C. In some embodiments,
for example when
intermediate A is a pyridazine compound (BI- = N), this substitution can be
carried out with a
suitable Lewis acid such as Zn(0Ac)2. In other embodiments, for example when
intermediate B
is a pyridine compound (B1 = CH), this substitution is carried out by
deprotonation of the amino
group with a suitable base, such as LDA. In still other embodiments,
intermediate C may be
accessed by a cross-coupling reaction of intermediates A and B. Cross-coupling
reactions may
be organometallic cross-couplings such as Suzuki-Miyaura reactions, Buchwald-
Hartwig
reactions, Heck reactions, Ullman couplings, Chan-Lam couplings, and the like.
Finally, in some
embodiments, intermediate C is converted to the final compound D (e.g.,
compound 1) via a
cross-coupling reaction. Cross-coupling reactions may be organometallic cross-
couplings such
as Suzuki-Miyaura reactions, Buchwald-Hartwig reactions, Heck reactions,
Ullman couplings,
Chan-Lam couplings, and the like.
[00207] In some embodiments, compounds are prepared as described in the
Examples.
Certain Terminology
[00208] Unless otherwise stated, the following terms used in this application
have the
definitions given below. The use of the term "including" as well as other
forms, such as
"include", "includes," and "included," is not limiting. The section headings
used herein are for
organizational purposes only and are not to be construed as limiting the
subject matter described.
[00209] As used herein, Cl-C includes Cl-C2, Ci-C3 . . . C,-C. By way of
example only, a
group designated as "Ci-C6" indicates that there are one to six carbon atoms
in the moiety, i.e.
groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon
atoms. Thus, by
way of example only, "Ci-C4 alkyl" indicates that there are one to four carbon
atoms in the alkyl
group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-
propyl, n-butyl, iso-
butylõsec-butyl, and 1-butyl.
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64
[00210] An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl
group is branched
or straight chain. In some embodiments, the "alkyl" group has 1 to 10 carbon
atoms, i.e. a Ci-
Cioalkyl. Whenever it appears herein, a numerical range such as "1 to 10"
refers to each integer
in the given range; e.g.,"1 to 10 carbon atoms" means that the alkyl group
consist of 1 carbon
atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon
atoms, although the
present definition also covers the occurrence of the term "alkyl" where no
numerical range is
designated. In some embodiments, an alkyl is a Ci-C6 alkyl. In one aspect the
alkyl is methyl,
ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical
alkyl groups include,
but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tertiary
butyl, pentyl, neopentyl, or hexyl.
[00211] An "alkylene" group refers to a divalent alkyl radical. Any of the
above mentioned
monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen
atom from the
alkyl. In some embodiments, an alkylene is a CI-C6 alkylene. In other
embodiments, an alkylene
is a Cl-C4a1kylene. Typical alkylene groups include, but are not limited to, -
CH2-, -CH2CH2-, -
CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, an alkylene is -
CH2-.
[00212] An "alkoxy- group refers to a (alkyl)O- group, where alkyl is as
defined herein.
[00213] The term "alkylamine" refers to the ¨N(alkyl)xl-ly group, where x is 0
and y is 2, or
where x is 1 and y is 1,01- where x is 2 and y is O.
[00214] An -hydroxyalkyl" refers to an alkyl in which one hydrogen atom is
replaced by a
hydroxyl. In some embodiments, a hydroxyalkyl is a C1-C4hydroxyalkyl. Typical
hydroxyalkyl
groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -
CH2CH2CH2CH2OH, and the like.
[00215] An "aminoalkyl" refers to an alkyl in which one hydrogen atom is
replaced by an
amino. In some embodiments, aminoalkyl is a C1-C4aminoalkyl. Typical
aminoalkyl groups
include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2C1-12CH2N112, -
CH2CH2CH2CH2NH2, and the like.
[00216] The term "alkenyl" refers to a type of alkyl group in which at least
one carbon-carbon
double bond is present. In one embodiment, an alkenyl group has the formula
¨C(R)=CR2,
wherein R refers to the remaining portions of the alkenyl group, which may be
the same or
different. In some embodiments, R is H or an alkyl. In some embodiments, an
alkenyl is selected
from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl,
pentadienyl, and the like. Non-
limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3,
-
C(CH3)=CHCH3, and ¨CH2CH=CH2.
[00217] The term "alkynyl" refers to a type of alkyl group in which at least
one carbon-carbon
triple bond is present. In one embodiment, an alkenyl group has the formula -
C=C-R, wherein R
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refers to the remaining portions of the alkynyl group. In some embodiments, R
is H or an alkyl.
In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl,
pentynyl,
hexynyl, and the like. Non-limiting examples of an alkynyl group include -CCH,
-CCCH.3 -
CCCH2CH3, -CH2CCH.
[00218] The term "heteroalkyl" refers to an alkyl group in which one or more
skeletal atoms of
the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen
(e.g. ¨NH-, -
N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the
rest of the molecule at
a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-
C6heteroa1kyl.
[00219] The term "aromatic" refers to a planar ring having a delocalized 7-
electron system
containing 4n+2 it electrons, where n is an integer. The term "aromatic"
includes both
carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl"
or "heteroaromatic")
groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic
(i.e., rings which
share adjacent pairs of carbon atoms) groups.
[00220] The term "carbocyclic" or "carbocycle" refers to a ring or ring system
where the atoms
forming the backbone of the ring are all carbon atoms. The term thus
distinguishes carbocyclic
from "heterocyclic" rings or "heterocycles" in which the ring backbone
contains at least one
atom which is different from carbon. In some embodiments, at least one of the
two rings of a
bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic
carbocycle are
aromatic. Carbocycles include aryls and cycloalkyls.
[00221] As used herein, the term "aryl" refers to an aromatic ring wherein
each of the atoms
forming the ring is a carbon atom. In one aspect, aryl is phenyl or a
naphthyl. In some
embodiments, an aryl is a phenyl. In some embodiments, an aryl is a phenyl,
naphthyl, indanyl,
indenyl, or tetrahydronaphthyl. In some embodiments, an aryl is a Co-Cioaryl.
Depending on the
structure, an aryl group is a monoradical or a diradical (i.e., an arylene
group).
[00222] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic,
non-aromatic
radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a
carbon atom. In
some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some
embodiments,
cycloalkyls are optionally fused with an aromatic ring, and the point of
attachment is at a carbon
that is not an aromatic ring carbon atom. Cycloalkyl groups include groups
having from 3 to 10
ring atoms. In some embodiments, cycloalkyl groups are selected from among
cyclopropyl,
cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,
cyclooctyl,
spiro[2 2]pentyl, norbornyl and bicycle[l 1 1 ]pentyl Tn some embodiments, a
cycloalkyl is a C3-
05cycloalkyl. In some embodiments, a cycloalkyl is a C3-C4cycloalkyl.
1002231 The term "halo" or, alternatively, "halogen" or "halide" means fluoro,
chloro, bromo or
iodo. In some embodiments, halo is fluoro, chloro, or bromo.
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[00224] The term "fluoroalkyl" refers to an alkyl in which one or more
hydrogen atoms are
replaced by a fluorine atom. In one aspect, a fluoroalkyl is a Ci-
C6fluoroalkyl
[00225] The term "heterocycle" or "heterocyclic" refers to heteroaromatic
rings (also known as
heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in
the ring(s), where
each heteroatom in the ring(s) is selected from 0, S and N, wherein each
heterocyclic group has
from 3 to 10 atoms in its ring system, and with the proviso that any ring does
not contain two
adjacent 0 or S atoms. Non-aromatic heterocyclic groups (also known as
heterocycloalkyls)
include rings having 3 to 10 atoms in its ring system and aromatic
heterocyclic groups include
rings having 5 to 10 atoms in its ring system. The heterocyclic groups include
benzo-fused ring
systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl,
tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl,
dihydropyranyl,
tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl,
piperazinyl,
aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl,
thiepanyl, oxazepinyl,
diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-
3-yl, indolinyl, 2H-
pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl,
dithiolanyl,
dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,
imidazolidinyl, 3-
azabicy clo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-
onyl, isoindolin-l-
onyl , i soi ndoli
onyl , 3,4-di hydroi soqui nol i n-1(2H)-onyl, 3,4-di hydroqui nol i n -
2(1H)-
onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-
benzo[d]imidazol-2(314)-onyl,
benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic
heterocyclic groups are
pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,
tetrazolyl, fury!, thienyl,
isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,
isoquinolinyl, indolyl,
benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,
phthalazinyl, pyridazinyl,
triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,
furazanyl, benzofurazanyl,
benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, and
furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-
attached where
such is possible. For instance, a group derived from pyrrole includes both
pyrrol-1-y1 (N-
attached) or pyrrol-3-y1 (C-attached). Further, a group derived from imidazole
includes
imidazol-1-y1 or imidazol-3-y1 (both N-attached) or imidazol-2-yl, imidazol-4-
y1 or imidazol-5-
yl (all C-attached). The heterocyclic groups include benzo-fused ring systems.
Non-aromatic
heterocycles are optionally substituted with one or two oxo (=0) moieties,
such as pyrrolidin-2-
one. In some embodiments, at least one of the two rings of a bicyclic
heterocycle is aromatic. In
some embodiments, both rings of a bicyclic heterocycle are aromatic.
[00226] The terms "heteroaryl" or, alternatively, "heteroaromatic" refers to
an aryl group that
includes one or more ring heteroatoms selected from nitrogen, oxygen and
sulfur. Illustrative
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examples of heteroaryl groups include monocyclic heteroaryls and bicyclic
heteroaryls.
Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,
triazolyl,
pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,
isothiazolyl, pyrrolyl,
pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic
heteroaryls include
indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole,
purine, quinolizine,
quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-
naphthyridine, and
pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring.
In some
embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some
embodiments, a heteroaryl
contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some
embodiments, a
heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring In
some
embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic
heteroaryl is a
Ci-05heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or
6-membered
heteroaryl. In some embodiments, bicyclic heteroaryl is a Co-C9heteroaryl
[00227] A "heterocycloalkyl" group refers to a cycloalkyl group that includes
at least one
heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a
heterocycloalkyl
is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl
is
oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl,
tetrahydrothiopyranyl, pi peri di nyl , morplioli nyl, thi oni orphol i nyl,
pi perazinyl , pi peri di n-2-onyl,
pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl,
imidazolidinyl, imidazolidin-2-
onyl, or thiazolidin-2-onyl. In one aspect, a heterocycloalkyl is a C2-
Cioheterocycloalkyl. In
another aspect, a heterocycloalkyl is a C4-Cioheterocycloalkyl. In some
embodiments, a
heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a
heterocycloalkyl is
monocyclic and is a 3, 4, 5, 6, 7, or 8-membered ring. In some embodiments, a
heterocycloalkyl
is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, a
heterocycloalkyl is
monocyclic and is a 3 or 4-membered ring. In some embodiments, a
heterocycloalkyl contains
0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2
N atoms, 0-2 0
atoms and 0-1 S atoms in the ring.
[00228] The term "bond" or "single bond" refers to a chemical bond between two
atoms, or two
moieties when the atoms joined by the bond are considered to be part of larger
substructure. In
one aspect, when a group described herein is a bond, the referenced group is
absent thereby
allowing a bond to be formed between the remaining identified groups.
[00229] The term "moiety" refers to a specific segment or functional group of
a molecule.
Chemical moieties are often recognized chemical entities embedded in or
appended to a
molecule.
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[00230] The term "optionally substituted" or "substituted" means that the
referenced group is
optionally substituted with one or more additional group(s) individually and
independently
selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -
0O2alkyl, -C(=0)NH2,
-C(=0)NH(alkyl), -C(=0)N(alky1)2, -S(=0)2NH2, -S(=0)2NH(alkyl), -
S(=0)2N(alky1)2, alkyl,
cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl,
aryl, heteroaryl,
aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and
arylsulfone. In some
other embodiments, optional substituents are independently selected from
halogen, -CN, -NH2, -
NH(CH3), -N(CH3)2, -OH, -CO2H, -0O2(C1-C4alkyl), -C(=0)NH2, -C(=0)NH(Ci-
C4alkyl), -
C(=0)N(Ci-C4alky1)2, -S(=0)2N1H2, -S(=0)2NH(Ci-C4alkyl), -S(=0)2N(Ci-
Caalkyl)2, C1-
C4alkyl, C3-C6cycloalkyl, Ci-C4fluoroalkyl, Ci-C4heteroalkyl, Ci-C4alkoxy, Ci-
C4fluoroalkoxy,
-SC1-C4alkyl, -S(=0)C1-C4alkyl, and -S(=0)2C1-C4alkyl. In some embodiments,
optional
substituents are independently selected from halogen, -CN, -NH2, -OH, H(CH3), -
N(CH3)2, -
CH3, -CH7CH3, -CHF), -CF3, -OCH3, -OCHT7, and -0CF3. In some embodiments,
substituted
groups are substituted with one or two of the preceding groups. In some
embodiments, an
optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes
oxo (=0).
[00231] In some embodiments, each substituted alkyl, substituted fluoroalkyl,
substituted
heteroalkyl, substituted carbocycle, and substituted heterocycle is
substituted with one or more
-11S groups independently selected from the group consisting of deuterium,
halogen, Ci-C6 alkyl,
monocyclic earboeyele, monocyclie heterocycle, -CN, -OR's, -CO2R18, -C(=O)N
(R'8)2, -
N-(Ri8).25 NRi8c(_0)R193 sR185 S(=0)R19, -SO2R19, or -SO2N(R18)2; each R18 is
independently
selected from hydrogen, Ci-C6 alkyl, Ci-C6 fluoroalkyl, Ci-C6 heteroalkyl, C3-
C6 cycloalkyl, C2-
C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered
heteroaryl; or two
R" groups are taken together with the N atom to which they are attached to
form a N-containing
heterocycle; each R19 is independently selected from C1-C6 alkyl, Ci-C6
fluoroalkyl, Ci-C6
heteroalkyl, C3-C6 cyeloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-
membered heteroaryl
and 6-membered heteroaryl.
[00232] The term "acceptable" with respect to a formulation, composition or
ingredient, as used
herein, means having no persistent detrimental effect on the general health of
the subject being
treated.
[00233] The term "modulate" as used herein, means to interact with a target
either directly or
indirectly so as to alter the activity of the target, including, by way of
example only, to enhance
the activity of the target, to inhibit the activity of the target, to limit
the activity of the target, or
to extend the activity of the target.
[00234] The term "modulator" as used herein, refers to a molecule that
interacts with a target
either directly or indirectly. The interactions include, but are not limited
to, the interactions of an
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agonist, partial agonist, an inverse agonist, antagonist, degrader, or
combinations thereof. In
some embodiments, a modulator is an antagonist. In some embodiments, a
modulator is an
inhibitor.
[00235] The terms "administer," "administering", "administration," and the
like, as used herein,
refer to the methods that may be used to enable delivery of compounds or
compositions to the
desired site of biological action. These methods include, but are not limited
to oral routes,
intraduodenal routes, parenteral injection (including intravenous,
subcutaneous, intraperitoneal,
intramuscular, intravascular or infusion), topical and rectal administration.
Those of skill in the
art are familiar with administration techniques that can be employed with the
compounds and
methods described herein. In some embodiments, the compounds and compositions
described
herein are administered orally.
[00236] The terms "co-administration" or the like, as used herein, are meant
to encompass
administration of the selected therapeutic agents to a single patient, and are
intended to include
treatment regimens in which the agents are administered by the same or
different route of
administration or at the same or different time.
[00237] The terms "effective amount- or "therapeutically effective amount,- as
used herein,
refer to a sufficient amount of an agent or a compound being administered,
which will relieve to
some extent one or more of the symptoms of the disease or condition being
treated. The result
includes reduction and/or alleviation of the signs, symptoms, or causes of a
disease, or any other
desired alteration of a biological system. For example, an "effective amount"
for therapeutic
uses is the amount of the composition comprising a compound as disclosed
herein required to
provide a clinically significant decrease in disease symptoms. An appropriate
"effective"
amount in any individual case is optionally determined using techniques, such
as a dose
escalation study.
[00238] The terms "enhance" or "enhancing," as used herein, means to increase
or prolong
either in potency or duration a desired effect. Thus, in regard to enhancing
the effect of
therapeutic agents, the term "enhancing" refers to the ability to increase or
prolong, either in
potency or duration, the effect of other therapeutic agents on a system. An
"enhancing-effective
amount," as used herein, refers to an amount adequate to enhance the effect of
another
therapeutic agent in a desired system.
