Substituted pyrazolopyrimidines and substituted purines and their use as inhibitors of ubiquitin-specific processing protease 1 (USP1)

Abstract

The present disclosure provides compounds having formula I, and pharmaceutically acceptable salts and solvates thereof, wherein X 1 , X 2 , X 11 , X 12 , R 1 , R 3 , R 5 , R 5’ , R 6 , and R 7 is defined as defined herein. The present disclosure also relates to the use of compounds of Formula I for inhibiting USP1 protein and / or treating disorders responsive to inhibition of USP1 protein and USP1 activity. The compounds of the present disclosure are particularly useful for treating cancer. [C456] TIFF2022511515000716.tif3856

Description

[Technical Field]

[0001] Background to the disclosure The present disclosure provides substituted pyrazolopyrimidines and substituted purines as inhibitors of ubiquitin-specific processing protease 1 (USP1), and methods of treating conditions and diseases in which inhibition of USP1 provides benefit. In particular, the present disclosure provides methods of treating cancer by administering USP1 inhibitors. [Background technology]

[0002] Ubiquitin is a small (76 amino acid) protein that is post-transcriptionally attached to target proteins. The outcome of ubiquitination is determined by the number and linkage topology of ubiquitin molecules conjugated to the target protein. For example, proteins exhibiting lysine 48-linked polyubiquitin chains are generally targeted to the proteasome for degradation, while monoubiquitinated or polyubiquitin chains linked through other lysines regulate non-proteolytic functions, such as cell cycle regulation, DNA damage repair, transcription, and endocytosis. Ubiquitination is a reversible process, and enzymes called deubiquitinases remove ubiquitin from target proteins.

[0003] USP1 is a deubiquitinase that plays a role in DNA damage repair. USP1 interacts with UAF1 (USP1-associated factor 1) to form a complex required for deubiquitinase activity. The USP1 / UAF1 complex deubiquitinates monoubiquitinated PCNA (proliferating cell nuclear antigen) and monoubiquitinated FANCD2 (Fanconi anemia complementation group D2), proteins that play important functions in the translesion synthesis (TLS) and Fanconi anemia (FA) pathways, respectively. The USP1 / UAF1 complex also deubiquitinates Fanconi anemia complementation group I (FANCI). These two pathways are essential for repair of DNA damage induced by DNA cross-linking agents such as cisplatin and mitomycin C (MMC).

[0004] Safe and effective treatments that target deubiquitinases are unknown, not yet commercially available, or not yet in clinical development. Summary of the Invention [Means for solving the problem]

[0005] In one aspect, the present disclosure relates to compounds having formula I, or a pharmaceutically acceptable salt or solvate thereof (also referred to herein as disclosed compounds): [ka] During the ceremony, X 1 and X 2 each independently represents N and CR 2 is selected from R 1 and R 2 each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 3 is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, or optionally substituted pyrazolyl; X 11 and X 12 are each independently selected from N and CH; R 5’ are independently hydrogen, optionally substituted (C-C) alkyl, optionally substituted (C-C) alkenyl, optionally substituted (C-C) alkynyl, optionally substituted (C-C) alkoxy, (C-C) haloalkyl, (C-C) haloalkoxy, (C-C) hydroxyalkyl, cyano, halo, sulfonamido, -C(=O)R 23 , -C(=O)OR 24 , -NR 32a R 32b , -NR 31a C(=O)R25 , -NR 31a C(=O)NR 31a R 31b , -C(=O)NR 31a R 31b , -S(O)2R 27 , -NR 31a SO2R 27 , optionally substituted (C6-C 14 ) aryl, optionally substituted (C6-C 14 )ar-(C1-C2)alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C1-C2)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted ((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C1-C2)alkyl, optionally substituted —O—(C6-C 14 ) aryl, optionally substituted —O—(C6-C 14 )ar-(C1-C2)alkyl, optionally substituted -O-heteroaryl, optionally substituted -O-heteroar-(C1-C2)alkyl, optionally substituted -O-(C3-C8)cycloalkyl, optionally substituted -O-((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted -O-heterocyclo, and optionally substituted -O-heterocyclo-(C1-C2)alkyl; R 5 are independently selected from optionally selected (C-C)alkyl, optionally selected (C-C)alkenyl, optionally selected (C-C)alkynyl, optionally selected (C-C)alkoxy, (C-C)haloalkyl, (C-C)haloalkoxy, (C-C)hydroxyalkyl, cyano, halo, sulfonamido, -C(=O)R 23 , -C(=O)OR 24 , -NR 32a R 32b , -NR 31a C(=O)R 25 , -NR 31a C(=O)NR 31a R 31b, -C(=O)NR 31a R 31b , -S(O)2R 27 , -NR 31a SO2R 27 , optionally selected (C6-C 14 ) aryl, optionally selected (C6-C 14 )ar-(C1-C2)alkyl, optionally heteroaryl, optionally heteroar-(C1-C2)alkyl, optionally (C3-C8)cycloalkyl, optionally ((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally heterocyclo, optionally heterocyclo-(C1-C2)alkyl, optionally —O—(C6-C 14 ) aryl, optionally selected from —O—(C6-C 14 )ar-(C1-C2)alkyl, optionally —O-heteroaryl, optionally —O-heteroar-(C1-C2)alkyl, optionally —O—(C3-C8)cycloalkyl, optionally —O—((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally —O-heterocyclo, and optionally —O-heterocyclo-(C1-C2)alkyl; or R on adjacent atoms 5 One of the following and R 5’ one of which, together with the atom to which they are attached, is optionally substituted (C6-C 14 ) form an aryl ring or R on adjacent atoms 5 One of the following and R 5’ together with the atom to which they are attached to form an optionally substituted heteroaryl ring, or R on an adjacent atom 5 One of the following and R 5’ together with the atom to which they are attached to form an optionally substituted (C-C)cycloalkyl ring, or R on an adjacent atom 5 One of the following and R 5’together with the atom to which they are attached to form an optionally substituted heterocycloalkyl ring, or on the same atom to which they are attached, R on adjacent atoms 5 One of the following and R 5’ are joined together to form an optionally substituted spirocycloalkyl ring, or are joined by R on adjacent atoms on the same atom to which they are attached. 5 One of the following and R 5’ one of which forms an optionally substituted spiroheterocycloalkyl ring; R 6 and R 7 each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 23 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl; R 31a and R 31b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, alkoxyalkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, aralkyl, and (heteroaryl)alkyl; R 24 , R 25 , R 27 , R32a , and R 32b is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl.

[0006] In some embodiments, the disclosed compounds exhibit improved solubility, for example, as measured by an ADME solubility assay as disclosed herein.

[0007] In some embodiments, the disclosed compounds exhibit improved metabolic stability, for example, as measured by liver microsome and hepatocyte metabolic stability assays as disclosed herein.

[0008] In other embodiments, the disclosed compounds exhibit improved duration of action and oral exposure in vivo.

[0009] In some embodiments, the disclosed compounds are compounds having formula I, wherein R 5’ is selected from hydrogen, halo, and optionally substituted (C1-C6) alkyl.

[0010] In some embodiments, the disclosed compounds are compounds having formula I, wherein X 11 and X 12 At least one of X is N. In some embodiments, 11 is N. In some embodiments, X 12is N.

[0011] In another embodiment, the disclosed compounds are compounds having formula I, wherein X 11 and X 12 In some embodiments, at least one of X is CH. 11 is CH. In some embodiments, X 12 is CH.

[0012] In one embodiment, the disclosed compounds are compounds having formula I, wherein X 11 and X 12 Each of is N.

[0013] In one embodiment, the disclosed compounds are compounds having formula I, wherein X 11 and X 12 Each of the is CH.

[0014] In some embodiments, X 11 and X 12 One of them is N and the other is X 11 and X 12 and the other is CH. In one embodiment, X 11 is N and X 12 is CH. In another embodiment, X 11 is CH and X 12 is N.

[0015] In some embodiments, [ka] teeth, [ka] is.

[0016] In some embodiments, [ka] teeth, [ka] is selected from.

[0017] In some embodiments, R 3 The above optional substituents are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkylaralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (C 1-4 )haloalkoxy)alkyl, and (heteroaryl)alkyl; or R 3 Two of the above optional substituents, together with the carbon or nitrogen atom to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted heterocyclo, an optionally substituted aryl, or an optionally substituted heteroaryl group.

[0018] In some embodiments, R 3 is an optionally substituted phenyl, wherein the phenyl is optionally substituted at the 2-position, optionally substituted at the 6-position, optionally disubstituted at the 2- and 6-positions, or optionally disubstituted at the 2- and 3-positions.

[0019] In some embodiments, R 3is an optionally substituted pyrid-3-yl or an optionally substituted pyrid-4-yl, wherein the pyrid-3-yl is optionally substituted at the 2-position, optionally substituted at the 4-position, or optionally disubstituted at the 2- and 4-positions, and the pyrid-4-yl is optionally substituted at the 3-position, optionally substituted at the 5-position, or optionally disubstituted at the 3- and 5-positions.

[0020] In some embodiments, R 3 is an optionally substituted pyrimidin-5-yl, wherein the pyrimidin-5-yl is optionally substituted at the 4-position, optionally substituted at the 6-position, optionally disubstituted at the 4- and 6-positions, or optionally trisubstituted at the 2-, 4-, and 6-positions.

[0021] In some embodiments, R 3 is an optionally substituted pyrazol-5-yl, wherein the pyrazol-5-yl is optionally substituted at the 1-position, optionally substituted at the 4-position, or optionally disubstituted at the 1- and 4-positions.

[0022] In some embodiments, R 3 is substituted, the substituents being independently selected from methoxy, deuteromethoxy, ethoxy, isopropoxy, t-butoxy, difluoromethoxy, 2-fluoroethoxy, 2-methoxyethoxy, cyclopropoxy, cyclobutoxy, (tetrahydrofuran-3-yl)oxy, benzyloxy, methyl, ethyl, isopropyl, 2-fluoroisopropyl, t-butyl, cyclopropyl, cyclobutyl, methylcyclopropyl, pyrrolidin-1-yl, azetidin-1-yl, methylamino, dimethylamino, cyano, halo, methylthio, methylsulfonyl, and ethylsulfonyl.

[0023] In some embodiments, R 3 teeth, [ka] [ka] is selected from the group consisting of:

[0024] In some embodiments, R 5 The above optional substituents are independently hydrogen, halo, nitro, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, hydroxy, carboxy, carboxyalkyl, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, aralkylamino, heteroaralkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkylamino, alkoxyalkyl, (alkoxyalkyl)amino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (carboxamido)alkyl, mercaptoalkyl, (cyano)alkyl, (cycloalkyl)alkyl, aralkyl, aralkyloxy, alkylcarbonyl, arylcarbonyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, (C 1-4 haloalkoxy)alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, carboxamido, sulfonyl, sulfonamido, sulfamido, alkylsulfonyl, alkylsulfonamido, alkylsulfamido, arylsulfonyl, aryloxy, heteroaryloxy, -C(=O)R 23 , -C(=O)OR 24 , -C(=O)NR 31a R 31b , -NR 31a C(=O)R 25 , -NR 31a C(=O)OR 26 , -NR 31a C(=O)NR 31a R 31b , -NR 31a SO2R 27 , -OC(=O)R 28 , -OC(=O)OR29 , -OC(=O)NR 31a R 31b , -OSO2R 30 , and -NR 32a R 32b Selected from or R 5 two of the above optional substituents, together with the carbon or nitrogen atom to which they are attached, form a cycloalkyl, heterocyclo, aryl, or heteroaryl group; R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 32a , and R 32b each is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl.

[0025] In some embodiments, R 5 is an optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, cyano, halo, sulfonamido, -C(=O)R 23 , -C(=O)OR 24 , -NR 32a R 32b , -NR31a C(=O)R 25 , -NR 31a C(=O)NR 31a R 31b , -C(=O)NR 31a R 31b , -S(O)2R 27 , and -NR 31a SO2R 27 , optionally substituted —O—(C6-C 14 ) aryl, optionally substituted —O—(C6-C 14 )ar-(C1-C2)alkyl, optionally substituted -O-heteroaryl, optionally substituted -O-heteroar-(C1-C2)alkyl, optionally substituted -O-(C3-C8)cycloalkyl, optionally substituted -O-((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted -O-heterocyclo, optionally substituted -O-heterocyclo-(C1-C2)alkyl.

[0026] In some embodiments, R 5 is optionally substituted (C6-C 14 ) aryl, optionally substituted (C6-C 14 )ar-(C1-C2)alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C1-C2)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted ((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C1-C2)alkyl.

[0027] In some embodiments, R 5 is optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazolyl, or optionally substituted tetrazolyl.

[0028] In some embodiments, R 5 is an optionally substituted imidazolyl.

[0029] In some embodiments, R 5 is an optionally substituted pyrazolyl.

[0030] In some embodiments, R 5 is an optionally substituted triazolyl.

[0031] In some embodiments, R 5 is an optionally substituted heteroaryl such as imidazolyl, pyrazolyl, or triazolyl, where the substituents are independently selected from halo, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, oxetan-3-yl, and methylazetidinyl.

[0032] In some embodiments, R 5 teeth, [ka] [ka] is selected from the group consisting of:

[0033] In some embodiments, the compound has formula II: [ka] In the formula, X 3 N and CR 10 Selected from X 4 N and CR 11 Selected from X 5 N and CR 12 is selected from R 8 , R 9 , R 10 , R 11 , and R 12each is independently hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkylaralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (C 1-4 (haloalkoxy)alkyl, or (heteroaryl)alkyl.

[0034] In some embodiments, the disclosed compounds have Formula III, Formula IV, Formula V, Formula VI, or Formula VIa: [ka] [ka] In the formula, X 1 , X 2 , R 1 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 11 Each of is as defined above for Formula II.

[0035] In some embodiments, R 5 teeth, [ka] and In the formula, X6 is NR 13 and CR 18 Selected from X 7 is NR 14 and CR 19 Selected from X 8 is NR 15 and CR 20 Selected from X 9 is NR 16 and CR 21 Selected from X 10 is NR 17 and CR 22 is selected from R 13 , R 14 , R 15 , R 16 , and R 17 each is absent or independently selected from hydrogen, halo, methyl, ethyl, isopropyl, cyclopropyl, methoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, and methylazetidinyl; R 18 , R 19 , R 20 , R 21 , and R 22 are each independently selected from hydrogen, halo, methyl, ethyl, isopropyl, cyclopropyl, methoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, and methylazetidinyl.

[0036] In some embodiments, the disclosed compounds have formula VII, formula VIII, formula IX, formula X, formula XI, or formula XII: [ka] [ka] In the formula, X 1 , X 2 , R 1 , R3 , R 6 , R 7 , R 15 , R 16 , R 17 , R 20 , R 21 and R 22 Each of is as defined above for Formula II.

[0037] In another aspect, the disclosure relates to a disclosed compound having formula XIII, or a pharmaceutically acceptable salt or solvate thereof: [ka] During the ceremony, X 1a and X 2a each independently represents N and CR 2a is selected from R 2a is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, alkoxyalkyl, alkylsulfonyl, alkylthio, aryl, heteroaryl, and heterocyclo; Each of the remaining substituents is defined as disclosed herein.

[0038] In some embodiments, the disclosed compound is one of the specific compounds listed in the detailed description, or a pharmaceutically acceptable salt or solvate thereof.

[0039] In some embodiments, the disclosed compounds inhibit the USP1 protein.

[0040] In some embodiments, the disclosed compounds have an IC of less than about 1 μM in a Ub-Rho deubiquitination assay. 50 Inhibits USP1 protein at high levels.

[0041] In some embodiments, the Ub-Rho deubiquitination assay is the assay disclosed in Example 26.

[0042] In one aspect, the disclosure relates to a method of treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt or solvate thereof.

[0043] In one aspect, the present disclosure relates to a pharmaceutical composition comprising a disclosed compound, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0044] In some embodiments, the present disclosure relates to pharmaceutical compositions for use in the treatment of cancer.

[0045] In some embodiments, the present disclosure relates to the disclosed compounds for use in the treatment of cancer.

[0046] In some embodiments, the disclosure relates to the use of a disclosed compound for the manufacture of a medicament for the treatment of cancer.

[0047] In one aspect, the disclosure relates to a kit comprising a disclosed compound, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a disclosed compound, and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition to a patient with cancer.

[0048] In one aspect, the disclosure relates to a method of treating cancer in a patient comprising administering to the patient a disclosed compound, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a disclosed compound.

[0049] In some embodiments, the cancer is selected from the group consisting of a hematological cancer, a lymphatic cancer, and a DNA damage repair pathway deficient cancer.

[0050] In some embodiments, the cancer comprises cancer cells having a mutation in the gene encoding p53. In some embodiments, the mutation in the gene encoding p53 is a germline mutation. In some embodiments, the mutation in the gene encoding p53 is a somatic mutation. In some embodiments, the cancer comprises cancer cells having a loss-of-function mutation in the gene encoding p53.

[0051] In some embodiments, the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, and breast cancer.

[0052] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0053] In some embodiments, the cancer is colon cancer.

[0054] In some embodiments, the cancer is bladder cancer.

[0055] In some embodiments, the cancer is ovarian cancer or breast cancer.

[0056] In some embodiments, the cancer is ovarian cancer.

[0057] In some embodiments, the cancer is breast cancer.

[0058] In some embodiments, the cancer is triple-negative breast cancer.

[0059] In some embodiments, the cancer comprises cancer cells that have elevated levels of RAD18.

[0060] In some embodiments, the elevated level of RAD18 is an elevated RAD18 protein level.

[0061] In some embodiments, the elevated levels of RAD18 are elevated RAD18 mRNA levels.

[0062] In some embodiments, elevated levels of RAD18 are detected prior to administration.

[0063] In another aspect, the present disclosure relates to a method further comprising detecting RAD18 levels in a cancer sample obtained from the subject.

[0064] In some embodiments, the cancer is selected from the group consisting of bone cancer, including osteosarcoma and chondrosarcoma; brain cancer, including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; soft tissue cancer, including rhabdoid and sarcoma; kidney cancer, bladder cancer, skin cancer, including melanoma; and lung cancer, including non-small cell lung cancer, colon cancer, uterine cancer, nervous system cancer, head and neck cancer, pancreatic cancer, and cervical cancer.

[0065] In some embodiments, the cancer is a DNA damage repair pathway deficient cancer.

[0066] In some embodiments, the cancer comprises cancer cells having a mutation in the gene encoding p53. In some embodiments, the mutation in the gene encoding p53 is a germline mutation. In some embodiments, the mutation in the gene encoding p53 is a somatic mutation. In some embodiments, the cancer comprises cancer cells having a loss-of-function mutation in the gene encoding p53.

[0067] In some embodiments, the cancer is a BRCA1 mutant cancer. In some embodiments, the BRCA1 mutation is a germline mutation. In some embodiments, the BRCA1 mutation is a somatic mutation. In some embodiments, the BRCA1 mutation results in a BRCA1 deficiency.

[0068] In some embodiments, the cancer is a BRCA2 mutant cancer. In some embodiments, the BRCA2 mutation is a germline mutation. In some embodiments, the BRCA2 mutation is a somatic mutation. In some embodiments, the BRCA2 mutation results in a BRCA2 deficiency.

[0069] In some embodiments, the cancer is a BRCA1 mutant cancer and a BRCA2 mutant cancer.

[0070] In some embodiments, the cancer is a BRCA1-deficient cancer.

[0071] In some embodiments, the cancer is a BRCA2-deficient cancer.

[0072] In some embodiments, the cancer is a BRCA1-deficient cancer and a BRCA2-deficient cancer.

[0073] In some embodiments, the cancer is a poly(ADP-ribose) polymerase ("PARP") inhibitor refractory or resistant cancer. In some embodiments, the cancer is a PARP inhibitor resistant or refractory BRCA1, BRCA2, or BRCA1 and BRCA2 mutant cancer. In some embodiments, the cancer is a PARP inhibitor resistant or refractory BRCA1, BRCA2, or BRCA1 and BRCA2 deficient cancer.

[0074] In some embodiments, the cancer has a mutation in the gene encoding ataxia telangiectasia mutated (ATM) protein kinase. In some embodiments, the ATM mutation is a germline mutation. In some embodiments, the ATM mutation is a somatic mutation. In some embodiments, the cancer is an ATM-deficient cancer.

[0075] In some embodiments, the cancer has a mutation in the genes encoding at least two of p53, BRCA1, BRCA2, and ATM.

[0076] In another aspect, the present disclosure relates to a method of treating a USP1 protein-mediated disorder, comprising administering to a patient in need thereof a disclosed compound, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the disclosed compound, in an amount effective to treat the USP1 protein-mediated disorder.

[0077] In some embodiments, the USP1 protein comprises the amino acid sequence of SEQ ID NO:1.

[0078] In another aspect, the present disclosure relates to a method of inhibiting USP1 protein, comprising contacting the USP1 protein with a disclosed compound, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a disclosed compound.

[0079] In some embodiments, the contacting occurs in vitro.

[0080] In some embodiments, the contacting occurs in vivo.

[0081] In another aspect, the disclosure relates to a method of treating cancer in a patient comprising administering a USP1 inhibitor to the subject, wherein the cancer comprises cancer cells having a mutation in the gene encoding p53.

[0082] In some embodiments, a mutation in the gene encoding p53 has been detected prior to administration.

[0083] In some embodiments, the method further comprises detecting a mutation in the gene encoding p53 in a cancer sample obtained from the patient.

[0084] In another aspect, the disclosure relates to a method of selecting a patient having cancer for treatment with a USP1 inhibitor, the method comprising detecting whether the cancer comprises cancer cells having a mutation in the gene encoding p53, and if the cancer comprises cancer cells having a mutation in the gene encoding p53, the patient is selected for treatment with the USP1 inhibitor.

[0085] In another aspect, the disclosure relates to a USP1 inhibitor for use in treating cancer in a patient, the cancer comprising cancer cells having a mutation in the gene encoding p53.

