Note: Descriptions are shown in the official language in which they were submitted.
WO 2019/079614 PCT/US2018/056539
PICOLINAMIDE COMPOUNDS
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Application Ser. No.
62/574,583, filed
October 19, 2017, the content of which is hereby incorporated by reference in
its entirety.
BACKGROUND
[0002] Indolamine 2,3-dioxygenase (IDO; also referred to as ID01) plays a
critical role in the
regulation of natural-, or self-, tolerance and control of inflammation. See,
e.g, Munn, et al.
(1998) Science 281: 1191-1193 and Ravishankar, et al. (2015) Proc Nati Acad
Sci USA 112:
10774-10779. DO is linked to cancer pathologies where high DO expression
correlates with
poor prognosis. DO, a heme-containing monomeric oxidoreductase is the rate-
limiting enzyme
in tryptophan catabolism, catalyzing the degradation of tryptophan (trp) to N-
formyl-
kynurenine. DO is a 41kD monomer and has high homology on the amino acid level
between
species: for example, human IDO1 has 62% homology with rat and 58% with mouse.
A lesser
studied homolog, indolamine 2,3-dioxygenase-2 (ID02) shares 43% homology with
DO, but
might be less effective in converting trp to N-formyl kynurenine. See, e.g,
Hunt, et al. (2009)
Int J Biochem Cell Biol 41: 467-471, Lob, et al. (2009) Cancer Immunol
Immunother 58: 153-
157, and Lob, et al. (2008) Blood 111: 2152-2154.
100031 Overall DO exerts an immune-inhibitory function. Specifically, DO
regulates immune
responses by acting on both the dendritic cell (DC) as well as the T-cell
axis. Expression of DO
in DCs can lead to immune suppression as well as allograft tolerance. See,
e.g., Mellor, et
(2003),//mmuno/ 171: 1652-1655, and Lan, et al. (2010) Transplantation 90:
1286-1293 T-
cells do not express DO, but both the depletion of tryptophan, as well as the
accumulation of
the bioactive tryptophan metabolite kynurenine, exert inhibitory effects on T-
cells. Local
depletion of tryptophan by DO also activates the stress response kinase GCN2,
which in T-cells
leads to inhibition of T-cell proliferation and directing their development
towards regulatory T-
cells (T-reg). See, e.g., Munn, et al. (2005) Immunity 22: 633-642 and
Fallarino, et al. (2006)J
Immunol 176: 6752-6761. In addition, the metabolite kynurenine binds to the
aryl hydrocarbon
receptor (AhR) and can thus promote the differentiation of T-regs.
[0004] T-regs are a subpopulation of T-cells that modulate the immune system,
maintain
tolerance to self-antigens, and thus prevent autoimmune disease. T-regs exert
a general
immunosuppressive effect, and suppress or downregulate the induction and
proliferation of
effector T-cells. See, e.g., Mezrich, et al (2010) Jimmuno/ 185: 3190-3198. DO
expression
acts as a prognostic marker in several cancer types, including melanoma ( See
Speeckaert, et al.
(2012) Eur J Cancer 48: 2004-2011), serous ovarian cancer (Okamoto, et al.
(2005) Clil
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Cancer Res 11: 6030-6039), high grade osteosarcoma (Urakawa , et al. (2009)
Clin Exp
Metastasis 26: 1005-1012), endometrial cancer (Ino, et al. (2006) Br I Cancer
95: 1555-1561),
acute monocytic leukemia (Yang, et al. (2007)J Exp Hematol 15: 478-82), acute
lymphocytic
leukemia (see Yang 2007), acute myeloid leukemia (Fuchs, et al. (2005) Cancer
Lett 223:323-
9), T-cell leukemia/lymphoma (Parmentier, et al. (2003) Nat Med 9:1269-74),
breast cancer
(Hu, et al. (2007) Clin Cancer Res 13:4016-25 and Parmentier 2003), gastric
cancer (see
Parmentier 2003), glioblastoma (see Parmentier 2003), head and neck cancers
(see Parmentier
2003), non-small cell lung cancer (NSCLC) (see Parmentier 2003), small cell
lung cancer (see
Parmentier 2003), mesothelioma (see Parmentier 2003), pancreatic cancer (see
Parmentier
2003), and colorectal cancer (Brandacher, et al. (2006) Clin Cancer Res 12:
1144-1151), where
higher DO expression correlated with poor clinical outcome (Ferdinande, et al.
(2012) Br J
Cancer 106: 141-147). For example, IDO expression in sentinel lymph nodes in
melanoma
patients is inversely correlated with progression-free survival and patients
with high IDO
expression showed a higher frequency of T-regs in the sentinel lymph node. See
Speeckaert
2012. As T-regs are involved in immune recognition of self-antigens, T-reg
expression in
cancer cells may suppress tumor immunity, thus impairing the body's innate
ability to detect and
destroy cancer cells.
[0005] Indeed, immune cells can recognize and kill tumor cells and approaches
to boost the
immune system have shown very promising results in recent years. Yet, many
challenges remain
where tumors avoid immune recognition or actively develop tolerance through
factors like IDO.
Infiltration of effector T-cells into tumors generally correlate with an
increased anti-tumor
immune response and tumor regression. However, those very same CD8+ T cells
that kill tumor
cells can also upregulate IDO in tumor cells as well as in DCs. As a result,
immune response
against tumors is inhibited or lessened. For instance, IDO has been found
upregulated in the
tumor microenvironment as a consequence of the presence of CD8+ T cells. See
Spranger, et al.
(2013) Sci Transl Med 5: 200-116. IDO-positive DCs have been detected in tumor
draining
lymph nodes (Munn, et al. (2004)J Gin Invest 114: 280-290) and have been
linked to the
activation of resting T-reg. See Sharma, et al. (2007)J Clin Invest 117: 2570-
2582.
Furthermore, DO expression is upregulated in response to some types of therapy
acting as a
negative feedback to block the immune response. For example IDO has been found
upregulated
in some melanoma patients in response to immunotherapy targeting CTLA-4. When
IDO
knockout mice were treated with anti-CTLA-4 antibody, a strong synergy in the
anti-tumor
response between the mechanisms was noted. See Allison, et al. (2013)J Exp Med
210: 1389-
1402. With the increased expression of IDO in both the tumor and the DCs in
the tumor
draining lymph nodes, IDO appears to play a major role in regulating the anti-
tumor immune
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response. By promoting the development and activation of T-regs and inhibiting
T effector cell
function IDO expression enhances tolerance to tumor antigens.
[0006] Pharmacological inhibition of IDO with 1-methyl-tryptophan (1-MT)
increases T-cell
dependent tumor immune responses in mouse models and can enhance the immune
response to
cancer vaccines. See Hou, et al. (2007) Cancer Res 67: 792-801, Friberg, et
al. (2002) Int J
Cancer 101: 151-155, Uyttenhove, et al. (2003) Nat Med 9: 1269-1274, and Ou,
et al. (2008)J
Cancer Res C lin Oncol 134: 525-533; see also, PCT Publication Nos.
W02016/073774,
W02015173764, and W02017048612. Thus, small molecule inhibitors of IDO will be
very
valuable as cancer treatments. In addition they can be used to strengthen the
immune response
in individuals with a weakened immune system, or to boost vaccine efficacy.
SUMMARY
[0007] This application provides compounds of Formula (I), or pharmaceutically
acceptable
salts thereof, compositions comprising compounds of Formula (I), or
pharmaceutically
acceptable salts thereof and methods of making and using compounds of Formula
(I), or
pharmaceutically acceptable salts thereof. Compounds of Formula (I), or
pharmaceutically
acceptable salts thereof, may be used for treating certain diseases,
disorders, and conditions,
either as mono-therapies or as components of combination therapies. For
example, with respect
to the treatment of cancer, compounds for Formula (I), or pharmaceutically
acceptable salts
thereof, may be used alone, or in combination with other standard of care
cancer therapies,
including radiation, chemotherapy, cancer vaccines, and checkpoint inhibitors.
DO inhibitors
such as compounds of Formula (I), or pharmaceutically acceptable salts
thereof, may be
beneficial in individuals with weakened immune responses as in the case of HIV-
1 infected
individuals. Furthermore, "DO antagonists may be applied to boost existing or
novel vaccines
against infectious disease in individuals that typically lack a sufficient
immune responses to
vaccines, for example, the very young or the elderly.
[0008] Some embodiments provide a compound of Formula (I):
R2a
X
0 H R3a
RI&N 1211 HAr
0
Rib N R2b R3b
or a pharmaceutically acceptable, solvate, or solvate of the salt thereof
[0009] In some embodiments, Arl is selected from the group consisting of:
phenyl, naphthyl and
pyridinyl.
[0010] In some embodiments, HAr is a 5- or 6-membered heteroaryl.
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[0011] In some embodiments, X is a bond or C(Ra)(Rb).
[0012] In some embodiments, Ria and Rib are independently selected from the
group consisting
of: H, Ci4alkyl, C3_6cycloalkyl optionally substituted with one or two halogen
atoms, and
heterocyclyl. In some embodiments, RI' and Rib together with the nitrogen atom
to which they
are attached form a 4- to 7-membered saturated ring optionally containing one
additional
heteroatom selected from 0, S and N-Rc, wherein said ring is optionally
substituted with one or
two groups independently selected from halogen, hydroxy and oxo; or wherein
said ring is
optionally spirofused to a 3- to 6-membered cycloalkyl or a 4- to 6-membered
heterocyclyl.
[0013] In some embodiments, Itc is selected from the group consisting of: H,
Ci.4alkyl,
C(0)C1.4alkyl, and S02-C1.4alkyl.
[0014] In some embodiments, R2a and R2b are each independently selected from
hydrogen and
halogen.
[0015] In some embodiments, R3a and R3b are independently selected from the
group consisting
of: hydrogen, halogen, CN, S(0)C1.4alkyl, Ci-4alkyl, Ci4haloalkyl, C2-
4alkenyl, Ci4alkoxy,
CI.4haloalkoxy, C3.6cyc1oa1ky1, and SF5.
[0016] In some embodiments, Ra and Rb are each independently selected from the
group
consisting of hydrogen, halogen, hydroxy, Ci.4alkyl, and Ci.4alkoxy. In some
embodiments, Ra
and Rb together represent =0.
[0017] In some embodiments, n is 0, 1 or 2.
[0018] In some embodiments, X is C(Ra)(Rb). In some embodiments, IV and Rb are
independently selected from hydrogen and halogen. In some embodiments, X is
CH2 or CF2.
[0019] In some embodiments, Ari is phenyl. In some embodiments, An is
pyridinyl.
[0020] In some embodiments, HAr is a 5-membered heteroaryl. In some
embodiments, HAr is
isoxazolyi. In some embodiments, HAr is a 6-membered heteroaryl. In some
embodiments,
HAr is pyridinyl. In some embodiment, HAr is pyrimidinyl.
[0021] In some embodiments, one of Ria or Rib is hydrogen, and the other is
selected from Ci-
Alkyl and C3.6cycloalkyl. In some embodiments, one of Ria or Rib is hydrogen,
and the other is
CI.4alkyl.
[0022] In some embodiments, R3a and R3b are independently selected from the
group consisting
of: hydrogen, halogen, CN, CI.4a1ky1, and Ci.4alkoxy. In some embodiments, one
of R3a and R3b
is selected from the group consisting of: halogen, CN, CI.4a1ky1, and
CI.4a1koxy.
[0023] In some embodiments, the compounds of Formula (I) is a compound having
the Formula
(Ia):
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PCT/US2018/056539
Ra Rb
R3a
0
R1&AGYb0
R3b
I I
Rib N
(Ia),
or a pharmaceutically acceptable salt, solvate, or solvate of the salt
thereof, wherein Y' is N or
CH.
[0024] In some embodiments the compound of Formula (I) is a compound having
the formula
(Ib):
Ra Rb
R3a
0 HAr
R1N)L.(XII 0
R3b
N I
Rib
(lb),
or a pharmaceutically acceptable salt, solvate, or solvate of the salt
thereof.
[0025] In some embodiments, the compound of Formula (I) is selected from the
group
consisting of:
4-(4-(3,3-difluoro-1-((2-methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpico1inamide;
4-(4-(1-((2-Methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide;
N-ethyl-4-(4-(1-((2-methoxypyrimidin-5-
yl)carbamoyl)cyclobutyl)phenyl)picolinamide;
N-cyclopropy1-4-(4-(1-((2-methoxypyrimidin-5-y1)-
carbamoyl)cyclobutyl)phenyl)picolinamide;
4-(4-(1-((2-methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)pheny1)-N-(methyl-
d3)picolinamide;
4-(4-(1-((5-chloropyrimidin-2-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide;
N-methyl-4-(4-(1-((3-methylisoxazol-5-
y1)carbamoyl)cyclobutyl)phenyl)picolinamide;
4-(4-(1-((5-bromopyridin-2-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide;
N-methyl-4-(4-(1-(pyridin-3-ylcarbamoyl)cyclobutyl)phenyl)picolinamide;
4-(4-(1-((5-fluoro-6-methoxypyridin-3-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide;
4-(4-(1-((2-ethylpyrimidin-5-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide;
4-(4-(1-((5-cyanopyrimidin-2-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide;
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N-methy1-4-(4-(1-(pyridin-2-ylcarbamoyl)cyclobutyl)phenyl)picolinamide;
4-(4-(14(5-chloropyridin-2-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide;
6-(1-((2-methoxypyrimidin-5-yl)carbamoyl)cyclobuty1)-N-methyl-[3,4'-
bipyridine]-2'-
carboxamide; and
6-(1-((5-chloropyrimidin-2-yl)carbamoyl)cyclobuty1)-N-methy143,4'-bipyridine]-
2'-
carboxamide;
or a pharmaceutically acceptable salt, solvate, or solvate of the salt of any
of the foregoing.
[0026] Some embodiments provide a pharmaceutical composition comprising a
compound of
Formula (I), or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable
carrier.
[0027] Some embodiments provide a method for the treatment of cancer
comprising
administering to a patient in need thereof a compound of Formula (I), or a
pharmaceutically
acceptable salt thereof, or a pharmaceutical composition comprising a compound
of Formula (I),
or a pharmaceutically acceptable salt thereof.
[0028] In some embodiments, said cancer is selected from the group consisting
of glioblastoma,
bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous
cell carcinoma,
adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal
cancer, colon cancer,
bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic
cancer, ovarian
cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.
[0029] In some embodiments, said cancer is selected from colon cancer, bladder
cancer,
hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer,
lung cancer, breast
cancer, and prostate cancer.
[0030] In some embodiments, said treatment further comprises an additional
agent selected from
an anti-PD-1 antibody and an anti-PD-Li antibody.
[0031] [Some embodiments provide a method of inhibiting DO, comprising
contacting a cell
with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[0032] In some embodiments, said cell is a cancer cell. In some embodiments,
said cancer cell
is from a cancer selected from the group consisting of glioblastoma, bone
cancer, head and neck
cancer, melanoma, basal cell carcinoma, squamous cell carcinoma,
adenocarcinoma, oral cancer,
esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder
cancer, hepatocellular
carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical
cancer, lung cancer,
breast cancer, and prostate cancer. In some embodiments, said cancer is
selected from colon
cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian
cancer, cervical
cancer, lung cancer, breast cancer, and prostate cancer.
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[0033] Some embodiments provide a method for decreasing proliferation of
regulatory T-cells,
comprising administering to a patient in need thereof a compound of any of
Formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutical composition
comprising a
compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[0034] In some embodiments, the patient in need thereof has a cancer selected
from the group
consisting of glioblastoma, bone cancer, head and neck cancer, melanoma, basal
cell carcinoma,
squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer,
gastric cancer,
intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma,
renal cell carcinoma,
pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast
cancer, and prostate
cancer. In some embodiments, said cancer is selected from colon cancer,
bladder cancer,
hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer,
lung cancer, breast
cancer, and prostate cancer.
[0035] Some embodiments provide a method of decreasing proliferation of
regulatory T-cells,
comprising contacting a cell with a compound of Formula (I), or a
pharmaceutically acceptable
salt thereof In some embodiments, said cell is a cancer cell. In some
embodiments, said cancer
cell is from a cancer selected from the group consisting of glioblastoma, bone
cancer, head and
neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma,
adenocarcinoma, oral
cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer,
bladder cancer,
hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian
cancer, cervical
cancer, lung cancer, breast cancer, and prostate cancer. In some embodiments,
said cancer is
selected from colon cancer, bladder cancer, hepatocellular carcinoma,
pancreatic cancer, ovarian
cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.