[00239] The term "pharmaceutical combination" as used herein, means a product
that results
from the mixing or combining of more than one active ingredient and includes
both fixed and
non-fixed combinations of the active ingredients. The term "fixed combination"
means that the
active ingredients, e.g. a compound of Formula (I), or a pharmaceutically
acceptable salt thereof,
and a co-agent, are both administered to a patient simultaneously in the form
of a single entity or
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dosage. The term "non-fixed combination" means that the active ingredients,
e.g. a compound of
Formula (I), or a pharmaceutically acceptable salt thereof and a co-agent, are
administered to a
patient as separate entities either simultaneously, concurrently or
sequentially with no specific
intervening time limits, wherein such administration provides effective levels
of the two
compounds in the body of the patient. The latter also applies to cocktail
therapy, e.g. the
administration of three or more active ingredients.
[00240] The terms "article of manufacture" and "kit" are used as synonyms.
[00241] The term "subject" or "patient" encompasses mammals. Examples of
mammals
include, but are not limited to, any member of the Mammalian class: humans,
non-human
primates such as chimpanzees, and other apes and monkey species; farm animals
such as cattle,
horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;
laboratory animals
including rodents, such as rats, mice and guinea pigs, and the like. In one
aspect, the mammal is
a human
[00242] The terms "treat," "treating" or "treatment," as used herein, include
alleviating, abating
or ameliorating at least one symptom of a disease or condition, preventing
additional symptoms,
inhibiting the disease or condition, e.g., arresting the development or
progression of the disease
or condition, relieving the disease or condition, causing regression of the
disease or condition,
relieving a secondary condition caused_ by the disease or condition, or
stopping the symptoms of
the disease or condition either prophylactically and/or therapeutically.
Pharmaceutical Compositions
1002431 In some embodiments, the compounds described herein are formulated
into
pharmaceutical compositions. Pharmaceutical compositions are formulated in a
conventional
manner using one or more pharmaceutically acceptable inactive ingredients that
facilitate
processing of the active compounds into preparations that are used
pharmaceutically. Proper
formulation is dependent upon the route of administration chosen. A summary of
pharmaceutical
compositions described herein is found, for example, in Remington: The Science
and Practice of
Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover,
John E.,
Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania
1975;
Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel
Decker, New
York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,
Seventh Ed.
(Lippincott Williams & Wilkins1999), herein incorporated by reference for such
disclosure.
1002441 A compound or a pharmaceutical composition of the present disclosure
is, in some
embodiments, useful for the treatment of a TYK2 mediated disease or disorder.
In some
embodiments, the pharmaceutical composition is effective at treating a disease
or disorder
wherein TYK2 is overexpressed or hyperactive. In some embodiments, the
pharmaceutical
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composition is effective at treating a disease or disorder which would benefit
from a reduction in
TYK2 activity or expression.
1002451 In some embodiments, the pharmaceutical composition is useful in the
treatment of
disease or disorder associated with high levels of cytokines driven by TYK2,
such as interferons
(e.g. IFN-a, IFN-13, IFN-K, IFN-6, IFN-s, IFN-r, IFN-co, and
(also known as limitin), and
interleukins (e.g. IL-4, LL-6, IL-10, IL-1 1, LL-12, IL-13, IL-22, IL-23, IL-
27, IL-31, oncostatin
M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine,
and LIT. In some
embodiments, the disease or disorder is an inflammatory disease or disorder,
an autoimmune
disease or disorder, a respiratory disease or disorder, type 1 diabetes, and
interferonopathies
such as Alcardi-Goutieres syndrome, or combinations thereof.
[00246] In some embodiments, the pharmaceutical composition is useful in the
treatment of an
inflammatory disease or disorder. In some embodiments, the inflammatory
disease or disorder is
an auto-inflammatory disease or disorder, a host-mediated inflammatory disease
or disorder, an
injury-related inflammatory disease or disorder, an infection-related
inflammatory disease or
disorder, a hyperproliferative (e.g., cancer, fibrosis) mediated inflammatory
disease or disorder.
In some embodiments, the inflammatory disease or disorder or infection-related
inflammatory
disease or disorder is a respiratory disease or disorder. In some embodiments,
the respiratory
disease or disorder is associated with a viral in microbial infection In some
embodiments, the
respiratory disease or disorder is a problematic immune response to a viral or
microbial
infection. In some embodiments, the respiratory disease or disorder is
associated with a
coronavirus such as MERS-CoV, SARS-CoV-1, or SARS-CoV-2. In some embodiments,
the
pharmaceutical composition is effective in decreasing symptoms associated with
COVID-19, or
an immune response associated therewith.
[00247] In some embodiments, the pharmaceutical composition is useful in the
treatment of an
autoimmune disease or disorders. In some embodiments, an autoimmune disease or
disorder is
rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis,
lupus, systemic lupus
erythematosus, Sjogren's syndrome, ankylosing spondylitis, vitiligo, atopic
dermatitis,
scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal
bowel disease,
Crohn's disease, ulcerative colitis, celiac disease, Bechet's disease, type 1
diabetes, systemic
sclerosis, and idiopathic pulmonary fibrosis. In some embodiments, an
autoimmunc disease or
disorder is lupus or systemic lupus erythematosus. In some embodiments, an
autoimmune
disease or disorder is psoriasis. In some embodiments, an autoimmune disease
or disorder is
irritable bowel disease (IBS) or irritable bowel disease with diarrhea (IB S-
D). In some
embodiments, an autoimmune disease or disorder is dry eye or uveitis. In some
embodiments, an
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autoimmune disease or disorder is Crohn's disease. In some embodiments, an
autoimmune
disease or disorder is atopic dermatitis.
1002481 In some embodiments, the compounds described herein are administered
either alone
or in combination with pharmaceutically acceptable carriers, excipients or
diluents, in a
pharmaceutical composition. Administration of the compounds and compositions
described
herein can be effected by any method that enables delivery of the compounds to
the site of
action. These methods include, though are not limited to delivery via enteral
routes (including
oral, gastric or duodenal feeding tube, rectal suppository and rectal enema),
parenteral routes
(injection or infusion, including intraarterial, intracardiac, intradermal,
intraduodenal,
intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal,
intravascular,
intravenous, intravitreal, epidural and subcutaneous), inhalational,
transdermal, transmucosal,
sublingual, buccal and topical (including epicutaneous, deiiiial, enema, eye
drops, ear drops,
intranasal, vaginal) administration, although the most suitable route may
depend upon for
example the condition and disorder of the recipient. By way of example only,
compounds
described herein can be administered locally to the area in need of treatment,
by for example,
topical application such as creams or ointments. Additional examples of local
administration of
the present compounds include eye drops, ocular creams, gels or hydrogels,
implants.
transdermal patches, or drug depots In some embodiments, a pharmaceutical
composition is
administered orally (e.g., in a liquid formulation, tablet, capsule, nebulized
liquid, aerosolized
liquid, dry powder spray).
1002491 In some embodiments, pharmaceutical compositions suitable for oral
administration
are presented as discrete units such as capsules, cachets or tablets each
containing a
predetermined amount of the active ingredient; as a powder or granules; as a
solution or a
suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water
liquid emulsion or
a water-in-oil liquid emulsion. In some embodiments, the active ingredient is
presented as a
bolus, electuary or paste.
[00250] Pharmaceutical compositions which can be used orally include tablets,
push-fit
capsules made of gelatin, as well as soft, sealed capsules made of gelatin and
a plasticizer, such
as glycerol or sorbitol. Tablets may be made by compression or molding,
optionally with one or
more accessory ingredients. Compressed tablets may be prepared by compressing
in a suitable
machine the active ingredient in a free-flowing form such as a powder or
granules, optionally
mixed with binders, inert diluents, or lubricating, surface active or
dispersing agents. Molded
tablets may be made by molding in a suitable machine a mixture of the powdered
compound
moistened with an inert liquid diluent. In some embodiments, the tablets are
coated or scored
and are formulated so as to provide slow or controlled release of the active
ingredient therein.
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All formulations for oral administration should be in dosages suitable for
such administration.
The push-fit capsules can contain the active ingredients in admixture with
filler such as lactose,
binders such as starches, and/or lubricants such as talc or magnesium stearate
and, optionally,
stabilizers. In soft capsules, the active compounds may be dissolved or
suspended in suitable
liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
In some embodiments,
stabilizers are added. Dragee cores are provided with suitable coatings. For
this purpose,
concentrated sugar solutions may be used, which may optionally contain gum
arabic, talc,
polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium
dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or
pigments may be
added to the tablets or Dragee coatings for identification or to characterize
different
combinations of active compound doses.
[00251] In some embodiments, pharmaceutical compositions are formulated for
parenteral
administration by injection, e.g., by bolus injection or continuous infusion
Formulations for
injection may be presented in unit dosage form, e.g., in ampoules or in multi-
dose containers,
with an added preservative. The compositions may take such forms as
suspensions, solutions or
emulsions in oily or aqueous vehicles, and may contain formulatory agents such
as suspending,
stabilizing and/or dispersing agents. The compositions may be presented in
unit-dose or multi-
dose containers, for example sealed ampoules and vials, and may be stored in
powder form or in
a freeze-dried (lyophilized) condition requiring only the addition of the
sterile liquid carrier, for
example, saline or sterile pyrogen-free water, immediately prior to use.
Extemporaneous
injection solutions and suspensions may be prepared from sterile powders,
granules and tablets
of the kind previously described.
[00252] Pharmaceutical compositions may also be formulated as a depot
preparation. Such long
acting formulations may be administered by implantation (for example
subcutaneously). Thus,
for example, the compounds may be formulated with suitable polymeric or
hydrophobic
materials (for example, as an emulsion in an acceptable oil) or ion exchange
resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble salt.
[00253] Pharmaceutical compositions may be administered topically, that is by
non-systemic
administration. This includes the application of a compound of the present
invention externally
to the epidermis or the buccal cavity and the installation of such a compound
into the car, eye
and nose, such that the compound does not significantly enter the blood
stream. In contrast,
systemic administration refers to oral, intravenous, intraperitoneal and
intramuscular
administration.
[00254] Pharmaceutical compositions suitable for topical administration
include liquid or semi-
liquid preparations suitable for penetration through the skin to the site of
inflammation such as
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gels, liniments, lotions, creams, ointments or pastes, and drops suitable for
administration to the
eye, ear or nose. The active ingredient may comprise, for topical
administration, from 0.001% to
10% w/w, for instance from 1% to 2% by weight of the foimulation.
[00255] Pharmaceutical compositions for administration by inhalation are
conveniently
delivered from an insufflator, nebulizer pressurized packs or other convenient
means of
delivering an aerosol spray. Pressurized packs may comprise a suitable
propellant such as
dichlorodifluoromethane, trichloraluoromethane, dichlorotetrafluoroethane,
carbon dioxide or
other suitable gas. In the case of a pressurized aerosol, the dosage unit may
be determined by
providing a valve to deliver a metered amount. Alternatively, for
administration by inhalation or
insufflation, pharmaceutical preparations may take the form of a dry powder
composition, for
example a powder mix of the compound and a suitable powder base such as
lactose or starch.
The powder composition may be presented in unit dosage form, in for example,
capsules,
cartridges, gelatin or blister packs from which the powder may be administered
with the aid of
an inhalator or insufflator.
[00256] It should be understood that in addition to the ingredients
particularly mentioned
above, the compounds and compositions described herein may include other
agents conventional
in the art having regard to the type of formulation in question, for example
those suitable for oral
administration may include flavoring agents
Methods of Dosing and Treatment Regimens
[00257] In one embodiment, the compound described herein, or a
pharmaceutically acceptable
salt, tautomer, or solvate thereof, are used in the preparation of medicaments
for the treatment of
diseases or conditions in a mammal that would benefit from modulation of TYK2
activity.
Methods for treating any of the diseases or conditions described herein in a
mammal in need of
such treatment, involves administration of pharmaceutical compositions that
include at least one
compound described herein, or a pharmaceutically acceptable salt, active
metabolite, prodrug, or
pharmaceutically acceptable solvate thereof, in therapeutically effective
amounts to said
mammal.
[00258] In certain embodiments, the compositions containing the compound(s)
described herein
are administered for prophylactic and/or therapeutic treatments. In certain
therapeutic
applications, the compositions are administered to a patient already suffering
from a disease or
condition, in an amount sufficient to cure or at least partially arrest at
least one of the symptoms
of the disease or condition. Amounts effective for this use depend on the
severity and course of
the disease or condition, previous therapy, the patient's health status,
weight, and response to the
drugs, and the judgment of the treating physician. Therapeutically effective
amounts are
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optionally determined by methods including, but not limited to, a dose
escalation and/or dose
ranging clinical trial.
[00259] In prophylactic applications, compositions containing the compounds
described herein
are administered to a patient susceptible to or otherwise at risk of a
particular disease, disorder
or condition. Such an amount is defined to be a "prophylactically effective
amount or dose." In
this use, the precise amounts also depend on the patient's state of health,
weight, and the like.
When used in patients, effective amounts for this use will depend on the
severity and course of
the disease, disorder or condition, previous therapy, the patient's health
status and response to
the drugs, and the judgment of the treating physician. In one aspect,
prophylactic treatments
include administering to a mammal, who previously experienced at least one
symptom of the
disease being treated and is currently in remission, a pharmaceutical
composition comprising a
compound described herein, or a pharmaceutically acceptable salt thereof, in
order to prevent a
return of the symptoms of the disease or condition.
[00260] In certain embodiments wherein the patient's condition does not
improve, upon the
doctor's discretion the administration of the compounds are administered
chronically, that is, for
an extended period of time, including throughout the duration of the patient's
life in order to
ameliorate or otherwise control or limit the symptoms of the patient's disease
or condition.
[00261] Once improvement of the patient's conditions has occurred, a
maintenance dose is
administered if necessary. Subsequently, in specific embodiments, the dosage
or the frequency
of administration, or both, is reduced, as a function of the symptoms, to a
level at which the
improved disease, disorder or condition is retained. In certain embodiments,
however, the
patient requires intermittent treatment on a long-term basis upon any
recurrence of symptoms.
[00262] The amount of a given agent that corresponds to such an amount varies
depending
upon factors such as the particular compound, disease condition and its
severity, the identity
(e.g., weight, sex) of the subject or host in need of treatment, but
nevertheless is determined
according to the particular circumstances surrounding the case, including,
e.g., the specific agent
being administered, the route of administration, the condition being treated,
and the subject or
host being treated.
[00263] In general, however, doses employed for adult human treatment are
typically in the
range of 0.01 mg-2000 mg per day. In one embodiment, the desired dose is
conveniently
presented in a single dose or in divided doses administered simultaneously or
at appropriate
intervals, for example as two, three, four or more sub-doses per day.
[00264] In one embodiment, the daily dosages appropriate for the compound
described herein,
or a pharmaceutically acceptable salt thereof, described herein are from about
0.01 to about 50
mg/kg per body weight. In some embodiments, the daily dosage or the amount of
active in the
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dosage form are lower or higher than the ranges indicated herein, based on a
number of variables
in regard to an individual treatment regime. In various embodiments, the daily
and unit dosages
are altered depending on a number of variables including, but not limited to,
the activity of the
compound used, the disease or condition to be treated, the mode of
administration, the
requirements of the individual subject, the severity of the disease or
condition being treated, and
the judgment of the practitioner.
[00265] Toxicity and therapeutic efficacy of such therapeutic regimens are
determined by
standard pharmaceutical procedures in cell cultures or experimental animals,
including, but not
limited to, the determination of the LD50 and the ED50 The dose ratio between
the toxic and
therapeutic effects is the therapeutic index and it is expressed as the ratio
between LD50 and
ED50. In certain embodiments, the data obtained from cell culture assays and
animal studies are
used in formulating the therapeutically effective daily dosage range and/or
the therapeutically
effective unit dosage amount for use in mammals, including humans. In some
embodiments, the
daily dosage amount of the compounds described herein lies within a range of
circulating
concentrations that include the ED50 with minimal toxicity. In certain
embodiments, the daily
dosage range and/or the unit dosage amount varies within this range depending
upon the dosage
form employed and the route of administration utilized.
[00266] Tn any of the aforementioned aspects are further embodiments in which
the effective
amount of the compound described herein, or a pharmaceutically acceptable salt
thereof, is: (a)
systemically administered to the mammal; and/or (b) administered orally to the
mammal; and/or
(c) intravenously administered to the mammal; and/or (d) administered by
injection to the
mammal; and/or (e) administered topically to the mammal; and/or (f)
administered non-
systemically or locally to the mammal
[00267] In any of the aforementioned aspects are further embodiments
comprising single
administrations of the effective amount of the compound, including further
embodiments in
which (i) the compound is administered once a day; or (ii) the compound is
administered to the
mammal multiple times over the span of one day.
[00268] In any of the aforementioned aspects are further embodiments
comprising multiple
administrations of the effective amount of the compound, including further
embodiments in
which (i) the compound is administered continuously or intermittently: as in a
single dose; (ii)
the time between multiple administrations is every 6 hours; (iii) the compound
is administered to
the mammal every 8 hours; (iv) the compound is administered to the mammal
every 12 hours;
(v) the compound is administered to the mammal every 24 hours. In further or
alternative
embodiments, the method comprises a drug holiday, wherein the administration
of the
compound is temporarily suspended or the dose of the compound being
administered is
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temporarily reduced; at the end of the drug holiday, dosing of the compound is
resumed. In one
embodiment, the length of the drug holiday varies from 2 days to I year.