[0086] In some embodiments, a patient is identified as responding to treatment with a USP1 inhibitor by detecting cancer cells having a mutation in the gene encoding p53 in a cancer sample obtained from the patient, wherein the cancer cells having a mutation in the gene encoding p53 in the cancer sample identify the patient as responding to treatment with a USP1 inhibitor.

[0087] In another aspect, the disclosure relates to a USP1 inhibitor for use in treating cancer in a subject identified as responsive to treatment with a USP1 inhibitor by cancer cells having a mutation in the gene encoding p53 in a cancer sample obtained from the subject, wherein the cancer cells having a mutation in the gene encoding p53 in the cancer sample identify the patient as responsive to treatment with the USP1 inhibitor.

[0088] In some embodiments, the USP1 inhibitor is not administered to the subject if a mutation in the gene encoding p53 is not detected in the cancer sample obtained from the subject.

[0089] In another aspect, the disclosure relates to an in vitro method for identifying a subject having cancer that will respond to treatment with a USP1 inhibitor, the method comprising detecting a mutation in a gene encoding p53 in a cancer sample obtained from the subject, wherein a mutation in the gene encoding p53 in the cancer sample indicates that the patient will respond to treatment with a USP1 inhibitor.

[0090] In another aspect, the present disclosure relates to the in vitro use of at least one agent capable of specifically detecting mutations in the gene encoding p53 to identify subjects with cancer that will respond to treatment with a USP1 inhibitor.

[0091] In some embodiments, the mutation in the gene encoding p53 is a loss-of-function mutation.

[0092] In another aspect, the disclosure relates to a method of treating cancer in a patient comprising administering a USP1 inhibitor to the subject, wherein the cancer comprises cancer cells having a mutation in the gene encoding BRCA1.

[0093] In some embodiments, a mutation in the gene encoding BRCA1 has been detected prior to administration.

[0094] In some embodiments, the method further comprises detecting a mutation in the gene encoding BRCA1 in a sample obtained from the patient (eg, a cancer sample or a blood sample).

[0095] In another aspect, the disclosure relates to a method of selecting a patient having cancer for treatment with a USP1 inhibitor, the method comprising detecting whether the cancer comprises cancer cells having a mutation in the gene encoding BRCA1, and if the cancer comprises cancer cells having a mutation in the gene encoding BRCA1, the patient is selected for treatment with the USP1 inhibitor.

[0096] In another aspect, the disclosure relates to a USP1 inhibitor for use in treating cancer in a patient, the cancer comprising cancer cells having a mutation in the gene encoding BRCA1.

[0097] In some embodiments, a patient is identified as responding to treatment with a USP1 inhibitor by detecting a mutation in the gene encoding BRCA1 in a sample obtained from the patient (e.g., a cancer sample or a blood sample), wherein the mutation in the gene encoding BRCA1 in the sample identifies the patient as responding to treatment with a USP1 inhibitor.

[0098] In another aspect, the disclosure relates to a USP1 inhibitor for use in treating cancer in a subject identified as responsive to treatment with a USP1 inhibitor by cancer cells having a mutation in the gene encoding BRCA1 in a sample (e.g., a cancer sample or a blood sample) obtained from the subject, wherein the cancer cells in the sample having a mutation in the gene encoding BRCA1 identify the patient as responsive to treatment with the USP1 inhibitor.

[0099] In some embodiments, the USP1 inhibitor is not administered to a subject if a mutation in the gene encoding BRCA1 is not detected in a sample obtained from the subject (e.g., a cancer sample or a blood sample).

[0100] In another aspect, the disclosure relates to an in vitro method for identifying a subject having cancer that will respond to treatment with a USP1 inhibitor, the method comprising detecting a mutation in the gene encoding BRCA1 in a sample (e.g., a cancer sample or a blood sample) obtained from the subject, wherein a mutation in the gene encoding BRCA1 in the sample indicates that the patient will respond to treatment with a USP1 inhibitor.

[0101] In another aspect, the present disclosure relates to the in vitro use of at least one agent capable of specifically detecting mutations in the gene encoding BRCA1 to identify subjects with cancer that will respond to treatment with a USP1 inhibitor.

[0102] In some embodiments, the mutation in the gene encoding BRCA1 is a loss-of-function mutation.

[0103] In another aspect, the disclosure relates to a method of treating cancer in a patient comprising administering a USP1 inhibitor to the subject, wherein the cancer comprises cancer cells having a mutation in the gene encoding BRCA2.

[0104] In some embodiments, a mutation in the gene encoding BRCA2 has been detected prior to administration.

[0105] In some embodiments, the method further comprises detecting a mutation in the gene encoding BRCA2 in a sample obtained from the patient (eg, a cancer sample or a blood sample).

[0106] In another aspect, the disclosure relates to a method of selecting a patient having cancer for treatment with a USP1 inhibitor, the method comprising detecting whether the cancer comprises cancer cells having a mutation in the gene encoding BRCA2, and if the cancer comprises cancer cells having a mutation in the gene encoding BRCA2, the patient is selected for treatment with the USP1 inhibitor.

[0107] In another aspect, the disclosure relates to a USP1 inhibitor for use in treating cancer in a patient, the cancer comprising cancer cells having a mutation in the gene encoding BRCA2.

[0108] In some embodiments, a patient is identified as responding to treatment with a USP1 inhibitor by detecting a mutation in the gene encoding BRCA2 in a sample obtained from the patient (e.g., a cancer sample or a blood sample), wherein the mutation in the gene encoding BRCA2 in the sample identifies the patient as responding to treatment with a USP1 inhibitor.

[0109] In another aspect, the disclosure relates to a USP1 inhibitor for use in treating cancer in a subject identified as responsive to treatment with a USP1 inhibitor by cancer cells having a mutation in the gene encoding BRCA2 in a sample (e.g., a cancer sample or a blood sample) obtained from the subject, wherein the cancer cells in the sample having a mutation in the gene encoding BRCA2 identify the patient as responsive to treatment with the USP1 inhibitor.

[0110] In some embodiments, the USP1 inhibitor is not administered to a subject if a mutation in the gene encoding BRCA2 is not detected in a sample obtained from the subject (e.g., a cancer sample or a blood sample).

[0111] In another aspect, the disclosure relates to an in vitro method for identifying a subject having cancer that will respond to treatment with a USP1 inhibitor, the method comprising detecting a mutation in the gene encoding BRCA2 in a sample (e.g., a cancer sample or a blood sample) obtained from the subject, wherein a mutation in the gene encoding BRCA2 in the sample indicates that the patient will respond to treatment with a USP1 inhibitor.

[0112] In another aspect, the present disclosure relates to the in vitro use of at least one agent capable of specifically detecting mutations in the gene encoding BRCA2 to identify subjects with cancer that will respond to treatment with a USP1 inhibitor.

[0113] In some embodiments, the mutation in the gene encoding BRCA2 is a loss-of-function mutation.

[0114] In another aspect, the disclosure relates to a method of treating cancer in a patient comprising administering a USP1 inhibitor to the subject, wherein the cancer comprises cancer cells having a mutation in the gene encoding ATM.

[0115] In some embodiments, a mutation in the gene encoding ATM has been detected prior to administration.

[0116] In some embodiments, the method further comprises detecting a mutation in the gene encoding ATM in a sample obtained from the patient.

[0117] In another aspect, the disclosure relates to a method of selecting a patient having cancer for treatment with a USP1 inhibitor, the method comprising detecting whether the cancer comprises cancer cells having a mutation in a gene encoding ATM, and if the cancer comprises cancer cells having a mutation in a gene encoding ATM, the patient is selected for treatment with the USP1 inhibitor.

[0118] In another aspect, the disclosure relates to a USP1 inhibitor for use in treating cancer in a patient, the cancer comprising cancer cells having a mutation in the gene encoding ATM.

[0119] In some embodiments, a patient is identified as responding to treatment with a USP1 inhibitor by detecting cancer cells having a mutation in the gene encoding ATM in a cancer sample obtained from the patient, wherein the cancer cells having a mutation in the gene encoding ATM in the cancer sample identify the patient as responding to treatment with a USP1 inhibitor.

[0120] In another aspect, the disclosure relates to a USP1 inhibitor for use in treating cancer in a subject identified as responsive to treatment with a USP1 inhibitor by cancer cells having a mutation in a gene encoding ATM in a cancer sample obtained from the subject, wherein the cancer cells having a mutation in a gene encoding ATM in the cancer sample identify the patient as responsive to treatment with the USP1 inhibitor.

[0121] In some embodiments, the USP1 inhibitor is not administered to the subject if a mutation in the gene encoding ATM is not detected in a cancer sample obtained from the subject.

[0122] In another aspect, the disclosure relates to an in vitro method for identifying a subject having cancer that will respond to treatment with a USP1 inhibitor, the method comprising detecting a mutation in a gene encoding ATM in a cancer sample obtained from the subject, wherein a mutation in the gene encoding ATM in the cancer sample indicates that the patient will respond to treatment with a USP1 inhibitor.

[0123] In another aspect, the present disclosure relates to the in vitro use of at least one agent capable of specifically detecting mutations in the gene encoding ATM to identify subjects with cancer that will respond to treatment with a USP1 inhibitor.

[0124] In some embodiments, the mutation in the gene encoding ATM is a loss-of-function mutation.

[0125] In some embodiments, the USP1 inhibitor is a disclosed compound.

[0126] In one aspect (A1), the disclosure provides a method of treating cancer in a subject comprising administering a USP1 inhibitor to the subject, wherein the cancer comprises cancer cells having elevated levels of RAD18.

[0127] In one aspect (A2), the disclosure provides a method of treating triple-negative breast cancer in a subject, comprising administering to the subject a USP1 inhibitor. In one aspect (A3) of A1, the cancer comprises cancer cells with elevated levels of RAD18.

[0128] In one embodiment (A4) of A1 or A3, elevated levels of RAD18 are detected prior to administration. In one embodiment (A5) of A4, the method further comprises detecting RAD18 levels in a cancer sample obtained from the subject.

[0129] In one aspect (A5), the disclosure provides a method of selecting a subject having cancer for treatment with a USP1 inhibitor, comprising detecting whether the cancer comprises cells with elevated levels of RAD18, and if the cancer comprises cells with elevated levels of RAD18, the subject is selected for treatment with the USP1 inhibitor.

[0130] In one aspect (A6), the present disclosure provides a USP1 inhibitor for use in treating cancer in a subject, the cancer comprising cancer cells having elevated levels of RAD18.

[0131] In one aspect (A7), the present disclosure provides a USP1 inhibitor for use in treating triple-negative breast cancer in a subject.

[0132] In one embodiment (A9) of A7 or A8, the subject is identified as responsive to treatment with a USP1 inhibitor by detecting RAD18 levels in a cancer sample obtained from the subject, wherein elevated levels of RAD18 in the cancer sample identify the patient as responsive to treatment with the USP1 inhibitor.

[0133] In one aspect (A10), the present disclosure provides a USP1 inhibitor for use in treating cancer in a subject identified as responsive to treatment with a USP1 inhibitor by detecting elevated levels of RAD18 in a cancer sample obtained from the subject, wherein elevated levels of RAD18 in the cancer sample identify the patient as responsive to treatment with the USP1 inhibitor.

[0134] In one aspect (A11), the present disclosure provides a USP1 inhibitor for use in any of A7-A10, wherein the USP1 inhibitor is not administered to the subject if non-elevated RAD18 levels are detected in a cancer sample obtained from the subject.

[0135] In one aspect (A12), the present disclosure provides an in vitro method for identifying a subject having cancer as responsive to treatment with a USP1 inhibitor, comprising detecting RAD18 levels in a cancer sample obtained from the subject, wherein an elevated level of RAD18 in the cancer sample indicates that the patient will respond to treatment with the USP1 inhibitor.

[0136] In one aspect (A13), the present disclosure provides an in vitro use of at least one agent capable of specifically detecting RAD18 to identify a subject having cancer that will respond to treatment with a USP1 inhibitor.

[0137] In one aspect (A14), the present disclosure provides a kit or kit of parts comprising: (a) a pharmaceutical composition comprising a USP1 inhibitor and one or more pharmaceutically acceptable excipients; and (b) a diagnostic kit comprising at least one agent capable of specifically detecting RAD18.

[0138] In one embodiment (A15) of A13 or A14, the at least one agent capable of specifically detecting RAD18 is capable of specifically hybridizing to RAD18 mRNA. In one embodiment (A16) of A13 or A14, the at least one agent capable of specifically detecting RAD18 is capable of specifically binding to RAD18 protein.

[0139] In one embodiment (A17) of A10, A12, or A13, the cancer is triple-negative breast cancer.

[0140] In one embodiment (A18) of A10, A12, A13, or A17, the cancer comprises cancer cells that have elevated levels of RAD18.

[0141] In one aspect (A19), the disclosure provides a method for classifying cancer in a subject, comprising detecting elevated RAD18 levels in a cancer sample obtained from the subject.

[0142] In one embodiment (A20) of any one of A1-A19, the cancer is not a BRCA1 mutant cancer. In one embodiment (A21) of any one of A1-A19, the cancer is not a BRCA2 mutant cancer. In one embodiment (A22) of any one of A1-A19, the cancer is not a BRCA1 mutant cancer or a BRCA2 mutant cancer.

[0143] In one embodiment (A23) of any one of A1 to A19, the cancer is not a homologous recombination deficient cancer. In one embodiment (A24) of any one of A1 to A19, the cancer is not a homologous recombination deficient cancer.

[0144] In one embodiment (A25) of any one of A1 to A23, the cancer comprises cancer cells having a mutation in the gene encoding p53, and optionally the mutation in the gene encoding p53 is a loss-of-function mutation.

[0145] In one embodiment (A26) of any one of A1, A3 to A7, A9 to A12, and A18 to A25, the elevated level of RAD18 is elevated RAD18 protein level. In one embodiment (A27) of A26, the elevated RAD18 protein level is detected by Western blot. In one embodiment (A28) of A26, the elevated RAD18 protein level is detected by fluorescence-activated cell sorting (FACS). In one embodiment (A29) of A26, the elevated RAD18 protein level is detected by immunohistochemistry.

[0146] In one embodiment (A30) of any one of A1, A3-A7, A9-A12, and A18-A25, the elevated level of RAD18 is elevated RAD18 mRNA level. In one embodiment (A31) of A30, detecting elevated RAD18 mRNA level is by quantitative reverse transcriptase (RT)-polymerase chain reaction (PCR), RNA-Seq, or microarray.

[0147] In one embodiment (A32) of any one of A1, A3-A7, A9-A12, and A18-A31, the elevated level of RAD18 is at least as high as the level of RAD18 in ES2 cells. In one embodiment (A33) of any one of A1, A3-A7, A9-A12, and A18-A31, the elevated level of RAD18 is higher than the level of RAD18 in HEP3B217 cells.

[0148] In one aspect (A34) of any one of A1, A4 to A7, A9 to A16, and A18 to A33, the cancer is ovarian cancer. In one aspect (A35) of any one of A1, A4 to A7, A9 to A16, and A18 to A33, the cancer is breast cancer. In one aspect (A36) of A35, the breast cancer is triple-negative breast cancer.

[0149] In one embodiment (A37) of any one of A1 to A19 and A24 to A36, the cancer is a BRCA1 mutant cancer. In one embodiment (A38) of any one of A1 to A19 and A24 to A36, the cancer is a BRCA2 mutant cancer. In one embodiment (A39) of any one of A1 to A19 and A24 to A36, the cancer is a BRCA1 mutant cancer or a BRCA2 mutant cancer.

[0150] In one embodiment (A40) of any one of A1 to A18 and A20 to A39, the USP1 inhibitor is selected from a small molecule, siRNA, antisense oligonucleotide, peptide, or aptamer. In one embodiment (A41) of any one of A1 to A18 and A20 to A40, the USP1 inhibitor specifically binds to the USP1 protein. In one embodiment (A42) of A41, the USP1 protein comprises the amino acid sequence (SEQ ID NO: 1).

[0151] In one embodiment (A43) of any one of A1 to A18 and A20 to A42, the USP1 inhibitor inhibits the formation and / or activity of the USP1 / UAF1 complex.

[0152] In one embodiment (A44) of any one of A1 to A18 and A20 to A40, the USP1 inhibitor specifically binds to the USP1 / UAF1 complex.

[0153] In one embodiment (A45) of any one of A1 to A18 and A20 to A40, the USP1 inhibitor specifically binds to USP1 mRNA.

[0154] In one embodiment (A46) of any one of A1 to A18 and A20 to A45, the USP1 inhibitor increases monoubiquitinated PCNA.

[0155] In one embodiment (A47) of any one of A1 to A18 and A20 to A46, the USP1 inhibitor increases monoubiquitinated FANCD2.

[0156] In one embodiment (A48) of any one of A1 to A18 and A20 to A39, the USP1 inhibitor is purinone. In one embodiment (A49) of any one of A1 to A18 and A20 to A39, the USP1 inhibitor is GW7647. In one embodiment (A50) of any one of A1 to A18 and A20 to A39, the USP1 inhibitor is pimozide. In one embodiment (A51) of any one of A1 to A18 and A20 to A39, the USP1 inhibitor is ML323.

[0157] In one embodiment (A52) of any one of A1 to A18 and A20 to A51, the subject is a human.

[0158] Additional embodiments and advantages of the disclosure will be set forth in part in the description which follows, and will arise from the description, or may be learned by the practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0159] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. In an embodiment of the present invention, for example, the following items are provided: (Item 1) Compounds having formula I: [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: X 1 and X 2 each independently represents N and CR 2 is selected from R 1 and R 2 each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 3 is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, or optionally substituted pyrazolyl; X 11 and X 12 are each independently selected from N and CH; R 5’ is hydrogen, optionally substituted (C 1 -C 6 ) alkyl, optionally substituted (C 2 -C 6 ) alkenyl, optionally substituted (C 2 -C 6 ) alkynyl, optionally substituted (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, cyano, halo, sulfonamide, -C(=O)R 23 , -C(=O)OR 24 , -NR 32a R 32b , -NR 31a C(=O)R 25 、 -NR 31a C(=O)NR 31a R 31b , -C(=O)NR 31a R 31b , -S(O) 2 R 27 , -NR 31a SO 2 R 27 , optionally replaced by (C 6 -C 14 ) aryl, optionally substituted (C 6 -C 14 )Al-(C 1 -C 2 ) alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C 1 -C 2 ) alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted ((C 3 -C 8 )cycloalkyl)-(C 1 -C 2 ) alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C 1 -C 2 ) alkyl, optionally substituted —O—(C 6 -C 14 ) aryl, optionally substituted —O—(C 6 -C 14 )Al-(C 1 -C 2 ) alkyl, optionally substituted -O-heteroaryl, optionally substituted -O-heteroar-(C 1 -C 2 ) alkyl, optionally substituted —O—(C 3 -C 8 )cycloalkyl, optionally substituted —O—((C 3 -C 8 )cycloalkyl)-(C 1 -C 2 ) alkyl, optionally substituted -O-heterocyclo, optionally substituted -O-heterocyclo-(C 1 -C 2 ) alkyl; R 5 , optionally replaced by (C 1 -C 6 ) alkyl, optionally substituted (C 2 -C 6 ) alkenyl, optionally substituted (C 2 -C 6 ) alkynyl, optionally substituted (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6) hydroxyalkyl, cyano, halo, sulfonamido, -C(=O)R 23 , -C(=O)OR 24 , -NR 32a R 32b , -NR 31a C(=O)R 25 , -NR 31a C(=O)NR 31a R 31b , -C(=O)NR 31a R 31b , -S(O) 2 R 27 , -NR 31a SO 2 R 27 , optionally replaced by (C 6 -C 14 ) aryl, optionally substituted (C 6 -C 14 )Al-(C 1 -C 2 ) alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C 1 -C 2 ) alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted ((C 3 -C 8 )cycloalkyl)-(C 1 -C 2 ) alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C 1 -C 2 ) alkyl, optionally substituted -O-(C 6 -C 14 ) aryl, optionally substituted —O—(C 6 -C 14 )Al-(C 1 -C 2 ) alkyl, optionally substituted -O-heteroaryl, optionally substituted -O-heteroar-(C 1 -C 2 ) alkyl, optionally substituted —O—(C 3 -C 8 )cycloalkyl, optionally substituted —O—((C 3 -C 8 )cycloalkyl)-(C 1 -C 2 ) alkyl, optionally substituted -O-heterocyclo, optionally substituted -O-heterocyclo-(C 1 -C 2 ) alkyl; or R on adjacent atoms 5 One of the following and R5’ one of which, together with the atom to which they are attached, is optionally replaced (C 6 -C 14 ) form an aryl ring or R on adjacent atoms 5 One of the following and R 5’ together with the atom to which they are attached form an optionally substituted heteroaryl ring, or R on an adjacent atom 5 One of the following and R 5’ one of which, together with the atom to which they are attached, is optionally replaced (C 3 -C 8 ) form a cycloalkyl ring or R on adjacent atoms 5 One of the following and R 5’ together with the atom to which they are attached to form an optionally substituted heterocycloalkyl ring, or R on adjacent atoms on the same atom to which they are attached 5 One of the following and R 5’ are joined together to form an optionally substituted spirocycloalkyl ring, or on the same atom to which they are attached, R on adjacent atoms 5 One of the following and R 5’ form an optionally substituted spiroheterocycloalkyl ring; R 6 and R 7 each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 23 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl; R 31a and R 31b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, alkoxyalkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, aralkyl, and (heteroaryl)alkyl; R 24 、R 25 、R 27 、R 32a , and R 32b or a pharmaceutically acceptable salt or solvate thereof, wherein each of: is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl. (Item 2)

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[0160] [Figure 1] USP1 dropout profiles across approximately 500 cancer cell lines are provided. Lower dropout scores indicate greater sensitivity to USP1 loss. Breast cancer cell lines are shown in white, and ovarian cancer cell lines are shown in black. Symbols indicate BRCA1 / 2 mutation or triple-negative breast cancer (TNBC) status. [Figure 2] Schematic diagram of PCNA ubiquitination from Jacquemont C. and Taniguchi T., BMC Biochemistry 8(Suppl 1):S10(2007). E3 ligase Rad18 monoubiquitinated PCNA. USP1 deubiquitinated monoubiquitinated PCNA. [Figure 3] Figure 1 shows the distribution of Rad18 mRNA expression across approximately 500 cancer cell lines. The x-axis shows normalized Rad18 mRNA expression values, and the y-axis shows the number of cell lines with the expression values ​​shown on the x-axis. The 20 cell lines with the lowest USP1 dropout scores are shown as dark bars reaching the top of the graph. [Figure 4] 1 provides plots showing USP1 dropout scores across Rad 18 mRNA expression levels in breast cancer cell lines (top left), ovarian cancer cell lines (top right), and triple-negative breast cancer cell lines (bottom). [Figure 5] Rad18 mRNA levels in USP1-sensitive (59M and ES2) and -insensitive (OVISE, JHH7, and HEP3B217) cell lines measured by qRT-PCR and normalized to GAPDH expression and normalized to OVISE are shown. [Figure 6] Figure 1 shows RAD18 protein levels in USP1-sensitive (59M and ES2) and insensitive (OVISE, JHH7, and HEP3B217) cell lines. The upper panel shows protein levels in Western blots, and the lower panel provides quantification of Western blot protein levels. "HCC1395" in the Western assay (upper panel) was determined to be contaminated with another cell line and therefore was not used in the quantification (lower panel). [Figure 7] Figure 1 provides a graph demonstrating that deletion of Rad18 rescues deletion of USP1. The graph shows relative cell viability in OR1A1 (negative control) knockout cells (left panel) or Rad18 knockout cells (right panel) with the addition of an OR1A1 negative control ("negative control"), an EEF2 pan-lethal positive control ("lethal control"), or four different USP1 guides ("USP1_1," "USP1_2," "USP1_3," and "USP1_4"). DETAILED DESCRIPTION OF THE INVENTION

[0161] One aspect of the present disclosure is based on the use of the disclosed compounds as inhibitors of the ubiquitin-specific processing protease 1 (USP1) protein. In view of this property, the disclosed compounds are useful for inhibiting the USP1 protein and treating diseases, disorders, or conditions that respond to the inhibition of the USP1 protein, such as cancer.