DETAILED DESCRIPTION
[0036] Some embodiments provide compounds of Formula (I):
R2a
X
0 HR3a
Ri&
HAr
0
Rib N R2b R3b (I)
or a pharmaceutically acceptable, solvate, or solvate of the salt thereof
[0037] In some embodiments, An is selected from the group consisting of
phenyl, naphthyl,
and pyridinyl. In some embodiments, An is phenyl. In some embodiments, An is
pyridinyl.
In some embodiments, HAr is a 5 membered heteroaryl, for example, pyrrole,
furan, thiophene,
imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole. In some
embodiments HAr is a 6
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membered heteroaryl, for example, pyridine, pyrazine, pyrimidine, pyridazine,
1,2,3-triazine,
1,2,4-triazine, and 1,3,5-triazine. In some embodiments, X is a bond or
C(Ra)(Rb).
[0038] In some embodiments, Rla and Rib are independently selected from the
group
consisting of: hydrogen, C1-4a1ky1, for example, methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-
butyl, or t-butyl, C3-6cyc1oa1ky1 optionally substituted with one or two
halogen atoms, for
example, cyclopropyl, cyclobutyl, 2,2-difluorocyclobutyl, cyclopentyl,
cyclohexyl,
bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl, and
heterocyclyl, for example
oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, and piperidinyl. In
some embodiments, Rd
and Re together with the nitrogen atom to which they are attached form a 4- to
7-membered
saturated ring optionally containing one additional heteroatom selected from
0, S and N-Rc,
wherein said ring is optionally substituted with one or two groups
independently selected from
halogen, hydroxy and oxo, for example azetidinyl, pyrrolidinyl, piperidinyl,
morpholinyl,
thiomorpholinyl, and piperazinyl; or wherein said ring is optionally
spirofused to a 3- to 6-
membered cycloalkyl or a 4- to 6-membered heterocyclyl, for example 6-oxa-1-
azaspiro[3.3]heptane or 2-oxa-6-azaspiro[3.3]heptane. In some embodiments, Rc
is selected
from the group consisting of: H, C1-4a1ky1, C(0)C1-4a1ky1, and S02-C1-4a1ky1.
In some
embodiments, one or both of Rla and Rib are C1-4a1ky1, for example, methyl,
ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, or t-butyl. In some embodiments, one or both of
Rla and Rib are
C3-6cyc1oa1ky1, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
bicyclo[1.1.1]pentyl, bicyclo[2.1.11hexyl, or bicyclo[3.1.0]hexyl. In some
embodiments, Rd and
Re together with the nitrogen atom to which they are attached form a 4- to 7-
membered
saturated ring optionally containing one additional heteroatom selected from
0, S and N-Re,
wherein said ring is optionally substituted with oxo.
[0039] In some embodiments, R2a and R2b are each independently selected from
hydrogen and
halogen, for example, fluoro, chloro, or bromo. In some embodiments, one or
both R2a and R2b
are hydrogen.
[0040] In some embodiments, R3a and R3b are independently selected from the
group
consisting of: hydrogen, halogen, CN, S(0)nC1-4a1ky1, C1-4a1ky1, C1-
4ha1oa1ky1, C2-4a1keny1,
C1-4a1koxy, C1-4ha1oa1koxy, C3-6cyc1oa1ky1, and SF5, and R3a and R3b are not
both
hydrogen. In some embodiments, one of R3a and R3b is hydrogen and the other of
R3a and
R3b is independently selected from the group consisting of: hydrogen, halogen,
CN, S(0)nC1-
4a1ky1, C1-4alkyl, C1-4haloalkyl, C2-4a1keny1, C1-4alkoxy, Cl -4ha1oa1koxy, C3-
6cyc1oa1ky1,
and SF5. In some embodiments, one or both of R3a and R3b are halogen, for
example, fluoro,
chloro, or bromo. In some embodiments, one or both of R3a and R3b are C1-
4a1ky1, for
example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or t-butyl.
In some
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embodiments, one or both of R3a and R3b are C1-4haloalkyl, for example, -CF3, -
CF2H, -
CH2CF3, -CF2C1,or -CH(CF3)2. In some embodiments, one or both of R3a and R3b
are C1-
4a1koxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-
butoxy, or t-
butoxy. In some embodiments, one or both of R3a and R3b are C1-4haloalkoxy,
for example, -
OCF3, -0CF2H, -OCH2CF3, -0CF2C1, or -OCH(CF3)2. In some embodiments, one or
both of
R3a and R3b are CN. In some embodiments, one or both of R3a and R3b are
S(0)nC1-4alkyl,
for example, methylsulfane, ethylsulfane, n-propylsulfane, isopropylsulfane, n-
butylsulfane, sec-
butylsulfane, t-butylsulfane, methyl sulfinyl, ethyl sulfinyl, n-
propylsulfinyl, isopropyl sulfinyl, n-
butylsulfinyl, sec-butylsulfinyl, t-butylsulfinyl, methyl sulfonyl,
ethylsulfonyl, n-propylsulfonyl,
isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, or t-butylsulfonyl. In
some embodiments,
one or both of R3a and R3b are C3-6cycloalkyl, for example, cyclopropyl,
cyclobutyl,
cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl. In some
embodiments,
one or both of R3a and R3b are SF5. In some embodiments, one or both of R3a
and R3b are
C2-4alkenyl, for example, vinyl, 1- or 2-propene, butene, isobutene, including
E and Z isomers.
[0041] In some embodiments, X is C(Ra)(Rb). In some embodiments, X is a bond.
In some
embodiments, Ra and Rb are each independently selected from the group
consisting of
hydrogen, halogen, hydroxy, C1-4alkyl, and C1-4a1koxy. In some embodiments, Ra
and Rb
together represent =0. In some embodiments, Ra and Rb are each hydrogen. In
some
embodiments, Ra and Rb are each halogen, for example, fluoro, chloro, or
bromo. In some
embodiments, Ra and Rb are each C1-4a1ky1, for example, methyl, ethyl, n-
propyl, isopropyl, n-
butyl, sec-butyl, or t-butyl. In some embodiments, Ra and Rb are each C1-
4a1koxy, for
example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, or t-
butoxy. In some
embodiments, Ra and Rb are each hydroxy. In some embodiments, one of Ra and Rb
is
hydrogen and the other of Ra and Rb is selected from the group consisting of
hydrogen, halogen,
hydroxy, C1-4alkyl, and C1-4alkoxy.
[0042] In some embodiments, n is 0, 1 or 2. In some embodiments, n is 0. In
some
embodiments, n is 1. In some embodiments, n is 2.
[0043] In some embodiments, An is phenyl. In some embodiments, An is
pyridinyl.
[0044] In some embodiments, HAr is a 5-membered heteroaryl. In some
embodiments, HAr is
isoxazolyl. In some embodiments, HAr is a 6-membered heteroaryl. In some
embodiments,
HAr is pyridinyl. In some embodiments HAr is pyrimidinyl.
[0045] In some embodiments, the compound of Formula (I) has the structure of
Formula (Ia):
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Ra Rb
R3a
0
Ri& N I 0
R3 b
I
Rib N (Ia)
or a pharmaceutically acceptable, solvate, or solvate of the salt thereof,
wherein Yl is N or CH.
[0046] In some embodiments, the compound of Formula (I) has the structure of
Formula (lb):
Ra Rb
R3a
0
0 CS
N R3b
I I
Rib N (1b)
or a pharmaceutically acceptable salt, solvate, or solvate of the salt
thereof.
[0047] In some embodiments, one of R3a and R3b is selected from the group
consisting of:
halogen, CN, C1-4a1ky1, and C1-4a1koxy.
[0048] In some embodiments, the compound of Formula (I) is selected from the
group
consisting of:
4-(4-(3,3-difluoro-1-((2-methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide;
4-(4-(1-((2-Methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide;
N-ethyl-4-(4-(1-((2-methoxypyrimidin-5-
yl)carbamoyl)cyclobutyl)phenyl)picolinamide;
N-cyclopropy1-4-(4-(1-((2-methoxypyrimidin-5-
yl)carbamoyl)cyclobutyl)phenyl)picolinamide;
4-(4-(1-((2-methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)pheny1)-N-(methyl-
d3)picolinamide;
4-(4-(1-((5-chloropyrimidin-2-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide;
N-m ethyl -4-(4-(1 -((3 -methyli soxazol -5 -yl)carbamoyl )cycl
obutyl)phenyl)pi col inami de;
4-(4-(1-((5-bromopyridin-2-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide;
N-methyl-4-(4-(1-(pyridin-3-ylcarbamoyl)cyclobutyl)phenyl)picolinamide;
4-(4-(1 -((5 -fluoro-6-m ethoxypyri din-3 -yl)carb am oyl)cyclobutyl)pheny1)-N-
methylpicolinami de;
4-(4-(1-((2-ethylpyrimidin-5-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide;
4-(4-(1 4(5 -cyan opyri mi din-2-y1 )carb am oyl)cycl obutyl)pheny1)-N-methyl
pi colinami de;
N-methy1-4-(4-(1-(pyridin-2-ylcarbamoyl)cyclobutyl)phenyl)picolinamide;
4-(4-(1-((5-chloropyridin-2-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide;
6-(14(2-methoxypyrimidin-5-yl)carbamoyl)cyclobuty1)-N-methy143,4'-bipyridine]-
2'-
carboxamide; and
6-(14(5-chloropyrimidin-2-yl)carbamoyl)cyclobuty1)-N-methy143,4Lbipyridine]-2'-
carboxamide;
- 10 -
Date recue/Date Received 2020-08-25
WO 2019/079614 PCT/US2018/056539
or a pharmaceutically acceptable, solvate, or solvate of the salt of any of
the foregoing.
[0049] Some embodiments provide a compound of Formula (I) selected from:
0
R2a
H R3a R23 ipp, H
R3a
0 N 0 N
IR1N 0 0 Ri..,N 0 co
0 0
1 1 R2b R3b 1 1 R26 R3b
Rib N / R1 b NJ ,--
OH
R2a .
H R3a 0 R2a .
H
N R3a
0 N 0 0
RN 0 0 0 R1N 0
\ I I R3b
I I R2b R3b ,,,, R2b
Ri b N ..-- Rib N
OC H3
R2a .
H R3a 0 R2a . H
R3a
0 N o N0
RiN 0 0 R1.N
\ 0 I I
Rib N /R311
1 I R2b R3b
Rib N ,- R2b -
CI
F
2a = H R3a 0 2a . H R3a
R
N
0 N 0 0
RN R o 0 RIN \ 0
N \ 0 1 1 D
I I R2b R3b Rib N , 2b R3bõ-- .-.
Rib N
F F R2a .
H R3a
R2a . H
NJ R 3a R1IN 0 N
0 0 0
.., 0
R. 0 0 I 1 R3b
., 0
1 1 R3b Rib N ,,- R2b
Rib N ........, R2b
H3C0 OCH3 H3C0
= _
R3a R2a H . R3a
0
R2a ri N 0 N
RV.N 0 0 IR1.N \ 0 0 0
., 0 I J
I I R2b R3b Rib R3b
R2b
Rib N / IN ,-
- 1 1 -
Date recue/Date Received 2020-08-25
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CI
R2a=R3a R2a
R3a
0 0
1131 0 0 R1QN1111 1211
R3b R3b
Rib N R2b
1b N R2b
F CI
OCH2CH3
R2a
R3a R2a
R3a
0 0
RN 12) 0 ID
Ill 0
2b R3b R3b
Rib N R Rib N R2b
or a pharmaceutically acceptable salt of any of the foregoing. In some
embodiment of this
paragraph, Ari is phenyl. In some embodiment of this paragraph, Ari is
pyridinyl. In some
embodiment of this paragraph, HAr is a 5 membered heteroaryl, for example,
pyrrole, furan,
thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole. In
some embodiments
HAr is a 6 membered heteroaryl, for example, pyridine, pyrazine, pyrimidine,
pyridazine, 1,2,3-
triazine, 1,2,4-triazine, and 1,3,5-triazine. In some embodiments of this
paragraph, Ria and Rib
are independently selected from the group consisting of: hydrogen, Ci_4a1ky1,
for example,
methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or t-butyl,
C3..6cycloalkyl optionally
substituted with one or two halogen atoms, for example, cyclopropyl,
cyclobutyl, 2,2-
difluorocyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.11pentyl,
bicyclo[2.1.11hexyl, or
bicyclo[3.1.0]hexyl, and heterocyclyl, for example oxetanyl, azetidinyl,
pyrrolidinyl,
tetrahydrofuranyl, and piperidinyl. In some embodiments, Rd and Re together
with the nitrogen
atom to which they are attached form a 4- to 7-membered saturated ring
optionally containing
one additional heteroatom selected from 0, S and N-Re, wherein said ring is
optionally
substituted with one or two groups independently selected from halogen,
hydroxy and oxo, for
example azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,
and piperazinyl; or
wherein said ring is optionally spirofused to a 3- to 6-membered cycloalkyl or
a 4- to 6-
membered heterocyclyl, for example 6-oxa-1-azaspiro[3.3]heptane or 2-oxa-6-
azaspiro[3.3]heptane. In some embodiments of this paragraph, Re is selected
from the group
consisting of: H, Ci4a1ky1, C(0)C1.4alkyl, and S02-Ci4alkyl. In some
embodiments of this
paragraph, R2a and R2b are each independently selected from hydrogen and
halogen, for
example, fluoro, chloro, or bromo. In some embodiments of this paragraph, lea
and R3b are
independently selected from the group consisting of: hydrogen, halogen, CN,
S(0)C1.4alkyl, C1-
4alkyl, CI.4haloalkyl, C24alkenyl, CiAalkoxy, CiAhaloalkoxy, C3_6cycloalkyl,
and SF5, and lea
and R3b are not both hydrogen. In some embodiments of this paragraph, one of
R3a and R3b is
hydrogen and the other of R3a and R3b is independently selected from the group
consisting of:
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hydrogen, halogen, CN, S(0)11C2.4alkyl, C2_4alky1, C2.4haloalkyl, C2.4alkenyl,
C2.4alkoxY,
C1.4haloalkoxy, C3.6cycloalkyl, and SF5. In some embodiments of this
paragraph, one or both of
R3a and R3b are halogen, for example, fluoro, chloro, or bromo. In some
embodiments of this
paragraph, one or both of R3a and R3b are C1.4a1ky1, for example, methyl,
ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, or t-butyl. In some embodiments of this
paragraph, one or both of
R3a and R3b are C1.4ha1oalkyl, for example, -CF3, -CF2H, -CH2CF3, -CF2C1,or -
CH(CF3)2. In
some embodiments of this paragraph, one or both of R3a and R3b are C1.4a1koxy,
for example,
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, or t-butoxy. In
some
embodiments of this paragraph, one or both of R3a and R3b are C1.4haloalkoxy,
for example, -
OCF3, -0CF2H,
-OCH2CF3, -0CF2C1, or -OCH(CF3)2. In some embodiments of this paragraph, one
or both of
R3a and R3b are CN. In some embodiments of this paragraph, one or both of R3a
and R3b are
S(0)õCi4alkyl, for example, methyl sul fan e, ethyl sul fane, n-propyl sul fan
e, i sopropylsulfane, n-
butylsulfane, sec-butylsulfane, t-butylsulfane, methylsulfinyl, ethylsulfinyl,
n-propylsulfinyl,
isopropylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl, t-butylsulfinyl,
methylsulfonyl,
ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-
butylsulfonyl, or t-
butylsulfonyl. In some embodiments of this paragraph, one or both of R3a and
R3b are
C3_6cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl. In some embodiments of this
paragraph, one or
both of R3a and R3b are SF. In some embodiments of this paragraph, one or both
of R3a and R3b
are C2.4a1kenyl, for example, vinyl, 1- or 2-propene, butene, isobutene,
including E and Z
isomers.
[0050] Some embodiments provide a compound of Formula (I) selected from:
- 13 -
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PCT/US2018/056539
R2a x
R2a X 0 H
0 H N N
N N R3b RI&
N \ ID
V
N
RI& y y ef I 0 ,/
I mI 0 c,,--A Ft' ,
Rib .. j ..--- R2b R3a
Rib .-. / R2b R3b
R2a v R3b
R2a X 0 '' H
0 H
N N
N N Ri&
N
RI& Ist, ......_..... ......õ.
I N
Rs'a
I I 0 3b,-R3a Rib j ...."- R2b
Rib N / R2b R
R2a X R2a v
's H
O H 0
Rl&
N ,,.., N RI& \ IS N -, N
N 411 N
.,j j.,,
0 iii, I pj .. R2b 0
R3b , R3a
I I R3a Rib ., =.."