Combination Treatments
[00269] In certain instances, it is appropriate to administer at least one
compound described
herein, or a pharmaceutically acceptable salt thereof, in combination with one
or more other
therapeutic agents.
[00270] In one embodiment, the therapeutic effectiveness of one of the
compounds described
herein is enhanced by administration of an adjuvant (i.e., by itself the
adjuvant has minimal
therapeutic benefit, but in combination with another therapeutic agent, the
overall therapeutic
benefit to the patient is enhanced). Or, in some embodiments, the benefit
experienced by a
patient is increased by administering one of the compounds described herein
with another agent
(which also includes a therapeutic regimen) that also has therapeutic benefit.
[00271] In one specific embodiment, a compound described herein, or a
pharmaceutically
acceptable salt thereof, is co-administered with a second therapeutic agent,
wherein the
compound described herein, or a pharmaceutically acceptable salt thereof, and
the second
therapeutic agent modulate different aspects of the disease, disorder or
condition being treated,
thereby providing a greater overall benefit than administration of either
therapeutic agent alone.
[00272] In any case, regardless of the disease, disorder or condition being
treated, the overall
benefit experienced by the patient may simply be additive of the two
therapeutic agents or the
patient may experience a synergistic benefit.
[00273] For combination therapies described herein, dosages of the co-
administered
compounds vary depending on the type of co-drug employed, on the specific drug
employed, on
the disease or condition being treated and so forth. In additional
embodiments, when co-
administered with one or more other therapeutic agents, the compound provided
herein is
administered either simultaneously with the one or more other therapeutic
agents, or
sequentially.
[00274] In combination therapies, the multiple therapeutic agents (one of
which is one of the
compounds described herein) are administered in any order or even
simultaneously. If
administration is simultaneous, the multiple therapeutic agents are, by way of
example only,
provided in a single, unified form, or in multiple forms (e.g., as a single
pill or as two separate
pills).
[00275] The compounds described herein, or a pharmaceutically acceptable salt
thereof, as well
as combination therapies, are administered before, during or after the
occurrence of a disease or
condition, and the timing of administering the composition containing a
compound varies. Thus,
in one embodiment, the compounds described herein are used as a prophylactic
and are
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administered continuously to subjects with a propensity to develop conditions
or diseases in
order to prevent the occurrence of the disease or condition. In another
embodiment, the
compounds and compositions are administered to a subject during or as soon as
possible after
the onset of the symptoms. In specific embodiments, a compound described
herein is
administered as soon as is practicable after the onset of a disease or
condition is detected or
suspected, and for a length of time necessary for the treatment of the
disease. In some
embodiments, the length required for treatment varies, and the treatment
length is adjusted to
suit the specific needs of each subject.
EXAMPLES
[00276] As used above, and throughout the description of the invention, the
following
abbreviations, unless otherwise indicated, shall be understood to have the
following meanings.
Abbreviations:
ACN acetonitrile
CAN ceric ammonium nitrate
DCM dichloromethane
DIBAL diisobutylaluminum hydride
DIPEA N,N-dii sopropyl ethyl amine
DMA dimethylacetamide
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
Et0Ac ethyl acetate
EGTA ethylene glycol-bis(0-aminoethyl ether)-N,N,N',N'-
tetraacetic acid
ES electrospray
FBS fetal bovine serum
GST glutathione S-transferase
HEK human embryonic kidney
HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
IHMDS bis(trimethylsilyl)amide
HPLC high pressure liquid chromatography
HTRF homogenous time resolved fluorescence
IC50 half maximal inhibitory concentration
IFN interferon
IL interl eukin
IPA isopropyl alcohol
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JAK Janus kinase
LCMS liquid chromatography-mass spectrometry
MDI metered drug inhalant
MW microwave
NMR nuclear magnetic resonance
SEAP secreted embryonic alkaline phosphatase
STAT signal transducer and activator of transcription
T3P propanephosphonic acid anhydride
TBAF tetra-n-butylammonium fluoride
TBDMS tert-butyl dimethyl silyl
TBDPS tert-butyldiphenylsilyl
TEA triethylamine
TFA trifluoroacetic acid
THY tetrahydrofuran
TLC thin-layer chromatography
TYK non-receptor tyrosine-protein kinase
[00277] The following examples are provided for illustrative purposes only and
not to limit the
scope of the claims provided herein
Synthesis of Compounds
Example 1: Preparation of 6-methy1-5,6-dihydrobenzo[h]11,61naphthyridin-7-
amine (1-1):
F
06
NO2
i) MrteN161.1121, Me0H
I ...,
ci).L
(13cc)20
II) NaBH4, 0 C-rt, 2 h I
___________________________________ ..- -=
1 KOAc, 1,4-
dioxane
NE1 TEIF6k,hD,CrtM ..õ-"-.,,,"-.1
N_Boc Pd(dPPOCl2-CH2C12
Step-1 Step-2 Step-3
I-1 a I-1 b I-1c
I I I I
NLN.- N TFA, DCM N Pd/C, H2 / N
0 C to rt, 2 h Me0H, rt, 2 h
F _____________________________________ " N __________ ' N
.- .-
Step-4 Step-5
02N 02N H2N
I-1d 1-le I-1
[00278] Step-1: 1-(2-chloropyridin-3-y1)-N-methylmethanamine (1-1b): To a
stirred solution
of 2-chloropyridine-3-carbaldehyde I-la (5.00 g, 35.3 mmol) in Me0H (50 mL)
was added 2M
MeNTI7 in Et0H (6.00 mL, 63.6 mmol), and the reaction mixture was stirred for
16 h (reaction
progress was monitored by TLC). After complete consumption of starting
material, reaction
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mixture was cooled to 0 C and NaBH4 (10.5 g, 293 mmol) was added to it
portion-wise. The
reaction mixture was all owed to warm to room temperature over 2 h. After
completion (as
indicated by TLC), volatiles were removed under reduced pressure and water (50
mL) was
added to it Extraction was carried out using DCM (50 mL x 3); the combined
organic extracts
were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and
concentrated under
reduced pressure to afford 1-(2-chloropyridin-3-y1)-N-methylmethanamine I-lb
(5.5 g) as a pale
yellow oil. LCMS (ES) In/z; 157.1 [M-FHr.
[00279] Step-2: tert-butyl ((2-ehloropyridin-3-yl)methyl)(methyl)carbamate (1-
1e): To a
stirred solution of I-lb (5.00 g, 31.9 mmol) in DCM (80.0 mL) was added TEA
(22.4 mL, 160
mmol) and (Boc)20 (36.7 mL, 160 mmol). The reaction mixture was stirred at
room temperature
for 16 h. The reaction progress was monitored by LCMS. After completion,
volatiles were
removed under reduced pressure and water (50 mL) was added to it. Extraction
was carried out
using DCM (50 mL x 3) The combined organic extracts were washed with brine (50
mL), dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
residue was
purified by Combi -Flash (using gradient elution of 0-20% Et0Ac in hexane) to
afford desired
compound tert-butyl ((2-chloropyridin-3-yl)methyl)(methyl)carbamate I-lc (7.00
g) as a pale
yellow oil. LCMS (ES) m/z; 257.1 [M-PFIr.
[00280] Step-3: tert-butyl ((2-(2-fluoro-3-nitrophenyl)pyridin-3-
yl)methyl)(methyl)carbamate (1-1d): Argon gas was purged through a stirred
suspension oft-
lc (3.0 g, 11.7 mmol), 2-(2-fluoro-3-nitropheny1)-4,4,5,5-tetramethy1-1,3,2-
dioxaborolane (3.43
g, 12.9 mmol) and KOAc (3.44 g, 35.1 mmol) in 1,4-dioxane (25.0 mL) for 15
min. To this was
then added Pd(dppf)C12.DCM (61.2 mg, 0.0749 mmol). The reaction mixture was
then stirred at
80 C for 16 h in a sealed tube. It was then cooled to room temperature,
filtered through celite
bed and washed with Et0Ac (50 mL x 2). The combined filtrate was concentrated
under reduced
pressure and the residue was purified by Combi-Flash (using gradient elution
of 0-30% Et0Ac
in hexane) to afford tert-butyl ((2-(2-fluoro-3-nitrophenyl)pyridin-3-
yl)methyl)(methyl)carbamate I-1d (1.3 g) as a yellow oil. LCMS (ES) m/z; 362.2
[M+11]+.
[00281] Step-4: 6-methyl-7-nitro-5,6-dihydrobenzo[h][1,6]naphthyridine (I-le):
To a
stirred solution of I-1d (1.3 g, 3.6 mmol) in DCM (10.0 mL) was added TFA (5.0
mL) at 0 C
under nitrogen atmosphere and the reaction mixture was allowed to warm to room
temperature
over 2 h. The progress of the reaction was monitored by LCMS. After
completion, volatiles
were removed under reduced pressure and saturated NaHCO3 solution (50 mL) was
added to the
residue. Extraction was carried out using DCM (3 x 30 mL); the combined
organic extracts were
washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4,
filtered and
evaporated under reduced pressure to afford 6-methyl-7-nitro-5,6-
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dihydrobenzo[h][1,6]naphthyridine 1-le (0.68 g) as a brown solid. LCMS (ES)
nilz; 242.1
[M+H].
[00282] Step-5: 6-methyl-5,6-dihydrobenzo[h] 11,61naphthyridin-7-amine (1-1):
To a stirred
solution of 1-le (0.278, 1.12 mmol) in Me0H (20.0 mL) was added 10% Pd/C (59
mg) at room
temperature. The reaction mixture was then stirred under hydrogen atmosphere
(balloon) for 2 h.
After completion, the catalyst was filtered off through celite and washed with
Me0H (5 mL x
2). The filtrate was concentrated under reduced pressure. The residue was then
stirred in pentane
(15 mL), filtered and dried to afford desired compound 6-methy1-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-amine I-I (0.2 g) as an orange solid. LCMS
(ES) nilz;
212.0 [M+H]t. IH NMR (400 MHz, DMSO-do) 6 8.52 (dd, Ji = 1.2 Hz, J2 = 4.8 Hz,
1H); 7.69
(d, J= 6.0 Hz, 1H); 7.46 (dd, Ji = 1.2 Hz, J2 = 7.6 Hz, 1H); 7.30 (dd, Ji =
4.8 Hz, J2 = 7.2 Hz,
1H); 6.96 (t, J= 7.6 Hz, 1H); 6.74 (dd, Ji = 1.2 Hz, J2 = 7.6 Hz, 1H); 4.95
(s, 2H); 4.14 (s, 2H),
2.40 (s, 311).
Example 2: Preparation of 6-m ethyl-5,6-dihydropyrimido[5,4-c[quinolin-7-amine
(I-2):
NH2 HN OH
B
methylacrylate sq. Li0H.H20, THF Br A
Eaton's reagent
r
11101 AcOH, 90 C, 48 h Br Me0H, 2 h, rt 70 C,
16h
Step-1 Step-2 Step-3
I-2a I-2b I-2c
HN ZnCl2, NI-140Ac Bon-NI-
12, Cs2CO3
Br
Mel, K2CO3 Br
CH(OEt)3, toluene, NN
Pd(OAc)2, Xantphos
0 DMF, 80 C, 24 h 0 100 C, 24 h Br 1,4-
dioxane, 100 C, 16 h
Step-4 Step-5 Step-
6
I-2d I-2e I-2f
, N
N TFA, DCM
I _I
1,0y N I

0 C-rt, 3 0 h H
N 2 N
0 Step-7
1-2g 1-2
[00283] Step-1: methyl 3-((2-bromophenyl)amino)propanoate (I-2b): A mixture of
2-
bromoaniline I-2a (6.00 g, 34.9 mmol) and methyl prop-2-enoate (9.48 mL, 105
mmol) in
AcOH (3.99 mL, 69.8 mmol) was stirred at 90 C for 48 h in a sealed tube. The
progress of the
reaction was monitored by TLC. After complete consumption of starting
material, the reaction
mixture was cooled to room temperature and concentrated under reduced pressure
Saturated
NaHCO3 solution (100 mL) was added to it and extraction was carried out using
Et0Ac (70 mL
x 3). The combined organic extracts were washed with brine (70 mL), dried over
anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The residue was
purified by Combi-
Flash (using gradient elution of 0-10% Et0Ac in hexane) to afford methyl 3-((2-

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bromophenyl)amino)propanoate I-2b (3.1 g) as a viscous liquid. LCMS (ES) in/z;
258.0
[M+H].
1002841 Step-2: 3-((2-bromophenyl)amino)propanoic acid (1-2c): To a stirred
solution of 1-
2b (2.50g, 9.69 mmol) in THF:Me0H (8.0:8.0:8.0 mL) was added an aqueous
solution of
Li0H-H20 (1.22 g, 29.1 mmol, in 8 mL water) and stirred for 2 h at room
temperature. After
completion, volatiles were removed under reduced pressure and the aqueous
layer was washed
with diethyl ether (30 mL x 2). The aqueous layer was then acidified using IN
HC1 and
extraction was carried out using Et0Ac (50 mL x 3). The combined organic
extracts were
washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and
concentrated under
reduced pressure to afford 3-((2-bromophenyl)amino)propanoic acid I-2c (1.9 g)
as a thick oil.
LCMS (ES) nilz; 244.0 [M-41]+.
1002851 Step-3: 8-bromo-2,3-dihydroquinolin-4(1H)-one (I-2d): A solution of 1-
2c (2.5 g,
10.2 mmol) in Eaton's reagent (100 mL) was stirred at 80 C for 16 h. It was
then cooled to
room temperature and ice cold water (100 mL) was added to it. The aqueous
layer was then
made alkaline by slow addition of 50% aqueous NaOH solution. Extraction was
carried out
using Et0Ac (100 mL x 2). The combined organic extracts were washed with brine
(50 mL),
dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
The residue was
purified by Conibi -Flash (using gradient elution of 0-10% FAO Ac in hexane)
to afford desired
compound 8-bromo-2,3-dihydroquinolin-4(1H)-one I-2d (1.8 g) as a pale yellow
oil. LCMS
(ES) m/z; 226.0 [M-41] .
1002861 Step-4: 8-bromo-1-methy1-2,3-dihydroquinolin-4(1H)-one (I-2e): To a
stirred
solution of I-2d (2.5 g, 11.1 mmol) in anhydrous DATE' (25 mL) was added
anhydrous K2CO3
(4.58 g, 33.3 mmol) and stirred for 10 min at room temperature. To this was
then added
iodomethane (1.38 mL, 22.2 mmol) and the reaction mixture was allowed to stir
at 80 C for 24
h in a sealed tube. The progress of the reaction was monitored by TLC. After
completion, water
(70 mL) was added to it and extraction was carried out using Et0Ac (70 mL x
3). The combined
organic extracts were washed with water (75 mL x 2), brine (100 mL), dried
over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The resulting crude
was purified by
Combi-Flash (using gradient elution of 0-10% Et0Ac in hexane) to afford
desired compound 8-
bromo-1-methy1-2,3-dihydroquinolin-4(1H)-one I-2e (1.1 g) as a yellow solid.
LCMS (ES) in/z;
239.9 [M+H]t.
1002871 Step-5: 7-bromo-6-methyl-5,6-dihydropyrimido15,4-elquinolone (I-21):
To a stirred
solution of anhydrous ZnC12 (56.8 mg, 0.416 mmol) and triethylorthoformate
(1.85 g, 12.5
mmol) in anhydrous toluene (10.0 mL) was added I-2e (1.08, 4.16 mmol) and
N1140Ac (0.648,
8.33 mmol). The reaction mixture was then allowed to stir at 100 C for 24 h
in a sealed tube.
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After completion, the reaction mixture was cooled to room temperature and
saturated NaHCO3
solution (30 mL) was added to it. Extraction was carried out using Et0Ac (30
mL x 3); the
combined organic extracts were washed with brine (50 mL), dried over anhydrous
Na2SO4,
filtered and concentrated under reduced pressure. The residue was purified by
Combi-Flash
(using gradient elution of 0-20% Et0Ac in hexane) to afford desired compound 7-
bromo-6-
methy1-5,6-dihydropyrimido[5,4-c]quinolone I-21' (0.62 g) as a pale yellow
solid. LCMS (ES)
In/z; 276.0 [M+H]+.
1002881 Step-6: tert-butyl (6-methyl-5,6-dihydropyrimido[5,4-dquinolin-7-
yl)earbamate
(I-2g): Argon gas was purged through a stirred suspension of I-2f (1.3 g, 4.71
mmol), tert-butyl
carbamate (1.1 g, 9.42 mmol) and Cs2CO3 (3.07 g, 9.42 mmol) in 1,4-dioxane (10
mL) for 15
min. To this was then added [5-(diphenylphosphany1)-9,9-dimethy1-9H-xanthen-4-
ylidiphenylphosphane (0.27 g, 0.47 mmol) and Pd(OAc)2 (0.11 g, 0.47 mmol). The
reaction
mixture was then stirred at 100 C for 16 h in a sealed tube. It was then
cooled to room
temperature, filtered through Celite bed and washed with Et0Ac (50 mL x 2).