[0162] In some embodiments, the disclosed compounds exhibit improved solubility, for example, as measured by an ADME solubility assay as disclosed herein.

[0163] In some embodiments, the disclosed compounds exhibit improved metabolic stability, for example, as measured by a liver microsomal metabolic stability assay as disclosed herein.

[0164] In other embodiments, the disclosed compounds exhibit improved duration of action and oral exposure in vivo.

[0165] In one embodiment, the disclosed compounds are compounds having formula I: [ka] and pharmaceutically acceptable salts or solvates thereof, e.g., hydrates, wherein: X 1 and X 2 each independently represents N and CR 2 is selected from R 1 and R 2 each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 3 is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, or optionally substituted pyrazolyl; R 5’is hydrogen, optionally substituted (C-C) alkyl, optionally substituted (C-C) alkenyl, optionally substituted (C-C) alkynyl, optionally substituted (C-C) alkoxy, (C-C) haloalkyl, (C-C) haloalkoxy, (C-C) hydroxyalkyl, cyano, halo, sulfonamido, -C(=O)R 23 , -C(=O)OR 24 , -NR 32a R 32b , -NR 31a C(=O)R 25 , -NR 31a C(=O)NR 31a R 31b , -C(=O)NR 31a R 31b , -S(O)2R 27 , -NR 31a SO2R 27 , optionally substituted (C6-C 14 ) aryl, optionally substituted (C6-C 14 )ar-(C1-C2)alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C1-C2)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted ((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C1-C2)alkyl, optionally substituted —O—(C6-C 14 ) aryl, optionally substituted —O—(C6-C 14 )ar-(C1-C2)alkyl, optionally substituted -O-heteroaryl, optionally substituted -O-heteroar-(C1-C2)alkyl, optionally substituted -O-(C3-C8)cycloalkyl, optionally substituted -O-((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted -O-heterocyclo, optionally substituted -O-heterocyclo-(C1-C2)alkyl; R 5is an optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, cyano, halo, sulfonamido, -C(=O)R 23 , -C(=O)OR 24 , -NR 32a R 32b , -NR 31a C(=O)R 25 , -NR 31a C(=O)NR 31a R 31b , -C(=O)NR 31a R 31b , -S(O)2R 27 , -NR 31a SO2R 27 , optionally substituted (C6-C 14 ) aryl, optionally substituted (C6-C 14 )ar-(C1-C2)alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C1-C2)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted ((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C1-C2)alkyl, optionally substituted —O—(C6-C 14 ) aryl, optionally substituted —O—(C6-C 14 )ar-(C1-C2)alkyl, optionally substituted -O-heteroaryl, optionally substituted -O-heteroar-(C1-C2)alkyl, optionally substituted -O-(C3-C8)cycloalkyl, optionally substituted -O-((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted -O-heterocyclo, optionally substituted -O-heterocyclo-(C1-C2)alkyl; R on adjacent atoms 5 One of the following and R 5’one of which, together with the atom to which they are attached, is optionally substituted (C6-C 14 ) form an aryl ring or R on adjacent atoms 5 One of the following and R 5’ together with the atom to which they are attached to form an optionally substituted heteroaryl ring, or R on an adjacent atom 5 One of the following and R 5’ together with the atom to which they are attached to form an optionally substituted (C-C)cycloalkyl ring, or R on an adjacent atom 5 One of the following and R 5’ together with the atom to which they are attached to form an optionally substituted heterocycloalkyl ring, or on the same atom to which they are attached, R on adjacent atoms 5 One of the following and R 5’ are joined together to form an optionally substituted spirocycloalkyl ring, or are joined by R on adjacent atoms on the same atom to which they are attached. 5 One of the following and R 5’ one of which forms an optionally substituted spiroheterocycloalkyl ring; R 6 and R 7 each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; X 11 and X 12 are each independently selected from N and CH; R 23is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl; R 31a and R 31b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, alkoxyalkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, aralkyl, and (heteroaryl)alkyl; R 24 , R 25 , R 27 , R 32a , and R 32b is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl.

[0166] In one embodiment, the disclosed compounds are compounds having formula I, wherein X 1 and X 2 Each of the 2 is.

[0167] In another embodiment, the disclosed compounds are compounds having formula I, wherein X 1 and X 2 At least one of X is N. In some embodiments, 1 is N. In some embodiments, X 2 is N.

[0168] In another embodiment, the disclosed compounds are compounds having formula I, wherein X 1 and X 2 At least one of the 2 In some embodiments, X 1 is CR 2 In some embodiments, X 2 is CR 2 is.

[0169] In another embodiment, the disclosed compounds are compounds having formula I, wherein X 1 and X 2 Each of is N.

[0170] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 5’ is selected from hydrogen, halo, and optionally substituted (C1-C6) alkyl.

[0171] In one embodiment, the disclosed compounds are compounds having formula I, wherein: [ka] is, independently, [ka] is selected from.

[0172] In another embodiment, [ka] teeth, [ka] is.

[0173] In another embodiment, [ka] teeth, [ka] is.

[0174] In another embodiment, [ka] teeth, [ka] is.

[0175] In another embodiment, [ka] teeth, [ka] is.

[0176] In another embodiment, [ka] is, independently, [ka] is selected from.

[0177] In another embodiment, [ka] teeth, [ka] is.

[0178] In another embodiment, [ka] teeth, [ka] is.

[0179] In another embodiment, [ka] teeth, [ka] is.

[0180] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 1 and R 2 Each of is independently selected from hydrogen, halo, and cyano.

[0181] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 1 and R 2 Each of is independently optionally substituted (C 1-4 ) alkyl, optionally substituted (C 2-4 ) alkenyl, and optionally substituted (C 2-4 ) alkynyl. In some embodiments, R 1 and R 2 Each of is independently optionally substituted (C 1-4 ) alkyl. In some embodiments, R 1 and R 2 Each of is independently optionally substituted (C 2-4) alkenyl. In some embodiments, R 1 and R 2 Each of is independently optionally substituted (C 2-4 ) alkynyl.

[0182] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 3 is an optionally substituted phenyl.

[0183] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 3 is an optionally substituted pyridyl.

[0184] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 3 is an optionally substituted pyrimidinyl.

[0185] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 3 is an optionally substituted pyrazinyl.

[0186] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 3 is an optionally substituted pyridazinyl.

[0187] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 3 is an optionally substituted pyrazolyl.

[0188] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 3The above optional substituents are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkylaralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (C 1-4 )haloalkoxy)alkyl, and (heteroaryl)alkyl.

[0189] In another embodiment, R 3 The above optional substituents are independently hydrogen, halo, nitro, cyano, hydroxy, amino, (C-C) alkylamino, di-(C-C) alkylamino, halo-(C-C) alkyl, hydroxy-(C-C) alkyl, (C-C) alkoxy, halo-(C-C) alkoxy, (C-C 10 )aryloxy, (C3-C6)heteroaryloxy, ar-(C1-C4)alkyl, ar-(C1-C4)alkyloxy, (C1-C4)alkylthio, carboxamide, sulfonamide, (C1-C4)alkylcarbonyl, (C6-C 10 )arylcarbonyl, (C1-C4)alkylsulfonyl, (C6-C 10)arylsulfonyl, carboxy, carboxy-(C1-C4)alkyl, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, alkoxy-(C1-C4)alkyl, (amino)-(C1-C4)alkyl, hydroxy-(C1-C4)alkylamino, (alkylamino)-(C1-C4)alkyl, (dialkylamino)-(C1-C4)alkyl, (cyano)-(C1-C4)alkyl, (carboxamido)-(C1-C4)alkyl, mercapto-(C1-C4)alkyl, (heterocyclo)-(C1-C4)alkyl, (cycloalkylamino)-(C1-C4)alkyl, (C 1-4 haloalkoxy)-(C1-C4)alkyl, and (heteroaryl)-(C1-C4)alkyl.

[0190] In another embodiment, R 3 The above optional substituents are independently (C3-C8)cycloalkyl, (C6-C 10 )aryl, (C3-C6)heteroaryl, and (C3-C8)heterocyclo.

[0191] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 3 Two of the above optional substituents, together with the carbon or nitrogen atom to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted heterocyclo, an optionally substituted aryl, or an optionally substituted heteroaryl group.

[0192] In another embodiment, R 3 Two of the above optional substituents, together with the carbon or nitrogen atom to which they are attached, may form an optionally substituted (C3-C8)cycloalkyl, an optionally substituted (C3-C8)heterocyclo, an optionally substituted (C6-C 10 )aryl, or optionally substituted (C3-C6)heteroaryl groups.

[0193] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 3 is an optionally substituted phenyl, wherein the phenyl is optionally substituted at the 2-position. In another embodiment, the phenyl is optionally substituted at the 6-position. In another embodiment, the phenyl is optionally disubstituted at the 2- and 6-positions. In another embodiment, the phenyl is optionally disubstituted at the 2- and 3-positions.

[0194] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 3 is an optionally substituted pyrid-3-yl or an optionally substituted pyrid-4-yl.

[0195] In another embodiment, R 3 is an optionally substituted pyrid-3-yl. In another embodiment, the pyrid-3-yl is optionally substituted at the 2-position. In another embodiment, the pyrid-3-yl is optionally substituted at the 4-position. In another embodiment, the pyrid-3-yl is optionally disubstituted at the 2- and 4-positions.

[0196] In another embodiment, R 3 is an optionally substituted pyrid-4-yl. In another embodiment, the pyrid-4-yl is optionally substituted at the 3-position. In another embodiment, the pyrid-4-yl is optionally substituted at the 5-position. In another embodiment, the pyrid-4-yl is optionally disubstituted at the 3- and 5-positions.

[0197] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 3is an optionally substituted pyrimidin-5-yl. In another embodiment, the pyrimidin-5-yl is optionally substituted at the 2-position. In another embodiment, the pyrimidin-5-yl is optionally substituted at the 4-position. In another embodiment, the pyrimidin-5-yl is optionally substituted at the 6-position. In another embodiment, the pyrimidin-5-yl is optionally disubstituted at the 4- and 6-positions. In another embodiment, the pyrimidin-5-yl is optionally disubstituted at the 2- and 6-positions. In another embodiment, the pyrimidin-5-yl is optionally disubstituted at the 2- and 4-positions. In another embodiment, the pyrimidin-5-yl is optionally trisubstituted at the 2-, 4-, and 6-positions.

[0198] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 3 is an optionally substituted pyrazol-3-yl or an optionally substituted pyrazol-5-yl.

[0199] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 3 is an optionally substituted pyrazol-5-yl. In another embodiment, the pyrazol-5-yl is optionally substituted at the 1-position. In another embodiment, the pyrazol-5-yl is optionally substituted at the 3-position. In another embodiment, the pyrazol-5-yl is optionally substituted at the 4-position. In another embodiment, the pyrazol-5-yl is optionally disubstituted at the 1- and 4-positions. In another embodiment, the pyrazol-5-yl is optionally disubstituted at the 1- and 3-positions. In another embodiment, the pyrazol-5-yl is optionally disubstituted at the 3- and 4-positions.

[0200] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 3is substituted, the substituents being independently selected from methoxy, deuteromethoxy, ethoxy, isopropoxy, t-butoxy, difluoromethoxy, 2-fluoroethoxy, 2-methoxyethoxy, cyclopropoxy, cyclobutoxy, (tetrahydrofuran-3-yl)oxy, benzyloxy, methyl, ethyl, isopropyl, 2-fluoroisopropyl, t-butyl, cyclopropyl, cyclobutyl, methylcyclopropyl, pyrrolidin-1-yl, azetidin-1-yl, methylamino, dimethylamino, cyano, halo, methylthio, methylsulfonyl, and ethylsulfonyl.

[0201] In one embodiment, R 3 teeth, [ka] [ka] is selected from the group consisting of:

[0202] In another embodiment, the disclosed compounds are compounds having formula I, wherein X 11 and X 12 At least one of X is N. In some embodiments, 11 is N. In some embodiments, X 12 is N.

[0203] In another embodiment, the disclosed compounds are compounds having formula I, wherein X 11 and X 12 In some embodiments, at least one of X is CH. 11 is CH. In some embodiments, X 12 is CH.

[0204] In one embodiment, the disclosed compounds are compounds having formula I, wherein X 11 and X 12 Each of is N.

[0205] In one embodiment, the disclosed compounds are compounds having formula I, wherein X 11 and X 12 Each of the is CH.

[0206] In some embodiments, X 11 and X 12 One of them is N and the other is X 11 and X 12 and the other is CH. In one embodiment, X 11 is N and X 12 is CH. In another embodiment, X 11 is CH and X 12 is N.

[0207] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 5 is selected from optionally substituted (C1-C4) alkyl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, optionally substituted (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl.

[0208] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 5 is cyano, halo, sulfonamide, -C(=O)R 23 , -C(=O)OR 24 , -NR 32a R 32b , -NR 31a C(=O)R 25 , -NR 31a C(=O)NR 31a R 31b , -C(=O)NR 31a R 31b , -S(O)2R 27 , -NR 31a SO2R 27 is selected from.

[0209] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 5 is optionally substituted (C6-C10 ) aryl, optionally substituted (C6-C 10 )ar-(C1-C2)alkyl, optionally substituted (C3-C6)heteroaryl, optionally substituted (C3-C6)heteroar-(C1-C2)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted ((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted (C3-C8)heterocyclo, optionally substituted (C3-C8)heterocyclo-(C1-C2)alkyl, optionally substituted —O—(C6-C 10 ) aryl, optionally substituted —O—(C6-C 10 )ar-(C1-C2)alkyl, optionally substituted —O—(C3-C6)heteroaryl, optionally substituted —O—(C3-C6)heteroar-(C1-C2)alkyl, optionally substituted —O—(C3-C8)cycloalkyl, optionally substituted —O—((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted —O—(C3-C8)heterocyclo, optionally substituted —O—(C3-C8)heterocyclo-(C1-C2)alkyl.

[0210] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 5 is optionally substituted heteroaryl. In another embodiment, R 5 is an optionally substituted 5- or 6-membered heteroaryl containing one or more nitrogen atoms. In another embodiment, R 5 is an optionally substituted 5- or 6-membered heteroaryl containing only nitrogen as the heteroatom(s).

[0211] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 5 One of the following and R 5’ together with the atoms to which they are attached, are optionally substituted (C6-C 10 ) forming an aryl ring.

[0212] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 5 One of the following and R 5’ together with the atoms to which they are attached form an optionally substituted (C3-C6)heteroaryl ring.

[0213] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 5 One of the following and R 5’ together with the atoms to which they are attached form an optionally substituted (C3-C8)cycloalkyl ring.

[0214] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 5 One of the following and R 5’ together with the atom to which they are attached form an optionally substituted (C3-C8)heterocycloalkyl ring.

[0215] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 5 One of the following and R 5’ together with the atoms to which they are attached form an optionally substituted spirocycloalkyl ring.

[0216] In another embodiment, the disclosed compounds are compounds having formula I, wherein R 5 One of the following and R 5’ together with the atom to which they are attached form an optionally substituted spiroheterocycloalkyl ring.

[0217] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 5The above optional substituents are independently hydrogen, halo, nitro, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, hydroxy, carboxy, carboxyalkyl, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, aralkylamino, heteroaralkylalkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkylamino, alkoxyalkyl, (alkoxyalkyl)amino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (carboxamido)alkyl, mercaptoalkyl, (cyano)alkyl, (cycloalkyl)alkyl, aralkyl, aralkyloxy, alkylcarbonyl, arylcarbonyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, (C 1-4 haloalkoxy)alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, carboxamido, sulfonyl, sulfonamido, sulfamido, alkylsulfonyl, alkylsulfonamido, alkylsulfamido, arylsulfonyl, aryloxy, heteroaryloxy, -C(=O)R 23 , -C(=O)OR 24 , -C(=O)NR 31a R 31b , -NR 31a C(=O)R 25 , -NR 31a C(=O)OR 26 , -NR 31a C(=O)NR 31a R 31b , -NR 31a SO2R 27 , -OC(=O)R 28 , -OC(=O)OR 29 , -OC(=O)NR 31a R 31b , -OSO2R 30 , and -NR 32a R 32bis selected from.

[0218] In another embodiment, R 5 The above optional substituents are independently selected from hydrogen, halo, nitro, cyano, optionally substituted (C1-C4) alkyl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C4) alkoxy, hydroxy, carboxy, carboxy-(C1-C4) alkyl, amino, (C1-C4) alkylamino, di-(C1-C4) alkylamino, (C3-C8) cycloalkylamino, heterocyclo-(C1-C4) alkylamino, ar-(C1-C4) alkylamino, heteroar-(C1-C4) alkylamino, (C1-C4) alkylthio, halo-(C1-C4) alkyl, halo-(C1-C4) alkoxy, hydroxy-(C1-C4) alkyl, hydroxy-(C1-C4) alkylamino, alkoxy-( C1-C4)alkyl, (alkoxyalkyl)amino, (amino)-(C1-C4)alkyl, (alkylamino)-(C1-C4)alkyl, (dialkylamino)-(C1-C4)alkyl, (cycloalkylamino)-(C1-C4)alkyl, (carboxamido)-(C1-C4)alkyl, mercapto-(C1-C4)alkyl, (cyano)-(C1-C4)alkyl, (cycloalkyl)-(C1-C4)alkyl, ar-(C1-C4)alkyl, ar-(C1-C4)alkyloxy, (C1-C4)alkylcarbonyl, arylcarbonyl, (heterocyclo)-(C1-C4)alkyl, (heteroaryl)-(C1-C4)alkyl, (amino)(hydroxy)-(C1-C4)alkyl, (aralkylamino)-(C1-C4)alkyl, and (C 1-4 haloalkoxy)-(C1-C4) alkyl.

[0219] In another embodiment, R 5 The above optional substituents include optionally substituted (C3-C8)heterocyclo, optionally substituted (C3-C6)heteroaryl, optionally substituted (C6-C 10 )aryl, and optionally substituted (C3-C8)cycloalkyl.

[0220] In another embodiment, R 5 The above optional substituents are independently selected from carboxamido, sulfonyl, sulfonamido, sulfamido, (C-C) alkylsulfonyl, (C-C) alkylsulfonamido, (C-C) alkylsulfamido, (C-C 10 ) arylsulfonyl, (C6-C 10 )aryloxy, (C3-C6)heteroaryloxy, -C(=O)R 23 , -C(=O)OR 24 , -C(=O)NR 31a R 31b , -NR 31a C(=O)R 25 , -NR 31a C(=O)OR 26 , -NR 31a C(=O)NR 31a R 31b , -NR 31a SO2R 27 , -OC(=O)R 28 , -OC(=O)OR 29 , -OC(=O)NR 31a R 31b , -OSO2R 30 , and -NR 32a R 32b is selected from.

[0221] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 5 Two of the above optional substituents, together with the carbon or nitrogen atom to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted heterocyclo, an optionally substituted aryl, or an optionally substituted heteroaryl group.

[0222] In another embodiment, R 5 Any two of the above optional substituents, taken together with the carbon atoms to which they are attached, may form an optionally substituted (C3-C8)cycloalkyl, an optionally substituted (C3-C8)heterocyclo, an optionally substituted (C6-C 10)aryl, or optionally substituted (C3-C6)heteroaryl groups.

[0223] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 5 is selected from optionally substituted (C-C) alkyl, optionally substituted (C-C) alkenyl, optionally substituted (C-C) alkynyl, optionally substituted (C-C) alkoxy, (C-C) haloalkyl, (C-C) haloalkoxy, and (C-C) hydroxyalkyl.

[0224] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 5 is cyano, halo, sulfonamide, -C(=O)R 23 , -C(=O)OR 24 , -NR 32a R 32b , -NR 31a C(=O)R 25 , -NR 31a C(=O)NR 31a R 31b , -C(=O)NR 31a R 31b , -S(O)2R 27 , and -NR 31a SO2R 27 is selected from.