Rib N ..-"" R2b
R3b
R2a X
R2a X 0 H
O H la N 'N
R ,,
N R3b
N al I I
RI& N 0 1 0 .
Raa---'Nf N
I KII 0
R3b I Rib IN / R2b
Rib vi ---"" R2b J
R3a
R2a ,
R2a X R3b 0 'µ H
O H
a N '' N-'"
R3b
R 1 ,, N 0 II
RI& N 0 N N
I I I 0 NR3a
I j 0 N<J-..R3a R1b N .. ." .. R2b
Rib vi ----- R2b
R2a y
R2a y 0 'S H
0
RI 0 's H
1a
N N R3b RN 0 N NR3b
& N .õ. ,T.
.,, 1 1 0 N ,,_,,.. N
I j 0 r-1 N Rib N ..." R2b I
Rib ., ...--- R2b R3a
R3a
R2a X R2a y
'' H
O H 0
N 0
N O IR ,,s 1a 0 -.-
Ri& N 4110 TL4N N
1 I I 0
Rib . = j ../ R2b R3b R32 Rib N ..--- R2b
R3 Nb
X H R3b
R2a X 0
0 H N
N RI& 0
Rl&N I N S
.NH I I 0 ..---
I ----
.....--
R 1 b N 0 ----- R2b R Rib
N3b .. R3a .. R3a
or
a pharmaceutically acceptable salt of any of the foregoing. In some embodiment
of this
paragraph, Ari is phenyl. In some embodiment of this paragraph, Ari is
pyridinyl. In some
embodiments of this paragraph, Ria and Rib are independently selected from the
group
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Date recue/Date Received 2020-08-25
WO 2019/079614 PCT/US2018/056539
consisting of: hydrogen, Ci4alkyl, for example, methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-
butyl, or t-butyl, C3.6cycloalkyl optionally substituted with one or two
halogen atoms, for
example, cyclopropyl, cyclobutyl, 2,2-difluorocyclobutyl, cyclopentyl,
cyclohexyl,
bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl, and
heterocyclyl, for example
oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, and piperidinyl. In
some embodiments, Rd
and Re together with the nitrogen atom to which they are attached form a 4- to
7-membered
saturated ring optionally containing one additional heteroatom selected from
0, S and N-Re,
wherein said ring is optionally substituted with one or two groups
independently selected from
halogen, hydroxy and oxo, for example azetidinyl, pyrrolidinyl, piperidinyl,
morpholinyl,
thiomorpholinyl, and piperazinyl; or wherein said ring is optionally
spirofused to a 3- to 6-
membered cycloalkyl or a 4- to 6-membered heterocyclyl, for example 6-oxa-1-
azaspiro[3.3]heptane or 2-oxa-6-azaspiro[3.3]heptane. In some embodiments, Re
is selected
from the group consisting of: H, Ci_4alkyl, C(0)C1.4alkyl, and S02-C1.4alkyl.
In some
embodiments, one or both of Ria and Rib are CI.4alkyl, for example, methyl,
ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, or t-butyl. In some embodiments, one or both of
Ria and Rib are
C3.6cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl. In some
embodiments, Rd and
Re together with the nitrogen atom to which they are attached form a 4- to 7-
membered saturated
ring optionally containing one additional heteroatom selected from 0, S and N-
Rc, wherein said
ring is optionally substituted with oxo. In some embodiments of this
paragraph, R2a and R2b are
each independently selected from hydrogen and halogen, for example, fluor ,
chloro, or bromo.
In some embodiments of this paragraph, R3a and le are independently selected
from the group
consisting of: hydrogen, halogen, CN, S(0)11Ci_4alkyl, C1_4alkyl,
Ci4haloalkyl, C2_4alkenyl, C t-
,talkoxy, Ci4haloalkoxy, C3.6cycloalkyl, and SF5, and R3a and R3b are not both
hydrogen. In
some embodiments of this paragraph, one of R3a and R3b is hydrogen and the
other of R3a and
R3b is independently selected from the group consisting of: hydrogen, halogen,
CN, S(0)nCi-
Ci.4a1ky1, C1.4haloalkyl, C24alkenyl, Ci4alkoxy, Ci4haloalkoxy,
C3.6cycloalkyl, and SF5.
In some embodiments of this paragraph, one or both of R3a and R3b are halogen,
for example,
fluoro, chloro, or bromo. In some embodiments of this paragraph, one or both
of R3a and le are
Ci.4alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-
butyl, or t-butyl. In some
embodiments of this paragraph, one or both of R3a and R3b are Ci4haloalkyl,
for example, -CF3,
-CF2H, -CH2CF3, -CF2C1,or -CH(CF3)2. In some embodiments of this paragraph,
one or both of
R3a and R3b are Ci4alkoxy, for example, methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy,
sec-butoxy, or t-butoxy. In some embodiments of this paragraph, one or both of
R3a and R3b are
CI.,thaloalkoxy, for example, -0CF3, -0CF2H, -OCH2CF3, -0CF2C1, or -OCH(CF3)2.
In some
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Date recue/Date Received 2020-08-25
WO 2019/079614 PCT/US2018/056539
embodiments of this paragraph, one or both of R3a and R3b are CN. In some
embodiments of
this paragraph, one or both of R3a and le are S(0)C1.4alkyl, for example,
methylsulfane,
ethylsulfane, n-propylsulfane, isopropylsulfane, n-butylsulfane, sec-
butylsulfane, t-butylsulfane,
methylsulfinyl, ethyl sulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-
butylsulfinyl, sec-
butylsulfinyl, t-butylsulfinyl, methyl sulfonyl, ethylsulfonyl, n-
propylsulfonyl, isopropylsulfonyl,
n-butylsulfonyl, sec-butylsulfonyl, or t-butylsulfonyl. In some embodiments of
this paragraph,
one or both of R3a and R3b are C3_6cycloalkyl, for example, cyclopropyl,
cyclobutyl, cyclopentyl,
cyclohexyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl. In some embodiments
of this
paragraph, one or both of lea and R3b are SF5. In some embodiments of this
paragraph, one or
both of R3a and R3b are C2_4alkenyl, for example, vinyl, 1- or 2-propene,
butene, isobutene,
including E and Z isomers. In some embodiments of this paragraph, Xis
C(Ra)(Rb). In some
embodiments of this paragraph, X is C(Ra)(Rb); and Ra and Rb are independently
selected from
hydrogen and halogen. In some embodiments of this paragraph, Ra and Rb are
both hydrogen.
In some embodiments of this paragraph, Ra and Rb are both halogen, for
example, bromo,
chloro, or fluoro. In some embodiments of this paragraph, one of Ra and Rb is
hydrogen and the
other of Ra and Rb is halogen, for example, bromo, chloro, or fluoro. In some
embodiments of
this paragraph, X is CH2 or CF2. In some embodiments of this paragraph, X is a
bond.
[0051] Some embodiments provide a compound of Formula (I) selected from:
- 16 -
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Ra Rb Ra Rb
H R3a H R3a
N N
0 0
H3C 0 0 r'' 0 0
N \ R3b H3C N 1 -, R3b
H NI N /
Ra Rb Ra Rb
H R38 H R3a
N H 3C N0
0
0 0
/ \ \ N 0 0
H3C""L N R3b \
H 14 H NI / R3b
Ra b
Ra Rb
H .3a H N R3a
F N
Ft\ 0
o 0 o3
, \ 0 el
N \ N =
R3b H NI R3b
H NI ,..,
Ra Rb Ra Rb
H R3a H R3a
N N
0
0 0
0 Cil 0
CiN I R3b ri, 1 , R3b
N / O.,) /
Ra Rb N Ra Rb
H R3a H R3a
N N
0 0 0
0 Ci 0
r----N 1 -.
0
R3b 1----iN
I R3b
C H3C(0 )_ N ..-1 N / N,-
- 17 -
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Ra Rb Ra Rb
H R3a H R3a
N N
0 0
0 0 .7.., 0 0
H 3C,
R3b H 3C 11 1 R3b
Ra Rb Ra Rb
H R3a H R3a
H 3C N 0 N
0
0
7L 0
'1\ \ 0 0
H 3C m II 1 R3b N
R3b
H N H N
Ra RbRa Rb
H R3a H R3a
N
F N
F.,,10, 0 0a,
0 111111D 0 0
N
R3b N .,
R3b
H NI /
H NI /
Ra Rb Ra Rb
H R3a H R3a
N N
0 0
0 Ci 0 0
CI
I R3b
R3b
N / 07J N /
Ra Rb Ra Rb
H R3a H R3a
N N
0 0 0
0 ell
r N 1
,./ 0 41111
I R3b
CH3C(0 r N .,) N R3b
or a pharmaceutically acceptable salt of any of the foregoing. In some
embodiments of this
paragraph, Ra and Rb are independently selected from hydrogen and halogen, for
example,
bromo, chloro, and fluor . In some embodiments of this paragraph, Ra and Rb
are both
hydrogen. In some embodiments of this paragraph, le and Rb are both halogen,
for example,
bromo, chloro, or fluoro. In some embodiments of this paragraph, one of Ra and
Rb is hydrogen
and the other of Ra and Rb is halogen, for example, bromo, chloro, or fluor .
In some
embodiments of this paragraph, HAr is a 5 membered heteroaryl, for example,
pyrrole, furan,
thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole. In
some embodiments
HAr is a 6 membered heteroaryl, for example, pyridine, pyrazine, pyrimidine,
pyridazine, 1,2,3-
triazine, 1,2,4-triazine, and 1,3,5-triazine. In some embodiments of this
paragraph, HAr is
pyridinyl. In some embodiments of this paragraph, HAr is pyrimidinyl. In some
embodiments
of this paragraph, R3a and R3b are independently selected from the group
consisting of:
hydrogen, halogen, CN, S(0)11Ci_4alkyl, Ci_4alkyl, Ci4haloalkyl, C2_4alkenyl,
Ci_4alkoxY,
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C1.4haloa1koxy, C3.6cyc1oa1ky1, and SF5, and R3a and R3b are not both
hydrogen. In some
embodiments of this paragraph, one of R3a and R3b is hydrogen and the other of
R3a and R3b is
independently selected from the group consisting of: hydrogen, halogen, CN,
S(0)õCi_4alkyl,
C1.4a1ky1, C1.4ha1oa1ky1, C2_4alkenyl, C1.4alkoxy, C1.4ha1oa1koxy,
C3.6cycloalkyl, and SF5. In
some embodiments of this paragraph, one or both of lea and R3b are halogen,
for example,
fluoro, chloro, or bromo. In some embodiments of this paragraph, one or both
of R3a and R3b are
C1.4alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-
butyl, or t-butyl. In some
embodiments of this paragraph, one or both of R3a and R3b are C1.4haloalkyl,
for example, -CF3,
-CF2H, -CH2CF3, -CF2C1,or -CH(CF3)2. In some embodiments of this paragraph,
one or both of
R3a and R3b are C1.4alkoxy, for example, methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy,
sec-butoxy, or t-butoxy. In some embodiments of this paragraph, one or both of
R3a and R3b are
C1.4haloalkoxy, for example, -0CF3, -0CF2H, -OCH2CF3, -0CF2C1, or -OCH(CF3)2.
In some
embodiments of this paragraph, one or both of R3a and R3b are CN. In some
embodiments of
this paragraph, one or both of lea and R3b are S(0)C1.4a1kyl, for example,
methylsulfane,
ethylsulfane, n-propylsulfane, isopropylsulfane, n-butylsulfane, sec-
butylsulfane, t-butylsulfane,
methylsulfinyl, ethyl sulfinyl, n-propylsulfinyl, isopropyl sulfinyl, n-
butylsulfinyl, sec-
butylsulfinyl, t-butylsulfinyl, methyl sulfonyl, ethylsulfonyl, n-
propylsulfonyl, isopropylsulfonyl,
n-butylsulfonyl, sec-butylsulfonyl, or t-butylsulfonyl. In some embodiments of
this paragraph,
one or both of lea and R3b are C3_6cycloalkyl, for example, cyclopropyl,
cyclobutyl, cyclopentyl,
cyclohexyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl. In some embodiments
of this
paragraph, one or both of R3a and R3b are SF5. In some embodiments of this
paragraph, one or
both of R3a and R3b are C2_4alkenyl, for example, vinyl, 1- or 2-propene,
butene, isobutene,
including E and Z isomers.
[0052] Some embodiments provide a pharmaceutical composition comprising a
compound of
Formula (I), or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable
carrier. Some embodiments provide a pharmaceutical composition comprising a
compound of
Formula (Ia), or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable
carrier. Some embodiments provide a pharmaceutical composition comprising a
compound of
Formula (lb), or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable
carrier.
[0053] Some embodiments provide a method for the treatment of cancer
comprising
administering to a patient in need thereof a compound of Formula (I), or a
pharmaceutically
acceptable salt thereof, or a pharmaceutical composition comprising a compound
of Formula (I),
or a pharmaceutically acceptable salt thereof. Some embodiments provide a
method for the
treatment of cancer comprising administering to a patient in need thereof a
compound of
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Formula (Ia), or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition
comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt
thereof. Some
embodiments provide a method for the treatment of cancer comprising
administering to a patient
in need thereof a compound of Formula (lb), or a pharmaceutically acceptable
salt thereof, or a
pharmaceutical composition comprising a compound of Formula (lb), or a
pharmaceutically
acceptable salt thereof.
[0054] In some embodiments, said cancer is selected from the group consisting
of glioblastoma,
bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous
cell carcinoma,
adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal
cancer, colon cancer,
bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic
cancer, ovarian
cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.
[0055] In some embodiments, said cancer is selected from colon cancer, bladder
cancer,
hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer,
lung cancer, breast
cancer, and prostate cancer.
[0056] In some embodiments, said treatment further comprises an additional
agent selected from
an anti-PD-1 antibody and an anti-PD-Li antibody.
[0057] Some embodiments provide a method of inhibiting MO, comprising
contacting a cell
with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Some
embodiments provide a method of inhibiting MO, comprising contacting a cell
with a
compound of Formula (Ia), or a pharmaceutically acceptable salt thereof Some
embodiments
provide a method of inhibiting IDO, comprising contacting a cell with a
compound of Formula
(lb), or a pharmaceutically acceptable salt thereof.
[0058] In some embodiments, IDO activity is inhibited by about 1% to about
20%, about 25% to
about 50%, about 600/0 to about 90%, about 95% to about 99%, about 20% to
about 30%, about
30% to about 40%, about 40% to about 500/0, about 50% to about 60%, about 60%
to about
70%, about70% to about 80%, about 80% to about 90%, about 90% to about 99%, or
any value
in between.
[0059] In some embodiments, said cell is a cancer cell. In some embodiments,
said cancer cell
is from a cancer selected from the group consisting of glioblastoma, bone
cancer, head and neck
cancer, melanoma, basal cell carcinoma, squamous cell carcinoma,
adenocarcinoma, oral cancer,
esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder
cancer, hepatocellular
carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical
cancer, lung cancer,
breast cancer, and prostate cancer. In some embodiments, said cancer is
selected from colon
cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian
cancer, cervical
cancer, lung cancer, breast cancer, and prostate cancer.
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[0060] Some embodiments provide a method for decreasing proliferation of
regulatory T-cells,
comprising administering to a patient in need thereof a compound of any of
Formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutical composition
comprising a
compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some
embodiments
provide a method for decreasing proliferation of regulatory T-cells,
comprising administering to
a patient in need thereof a compound of any of Formula (Ia), or a
pharmaceutically acceptable
salt thereof, or a pharmaceutical composition comprising a compound of Formula
(Ia), or a
pharmaceutically acceptable salt thereof. Some embodiments provide a method
for decreasing
proliferation of regulatory T-cells, comprising administering to a patient in
need thereof a
compound of any of Formula (lb), or a pharmaceutically acceptable salt
thereof, or a
pharmaceutical composition comprising a compound of Formula (lb), or a
pharmaceutically
acceptable salt thereof
[0061] In some embodiments, the proliferation of regulatory T-cells is
decreased by about 1% to
about 50%, about 2% to about 45%, about 3% to about 40%, about 4% to about
35%, about 5%
to about 30%, about 6% to about 25% about 7% to about 20%, about 8% to about
15%, about
1% to about 10%, about 35% to about 50, about 10% to about 25%, or any value
in between.
[0062] In some embodiments, the patient in need thereof has a cancer selected
from the group
consisting of glioblastoma, bone cancer, head and neck cancer, melanoma, basal
cell carcinoma,
squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer,
gastric cancer,
intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma,
renal cell carcinoma,
pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast
cancer, and prostate
cancer. In some embodiments, said cancer is selected from colon cancer,
bladder cancer,
hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer,
lung cancer, breast
cancer, and prostate cancer.