The combined
filtrate was concentrated under reduced pressure and the residue was purified
by Combi-Flash
(using gradient elution of 0-50% Et0Ac in hexane) to afford I-2g (1.3 g). LCMS
(ES) nilz;
313.0 [M-FI-1]+.
1002891 Step-7: 6-methy1-5,6-dihydropyr1mid015,4-clquinolin-7-amine (1-2): To
a stirred
solution of 1-2g (1.3 g, 4.16 mmol) in DCM (20.0 mL) was added TFA (5.0 mL) at
0 C under
nitrogen atmosphere and the reaction mixture was allowed to warm to room
temperature over 2
h. The progress of the reaction was monitored by TLC. After completion,
volatiles were
removed under reduced pressure and saturated NaHCO3 solution (50 mL) was added
to the
residue_ Extraction was carried out using Et0Ac (3 x 30 mL); the combined
organic extracts
were washed with water (30 mL), brine (30 mL), dried over anhydrous Na2SO4,
filtered and
evaporated under reduced pressure to afford 1-2 (0.7 g). LCMS (ES) rn/z; 213.2
[M+11] . 1H
NMR (400 MHz, DMSO-d6) 6 9.07 (s, 1H); 8.66 (s, 1H); 7.44 (dd, Ji = 1.6 Hz, J2
= 7.6 Hz,
1H); 6.99 (t, J= 7.6 Hz, 1H); 6.83 (dd, Ji = 1.2 Hz, J2 = 7.6 Hz, 1H); 5.07
(s, 2H); 4.17 (s, 2H);
2.39 (s, 3H).
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Example 3: Preparation of 6-m ethyl-5,6-dihydropyrazino[2,3-c[quinolin-7-amine
(I-3):
>%0 F
NO2
0-6 110
Pc1(0Ac)2, SPhos
DIPEA : T 2 h, rt Boc Na 0 H C

-rt,
THF
C,l, 2 T h ElF
(Boc)20 Me 70 C, 16 h
H
CI N
HCI salt Step-1 CI N Step-2 ClN Step-3
I-3a I-3b 1-3c
Raney Ni
TFA, N DCM N
02N y
I 0 C to rt 16 h 021'.1 Me0H, rt, 1 h H2N
Step-4 I Step-5
I-3d I-3e 1-3
[00290] Step-1: tert-butyl ((3-chloropyrazin-2-ylimethyl)carbamate (I-3b): To
a stirred
solution of 1-3a (6.00 g, 33.3 mmol) in THF (100.0 mL) were added DLPEA (11.4
mL, 66.7
mmol) and (Boc)20 (7.61 mL, 33.3 mmol) at 0 'C. The reaction mixture was then
stirred at
room temperature for 2 h. After completion, water (50 mL) was added to it and
and extracted
with Et0Ac (2 x 60 mL). The combined organic extracts were washed with brine
(50 mL), dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
resulting crude
was purified by Combi-Flasli (using gradient elution 0-20% Et0Ac in Heptane)
to afford desired
compound tert-butyl ((3-chloropyrazin-2-yl)methyl)carbamate I-3b (7.0 g) as an
off-white solid.
LCMS (ES) m/z; 244.1 [M+Hr.
[00291] Step-2: tert-butyl ((3-chloropyrazin-2-yl)methyl)(methyl)carbamate (I-
3c): To a
stirred solution of I-3b (9.50 g, 39.0 mmol) in TI-fF (100.0 mL) was added
sodium hydride (60%
in mineral oil) (2.34 g, 58.5 mmol) at 0 C and stirred for 1 h at the same
temperature. To this
was then added iodomethane (7.28 mL, 117 mmol) at 0 C. It was then slowly
allowed to warm
to room temperature over 1 h. After complete consumption of starting material,
water (50.0 mL)
was added to it and extracted with Et0Ac (3 x 70 mL). The combined organic
extracts were
washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and
concentrated under
vacuum. The resulting crude was purified by Combi-Flash (using gradient
elution 0-20% Et0Ac
in Heptane) to afford desired compound tert-butyl ((3-chloropyrazin-2-
yl)methyl)(methyl)carbamate I-3c (7.0 g) as a yellow liquid. LCMS (ES) nviz;
258.1 [M-41]'.
[00292] Step-3: tert-butyl ((3-(2-fluoro-3-nitrophenyl)pyrazin-2-
yl)methyl)(methyl)carbamate (I-3d): Argon gas was purged through a stirred
suspension of I-
3c (2.5 g, 9.7 mmol), 2-(2-fluoro-3-nitropheny1)-4,4,5,5-tetramethy1-1,3,2-
dioxaborolane (3.89
g, 14.6 mmol) and KF (1.69 g, 29.1 mmol) in THE' (30.0 mL) for 15 min. To this
was then added
Pd(OAc)2 (0.109 g, 0.485 mmol) and dicyclohexyl({2',6'-dimethoxy-[1, 1'-
bipheny11-2-
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ylpphosphane (0.398 g, 0.97mm01). The reaction mixture was then stirred at 70
'V for 16 h in a
sealed tube. It was then cooled to room temperature, filtered through celite
bed and washed with
Et0Ac (50 mL x 2). The combined filtrate was concentrated under reduced
pressure and the
residue was purified by Combi-Flash (using gradient elution of 0-30% Et0Ac in
hexane) to
afford tert-butyl ((3-(2-fluoro-3-nitrophenyl)pyrazin-2-
yl)methyl)(methyl)carbamate I-3d (3.3 g)
as a yellow solid. LCMS (ES) rn/z; 363.2 [M+H]t
[00293] Step-4: 6-methyl-7-nitro-5,6-dihydropyrazino[2,3-c[quinoline (I-3e):
To a stirred
solution of 1-3d (3.8 g, 10.5 mmol) in DCM (60.0 mL) was added TFA (20.0 mL)
at 0 'V under
nitrogen atmosphere and the reaction mixture was allowed to warm to room
temperature over 16
h. After completion, volatiles were removed under reduced pressure and
saturated NaHCO3
solution (50 mL) was added to the residue. Extraction was carried out using
Et0Ac (2 x 50 mL);
the combined organic extracts were washed with water (20 mL), brine (10 mL),
dried over
anhydrous Na7SO4, filtered and evaporated under reduced pressure to afford 6-
methy1-7-nitro-
5,6-dihydropyrazino[2,3-c]quinoline I-3e (2.2 g) as an orange solid. LCMS (ES)
in/z; 243.1
[M+H]+.
[00294] Step-5: 6-methyl-5,6-dihydropyrazino[2,3-e[quinolin-7-amine (1-3): To
a stirred
solution of Raney Ni (500 mg, 8.52 mmol) in Me0H (30.0 mL) was added hydrazine
hydrate
(5.27 mIõ 108.0 mmol) and 1-3e (2.10 g, 8.67 mmol) in Me0H (30.0 niI,) at 0
C. The reaction
mixture was then stirred at room temperature. After completion (as indicated
by LCMS), it was
filtered through celite bed and washed with 20% Me0H in DCM (30 mL x 2). The
combined
filtrate was concentrated under pressure and the residue was purified by Combi-
Flash (using
gradient elution of 0-55% Et0Ac in hexane) to afford desired compound 6-methy1-
5,6-
dihydropyrazino[2,3-c]quinolin-7-amine 1-3 (1_80 g) as a yellow solid. LCMS
(ES) nilz; 213.1
[M+H]'. 1H NMR (400 MHz, DMSO-d6) 6 8.57 (d, J = 2.8 Hz, 1H); 8.51 (d, J = 2.4
Hz, 1H);
7.42(dd,J1= 1.2 Hz, J2 = 7.6 Hz, 1H); 7.01 (t, J = 8.0 Hz, 1H); 6.81 (dd, =
1.2 Hz, J2 = 8.0
Hz, 1H); 5.08 (s, 2H); 4.24 (s, 2H); 2.46 (s, 3H).
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Example 4: Preparation of 6-(methyl-d3)-5,6-dihydropyrazino12,3-clquinolin-7-
amine (I-
4):
4-9 F
B NO2
0- 40
Boc,N,CD3
Pd(OAc)2, SPhos
N NaH, CD3I, THF N CI KF, THF
Boc,
0 C-rt 2 h CD 3 70 C, 16 h
I C)2N
N
CI Step-1 N" N-Boc Step-2
I-3b I-4a I-4b
Raney Ni
TFA, DCM D3C 'N N-) NH2NH2.H20
D3C,N
0 C-rt, 16 h 02N IV1e0H, nt, 1 h. H2N
N
Step-3 Step-4
I-4c 1-4
[00295] Step-1: tert-butyl ((3-chloropyrazin-2-ylUnethyl)(methyl-d3)carbamate
(I-4a): I-
4a (2.5 g) was synthesized by following procedure as described for the
synthesis of 1-3 (step-2)
using I-3b (3.0 g, 12.3 mmol) and iodomethane-d3 (1.15 mL, 18.5 mmol) as the
starting
materials. LCMS (ES)n/; 261.1 [M+H]t
1002961 Step-2: tert-butyl ((3-(2-fluoro-3-nitrophenyl)pyrazin-2-
yl)methyl)(methyl-
d3)carbamate (I-4b): I-4b (2.9 g) was synthesized by following procedure as
described for the
synthesis of 1-3 (step-3) using I-4a (2.5 g, 9.59 mmol) and 2-(2-fluoro-3-
nitropheny1)-4,4,5,5-
tetramethy1-1,3,2-dioxaborolane (3.84 g, 14.4 mmol) as the starting materials.
LCMS (ES) m/z;
366.1 [M+H]t.
[00297] Step-3: 6-(methyl-d3)-7-nitro-5,6-dihydropyrazino[2,3-c[quinoline (I-
4c): I-4c (1.8
g) was synthesized by following procedure as described for the synthesis of I-
3 (step-4) using I-
4b (2.9 g, 7.94 mmol) as the starting material. LCMS (ES) m/z; 246.1 [M-41]".
[00298] Step-4: 6-(methyl-d3)-5,6-dihydropyrazino[2,3-e[quinolin-7-amine (I-
4): 1-4 (1.6
g) was synthesized by following procedure as described for the synthesis of I-
3 (step-5) using I-
4c (1.9 g, 7.75 mmol) as the starting material. LCMS (ES) m/z; 216.0 [M+Hr. 1H
NMR (400
MHz, DMS046) c5 8.57 (d, J= 2.4 Hz, 1H), 8.51 (d, J= 2.8 Hz, 1H); 7.42 (dd, Ji
= 1.6 Hz, J2 =
7.6 Hz, 11-1); 7.01 (t, J= 8.0 Hz, 1H); 6.82 (dd, Ji = 1.2 Hz, J2 = 8.0 Hz,
1H); 5.07 (s, 2H); 4.24
(s, 2H).
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Example 5: 6-methyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7-amine (I-5):
CI F CI
Nbi _B7 F
N I i) 4 M HCI in 1,4-dioxane
OH N-71
N 0 C-rt, 4 h
Pd2(db03, [(t-Bu)3PHIE/F4 ii) DIPEA, 1,4-
dioxane
Boc,N CsF, THF, 50 C, 16 h 85 C, 5
h
,õ.
CI N Step-1 N Boc Step-2
CI
N
1-3c I-5a
I-5b
cyclopropanecarboxamide
Pd2(dba)3, Xentphos, Cs2CO3 N eq. Li0H.H20, THF
1,4-dioxane, 130 C, 16 h
50 C, 16 h
_________________________________ -
Step-3 HN N Step-4
H2N
\y-Co
I-5c 1-5
[00299] Step-1: tert-butyl ((3-(2-chloro-3-fluoropyridin-4-yl)pyrazin-2-
yOmethyl)(methypcarbamate (I-5a): Argon gas was purged through a solution of I-
3c (5.3 g,
20.6 mmol), (2-chloro-3-fluoropyridin-4-yl)boronic acid (12.6 g, 72.0 mmol)
and CsF (9.37 g,
61.7 mmol) in THF (50.0 mL) for 15 min. To this was then added tri-tert-
butylphosphonium
tetrafluoroborate (0.36 g, 1.23 mmol) and tris(1,5-diphenylpenta-1,4-dien-3-
one) dipalladium
(0.94 g, 1.03 mmol). The reaction mixture was then stirred at 50 C for 16 h
in a sealed tube
After completion, the reaction mixture was filtered through celite bed and
washed with Et0Ac
(50 mL x 2). The combined filtrate was concentrated under reduced pressure and
the residue was
purified by Combi -Flash (using gradient elution of 0-30% Et0Ac in hexane) to
afford tert-butyl
((3-(2-chloro-3-fluoropyridin-4-yl)pyrazin-2-yOmethyl)(methyl)carbamate I-5a
(3.8 g) as a
yellow oil. LCMS (ES) m/z; 353.1 [M-PH]t
[00300] Step-2: 7-chloro-6-methyl-5,6-dihydropyrazino12,3-c]11,71naphthyridine
(I-5b): A
4M solution of HC1 in 1,4-dioxane (80 mL) was added to I-5a (4.1 g, 11.6 mmol)
at 0 C and
the reaction mixture was stirred at room temperature for 16 h. After
completion, volatiles were
removed under reduced pressure and dried (co-evaporation with 1,4-dioxane). To
this was then
added 1,4-dioxane (40 mL) and DIPEA (13.6 mL, 79.2 mmol) at room temperature.
The
reaction mixture was then stirred at 85 C for 5 h. After completion,
volatiles were removed
under reduced pressure and residue was purified by Combi-Flash (using gradient
elution of 0-
55% Et0Ac in hexane) to afford desired compound 7-chloro-6-methy1-5,6-
dihydropyrazino[2,3-
c][1,7]naphthyridine I-5b (2.4 g) as a yellow solid. LCMS (ES) m/z; 233.1 [M-
h1-1]' .
[00301] Step-3: N-(6-methy1-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7-
y1)cyclopropanecarboxamide (I-5c): Argon gas was purged through a stirred
suspension of I-
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5b (2.3 g, 9.89 mmol), cyclopropanecarboxamide (1.68 g, 19.8 mmol) and Cs2CO3
(9.66 g, 29.7
mmol) in 1,4-dioxane (30 mL) for 15 min. To this was then added [5-
(diphenylphosphany1)-9,9-
dimethy1-911-xanthen-4-yl]diphenylphosphane (0.57 g, 0.989 mmol) and Pd2(dba)3
(0.9 g, 0.989
mmol). The reaction mixture was then stirred at 130 C for 16 h in a sealed
tube. It was then
cooled to room temperature, filtered through celite bed and washed with Et0Ac
(50 mL x 2).
The filtrate was concentrated under reduced pressure and the residue was
purified by Combi-
Flash (using gradient elution of 0-80% Et0Ac in hexane) to afford N-(6-methy1-
5,6-
dihydropyrazino[2,3-c][1,7]naphthyridin-7-y1)cyclopropanecarboxamide 1-5c (1.8
g) as a pale
yellow solid. LCMS (ES) m/z; 282.1 [M+H].
[00302] Step-4: 6-methy1-5,6-dihydropyrazino12,3-c][1,71naphthyridin-7-amine
(1-5): To a
stirred solution of I-5c (1.8 g, 6.4 mmol) in THF (20 mL) was added an aqueous
solution of
Li0H-H20 (1.07 g, 25.6 mmol, ins mL water) and the reaction mixture was
stirred at 50 C for
16 h. After completion, it was cooled to room temperature and water (20 mL)
was added to it.
Extraction was carried out using 10% Me0H in DCM (50 mL x 2); the combined
organic
extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered
and evaporated
under reduced pressure. The residue was purified by Combi-Flash (using
gradient elution of 0-
10% Me0H in DCM) to afford desired compound 6-methy1-5,6-dihydropyrazino[2,3-
c][1,7]riaphthyridin-7-ami ne I-5 (0.8 g) as a yellow solid. T,CMS (ES) 111/7;
214.1 [M+Hr.
NMR (400 MHz, CDC13) 6 8.59 (d, J= 2.4 Hz, 1H); 8.54 (d, J= 2.4 Hz, 1H); 8.03
(d, J= 5.2
Hz, 1H); 7.59 (d, J= 5.2 Hz, 1H); 4.93 (s, 2H); 4.36 (s, 2H); 2.65 (s, 3H).