[0225] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 5 is an optionally substituted -O-(C6-C 14 ) aryl, optionally substituted —O—(C6-C 14 )ar-(C1-C2)alkyl, optionally substituted -O-heteroaryl, optionally substituted -O-heteroar-(C1-C2)alkyl, optionally substituted -O-(C3-C8)cycloalkyl, optionally substituted -O-((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted -O-heterocyclo, optionally substituted -O-heterocyclo-(C1-C2)alkyl. In another embodiment, R5 is an optionally substituted -O-(C6-C 10 ) aryl, optionally substituted —O—(C6-C 10 )ar-(C1-C2)alkyl, optionally substituted —O—(C3-C6)heteroaryl, optionally substituted —O—(C3-C6)heteroar-(C1-C2)alkyl, optionally substituted —O—(C3-C8)cycloalkyl, optionally substituted —O—((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted —O—(C3-C8)heterocyclo, optionally substituted —O—(C3-C8)heterocyclo-(C1-C2)alkyl.

[0226] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 5 is optionally substituted (C6-C 14 ) aryl, optionally substituted (C6-C 14 )ar-(C1-C2)alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C1-C2)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted ((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C1-C2)alkyl. In another embodiment, R 5 is optionally substituted (C6-C 10 ) aryl, optionally substituted (C6-C 10 )ar-(C1-C2)alkyl, optionally substituted (C3-C6)heteroaryl, optionally substituted (C3-C6)heteroar-(C1-C2)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted ((C3-C8)cycloalkyl)-(C1-C2)alkyl, optionally substituted (C3-C8)heterocyclo, optionally substituted (C3-C8)heterocyclo-(C1-C2)alkyl.

[0227] In one embodiment, the disclosed compounds are compounds having formula I, wherein R5 is optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazolyl, or optionally substituted tetrazolyl. 5 is optionally substituted pyrrolyl. In another embodiment, R 5 is optionally substituted imidazolyl. In another embodiment, R 5 is optionally substituted pyrazolyl. In another embodiment, R 5 is an optionally substituted triazolyl. In another embodiment, R 5 is an optionally substituted tetrazolyl.

[0228] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 5 is substituted, the substituents being independently selected from halo, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, oxetan-3-yl, and methylazetidinyl.

[0229] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 5 teeth, [ka] [ka] is selected from the group consisting of:

[0230] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 6 and R 7 Each of is independently selected from hydrogen, halo, and cyano.

[0231] In another embodiment, the disclosed compounds are compounds having formula I, wherein R6 and R 7 are each independently selected from optionally substituted (C1-C4) alkyl, optionally substituted (C2-C4) alkenyl, and optionally substituted (C2-C4) alkynyl.

[0232] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 23 is hydrogen, optionally substituted (C1-C4) alkyl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, amino, (C1-C4) alkylamino, di-(C1-C4) alkylamino, cyclo-(C1-C4) alkylamino, hydroxy-(C1-C4) alkyl, (amino)-(C1-C4) alkyl, (alkylamino)-(C1-C4) alkyl, (dialkylamino)-(C1-C4) alkyl, (cycloalkylamino)-(C1-C4) alkyl, (cycloalkyl)-(C1-C4) alkyl, ar-(C6-C 10 )alkyl, (heterocyclo)-(C1-C4)alkyl, (heteroaryl)-(C1-C4)alkyl, (amino)-(hydroxy)-(C1-C4)alkyl, (aralkylamino)-(C1-C4)alkyl, optionally substituted (C3-C8)heterocyclo, optionally substituted (C3-C6)heteroaryl, optionally substituted (C6-C 10 )aryl, and optionally substituted (C3-C8)cycloalkyl.

[0233] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 31a and R 31beach is independently selected from the group consisting of hydrogen, optionally substituted (C-C)alkyl, optionally substituted (C-C)alkenyl, optionally substituted (C-C)alkynyl, hydroxy-(C-C)alkyl, (amino)-(C-C)alkyl, (alkylamino)-(C-C)alkyl, (dialkylamino)-(C-C)alkyl, alkoxy-(C-C)alkyl, (C-C)cycloalkyl, (cycloalkyl)-(C-C)alkyl, (heterocyclo)-(C-C)alkyl, ar-(C-C)alkyl, and (heteroaryl)-(C-C)alkyl.

[0234] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 24 , R 25 , R 27 , R 32a , and R 32b each independently represents hydrogen, optionally substituted (C1-C4) alkyl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, amino, (C1-C4) alkylamino, di-(C1-C4) alkylamino, (C3-C8) cycloalkylamino, hydroxy-(C1-C4) alkyl, (amino)-(C1-C4) alkyl, (alkylamino)-(C1-C4) alkyl, (dialkylamino)-(C1-C4) alkyl, (cycloalkylamino), (amino)-(C1-C4)alkyl, (cycloalkyl)-(C1-C4)alkyl, ar-(C1-C4)alkyl, (heterocyclo)-(C1-C4)alkyl, (heteroaryl)-(C1-C4)alkyl, (amino)(hydroxy)-(C1-C4)alkyl, (aralkylamino)-(C1-C4)alkyl, alkoxy-(C1-C4)alkyl, optionally substituted (C3-C8)heterocyclo, optionally substituted (C3-C6)heteroaryl, optionally substituted (C6-C 10 )aryl, and optionally substituted (C3-C8)cycloalkyl.

[0235] In one embodiment, the disclosed compounds are compounds having formula I, wherein R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 32a , and R 32b each is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl.

[0236] In another embodiment, R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 32a , and R 32beach of which is hydrogen, optionally substituted (C1-C4) alkyl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, amino, (C1-C4) alkylamino, di-(C1-C4) alkylamino, (C3-C8) cycloalkylamino, hydroxy-(C1-C4) alkyl, (amino)-(C1-C4) alkyl, (alkylamino)-(C1-C4) alkyl, (dialkylamino)-(C1-C4) alkyl, (cycloalkylamino) -(C1-C4)alkyl, (cycloalkyl)-(C1-C4)alkyl, ar-(C1-C4)alkyl, (heterocyclo)-(C1-C4)alkyl, (heteroaryl)-(C1-C4)alkyl, (amino)(hydroxy)-(C1-C4)alkyl, (aralkylamino)-(C1-C4)alkyl, alkoxy-(C1-C4)alkyl, optionally substituted (C3-C8)heterocyclo, optionally substituted (C3-C6)heteroaryl, optionally substituted (C6-C 10 )aryl, and optionally substituted (C3-C8)cycloalkyl.

[0237] In another embodiment, the disclosed compounds are compounds having formula II: [ka] and pharmaceutically acceptable salts or solvates thereof, e.g., hydrates, wherein: X 1 , X 2 , R 1 , R 5 , R 6 , and R 7 each is as defined above for Formula I, X 3 N and CR 10 Selected from X 4 N and CR 11 Selected from X 5 N and CR 12 is selected from R 8 , R 9 , R 10 , R11 , and R 12 each is independently hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkylaralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (C 1-4 (haloalkoxy)alkyl, or (heteroaryl)alkyl.

[0238] In another embodiment, R 8 , R 9 , R 10 , R 11 , and R 12 each independently represents hydrogen, halo, nitro, cyano, hydroxy, amino, (C-C) alkylamino, di-(C-C) alkylamino, halo-(C-C) alkyl, hydroxy-(C-C) alkyl, (C-C) alkoxy, halo-(C-C) alkoxy, (C-C 10 )aryloxy, (C3-C6)heteroaryloxy, ar-(C1-C4)alkylar-(C1-C4)alkyloxy, (C1-C4)alkylthio, carboxamide, sulfonamide, (C1-C4)alkylcarbonyl, (C6-C 10 )arylcarbonyl, (C1-C4)alkylsulfonyl, (C6-C 10)arylsulfonyl, carboxy, carboxy-(C1-C4)alkyl, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, alkoxy-(C1-C4)alkyl, (amino)-(C1-C4)alkyl, hydroxy-(C1-C4)alkylamino, (alkylamino)-(C1-C4)alkyl, (dialkylamino)-(C1-C4)alkyl, (cyano)-(C1-C4)alkyl, (carboxamido)-(C1-C4)alkyl, mercapto-(C1-C4)alkyl, (heterocyclo)-(C1-C4)alkyl, (cycloalkylamino)-(C1-C4)alkyl, (C 1-4 haloalkoxy)-(C1-C4)alkyl, and (heteroaryl)-(C1-C4)alkyl.

[0239] In another embodiment, R 8 , R 9 , R 10 , R 11 , and R 12 each independently represents an optionally substituted (C-C)cycloalkyl, an optionally substituted (C-C 10 )aryl, optionally substituted (C3-C6)heteroaryl, and optionally substituted (C3-C8)heterocyclo.

[0240] In one embodiment, the disclosed compound is a compound having formula III, formula IV, formula V, formula VI, or formula VIa, [ka] [ka] In the formula, X 1 , X 2 , R 1 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 11 Each of is as defined above for Formula II.

[0241] In another embodiment, R 5 teeth, [ka] and During the ceremony, X 6 is NR 13 and CR 18 Selected from X 7 is NR 14 and CR 19 Selected from X 8 is NR 15 and CR 20 Selected from X 9 is NR 16 and CR 21 Selected from X 10 is NR 17 and CR 22 is selected from R 13 , R 14 , R 15 , R 16 , and R 17 each is absent or independently selected from hydrogen, halo, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, oxetan-3-yl, and methylazetidinyl; R 18 , R 19 , R 20 , R 21 , and R 22 are each independently selected from hydrogen, halo, methyl, ethyl, isopropyl, cyclopropyl, methoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, and methylazetidinyl.

[0242] In one embodiment, the disclosed compound is a compound having formula VII, formula VIII, formula IX, formula X, formula XI, or formula XII, [ka] [ka] In the formula, X 1 , X 2 , R 1 , R 3 , R 6 , R 7 , R 15 , R 16 , R 17 , R 20 , R 21 , and R 22 Each of is as defined above for Formula II.

[0243] In one embodiment, the disclosed compound is a compound having formula XIII: [ka] During the ceremony, X 1a and X 2a each independently represents N and CR 2a is selected from R 2a is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, alkoxyalkyl, alkylsulfonyl, alkylthio, aryl, heteroaryl, and heterocyclo; Each of the remaining substituents is defined as disclosed herein.

[0244] In one embodiment, the disclosed compounds are 6-(3-methoxypyridin-4-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 8), 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-(methylsulfonyl)-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 3), 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-methyl-6-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 23), 6-(2-(ethylsulfonyl)phenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 7), 1-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)benzyl)-6-(2-isopropylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (Example 20), 6-(2-methoxy-4-methylpyridin-3-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 6), 6-(4-methoxy-6-methylpyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 21), 6-(2-isopropylpyridin-3-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 18), 6-(2,6-dimethoxyphenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 4), 6-(2-methoxyphenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 2), 6-(2-isopropylphenyl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 15), 6-(2-methoxy-6-methylphenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 5), 2-Methoxy-3-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)isonicotinonitrile (Example 22), 2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine (Example 24), 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 12), 6-(2-isopropylpyridin-3-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 9), 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-methyl-6-(methylthio)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 13), 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 19), 6-(2-cyclopropyl-6-methoxyphenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 11), 6-(2-isopropylphenyl)-1-(4-(1-(1-methylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 25), 6-(2-isopropylphenyl)-1-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 16), 6-(2-isopropylphenyl)-4-methyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 14), 6-(3-fluoro-2-isopropylphenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 10), 6-(2-isopropylphenyl)-3-methyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 17), 6-(2-isopropylphenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 1), 6-(4-(tert-butyl)-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(2-fluoropropan-2-yl)-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-methoxy-6-(1-methylcyclopropyl)pyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclobutyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, (S)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, (R)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-ethoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-isopropoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-cyclopropyl-5-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidine-4-carbonitrile, 6-cyclopropyl-N,N-dimethyl-5-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidin-4-amine, 6-(4,6-dimethoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-isopropyl-6-methylpyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6-(4-methyl-6-(methylthio)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-methyl-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-purine, 1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6-(4-methyl-6-(methylsulfonyl)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(2-methoxyethoxy)-6-methylpyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(1-isopropyl-4-methoxy-1H-pyrazol-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-1-isopropyl-1H-pyrazol-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine, and 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine, or a pharmaceutically acceptable salt or solvate, such as a hydrate, of any of the above.

[0245] In another embodiment, the disclosed compounds are 6-(4,6-diethoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(1-cyclopropyl-4-methoxy-1H-pyrazol-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-((6-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine, (R)-6-(4-cyclobutyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, (S)-6-(4-cyclobutyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, (R)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, (S)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(2-fluoropropan-2-yl)-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-ethoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-((6-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine, 1-(4-((6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)-5-methyl-1H-pyrazole-3-carbonitrile, 6-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-cyclopropyl-5-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidine-4-carbonitrile, 6-(4-cyclopropoxy-6-cyclopropylpyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclobutoxy-6-cyclopropylpyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxy-2-methylpyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(tert-butyl)-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(tert-butoxy)-6-cyclopropylpyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-(2-fluoroethoxy)pyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 1-(4-(1-cyclobutyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4,6-dimethoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 1-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-(2-fluoroethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2,4-dimethoxy-6-methylpyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-(2-methoxyethoxy)pyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-(2-methoxyethoxy)pyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-methoxy-6-(1-methylcyclopropyl)pyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, (S)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, (R)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclobutyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-isopropoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-isopropyl-6-methylpyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-ethoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, N,N,6-trimethyl-5-(1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidin-4-amine, 1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6-(4-methyl-6-(methylthio)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4,6-dimethoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(2-methoxyethoxy)-6-methylpyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-(1-methylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-methoxy-6-methylpyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 3-(1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)picolinonitrile, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-cyclopropyl-N-methyl-5-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidin-4-amine, 1-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6-(4-methoxy-6-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(benzyloxy)-6-cyclopropylpyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(3-(difluoromethyl)-1-methyl-1H-1,2,4-triazol-5-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(benzyloxy)-6-cyclopropylpyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 2-(2-(4-((6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)-N,N-dimethylacetamide, 6-cyclopropyl-N,N-dimethyl-5-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidin-4-amine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-(difluoromethyl)-1-methyl-1H-1,2,4-triazol-3-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-(pyrrolidin-1-yl)pyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(azetidin-1-yl)-6-cyclopropylpyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, and 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine, or a pharmaceutically acceptable salt or solvate, such as a hydrate, of any of the above.

[0246] In another embodiment, the disclosed compounds are 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-((4-methoxybenzyl)thio)-1H-pyrazolo[3,4-d]pyrimidine, (S)-1-(1-(4-(5-bromo-1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methoxy-1H-pyrazolo[3,4-d]pyrimidine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-8-(methoxymethyl)-9H-purine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-isopropyl-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine, 3-cyclobutoxy-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-2-(trifluoromethyl)-1H-imidazol-4-yl)benzyl)-3-methoxy-1H-pyrazolo[3,4-d]pyrimidine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-ethyl-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine, (S)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-(2-fluoroethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-3-methoxy-1H-pyrazolo[3,4-d]pyrimidine, 3-(azetidin-1-yl)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 1-(4-(5-bromo-1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methoxy-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-(2-fluoroethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-3-methoxy-1H-pyrazolo[3,4-d]pyrimidine, (S)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-3-methoxy-1H-pyrazolo[3,4-d]pyrimidine, (S)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-3-methoxy-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-ethoxypyrimidin-5-yl)-3-ethoxy-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-ethoxy-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-fluorobenzyl)-3-methoxy-1H-pyrazolo[3,4-d]pyrimidine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-methoxy-1H-pyrazolo[3,4-d]pyrimidine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine, 8-cyclopropyl-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-purine, 8-cyclobutyl-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-purine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-isopropyl-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-purine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-ethyl-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-purine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-methyl-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-purine, 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine, 2-(4-methoxy-6-methylpyrimidin-5-yl)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-purine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-purine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine, and 2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine.

[0247] definition For purposes of this disclosure, the term "alkyl," when used by itself or as part of another group, refers to alkyl groups containing 1 to 12 carbon atoms (i.e., C 1-12 alkyl) or the number of carbon atoms specified (i.e., C1 alkyl such as methyl, C2 alkyl such as ethyl, C3 alkyl such as propyl or isopropyl, etc.). An alkyl group is a straight-chain C 1-10 Alkyl group, branched chain C 3-10 Alkyl group, linear C 1-6 Alkyl group, branched chain C 3-6 Alkyl group, linear C 1-4 Alkyl group, branched chain C 3-4 Alkyl group, straight or branched C 3-4The alkyl group may be suitably selected from alkyl groups. The alkyl group may be partially or fully deuterated, i.e., one or more hydrogen atoms of the alkyl group are replaced with deuterium atoms. Non-limiting exemplary C 1-10 Alkyl groups include methyl (including -CD3), ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1-4 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.

[0248] For purposes of this disclosure, the term "optionally substituted alkyl," when used by itself or as part of another group, means that alkyl, as defined above, is either unsubstituted or substituted with one, two, or three substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl. Alkyl is an optionally substituted C 1-4 The optionally substituted alkyl may be substituted with two substituents or with one substituent. Non-limiting exemplary optionally substituted alkyl groups are -CH2CH2NO2, -CH2CH2CO2H, -CH2CH2SO2CH3, -CH2CH2COPh, and -CH2CH6H 11 Includes.

[0249] For purposes of this disclosure, the term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by abstraction of a second hydrogen atom from the alkyl. An alkylene group can also be a C-C alkylene or a C-C alkylene. Non-limiting exemplary alkylene groups include -CH-, -CH(CH)-, -C(CH)-, -CHCH-, -CHCH(CH)-, -CHC(CH)-, -CHCHCH-, and -CHCHCHCHCH-.

[0250] For purposes of this disclosure, the term "cycloalkyl," when used by itself or as part of another group, refers to alkyl groups containing 3 to 12 carbon atoms (i.e., C 3-12 Cycloalkyl refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having the specified number of carbon atoms. Cycloalkyl groups can have two rings or one ring. Cycloalkyl groups are defined as C 3-8 Cycloalkyl groups and C 3-6 The cycloalkyl group may be selected from cycloalkyl groups. The cycloalkyl group may contain one or more carbon-to-carbon double bonds or one carbon-to-carbon double bond. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro[3.3]heptane.

[0251] For the purposes of this disclosure, the term "optionally substituted cycloalkyl," when used by itself or as part of another group, means that cycloalkyl, as defined above, is unsubstituted or substituted with one, two, or three substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl. An optionally substituted cycloalkyl can be substituted with two substituents or one substituent.

[0252] For the purposes of this disclosure, the term "alkenyl," when used by itself or as part of another group, refers to an alkyl group, as defined above, containing one, two, or three carbon-to-carbon double bonds. An alkenyl group is one of the C 2-6 Alkenyl groups and C 2-4 The alkyl group may be selected from alkenyl groups. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0253] For purposes of this disclosure, the term "optionally substituted alkenyl," as used herein by itself or as part of another group, means that alkenyl, as defined above, is either unsubstituted or substituted with one, two, or three substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo.

[0254] For purposes of this disclosure, the term "alkynyl," when used by itself or as part of another group, refers to an alkyl group as defined above containing one to three carbon-to-carbon triple bonds. An alkynyl may have one carbon-to-carbon triple bond. An alkynyl group is one of the C 2-6 Alkynyl groups and C 2-4 The alkynyl groups may be selected from alkynyl groups. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0255] For purposes of this disclosure, the term "optionally substituted alkynyl," as used herein by itself or as part of another group, means that alkynyl, as defined above, is either unsubstituted or substituted with one, two, or three substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo.

[0256] For purposes of this disclosure, the term "haloalkyl," when used by itself or as part of another group, refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. The alkyl group may be substituted with one, two, or three fluorine and / or chlorine atoms. A haloalkyl group is any group having a C 1-4 Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

[0257] For purposes of this disclosure, the term "hydroxyalkyl," when used by itself or as part of another group, refers to an alkyl group substituted with one or more, e.g., one, two, or three, hydroxy groups. Hydroxyalkyl groups include monohydroxyalkyl groups, i.e., substituted with one hydroxy group, dihydroxyalkyl groups, i.e., substituted with two hydroxy groups, and C 1-4Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.

[0258] For purposes of this disclosure, the term "alkoxy," when used by itself or as part of another group, refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted alkenyl, or optionally substituted alkynyl attached to a terminal oxygen atom. An alkoxy group is a C 1-4 Alkoxy groups and C 1-4 Alkyl may be selected from, for example, methoxy, ethoxy, and tert-butoxy.

[0259] For purposes of this disclosure, the term "alkylthio," when used by itself or as part of another group, refers to a sulfur atom substituted by an optionally substituted alkyl group. An alkylthio group is a C 1-4 Non-limiting exemplary alkylthio groups include -SCH3 (i.e., methylthio) and -SCH2CH3.

[0260] For purposes of this disclosure, the term "alkoxyalkyl," when used by itself or as part of another group, refers to an alkyl group substituted with an alkoxy group. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.

[0261] For purposes of this disclosure, the term "halo," when used by itself or as part of another group, refers to a halogen atom. Non-limiting exemplary halo groups include fluoro, chloro, bromo, and iodo.

[0262] For purposes of this disclosure, the term "haloalkoxy" when used by itself or as part of another group refers to a haloalkyl attached to a terminal oxygen atom. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0263] For purposes of this disclosure, the term "heteroalkyl," when used by itself or as part of another group, refers to a stable straight- or branched-chain hydrocarbon radical containing 1 to 10 carbon atoms and at least two heteroatoms selected from O, N, or S, which can be the same or different, wherein 1) the nitrogen atom(s) and sulfur atom(s) can be optionally oxidized and / or 2) the nitrogen atom(s) can be optionally quaternized. The heteroatoms can be placed at any interior position of the heteroalkyl group or at the position at which the heteroalkyl group is attached to the remainder of the molecule. The heteroalkyl group can contain two oxygen atoms, one oxygen atom and one nitrogen atom, or two nitrogen atoms. Non-limiting exemplary heteroalkyl groups include -CH2OCH-2CH2OCH3, -OCH2CH2OCH2CH2OCH3, -CH2NHCH2CH2OCH2, -OCH2CH2NH2, -NHCH2CH2N(H)CH3, -NHCH2CH2OCH3, and -OCH2CH2OCH3.