[0063] Some embodiments provide a method of decreasing proliferation of
regulatory T-cells,
comprising contacting a cell with a compound of Formula (I), or a
pharmaceutically acceptable
salt thereof Some embodiments provide a method of decreasing proliferation of
regulatory T-
cells, comprising contacting a cell with a compound of Formula (Ia), or a
pharmaceutically
acceptable salt thereof Some embodiments provide a method of decreasing
proliferation of
regulatory T-cells, comprising contacting a cell with a compound of Formula
(lb), or a
pharmaceutically acceptable salt thereof.
[0064] In some embodiments, said cell is a cancer cell. In some embodiments,
said cancer cell
is from a cancer selected from the group consisting of' glioblastoma, bone
cancer, head and neck
cancer, melanoma, basal cell carcinoma, squamous cell carcinoma,
adenocarcinoma, oral cancer,
esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder
cancer, hepatocellular
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carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical
cancer, lung cancer,
breast cancer, and prostate cancer. In some embodiments, said cancer is
selected from colon
cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian
cancer, cervical
cancer, lung cancer, breast cancer, and prostate cancer.
[0065] Some embodiments provide pharmaceutical compositions comprising a
compound of
any of the preceding embodiments, or a pharmaceutically acceptable salt of any
of the
foregoing, for example, a compound of Formula (I), a compound of Formula (Ia),
a compound
of Formula (lb), or a combination thereof, or a pharmaceutically acceptable
salt of any of the
foregoing, and a pharmaceutically acceptable carrier.
[0066] Some embodiments provide methods for the treatment of cancer comprising
administering to a patient in need thereof a compound of any of the preceding
embodiments or a
pharmaceutical composition of any of the preceding embodiments, for example, a
compound of
Formula (I), a compound of Formula (Ia), a compound of Formula (lb) or a
combination thereof,
or a pharmaceutically acceptable salt of any of the foregoing, or a
pharmaceutical composition
comprising any of the foregoing and a pharmaceutically acceptable carrier.
Some embodiments
a method of treating cancer comprising administering a therapeutically
effective amount of a
compound of any of the preceding embodiments or a pharmaceutical composition
of any of the
preceding embodiments, for example, a compound of Formula (I), a compound of
Formula (Ia),
a compound of Formula (lb), or a combination thereof, or a pharmaceutically
acceptable salt of
any of the foregoing, or a pharmaceutical composition comprising any of the
foregoing and a
pharmaceutically acceptable carrier.
[0067] In some embodiments the cancer is selected from the group consisting of
glioblastoma,
bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous
cell carcinoma,
adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal
cancer, colon cancer,
bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic
cancer, ovarian
cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. In
some embodiments
the cancer is a metastatic or secondary cancer.
[0068] In some embodiments, the cancer is selected from colon cancer, bladder
cancer,
hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer,
lung cancer, breast
cancer, and prostate cancer. In some embodiments the cancer is a metastatic or
secondary
cancer.
[0069] In some embodiments the cancer is glioblastoma. Ti some embodiments the
cancer is
bone cancer. In some embodiments the cancer is head and neck cancer. In some
embodiments
the cancer is melanoma. In some embodiments the cancer is basal cell
carcinoma. In some
embodiments the cancer is squamous cell carcinoma. In some embodiments the
cancer is
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adenocarcinoma. In some embodiments the cancer is oral cancer. In some
embodiments the
cancer is esophageal cancer. In some embodiments the cancer is gastric cancer.
In some
embodiments the cancer is intestinal cancer. In some embodiments the cancer is
colon cancer.
In some embodiments the cancer is bladder cancer. In some embodiments the
cancer is
hepatocellular carcinoma. In some embodiments the cancer is renal cell
carcinoma. In some
embodiments the cancer is pancreatic cancer. In some embodiments the cancer is
ovarian
cancer. In some embodiments the cancer is cervical cancer. In some embodiments
the cancer is
lung cancer. In some embodiments the cancer is breast cancer. In some
embodiments the
cancer is prostate cancer. In some embodiments the cancer is a metastatic or
secondary cancer.
[0070] In some embodiments the treatment further comprises an additional agent
selected from
an anti-PD-1 antibody and an anti-PD-Li antibody, including, but not limited
to atezolizumab,
avelumab, durvalumab, nivolumab, and pembrolizumab.
[0071] Any of the features of an embodiment is applicable to all embodiments
identified
herein. Moreover, any of the features of an embodiment is independently
combinable, partly or
wholly with other embodiments described herein in any way, e.g., one, two, or
three or more
embodiments may be combinable in whole or in part. Further, any of the
features of an
embodiment may be made optional to other embodiments. Any embodiment of a
method can
comprise another embodiment of a compound, and any embodiment of a compound
can be
configured to perform a method of another embodiment.
Definitions
[0072] Unless defined otherwise, all technical and scientific terms used
herein have the same
meaning as is commonly understood by one of ordinary skill in the art. All
patents, applications,
published applications and other publications referenced herein are
incorporated by reference in
their entirety unless stated otherwise. In the event that there are a
plurality of definitions for a
term herein, those in this section prevail unless stated otherwise.
[0073] As used in the specification and the appended claims, the singular
forms "a," "an" and
"the" include plural referents unless the context clearly dictates otherwise.
Unless otherwise
indicated, mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry,
recombinant DNA
techniques and/or pharmacology are employed to characterize compounds and
salts thereof. The
use of "or" or "and" means "and/or" unless stated otherwise. Furthermore, use
of the term
"including" as well as other forms, such as "include", "includes," and
"included," is not limiting.
As used in this specification, whether in a transitional phrase or in the body
of the claim, the
terms "comprise(s)" and "comprising" are to be interpreted as having an open-
ended meaning.
That is, the terms are to be interpreted synonymously with the phrases "having
at least" or
"including at least." When used in the context of a process, the term
"comprising" means that
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the process includes at least the recited steps, but may include additional
steps. When used in
the context of a compound, composition, or device, the term "comprising" means
that the
compound, composition, or device includes at least the recited features or
components, but may
also include additional features or components.
[0074] The term "patient" includes mammals such as mice, rats, cows, sheep,
pigs, rabbits,
goats, horses, monkeys, dogs, cats, and humans. In some embodiments, the
patient is a human.
[0075] The term "halo" or "halogen" refers to any radical of fluorine,
chlorine, bromine or
iodine.
[0076] The term "alkyl" refers to a saturated hydrocarbon chain that may be a
straight chain or
branched chain, containing the indicated number of carbon atoms. For example,
C1-C6 alkyl
indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it.
In some
embodiments, an alkyl is a C1-C6 alkyl, which represents a straight-chain or
branched saturated
hydrocarbon radical having Ito 6 carbon atoms. Examples of alkyl include
without limitation
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-
butyl.
[0077] The term "cycloalkyl" refers to a fully saturated monocyclic, bicyclic,
tricyclic or other
polycyclic hydrocarbon group having the indicated number of ring carbon atoms.
Multicyclic
cycloalkyl may be fused, bridged or spiro ring systems. Cycloalkyl groups
include, but are not
limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl and
norbornyl. In some embodiments, cycloalkyl is a monocyclic C3-C8 cycloalkyl.
[0078] The term "haloalkyl" refers to an alkyl group in which at least one
hydrogen atom is
replaced by halo. In some embodiments, more than one hydrogen atom (e.g., 2,
3, 4, 5 or 6) are
replaced by halo. In these embodiments, the hydrogen atoms can each be
replaced by the same
halogen (e.g., fluoro) or the hydrogen atoms can be replaced by a combination
of different
halogens (e.g., fluoro and chloro). "Haloalkyl" also includes alkyl moieties
in which all
hydrogens have been replaced by halo (sometimes referred to herein as
perhaloalkyl, e.g.,
perfluoroalkyl, such as trifluoromethyl).
[0079] As referred to herein, the term "alkoxy" refers to a group of formula -
0-(alkyl). Alkoxy
can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy,
sec-butoxy,
pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy. Likewise, the term "thioalkoxy"
refers to a group
of formula -S-(alkyl). The terms "haloalkoxy" and "thiohaloalkoxy" refer to -0-
(haloalkyl) and -
S-(haloalkyl), respectively.
[0080] In any of the aforementioned groups, one or more hydrogen atoms in the
alkyl portion of
the group may be replaced with deuterium, for example, a deutero methoxy group
(-0CD3) or a
deutero methyl group (-CD3).
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[0081] The term "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen
atom is replaced
by an aryl group. One of the carbons of the alkyl moiety serves as the point
of attachment of the
aralkyl group to another moiety. Non-limiting examples of "aralkyl" include
benzyl, 2-
phenylethyl, and 3-phenylpropyl groups.
[0082] The term "alkenyl" refers to a straight or branched hydrocarbon chain
containing the
indicated number of carbon atoms and having one or more carbon-carbon double
bonds. Alkenyl
groups can include, e.g., vinyl, allyl, 1-butenyl, and 2-hexenyl. In some
embodiments, an
alkenyl is a C2-C6 alkenyl.
[0083] The term "cycloalkenyl" refers to partially unsaturated monocyclic,
bicyclic, tricyclic, or
other polycyclic hydrocarbon groups. A ring carbon (e.g., saturated or
unsaturated) is the point
of attachment of the cycloalkenyl substituent. Any atom can be optionally
substituted e.g., by
one or more substituents. Cycloalkenyl moieties can include, e.g.,
cyclopentenyl, cyclohexenyl,
cyclohexadienyl, or norbornenyl.
[0084] The term "alkynyl" refers to a straight or branched hydrocarbon chain
containing the
indicated number of carbon atoms and having one or more carbon-carbon triple
bonds. Alkynyl
groups can include, e.g., ethynyl, propargyl, 1-butynyl, and 2-hexynyl. In
some embodiments, an
alkynyl is a C2-C6 alkynyl.
[0085] The term "heterocycle", "heterocyclyl" or "heterocyclic" as used herein
except where
noted, represents a stable 4-, 5-, 6-or 7-membered monocyclic- or a stable 6-,
7-, 8-, 9-, 10-, 11-,
or 12-membered bicyclic heterocyclic ring system which comprises at least one
non-aromatic
(i.e. saturated or partially unsaturated) ring which consists of carbon atoms
and from one to four,
preferably up to three, heteroatoms selected from the group consisting of N, 0
and S, wherein
the nitrogen and sulfur atoms may optionally be oxidized as N-oxide, sulfoxide
or sulfone, and
wherein the nitrogen atom may optionally be quaternized. A heterocycle can be
bonded via a
ring carbon atom or, if available, via a ring nitrogen atom. Bicyclic
heterocyclic ring systems
may be fused, bridged, or Spiro bicyclic heterocyclic ring system(s). In some
embodiments,
heterocyclyl is monocyclic having 4 to 7, preferably 4 to 6, ring atoms, of
which 1 or 2 are
heteroatoms independently selected from the group consisting of N, 0 and S. In
some
embodiments, a heterocyclyl group is bicyclic, and in which case, the second
ring may be an
aromatic or a non-aromatic ring which consists of carbon atoms and from one to
four, preferably
up to three, heteroatoms independently selected from the group consisting of
N, 0 and S, or the
second ring may be a benzene ring, or a "cycloalkyl", or a "cycloalkenyl", as
defined herein.
Examples of such heterocyclic groups include, but are not limited to
azetidine, chroman,
dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine,
imidazolidine, imidazoline,
indoline, isochroman, isoindoline, isothiazoline, isothiazolidine,
isoxazoline, isoxazolidine,
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morpholine, oxazoline, oxazolidine, oxetane, piperazine, piperidine,
dihydropyridine,
tetrahydropyridine, dihydropyridazine, pyran, pyrazolidine, pyrazoline,
pyrrolidine, pyrroline,
tetrahydrofuran, tetrahydropyran, thiamorpholine, tetrahydrothiophene,
thiazoline, thiazolidine,
thiomorpholine, thietane, thiolane, sulfolane, 1,3-dioxolane, 1,3-oxazolidine,
1,3-thiazolidine,
tetrahydrothiopyran, tetrahydrotriazine, 1,3-dioxane, 1,4-dioxane,
hexahydrotriazine, tetrahydro-
oxazine, tetrahydropyrimidine, perhydroazepine, perhydro-1,4-diazepine,
perhydro-1,4-
oxazepine, 7-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.2.0]heptane, 7-
azabicyclo[4.1.0]heptane,
2,5-diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, tropane, 2-
oxa-6-
azaspiro[3.3]heptane, dihydrobenzofuran, diydrobenzimidazolyl,
dihydrobenzoxazole, and
dihydrobenzothiazolyl, and N-oxides or sulfones or sulfoxides thereof
[0086] The term "aryl" as used herein, is intended to mean any stable
monocyclic or bicyclic
carbon ring of up to 6 members in each ring (i.e., 6 to 10 total ring atoms)
wherein at least one
ring is aromatic For example, a C6-C10 aryl group such as phenyl, naphthyl,
tetrahydronaphthyl, indanyl, or 1H-indenyl.
[0087] The term "heteroaryl", as used herein except where noted, represents a
stable 5-, 6- or 7-
membered monocyclic- or stable 9- or 10-membered fused bicyclic ring system
which
comprises at least one aromatic ring, which consists of carbon atoms and from
one to four,
preferably up to three, heteroatoms selected from the group consisting of N, 0
and S wherein the
nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen
heteroatom may
optionally be quaternized. In the case of a "heteroaryl" which is a bicyclic
group, the second
ring need not be aromatic and need not comprise a heteroatom. Accordingly,
bicyclic
"heteroaryl" includes, for example, a stable 5- or 6-membered monocyclic
aromatic ring
consisting of carbon atoms and from one to four, preferably up to three,
heteroatoms, as defined
immediately above, fused to a benzene ring, or a second monocyclic
"heteroaryl", or a
"heterocyclyl", a "cycloalkyl", or a "cycloalkenyl", as defined above.
Examples of heteroaryl
groups include, but are not limited to, benzimidazole, benzopyrazole,
benzisothiazole,
benzisoxazole, benzofuran, isobenzofuran, benzothiazole, benzothiophene,
benzotriazole,
benzoxazole, cinnoline, furan, furazan, imidazole, indazole, indole,
indolizine, isoquinoline,
isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine,
pteridine, purine,
pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline,
quinoline,
quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole,
benzimidazole,
benzothiadiazole, isoindole, pyrrolopyridines, imidazopyridines such as
imidazo[1,2-a]pyridine,
pyrazolopyridine, pyrrolopyrimidine and N-oxides thereof.
[0088] The term "treating", "treat", or "treatment" refers generally to
controlling, alleviating,
ameliorating, slowing the progress of or eliminating a named condition once
the condition has
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been established. In addition to its customary meaning, the term "preventing",
"prevent", or
"prevention" also refers to delaying the onset of, or reducing the risk of
developing a named
condition or of a process that can lead to the condition, or the recurrence of
symptoms of a
condition.
[0089] The term "therapeutically effective amount" or "effective amount" is an
amount
sufficient to effect beneficial or desired clinical results. An effective
amount can be administered
in one or more administrations. An effective amount is typically sufficient to
palliate,
ameliorate, stabilize, reverse, slow or delay the progression of the disease
state.
[0090] As used herein, the abbreviations for any protective groups, amino
acids and other
compounds, are, unless indicated otherwise, in accord with their common usage,
recognized
abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See,
Biochem.
11:942-944 (1972)).
Compound Forms and Salts
[0091] The compounds of this disclosure may contain one or more asymmetric
centers and thus
occur as racemates and racemic mixtures, enantiomerically enriched mixtures,
single
enantiomers, individual diastereomers and diastereomeric mixtures. The
compounds of the
present disclosure may, either by nature of asymmetric centers or by
restricted rotation, be
present in the form of isomers (e.g., enantiomers, diastereomers).
[0092] It will also be appreciated that when two or more asymmetric centers
are present in the
compounds of the disclosure, several diastereomers and enantiomers of the
exemplified
structures will often be possible, and that pure diastereomers and pure
enantiomers represent
preferred embodiments. It is intended that pure stereoisomers, pure
diastereomers, pure
enantiomers, and mixtures thereof, are within the scope of the disclosure.
[0093] All isomers, whether separated, pure, partially pure, or in racemic
mixture, of the
compounds of this disclosure are encompassed within the scope of this
disclosure. The
purification of said isomers and the separation of said isomeric mixtures may
be accomplished
by various methods. For example, diastereomeric mixtures can be separated into
the individual
isomers by chromatographic processes or crystallization, and racemates can be
separated into the
respective enantiomers either by chromatographic processes on chiral phases or
by resolution.