Example 6: Preparation of 6-methyl-5,6-dihydropyrido [3,4-h] [1,6]naphthyridin-
7-amine
(1-6):
CI F
Nn_ BoH
Boc i) 4 M HCI in 1,4-dioxane
ral
Pd2(dba)3, [(t-Bu)3PHpF4 ii) DIPEA, 1,4-
dioxane
Boc,Nrr CsF, THF, 50 C, 16 h 85 C, 5 h
I
C, N Step-1 CI N Step-2
CINI-6a 1-6 b
cyclopropanecarboxamide
N NI
Pd2(dba)3, Xantphos, Cs2CO3
1,4-dioxane, 130 C, 16 h N aq. LIOH.H20, THF
60 C, 16 h
Step-3 HN N Step-4
H2N N
,KyLO
I-6c 1-6
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[00303] Step-1: tert-butyl ((2'-chloro-3'-fluoro-12,4'-bipyridin1-3-
yOmethyl)(methypcarbamate (1-6a): 1-6a (5.9 g) was synthesized by following
procedure as
described for the synthesis of 1-5 (step-1) using 1-1c (6.0 g, 19.9 mmol) and
(2-chloro-3-
fluoropyridin-4-yl)boronic acid (8.73 g, 49.8 mmol) as the starting materials.
LCMS (ES) m/z;
352.1 [M+H]t.
[00304] Step-2: 7-chloro-6-methyl-5,6-dihydropyrido[3,4-h][1,61naphthyridine
(I-6b): I-6b
(4.1 g) was synthesized by following procedure as described for the synthesis
of 1-5 (step-2)
using I-6a (6.0 g, 20.8 mmol) as the starting material. LCMS (ES) m/z; 232.0
[M+Hr.
[00305] Step-3: N-(6-methyl-5,6-dihydropyrido[3,4-h][1,6[naphthyridin-7-
y1)cyclopropanecarboxamide (I-6c): I-6c (1.3 g) was synthesized by following
procedure as
described for the synthesis of 1-5 (step-3) using 1-6b (4.0 g, 7.18 mmol) and
cyclopropanecarboxamide (1.22 g, 14.4 mmol) as the starting materials. LCMS
(ES) m/z; 281.0
[M+H]
[00306] Step-4: 6-methyl-5,6-dihydropyrido13,4-h]11,61naphthyridin-7-amine (I-
6): 1-6
(0.45 g) was synthesized by following procedure as described for the synthesis
of 1-5 (step-4)
using I-6c (1.3 g, 4.64 mmol) as the starting material. LCMS (ES) m/z; 213.1
[M-hEl]t 1H NMR
(400 MHz, CDC13) 6 11-1N-MR (400 MHz, CDC13) 6 8.67 (dd, II= 1.6 Hz, J2 = 8.0
Hz, 1H); 8.03
(d, J= 5.2 Hz, 1H); 7 60-7.49 (m, 2H); 7.37-7.26 (m, 1H); 4.89 (s, 2H); 4.20
(s, 2H); 2 56 (s,
3H).
Example 7: Preparation of 6-methyl-5,6-dihydrobenzo[h]11,61naphthyridin-5,5-d2-
7-amine
(I-7):
MeNH2, Me0H
rt' D D
16 h
aq. NaHCO3
HATU, DIPEA 0 0
THF NaBD4, Me0H
(Boc)20
DMF, rt N.O., -78 C-0 C, 1 h D 0 C-
rt, 2 h (e. THF, 16 h, rt
I I I
N CI
Step-1 N CI Step-2 Step-3 Nr- CI
Step-4
N CI
I-7a I-7b I-7c I-7d
F
0.13 co NO,
D Pd(OAc)2, SPhos I D I D I
D
Boc KF, THF Boe,N N TFA, DCM D N Pd/C, H2 D
N
D
70 C, 16 h 0 C-it, 16 11,. DMeOH' rt'
2
N CI Step-6 Step-6 Step-7
NO2 02N 1-12N
I-7e I-7f I-7g 1-7
[00307] Step-1: 2-chloro-N-methoxy-N-methylnicotinamide (I-7b): To a stirred
solution of
I-7a (4.5 g, 28.6 mmol) in DMIT (40 mL) were added DIPEA (14.6 mL, 85.7 mmol)
and IIATU
(21.7 g, 57.1 mmol) at 0 C. To this was then added N,0-dimethylhydroxylamine
hydrochloride
(5.57 g, 57.1 mmol) and the reaction mixture was allowed to stir at room
temperature for 2 h.
After complete consumption of starting material, water (30 mL) was added and
extracted with
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Et0Ac (75 x 3 mL). The combined organic extracts were washed with brine (50 mL
x 2), dried
over Na2SO4, filtered and concentrated under reduced pressure. The residue was
purified by
Combi-Flash (using gradient elution of (0-50% Et0Ac in Heptane) to afford 2-
chloro-N-
methoxy-N-methylnicotinamide I-7b (3.5 g) as an off-white solid. LCMS (ES)
in/z; 201.1
[M+1-1] .
[00308] Step-2: 2-chloronicotinaldehyde-d (1-7c): To a stirred solution of I-
7b (3.2 g, 16.0
mmol) in anhydrous THE (15.0 mL) was added LiAlD4 (0.65 g, 16.0 mmol) portion-
wise at -78
'C. It was then stirred at 0 'V for 1 h. After completion, saturated NH4CI
solution (20 mL) was
added to it and extraction was carried out using Et0Ac (50 mL x 3). The
combined organic
extracts were washed with brine (50 mL x 2), dried over Na2SO4, filtered and
concentrated
under reduced pressure. The residue was purified by Combi-Flash (using
gradient elution of 0-
25% Et0Ac in Heptane) to afford 2-chloronicotinaldehyde-d I-7c (6 g) as an-off
white solid.
LCMS (ES) nilz; 143.1 [M+H].
[00309] Step-3: 1-(2-chloropyridin-3-y1)-N-methylmethan-d2-amine (I-7d): To a
stirred
solution of I-7c (1.1 g, 7.72 mmol) in Me0H (15.0 mL) were added TEA (2.3 mL,
15.4 mmol)
and methyl amine hydrochloride (1.04 g, 15.4 mmol) at 0 C . The reaction
mixture was stirred
for 16 h at room temperature. After completion, it was cooled to 0 C and
NaBD4 (0.65 g, 15.4
mmol) was added to it portion-wise. The reaction mixture was stirred at room
temperature for 2
h. After completion, saturated NaHCO3 solution (10 mL) was added to it and
washed with
Et0Ac (10 mL x 2). The resulting aqueous NaHCO3 solution containing 1-(2-
chloropyridin-3-
y1)-N-methylmethan-d2-amine I-7d was used for the next step. LCMS (ES) m/z;
159.1 [M-h1-1]'.
[00310] Step-4: tert-butyl ((2-chloropyridin-3-yl)methyl-d2)(methyl)carbamate
(I-7e): A
solution of (Boc),70 (9.0 mL, 39.4 mmol) in THF (20 mL) was added to an
aqueous NaHCO3
solution containing I-7d and the reaction mixture was stirred at room
temperature for 16 h. After
completion, water (50 mL) was added to it and extraction was carried out using
Et0Ac (30 mL x
3). The combined organic extracts were washed with brine (50 mL), dried over
anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The residue was
purified by Combi-
Flash (using gradient elution of 0-10% Et0Ac in hexane) to afford desired
compound tert-butyl
((2-chloropyridin-3-yl)methyl-d2)(methyl)carbamate I-7e (1.2 g) as a colorless
thick oil. LCMS
(ES) in/; 259. [m-q-i].
[00311] Step-5: tert-butyl ((2-(2-fluoro-3-nitrophenyl)pyridin-3-yl)m ethyl-
d2)(methyl)carbamate (I-71): I-7f (1.3 g) was synthesized by following
procedure as described
for the synthesis of 1-3 (step-3) using I-7e (1.0 g, 3.86 mmol) and 2-(2-
fluoro-3-nitropheny1)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.55 g, 5.8 mmol) as the starting
materials. LCMS (ES)
m/z; 364.1 [MA-1r
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[00312] Step-6: 6-methyl-7-nitro-5,6-dihydrobenzo[h]11,61naphthyridine-5,5-d2
(I-7g): I-
7g (0.75 g) was synthesized by following procedure as described for the
synthesis of I-3 (step-4)
using I-7e (1.4 g, 3.86 mmol) as the starting material. LCMS (ES) m/z; 244.1
[M+H]P.
[00313] Step-7: 6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-5,5-d2-7-amine
(I-7): To a
stirred solution of I-7g (0.75 g, 3.08 mmol) in Me0H (20.0 mL) was added 10%
Pd/C (250 mg)
at room temperature. It was then allowed to stir under hydrogen atmosphere (H2
balloon) for 2 h.
After completion, the catalyst was filtered off through celite bed and washed
with Me0H (20
mL x 2). The combined filtrate was concentrated under reduced pressure and the
residue was
purified by Combi -Flash (using gradient elution of 0-55% Et0Ac in hexane) to
afford 6-methyl-
5,6-dihydrobenzo[h][1,6]naphthyridin-5,5-d2-7-amine 1-7 (0.54) as a yellow
solid. LCMS (ES)
m/z; 214.0 [M-HEIr 11-1 NMR (400 MHz, DMSO-d6) 6 8.61 (dd,.// = 1.6 Hz, J2 =
4.8 Hz, 1H);
7.75 (dd, .// = 1.2 Hz, J2 = 7.6 Hz, 1H),7.53 (dd,
= 1.2 Hz, J2 = 7.6 Hz, 1H); 7.21 (dd, = 4.8
Hz, .12 = 7.2 Hz, 1H); 7.11 (t, = 7.6 Hz, 1H); 6.82 (dd, = 1.2 Hz, .12 = 7.6
Hz, 1H); 4.17 (s,
2H); 2.53 (s, 3H).
Example 8: Preparation of 3-fluoro-6-methyl-5,6-
dihydrobenzo[h1[1,6]naphthyridin-5,5-
d2-7-amine (1-8):
N i) MeN H2,
Me0H
rt, 16 h
0 0 D D
HATU, D1PEA I 0 THF ii)NaBD,s,
Me0H F
I'`=-=
DMF, rt F -78 C-0 C, 1 h I D
Step-1 Step-2 Step-3
N CI N CI N CI N CI
I-8a I-8b
.>% F
No2
eq. NaHCO3 Pd(OAc)2, SPhos 1 ,
D
D I
(Boc)20 F D ,Boc KF, THF ,IN N TFA, DCM D
N Pd/C, H2 D N
THF, 16 h, rt N 70 C, 16 h
Boc Me0H rt 2 h
Step-4 CI Step-5 Step-6 Step-7
NO2 02N
H2N
I-8f I-8g
1-8
[00314] Step-1: 2-chloro-5-fluoro-N-methoxy-N-methylnicotinamide (I-8b): I-8b
(2.6 g)
was synthesized by following procedure as described for the synthesis of 1-7
(step-1) using I-8a
(2.5 g, 14.2 mmol) as the starting material. LCMS (ES) m/z; 219.1 [M+H].
1003151 Step-2: 2-chloro-5-fluoronicotinaldehyde-d (I-8c): I-8c (1.5 g) was
synthesized by
following procedure as described for the synthesis of 1-7 (step-2) using I-8b
(2.5 g, 11.4 mmol)
as the starting material. LCMS (ES) m/z; 161.0 [M+H]
[00316] Step-3-4: tert-butyl ((2-chloro-5-fluoropyridin-3-yflmethyl-
d2)(methyl)carbamate
(I-8e): I-8e (1.3 g) was synthesized by following procedure as described for
the synthesis of 1-7
(step-3-4) using 1-8c (2.0 g, 12.5 mmol) as the starting material. LCMS (ES)
m/z; 277.1 [M+H].
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[00317] Step-5: tert-butyl ((5-fluoro-2-(2-11uoro-3-nitrophenyl)pyridin-3-
yl)methyl-
d2)(methyl)carbamate (I-81): I-8f (1.0 g) was synthesized by following
procedure as described
for the synthesis of 1-3 (step-3) using I-8e (0.9 g, 3.25 mmol) and 2-(2-
fluoro-3-nitropheny1)-
4,4,5,5-tetramethy1-1,3,2-dioxaborolane (1.3 g, 4.88 mmol) as the starting
materials. LCMS (ES)
m/z; 382.1 [M+Hr.
[00318] Step-6: 3-fluoro-6-methy1-7-nitro-5,6-
dihydrobenzo[h][1,6]naphthyridine-5,5-d2
(I-8g): I-8g (0.75 g) was synthesized by following procedure as described for
the synthesis of I-
3 (step-4) using 1-8f(1.3 g, 3.41 mmol) as the starting material. LCMS (ES)
m/z; 262.1 [M+1-1] .
[00319] Step-7: 3-fluoro-6-methy1-5,6-dihydrobenzo[h]11,61naphthyridin-5,5-d2-
7-amine
(I-8): 1-8 (0.8 g) was synthesized by following procedure as described for the
synthesis of 1-7
(step-7) using I-8g (1.1 g, 4.21 mmol) as the starting material. LCMS (ES)
m/z; 232.2 [M-hEl]+.
Example 9: Preparation of 2,6-dimethy1-5,6-dihydrobenzo[h][1,6[naphthyridin-
5,5-d2-7-
amine (I-9):
i) MeNH2, Me0H
H rt, 16 h
D D
, ,..... oti HATU, DIPEA
I
.......C1ILCI N CI LiAID4, THF a) NaBD4,
Me0H
-78 C-0 C, 1 h -...õ D 0 C-
rt, 2 h . 1 ----,
N-
Step-1 ' I I
I
Step-2 ,..---..N-..-----õCI
Step-3 N CI N
I-9a I-9b I-9c I-9d
4-9 F
B
cy.13õNo2
aq. NaHCO3
(Boc)20 D D Pd(OAc)2, SPhos I .---' I /
D I
/
D
I
THF, 16 h, rt,,,,c 70 6, 16 h 016 h Me0H, rt, 2 h.
N_Boc
* I , I
KF, THF Boc,N ---, N TFA, DCM D
___________________________________________________________ - -- D
Step-4 N CI Step-5 Step-6 Step-7
NO2 02N
H2N
I-9e 1-9f 1-9g
1-9
[00320] Step-1: 2-chloro-N-methoxy-N,6-dimethylnicotinamide (I-9b): I-9b (2.6
g) was
synthesized by following procedure as described for the synthesis of I-7 (step-
1) using I-9a (2.5
g, 14.2 mmol) as the starting material. LCMS (ES) in/z; 215.1 [M-F1-11+.
[00321] Step-2: 2-chloro-6-methylnicotinaldehyde-d (I-9c): I-9c (5.8 g) was
synthesized by
following procedure as described for the synthesis of 1-7 (step-2) using I-9b
(5.0 g, 29.1 mmol)
as the starting material. LCMS (ES) ni/z; 157.0 [M+H] .
[00322] Step-3-4: tert-butyl ((2-chloro-6-methylpyridin-3-yl)methyl-
d2)(methyl)carbamate (I-9e): I-9e (3.3 g) was synthesized by following
procedure as
described for the synthesis of 1-7 (step-3-4) using 1-9c (2.3 g, 14.7 mmol) as
the starting
material. LCMS (ES) m/z; 273.1 [M+H]t
[00323] Step-5: tert-butyl 42-(2-fluoro-3-nitropheny1)-6-methylpyridin-3-
yl)methyl-
d2)(methyl)carbamate (I-91): I-9f (2.8 g) was synthesized by following
procedure as described
for the synthesis of 1-3 (step-3) using I-9e (3.5 g, 12.8 mmol) and 2-(2-
fluoro-3-nitrophenyI)-
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4,4,5,5-tetramethy1-1,3,2-dioxaborolane (5.14 g, 19.2 mmol) as the starting
materials. LCMS
(ES) m/z; 378.2 [M+H]h.
[00324] Step-6: 2,6-dimethy1-7-nitro-5,6-dihydrobenzo[h]11,61naphthyridine-5,5-
d2 (1-9g):
I-9g (1.5 g) was synthesized by following procedure as described for the
synthesis of 1-3 (step-
4) using I-9f (2.8 g, 7.42 mmol) as the starting material. LCMS (ES) m/z;
258.1 [M+Hr.
[00325] Step-7: 2,6-dimethy1-5,6-dihydrobenzo[h][1,6]naphthyridin-5,5-d2-7-
amine (I-9):
1-9 (0.49 g) was synthesized by following procedure as described for the
synthesis of 1-7 (step-
7) using I-9g (0.6 g, 2.33 mmol) as the starting material. LCMS (ES) ni/z;
228.2 I_M+H_I . 1H
NMR (400 MHz, DMSO-d6) 6 7.54 (d, J= 7.6 Hz, 1H); 7.42 (dd, Ji = 1.2 Hz, J2 =
8.0 Hz, 1H);
7.12 (d, J = 8.0 Hz, 1H); 6.91 (t, J = 7.6 Hz, 1H); 6.99 (dd, Ji = 1.6 Hz, J2
= 7.6 Hz, 1H); 4.91
(s, 2H); 2.45 (s, 3H); 2.35 (s, 3H).