[0264] For purposes of this disclosure, the term "aryl," when used by itself or as part of another group, refers to a monocyclic or bicyclic aromatic ring system having 6 to 14 carbon atoms (i.e., C 6-14 The aryl group is C 6-14 Aryl groups and C 6-10The aryl group may be selected from phenyl or naphthyl. The aryl group may be phenyl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. The aryl group may be selected from phenyl or naphthyl. The aryl group may be phenyl.

[0265] For the purposes of this disclosure, the term "optionally substituted aryl," as used herein by itself or as part of another group, means that aryl, as defined above, is unsubstituted or is selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkylaralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (C 1-4(haloalkoxy)alkyl, (heteroaryl)alkyl. The optionally substituted aryl may be an optionally substituted phenyl. The optionally substituted phenyl may have four substituents, three substituents, two substituents, or one substituent. The optionally substituted phenyl may have one amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl substituent. Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylpropan-2-amine. The term optionally substituted aryl is intended to include groups having fused, optionally substituted cycloalkyl and fused, optionally substituted heterocyclic rings. Examples include: [ka] Includes.

[0266] For purposes of this disclosure, the term "aryloxy," when used by itself or as part of another group, refers to an optionally substituted aryl attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO-.

[0267] For purposes of this disclosure, the term "heteroaryloxy," when used by itself or as part of another group, refers to an optionally substituted heteroaryl attached to a terminal oxygen atom.

[0268] For purposes of this disclosure, the terms "aralkyloxy" or "arylalkyloxy," when used by themselves or as part of another group, refer to an aralkyl group attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCHO-.

[0269] For purposes of this disclosure, the term "heteroaryl" or "heteroaromatic" refers to a heteroaryl having 5 to 14 ring atoms (i.e., C 5-14 Heteroaryl) and monocyclic and bicyclic aromatic ring systems having 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen, or sulfur. Heteroaryl groups include C 5-14 Heteroaryl groups and C 3-6The heteroaryl group may be selected from heteroaryl groups. The heteroaryl may have three heteroatoms, two heteroatoms, or one heteroatom. The heteroaryl may be a C5 heteroaryl or a C6 heteroaryl. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzoxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, triazolyl, tetrazolyl, and phenoxazinyl. Heteroaryl includes thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidine-4-yl), and pyrimidine-5-yl. -4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl), isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl), triazolyl (e.g., 1,2,4-triazolyl and 1,2,3-triazolyl).The term "heteroaryl" is also meant to include possible N-oxides. Exemplary N-oxides include pyridyl N-oxides.

[0270] For the purposes of this disclosure, the term "optionally substituted heteroaryl," when used by itself or as part of another group, means that heteroaryl, as defined above, is unsubstituted or is selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkylaryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, heteroaryl(alkyl), (heteroaryl)alkyl, -N(R 33 )(R 34 ), or -N(H)C(=O)-R 35 and wherein R 33 is hydrogen or C 1-4 alkyl, and R 34 is an alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl; R 35is alkyl, optionally substituted aryl, or optionally substituted heteroaryl. The optionally substituted heteroaryl may have one substituent. The substituents include amino, alkylamino, dialkylamino, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, -N(R 33 )(R 34 ), or -N(H)C(=O)-R 35 The optionally substituted heteroaryl may be an optionally substituted pyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogen atom may be substituted.

[0271] For purposes of this disclosure, the terms "heterocycle" or "heterocyclo," when used by itself or as part of another group, refer to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups containing one, two, or three rings having 3 to 14 ring members (i.e., 3- to 14-membered heterocyclos) and at least one heteroatom. Heterocyclo groups include C 3-14 Heterocyclo groups and C 3-8Heterocyclo groups may be selected from the group consisting of: heteroatoms, each independently selected from the group consisting of oxygen, sulfur, and / or nitrogen atoms, including sulfoxide and sulfone, and may be quaternized. The term "heterocyclo" is intended to include cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as β-lactam, γ-lactam, δ-lactam, and ε-lactam, and cyclic carbamate groups such as oxazolidinyl-2-one. The term "heterocyclo" is also intended to include groups having a fused, optionally substituted aryl group, such as indolinyl, indolinyl-2-one, benzo[d]oxazolyl-2(3H)-one. The term "heterocyclo" is also intended to include groups having a fused, optionally substituted heteroaryl group, such as 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine. Heterocyclo groups can be selected from 4-, 5-, 6-, 7-, or 8-membered ring groups containing one ring and one or two oxygen and / or nitrogen atoms, 5- or 6-membered ring groups containing one ring and one or two nitrogen atoms, and 8-, 9-, 10-, 11-, or 12-membered ring groups containing two rings and one or two nitrogen atoms. The heterocyclo can be optionally linked to the remainder of the molecule through a carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include 2-oxopyrrolidin-3-yl, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, azetidinyl, 8-azabicyclo[3.2.1]octane (nortropane), 6-azaspiro[2.5]octane, 6-azaspiro[3.4]octane, indolinyl, indolinyl-2-one, 1,3-dihydro-2H-benzo[d]imidazol-2-one.

[0272] For purposes of this disclosure, the term "optionally substituted heterocyclo," as used herein by itself or as part of another group, means that the heterocyclo defined above is either unsubstituted or substituted with one to four substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkylaralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. The substitution may occur on any available carbon or nitrogen atom, resulting in the formation of a spirocyclic ring.

[0273] For purposes of this disclosure, the term "amino," when used by itself or as part of another group, refers to --NH.sub.2.

[0274] For purposes of this disclosure, the term "alkylamino" when used by itself or as part of another group refers to -NHR 36 In the formula, R 36 is C 1-6 R is alkyl. 36 is C 1-4 Non-limiting exemplary alkylamino groups include -N(H)CH3 and -N(H)CH2CH3.

[0275] For purposes of this disclosure, the term "dialkylamino," when used by itself or as part of another group, refers to -NR 37a R 37b In the formula, R 37a and R 37bare each independently C 1-6 R is alkyl. 37a and R 37b are each independently C 1-4 Non-limiting exemplary dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.

[0276] For purposes of this disclosure, the term "hydroxyalkylamino" when used by itself or as part of another group refers to -NHR 38 In the formula, R 38 is hydroxyalkyl.

[0277] For purposes of this disclosure, the term "cycloalkylamino," when used by itself or as part of another group, refers to -NR 39a R 39b In the formula, R 39a is an optionally substituted cycloalkyl, and R 39b is hydrogen or C 1-4 It is alkyl.

[0278] For purposes of this disclosure, the term "aralkylamino," when used by itself or as part of another group, refers to -NR 40a R 40b In the formula, R 40a is aralkyl and R 40b is hydrogen or C 1-4 Non-limiting exemplary aralkylamino groups include —N(H)CH Ph and —N(CH)CH Ph.

[0279] For purposes of this disclosure, the term "(amino)alkyl," when used by itself or as part of another group, refers to an alkyl group substituted with an amino group. 1-4Non-limiting exemplary (amino)alkyl groups include -CH2NH2, -C(NH2)(H)CH3, -CH2CH2NH2, -CH2C(NH2)(H)CH3, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, and -CH2C(CH3)2CH2NH2.

[0280] For purposes of this disclosure, the term "(alkylamino)alkyl," when used by itself or as part of another group, refers to an alkyl group substituted with an alkylamino group. 1-4 It can be alkyl. A non-limiting exemplary (alkylamino)alkyl group is —CH 2 CH 2 N(H)CH 3 .

[0281] For purposes of this disclosure, the term "(dialkylamino)alkyl," when used by itself or as part of another group, refers to an alkyl group substituted with a dialkylamino group. 1-4 A non-limiting exemplary (dialkylamino)alkyl group is —CH 2 CH 2 N(CH 3 ) 2 .

[0282] For purposes of this disclosure, the term "(cycloalkylamino)alkyl," when used by itself or as part of another group, refers to an alkyl group substituted with a cycloalkylamino group. 1-4 Non-limiting exemplary (cycloalkylamino)alkyl groups include —CHN(H)cyclopropyl, —CHN(H)cyclobutyl, and —CHN(H)cyclohexyl.

[0283] For purposes of this disclosure, the term "(aralkylamino)alkyl," when used by itself or as part of another group, refers to an alkyl group substituted with an aralkylamino group. 1-4 A non-limiting exemplary (aralkylamino)alkyl group is —CH 2 CH 2 CH 2 N(H)CH 2 Ph.

[0284] For purposes of this disclosure, the term "(cyano)alkyl," when used by itself or as part of another group, refers to an alkyl group substituted with one or more cyano, e.g., -CN, groups. 1-4 Non-limiting exemplary (cyano)alkyl groups include -CH2CH2CN, -CH2CH2CH2CN, and -CH2CH2CH2CH2CN.

[0285] For the purposes of this disclosure, the term "(amino)(hydroxy)alkyl," when used by itself or as part of another group, refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino group and one hydroxy group. 1-6 Alkyl or C 1-4 It is alkyl.

[0286] For the purposes of this disclosure, the term "(amino)(aryl)alkyl," when used by itself or as part of another group, refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino group and one optionally substituted aryl group. 1-6 The optionally substituted aryl group may be an optionally substituted phenyl.

[0287] For the purposes of this disclosure, the term "(cycloalkyl)alkyl," when used by itself or as part of another group, refers to an alkyl group substituted with one optionally substituted cycloalkyl group. 1-4 Alkyl or C 3-6 Optionally substituted cycloalkyl groups may be substituted with amino or (amino)alkyl groups.

[0288] For purposes of this disclosure, the term "(hydroxy)(aryl)alkyl," when used by itself or as part of another group, refers to an alkyl group substituted with one hydroxy group and one optionally substituted aryl group. 1-6 The optionally substituted aryl group can be an optionally substituted phenyl. Non-limiting exemplary (hydroxy)(aryl)alkyl groups include: [ka] Includes.

[0289] For purposes of this disclosure, the term "carboxamide," when used by itself or as part of another group, refers to a group of formula -C(=O)NR 41a R 41b where R 41a and R 41b are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or R 41a and R 41b R together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclic group. 41a and R 41b may each independently be hydrogen or an optionally substituted alkyl. Non-limiting exemplary carboxamide groups include -CONH, -CON(H)CH, -CON(CH), and -CON(H)Ph.

[0290] For purposes of this disclosure, the term "(carboxamido)alkyl," when used by itself or as part of another group, refers to an alkyl group substituted with a carboxamido group. Non-limiting exemplary (carboxamido)alkyl groups include -CHCONH, -C(H)CH-CONH, and -CHCON(H)CH.

[0291] For purposes of this disclosure, the term "sulfonamide," when used by itself or as part of another group, refers to a group of formula -SONR42a R 42b where R 42a and R 42b are each independently hydrogen, optionally substituted alkyl, or optionally substituted aryl, or R 42a and R 42b taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group. Non-limiting exemplary sulfonamide groups include -SO2NH2, -SON2N(H)CH3, and -SON(H)Ph.

[0292] For purposes of this disclosure, the term "alkylcarbonyl," when used by itself or as part of another group, refers to a carbonyl group substituted with an alkyl group, i.e., -C(=O)-. A non-limiting exemplary alkylcarbonyl group is -COCH3.

[0293] For purposes of this disclosure, the term "arylcarbonyl," when used by itself or as part of another group, refers to a carbonyl group substituted by an optionally substituted aryl group, i.e., -C(=O)-. A non-limiting exemplary arylcarbonyl group is -COPh.

[0294] For purposes of this disclosure, the term "alkylsulfonyl," when used by itself or as part of another group, refers to a sulfonyl group substituted with any of the above optionally substituted alkyl groups, i.e., -SO-. Non-limiting exemplary alkylsulfonyl groups are -SOCH (i.e., methylsulfonyl) and -SOCHCH (i.e., ethylsulfonyl).

[0295] For purposes of this disclosure, the term "arylsulfonyl," when used by itself or as part of another group, refers to a sulfonyl group substituted with any of the above optionally substituted aryl groups, i.e., -SO2-. A non-limiting exemplary arylsulfonyl group is -SO2Ph.

[0296] For purposes of this disclosure, the term "mercaptoalkyl," when used by itself or as part of another group, refers to any of the above alkyl groups substituted with an --SH group.

[0297] For purposes of this disclosure, the term "carboxy," when used by itself or as part of another group, refers to a radical of formula --COOH.

[0298] For purposes of this disclosure, the term "carboxyalkyl," when used by itself or as part of another group, refers to any of the above alkyl groups substituted with -COOH. A non-limiting exemplary carboxyalkyl group is -CHCOH.

[0299] For purposes of this disclosure, the term "alkoxycarbonyl," when used by itself or as part of another group, refers to a carbonyl group substituted with an alkoxy group, i.e., -C(=O)-. Non-limiting exemplary alkoxycarbonyl groups are -COMe and -COEt.

[0300] For purposes of this disclosure, the terms "aralkyl" or "arylalkyl," when used by itself or as part of another group, refer to an alkyl group substituted with one, two, or three optionally substituted aryl groups. An aralkyl group is a C substituted with one optionally substituted aryl group. 1-4 Non-limiting exemplary aralkyl groups include benzyl, phenethyl, -CHPh, -CH(4-OH-Ph), and -CH(4-F-Ph).

[0301] For purposes of this disclosure, the term "(heterocyclo)alkyl," when used by itself or as part of another group, refers to an alkyl group substituted with one, two, or three optionally substituted heterocyclo groups. (Heterocyclo)alkyl refers to a C substituted with one optionally substituted heterocyclo group. 1-4The heterocyclo can be linked to the alkyl group through a carbon or nitrogen atom. Non-limiting exemplary (heterocyclo)alkyl groups include: [ka] Includes.

[0302] For purposes of this disclosure, the term "heteroaralkyl" or "(heteroaryl)alkyl," when used by itself or as part of another group, refers to an alkyl group substituted with one, two, or three optionally substituted heteroaryl groups. A (heteroaryl)alkyl group is a C substituted with one optionally substituted heteroaryl group. 1-4 Non-limiting exemplary (heteroaryl)alkyl groups include: [ka] Includes.

[0303] For purposes of this disclosure, the term "alkylcarbonylamino," when used by itself or as part of another group, refers to an alkylcarbonyl group attached to an amino. A non-limiting exemplary alkylcarbonylamino group is -NHCOCH3.

[0304] The present disclosure encompasses any of the disclosed compounds that are isotopically labeled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds are: 2 H (or deuterium (D)), 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36Isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as Cl, e.g., 3 H, 11 C, and 14 C. The present disclosure also provides compositions in which substantially all of the atoms at positions within the disclosed compounds are replaced by atoms having a different atomic mass or mass number. The present disclosure also provides compositions in which a portion of the atoms at positions within the disclosed compounds are replaced, i.e., the disclosed compounds are enriched at positions with atoms having different atomic masses or mass numbers. In one embodiment, the present disclosure provides compositions in which the disclosed compounds have 1 to 8 hydrogens replaced with deuterium. The disclosed isotopically labeled compounds can be prepared by methods known in the art.

[0305] The disclosed compounds may contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure is meant to encompass the use of all such possible forms, as well as their racemic and resolved forms, and mixtures thereof. Individual enantiomers can be separated according to methods known in the art in light of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they are intended to include both E and Z geometric isomers. All tautomers are also intended to be encompassed by the present disclosure.

[0306] As used herein, the term "stereoisomer" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with two or more chiral centers that are not mirror images of one another (diastereomers).

[0307] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are bonded.

[0308] The terms "enantiomer" and "enantiomeric" refer to a molecule that is not superimposable on its mirror image and is therefore optically active; an enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.

[0309] The term "racemic" refers to a mixture of equal parts of enantiomers, which mixture is optically inactive.

[0310] The term "absolute configuration" refers to the arrangement in space of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

[0311] Stereochemical terms and conventions used herein, unless otherwise indicated, are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996).

[0312] The term "enantiomeric excess" or "ee" refers to a measure of how much of one enantiomer is present relative to the other. For a mixture of R and S enantiomers, percent enantiomeric excess is defined as |RS|*100, where R and S are the mole or weight fractions of each of the enantiomers in the mixture such that R+S=1. Using knowledge of the optical rotation of chiral substances, percent enantiomeric excess can be calculated as ([α] obs / [α] max )*100, where [α] obs is the optical rotation of the mixture of enantiomers, and [α] max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, or optical polarimetry.

[0313] The terms "enantiomerically pure" or "enantiopure" refer to a sample of a chiral substance in which all of its molecules have the same sense of chirality (within the limits of detection).

[0314] The terms "enantiomerically enriched" or "enantioenriched" refer to a sample of a chiral substance whose ratio of enantiomers is greater than 50:50. An enantiomerically enriched compound may be enantiomerically pure.

[0315] It is understood that embodiments of the invention described herein include "consisting of" and / or "consisting essentially of" embodiments. As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated. The use of the term "or" herein is not meant to imply that alternatives are mutually exclusive.

[0316] In this application, the use of "or" means "and / or" unless expressly stated or understood by one of ordinary skill in the art. In the context of multiple dependent claims, the use of "or" refers to two or more preceding independent or dependent claims.

[0317] The term "about," as used herein, includes the recited number ±10%. Thus, "about 10" means 9 to 11. As will be understood by those skilled in the art, reference herein to "about" a value or parameter includes (and describes) an example of that value or parameter itself. For example, a description that refers to "about X" includes a description of "X."

[0318] The present disclosure encompasses the preparation and use of salts of the disclosed compounds, including non-toxic pharmaceutically acceptable salts. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts. Pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, and cesium salt; alkaline earth metal salts such as calcium salt and magnesium salt; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, and N,N'-dibenzylethylenediamine salt; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, and sulfate; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, and formate; sulfonate salts such as methanesulfonate, benzenesulfonate, and p-toluenesulfonate; and amino acid salts such as alginate, aspartate, and glutamate. The term "pharmaceutically acceptable salt," as used herein, refers to any salt obtained, for example, by reaction of a disclosed compound with an acid or base, that is physiologically tolerated in a target patient (e.g., a mammal, e.g., a human).

[0319] Acid addition salts can be formed by mixing a solution of certain disclosed compounds with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, etc. Base salts can be formed by mixing a solution of a disclosed compound with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, etc.

[0320] The present disclosure encompasses the preparation and use of solvates of the disclosed compounds. Solvates typically do not significantly alter the physiological activity or toxicity of the compound and therefore may function as pharmacological equivalents. As used herein, the term "solvate" refers to a combination, physical association, and / or solvation of a compound of the present disclosure with solvent molecules, such as a disolvate, monosolvate, or hemisolvate, in which the ratio of solvent molecules to the compound of the present disclosure is about 2:1, about 1:1, or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, a solvate may be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates. The disclosed compounds may exist in solvated forms with pharmaceutically acceptable solvents such as water, methanol, ethanol, etc., and the disclosure is intended to encompass both solvated and unsolvated forms of the disclosed compounds. One type of solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates in which the solvent molecule is water. Solvates can typically function as pharmacological equivalents. The preparation of solvates is known in the art. See, for example, M. Caira et al., J. Pharmaceut. Sci., 93(3)601-611(2004), which describes the preparation of a solvate of fluconazole using ethyl acetate and water. The preparation of similar solvates, hemisolvates, hydrates, and the like is described by EC van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004), and ALBingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting process for preparing a solvate would involve dissolving a disclosed compound in a desired solvent (organic, aqueous, or a mixture thereof) at a temperature above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, for example, filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of solvent in the solvate crystals.

[0321] Because the disclosed compounds are inhibitors of USP1 protein, the present disclosure provides methods for inhibiting USP1 protein, comprising contacting USP1 protein or a composition comprising USP1 protein with one or more disclosed compounds.

[0322] Because the disclosed compounds are inhibitors of USP1 protein, some diseases, conditions, or disorders mediated by USP1 protein can be treated by using these compounds. Accordingly, the present disclosure generally relates to a method for treating a disease, condition, or disorder responsive to inhibition of USP1 protein in an animal suffering from or at risk of suffering from the disorder, the method comprising administering to the animal an effective amount of one or more disclosed compounds.

[0323] The present disclosure further relates to methods of inhibiting USP1 protein in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one disclosed compound.

[0324] As used herein, "treatment" refers to an approach to obtain beneficial or desired clinical results. As used herein, "treatment" encompasses any administration or application of a therapeutic agent to a disease in a mammal, including a human. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, any one or more of the following: alleviation of one or more symptoms, reduction in the extent of the disease, preventing or slowing the spread (e.g., metastasis) of the disease, preventing or slowing the recurrence of the disease, delaying or slowing the progression of the disease, amelioration of the disease state, inhibiting the disease or its progression, inhibiting or slowing the disease or its progression, halting its onset, and remission (whether partial or complete). Also encompassed by "treatment" is the reduction of the pathological consequences of a proliferative disease. The methods provided herein contemplate any one or more of these aspects of treatment. In line with the above, the term treatment does not require 100% elimination of all aspects of the disorder.

[0325] In the context of cancer, the term "treating" includes, but is not limited to, inhibiting the growth of cancer cells, inhibiting the replication of cancer cells, reducing the overall tumor burden, and delaying, halting, or slowing tumor growth, progression, or metastasis.

[0326] As used herein, "delaying" means to prolong, prevent, slow, retard, stabilize, inhibit, and / or postpone the onset or progression of a disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated.

[0327] A "therapeutically effective amount" of a substance can vary depending on factors such as the disease state, age, sex, and weight of the individual, as well as the ability of the substance to induce a desired response in the individual. A therapeutically effective amount is also one in which the therapeutically beneficial effects outweigh any toxic or harmful effects of the substance. A therapeutically effective amount can be delivered in one or more administrations. A therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic effect.