[0094] The compounds of the present disclosure include all cis, trans, syn,
anti, entgegen (E),
and zusammen (Z) isomers as well as mixtures thereof. The compounds of the
present disclosure
may also be represented in multiple tautomeric forms, in such instances, the
present disclosure
expressly includes all tautomeric forms of the compounds described herein,
even though only a
single tautomeric form may be represented. In addition, where a term used in
the present
disclosure encompasses a group that may tautomerize, all tautomeric forms are
expressly
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included thereunder. For example, hydroxy substituted heteroaryl groups
include, but are not
limited to, 2-hydroxypyridine as well as 2-pyridone, 1-hydroxyisoquinoline as
well as 1-oxo-
1,2-dihyroisoquinoline, 2-hydroxypyrimidine as well as 2-pyrimidone, 2-
hydroxyquinoline as
well as 2-quinolinone, 5-hydroxy-1,2,4-oxadiazole as well as 1,2,4-oxadiazole-
5(4H)one, and
the like. All such isomeric forms of such compounds are expressly included in
the present
disclosure.
[0095] The compounds of the present disclosure include the compounds
themselves, as well as
their salts, solvate, and solvate of the salt, if applicable. Salts for the
purposes of the present
disclosure are preferably pharmaceutically acceptable salts of the compounds
according to the
present disclosure. Salts which are not themselves suitable for pharmaceutical
uses but can be
used, for example, for isolation or purification of the compounds according to
the disclosure are
also included. A salt, for example, can be formed between an anion and a
positively charged
substituent (e.g., amino) on a compound described herein. Suitable anions
include chloride,
bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate,
trifluoroacetate, and
acetate. Likewise, a salt can also be formed between a cation and a negatively
charged
substituent (e.g., carboxylate) on a compound described herein. Suitable
cations include sodium
ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as
tetramethylammonium ion.
[0096] As used herein, "pharmaceutically acceptable salts" refer to
derivatives wherein the
parent compound is modified by making acid or base salts thereof Examples of
pharmaceutically acceptable salts include, but are not limited to, mineral or
organic acid salts of
basic residues such as amines; alkali or organic salts of acidic residues such
as carboxylic acids;
and the like When the compound of the present disclosure is basic,
pharmaceutically acceptable
salts include non-toxic salts or quaternary ammonium salts of the parent
compound formed, for
example, from non-toxic inorganic or organic acids. For example, such non-
toxic salts include
those derived from inorganic acids such as hydrochloric, hydrobromic,
sulfonic, sulfuric,
sulfamic, phosphoric, nitric and the like; and the salts prepared from organic
acids such as
acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,
citric, ascorbic, pamoic,
maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,
2-acetoxybenzoic,
fumaric, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic,
methanesulfonic,
ethanesulfonic, ethanedisulfonic, camphorsulfonic, gluconic, mandelic, mucic,
pantothenic,
oxalic, isethionic, and the like.
[0097] When the compound of the present disclosure is acidic, salts may be
prepared from
pharmaceutically acceptable non-toxic bases, including inorganic and organic
bases. Such salts
that may be prepared include lithium salt, sodium salt, potassium salt,
magnesium salt, calcium
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salt, dicyclohexylamine salt, N-methyl-D-glucamine salt,
tris(hydroxymethyl)methylamine salt,
arginine salt, lysine salt, and the like.
[0098] Lists of suitable salts may be found in Remington's Pharmaceutical
Sciences, 17th ed.,
Mack Publishing Company, Easton, Pa., 1985, p. 1418; S. M. Berge et al.,
"Pharmaceutical
Salts", J. Pharm. Sci. 1977, 66, 1-19; and "Pharmaceutical Salts: Properties,
Selection, and Use.
A Handbook"; Wermuth, C. G. and Stahl, P. H. (eds.) Verlag Helvetica Chimica
Acta, Zurich,
2002 [ISBN 3-906390-26-8]; each of which is incorporated herein by reference
in its entirety.
[0099] Solvates in the context of the present disclosure are designated as
those forms of the
compounds according to the present disclosure, which form a complex in the
solid or liquid state
by stoichiometric coordination with solvent molecules. Hydrates are a specific
form of solvates,
in which the coordination takes place with water. Hydrates are preferred
solvates in the context
of the present disclosure. The formation of solvates is described in greater
detail in "Solvents
and Solvent Effects in Organic Chemistry"; Reichardt, C. and Welton T.; John
Wiley & Sons,
2011 [ISBN: 978-3-527-32473-6], the contents of which is incorporated herein
by reference in
its entirety.
[00100] The present disclosure also encompasses all suitable isotopic variants
of the
compounds according to the present disclosure, whether radioactive or not. An
isotopic variant
of a compound according to the present disclosure is understood to mean a
compound in which
at least one atom within the compound according to the present disclosure has
been exchanged
for another atom of the same atomic number, but with a different atomic mass
than the atomic
mass which usually or predominantly occurs in nature. Examples of isotopes
which can be
incorporated into a compound according to the present disclosure are those of
hydrogen, carbon,
nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as 2H
(deuterium), 3H (tritium),
13C, 14C, 15N, 170, 180, 18F, 36C1, 82Br, 1231, 1241, 1251, 1291 and 1311.
Particular isotopic
variants of a compound according to the present disclosure, especially those
in which one or
more radioactive isotopes have been incorporated, may be beneficial, for
example, for the
examination of the mechanism of action or of the active compound distribution
in the body. Due
to comparatively easy preparability and detectability, especially compounds
labeled with 3H,
14C and/or 18F isotopes are suitable for this purpose. In addition, the
incorporation of isotopes,
for example of deuterium, can lead to particular therapeutic benefits as a
consequence of greater
metabolic stability of the compound, for example an extension of the half-life
in the body or a
reduction in the active dose required. Such modifications of the compounds
according to the
present disclosure may therefore in some cases also constitute a preferred
embodiment of the
present disclosure. In some embodiments, hydrogen atoms of the compounds
described herein
may be replaced with deuterium atoms. Isotopic variants of the compounds
according to the
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present disclosure can be prepared by processes various methods, including,
for example, by the
methods described below and in the working examples, by using corresponding
isotopic
modifications of the particular reagents and/or starting compounds therein.
Pharmaceutical Compositions
[00101] The term "pharmaceutical composition" as used herein is intended to
encompass a
product comprising the active ingredient(s), and the inert ingredient(s) that
make up the carrier,
as well as any product which results, directly or indirectly, from
combination, complexation or
aggregation of any two or more of the ingredients, or from dissociation of one
or more of the
ingredients, or from other types of reactions or interactions of one or more
of the ingredients.
Accordingly, the pharmaceutical compositions of the present disclosure
encompass any
composition made by admixing a compound of the present disclosure, or a
pharmaceutically
acceptable salt, or solvate or solvate of the salt thereof, and a
pharmaceutically acceptable
carrier.
[00102] The term "pharmaceutically acceptable carrier" refers to a carrier or
an adjuvant that
may be administered to a patient, together with a compound of the present
disclosure, or a
pharmaceutically acceptable salt, solvate, or salt of the solvate thereof, and
which does not
destroy the pharmacological activity thereof and is nontoxic when administered
in doses
sufficient to deliver a therapeutic amount of the compound
[00103] In some embodiments, the compounds of the present application are
administered at
about 1 mg to 1,000 mg, about 2 mg to 900 mg, about 3 mg to 800 mg, about 4 mg
to 700 mg,
about 5 mg to 600 mg, about 10 mg to 500 mg, about 50 mg to 400 mg, about 100
mg to 300
mg, about 150 mg to 250 mg, or any value in between. In some embodiments, the
total daily
dosage may be divided and administered in portions during the day, for
example, once per day,
twice per day, three times per day or four times per day. In some embodiments,
the total dosage
may be administered once per week, twice per week, three times per week, four
times per week,
five times per week or six times per week.
[00104] In some embodiments, the pharmaceutical compositions of the present
disclosure for
injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous
solutions,
dispersions, suspensions or emulsions as well as sterile powders for
reconstitution into sterile
injectable solutions or dispersions prior to use. Examples of suitable aqueous
and non-aqueous
carriers, diluents, solvents or vehicles include water, ethanol, polyols (such
as glycerol,
propylene glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable
oils (such as olive oil), and injectable organic esters such as ethyl oleate.
Proper fluidity can be
maintained, for example, by the use of coating materials such as lecithin, by
the maintenance of
the required particle size in the case of dispersions, and by the use of
surfactants.
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[00105] In some embodiments, the pharmaceutical compositions may also contain
adjuvants
such as preservative, wetting agents, emulsifying agents, and dispersing
agents. Prevention of
the action of micro-organisms may be ensured by the inclusion of various
antibacterial and
antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid,
and the like. It may
also be desirable to include isotonic agents such as sugars, sodium chloride,
and the like.
Prolonged absorption of the injectable pharmaceutical form may be brought
about by the
inclusion of agents that delay absorption such as aluminium monostearate and
gelatin. The
compounds can be incorporated into slow release or targeted delivery systems
such as polymer
matrices, liposomes, and microspheres. Such formulations may provide more
effective
distribution.
[00106] In some embodiments, the pharmaceutical compositions that are
injectable
formulations can be sterilized, for example, by filtration through a bacterial-
retaining filter, or
by incorporating sterilizing agents in the form of sterile solid
pharmaceutical compositions that
can be dissolved or dispersed in sterile water or other sterile injectable
medium prior to use.
[00107] In some embodiments, solid dosage forms of the instant pharmaceutical
compositions
for oral administration. In some embodiments, the oral dosage forms include
capsules, tablets,
pills, powders, and granules. In such solid dosage forms, the active compound
is mixed with at
least one inert, pharmaceutically acceptable excipient or carrier such as
sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as starches, lactose,
sucrose, glucose,
mannitol, and silicic acid, b) binders such as, for example,
carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as
glycerol, d)
disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca
starch, alginic acid,
certain silicates, and sodium carbonate, e) solution retarding agents such as
paraffin, f)
absorption accelerators such as quaternary ammonium compounds, g) wetting
agents such as,
for example, cetyl alcohol and glycerol monostearate, h) absorbents such as
kaolin and bentonite
clay, and i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene
glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules,
tablets and pills, the
dosage form may also comprise buffering agents.
[00108] Solid pharmaceutical compositions of a similar type may also be
employed as fillers in
soft and hard-filled gelatin capsules using such excipients as lactose or milk
sugar as well as
high molecular weight polyethylene glycols and the like.
[00109] The solid dosage forms of the instant pharmaceutical compositions of
tablets, dragees,
capsules, pills, and granules can be prepared with coatings and shells such as
enteric coatings
and other coatings. They may optionally contain opacifying agents and can also
be of a
formulation that they release the active ingredient(s) only, or
preferentially, in a certain part of
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the intestinal tract, optionally, in a delayed manner. Examples of embedding
pharmaceutical
compositions, which can be used include polymeric substances and waxes.
[00110] The active compounds can also be in microencapsulated form, if
appropriate, with one
or more of the above-mentioned excipients.
[00111] Some embodiments provide liquid dosage forms of the instant
pharmaceutical
compositions for oral administration. In some embodiments, the liquid dosages
include
pharmaceutically acceptable emulsions, solutions, suspensions, syrups and
elixirs. In addition to
the active compounds, the liquid dosage forms may contain inert diluents
commonly used in the
art such as, for example, water or other solvents, solubilizing agents and
emulsifiers such as
ethyl alcohol, isopropyl alcohol, ethyl carbonate, Et0Ac, benzyl alcohol,
benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed,
groundnut, corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
[00112] Besides inert diluents, the oral pharmaceutical compositions can also
include adjuvants
such as wetting agents, emulsifying and suspending agents, sweetening,
flavoring, and
perfuming agents.
[00113] Suspensions of the instant compounds, in addition to the active
compounds, may
contain suspending agents as, for example, ethoxylated isostearyl alcohols,
polyoxyethylene
sorbitol and sorbitan esters, microcrystalline cellulose, aluminium
metahydroxide, bentonite,
agar-agar, and tragacanth, and mixtures thereof.
[00114] Pharmaceutical compositions for rectal or vaginal administration are
preferably
suppositories which can be prepared by mixing the compounds with suitable non-
irritating
excipients or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are
solid at RT but liquid at body temperature and therefore melt in the rectum or
vaginal cavity and
release the active compound.
[00115] Dosage forms for topical administration of a compound or
pharmaceutical composition
of the present disclosure include powders, patches, sprays, ointments and
inhalants. The active
compound is mixed under sterile conditions with a pharmaceutically acceptable
carrier and any
needed preservatives, buffers, or propellants which may be required.
Uses
[00116] Some embodiments provide methods of treating cancer, comprising
administering to a
patient in need thereof a therapeutically effective amount of a compound of
Formula (I), or a
pharmaceutically acceptable salt, solvate, or solvate of a salt thereof. In
some embodiments the
cancers include, but are not limited to: glioblastoma, bone cancer, head and
neck cancer,
melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral
cancer,
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esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder
cancer, hepatocellular
carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical
cancer, lung cancer,
breast cancer, and prostate cancer. In some embodiments, the cancer is
glioblastoma. In some
embodiments, the cancer is melanoma, basal cell carcinoma, or squamous cell
carcinoma. In
some embodiments, the cancer is head and neck cancer, oral cancer, or
esophageal cancer. In
some embodiments, the cancer is bone cancer. In some embodiments, the cancer
is
adenocarcinoma. In some embodiments, the cancer is gastric cancer, intestinal
cancer, colon
cancer, or bladder cancer. In some embodiments, the cancer is hepatocellular
carcinoma or renal
cell carcinoma. In some embodiments, the cancer is pancreatic cancer. In some
embodiments,
the cancer is lung cancer. In some embodiments, the cancer is non-small cell
lung cancer. In
some embodiments, the cancer is prostate cancer. In some embodiments, the
cancer is ovarian
cancer or cervical cancer. In some embodiments, the cancer is breast cancer.
In some
embodiments, the compound of Formula (I), or a pharmaceutically acceptable
salt thereof, is a
compound of Formulae (Ia) or (lb) or a pharmaceutically acceptable salt of any
of the foregoing.
[00117] Some embodiments provide methods preventing the onset of and/or
recurrence of
cancer, comprising administering to a patient in need thereof a
therapeutically effective amount
of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate,
or solvate of a salt
thereof.
[00118] Some embodiments provide methods of treating cancer, comprising
administering to a
patient in need thereof a therapeutically effective amount of a composition
comprising a
compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or
solvate of a salt
thereof In some embodiments the cancers include, but are not limited to:
glioblastoma, bone
cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell
carcinoma,
adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal
cancer, colon cancer,
bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic
cancer, ovarian
cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. In
some embodiments,
the cancer is glioblastoma. In some embodiments, the cancer is melanoma, basal
cell
carcinoma, or squamous cell carcinoma. In some embodiments, the cancer is head
and neck
cancer, oral cancer, or esophageal cancer. In some embodiments, the cancer is
bone cancer. In
some embodiments, the cancer is adenocarcinoma. In some embodiments, the
cancer is gastric
cancer, intestinal cancer, colon cancer, or bladder cancer. In some
embodiments, the cancer is
hepatocellular carcinoma or renal cell carcinoma. In some embodiments, the
cancer is pancreatic
cancer. In some embodiments, the cancer is lung cancer. In some embodiments,
the cancer is
non-small cell lung cancer. In some embodiments, the cancer is prostate
cancer. In some
embodiments, the cancer is ovarian cancer or cervical cancer. In some
embodiments, the cancer
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is breast cancer. In some embodiments, the compound of Formula (I), or a
pharmaceutically
acceptable salt thereof, is a compound of Formulae (Ia) or (lb) or a
pharmaceutically acceptable
salt of any of the foregoing.
[00119] Some embodiments provide methods preventing the onset of and/or
recurrence of
cancer, comprising administering to a patient in need thereof a
therapeutically effective amount
of a composition comprising a compound of Formula (I), or a pharmaceutically
acceptable salt,
solvate, or solvate of a salt thereof.
[00120] Some embodiments provide a compound of Formula (I), or
pharmaceutically
acceptable salts thereof, for use in treating cancer. In some embodiments the
cancers include,
but are not limited to: glioblastoma, bone cancer, head and neck cancer,
melanoma, basal cell
carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal
cancer, gastric
cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular
carcinoma, renal cell
carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer,
breast cancer, and
prostate cancer. In some embodiments, the cancer is glioblastoma. In some
embodiments, the
cancer is melanoma, basal cell carcinoma, or squamous cell carcinoma. In some
embodiments,
the cancer is head and neck cancer, oral cancer, or esophageal cancer. In some
embodiments,
the cancer is bone cancer. In some embodiments, the cancer is adenocarcinoma.