Example 10: Preparation of 6-methyl-2-(trifluoromethyl)-5,6-
dihydrobenzo[h]111,61naphthyridin-5,5-d2-7-amine (I-10):
I) MeNh12, Me0H
HATU, DIPEA 0 rt, 16 h
LiA1134, THF 0 NaBD4,MeOH D D
OH
DMF, rt N...0-, -78 C-0 C, 1 h D o C 2 h
=-===
CX.11.-
I I I I
H
Step-1 Step-2 Step-3
F3C N CI F3C N CI F3C N CI F30 NI' CI
I-10a I-10b I-10c
I-10d
NO2OF
CF3 CF3
CF3
eq. NaHCO3 Pd(OAc)2, SPhos D I D I
(Boc)20
THF, 1h, KF, THF goo,. N
oTrC-,ArtDCM16h, D N m e0H pd/c ,rt" i-122 h D N
6 rt N C N
I I
step-4 F3C Nr CI 70 '16 h . D D F
Step-5 Step-6 Step-7
NO2 0214
H2N
I-10e I-10f I-10g
1-10
[00326] Step-1: 2-chloro-N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (I-
10b): I-
10b (5.7 g) was synthesized by following procedure as described for the
synthesis of 1-7 (step-1)
using I-10a (5.0g. 22.2 mmol) as the starting material. LCMS (ES) nilz; 269.1
[M+Hr.
[00327] Step-2: 2-chloro-6-(trifluoromethyl)nieotinaldehyde-d (I-10e): I-1 0e
(3.2 g) was
synthesized by following procedure as described for the synthesis of I-7 (step-
2) using I-10b
(5.7 g, 21.2 mmol) as the starting material. LCMS (ES) m/z; 211.0 [M+11]'.
[00328] Step-3-4: tert-butyl 42-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl-
d2)(methyl)carbamate (I-10e): I-10e (2.2 g) was synthesized by following
procedure as
described for the synthesis of 1-7 (step-3-4) using I-10c (3.2 g, 15.2 mmol)
as the starting
material. LCMS (ES) m/z; 327.1 [M+Hr.
[00329] Step-5: tert-butyl 42-(2-fluoro-3-nitropheny1)-6-
(trifluoromethyl)pyridin-3-
y1)methyl-d2)(methyl)carbamate (I-10f): I-10f (2.6 g) was synthesized by
following
procedure as described for the synthesis of 1-3 (step-3) using I-10e (2.2 g,
6.73 mmol) and 2-(2-
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fluoro-3-nitropheny1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (2.7 g, 10.1
mmol) as the starting
materials. LCMS (ES) m/z; 432.2 [M+Hr.
[00330] Step-6: 6-methyl-7-nitro-2-(trifluoromethyl)-5,6-
dihydrobenzo[h][1,61naphthyridine-5,5-d2 (I-10g): I-10g (1.48) was synthesized
by
following procedure as described for the synthesis of 1-3 (step-4) using 1-10f
(2.6 g, 6.03 mmol)
as the starting material. LCMS (ES) m/z; 312.1 [M+H].
[00331] Step-7: 6-methyl-2-(trifluoromethyl)-5,6-
dihydrobenzo[h]11,61naphthyridin-5,5-
d2-7-amine (1-10): 1-10 (1.2 g) was synthesized by following procedure as
described for the
synthesis of 1-7 (step-7) using I-10g (1.4 g, 4.63 mmol) as the starting
material. LCMS (ES) m/z;
282.1 [M+H]t. NMR (400 MHz, DMSO-do) 6 7.99 (d, J= 7.6 Hz, 1H); 7.79 (d, J=
7.6 Hz,
1H); 7.45 (dd, Jj = 1.6 Hz, J2 = 8.0 Hz, 1H); 7.00 (t, J= 7.6 Hz, 1H); 6.81
(dd, Ji = 1.2 Hz, J2 =
8.0 Hz, 111), 5.04 (s, 2H), 2.37 (s, 3H).
Example 11: Preparation of 7-amino-2,6-dimethyl-5,6-dihydropyridazino14,5-
elquinolin-
1(2H)-one (I-11):
(E)-styrylboronic acid
K2CO3, Pd(PPh3)2Cl2
T01-IsF0:H4,2N0a(12 :41.) CI .-
0 Nal, DMF 0 1,4-diexanemater
(2:1) .. 0
N., 160 C, 36 h CI 90 "C, 2h rt, 16 h Ii
I I N N
Step-1 I 7
Ph o I Step-2 Step-3
I-11a 1-lib I-11e
1-11d
0 F
>%
CT 4,o' hl(3
i) MeN H2, Me0H Bee,
rt, 16 h o aq. NaHCO3
0 Pd(OAc)2, SPhos
ii) NaBH4, Me0H (Boc)20 II KF,
TI-IF F YN
0 C-rt, 2 h CI
re. THF, 16 h, rt BgThJ=-- 70 C, 16 h
02N I N
Step-4 N Step-5 Step-6 tii 0
1-11e I-11f 1-119
Hydrazine hydrate
N
TFA, DCM Thµl N
I Raney Nickel, Me0H I I
0 C-rt, 16 h... 0 C-rt. 1 h H2N
Step-7 iii0 Step-8 iLi0
I-11h 1-11
[00332] Step-1: 4-ehloro-5-iodo-2-methylpyridazin-3(211)-one (I-11b): To a
stirred solution
of 1-ha (36.0 g, 201.0 mmol) in DMF (360 mL) was added sodium iodide (90.4 g,
603.0 mmol)
at room temperature. The reaction was then stirred at 160 C for 36 h. After
completion, it was
cooled to room temperature and ice cold water (700 mL) was added to it.
Extraction was carried
out using Et0Ac (3 x 100 mL), the combined organic extracts were washed with
brine (100 mL
x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The
resulting crude was dissolved in Me0H (170.0 mL) at 65 C and then water (340
mL) was
added to it with continuous stirring. The precipitated solid was filtered,
washed with water (200
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mL) and dried. It was then stirred in n-pentane (100 mL), filtered and dried
to afford desired
compound 4-chloro-5-iodo-2-methyl-2,3-dihydropyridazin-3-one I-11 b (11.6 g)
as a pale brown
solid. LCMS (ES) m/z; 271.0 [M+H]. 1H NMR (400 M_Hz, CDC13) 67.96 (s, 1H);
3.78 (s, 3H).
[00333] Step-2: (E)-4-ehloro-2-methyl-5-styrylpyridazin-3(211)-one (I-11c): To
a stirred
solution of 1-lib (11.6 g, 35.6 mmol) in 1,4-dioxane (100.0 mL) and water
(50.0 mL) were
added (E)-styrylboronic acid (5.3 g, 35.6 mmol) and potassium carbonate (7.38
g, 534 mmol).
Argon gas was purged through it for 10 min. To this was then added
PdC1_2(PPh3)2. (1.0 g, 1.42
mmol) and the reaction was stirred at 90 'V for 2 h in a sealed tube. After
complete consumption
of starting material, it was cooled to room temperature and diluted with Et0Ac
(300 mL). The
organic layer was washed with water (80 mL), brine (100 mL x 2), dried over
anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The residue was
washed with DCM
(50 mL), n-pentane (80 mL) and dried under reduced pressure to afford (E)-4-
chloro-2-methy1-
5-styrylpyridazin-3(2H)-one I-11c (7.0 g) as a pale yellow solid. LCMS (ES) rn
/z: 247.0
[M+H]t 11-1 NMR (4001V[Elz, CDC13) 6 8.05 (s, 1H); 7.59-7.58 (m, 2H); 7.42-
7.38 (m, 3H); 7.29
(s, 2H); 3.84 (s, 3H).
[00334] Step-3: 5-chloro-l-methy1-6-oxo-1,6-dihydropyridazine-4-carbaldehyde
(1-11d):
To a stirred solution of I-11c (7.0 g, 28.4 mmol) in TIEF (70.0 mL) and water
(35.0 mL) was
added osmium tetrc-pcide (2 5 wt.% in n-butanol) (14 4 niIõ 1.42 mmol) at room
temperature and
stirred for 30 min. To this was then added NaI04 (12.1 g, 56.8 mmol) portion
wise and the
reaction was stirred for another 16 h at room temperature. After completion of
the reaction,
water (60 mL) was added to it and extraction was carried out using Et0Ae (3 x
70 mL). The
combined organic extracts were washed with brine (100 mL x 2), dried over
anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The residue was purified by
Combi-Flash
(using gradient elution of 0-2% Me0H in DCM) to afford desired compound 5-
chloro-1-methy1-
6-oxo-1,6-dihydropyridazine-4-carbaldehyde 1-11d (2.5 g) as a pale yellow
solid. 1H NAAR (400
MHz, CDC13) 6 10.43 (s, 1H); 8.08 (s, 1H); 3.90 (s, 3H).
[00335] Step-4-5: tert-butyl ((5-chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4-
yl)methyl)(methyl)carbamate (I-11f): I-11f (2.0 g) was synthesized by
following procedure as
described for the synthesis of 1-7 (step-3-4) using I-11d (4.0 g, 23.2 mmol)
as the starting
material and NaBH4 (1.71 g, 46.4 mmol) as a reducing agent. LCMS (ES)in/z;
288.0 [M-41] .
[00336] Step-6: tert-butyl ((5-(2-fluoro-3-nitropheny1)-1-methyl-6-oxo-1,6-
dihydropyridazin-4-yl)methyl)(methyl)carbamate (I-11g): 1-11g (2.3 g) was
synthesized by
following procedure as described for the synthesis of 1-3 (step-3) using I-11f
(1.5 g, 5.21 mmol)
and 2-(2-fluoro-3-nitropheny1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (2.10
g, 7.82 mmol) as
the starting materials. LCMS (ES) rn/z; 393.2 [M+Hr.
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[00337] Step-7: 2,6-dimethy1-7-nitro-5,6-dihydropyridazino[4,5-c]quinolin-
1(211)-one
11 i): I-11h (1.4 g) was synthesized by following procedure as described for
the synthesis of 1-3
(step-4) using 1-11h (2.3 g, 5.86 mmol) as the starting material. LCMS (ES)
m/z; 273.0 [M+H]t
[00338] Step-8: 7-amino-2,6-dimethy1-5,6-dihydropyridazino14,5-clquinolin-
1(2H)-one (I-
11): I-11 (0.65 g) was synthesized by following procedure as described for the
synthesis of 1-3
(step-5) using I-11h (1.3 g, 4.77 mmol) as the starting material. LCMS (ES)
m/z; 243.1 [M+H]t
'H NMR (400 MHz, CDC13) 6 8.32 (dd, ii = 1.2 Hz, J2 = 8.0 Hz, 1H); 7.68 (s,
1H); 7.09 (t, J =
8.0 Hz, 111); 6.83 (dd, ii = 1.2 Hz, d2 = 8.0 Hz, 1H); 4.06 (s, 2H); 3.97 (s,
21-1); 3.89 (s, 3H);
2.49 (s, 3H).
Example 12: 3-fluoro-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-amine (I-
12):
>t .9B gio NO
i) MeN H2, Me0H
0 rt, 16 h aq. NaHCO3 Pd(0Ac)2, THE
ii) NaBH4, MeON F (Boo)20 F
,Boc KF, SPhos
H 0 C-rt, 2 h THF, 16 h, rt 70 C,
16 h
I I I
NCI Step-1 N CI Step-2 N CI Step-3
I-12a I-12b I-12c
I I
BooõN N TFA, DCM N Pd/C, H2 N
0 C-rt, 2 h Me0H, rt, 2 h
Step-4 Step-5 N
02N 02N H2N
I-12d I-12e 1-12
[00339] Step-1-2: tert-butyl ((2-chloro-5-fluoropyridin-3-
yl)methyl)(methyl)carbamate (I-
12c): I-12c (3.5 g) was synthesized by following procedure as described for
the synthesis of 1-7
(step-3-4) using I-12a (4.5 g, 28.2 mmol) as the starting material. LCMS (ES)
m/z; 275.1
[M+1-1] .
[00340] Step-3: tert-butyl ((5-fluoro-2-(2-11uoro-3-nitrophenyl)pyridin-3-
yl)methyl)(methyl)carbamate (1-12d): 1-12d (1.6 g) was synthesized by
following procedure
as described for the synthesis of 1-3 (step-3) using I-12c (3.5 g, 12.7 mmol)
and 2-(2-fluoro-3-
nitropheny1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (4.42 g, 16.6 mmol) as
the starting
materials. LCMS (ES) m/z; 380.1 [M+1-1]+.
[00341] Step-4: 3-fluoro-6-methy1-7-nitro-5,6-
dihydrobenzo111111,61naphthyridine (I-12e):
I-12e (0.6 g) was synthesized by following procedure as described for the
synthesis of 1-3 (step-
4) using 1-12d (1.6 g, 4.22 mmol) as the starting material. LCMS (ES) m/z;
260.1 [M+H]t
[00342] Step-5: 3-fluoro-6-methy1-5,6-dihydrobenzo[h]11,61naphthyridin-7-amine
(I-12):
1-12 (0.3 g) was synthesized by following procedure as described for the
synthesis of 1-7 (step-
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7) using I-112e (0.6 g, 2.31 mmol) as the starting material. LCMS (ES) in/z;
230.2 [M+H]t. 111
NMR (400 MHz, DMSO-d6) 6 8.48 (dõI = 2.4 Hz, 1H); 7.68 (dd, Ii = 2.8 Hz, J2 =
8.4 Hz, 1H);
7.37 (dd, Ii = 2.4 Hz, J2 = 8.0 Hz, 1H); 6.93 (t, J= 7.6 Hz, 1H); 6.71 (dd, Ji
= 2.8 Hz, J2 = 8.0
Hz, 1H); 4.97 (s, 2H): 4.14 (s, 2H); 2.36 (s, 3H).
Example 13: Preparation of 4,6-dichloro-N-methylpyridazine-3-carboxamide (A-
1):
i) oxalyl chloride, DCM
cat. DMF, rt, 2 h
0 CI 0 CI
ii) CH3NH2.HCI, DIPEA
, ,
LiO)YL, DCM rt 16 h
I
H I
N,N-;.----,CI Step-1 N,N-5--,.CI
A-la A-1
[00343] To a stirred solution of A-la (10.0 g, 50.3 mmol) in anhydrous DCM
(100 mL) was
added catalytic amount of DIV1F (2 to 3 drops) and oxalyl chloride (9.11 mL,
101.0 mmol) drop
wise at 0 C. The reaction mixture was then allowed to warm to room
temperature over 2 h.
After completion, volatiles were removed under reduced pressure and the
residue was dried. It
was then dissolved in anhydrous DCM (50 mL) and added to a stirred solution of
methylamine
hydrochloride (5.09 g, 75.4 mmol) and DIPEA (13.2 mL, 75.4 mmol) in DCM (50
mL) at 0 C
under nitrogen atmosphere. The reaction mixture was then stirred at room
temperature for 16 h.
Water (50 mL) was then added to it and the organic layer was separated. It was
then washed
with saturated NaHCO3 solution (30 mL), brine (50 mL), dried over anhydrous
Na2SO4, filtered
and concentrated under reduced pressure. The residue was then purified by
Combi-Flash (using
gradient elution of 0-40% Et0Ac in hexane) to afford desired compound 4,6-
dichloro-N-
methylpyridazine-3-carboxamide A-1 (3.2 g) as an off-white solid. LCMS (ES)
m/z; 206.0
[M+H] .
Example 14: Preparation of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide
(A-2):
i) oxalyl chloride, DCM
cat. DMF, rt, 2 h
0 CI 0 Cl
Li0 NI1 ,N.'-: CI
"J Step-1 Y ii) CD3NH2.HCI, DIPEA
DCM, rt, 16 h
.._ ID3C'N--iyõ..,
H NI, NI:..------
õCl
A-1 a A-2
[00344] To a stirred solution of A-la (5.0 g, 25.1 mmol) in anhydrous DCM (40
mL) was
added catalytic amount of DMF (2 to 3 drops) and oxalyl chloride (4.6 mL, 50.3
mmol) drop
wise at 0 'C. The reaction mixture was then allowed to warm to room
temperature over 2 h.
After completion, volatiles were removed under reduced pressure and the
residue was dried. It
was then dissolved in anhydrous DCM (25 mL) and added to a stirred solution of
methan-d3-
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amine hydrochloride (2.13 g, 30.2 mmol) and DIPEA (13.2 mL, 75.4 mmol) in
anhydrous DCM
(25 mL) at 0 C under nitrogen atmosphere The reaction mixture was then
stirred at room
temperature for 16 h. Water (50 mL) was then added to it and the organic layer
was separated. It
was then washed with saturated NaHCO3 solution (30 mL), brine (50 mL), dried
over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The residue was then
purified by
Combi-Flash (using gradient elution of 0-40% Et0Ac in hexane) to afford
desired compound
4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide A-2 (2.6 g) as an off-white
solid. LCMS
(ES) m/z; 209.0 [M+Ht
Example 15: Preparation of 4,6-diehloro-N-(methyl-d3)nieotinamide (A-3):
i) oxalyl chloride, DCM
cat. DMF, it, 2 h
0 CI 0 CI
ii) CD3NF12.HCI, DIPEA
DCM, it, 16 h D3C..