[0328] The terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a therapeutic agent to a desired site of biological action. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon, and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0329] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a preparation that is in a form that allows the biological activity of the active ingredient(s) to be effective and that does not contain additional components that are unacceptably toxic to the subject to which the formulation will be administered. Such formulations may be sterile.

[0330] A "pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, formulation aid, or carrier conventional in the art for use with therapeutic agents that together comprise a "pharmaceutical composition" for administration to a subject. Pharmaceutically acceptable carriers are non-toxic to recipients at the dosages and concentrations employed and are compatible with the other ingredients of the formulation. Pharmaceutically acceptable carriers are appropriate for the formulation with which they are employed.

[0331] A "sterile" preparation is aseptic or essentially free of viable microorganisms and their spores.

[0332] The term "container" therefore refers to any receptacle and closure suitable for storing, transporting, dispensing, and / or handling a pharmaceutical product.

[0333] The term "package insert" or "package insert" means the information that accompanies a pharmaceutical product that provides instructions on how to administer the product, along with safety and effectiveness data needed to enable physicians, pharmacists, and patients to make informed decisions regarding the use of the product. The package insert is generally considered the "label" for a pharmaceutical product.

[0334] The terms "disease" or "condition" or "disorder," as used herein, refer to a condition for which treatment is necessary and / or desirable, and refer to a disturbance and / or abnormality that is primarily considered a pathological condition or function and may manifest itself in the form of specific signs, symptoms, and / or dysfunction. As demonstrated below, the disclosed compounds inhibit the USP1 protein and can be used to treat diseases and conditions, such as proliferative diseases, in which inhibition of the USP1 protein provides a benefit.

[0335] The terms "polypeptide" and "protein" are used interchangeably to refer to polymers of amino acid residues and are not limited to a minimum length. Such polymers of amino acid residues may contain natural or unnatural amino acid residues and include, but are not limited to, peptides, oligopeptides, dimers, trimers, and multimers of amino acid residues. Both full-length proteins and fragments thereof are encompassed by the definition. The term also includes post-expression modifications of the polypeptide, such as glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of this disclosure, "polypeptide" refers to proteins containing modifications such as deletions, additions, and substitutions (generally conservative in nature) to the native sequence, so long as the protein maintains the desired activity. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through host mutations that generate proteins or errors resulting from PCR amplification.

[0336] "USP1" and "ubiquitin-specific processing protease 1," as used herein, refer to any naturally occurring polypeptide or USP1-encoding polynucleotide. The term "USP1" encompasses "full-length," unprocessed USP1 polypeptides, as well as any form of USP1 that results from processing within a cell (e.g., removal of the signal peptide). The term also encompasses naturally occurring variants of USP1, such as those encoded by splice variants and allelic variants. The USP1 polypeptides described herein can be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods. Human USP1 sequences are known and include, for example, the sequence publicly available as UniProt No. O94782 (including isoforms). As used herein, the term "human USP1 protein" refers to the USP1 protein comprising the amino acid sequence set forth in SEQ ID NO: 1 in U.S. Provisional Patent Application No. 62 / 857,986, filed June 6, 2019.

[0337] USP1 is a deubiquitinating enzyme that acts as part of a complex with UAF1. The "deubiquitinase activity" of USP1 includes its ability to deubiquitinate as part of the USP1-UAF1 complex.

[0338] The term "specifically binds" to a protein or domain of a protein is a term well understood in the art, and methods for determining such specific binding are also well known in the art. A molecule is said to exhibit "specific binding" or "preferential binding" if it reacts or associates with a particular protein or domain of a protein more frequently, more rapidly, with a longer duration, and / or with a higher affinity than with alternative proteins or domains. It should be understood that a molecule that specifically or preferentially binds to a first protein or domain may or may not specifically or preferentially bind to a second protein or domain. Thus, "specific binding" or "preferential binding" does not necessarily require (but can include) exclusive binding. Generally, but not necessarily, reference to binding refers to preferential binding. For example, a USP1 inhibitor that specifically binds to USP1, UAF1, and / or the USP1-UAF1 complex may not bind to other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1), or may bind to other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) with reduced affinity compared to binding to USP1.

[0339] The terms "reduce" or "reducing" or "inhibition" or "inhibiting" refer to a decrease or cessation of any phenotypic characteristic, or a decrease or cessation of the incidence, degree, or likelihood of that characteristic. "Reduce" or "inhibiting" is a decrease, reduction, or cessation of an activity, function, and / or amount compared to a reference. In some embodiments, by "reduce" or "inhibit" it refers to the ability to cause an overall decrease of 20% or more. In some embodiments, by "reduce" or "inhibit" it refers to the ability to cause an overall decrease of 50% or more. In some embodiments, by "reduce" or "inhibit" it refers to the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or more. In some embodiments, the amount is inhibited or reduced over a period of time relative to a control over the same period of time.

[0340] In some embodiments, inhibiting the USP1 protein refers to the inhibition of one or more activities or functions of the USP1 protein. It should be understood that one or more activities or functions of the USP1 protein can be inhibited in vitro or in vivo. Non-limiting examples of USP1 activities and functions include deubiquitinase activity and the formation of a complex with UAF1, and are described herein. Exemplary levels of inhibition of one or more activities of the USP1 protein include at least 10% inhibition, at least 20% inhibition, at least 30% inhibition, at least 40% inhibition, at least 50% inhibition, at least 60% inhibition, at least 70% inhibition, at least 80% inhibition, at least 90% inhibition, and up to 100% inhibition.

[0341] The terms "individual" or "subject" are used interchangeably herein to refer to an animal, e.g., a mammal such as a human. In some cases, methods of treating mammals, including but not limited to humans, rodents, monkeys, cats, dogs, horses, cows, pigs, sheep, goats, mammalian laboratory animals, mammalian farm animals, mammalian sport animals, and mammalian pets, are provided. In some instances, "individual" or "subject" refers to an individual or subject in need of treatment for a disease or disorder. In some instances, a subject receiving treatment may be a patient, designating the fact that the subject has been identified as having or at particular risk for the disorder relevant to the treatment.

[0342] As used herein, the terms "cancer" and "tumor" refer to or describe a physiological condition in a mammal in which a population of cells is characterized by unregulated cell growth. The terms encompass solid and hematological / lymphatic cancers. Examples of cancer include, but are not limited to, DNA damage repair pathway-deficient cancers. Additional examples of cancer include, but are not limited to, ovarian cancer, breast cancer (including triple-negative breast cancer), non-small cell lung cancer (NSCLC), and osteosarcoma. The cancer may be BRCA1 or BRCA2 wild-type. The cancer may also be BRCA1 or BRCA2 mutant. The cancer may further be a PARP inhibitor-resistant or refractory cancer, or a PARP inhibitor-resistant or refractory BRCA1 or BRCA2 mutant cancer.

[0343] As used herein, the term "loss-of-function" mutation refers to a mutation that results in the absence of a gene, reduced expression of a gene, or a gene product (e.g., a protein) with reduced or no activity. Loss-of-function mutations include, for example, missense mutations, nucleotide insertions, nucleotide deletions, and gene deletions. Loss-of-function mutations also include dominant-negative mutations. Thus, cancer cells with a loss-of-function mutation in the gene encoding p53 include cancer cells with a missense mutation in the gene encoding p53, as well as cancer cells lacking the gene encoding p53.

[0344] USP1 inhibitors In various embodiments, the disclosed compounds are USP1 inhibitors that reduce the level of USP1 protein and / or inhibit or reduce at least one biological activity of USP1 protein.

[0345] In some embodiments, the disclosed compounds specifically bind to USP1 protein. In some embodiments, the disclosed compounds specifically bind to USP1 protein in a USP1-UAF1 complex. In some embodiments, the disclosed compounds specifically bind to USP1 mRNA. In some embodiments, the disclosed compounds specifically bind to USP1 protein (alone or in a USP1-UAF1 complex) or USP1 mRNA. In some embodiments, the disclosed compounds specifically bind to UAF1 (alone or in a USP1-UAF1 complex) and inhibit or reduce the formation or activity of the USP1-UAF1 complex.

[0346] In some embodiments, the disclosed compounds decrease the formation of the USP1-UAF1 complex. In some embodiments, the disclosed compounds decrease the activity of the USP1-UAF1 complex. In some embodiments, the disclosed compounds decrease the deubiquitinase activity of USP1. In some embodiments, the disclosed compounds increase monoubiquitinated PCNA. In some embodiments, the disclosed compounds increase monoubiquitinated FANCD2. In some embodiments, the disclosed compounds increase monoubiquitinated FANCI.

[0347] In some embodiments, the disclosed compounds do not bind to other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1), or bind to deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) with an affinity that is reduced by at least 5-fold, at least 10-fold, at least 20-fold, or at least 100-fold compared to the affinity for USP1 (i.e., the K of a USP1 inhibitor for other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1)). D is the K D at least 5 times, at least 10 times, at least 20 times, or at least 100 times higher than

[0348] In some embodiments, the disclosed compounds inhibit USP1 deubiquitinase activity with an IC50 of less than about 50 nM, about 50 nM to about 200 nM, about 200 nM to about 2 pM, or greater than 2 pM, as measured, for example, using the assay disclosed in U.S. Patent Application Publication No. 2017 / 0145012 or an IC50 of 50 nM to 1000 nM, as measured, for example, using the assay disclosed in Liang et al., Nat Chem Biol 10:289-304 (2014). In some embodiments, the disclosed compounds inhibit USP1 deubiquitinase activity with an IC50 as measured, for example, using the assay disclosed in Chen, et al., Chem Biol., 18(11):1390-1400 (2011). In some embodiments, the disclosed compounds do not inhibit the activity of other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1), or inhibit the activity of other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) with an IC50 that is at least 5-fold, at least 10-fold, at least 20-fold, or at least 100-fold higher than the IC50 for inhibiting USP1 deubiquitinase activity.

[0349] In some embodiments, the disclosed compounds bind to USP1 protein with an affinity ranging from 1 pM to 100 μM, or from 1 pM to 1 μM, or from 1 pM to 500 nM, or from 1 pM to 100 nM. In some embodiments, the disclosed compounds bind to USP1 protein with an affinity of about 1 pM to about 100 μM, about 1 nM to about 100 μM, about 1 μM to about 100 μM, about 1 μM to about 50 μM, about 1 μM to about 40 μM, about 1 μM to about 30 μM, about 1 μM to about 20 μM, or about 1 μM to about 10 μM, about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, or about 100 μM. In some embodiments, the disclosed compounds may have a serotonin concentration of about 100 nM to about 1 μM, about 100 nM to about 900 nM, about 100 nM to about 800 nM, about 100 nM to about 700 nM, about 100 nM to about 600 nM, about 100 nM to about 500 nM, about 100 nM to about 400 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 200 nM to about 1 μM, about 300 nM, The antibody binds to the USP1 protein with an affinity of about 1 μM, about 400 nM to about 1 μM, about 500 nM to about 1 μM, about 600 nM to about 1 μM, about 700 nM to about 1 μM, about 800 nM to about 1 μM, about 900 nM to about 1 μM, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, or about 900 nM.In some embodiments, the disclosed compounds may be administered at a concentration of from about 1 nM to about 100 nM, 1 nM to about 90 nM, 1 nM to about 80 nM, 1 nM to about 70 nM, 1 nM to about 60 nM, 1 nM to about 50 nM, 1 nM to about 40 nM, 1 nM to about 30 nM, 1 nM to about 20 nM, 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM to about 100 nM, about 50 nM to about 10 The disclosed compounds bind to USP1 protein with an affinity of 0 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, or about 100 nM. In some embodiments, the disclosed compounds bind to USP1 protein with an affinity of less than 1 μM, less than 500 nM, less than 100 nM, less than 10 nM, or less than 1 nM. In some embodiments, the disclosed compounds bind to USP1 protein with an affinity of less than 1 nM.

[0350] In some embodiments, disclosed compounds have an IC of 1 pM to 100 μM, or 1 pM to 1 μM, or 1 pM to 500 nM, or 1 pM to 100 nM. 50 In some embodiments, disclosed compounds inhibit USP1 activity with an IC of about 1 pM to about 100 μM, about 1 nM to about 100 μM, about 1 μM to about 100 μM, about 1 μM to about 50 μM, about 1 μM to about 40 μM, about 1 μM to about 30 μM, about 1 μM to about 20 μM, or about 1 μM to about 10 μM, about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, or about 100 μM. 50In some embodiments, the disclosed compounds inhibit USP1 activity at concentrations of about 100 nM to about 1 μM, about 100 nM to about 900 nM, about 100 nM to about 800 nM, about 100 nM to about 700 nM, about 100 nM to about 600 nM, about 100 nM to about 500 nM, about 100 nM to about 400 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 200 nM to about 1 μM. IC50 of about 1 μM, about 300 nM to about 1 μM, about 400 nM to about 1 μM, about 500 nM to about 1 μM, about 600 nM to about 1 μM, about 700 nM to about 1 μM, about 800 nM to about 1 μM, about 900 nM to about 1 μM, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, or about 900 nM 50 In some embodiments, the disclosed compounds inhibit USP1 activity at concentrations of about 1 nM to about 100 nM, 1 nM to about 90 nM, 1 nM to about 80 nM, 1 nM to about 70 nM, 1 nM to about 60 nM, 1 nM to about 50 nM, 1 nM to about 40 nM, 1 nM to about 30 nM, 1 nM to about 20 nM, 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM to about 100 nM, or about IC of 50 nM to about 100 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, or about 100 nM 50 In some embodiments, the disclosed compounds inhibit USP1 activity with an IC of less than 1 μM, less than 500 nM, less than 100 nM, less than 10 nM, or less than 1 nM. 50 In some embodiments, the disclosed compounds inhibit USP1 activity at an IC of less than 1 nM. 50 inhibits USP1 activity.

[0351] Exemplary Assays Any suitable assay in the art can be used to determine activity, detect outcomes or effects, determine efficacy, etc. Certain non-limiting exemplary assays that can be used in the methods provided herein are described.

[0352] In some cases, the method for determining whether a disclosed compound inhibits USP1 deubiquitinase activity measures the change in mass upon cleavage of diubiquitin from the deubiquitinase bond. For example, ubiquitin aldehyde and ubiquitin vinyl sulfone form a covalent, irreversible linkage to the deubiquitinase, resulting in an observable mass change for the deubiquitinase. Similarly, cleavage of diubiquitin results in an observable mass change.

[0353] In some cases, methods for determining whether a disclosed compound inhibits USP1 deubiquitinase activity involve an increase in luminescence or fluorescence upon cleavage, which can be monitored, for example, on a plate reader. Such assays can use ubiquitin linked to a fluorophore through a linker linkage, such as ubiquitin-7-amino-4-methylcoumarin (Ub-AMC) or ubiquitin-rhodamine 110. Such assays can also use diubiquitins containing an isopeptide linkage. An exemplary diubiquitin can contain a fluorophore on one ubiquitin and a quencher on the other ubiquitin, such that fluorescence increases and the diubiquitin is then cleaved. Such assays can also use enzyme-linked systems in which ubiquitin is coupled to an enzyme that is only active in generating a fluorescent enzyme product upon release from the ubiquitin.

[0354] Exemplary deubiquitination assay for USP1 / UAF1 activity and inhibitor testing. Deubiquitinase activity can be measured using ubiquitin-rhodamine 110 as a substrate. Cleavage of the amide bond between rhodamine and the c-terminal glycine of ubiquitin results in an increase in fluorescent signal. The assay can be performed in a total volume of 20 μl of assay buffer (50 mM Tris-HCl, pH 7.8, 0.5 mM EDTA, 0.01% bovine serum albumin, 1 mM DTT, 0.01% Tween-20) and 0.05 nM USP1 / UAF1 enzyme. The reaction can be initiated by the addition of 150 nM ubiquitin-rhodamine (Boston Biochem) substrate.

[0355] Disclosed compounds can be dissolved in DMSO and tested in a dose-response format starting at 10 μM.

[0356] The disclosed compounds can be added to the enzyme / assay buffer mixture and incubated for 10 minutes. Substrate mixture can be added, and the reaction mixture can be read in kinetic mode at Ex480 / Em540 for 30 minutes, and IC50 response curves can be plotted. See, for example, Chen, et al., Chem Biol., 18(11):1390-1400 (2011).

[0357] How to use In some embodiments, the disclosed compounds can be used to inhibit the activity of USP1 protein. For example, in some embodiments, a method for inhibiting USP1 protein includes contacting USP1 protein with a disclosed compound. The contacting can occur in vitro or in vivo.

[0358] In some embodiments, the disclosed compounds can be used to treat a "USP1 protein-mediated disorder." A USP1 protein-mediated disorder is any pathological condition in which USP1 protein is known to play a role. In some embodiments, the USP1 protein-mediated disorder is a proliferative disease, such as cancer.

[0359] Various methods of treating diseases and disorders with the disclosed compounds are provided herein. Exemplary diseases and disorders that can be treated with the disclosed compounds include, but are not limited to, cancer.

[0360] In some embodiments, methods of treating cancer with the disclosed compounds are provided, including administering to a subject with cancer a therapeutically effective amount of the disclosed compound.

[0361] In some embodiments, the cancer treated with the disclosed compounds is selected from hematological cancers, lymphatic cancers, and DNA damage repair pathway deficient cancers. In some embodiments, the cancer treated with the disclosed compounds is a cancer comprising cancer cells with a mutation in the gene encoding p53. In some embodiments, the cancer treated with the disclosed compounds is a cancer comprising cancer cells with a loss-of-function mutation in the gene encoding p53. In some embodiments, the cancer treated with the disclosed compounds is a cancer comprising cancer cells with a mutation in the gene encoding BRCA1. In some embodiments, the cancer treated with the disclosed compounds is a cancer comprising cancer cells with a mutation in the gene encoding BRCA2. In some embodiments, the cancer treated with the disclosed compounds is a cancer comprising cancer cells with a loss-of-function mutation in the gene encoding ATM.

[0362] In some embodiments, the cancer treated with the disclosed compounds is selected from non-small cell lung cancer (NSCLC), osteosarcoma, ovarian cancer, and breast cancer. In some embodiments, the cancer is ovarian cancer or breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is triple-negative breast cancer.

[0363] In some embodiments, the cancer treated with the disclosed compounds is selected from the group consisting of bone cancer, including osteosarcoma and chondrosarcoma; brain cancer, including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; soft tissue cancer, including rhabdoid and sarcoma; kidney cancer, bladder cancer, skin cancer, including melanoma; and lung cancer, including non-small cell lung cancer, colon cancer, uterine cancer, nervous system cancer, head and neck cancer, pancreatic cancer, and cervical cancer.

[0364] Various methods of treating cancer with the disclosed compounds are provided herein. In some embodiments, a therapeutically effective amount of a disclosed compound is administered to a subject having cancer, wherein the cancer comprises cancer cells with elevated levels of RAD18. In some embodiments, the elevated level of RAD18 is elevated RAD18 protein level. In some embodiments, the elevated level of RAD18 is elevated RAD18 mRNA level. In some embodiments, elevated levels of RAD18 (e.g., RAD18 protein and / or RAD18 mRNA) are detected prior to administration (e.g., in a cancer sample obtained from the subject). That is, in some embodiments, the subject's cancer is tested for RAD18 protein or mRNA before initiating treatment with a USP1 inhibitor.

[0365] In some embodiments, such methods include (a) identifying a cancer in a subject as a USP1 inhibitor-sensitive cancer, and then (b) administering to the subject a therapeutically effective amount of a disclosed compound.

[0366] In some embodiments, such methods include (a) detecting levels of RAD18 (e.g., RAD18 protein and / or RAD18 mRNA) in cancer cells (e.g., in a cancer sample obtained from a subject), and then (b) administering a therapeutically effective amount of a disclosed compound to a subject having a cancer comprising cells with elevated levels of RAD18.

[0367] In some embodiments, such methods comprise administering a therapeutically effective amount of a disclosed compound to a subject with triple-negative breast cancer.

[0368] In some embodiments, the disclosed compounds are used to treat cancer, wherein the cancer is a homologous recombination-deficient cancer. In some embodiments, the disclosed compounds are used to treat cancer, wherein the cancer comprises cancer cells with a mutation in the gene encoding p53. In some embodiments, the disclosed compounds are used to treat cancer, wherein the cancer comprises cancer cells with a loss-of-function mutation in the gene encoding p53. In some embodiments, the disclosed compounds are used to treat cancers that do not have a defect in the homologous recombination pathway.

[0369] In some embodiments, disclosed compounds are used to treat cancer, wherein the cancer is a BRCA1 mutant cancer. In some embodiments, disclosed compounds are used to treat cancer, wherein the cancer is a BRCA2 mutant cancer. In some embodiments, disclosed compounds are used to treat cancer, wherein the cancer is a BRCA1 mutant cancer and a BRCA2 mutant cancer. In some embodiments, the cancer is not a BRCA1 mutant cancer or a BRCA2 mutant cancer. In some embodiments, the cancer is a BRCA1 deficient cancer. In some embodiments, the cancer is a BRCA2 deficient cancer. In some embodiments, the cancer is a BRCA1 deficient cancer and a BRCA2 deficient cancer.

[0370] In some embodiments, the disclosed compounds are used to treat cancer, and the cancer is an ATM mutant cancer. In some embodiments, the cancer is not an ATM mutant cancer. In some embodiments, the cancer is an ATM deficient cancer.

[0371] In some embodiments, the disclosed compounds are used to treat cancer, wherein the cancer is a PARP inhibitor-resistant or refractory cancer. In some embodiments, the disclosed compounds are used to treat cancer, wherein the cancer is a PARP inhibitor-resistant or refractory BRCA1-deficient cancer.

[0372] In some embodiments, the cancer is a BRCA1 and / or BRCA2 mutant cancer, and the cancer comprises cells with elevated levels of RAD18, e.g., the elevated level of RAD18 is at least as high as the RAD18 protein and / or mRNA level in ES2 cells, or the elevated level of RAD18 is higher than the RAD18 protein and / or mRNA level in HEP3B217 cells. In some embodiments, the triple-negative breast cancer is a BRCA1 and / or BRCA2 mutant cancer.