In some
embodiments, the cancer is gastric cancer, intestinal cancer, colon cancer, or
bladder cancer. In
some embodiments, the cancer is hepatocellular carcinoma or renal cell
carcinoma. In some
embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer
is lung cancer.
In some embodiments, the cancer is non-small cell lung cancer. In some
embodiments, the
cancer is prostate cancer. In some embodiments, the cancer is ovarian cancer
or cervical cancer.
In some embodiments, the cancer is breast cancer.
[00121] Some embodiments provide a compound of Formula (I), or
pharmaceutically
acceptable salts thereof, for use in preventing the onset of and/or recurrence
of cancer.
[00122] Some embodiments provide a compound of Formula (I), or
pharmaceutically
acceptable salts thereof, for the preparation of a medicament for treating
cancer. In some
embodiments the cancers include, but are not limited to: glioblastoma, bone
cancer, head and
neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma,
adenocarcinoma, oral
cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer,
bladder cancer,
hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian
cancer, cervical
cancer, lung cancer, breast cancer, and prostate cancer. In some embodiments,
the cancer is
glioblastoma. In some embodiments, the cancer is melanoma, basal cell
carcinoma, or
squamous cell carcinoma. In some embodiments, the cancer is head and neck
cancer, oral
cancer, or esophageal cancer. In some embodiments, the cancer is bone cancer.
In some
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embodiments, the cancer is adenocarcinoma. In some embodiments, the cancer is
gastric cancer,
intestinal cancer, colon cancer, or bladder cancer. In some embodiments, the
cancer is
hepatocellular carcinoma or renal cell carcinoma. In some embodiments, the
cancer is
pancreatic cancer. In some embodiments, the cancer is lung cancer. In some
embodiments, the
cancer is non-small cell lung cancer. In some embodiments, the cancer is
prostate cancer. In
some embodiments, the cancer is ovarian cancer or cervical cancer. In some
embodiments, the
cancer is breast cancer.
[00123] Some embodiments provide a compound of Formula (I), or
pharmaceutically
acceptable salts thereof, for the preparation of a medicament for use in
preventing the onset of
and/or recurrence of cancer.
[00124] Some embodiments provide a method for inhibiting the activity of lDO,
comprising
contacting a cell with a compound of Formula (I), or a pharmaceutically
acceptable salt thereof.
In some embodiments, the compound of Formula (I) is selected from a compound
of Formula
(Ia), a compound of Formula (lb), or a pharmaceutically acceptable salt of any
of the foregoing.
In some embodiments, the cell is a cancer cell. In some embodiments, the
cancer cell is a cell
selected from glioblastoma, bone cancer, head and neck cancer, melanoma, basal
cell carcinoma,
squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer,
gastric cancer,
intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma,
renal cell carcinoma,
pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast
cancer, or prostate cancer.
Administration
[00125] The compounds and compositions described herein can, for example, be
administered
orally, parenterally (e.g., subcutaneously, intracutaneously, intravenously,
intramuscularly,
intraarticularly, intraarterially, intrasynovially, intrasternally,
intrathecally, intralesionally and
by intracranial injection or infusion techniques), by inhalation spray,
topically, rectally, nasally,
buccally, vaginally, via an implanted reservoir, by injection, subdermally,
intraperitoneally,
transmucosally, or in an ophthalmic preparation, with a dosage ranging from
about 0.01 mg/kg
to about 1000 mg/kg, or any value in between (e.g., from about 0.01 to about
100 mg/kg, from
about 0.1 to about 100 mg/kg, from about 1 to about 100 mg/kg, from about 1 to
about 10
mg/kg, or any value in between) every 4 to 120 hours, or any value in between.
The
interrelationship of dosages for animals and humans (based on milligrams per
meter squared of
body surface) is described by, for example, Freireich et al., Cancer
Chemother. Rep. 50, 219-244
(1966). Body surface area may be approximately determined from height and
weight of the
patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y.,
537 (1970). In
certain embodiments, the compositions are administered by oral administration
or by injection.
The methods herein contemplate administration of an effective amount of
compound or
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compound composition to achieve a desired or stated effect. Typically, the
pharmaceutical
compositions of the present disclosure will be administered from about 1 to
about 6 times per
day or alternatively, as a continuous infusion. Such administration can be
used as a chronic or
acute therapy.
[00126] Lower or higher doses than those recited above may be required.
Specific dosage and
treatment regimens for any particular patient will depend upon a variety of
factors, including the
activity of the specific compound employed, the age, body weight, general
health status, sex,
diet, time of administration, rate of excretion, drug combination, the
severity and course of the
disease, condition or symptoms, the patient's disposition to the disease, and
the judgment of the
treating physician.
[00127] In some embodiments, dosage forms include from about 0.001 milligrams
to about
2,000 milligrams, or any value in between (including, from about 0.001
milligrams to about
1,000 milligrams, from about 0.001 milligrams to about 500 milligrams, from
about 0.01
milligrams to about 250 milligrams, from about 0.01 milligrams to about 100
milligrams, from
about 0.05 milligrams to about 50 milligrams, and from about 0.1 milligrams to
about 25
milligrams, or any value in between) of a compound of Formula (I) (and/or a
compound of any
of the other formulae described herein) or a salt (e.g., a pharmaceutically
acceptable salt) thereof
as defined anywhere herein. The dosage forms can further include a
pharmaceutically acceptable
carrier and/or an additional therapeutic agent.
[00128] Appropriate dosage levels may be determined by any suitable method.
Preferably, the
active substance is administered at a frequency of 1 to 4 times per day for
topical administration,
or less often if a drug delivery system is used.
[00129] Nevertheless, actual dosage levels and time course of administration
of the active
ingredients in the pharmaceutical compositions of the present disclosure may
be varied so as to
obtain an amount of the active ingredient which is effective to achieve a
desired therapeutic
response for a particular patient, composition and mode of administration,
without being toxic to
the patient. In certain cases, dosages may deviate from the stated amounts, in
particular as a
function of age, gender, body weight, diet and general health status of the
patient, route of
administration, individual response to the active ingredient, nature of the
preparation, and time
or interval over which administration takes place. Thus, it may be
satisfactory in some cases to
manage with less than the aforementioned minimum amount, whereas in other
cases the stated
upper limit may be exceeded. It may in the event of administration of larger
amounts be
advisable to divide these into multiple individual doses spread over the day.
[00130] In some embodiments, the compounds of the present disclosure may be co-
administered with one or more additional agents used in the treatment of
cancer. In some
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embodiments, the additional agents include, but are not limited to: alkylating
agents such as
cyclophosphamide, chlorambucil, meclorethamine, ifosfamide, or melphalan;
antimetabolites
such as methotrexate, cytarabine, gemcitabine, fludarabine, 6-mercaptopurine,
azathioprene, or
5-fluorouracil; antimitotic agents such as vincristine, vinblastine,
vindesine, vinorelbine,
paclitaxel, or docetaxel; platinum derivatives such as cisplatin, carboplatin
or oxaliplatin;
hormone therapeutics such as tamoxifen; aromatase inhibitors such as
bicalutamide, anastrozole,
exemestane or letrozole; signaling inhibitors such as imatinib (tyrosine
kinase inhibitor;
Gleevac), gefitinib (EGFR inhibitor; Iressa) or erlotinib (receptor TKI, which
acts on EGFR;
Tarceva); monoclonal antibodies such as trastuzumab, pertuzumab, inotuzumab,
or ozogamicins
thereof, as well as other antibody-drug conjugates such as ado-trastuzumab
emtansine;
antiangiogenic agents such as bevacizumab, sorafenib (tyrosine protein
kinase), pazopanib or
sunitinib (receptor tyrosine kinase inhibitor); tivozanib, axitinib, and
cediranib; -tinibs (tyrosine
kinase inhibitors) such as lapatinib; biologic response modifiers such as
interferon-alpha;
topoisomerase inhibitors such as camptothecins (including irinotecan and
topotecan), amsacrine,
etoposide, etoposide phosphate, or teniposide; anthracyclines such as
doxorubicin, daunorubicin,
epirubicin, idarubicin, sabarubicin, aclarubicin, carubicin and valrubicin;
other cytotoxic agents
such as actinomycin, bleomycin, plicamycin or mitomycin; mTOR inhibitors such
as rapamycin,
temsirolimus and everolimus; and antibody therapy such as CTLA4 antibody
therapy, PDL1
antibody therapy, and PD1 antibody therapy.
[00131] The terms "CTLA4 antibody" and "anti-CTLA4" refer to an antibody or
antibodies
directed towards cytotoxic t-lymphocyte antigen 4 (CTLA4). Exemplary
antibodies include, but
are not limited to, antibodies that are CTLA4 antagonists or the CTLA4
antibodies as set forth in
U.S. Patent Nos. 8,685,394 and 8,709,417. Some embodiments of the antibody
include
ipilimumab (YERVOYO, Bristol-Myers Squibb) and CP-675,206 (tremelimumab,
Pfizer). In a
particular embodiment, the antibody is ipilimumab.
[00132] "PDL1 antibody" or "anti-PDL1" refers to an antibody directed towards
programmed
death ligand 1 (PDL1). Exemplary antibodies include, but are not limited to,
the antibodies set
forth in U.S. Patent Nos. 8,217,149, 8,383,796, 8,552,154 and 8,617,546. Some
embodiments of
the antibody include avelumab (Merck KGA/Pfizer), durvalumab (AstraZeneca) and
atezolizumab (TECENTRIQ , Roche). In a particular embodiment, the antibody is
atezolizumab.
[00133] The terms "PD1 antibody" and "anti-PD1" refers to an antibody directed
towards
programmed death protein 1 (PD1). Exemplary antibodies include, but are not
limited to, the
antibodies set forth in U.S. Patent Nos. 7,029,674, 7,488,802, 7,521,051,
8,008,449, 8,354,509,
8,617,546 and 8,709,417. Particular embodiments of the antibody include BGB-
A317,
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nivolumab (OPDIVO , Bristol-Myers Squibb), labrolizumab (Merck), and
pembrolizumab
(KEYTRUDA , Merck).
[00134] In some embodiments, the antibody, e.g., anti-CTLA4, anti-PDL1 or anti-
PD!, will be
mixed, prior to administration, with a non-toxic, pharmaceutically acceptable
carrier substance
(e.g., normal saline or phosphate-buffered saline), and may be administered
using any medically
appropriate procedure, for example, including but not limited to, intravenous
or intra-arterial
administration, and injection into the cerebrospinal fluid. In certain cases,
intraperitoneal
intradermal, intracavity, intrathecal or direct administration to a tumor or
to an artery supplying
the tumor may be advantageous.
[00135] The terms "antibody" and "antibodies" as used herein is inclusive of
all types of
immunoglobulins, including IgG, IgM, IgA, IgD, and IgE, or fragments thereof,
that may be
appropriate for the medical uses disclosed herein. The antibodies may be
monoclonal or
polyclonal and may be of any species of origin, including, for example, mouse,
rat, rabbit, horse,
or human. Antibody fragments that retain specific binding to the protein or
epitope, for example,
CTLA4, PDL1 or PD1, bound by the antibody used in the present disclosure are
included within
the scope of the term "antibody." The antibodies may be chimeric or humanized,
particularly
when they are used for therapeutic purposes. Antibodies and antibody fragments
may be
obtained or prepared using various methods.
[00136] In some embodiments, the additional agents may be administered
separately from the
compounds of the present disclosure as part of a multiple dose regimen (e.g.,
sequentially, or on
different overlapping schedules with the administration of one or more
compounds of Formula
(I), or pharmaceutically acceptable salts thereof). In other embodiments,
these agents may be
part of a single dosage form, mixed together with the compounds of the present
disclosure in a
single composition. In some embodiments, these agents can be given as a
separate dose that is
administered at about the same time as one or more compounds of Formula (I),
or
pharmaceutically acceptable salts thereof, are administered (e.g.,
simultaneously with the
administration of one or more compounds of Formula (I), or pharmaceutically
acceptable salts
thereof, (and/or a compound of any of the other formulae, including any
subgenera or specific
compounds thereof)). In some embodiments, at least one of the therapeutic
agents in the
combination therapy is administered using the same dosage regimen (dose,
frequency and
duration of treatment) that is typically employed when the agent is used as
monotherapy for
treating the same cancer. In some embodiments, the patient receives a lower
total amount of at
least one of the therapeutic agents in the combination therapy than when the
agent is used as
monotherapy, e.g., smaller doses, less frequent doses, and/or shorter
treatment duration.
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[00137] When the compositions of the present disclosure include a combination
of a
compound of the formulae described herein and one or more additional agents,
both the
compound and the additional agent can be present at dosage levels of between
about 1 to 100%,
and more preferably between about 5 to 95% of the dosage normally administered
in a
monotherapy regimen.
Cell based IDO1 inhibition assay
[00138] Compounds were screened for their ability to inhibit 1D01 by measuring
the change
in production of L-kynurenine. HeLa cells were maintained in DMEM, high
glucose (Sigma
D5671) with 10% FCS, 1% Pen/Strep, 4mM L-Glutamine, 1% non-essential amino
acids and
1mM sodium pyruyate at 37oC and 5% CO2.
[00139] For the assay, HeLa cells were harvested and plated in growth media
except that FCS
was replaced with 10% human serum (Valley Biomedical # HS101HI). Cells were
plated at
2x104/well in flat-bottom 96-well plates (Corning #3595, Low evaporation
lids). The next day
tryptophan (2500/1, Sigma-Aldrich #T0254) and IFN-y (lOng/ml, Peprotech #300-
02) were
added, followed by addition of compounds. A serial dilution of compounds was
first performed
in 100% DMSO, followed by a second dilution step in culture media. The final
concentration of
DMSO in each well was 0.1% and 0.1% DMSO was used as vehicle control. Cells
were
incubated for additional 48h at 37 C and 5% CO2.
[001401 To measure L-Kynurenine in the cell cultures, plates were centrifuged
at 1000 rpm for
min and 130p1 of the cell culture supernatant was collected and transferred to
a 96-well
polypropylene conical bottom plate (Nunc#249944). After addition of 20111 26%
trichloroacetic
acid, the plate was sealed and incubated at 50 C for 30 min. The plate was
centrifuged at 3400
rpm for 10 min and 60 1 of the supernatant was transferred to a polystyrene
flat bottom 96-well
plate (Corning#3596). Kynurenine was detected by adding 60111 of 1% diethyl
amino 2-
methoxy benzaldehyde in glacial acetic acid and absorbance was read at 460nm
using the
Molecular Devices FlexStation 3 microplate reader. IC50 values were obtained
using CBIS
software.
Human whole blood IDO1 inhibition assay
[00141] Blood was obtained by yenipuncture from healthy volunteers and
collected in
heparinized vials. 170 IL of whole blood was plated into a 96-well flat bottom
plate. A serial
dilution of compounds was first performed in 100% DMSO, followed by a second
dilution step
in culture media. The final concentration of DMSO in each well was 0.1% and
0.1% DMSO was
used as vehicle control. Compounds were added to the blood 15 minutes prior to
the addition of
LPS (10Ong/mL 0111:B4 Sigma-Aldrich L3012), Tryptophan (25004, Sigma-Aldrich
#T0254)
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PCT/US2018/056539
and IFN-y (lOng/ml, Peprotech #300-02). The blood was incubated for 24h at
37oC and 5%
CO2. The next day the plasma was collected and Kynurenine was detected by
Kynurenine
ELISA (ImmuSmol #BA E220) and absorbance was measured using the Molecular
Devices
FlexStation 3 microplate reader. IC50 values were obtained using CBIS
software.
[001421 Results in the cell based IDO1 inhibition assay are provided for
selected compounds.
An IC50 value of "A" is less than or equal to 1 nM, "B" is greater than 1 nM
but less than or
equal to 2 nM, "C" is greater than 2 nM but less than or equal to 5 nM, and
"D" is greater than
nM.