HO INCI s*--.
H ii
Step-1 NCI
A-3a A-3
[00345] A-3 (2.6 g) was synthesized by following procedure as described for
the synthesis of
A-2 using A-3a (3 g) as the starting material. LCMS (ES) m/z 208.0 [M+1-1]'.
Example 16: Preparation of 4,6-dichloro-N-methylnicotinamide (A-4):
i) oxalyl chloride, DCM
cat. DMF, it, 2 h
0 CI 0 CI
HOr'-=
II) CH3NH2.HCI, DIPEA
DCM, rt, 16 h
CI Step-1
A-3a A-4
[00346] A-4 (2.5 g) was synthesized by following procedure as described for
the synthesis of
A-1 using A-3a (3 g) as the starting material. LCMS (ES) m/z; 204.9 [M+H].
Example 17: Preparation of 4-bromo-6-ehloro-N-(methyl-d3)nicotinamide (A-5):
CD3NH2.HCI
0 Br 0 Br
HATU, DIPEA
HO -"'(1 DCM, 0 C-rt, 3 h D3C,
1
)Y)
N CI Step-1 N CI
A-5a A-5
1003471 To a stirred solution of A-5a (4.75 g, 20.1 mmol), methan-d3-amine
hydrochloride (1.7
g, 24.1 mmol) and DIPEA (10.4 mL, 60.3 mmol) in DCM (15 mL) was added HATU
(11.5 g,
30.1 mmol) at 0 C and the reaction mixture was allowed to stir at room
temperature for 3 h.
After completion, water (50 mL) was added to it and extracted with DCM (75 mL
x 2). The
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combined organic extracts were washed with brine (50 mL), dried over anhydrous
Na2SO4,
filtered and concentrated under reduced pressure The residue was then purified
by Combi-Flash
(using gradient elution 0-20% Et0Ac in Heptane) to afford desired compound 4-
bromo-6-
chloro-N-(methyl-d3)nicotinamide A-7 (3.1 g) as an off-white solid. LCMS (ES)
m/z; 252.0
[M+1-1] .
Example 18: Preparation of 6-(eyelopropanecarboxamido)-N-(methyl-d3)-4-((6-
methyl-
5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-earboxamide
(Compound
1)
0

3c,N j(NrICI
N cyclopropanecarboxamide
N
A-2 r4 CI Cs2CO3, Xantphos
1
N LiHMDS, DMA Pd2(dba)3, 1,4-dioxane
0 C, 1 h 130 C, 3h
0 HN 0 HN
D3C
H2N
Step-1 Dac,N Step-2
Isl:N CI
1-1 1a
Compound 1
[00348] Step-1: 6-chloro-N-(methyl-d3)-44(6-inethyl-5,6-
dihydrobenzo[h][1,61naphthyridin-7-yl)amino)pyridazine-3-carboxamide (1a): To
a stirred
solution of I-1 (0.35 g, 1.66 mmol) and A-2 (0.74 g, 2.48 mmol) in anhydrous
DMA (10.0 mL)
was added a 1M solution of LiHMDS (in THF) (6.63 mL, 6.63 mmol) drop wise at 0
'C. The
reaction mixture was then allowed to stir at the same temperature for 1 h,
while monitoring
reaction progress by TLC. After completion, it was quenched by addition of
water (20 mL) and
extraction was carried out using 10% Me0H in DCM (30 mL x 3). The combined
organic
extracts were washed with brine (30 mL), dried over anhydrous Na7SO4, filtered
and
concentrated under reduced pressure. The residue was then purified by Combi-
Flash (using
gradient elution of 0-5% Me0H in DCM) to afford desired compound 6-chloro-N-
(methyl-d3)-
4-06-methy1-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yDamino)pyridazine-3-
carboxamide 1a
(0.27 g) as an off-white solid. LCMS (ES) in/z; 384.2 [M-41]+.
[00349] Step-2: 6-(eyeloproparieearboxamido)-N-(methyl-d3)-4-46-methyl-5,6-
dihydrobenzo[h][1,6]naphthyridin-7-y1)amino)pyridazine-3-carboxamide (Compound
1):
Argon gas was purged through a stirred suspension of 6-chloro-N-(methyl-d3)-
446-methy1-5,6-
dihydrobenzo[h]11,61naphthyridin-7-yl)amino) pyridazine-3-carboxamide 1a (0.27
g, 0.703
mmol), cyclopropanecarboxamide (0.078 g, 0.914 mmol) and Cs2CO3 (0.46 g, 1.41
mmol) in
1,4-dioxane (8.0 mL) for 15 min. To this was then added [5-
(diphenylphosphany1)-9,9-dimethyl-
9H-xanthen-4-yl]diphenylphosphane (0.041 g, 0.07 mmol) and Pd2(dba)3 (0.064 g,
0.07 mmol).
The reaction mixture was then stirred at 130 C for 3 h in a sealed tube.
After completion, it was
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cooled to room temperature and filtered through Celite bed. It is washed with
Et0Ac (50 mL x
2) and the filtrate was concentrated under reduced pressure. The residue was
purified by Combi-
Flash (using gradient elution of 0-5% Me0H in DCM) to afford desired compound
6-
(cyclopropanecarboxamido)-N-(methyl-d3)-446-methy1-5,6-
dihydrobenzo[h]11,61naphthyridin-7-yl)amino)pyridazine-3-carboxamide 1 (0.15
g) as a pale
yellow solid. LCMS (ES) m/z; 433.2 [M-H]. 111 NIVIR (400 MHz, DMSO-d6) 6 11.27
(s, 1H);
10.86 (s, 1H); 9.07 (s, 1H); 8.56 (d, J = 3.2 Hz, 1H); 8.19 (s, 1H); 8.02 (d,
J= 7.6 Hz, 1H); 7.72
(d, J = 6.8 Hz, 1H); 743 (d, I = 7.6 Hz, 1H); 7.36-7.33 (m, 1H); 7.24
(apparent t, J = 7.6 Hz,
1H); 4.24 (s, 2H); 2.44 (s, 3H); 2.10-2.00 (m, 1H); 0.82-0.72 (m, 4H).
Example 19: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methy1-5,6-
dihydropyrazino[2,3-c][1,71naphthyridin-7-yl)amino)nicotinamide (Compound 14):
NIM
N I
-µ's N cyclopropanecarboxamide
0 Br Cs2CO3, Xantphos
'*--N ,N) Dac, )1,,....cl..x Pd2(d1:1123),.4;Itoxane
H2N 'Nl rl 1 --'
N , I +
._..j.
N CI Step-I ,N
:-.N1
D3C, 1 Cs2CO3, Xantphos
Pd2(dba)3. 1,4-dioxene
130 *C, 3 h
Step-2 D3C, N
1
0 HN N
il'ArLI
r-II
N NIN7
N CI H
1-5 A-5 14a
Compound 14
[00350] Step-1: 6-chloro-N-(methyl-d3)-4-((6-methy1-5,6-dihydropyrazino[2,3-
c][1,7]naphthyridin-7-yl)amino)nicotinamide (11a): 14a (0.15 g) was
synthesized by
following procedure as described for the synthesis of compound 1 (step-2)
using 1-5 (0.203 g,
0.95 mmol) and A-5 (0.28, 0.792 mmol) as the starting materials. LCMS (ES)
in/z; 385.1
[M+H].
[00351] Step-2: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-46-methy1-5,6-
dihydropyrazino[2,3-c][1,71naphthyridin-7-yl)amino)nicotinamide (Compound 14):

Compound 14 (51 mg) was synthesized by following procedure as described for
the synthesis
of compound 1 (step-2) using 14a (0.18 g, 0.468 mmol) and
cyclopropanecarboxamide (0.06 g,
0.702 mmol) as the starting materials. LCMS (ES) in/z; 434.3 [M+H]. 1-1-1NMR
(400 MHz,
DMSO-d6) 6 11.68(s, 111); 10.67(s, 1H); 9.49(s, 1H); 8_63 (dd, li = 2.4 Hz,
./2= 8.4 Hz, 2H);
8.55 (s, 1H); 8.51 (s, 1H); 8.13 (d, J= 5.2 Hz, 1H); 7.58 (d, 1= 5.2 Hz, 1H);
4.37 (s, 2H); 2.55
(s, 3H); 1.97-1.95 (m, 1H); 0.77-0.73 (m, 4H).
[00352] The following compounds were synthesized by following the procedures
described in
the previous examples, using appropriate intermediates. For final Buchwald
coupling,
corresponding amine coupling partners (e.g., 2-amino-5-fluoropyridine or 2-
amino-4,6-
dimethylpyrimidine) or amide coupling partner (e.g., cyclopropanecarboxamide)
were used, as
appropriate.
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Compound
Structure Analytical Data
No.
LCMS (ES) in/z; 460.2 [M-H]t 1H NMR (400
NI
MHz, DMSO-d6) 6 10.89 (s, 1H); 10.18 (s, 1H);
,.N
9.05 (s, 1H); 8.57 (d, J= 3.2 Hz, 1H); 8.17 (s,
2
0 HN 1H); 8.04 (s, 1H); 8.00 (d, J=
7.6 Hz, 1H); 7.76-
D3c_N)y,
H I 7.66 (m, 3H); 7.57 (d, J= 8.0
Hz, 1H); 7.38-7.30
(m, 2H); 4.26 (s, 2H); 2.48 (s, 3H).
LCMS (ES) in/z; 430.2 [M-H_I+. 1H NMR (400
MHz, DMSO-d6) 6 10.71 (s, 1H); 10.52 (s, 1H);
I 8.58 (dd, Ji= 1.6 Hz, .12 = 4.8
Hz, 1H); 8.53 (s,
N
1H); 8.50 (s, 1H); 8.11 (s, 1H); 7.96 (dd,.// = 0.8
HN 3 Hz, J2 = 7.6 Hz, 1H); 7.74 (dd,
= 1.2 Hz, J2 =
D3c,)L)0 7.6 Hz, 1H); 7.43 (dd, Ji = 1.2
Hz, J2 = 8.0 Hz,
H I
Thsr'..N)-C7 1H); 7.38-7.34 (m, 1H); 7.23
(apparent t, J= 8.0
Hz, 1H); 4.26 (s, 2H); 2.46 (s, 3H); 2.01-1.96 (m,
1H); 0.80-0.74 (m, 4H).
LCMS (ES) in/z; 433.3 [M-41]+. 111 NMR (400
N MHz, DMSO-d6) 6 10.73 (s, 1H);
10.54 (s, 1H);
9.16 (s, 1H); 8.73 (s, 1H); 8.56 (s, 1H); 8.51 (s,
4 HN 1H); 8.07 (s, 1H); 7.98 (ddõ/i -
0.8 Hz, J2 - 7.6
0
D3C,N,IL& 0 Hz, 1H); 7.55 (d, J= 7.6 Hz,
1H); 7.28 (app t, J
H I õILv = 8.0 Hz, 1H); 4.32 (s, 2H); 2.44
(s, 3H); 2.01-
N N
1.95 (m, 1H); 0.80-0.77 (m, 4H).
LCMS (ES) m/z; 450.2 [M1-H]. 'H NMR (400
MHz, DMSO-d6) 6 10.71 (s; 1H); 10.52 (s, 1H);
N 8.57 (d, J= 2.8 Hz, 1H); 8.54
(s, 111); 8.50 (s,
1H); 8.10 (s, 1H); 7.90 (dd, Ji = 1.2 Hz, J2 = 7.6
HN Hz, 1H); 7.74 (dd, Ji= 2.8 Hz,
J2 = 8.8 Hz, 1H);
0
D3C..rsj 7.43 (d, J= 6.8 Hz, 1H); 7.24
(t, J= 8.0 Hz, 1H);
y 0
H I õkv 428 (s, 2H); 246 (s, 3H); 200-1 96
(in, 1H);
N N
0.78-0.76 (m, 4H).
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Compound
Structure Analytical Data
No.
LCMS (ES) m/z; 434.2 [M+H]t 1H NMR (400
I I
N MHz, DMSO-d6) 6 11.30 (s, 1H);
10.88 (s, 1H);
9.16 (s, 1H); 9.10 (s, 1H); 8.74 (s, 1H); 8.16 (s,
6 1H); 8.07 (dd, Ji = 0.8 Hz, J2 = 7.6 Hz, 1H); 7.58
o HN
(d, J= 6.8 Hz, 1H); 7.31 (app t, J= 8.0 Hz, 1H);
D3C,N)yL 0
NIN NL õjt...\/ 4.33 (s, 2H); 2.44 (s, 3H); 2.11-2.07 (m, 1H);
0.84-0.80 (m, 4H).
LCMS (ES) m/z; 451.2 I_M-httr. 1H NMR (400
MHz, DMSO-d6) 6 11.28 (s, 1H); 10.88 (s, 1H);
9.08 (s, 1H); 8.58 (d, .1= 2.8 Hz, 1H); 8.20 (s,
1H); 8.00 (dd, Ji = 1.2 Hz, J2 = 8.0 Hz, 1H); 7.74
7
O HN (dd, = 2.8 Hz, J2 = 8.8 Hz, 1H); 7.46 (d, J-
DfAC, 6.8 Hz, 1H); 7.28 (t, J= 8.0 Hz,
1H); 4.29 (s,
H I
NN N
, )-Lv 2H); 2.47 (s, 3H); 2.11-2.05 (m, 1H); 0.83-0.79
(m, 4H).
LCMS (ES) m/z; 433.3 [M+Hr. 1H NMR (400
N MHz, DMSO-d6) 6 10.75 (s, 1H);
10.59 (s, 1H);
FJ 8.64 (d, J= 2.4 Hz, 1H); 8.58-8.56 (m, 2H); 8.51
8 HN (s, 1H); 8.11 (s, 1H); 7.92 (d,
J= 7.6 Hz, 1H);
0
7.50 (dõ I- 7.6 Hz, 1H); 7.29 (tõ I- 7.6 Hz, 1H);
D3C.,N) 0
I v
4.37 (s, 2H); 2.55 (s, 3H); 2.00-1.95 (m, 1H);
H
0.78-0.76 (m, 4H).
LCMS (ES) m/z; 429.3 [M-H]. 1H NMR (400
MHz, DMSO-d6) 10.72 (s, 1H); 10.50 (s, 1H)N. ;
NI
8.56 (d, J= 1.2 Hz, 2H); 8.47 (s, 1H); 8.09 (s,
1H); 7.93 (dd, Jr= 1.2 Hz, J2 = 7.6 Hz, 1H); 7.71
15 0 HN (dd, = 1.2 Hz, J2 = 8.0 Hz, 1H);
7.41 (d, J-
0 6.8 Hz, 1H); 7.36-7.32 (m, 1H);
7.20 (apparent t,
I N NV
J= 8.0 Hz, 1H); 4.23 (s, 2H); 2.78 (d, J= 4.4 Hz,
3H); 243 (s, 3H); 1 97-1 91 (rn, 1H); 0 76-0 70
(m, 4H).
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Compound
Structure Analytical Data
No.
N LCMS (ES) m/z; 434.3 [M+H]t
1HINMR (400
N MI-1z, DMSO-d6) 6 11.31 (s, 1H);
10.93 (s, 1H);
9.11(s, 1H); 8.64 (d, J= 2.4 Hz, 1H); 8.58 (d, J
16 HN = 2.8 Hz, 1H); 8.20 (s, 1H); 8.01 (dd, = 1.2
0
D3CN)Yj Hz, J2 = 8.0 Hz, 1H); 7.53 (d,
J= 6.8 Hz, 1H);
, 0
= N I .. 7.32 (t, J= 8.0 Hz, 1H);
4.38 (s, 2H); 2.55 (s,
N N
3H); 2.11-2.06 (m, 1H); 0.84-0.80 (m, 4H).
LCMS (ES) m/z; 436.3 I_M-PHJ+. 1I-INMR (400
N
MHz, DMSO-d6) 6 10.68 (s, 1H); 10.58 (s, 1H);
N
8.63 (d, = 2.4 Hz, 1H); 8.57 (d, = 2.4 Hz,
D3C
1H); 8.55 (s, 1H); 8.51 (s, 1H); 8.10 (s, 1H); 7.93
17
0 HN (dd, Ji = 1.2 Hz, J2 = 7.6 Hz, 1H); 7.52 (dd, Ji -
D3C,N). 0 1.2 Hz, J2 = 7.6 Hz, 1H); 7.28
(t, J= 7.6 Hz, 1H);
= 'NAV 4.37 (s, 2H); 2.02-1.97 (m, tH); 0.80-0.75 (m,
4H).