[0373] In some cases, the cancer is a solid tumor. In some cases, the cancer is a blood / lymphatic cancer. In some cases, the cancer is a DNA damage repair pathway deficient cancer. In some cases, the cancer is a homologous recombination deficient cancer. In some cases, the cancer comprises cancer cells with a mutation in the gene encoding p53. In some cases, the cancer comprises cancer cells with a loss-of-function mutation in the gene encoding p53. In some cases, the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), osteosarcoma, ovarian cancer, and breast cancer (including triple-negative breast cancer). In some cases, the cancer is ovarian cancer or breast cancer (including triple-negative breast cancer). In some cases, the cancer is ovarian cancer. In some cases, the cancer is breast cancer (including triple-negative breast cancer).

[0374] In some embodiments, the disclosed compounds are used in combination with one or more additional therapeutic agents to treat cancer. It has been reported that p53 status determines PARP inhibitor sensitivity (Sa et al. Genome Biology, (2019) 20:253), and BRCA1 / 2 status predicts clinical efficacy of PARP inhibitors (Audeh et al. Lancet (2010) 376(9737), 245-51). As shown below, p53 mutant cancers and BRCA mutant cancers have increased sensitivity to USP1 inhibitors. Therefore, in some embodiments, the disclosed compounds are used in combination with PARP inhibitors to treat cancer.

[0375] In some embodiments, provided herein are disclosed compounds for use as a medicament or for use in preparing a medicament, e.g., for the treatment of cancer. In some embodiments, provided herein are disclosed compounds for use in a method for the treatment of cancer.

[0376] Pharmaceutical Compositions The disclosed compounds can be administered to mammals in the form of raw chemicals without the presence of any other components, or the disclosed compounds can be administered to mammals as part of a pharmaceutical composition containing the compound combined with a suitable pharmaceutically acceptable carrier (see, for example, Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)). Such carriers can be selected from pharmaceutically acceptable excipients and adjuvants. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" includes any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Standard pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.

[0377] Pharmaceutical compositions of the present disclosure may be prepared as liquid suspensions or solutions using oil, water, alcohol, and combinations thereof.

[0378] The pharmaceutical compositions of the present disclosure may be prepared as a sterile injectable preparation which may be an aqueous or oleaginous suspension, which may be formulated according to techniques known in the art.

[0379] The pharmaceutical compositions of the present disclosure may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions.

[0380] The pharmaceutical compositions of the present disclosure may be administered in the form of suppositories for rectal administration.

[0381] The pharmaceutical composition of the present disclosure can also be administered locally, especially when the target of treatment comprises areas or organs that are easily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract.Topical application to the lower intestinal tract can be carried out in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches can also be used.For topical application, the pharmaceutical composition can be formulated into a suitable ointment, lotion, or cream containing the active ingredient suspended or dissolved in one or more carriers.

[0382] The pharmaceutical compositions of the present disclosure can also be administered ophthalmologically and formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, with or without preservatives such as benzylalkonium chloride, or preferably as a solution in isotonic, pH-adjusted sterile saline. Alternatively, for ophthalmic use, the pharmaceutical compositions can be formulated into an ointment such as petrolatum.

[0383] The pharmaceutical compositions of the present disclosure may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0384] Pharmaceutical compositions to be used for in vivo administration can be sterile, which is readily accomplished, for example, by filtration through sterile filtration membranes.

[0385] Pharmaceutical compositions within the scope of the present disclosure include any composition in which the disclosed compounds are combined with one or more pharmaceutically acceptable carriers. In one embodiment, the disclosed compounds are present in the composition in an amount effective to achieve its intended therapeutic purpose.

[0386] The pharmaceutical compositions of the present disclosure can be administered to any patient who can experience the beneficial effects of the disclosed compounds. Foremost among such patients are mammals, such as humans and companion animals, although the disclosure is not intended to be so limited. In one embodiment, the patient is a human. In another embodiment, the pharmaceutical compositions of the present disclosure can be administered to patients with PARP inhibitor-resistant or refractory cancer. In another embodiment, the pharmaceutical compositions of the present disclosure can be administered to patients with PARP inhibitor-resistant or refractory BRCA1-deficient cancer. In another embodiment, the pharmaceutical compositions of the present disclosure can be administered to patients in combination with a PARP inhibitor.

[0387] In another embodiment, the present disclosure provides kits comprising the disclosed compounds (or compositions comprising the disclosed compounds) packaged in a manner that facilitates their use to practice the disclosed methods. In one embodiment, the kit comprises the disclosed compounds (or compositions comprising the disclosed compounds) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes the use of the compound or composition to practice the disclosed methods. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit may further comprise a device suitable for administering the composition according to the intended route of administration. In some embodiments, the present disclosure provides kits comprising the disclosed compound, or a pharmaceutically acceptable salt or solvate thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, to a patient with cancer.

[0388] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a disclosed compound, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0389] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula I, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0390] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula II, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0391] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula III, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0392] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula IV, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0393] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having formula V, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0394] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having formula VI, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0395] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having formula VIa, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0396] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula VII, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0397] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0398] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula IX, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0399] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having formula X, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0400] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having formula XI, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0401] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula XII, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0402] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a disclosed compound, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, wherein the compound binds to a protein encoded by the USP1 gene.

[0403] In some embodiments, the disclosure provides a pharmaceutical composition comprising a disclosed compound, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is for use in treating cancer.

[0404] In some embodiments, the disclosure provides a pharmaceutical composition comprising a disclosed compound, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is for the manufacture of a medicament for the treatment of cancer. [Example]

[0405] General synthesis method The disclosed compounds are prepared using methods known to those skilled in the art in light of this disclosure or by the exemplary methods shown in the following general schemes. In any of the general schemes, suitable protecting groups can be used in the synthesis. (See Wuts, PGM; Greene, TW, "Greene's Protective Groups in Organic Synthesis", 4th Ed., J. Wiley & Sons, NY, 2007).

[0406] Unless otherwise indicated, all reagents were used without further purification. 1 H-NMR spectra were obtained in DMSO-d or CD 0D at room temperature on a Bruker 300 MHz instrument. When more than one conformer was detected, the chemical shifts for the most abundant one are reported. 1 Chemical shifts for H NMR spectra were reported in parts per million (ppm) on the δ scale from an internal standard of residual solvent. Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and br, broad. LC-MS and preparative HPLC conditions are described below. [Table 8-1] [Table 8-2] [Table 8-3]

[0407] The following abbreviations are used in the text: PE = petroleum ether EA or EtOAc = ethyl acetate DMSO = dimethyl sulfoxide DMF = N,N-dimethylformamide DMA = N,N-dimethylacetamide MeOH = methanol MTBE = methyl tert-butyl ether DCM = dichloromethane TEA = trimethylamine DIPEA = diisopropylethylamine TFA = trifluoroacetic acid MeCN or ACN = acetonitrile TLC = thin layer chromatography (BPin)2 = Bis(pinacolato)diboron HFIP = 1,1,1,3,3,3-hexafluoropropan-2-ol DIBAL-H = diisobutylaluminum hydride MeI = iodomethane hex or n-hex = n-hexane DCE = 1,2-dichloroethane TBSCl = tert-butyldimethylsilyl chloride TfO = trifluoromethanesulfonic anhydride n-BuLi = n-butyllithium DMAP = 4-dimethylaminopyridine KOAc = potassium acetate NaOAc = sodium acetate TFAA = trifluoroacetic anhydride m-CPBA = meta-chloroperoxybenzoic acid DME = 1,2-dimethoxyethane TPP = triphenylphosphine DTAD = di-tert-butyl azodicarboxylate DEAD = diethyl azodicarboxylate DIAD = diisopropyl azodicarboxylate PS-TPP = polystyrene-supported triphenylphosphine NBS = N-bromosuccinimide.

[0408] Preparation of common intermediate I-1: [ka] Step 1: Synthesis of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate: [ka] To a mixture of 3,3-dibromo-1,1,1-trifluoropropan-2-one (3.1 g, 11.49 mmol) in water (6 mL) was added NaOAc (951.8 mg, 11.60 mmol). The mixture was heated at 100° C. for 1 h and then cooled to room temperature. A solution of methyl 4-formylbenzoate (1.7 g, 10.34 mmol) in MeOH (47 mL) and NH4OH (11 mL) was then added to the reaction mixture at room temperature. After 40 min, the reaction was warmed to 100° C. and stirred for 2 h. The mixture was quenched with water (50 mL) and then extracted with EA (100 mL × 2). The organic layer was dried over Na2SO4 (30 g), filtered, and concentrated. The concentrated residue was purified by silica gel chromatography (PE:EA=20:1 to 5:1) to give 1.9 g of the title compound. LC-MS (Method A) (ESI+): m / z 271 (M+H) + ; 1 H-NMR (300 MHz, CD3OD) δ 8.12 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 8.7 Hz, 2H), 7.72 (s, 1H), 3.93 (s, 3H).

[0409] Step 2: Synthesis of methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate: [ka] To a solution of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (1.9 g, 7.03 mmol) in THF (50 ml) at 0° C., NaH (60% dispersion) (338 mg, 8.44 mmol) was added portionwise over 5 min. After the mixture was stirred at 0° C. for 30 min, MeI (1.2 g, 8.44 mmol) was added dropwise to the reaction mixture over 2 min. The reaction was allowed to warm to room temperature over 3 h and then quenched with ice water (30 g). The resulting solution was extracted with EA (50 mL × 3), and the combined organic layers were dried over NaSO (30 g), filtered, and concentrated. The resulting residue was purified by silica gel chromatography (PE:EA = 20:1 to 5:1) to give 1.4 g of the title compound. LC-MS (Method A) (ESI+): m / z 285 (M+H) + ; 1 H-NMR (300 MHz, CD3OD) δ 8.17 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.75 (s, 1H), 3.94 (s, 3H), 3.83 (s, 3H).

[0410] Step 3: Synthesis of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol: [ka] To a solution of methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (1.4 g, 4.93 mmol) in THF (40 ml) at 0 °C, DIBAL-H (24 ml, 24.6 mmol, 1 M in toluene) was added via syringe. After the addition, the reaction was stirred at 0 °C for 20 min and then warmed to room temperature over 30 min. After the reaction was complete as indicated by TLC analysis, the mixture was quenched with ice water (10 mL) and the pH was adjusted to 5 with 1 N HCl solution. The resulting mixture was extracted with EA (50 mL × 2), and the combined organic layers were washed with brine (30 mL), dried over Na SO (30 g), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE:EA = 20:1 to 5:1) to give 1.2 g of the title compound. LC-MS (Method A) (ESI+): m / z 257 (M+H) + ; 1 H-NMR (300 MHz, CD3OD) δ 7.69 (s, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 4.69 (s, 2H), 3.78 (s, 3H).

[0411] Step 4: Synthesis of 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole: [ka] To a mixture of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (1.2 g, 4.68 mmol) in DCE (40 ml) was added SOCl (1.7 g, 14.1 mmol) in one portion. After the addition, the reaction was stirred at 50° C. for 20 min and then concentrated to dryness to give 1.28 g of crude title compound. LC-MS (Method A) (ESI+): m / z 275, 277 (M+H) + ; 1H-NMR (300 MHz, CD3OD) δ 8.04 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 4.75 (s, 2H), 3.87 (s, 3H).

[0412] Step 5: Synthesis of 6-chloro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-1): [ka] To a solution of 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (1 g, 3.64 mmol) in DMF (25 ml) were added 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (675 mg, 4.37 mmol) and K2CO3 (1.26 g, 9.10 mmol). The resulting mixture was stirred at 35 °C for 20 h, then quenched with water (50 mL) and extracted with EA (100 mL × 2). The combined organic phases were washed with water and brine, dried over Na2SO4 (50 g), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE:EA = 20:1 to 10:1) to give 580 mg of the title compound with a small amount of its regioisomer. LC-MS (Method A) (ESI+): m / z 393, 395 (M+H) + ; 1 H-NMR (300 MHz, CDCl3) δ 9.06 (s, 1H), 8.18 (s, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.30 (s, 1H), 5.69 (s, 2H), 3.74 (s, 3H). The following intermediates were prepared from the appropriate heterocycle and alkylating reagent following the method for preparation of I-1. [Table 9-1] [Table 9-2] [Table 9-3]

[0413] Preparation of common intermediate I-8: [ka] Step 1: Synthesis of 3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde: [ka] A solution of 2-chloro-1-methyl-4-(trifluoromethyl)-1H-imidazole (1.00 g, 5.40 mmol), (2-fluoro-4-formylphenyl)boronic acid (1.00 g, 6.50 mmol), and KPO (3.40 g, 16.30 mmol) in dioxane (20 mL) and HO (5 mL) was degassed with argon for 5 minutes. To the resulting reaction mixture, Xphos-Pd-G (0.42 g, 0.54 mmol) and X-Phos (1.03 g, 2.10 mmol) were added sequentially, and the reaction mixture was heated in a sealed tube at 100 °C for 16 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was diluted with water and extracted with EA. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound thus obtained was purified by silica gel chromatography using 0-30% EA in hexane to give 1.40 g of the title compound. LC-MS (Method B) (ESI+): m / z 272.90 (M+H) + ; 1 H-NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.08 (s, 1H), 7.83-7.94 (m, 3H), 3.66 (s, 3H).

[0414] Step 2: Synthesis of (3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol: [ka] To an ice-cold solution of 3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (1.40 g, 5.14 mmol) in MeOH (30 mL) was added NaBH4 (0.293 g 7.70 mmol) and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude reaction mixture was dissolved in water and extracted with EA. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.40 g of the title compound, which was used without further purification. LC-MS (Method B) (ESI+): m / z 274.85 (M+H) + ; 1 H-NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.28-7.34 (m, 2H), 5.46 (t, J = 5.6 Hz, 1H), 4.60 (d, J = 5.4 Hz, 2H), 3.59 (s, 3H).

[0415] Step 3: Synthesis of 2-(4-(chloromethyl)-2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole: [ka] To an ice-cold solution of (3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-methanol (1.40 g, 5.10 mmol) in DCM (15 mL) was added SOCl (1.80 g, 15.0 mmol) and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated NaHCO solution and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1.42 g of the title compound, which was used without further purification. LC-MS (Method B) (ESI+): m / z 292.85 (M+H) + .

[0416] Step 4: Synthesis of 6-chloro-1-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-8): [ka] A solution of 2-(4-(chloromethyl)-2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (1.41 g, 4.80 mmol), 6-chloro-1H-pyrazolo[3,4-d]pyrimidine 5 (0.65 g, 4.20 mmol), and K2CO3 (1.45 g, 10.50 mmol) in DMF (12 mL) was stirred at 35 °C for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with EA. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 0-15% EA in hexane to give 0.70 g of the title compound. LC-MS (Method B) (ESI+): m / z 410.85 (M+H) + ; 1H-NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.54 (s, 1H), 7.99 (s, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 10.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 5.76 (s, 2H), 3.58 (s, 3H). The following intermediates were made from the appropriate aldehyde and alkylating reagent following the procedure for Intermediate I-8. [Table 10-1] [Table 10-2] [Table 10-3]

[0417] Preparation of common intermediate I-15: [ka] Step 1: Synthesis of 1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazole: [ka] To a stirred solution of 4-(trifluoromethyl)-1H-imidazole (4.0 g, 29.4 mmol) in dry THF (100 mL) at 0 °C was added sodium hydride (60% dispersion, 1.294 g, 32.35 mmol). The resulting mixture was stirred for 15 min, and then iodomethane-d3 (4.26 g, 29.4 mmol) was added at 0 °C, and the reaction was stirred for 30 min. The reaction mixture was then warmed to room temperature and stirred for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with EA (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude product was purified by silica gel chromatography (50-100% EA in n-hexane) to give 3.0 g of the title compound. LC-MS (Method B) (ESI+): m / z 154.45 (M+H) + ; 1 H-NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.27 (s, 1H)

[0418] Step 2: Synthesis of 2-chloro-1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazole: [ka] To a stirred solution of 1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazole (2.70 g, 17.6 mmol) in THF (50 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in n-hexane (7 mL, 17.64 mmol). The resulting mixture was stirred at −78° C. for 30 min and then treated with hexachloroethane (2.08 g, 8.82 mmol). After 1 h, the reaction mixture was warmed to room temperature, whereupon stirring was continued for another 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (25 mL) and extracted with EA (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude compound was purified by silica gel chromatography (30–100% EA in n-hexane) to give 1.30 g of the title compound. LC-MS (Method B) (ESI+): m / z 188.30 (M+H) + .

[0419] Step 3: Synthesis of 4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde: [ka] To a solution of 2-chloro-1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazole (1.40 g, 7.49 mmol) in 1,4-dioxane (60 mL) was added X-Phos-Pd-G2 catalyst (0.294 g, 0.374 mmol). The resulting mixture was purged with argon gas for 10 minutes, after which solid K3PO4 (4.76 g, 22.5 mmol) and (4-formylphenyl)boronic acid (2.24 g, 14.97 mmol) were added, followed by an additional purging with argon gas for 5 minutes. The reaction mixture was then heated at 90 °C for 16 hours. After completion of the reaction (monitored by TLC), the mixture was diluted with water (60 mL) and EA (60 mL). The organic layer was separated, and the aqueous layer was extracted with EA (2 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (0-30% EA in n-hexane) to give 1.62 g of the title compound. LC-MS (Method B) (ESI+): m / z 258.00 (M+H) + ; 1 H-NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.00 (d, J = 7.88 Hz, 2H), 7.86 (d, J = 7.88 Hz, 2H), 7.37 (s, 1H).

[0420] Step 4: Synthesis of (4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol: [ka] To a stirred solution of 4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (1.60 g, 6.23 mmol) in methanol (50 mL) at 0 °C was added NaBH4 (0.118 g, 3.11 mmol). After completion of the reaction (monitored by TLC), the mixture was quenched with ice-water (30 mL) and extracted with 10% methanol in DCM (4 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude compound was purified by silica gel chromatography (0-60% EA in n-hexane) to give 1.30 g of the title compound. LC-MS (Method B) (ESI+): m / z 259.80 (M+H) + ; 1 H-NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.31 Hz, 2H), 7.45 (d, J = 7.83 Hz, 2H), 7.31 (s, 1H), 4.76 (s, 2H).

[0421] Step 5: Synthesis of 6-chloro-1-(4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-15): [ka] To a mixture of (4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (0.500 g, 1.930 mmol) and 6-chloro-1H-pyrazolo[3,4-d]pyrimidine 7 (0.335 g, 2.181 mmol) in dry THF (5 mL) at 0 °C was added triphenylphosphine (0.657 g, 2.509 mmol). The resulting mixture was stirred for 5 min and then treated dropwise with diethyl azodicarboxylate (0.434 g, 2.509 mmol). The mixture was further stirred at 0 °C for 2 h. After completion of the reaction (monitored by TLC), the mixture was diluted with water (30 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude compound was purified by silica gel chromatography (0-3% methanol in DCM) to give 0.400 g of the title compound. LC-MS (Method B) (ESI+): m / z 396.00 (M+H) + ; 1 H-NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.18 (s, 1H), 7.61 (d, J = 8.31 Hz, 2H), 7.47 (d, J = 7.82 Hz, 2H), 7.30 (s, 1H), 5.69 (s, 2H).

[0422] Preparation of common intermediate I-16: [ka] Step 1: Synthesis of methyl 4-(2-bromoacetyl)benzoate: [ka] To a stirred solution of methyl 4-acetylbenzoate (5.00 g, 28.0 mmol) in AcOH (40 mL), Br2 (1.00 mL, 19.6 mmol) in AcOH (10 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 6 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured onto ice water (100 mL), and the resulting solid was filtered and dried. The crude compound was purified by silica gel chromatography using 5-7% EA in hexane to give 3.50 g of the title compound. LC-MS (Method C) (ESI+): m / z 278.95 (M+Na) + ; 1 H-NMR (400 MHz, DMSO-d6) δ 8.04 - 8.15 (m, 4H), 5.00 (s, 2H), 3.89 (s, 3H).

[0423] Step 2: Synthesis of methyl 4-(2-(trifluoromethyl)-1H-imidazol-4-yl)benzoate: [ka] To a stirred solution of 2,2,2-trifluoroacetimidamide (4.37 g, 39.0 mmol) in THF (30 mL), methyl 4-(2-bromoacetyl)benzoate (2.00 g, 7.80 mmol) was added, and the reaction mixture was stirred at room temperature for 5 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with EA (20 mL) and washed with brine (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 10-15% EA in hexane to give 0.81 g of the title compound. LC-MS (Method B) (ESI+): m / z 270.90 (M+H) + ; 1 H-NMR (400 MHz, DMSO-d6) δ 13.89 (s, 1H), 8.14 (s, 1H), 7.98 (s, 4H), 3.86 (s, 3H).

[0424] Step 3: Synthesis of methyl 4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)benzoate: [ka] To a stirred solution of methyl 4-(2-(trifluoromethyl)-1H-imidazol-4-yl)benzoate (0.80 g, 2.9 mmol) in THF (15 mL) at 0° C., NaH (60% dispersion in mineral oil, 0.178 g, 4.40 mmol) was added portionwise, and the reaction mixture was stirred at the same temperature for 15 min. To the resulting reaction mixture, methyl iodide (0.624 g, 4.40 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-water (50 mL) and extracted with EA (2×30 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 0.80 g of the title compound. LC-MS (Method B) (ESI+): m / z 284.95 (M+H) + ; 1 H-NMR (400 MHz, DMSO-d6) δ 8.12-8.17 (m, 1H), 7.96-8.02 (m, 2H), 7.88-7.94 (m, 2H), 3.86 (s, 6H).

[0425] Step 4: Synthesis of (4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)phenyl)methanol: [ka] To a stirred solution of methyl 4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)benzoate (0.80 g, 2.8 mmol) in THF (10 mL) at 0° C., DIBAL-H (1 M in toluene, 5.63 mL, 5.63 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with 2 N HCl (20 mL) and extracted with EA (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 0.65 g of the title compound, which was used in the subsequent reaction without further purification. LC-MS (Method B) (ESI+): m / z 256.85 (M+H) + .