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Date recue/Date Received 2020-08-25
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PCT/US2018/056539
Ex. 1050 (nM)
1
2 A
3
4
6 A
7
8 A
9
11 A
12
13
14 A
16
Abbreviations
[00143] The following abbreviations may be referred to in the Examples and
schemes in the
disclosure:
Ac Acetate/acetic
ACN/MeCN Acetoni tri I e
Aq. Aqueous
Boc/t-Boc t-butoxycarb onyl
DCC N,N' -di cycl oh exyl carb odiimi de
DCM Di chl orom ethane
DIEA Di i sopropyl ethyl ami ne
DMAP 4-dimethylaminopyridine
DMF Dimethylformami de
DMSO Dimethyl sulfoxide
EDCI 1-Ethyl-3 -(3 -di m ethyl am inopropyl)carb odi im i de
Eq. Equivalent(s)
Et0Ac Ethyl acetate
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Date recue/Date Received 2020-08-25
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hr(s) Hour(s)
HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxide
hexafluorophosphate
Hex Hexanes
HOBt 1-Hydroxybenzotriazole
HBTU N,N,N',INT1-Tetramethy1-0-(1H-benzotriazol-1-yOuronium
hexafluorophosphate
KHMDS Potassium hexamethyldisilazide
LC-MS Liquid chromatography/mass spectrometry (Shimazu, Model#: LCMS-
2020)
Molar
Me-THF 2-methyltetrahydrofuran
min Minute(s)
Normal
NMP N-methyl-2-pyrrolidone
0/N Overnight
++PBS Phosphate buffered saline with added calcium(II) and magnesium(II)
Pd(dpp0C12 [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
RT Room temperature
TFA Trifluoracetic acid
THF Tetrahydrofuran
volume
Alkyl abbreviations include: Me (methyl), Et (ethyl), Pr (propyl), iPr
(isopropyl), Bu (butyl),
sBu (sec-butyl), tBu (tertiary butyl).
General Synthetic Schemes
[00144] Compounds of Formula (I) of the present disclosure may be prepared
using various
methods such as those illustrated in the general reaction schemes below, and
in the Examples
section. In the schemes, LG is an appropriate leaving group (e.g., Cl, Br, I,
triflate, and the like),
and R is hydrogen or an alkyl group such as methyl or ethyl. Scheme 1 shows
the preparation of
intermediate 3 from an acid/ester 1 and amine 2 using amide coupling methods.
For example
the acid is coupled with an appropriate amine using amide coupling techniques
(for example,
HATU, EDCI, DCC, HOBt/HBTU, and the like, with an organic base such as
triethylamine or
diisopropylethyl amine), or the ester is coupled with an appropriate amine
using amide coupling
techniques (e.g., iPrMgBr in THF). The acid/ester 1, in turn, are either
commercially available
or can be prepared from a substituted aryl acetonitrile or a substituted aryl
acetic acid ester by
reacting with a substituted or unsubstituted dihalo alkane using an
appropriate base (e.g., NaH,
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KOtBu, KHMDS, and the like) in a polar aprotic solvent (e.g., DMF, DMSO, THF,
and the
like). The cycloalkylarylcarbonitrile is hydrolyzed to the corresponding acid
using aqueous
KOH in an appropriate polar protic solvent (e.g., Me0H, ethanol, ethylene
glycol, and the like).
Scheme 1
R38
R X H2N 0, x R3.
1 R H
LG GO 0 Br,XBr
_mi. LG le O 2 R3b
70- LG 0 N 6
0 NaH 0 a. hydrolysis, followed by R2a R2b
o 3 R3b
R2a R2b
R2a .-,2b amide coupling reagent; or
R2b 1
4 b. iPrMgBr
1) hydrolysis; and
1
2) optional esterification
Br., _, X Br X
-...-- -...--
LG cil LG
CN -VP- is
NaH CN
R2a R2b
R2a R2b
[00145] Compounds of Formula (I) can be prepared from Intermediate 1 or
Intermediate 3 as
shown in Scheme 2. Treatment of 1 with bis(pinacolato)diboron in the presence
of palladium
catalyst and a base to provide the boronate I a, followed by coupling with
bromide 5, and amide
formation with 2 using methods as described in Scheme 1, provides compounds of
Formula (I).
Alternatively, converting 3 to the corresponding boronate 3a using
bis(pinacolato)diboron,
followed by coupling with a bromide 5 provides compounds of Formula (I).
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Date recue/Date Received 2020-08-25
WO 2019/079614 PCT/US2018/056539
Scheme 2
Rla\ 0
N
X R Rib' R' a\ 0
>1--- 9 131 N / \ Br N X
R
0-13 0 ,_
R1 13'
6
N' \
_ 0
0
R2a R2b 1
R2a R2b 0
Pd catalyst, base
la 4
R3a /
bis(pinacolato) a. hydrolysis, followed by
I
R3b
diboron
Pd catalyst,
base H2N 41:1
2
amide coupling reagent; or
b. iPrMgBr
X R
I Ria\ 0 X R3a
LG 0 0 N H
Rib'
N
0 N/ \ = 0 .
R2a R2b
R3b
1 R2a R2b Rla\ 0
I
\N4R1V
N / yBr , Pd catalyst,
\_ base
5
X R3a
X R38 bis(pinacolato) oN H
H e diboron 0-B till N to
LG 43, N 1.
Pd catalyst, 0
0 R3b
Rsb base
R2a R2b
R2a R2b a 3a
EXAMPLES
Intermediate 1. 1-(4-Bromopheny1)-3,3-difluorocyclobutanecarboxylic acid
[00146] Step 1. To a stirring mixture of 2-(4-bromophenyl)acetonitrile (4.00
g, 20.40 mmol)
in DMF (100 mL) at 0 C was added NaH (0.898 g, 22.44 mmol, 60% dispersion in
mineral oil).
After stirring for 15 min, 1,3-dibromo-2,2-dimethoxypropane (5.34 g, 20.40
mmol) was added
and the reaction was heated to 60 C for 12 h. The solution was quenched with
H20 and diluted
with Et0Ac and brine. The organic phase was washed with H20 (3X) and
concentrated. The
crude material was purified on silica gel eluting with 0% to 40% Et0Ac in
hexanes to afford 1-
(4-bromopheny1)-3,3-dimethoxycyclobutanecarbonitrile.
[00147] Step 2. To a stirring mixture of 1-(4-bromopheny1)-3,3-
dimethoxycyclobutanecarbonitrile (4.00 g, 13.50 mmol) in Et0H (40 mL) and H20
(20 mL)
was added 2.5 M aq. NaOH (27.00 mL, 67.52 mmol). The mixture was stirred at
reflux for 16 h
and partitioned between Et0Ac and aq. 1M HC1. The organics were washed with
H20 (3X) and
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Date recue/Date Received 2020-08-25
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concentrated. The crude material containing 1-(4-bromopheny1)-3,3-
dimethoxycyclobutanecarboxylic acid was coevaporated with heptanes and used in
the next step.
[00148] Step 3. To a stirring solution of 1-(4-bromopheny1)-3,3-dimethoxycyclo
butanecarboxylic acid (4.10 g, 13.01 mmol), K2CO3 (5.39, 39.03 mmol) ill DMF
(100 mL) at 0
C was added iodomethane (0.81 mL, 13.01 mmol). The ice-bath was removed and
the mixture
was stirred for 16h at rt then partitioned between Et0Ac and 1:1 H20/brine.
The organics were
washed sequentially with water (1X), aq. 1M citric acid, H20 (2X),
concentrated in vacuo, and
coevaporated twice with Et0Ac. The crude material was sufficiently pure and
afforded methyl
1-(4-bromopheny1)-3,3-dimethoxycyclobutanecarboxylate.
[00149] Step 4. To a stirring mixture of methyl 1-(4-bromopheny1)-3,3-
dimethoxy-
cyclobutanecarboxylate (4.20 g, 12.76 mmol) in dioxane (100 mL) was added aq.
6M HCl
(12.76 mL, 76.55 mmol). The reaction was stirred at 50 C for 16 h, cooled to
rt, and partitioned
between Et0Ac and aq. 1M citric acid. The organics were washed with H20 (3X),
concentrated
in vacuo and coevaporated once with Et0Ac. The residue was purified on silica
gel eluting with
0% to 50% Et0Ac in hexanes to afford methyl 1-(4-bromopheny1)-3-
oxocyclobutanecarboxylate.
[00150] Step 5. Methyl 1-(4-bromopheny1)-3-oxocyclobutanecarboxylate (3.00 g,
10.59
mmol) in DCM (75 mL) was stirred at -20 C and DAST (2.80 mL, 21.18 mmol) was
added.
The reaction was stirred slowly to RT over 16 h and the solvents were removed.
The residue
was partitioned between Et0Ac and saturated aq. NaHCO3. The organic phase was
washed
once more with saturated aq. NaHCO3, H20, and concentrated in vacuo. The crude
material
was purified on silica gel eluting with 0% to 40% Et0Ac in hexanes to afford
methyl 1-(4-
bromopheny1)-3,3-difluorocyclobutanecarboxylate.
[00151] To methyl 1-(4-bromopheny1)-3,3-difluorocyclobutanecarboxylate (1.85g,
6.1 mmol)
in THF (50 mL) was added LiOH (1M, 12 mL). The solution was stirred 0/N,
diluted with
Et0Ac and 1M citric acid and the organic layer was washed with water. The
organic layer was
dried (MgSO4), filtered and evaporated to yield a white solid.
Example 1. 4-(4-(3,3-difluoro-1-((2-methoxypyrimidin-5-
yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide
NN
F F y
NH
0
0
H
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[00152] Step 1. 1-(4-Bromopheny1)-3,3-difluorocyclobutanecarboxylic acid (0.50
g, 1.72
mmol,), HATU (0.79 g, 2.06 mmol) and DMF (20 mL) were combined in an RBF and
stirred at
rt for 5 min followed by the addition of 2-methoxypyrimidin-5-amine (0.22 g,
1.72 mmol) and
D1EA (0.90 mL, 5.16 mmol). The mixture was stirred at RI for 16 h and diluted
with Et0Ac
and aq. 0.5 M HC1. The organics were washed once more with 0.5 M HC1, H20
(2X),
concentrated in vacuo and coevaporated once with Et0Ac. The crude solid
containing 1-(4-
bromopheny1)-3,3-difluoro-N-(2-methoxypyrimidin-5-yl)cyclobutanecarboxamide
was carried
on to the next step.
[00153] Step 2. 1-(4-Bromopheny1)-3,3-difluoro-N-(2-methoxypyrimidin-5-
yl)cyclobutanecarboxamide (0.33 g, 0.82 mmol), bis(pinacolato)diborane (0.31
g, 1.23 mmol),
KOAc (0.20 g, 2.05 mmol) were combined with dioxane (10 mL), and the solution
was purged
with N2 for 5 minutes. Pd(dppf)C12 (0.03 g, 0.04 mmol) was added and the
mixture was stirred
at 90 C for 16 hrs. The cooled solution was filtered through a pad of celite
and the crude 3,3-
difluoro-N-(2-methoxypyrimi din-5-y1)-1-(4-(4,4,5,5 -tetramethyl-1,3 ,2-dioxab
orolan-2 -
yl)phenyl)cyclobutanecarboxamide, was carried on to the next step.
[00154] Step 3. To a solution of 3,3-difluoro-N-(2-methoxypyrimidin-5-y1)-1-(4-
(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanecarboxamide (0.36 g,
0.82 mmol) in
dioxane (10 mL) and saturated aq. NaHCO3 (5 mL) was added 4-bromo-N-
methylpicolinamide
(0.26 mg, 1.23 mmol). The mixture was sparged with N2 for 5 min before
tetrakis(triphenylphosphine) palladium(0) (0.05 g, 0.04 mmol) was added. The
reaction was
heated at 90 C for 16 h under a nitrogen atmosphere and partitioned between
Et0Ac and brine.
The organic phase was extracted with water (2X), concentrated in vacuo and
coevaporated once
with Et0Ac. The crude material was purified on silica gel eluting with a
solvent gradient of
20% to 100% Et0Ac in hexanes to afford 4-(4-(3,3-difluoro-142-methoxypyrimidin-
5-
yl)carbamoyl)cyclobutyl)pheny1)-N-methylpicolinamide. LC-MS: 454 (M-H)+.
Example 2. 4-(4-(1-((2-Methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide
N N
NH
0
0
HN
I N
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[00155] Step 1. 1-(4-Bromopheny1)-N-(2-methoxypyrimidin-5-yl)cyclobutane-1-
carboxamide: Into a 200 mL round bottom flask equipped with a magnetic stir
bar and under N2
was added 2-methoxypyrimidin-5-amine (1.23 g, 9.80 mmol) and 1-(4-
bromophenyl)cyclo-
butanecarboxylic acid (2 g, 7.84 mmol). The solids were dissolved in Et0Ac (20
mL) and
treated with pyridine (1.24 g, 15.68 mmol, 1.27 mL) followed by
propylphosphonic anhydride
(7.48 g, 11.76 mmol, 6.99 mL, 50% purity) in Et0Ac. The yellow-orange solution
was stirred at
24 C for 5 hr, the reaction was worked up by adding HC1 ( 1M, 20 mL). The
Et0Ac layer was
concentrated and purified by column chromatography eluting with 10% to 100 %
Et0Ac/hexanes gradient over 10 min. The desired fractions were combined,
concentrated
and further dried under high vacuum 0/N, yielding a white solid (2 g). LCMS
(ESI+) m/z =
362,364 (M+1, M+3).
[00156] Step 2. N-(2-Methoxypyrimidin-5-y1)-1-(4-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-
2-yl)phenyl)cyclobutane-1-carboxamide: Into a 250 mL round-bottom flask
equipped with a
magnetic stir bar and under N2 was added 4,4,5,5-tetramethy1-2-(4,4,5,5-
tetramethy1-1,3,2-
dioxaborolan-2-y1)-1,3,2-dioxaborolane (1.68 g, 6.63 mmol), 1-(4-bromopheny1)-
N-(2-
methoxypyrimidin-5-yl)cyclobutanecarboxamide (2 g, 5.52 mmol), Pd(dppf)C12,
complex with
DCM (228.24 mg, 276.07 mop and potassium acetate (1.63 g, 16.56 mmol). The
flask was
evacuated under vacuum and refilled with N2. DMF (50 mL) was added, and the
mixture was
degassed for 10 minutes with N2 and then heated to 100 C 0/N. The black
reaction mixture
was cooled to RT, diluted with Et20 (50 mL) and poured into a 250 mL
separatory funnel
containing water (150 mL) and extracted with Et20 (3 x 50 mL). The combined
organic layers
were washed with brine (75 mL), dried over MgSO4, filtered and concentrated
under reduced
pressure. The material was purified on silica gel eluting with 100:0 to 60:40
Hexanes:Et0Ac as
a gradient over 25 minutes. The desired fractions were combined, concentrated
and further dried under high vacuum 0/N to provide a yellow solid (1 g) LCMS
(ESI+) m/z =
410 (M+1).
[00157] Step 3. 4-(4-(1-((2-methoxypyrimidin-5-
yl)carbamoyl)cyclobutyl)phenyl)picolinic
acid: Into a 100 mL round-bottom flask equipped with a magnetic stir bar and
under N2 was
added methyl 4-bromopyridine-2-carboxylate (791 mg, 3.66 mmol), N-(2-
methoxypyrimidin-5-
y1)-1-[4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yOphenyl]cyclobutanecarboxamide (1 g, 2.44
mmol), tetrakis[triphenylphosphine] palladium (282mg, 244.33 mol), sodium
carbonate
(517mg, 4.89 mmol), 1,4-dioxane (15 mL) and water (3 mL). The vial was sealed
and the
suspension degassed with N2 for 10 minutes and the mixture was heated to 100
C 0/N. The
reaction mixture was cooled to RI and diluted with water (30 mL) and acidified
to pH = 5 with
1M citric acid solution (approx 30 mL). The mixture was poured into a Cl-phase
separatory
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cartridge and extracted with CH2C12 (3 x 30 mL), and the combined organic
layers were
concentrated under reduced pressure. The off-white solid was used directly
without further
purification.
[00158] Step 4. 4-(4-(1-((2-Methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)pheny1)-
N-methyl-
picolinamide: Into a 20 mL vial was added 4-(4-(1-((2-methoxypyrimidin-5-
yl)carbamoy1)-
cyclobutyl)phenyl)picolinic acid (80 mg), methyl amine (HC1 salt, 14 mg), HATU
(112 mg) and
DMF (2 mL), followed by N,N-diisopropylethylamine (77 mg). The solution was
stirred for 30
minutes, then water (1 mL) was added. The solution was loaded on a reverse
phase column (50
g) eluting with 100:0 to 0:100 water (0.1% formic acid):MeCN (0.1% formic
acid) as a gradient
over 25 minutes to provide the product. LCMS (ESI+) m/z = 418 (M+1).
[00159] The following compounds were prepared using a similar procedure as
described in
Example 2.