N LCMS (ES) m/z; 437.3 [M+Ht
lEINMR (400
N MI-1z, DMSO-d6) 6 11.30 (s, 1H);
10.91 (s, 1H);
rõ..N 9.10 (s, 1H); 8_62 (d, J = 2.8 Hz, 1H); 8.56 (d, J
18 0 HN = 2.4 Hz, 1H); 8.18 (s, 1H);
7.98 (dd, Ji = 0.8
0
Hz, .1:2 - 8.0 Hz, I H); 7.52 (dd,J10.8Hz,J2-
D3C,NI)Y-I`i N
= k. N I HAv 8.0 Hz, 1H); 7.30 (t, J= 8.0 Hz, 1H); 4.36 (s,
pi
2H); 2.10-2.02 (m, 1H); 0.82-0.76 (m, 4H).
LCMS (ES) m/z; 433.2 [M+H]. 1FINMIR (400
MHz, DMSO-d6) c 11.64 (s, 1H); 10.71 (s, 1H),
9.53 (s, 1H); 8.62 (d, J= 4.8 Hz, 1H); 8.60 (s,
19 1H); 8.55 (s, 1H); 8.13 (d, J=
5.6 Hz, 1H); 7.79
0 N
D3C, (d, J = 8.0 Hz, 1H); 7.67 (d, J
= 5.2 Hz, 1H);
N'k=
LNNtL.77.48-7.44 (m, 1H); 4.31 (s, 2H); 2.51 (s, 3H);
H
2.03-1.97 (m, 1H); 0.82-0.76 (m, 4H).
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Compound
Structure Analytical Data
No.
LCMS (ES) m/z; 434.3 [M H]t 1-FINMR (400
MHz, DMSO-d6) 6 10.71 (s, 1H); 10.52 (s, 1H);
D I
N 8.58 (dd,
= 1.6 Hz, J2 = 4.8 Hz, 1H); 8.53 (s,
1H); 8.50 (s, 1H); 8.11 (s, 1H); 7.96 (dd,
= 1.2
20 HN Hz, J2 = 7.6 Hz, 1H); 7.74 (dd,
= 1.6 Hz, J2=
0
D3Crsj)-1 7.6 Hz, 1H); 7.43 (dd, = 0.8 Hz,
J2 = 8.0 Hz,
, 0
I 1H); 7.38-7.34 (m, 1H); 7.23 (t,
J= 7.6 Hz, 1H);
N
2.50 (s, 3H); 2.01-L93 (m, tH); 0.78-0.74 (m,
4H).
LCMS (ES) m/z; 453.3 [M+H]. 11-1 NMR (400
1 MHz, DMSO-d6) 6 11.28 (s, 1H);
10.89 (s, 1H);
N
9.09 (s, 1H); 8.58 (d, J= 2.8 Hz, 1H); 8.20 (s,
21 1H); 8.00 (dd, Ji = 1.2 Hz, J2 =
8.0 Hz, 1H); 7.75
0 HN (dd, = 2.8 Hz, J2 = 8.8 Hz, 1H);
7.46 (d, J =
D3C.,N)yL 0
6.8 Hz, 1H); 7.28 (t, J= 8.0 Hz, 1H); 2.47 (s,
NNNA
3H); 2.11-2.07 (m, 1H); 0.83-0.79 (m, 4H).
LCMS (ES) m/z; 452.3 [M-4-1]'. 11-1 NMR (400
1 MHz, DMSO-d6) 6 10.71 (s, 1H);
10.53 (s, 1H);
N
8.57 (d, J= 2.8 Hz, 1H); 8.54(s, 1H); 8.50(s,
22 1H); 8.10 (s, 1H); 7.91 (d, J=
7.2 Hz, 1H); 7.74
0 HN (dd, .h = 2.8 Hz, ./2= 8.8 Hz,
1H); 7.43 (d, =
D3C,N4,..-11...,õ 0
H 1 6.8 Hz, 1H); 7.24 (t, J= 8.0 Hz,
1H); 2.46 (s,
3H); 2.01-1.97 (m, 1H); 0.79-0.76 (m, 4H).
LCMS (ES) rn/z; 449.3 [MH-1]+. 'H NMR (400
NI
MHz, DMSO-d6) 6 11.27 (s, 1H); 10.88 (s, 1H);
9.08 (s, 1H); 8.21 (s, 1H); 8.03 (dd, Ji = 1.2 Hz,
23 0 HN J2 = 7.6 Hz, 1H); 7.62 (d, J=
7.6 Hz, 1H); 7.44
D3CNJL.L 0 (d, J = 7.2 Hz, 1H); 7.27-7.22
(m, 2H); 2.55 (s,
H 3H), 2.45 (s, 3H), 2.10-2.06 (m,
1H), 0.83-0.79
(m, 4H).
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Compound
Structure Analytical Data
No.
LCMS (ES) m/z; 448.3 [M+H]t NMR (400
Nz, DMS0-6/6) 6 10.72 (s, 1H); 10.53 (s, 1H);
8.54 (s, 1H); 8.49 (s, 1H); 8.11 (s, 1H); 7.94 (dd,
24 0 HN Ji = 1.2 Hz, J2 = 8.0 Hz, 1H);
7.62 (d, J= 8.0 Hz,
D3CN) 1H); 7.42 (d, J= 8.0 Hz, 1H);
7.24-7.20 (m, 2H);
, 0
H I 2.54 (s 3H). 2.45 (s, 3H); 2.01-1.97 (m, 1H);
0.80-0.75 (m, 4H).
CF3 LCMS (ES) in/z; 502.3 I_M-41_1'.
1H NMR (400
N MHz, DMSO-d6) 6 10.73 (s, 1H);
10.56 (s, 1H);
8.55 (s, 1H); 8.51 (s, 1H); 8.10 (s, 1H); 8.04 (d,
25 = 7.6 Hz, 1f1); 7.95 (dd, Ji =
1.2 Hz, J2 = 7.6 Hz,
O HN
D3C
0 1H); 7.86 (d, J= 7.6 Hz, 1H);
7.50 (d, J= 8.0
H I jcv Hz, 1H); 7.28 (t, J = 8.0 Hz, 1H); 2.51 (s, 3H);
2.01-1.95 (m, 1H); 0.80-0.72 (m, 4H).
CF3
LCMS (ES) m/z; 503.3 [M-41]+. 11-1 NMR (400
N
MHz, DMSO-d6) 6 11.30 (s, 1H); 10.90 (s, 1H);
9.10 (s, 1H); 8.18 (s, 1H); 8.02-7.98 (m, 2H);
26
O HN 7.86 (d, J = 8.0 Hz, 1H);
7.51 (d, J = 7.6 Hz,
D3C..
0 1H); 7.29 (t, J= 8.0 Hz, 1H);
2.47 (s, 3H); 2.10-
NNN H I
2.02 (m, 1H); 0.82-078 (m, 4H).
N,-- LCMS (ES) in,/z; 464.2 [M+H]t 1H
NMR (400
MHz, DMSO-do) o 11.30 (s, 1H); 10.85 (s, 1H);
0
9.10 (s, 1H); 8.62 (dd, Ji = 0.8 Hz, J2 = 8.0 Hz,
27 1H); 8.17 (s, 1H); 7.97 (s, 1H);
7.47 (d, J = 7.2
O HN
D3CN)..y.L....s Hz, 1H); 7.25 (t, J= 8.0 Hz,
1H); 4.11 (s, 2H);
, 0
H 3.77 (s, 3H); 2.45 (s, 3H); 2.09-2.07 (m, 1H);
N N
0.83-0.79 (m, 4H)_
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Compound
Structure Analytical Data
No.
N,
N LCMS (ES) in/z; 463.3 [M+H]t -
IHNMIR (400
0 MHz, DMSO-d6) (510.71 (s, 1H);
10,49 (s, 1H);
8.56-8.52 (m, 2H); 8.49 (s, 1H); 8.06 (s, 1H);
28
0 HN 7.96 (s, 1H); 7.44 (d, J= 7.2 Hz, 1H); 7.20 (t, J=
D,c,
N) 8.0 Hz, 11-1); 4.10 (s, 2H); 3.77 (s, 3H); 2.46 (s,
N N 3H); 2.01-1.95 (m, 1H); 0.80-0.74 (m, 4H).
Example A-1: Oral Tablet
[00353] A tablet is prepared by mixing 20-50% by weight of a compound of
Formula (Al), or a
pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline
cellulose, 1-10%
by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of
magnesium
stearate or other appropriate excipients. Tablets are prepared by direct
compression. The total
weight of the compressed tablets is maintained at 100 -500 mg.
Example A-2: Topical Cream
[00354] A topical cream (or an ointment, gel, oil, or the like) is prepared by
mixing a
compound of Formula (Al) with a non-toxic vehicle such as an oil and water
emulsion,
optionally diluted with additional buffering agents, stabilizing agents, scent
ingredients,
emulsifiers, oils, alcohols, or other excipients A cream, for purposes of the
present disclosure,
encompasses topical compositions of various viscosities (e.g., lotions,
ointments, pastes, gels,
tinctures, and the like).
Example A-3: Eye Drops
[00355] Eye drops comprising a compound of Formula (Al) are prepared by
dissolving an
appropriate amount of the compound in water or a buffered solution (e g ,
buffered for salinity
and/or pH), and optionally diluted with additional excipients or vehicles. An
eye drop may be
further compounded with stabilizers, time-release polymers, or other diluents
to enhance the
therapeutic effect or duration of action at the treated site (e.g., ocular
tissues or surrounding
areas). Viscous liquids and gels are also included within the definition of
eye drops.
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Example A-4: Metered-Dose Inhaler (MDI)
[00356] A compound of Formula (Al) is dissolved in a liquid or liquified gas
propellant,
optionally in combination with stabilizing or flavor excipients, to be
administered via an aerosol
spray in a metered dose to a patient's lungs or respiratory tract. The aerosol
may optionally be
further compounded with a bronchodilator, a corticosteroid, or a combination
of the two. An
MDI for use with a compound of Formula (Al) may be self-administered, or in
the case of
critical host-mediated lung inflammation requiring artificial ventilation
(e.g., Covid-19
associated respiratory inflammation), the inhalant may be administered via
tracheal intubation,
nasopharyngeal catheterization, or similar devices in accordance with advanced
airway
management procedures.
Example B-1: HEK-BlueTM IL-23 and IFNa/fl Reporter Assays for Profiling TYK2
Pseudokinase (JI12) Inhibition
[00357] HEKBlueTM IL-23 and IFNa/13 cells with a stably-integrated cytokine
receptor and
STAT3 or STAT1 express STAT-inducible secreted embryonic alkaline phosphatase
(SEAP)
reporter gene upon cytokine stimulation. These cells are plated in DMEM
(Gibco) containing
10% heat-inactivated FBS (Gibco) and 100 U/mL PenStrep (Gibco) at 37 C under
5% CO2
conditions for 20-22 hours The cells are then pretreated with serially diluted
test compounds for
60 min prior to stimulation with either 10 ng/mL human recombinant 1L-23
(Miltenyl Biotech)
or lng/mL human recombinant lFNa (InvivoGen) for 22- 24 hours for LL-23 or 16-
18 h for
IFNa. SEAP induction is measured using the QUANTI BlueTM Solution (InvivoGen)
according
to the manufacturer's instructions. Inhibition data are calculated by
comparison to no inhibitor
control wells for 0% inhibition and non-stimulated control wells for 100%
inhibition. Dose
response curves are generated to determine the concentration required to
inhibit 50% of cellular
response (IC50) as derived by non-linear regression analysis.
[00358] Table B-1 provides TYK2 inhibitory activity of illustrative compounds,
where A
means IC50 <30 nM; B means ICso is between 30 and 300 nA/I; C means ICso is
between 300
and 1000 nM; D means ICso > 1000 nM; n/a means no observed activity at 1000
nM, and n.d.
means not determined.
Table B-1: Representative TYK2 Inhibitory Activity
Compound No. IL23 IFNa Compound No. 1123 IFNa
A A 4 A A
2 A A 5 A A
3 A A 6 A A
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Compound No. IL23 IFNa Compound No. IL23 IFNa
7 A B 23 A A
8 A A 24 A
14 A A 25
15 A A 26
16 A A 27 A A
17 A A 28 A A
18 A A 34 A A
19 A A 35 A A
20 A A 36 A A
21 A B 37 A n.d.
22 A B 38 A n.d.
Example B-2: HTRF-Based Selectivity Assay:
1003591 The ability of compounds to inhibit the activity of JAK1, JAK2, JAK3
and TYK2 is
measured using a recombinant purified His or GST-tagged catalytic domain for
each enzyme
(JAK1, JAK2 and TYK2 are generated in-house, JAK3 was purchased from Cama
biosciences,
Cat# 08-046) in an HTRF format biochemical assay. The reactions employs a
commercial
peptide substrate from Cisbio (Cat# 62TKOPEC). The basic assay protocol is as
follows: first,
2.5 I, of diluted compounds (4x) in DMSO are dispensed into a 384-well
Optiplate. Next, 2.5
gL of enzyme (final concentrations for enzymes are: TYK2- 700 ng/mL, JAK1-
80.6 ng/mL,
JAK2- 2.1 ng/mL and JAK3- 171.8 ng/mL) is added and incubated at RT for 5-20
min. Finally,
1 of mixture of 2X ATP [Final concentration 20 M for TYK2, 21.43 [iM for
JAK1, 14.7 1,1M
for JAK2 and 2.12 tIM for JAK3] + 2X Substrate [Final concentration 217 nM for
TYK2, 454.7
nM for JAK1, 200 nM for JAK2 and 257.4 nM for JAK3] is added to 384 well
Optiplate.
Composition of Kinase assay buffer used in the assay is as follows: HEPES
50mM, EGTA
1mM, MgCl2 10mM, DTT 2mM, Tween-20 0.01% and water. Then the plates are shaken
and
then incubated at 26.5 C for 60 min. At the end of the incubation, 101aL of
mixture of 2X
detection mix [(EU3+Cryptate(1X) + Streptavidin-XL665(final concentration:
62.5nM) (HTRF
KinEASE-TK kit Cat462TKOPEC)] is added to the assay plate, shaken and
incubated at 26.5 C
for 60 min Plates are then read on a Perkin Elmer Envision for HTRF signal
(665 nm reading /
615 nm reading). After normalization to untreated controls, the percent
inhibition of the HTRF
signal at each compound concentration is calculated. The plot of percent
inhibition versus the
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log of compound concentration is fit with a 4-parameter dose response equation
to calculate IC50
values.
[00360] Table B-2 provides selectivity data of illustrative compounds across
the JAK family
(TYK2, JAK1, JAK2, and JAK3) at the kinase domain (JH1), where A means ICso <
30 nM; B
means IC50 is between 30 and 300 nM; C means IC50 is between 300 and 1000 nM;
D means
IC50> 1000 nM; and n/a means no observed activity at 1000 n1\4.
Table B-2: HTRF-Based TYK2 Selectivity Data
Cmpd No. TYK2-JH1 JAK1-JH1 JAK2-JH1 JAK3-JH1
1
2
3
4
6
7
8
16
17
18
27
28
34
Example B-3: HEKBlueTM IL-2 and IFN7 Reporter Assays for determining
selectivity
[00361] HIEKBlueTM IL-2 and IFNy reporter cells with a stably-integrated
cytokine receptor
and STAT5 or STAT1 express STAT-inducible secreted embryonic alkaline
phosphatase
(SEAP) reporter gene upon cytokine stimulation. These cells were plated in
DMEM (Gibco)
containing 10% heat-inactivated FBS (Gibco) and 100 U/mL PenStrep (Gibco) at
37 C under
5% CO2 conditions for 20-22 hours. The cells were then pretreated with
serially diluted test
compounds for 60 min prior to stimulation with either 4 ng/mL human
recombinant IL-2
(Miltenyl Biotech) or 50 ng/mL human recombinant IFNy (InvivoGen) for 24
hours. SEAP
induction was measured using the QUANTI-Bluem Solution (InvivoGen) according
to the
manufacturer's instructions. Inhibition data were calculated by comparison to
no inhibitor
control wells for 0% inhibition and non-stimulated control wells for 100%
inhibition. Dose
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response curves were generated to determine the concentration required to
inhibit 50% of
cellular response (TC50) as derived by non-linear regression analysis
1003621 Table B-3 provides selectivity data (SEAP) of illustrative compounds
for LL-2 and
IFN- y, where A means IC50 <30 nM; B means ICso is between 30 and 300 nM; C
means IC50 is
between 300 and 1000 nM, D means IC50 > 1000 nM; and n/a means no observed
activity at
1000 nM.
Table B-3: SEAP Selectivity Assay Data at IL-2 and IFN-y
Compound No. 1L-2 IFN-y Compound No. 1L-2 1FN-
y
1 D D 19 D C
2 D D 20 D B
3 D D 21 C B
4 D D 23 D B
D D 24 D D
6 D B 26 D B
7 C B 27 C B
8 D B 28 D B
14 D S 35 D C
D B 36 C B
16 D B 37 D B
17 D B 38 D B
18 C B
1003631 The examples and embodiments described herein are for illustrative
purposes only and
various modifications or changes suggested to persons skilled in the art are
to be included within
the spirit and purview of this application and scope of the appended claims
CA 03208507 2023-8- 15