Example Structure and Name MW MS
(ESI+)
o
N
NH
0 432
3 431.49
HN (M+1)(+)
)
N-ethy1-4-(4-(1-((2-methoxypyrimidin-5-y1)-
carbamoyl)cyclobutyl)phenyl)picolinamide
N
NH
0 444
4 443.5
HN
A IV (M+1)9
N-cyclopropy1-4-(4-(1-((2-methoxypyrimidin-5-y1)-
carbamoyl)cyclobutyl)phenyl)picolinamide
N N
NH 422
HN 421.5
1
N
4-(4-(1-((2-methoxypyrimidin-5-yl)carbamoy1)-
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cyclobutyl)pheny1)-N-(methyl-d3)picolinamide
Example 6. 4-(4-(14(5-chloropyrimidin-2-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide
CI
NH
0
HN 0
I N
[00160] Step 1. Methyl 1-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenyl)cyclobutane-1-carboxylate: Into a 40 ml vial equipped with a
magnetic stir bar and
under N2 were added 4,4,5,5-tetramethy1-2-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-y1)-1,3,2-
dioxaborolane (2.26 g, 8.92 mmol), methyl 1-(4-
bromophenyl)cyclobutanecarboxylate (2 g, 7.43
mmol), Pd(dppf)C12, complex with DCM (307.18 mg, 371.56 [tmol) and potassium
acetate (2.19
g, 22.29 mmol). The vial was evacuated under vacuum and refilled with N2. DMF
(15 mL) was
added, and the mixture was degassed for 10 minutes with N2 and then heated to
100 C 0/N.
The black reaction mixture was cooled to RT, and purified by column
chromatography through
silica gel eluting with 100:0 to 0:100 Hexanes:Et0Ac as a gradient over 25
minutes. The desired
fractions were combined, concentrated and further dried under high vacuum 0/N
to provide a
yellow solid (1.6 g) LCMS (ESI+) m/z = 317 (MA).
[00161] Step 2. Methyl 1-(4-(2-(methylcarbamoyl)pyridin-4-
yl)phenyl)cyclobutane-1-
carboxylate: Into a 20 mL microwave vial equipped with a magnetic stir bar and
under N2 were
added 4-bromo-N-methyl-pyridine-2-carboxamide (204mg, 948.77 mol), methyl 1-[4-
(4,4,5,5-
tetramethy1-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutanecarboxylate (300 mg,
948.77 mol),
tetrakis(triphenylphosphine)palladium(0) (109mg, 94.88 mol), potassium
carbonate (393 mg,
2.85 mmol), Me0H (3 mL) and DMF (6 mL). The vial was sealed and the suspension
degassed
with nitrogen for 10 minutes and the mixture was heated to 150 C for 10
minutes. The mixture
was purified by column chromatography through silica gel eluting with 100:0 to
0:100
hexanes:Et0Ac as a gradient over 25 minutes. The desired fractions were
combined,
concentrated and further dried under high vacuum 0/N to provide a yellow solid
(250 mg).
LCMS (ESI+) m/z = 325 (M+1).
[00162] Step 3. 4-(4-(145-chloropyrimidin-2-yl)carbamoyl)cyclobutyl)pheny1)-N-
methylpicolinamide: In a 20 ml vial were added 5-chloropyrimidin-2-amine (93
mg, 721.39
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mol) and THF (5 mL), and the mixture was cooled to 00C. A solution of i-BuMgBr
(2 M, 360
[LL) in ether was added dropwise. After 10 minutes at 23 OC, a solution of
methyl 1-[4-[2-
(methylcarbamoy1)-4-pyridinyl]phenyl]cyclobutanecarboxylate (39 mg, 120.23
pmol) in THE (3
mL) was added, and the mixture stirred at 50 OC for 16 hours. The reaction was
quenched by
adding water (8 mL) and 2 mL of brine. The top organic layer was purified by
column
chromatography through silica gel eluting with 100:0 to 0:100 hexanes:Et0Ac
(10% Me0H) as
a gradient over 25 minutes. The desired fractions were combined, concentrated
and further dried under high vacuum 0/N to provide a yellow solid (250 mg).
LCMS (EST+)
m/z = 422 (M+1)
[00163] The following compounds were prepared using a similar procedure as
described in
Example 6.
N 0
NH
0 391
7 HN 0 390.44
I 1,i (M+1)
N-methy1-4-(4-(1-((3-methylisoxazol-5-y1)carbamoy1)-
cyclobutyl)phenyl)picolinamide
Br
NH
0 466
8 465.34
HN (M+1)
I N
4-(4-(1-((5-bromopyridin-2-yl)carbamoyl)cyclobuty1)-
phenyl)-N-methylpicolinamide
N
NH
0
433
9 HN 432.48
I N (M+1)
N-methy1-4-(4-(1-(pyridin-3-ylcarbamoy1)-
cyclobutyl)phenyl)picolinamide
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FN
NH
0 435
0 434.47
HN (M+1)(p
N
4-(4-(145-fluoro-6-methoxypyridin-3-yl)carbamoy1)-
cyclobutyl)pheny1)-N-methylpicolinamide
N N
NH
0 416
11 415.49
HN (M+1)
I N
4-(4-(1-((2-ethylpyrimidin-5-yl)carbamoy1)-
cyclobutyl)pheny1)-N-methylpicolinamide
CN
NN
NH
0 413
12 HN)O 412.16
04+0
4-(4-(1-((5-cyanopyrimidin-2-yl)carbamoy1)-
cyclobutyl)pheny1)-N-methylpicolinamide
NH
0
13 H30,N 0
386.46
387
H NI
N-methy1-4-(4-(1-(pyridin-2-ylcarbamoyl)cyclobuty1)-
phenyl)picolinamide
ci
NH
0 421
14 H3cN
, 420.90
NI
(1\4+1)
H
4-(4-( 1-((5 -chloropyridin-2-yl)carbamoyl)cyclobutyl)-
phenyl)-N-methylpicolinamide
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Example 15. 6-(142-methoxypyrimidin-5-yl)carbamoyl)cyclobuty1)-N-methy143,4'-
bipyridine]-2'-carboxamide
N = N
0 NH
N 0
,
H NI
[00164] Step 1: 1-(5-bromopyridin-2-yl)cyclobutanecarbonitrile: n-Butyllithium
solution (4.8
mL of a 2.5 M solution in hexanes, 12.0 mmol) was added slowly to a stirred, 0
C solution of
diisopropylamine (1.68 mL, 12.0 mmol) in THE (25 mL). Stirring was continued
at 0 C for 10
min, then the mixture was cooled further to -78 C, at which time cyclobutane
carbonitrile (0.80
mL, 8.56 mmol) was added neat, via syringe. Stirring was continued at -78 C
for 30 min, after
which time a solution of 2,5-dibromopyridine (2.12 g, 8.94 mmol) in THF (6 mL)
was added via
syringe. The cooling bath was then removed, and the reaction was left to stir
at RT 0/N. The
mixture was then diluted with water (100 mL) and EtOAc (200 mL) and
transferred to a
separatory funnel where layers were separated. The aqueous layer was drained,
and the organic
layer was washed with an additional portion of water (50 mL). The combined
aqueous layers
were back-extracted with EtOAc (50 mL), and the organic layers were then
combined, dried
over MgSO4, filtered and concentrated to dryness. The crude residue was
purified by silica gel
column chromatography, eluting with 0% to 30% EtOAc in hexanes to afford,
following
removal of volatiles, 1-(5-bromopyridin-2-yl)cyclobutanecarbonitrile (1.05 g)
as waxy
crystalline solid. LC-MS: 237, 239 (M+H)+.
[00165] Step 2: 1-(5-bromopyridin-2-yl)cyclobutanecarboxylic acid: To a vial
containing 1-(5-
bromopyridin-2-yl)cyclobutanecarbonitrile (1.0 g, 4.2 mmol) and a stirbar were
added H20 (4
mL), concentrated H2SO4, (4 mL) and acetic acid (4 mL). The mixture was warmed
to 115 ,
stirred for 90 min, then cooled to RT and diluted with water (50 mL) and EtOAc
(100 mL), and
then treated with 1M aqueous NaOH (75 mL). The biphasic mixture was then
transferred to a
separatory funnel where layers were separated. The aqueous layer was drained
and discarded,
and the organic layer was washed with water (50 mL), dried over MgSO4,
filtered and
concentrated to dryness to afford 1-(5-bromopyridin-2-yl)cyclobutanecarboxylic
acid (0.94 g) as
a white solid. LC-MS: 256, 258 (M+H)+.
[00166] Step 3: 1-(5-bromopyridin-2-y1)-N-(2-methoxypyrimidin-5-
yl)cyclobutanecarboxamide: To a stirred, RT solution of 1-(5-bromopyridin-2-
yl)cyclobutanecarboxylic acid (0.255 g, 1.0 mmol), 2-methoxypyrimidin-5-amine
(0.150 g, 1.2
mmol) and diisopropylethylamine (0.52 mL, 3.0 mmol) in DMF (6 mL) was added
HATU
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(0.418 g, 1.1 mmol) in one portion. The mixture was stirred at RT for 2 h,
then diluted with
brine (20 mL), water (20 mL), and 1:1 Et0Ac:hexanes (100 mL) and transferred
to a separatory
funnel where layers were separated. The aqueous layer was drained, and the
organic layer was
washed with additional portions of water (3X20 mL) and brine (50 mL). The
combined aqueous
layers were back-extracted with Et0Ac (50 mL). The organic portions were
combined, dried
over MgSO4, filtered and concentrated to dryness. The crude residue was
purified by silica gel
column chromatography, eluting with 0% to 100% Et0Ac in hexanes to afford,
following
removal of volatiles, 1-(5-bromopyridin-2-y1)-N-(2-methoxypyrimidin-5-
yl)cyclobutanecarboxamide (0.28 g) as a tan solid. LC-MS: 363, 365 (M+H)+.
[00167] Step 4: 6-(14(2-methoxypyrimidin-5-yl)carbamoyl)cyclobuty1)-N-methyl-
[3,4'-
bipyridine]-2'-carboxamide: 1-(5-Bromopyridin-2-y1)-N-(2-methoxypyrimidin-5-
yl)cyclobutanecarboxamide (0.28 g, 0.77 mmol), bis(pinacolato)diboron (0.236
g, 0.93 mmol),
and potassium acetate (0.226 g, 2.31 mmol) were combined in dioxane (10 mL)
and the mixture
was bubbled with nitrogen for 5 min at RT. Pd(dppf)C12 complex with DCM
(0.031g, 0.038
mmol) was then added, and the mixture was warmed to 100 C, stirred for 2 hrs,
then cooled to
RT and diluted with Et0Ac (20 mL). The mixture was filtered through celite and
concentrated
to dryness. The residue was redissolved in dioxane (6 mL) and 4-bromo-N-
methylpyridine-2-
carboxamide (0.200 g, 0.93 mmol) was added, followed by saturated aqueous
sodium
bicarbonate (2 mL). The mixture was again bubbled with nitrogen for 5 min,
after which time
Pd(dppf)C12 complex with DCM (0.031g, 0.038 mmol) was added. The mixture was
warmed to
75 C, stirred for 2 hrs, then cooled to RT and diluted with Et0Ac (50 mL) and
water (20 mL).
The aqueous layer was separated and discarded, and the organic layer was dried
over MgSO4,
filtered, and concentrated to dryness. The crude residue was purified by
silica gel column
chromatography, eluting with 0% to 20% Et0Ac in hexanes to afford 6-(1-((2-
methoxypyrimidin-5-yl)carbamoyl)cyclobuty1)-N-methyl-13,4'-bipyridinel-2-
carboxamide
(0.063 g) as a tan solid. LC-MS: 419 (M+H)+.
Example 16. 6-(145-chloropyrimidin-2-yl)carbamoyl)cyclobuty1)-N-methyl-[3,4'-
bipyridine]-
21-carboxamide
rj
N,Aki
0 NH
fJN 0
H NI ,--
[00168] Step 1: methyl 1-(5-bromopyridin-2-yl)cyclobutanecarboxylate:
(Trimethylsilyl)diazomethane (4.42 mmol, 2.21 mL of a 2.0M solution in
hexanes) was added
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slowly over 2 min to a stirred, RT, nitrogen flushed solution of 1-(5-
bromopyridin-2-
yl)cyclobutanecarboxylic acid (0.94 g, 3.69 mmol) in Et0Ac (30 mL) and Me0H (3
mL).
Bubbles were observed during addition, but subsided after approximately 3 min.
The reaction
was left to stir at RT for a total of 20 min, after which time the mixture was
concentrated via
rotary evaporation, redissolved in Et0Ac (100 mL), transferred to a separatory
funnel and
partitioned with saturated aqueous sodium bicarbonate solution (30 mL). The
aqueous layer was
drained and discarded, and the organic layer was dried over MgSO4, filtered,
and concentrated
to dryness. The crude residue was purified using automated silica gel column
chromatography,
eluting with 0% to 20% Et0Ac in hexanes to afford methyl 1-(5-bromopyridin-2-
yl)cyclobutanecarboxylate (0.79 g) as a tan solid. LC-MS: 270, 272 (M+H)+.
[00169] Step 2: 1-(5-bromopyridin-2-y1)-N-(5-chloropyrimidin-2-
yl)cyclobutanecarboxamide:
Isopropylmagnesium bromide solution (2.57 mL of a 2.9M solution in 2-methyl-
THF, 7.46
mmol) was added to a 0 C solution of 5-chloropyrimidin-2-amine (092 g, 7.1
mmol) in THE
(20 mL). The mixture was warmed slowly to RT and left to stir for 20 min,
after which time it
was added via syringe to a stirred, 0 C solution of methyl 1-(5-bromopyridin-2-
yl)cyclobutanecarboxylate (0.96 g, 3.55 mmol) in THF (10 mL). The reaction was
warmed to
RT, stirred for 30 min, and then quenched with 1M aqueous HC1 (20 mL). The
crude mixture
was diluted with Et0Ac (150 mL) and saturated aqueous sodium bicarbonate (100
mL) then
transferred to a separatory funnel where layers were separated. The aqueous
layer was drained,
and the organic layer was washed water (50 mL), then dried over MgSO4,
filtered, and
concentrated. The residue was purified by silica gel column chromatography,
eluting with 0%
to 100% Et0Ac in hexanes to afford, following removal of volatiles, 1-(5-
bromopyridin-2-y1)-
N-(5-chloropyrimidin-2-yl)cyclobutanecarboxamide (0.91 g) as tan solid. LC-MS:
369
(M+H)+.
[00170] Step 3: 6-(1-((5-chloropyrimidin-2-yl)carbamoyl)cyclobuty1)-N-methyl-
[3,4'-
bipyridine]-2'-carboxamide: 1-(5-Bromopyridin-2-y1)-N-(5-chloropyrimidin-2-
yl)cyclobutanecarboxamide (0.55 g, 1.5 mmol), bis(pinacolato)diboron (0.495 g,
1.95 mmol),
and potassium acetate (0.441 g, 4.5 mmol) were combined in dioxane (20 mL) and
the mixture
was bubbled with nitrogen for 5 min at RT. Pd(dppf)C12 complex with DCM
(0.060g, 0.074
mmol) was then added, and the mixture was warmed to 100 C, stirred for 2 hrs,
then cooled to
RT and 4-bromo-N-methylpyridine-2-carboxamide (0.39 g, 1.8 mmol) was added,
followed by
saturated aqueous sodium bicarbonate (4 mL). The mixture was again bubbled
with nitrogen for
min, after which time additional Pd(dppf)C12 complex with DCM (0.030 g, 0.037
mmol) was
added. The mixture was warmed to 85 C, stirred 0/N, then cooled to RT and
diluted with
Et0Ac (100 mL) and water (30 mL). The aqueous layer was separated and
discarded, and the
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organic layer was dried over MgSO4, filtered, and concentrated to dryness. The
crude residue
was purified by reversed-phase column chromatography, eluting with 5% to 100%
ACN
(modified with 0.5% formic acid) in water (modified with 0.5% formic acid).
Product-
containing fractions were then combined in a separatory funnel and partitioned
with Et0Ac (100
mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was
drained and
discarded, and the organic layer was dried over MgSO4, filtered, and
concentrated to dryness to
afford 6-(14(5-chloropyrimidin-2-yl)carbamoyl)cyclobuty1)-N-methyl-[3,4'-
bipyridine]-2'-
carboxamide (0.49 g) as a tan solid. LC-MS: 423 (M+H)+.
[00171] While preferred embodiments of the present disclosure have been shown
and
described herein, it will be obvious to those skilled in the art that such
embodiments are
provided by way of example only. Numerous variations, changes, and
substitutions will now
occur to those skilled in the art without departing from the present
disclosure. It should be
understood that various alternatives to the embodiments of the present
disclosure described
herein may be employed in practicing the present disclosure. It is intended
that the following
claims define the scope of the present disclosure and that methods and
structures within the
scope of these claims and their equivalents be covered thereby.
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