[0426] Step 5: Synthesis of 4-(4-(chloromethyl)phenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazole: [ka] To a stirred solution of (4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)phenyl)methanol (0.65 g, 2.5 mmol) in DCM (10 mL) at 0 °C, SOCl (0.27 mL, 3.80 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with DCM (50 mL) and washed with saturated NaHCO solution (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 0.65 g of the title compound, which was used in the subsequent reaction without further purification. LC-MS (Method B) (ESI+): m / z 274.90 (M+H) + ; 1 H-NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.77 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H), 4.78 (s, 2H), 3.84 (s, 3H).

[0427] Step 6: Synthesis of 6-chloro-1-(4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-16): [ka] To a stirred solution of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.40 g, 2.5 mmol) in DMF (10 mL) was added K2CO3 (0.517 g, 3.70 mmol) in one portion. After stirring at room temperature for 10 minutes, 4-(4-(chloromethyl)phenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazole (0.638 g, 2.30 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was poured onto ice water (50 mL) and extracted with EA (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 0 to 50% EA in hexanes to give 0.15 g of the title compound. LC-MS (Method B) (ESI+): m / z 392.95 (M+H) + ; 1 H-NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.49 (s, 1H), 7.94 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 5.63 (s, 2H), 3.82 (s, 3H). The following intermediates were made from the appropriate reagents following the procedure for Intermediate I-16. [Table 11]

[0428] Preparation of common intermediate I-18: [ka] Step 1: Synthesis of ethyl 4-acetyl-3-methoxybenzoate: [ka] To a stirred solution of 1-(4-bromo-2-methoxyphenyl)ethan-1-one 1 (3.00 g, 13.1 mmol) in ethanol (60 mL), triethylamine (3.67 mL, 26.2 mmol) was added, and the mixture was degassed with argon for 10 minutes. PdCl(dppf) (0.957 g, 0.131 mmol) was added to the reaction mixture at room temperature, and the resulting mixture was heated at 80 °C under carbon monoxide (20 psi pressure) for 3 hours. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 0-5% EA in hexane as the eluent to give the title compound (2.50 g). LC-MS (Method B) (ESI+): m / z 223.00 (M+H) + ; 1 H-NMR (400 MHz, CDCl3) δ 7.72-7.76 (m, 1H), 7.64-7.70 (m, 2H), 4.42 (dq, J = 3.99, 7.15 Hz, 2H), 4.00 (br s, 1H), 3.99 (s, 2H), 2.65 (s, 1H), 2.64 (s, 2H), 1.43 (dt, J = 3.99, 6.98 Hz, 3H).

[0429] Step 2: Synthesis of ethyl 4-(2,2-dibromoacetyl)-3-methoxybenzoate: [ka] To a stirred solution of ethyl 4-acetyl-3-methoxybenzoate 2 (1.00 g, 4.50 mmol) in acetic acid (10 mL) was added bromine (0.16 mL, 3.153 mmol) at room temperature. The resulting mixture was stirred for 3 hours, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude residue was diluted with water (30 mL) and EA (50 mL) and then neutralized using saturated Na2CO3 solution. The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.20 g). 1 H-NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.98 Hz, 1H), 7.69 (d, J = 8.48 Hz, 1H), 7.67 (s, 1H), 4.59 (s, 1H), 4.41 (q, J = 7.15 Hz, 2H), 4.01 (s, 3H), 1.42 (t, J = 6.98 Hz, 3H).

[0430] Step 3: Synthesis of ethyl 4-(2-bromoacetyl)-3-methoxybenzoate: [ka] To a stirred solution of ethyl 4-(2,2-dibromoacetyl)-3-methoxybenzoate 3 (1.20 g, 3.17 mmol) in THF (15 mL) was added triethylamine (0.44 mL, 3.17 mmol) and diethyl phosphite (0.433 g, 3.166 mmol) at room temperature. The resulting mixture was stirred for 3 h, and the progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with EA (30 mL) and washed with brine (3 × 10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 10-15% EA in hexane as the eluent to give the title compound (0.900 g). LC-MS (Method B) (ESI+): m / z 300.80 (M) + ; 1H-NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.98 Hz, 1H), 7.69 (d, J = 7.98 Hz, 1H), 7.67 (s, 1H), 4.60 (s, 2H), 4.41 (q, J = 7.15 Hz, 2H), 4.02 (s, 3H), 1.42 (t, J = 6.98 Hz, 3H).

[0431] Step 4: Synthesis of ethyl 3-methoxy-4-(2-(trifluoromethyl)-1H-imidazol-4-yl)benzoate: [ka] To a stirred solution of ethyl 4-(2-bromoacetyl)-3-methoxybenzoate 4 (0.900 g, 3.00 mmol) in THF (20 mL) was added 2,2,2-trifluoroacetimidamide (1.68 g, 15.0 mmol) at room temperature. The reaction mixture was then heated at 60 °C for 16 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with EA (50 mL) and washed with saturated NaHCO3 solution (2 × 30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using 20-30% EA in hexane as the eluent to give the title compound (0.300 g). LC-MS (Method B) (ESI+): m / z 315.10 (M+H) + ; 1 H-NMR (400 MHz, DMSO-d6) δ 13.82 (br s, 1H), 8.17 (d, J = 7.48 Hz, 1H), 7.92 (br s, 1H), 7.64 (d, J = 7.98 Hz, 1H), 7.59 (s, 1H), 4.33 (q, J = 7.31 Hz, 2H), 4.00 (s, 3H), 1.34 (t, J = 6.98 Hz, 3H).

[0432] Step 5: Synthesis of ethyl 3-methoxy-4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)benzoate: [ka] To a stirred solution of ethyl 3-methoxy-4-(2-(trifluoromethyl)-1H-imidazol-4-yl)benzoate 5 (0.300 g, 0.955 mmol) in DMF (10 mL) at 0 °C was added a 60% dispersion of sodium hydride (0.057 g, 1.43 mmol) and methyl iodide (0.089 mL, 1.43 mmol) in oil. The reaction mixture was warmed to room temperature and then stirred for 2 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was poured onto ice-cold water (50 mL) and extracted with EA (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 0-15% EA in hexane as the eluent to give the title compound (0.240 g). LC-MS (Method B) (ESI+); m / z 328.90 (M+H) + ; 1 H-NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 8.48 Hz, 1H), 8.04 (s, 1H), 7.64 (dd, J = 1.50, 7.98 Hz, 1H), 7.59 (s, 1H), 4.33 (q, J = 7.15 Hz, 2H), 4.00 (s, 3H), 3.87 (s, 3H), 1.33 (t, J = 7.23 Hz, 3H).

[0433] Step 6: Synthesis of (3-methoxy-4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)phenyl)methanol: [ka] To a stirred solution of ethyl 3-methoxy-4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)benzoate 6 (0.320 g, 0.975 mmol) in dry THF (10 mL) at 0 °C was added DIBAL-H (1 M solution in toluene, 1.46 mL, 1.46 mmol). The reaction mixture was warmed to room temperature and then stirred for 2 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with 1 N HCl (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound (0.260 g). LC-MS (Method B) (ESI+): m / z 287.30 (M+H) + ; 1 H-NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 7.83 Hz, 1H), 7.84 (s, 1H), 7.05 (s, 1H), 6.95 (d, J = 7.82 Hz, 1H), 5.21 (t, J = 4.89 Hz, 1H), 4.51 (d, J = 4.89 Hz, 2H), 3.92 (s, 3H), 3.84 (s, 3H).

[0434] Step 7: Synthesis of 4-(4-(chloromethyl)-2-methoxyphenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazole: [ka] To a stirred solution of (3-methoxy-4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)phenyl)methanol 7 (0.260 g, 0.909 mmol) in DCM (10 mL) at 0 °C was added thionyl chloride (0.065 mL, 0.91 mmol). The mixture was stirred for 1 h and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with DCM (20 mL) and washed with saturated Na2CO3 solution (3 x 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound (0.260 g). LC-MS (Method B) (ESI+): m / z 304.80 (M+H)+ ; 1 H-NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 7.98 Hz, 1H), 7.90 (s, 1H), 7.18 (s, 1H), 7.08 (d, J = 7.98 Hz, 1H), 4.78 (s, 2H), 3.94 (s, 3H), 3.85 (s, 3H).

[0435] Step 8: Synthesis of 6-chloro-1-(3-methoxy-4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-18): [ka] To a stirred solution of 4-(4-(chloromethyl)-2-methoxyphenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazole 8 (0.250 g, 0.822 mmol) in DMF (5 mL) was added potassium carbonate (0.170 g, 1.23 mmol) and 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.126 g, 0.822 mmol) at room temperature. The resulting mixture was stirred for 16 h, and the progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was poured onto ice-cold water (30 mL) and extracted with EA (2 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 30–50% EA in hexane as the eluent to give the title compound (0.150 g). LC-MS (Method B) (ESI+): m / z 423.00 (M+H) + ; 1 H-NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.50 (s, 1H), 7.92 (d, J = 7.98 Hz, 1H), 7.86 (s, 1H), 7.11 (s, 1H), 6.82 (d, J = 7.98 Hz, 1H), 5.64 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H).

[0436] Preparation of common intermediate I-19: [ka] Step 1: Synthesis of methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate: [ka] To a solution of methyl 4-hydrazinylbenzoate hydrochloride (1.0 g, 4.92 mmol) and 1,1,1-trifluoropentane-2,4-dione (758 mg, 4.92 mmol) in HFIP (5 mL) cooled to 0 °C, a solution of TEA (994 mg, 9.84 mmol) in HFIP (3 mL) was added dropwise over 5 min. After the addition, the resulting mixture was stirred at room temperature for 1 h, then quenched with water (20 mL) and extracted with DCM (100 mL × 3). The combined organics were dried over anhydrous NaSO (30 g), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EA:n-Hex = 1:20) to give 1.1 g of the title compound. LC-MS (Method A) (ESI+): m / z 285 (M+H) + ; 1 H-NMR (300 MHz, CDCl3) δ 8.18 (d, J = 8.7 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 6.50 (s, 1H), 3.96 (s, 3H), 2.41 (s, 3H).

[0437] Step 2: Synthesis of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol: [ka] To a solution of methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-benzoate (1.0 g, 3.52 mmol) in dry THF (20 mL) at 0 °C, DIBAL-H (10.5 mL, 10.56 mmol, 1 M in toluene) was added over 10 min. After the addition, the reaction mixture was warmed to room temperature. After the reaction was complete as shown by TLC analysis, the reaction was quenched with saturated NH4Cl solution (20 mL) and extracted with EA (100 ml × 3). The combined organic layers were dried over anhydrous Na2SO4 (50 g), filtered, and concentrated. The crude product was purified by silica gel chromatography (PE:EA = 20:1 to 10:1) to give 1.1 g of the title compound. 1 H-NMR (300 MHz, CDCl3) δ 7.40-7.49 (m, 4H), 6.46 (s, 1H), 4.76 (s, 2H), 2.34 (s, 3H), 2.17 (br s, 1H).

[0438] Step 3: Synthesis of 1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole: [ka] To a solution of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (0.82 g, 3.20 mmol) in DCE (20 mL) was added SOCl (1.14 g, 9.61 mmol) in one portion. After stirring the reaction at 50 °C for 30 min, the mixture was cooled to 0 °C and quenched with water (10 mL). The resulting solution was neutralized with saturated NaHCO (aq) solution and extracted with DCM (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO (50 g), filtered, and concentrated to dryness to give 480 mg of crude product, which was used directly for the next step. LC-MS (Method A) (ESI+): m / z 275 (M+H) + ; 1H-NMR (300 MHz, CDCl3) δ 7.53 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 6.47 (s, 1H), 4.64 (s, 2H), 2.37 (s, 3H).

[0439] Step 4: Synthesis of 6-chloro-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-19): [ka] To a solution of 1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole (0.48 g, 1.75 mmol) in DMF (8 mL) was added 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.27 g, 1.75 mmol) and K2CO3 (0.60 g, 4.38 mmol). The reaction was stirred at room temperature for 2 h, then quenched with water (20 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 (30 g), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE:EA = 20:1 to 10:1) to give 370 mg of the title product with a small amount of regioisomer. LC-MS (Method A) (ESI+): m / z 393,395 (M+H) + ; 1 H-NMR (300 MHz, CDCl3) δ 9.06 (s, 1H), 8.19 (s, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.7 Hz, 2H), 6.44 (s, 1H), 5.70 (s, 2H), 2.33 (s, 3H). The following general intermediates were prepared from the appropriate reagents following the procedure of I-19. [Table 12]

[0440] Preparation of common intermediate I-22: [ka] Step 1: Synthesis of 6-chloro-4-methoxy-1H-pyrazolo[3,4-d]pyrimidine: [ka] To a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine 1 (330 mg, 1.74 mmol) in methanol (10 mL) was added potassium carbonate (240 mg, 1.74 mmol). After stirring the mixture at room temperature for 24 hours, the reaction was quenched with saturated ammonium chloride (30 mL) solution and extracted with EA (20 mL × 3). The combined organic layers were dried over sodium sulfate (30 g), filtered, and concentrated. The residue was purified by silica gel chromatography (eluent: EA / n-Hex=1 / 10) to give 120 mg of the title compound. LC-MS (Method A) (ESI+): m / z 185 (M+H) + ; 1 H-NMR (300 MHz, CDCl3) δ 10.69 (br s, 1H), 8.09 (s, 1H), 4.19 (s, 3H).

[0441] Step 2: Synthesis of 6-chloro-4-methoxy-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-22): [ka] The compound was synthesized according to the procedure for the preparation of common intermediate I-19. LC-MS (Method A) (ESI+): m / z 423 (M+H) + ; 1 H-NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.45 (m, 4H), 6.44 (s, 1H), 5.63 (s, 2H), 4.15 (s, 3H), 2.31 (s, 3H). The following general intermediates were prepared from the appropriate reagents according to the procedure of I-22. [Table 13]

[0442] Preparation of common intermediate I-23: [ka] Step 1: Synthesis of methyl 4-hydrazinyl-3-methoxybenzoate: [ka] To a stirred solution of methyl 4-amino-3-methoxybenzoate 1 (5.0 g, 27.6 mmol) in concentrated HCl (55 mL) at −10° C. was added dropwise an aqueous solution of NaNO (1.99 g, 29.0 mmol) in water (5 mL). To the resulting reaction mixture was added dropwise a solution of SnCl (26.0 g, 138 mmol) in concentrated HCl (35 mL), and the reaction was stirred for 2 h. The reaction progress was monitored by TLC. Upon completion, the resulting solid was filtered and dried under reduced pressure. The crude compound was washed with diethyl ether (50 mL), filtered, and dried under reduced pressure to give the crude title compound (8.0 g), which was used in the next step without purification. 1 H-NMR (400 MHz, DMSO-d6) δ 10.43 (br s, 2H), 7.95-8.40 (m, 1H), 7.57 (d, J = 8.31 Hz, 1H), 7.44 (s, 1H), 7.09 (d, J = 8.31 Hz, 1H), 3.88 (s, 3H).

[0443] Step 2: Synthesis of methyl 3-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate: [ka] A stirred solution of methyl 4-hydrazinyl-3-methoxybenzoate 2 (2.0 g, 12.98 mmol) and 1,1,1-trifluoropentane-2,4-dione (6.09 g, 25.97 mmol) in ethanol (20 mL) was heated at 90 °C for 16 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 0-30% EA in hexane to give the title compound (2.5 g). LC-MS (Method B) (ESI+): m / z 315.05 (M+H) + .

[0444] Step 3: Synthesis of (3-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol: [ka] To a stirred solution of methyl 3-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate 3 (2.5 g, 7.96 mmol) in THF (40 mL) at 0° C., DIBAL-H (16 mL, 15.9 mmol, 1.0 M solution in THF) was added dropwise. The resulting mixture was stirred at 0° C. for 2 h and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with 1 N HCl (4 mL) at 0° C. and extracted with EA (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 4 (1.5 g). The crude product was used directly without purification. LC-MS (Method B) (ESI+): m / z 287.45 (M+H) + ; 1 H-NMR (400 MHz, DMSO-d6) δ 7.31 (d, J = 7.98 Hz, 1H), 7.21 (s, 1H), 7.05 (d, J = 7.98 Hz, 1H), 6.67 (s, 1H), 5.40 (br s, 1H), 4.59 (br s, 2H), 3.79 (s, 3H), 2.09 (s, 3H).

[0445] Step 4: Synthesis of 6-chloro-1-(3-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-23): [ka] To an ice-cold solution of (3-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol 4 (1.0 g, 3.494 mmol) in THF (10 mL) was added 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.486 g, 3.144 mmol), DTAD (1.20 g, 5.240 mmol), and TPP (2.747 g, 10.48 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was quenched with water (30 mL) and extracted with EA (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 0-40% EA in hexane as the eluent to give the title compound (1.0 g). LC-MS (Method B) (ESI+): m / z 423 (M+H) + .

[0446] Preparation of common intermediate I-24: [ka] Step 1: Synthesis of (4-(4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol: [ka] A solution of 3,3-dibromo-1,1,1-trifluoropropan-2-one (1.0 g, 7.3 mmol) and NaOAc (533.5 mg, 8.1 mmol) in HO (7.3 mL) was stirred at 100 °C for 1 h. The reaction mixture was then cooled to 0 °C, and a solution of 4-(hydroxymethyl)benzaldehyde (2.18 g, 8.08 mmol) and NH OH (9.3 mL) in MeOH (37 mL) was added over 10 min. After the addition, the reaction mixture was stirred overnight at ambient temperature. The resulting mixture was concentrated under reduced pressure to remove most of the solvent. Water (20 mL) was added to the concentrated residue, and the mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na SO (50 g), filtered, and concentrated to dryness in vacuo. The resulting crude product was slurried in DCM (30 mL), collected by filtration and dried in vacuo to give 1.1 g of the title compound. 1 H-NMR (300 MHz, CD3OD) δ 7.88 (d, J = 8.4 Hz, 2H), 7.64 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 4.66 (s, 2H).

[0447] Step 2: Synthesis of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde: [ka] To a solution of (4-(4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (1 g, 4.1 mmol) in EA (80 mL) was added Dess-Martin reagent (2.6 g, 6.2 mmol) in portions over 5 min at 0 °C. After the addition, the reaction was stirred at ambient temperature overnight. The resulting suspension was filtered, and the filter cake was rinsed with EA (20 mL). The filtrate was washed with saturated aqueous NH4Cl (20 mL), dried over anhydrous Na2SO4 (20 g), filtered, and concentrated in vacuo. The concentrated residue was purified by silica gel chromatography (PE:EA = 20:1 to 5:1) to give 0.9 g of the title compound. 1H-NMR (300 MHz, CD3OD) δ 10.04 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.74 (s, 1H).

[0448] Step 3: Synthesis of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde: [ka] To a solution of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (0.9 g, 3.8 mmol) in DMF (40 mL) were added CsCO (3.7 g, 11.2 mmol) and MeI (1.1 g, 7.5 mmol) in one portion. After stirring the reaction at ambient temperature for 1 h, the reaction was quenched with water (100 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with water (50 mL × 2), dried over anhydrous NaSO (50 g), and concentrated in vacuo. The concentrated residue was purified by silica gel chromatography (PE:EA = 20:1 to 5:1) to give 0.8 g of the title compound. 1 H-NMR (300 MHz, CDCl3) δ 10.09 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.38 (s, 1H), 3.85 (s, 3H).

[0449] Step 4: Synthesis of 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan-1-ol: [ka] To a solution of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (0.8 g, 3.2 mmol) in THF (30 mL) was added CHMgBr (4.7 mL, 4.7 mmol, 1 M in THF) dropwise over 10 min at 0° C. After the addition, the reaction was stirred at 0° C. for 1.5 h and then quenched by the addition of saturated aqueous NHCl (20 mL). The resulting mixture was extracted with EA (100 mL × 2), and the combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO (30 g), and concentrated in vacuo to give 0.9 g of the crude title compound. 1 H-NMR (300 MHz, CDCl3) δ 7.60 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.31 (s, 1H), 4.97 (q, J = 6.3, 1H), 3.81 (s, 3H), 1.52 (d, J = 6.3Hz, 3H).

[0450] Step 5: Synthesis of 2-(4-(1-chloroethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole: [ka] To a solution of 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan-1-ol (570 mg, 2.1 mmol) in DCE (20 mL) was added SOCl (753.8 mg, 6.3 mmol) in one portion. After the addition, the reaction was stirred at 60 °C for 1 h and then concentrated to dryness in vacuo. The residue was dissolved in EA (100 mL) and then treated with saturated NaHCO solution. After separation, the organic layer was dried over anhydrous NaSO (30 g) and concentrated in vacuo. The concentrated crude product was purified by silica gel chromatography (PE:EA = 20:1) to give 330 mg of the title compound. 1H-NMR (300 MHz, CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.32 (s, 1H), 5.13 (q, J = 6.6 Hz, 1H), 3.79 (s, 3H), 1.87 (d, J = 6.6 Hz, 3H).

[0451] Step 6: Synthesis of 6-chloro-1-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (I-24): [ka] To a solution of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (321.2 mg, 2.1 mmol) in DMF (14 mL) were added 2-(4-(1-chloroethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (400 mg, 1.4 mmol) and K2CO3 (574.5 mg, 4.2 mmol). After the addition, the reaction mixture was stirred at 65 °C overnight, then quenched with water (30 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with water (20 mL × 2), dried over anhydrous Na2SO4 (30 g), filtered, and concentrated to dryness in vacuo. The concentrated residue was purified by silica gel chromatography (PE:EA = 5:1 to 3:1) to give 40 mg of the title compound. The regioisomer was obtained as the major product after purification. 1 H-NMR (300 MHz, CDCl3) δ 9.03 (s, 1H), 8.19 (s, 1H), 7.50-7.64 (m, 4H), 7.29 (s, 1H), 6.26 (q, J = 7.2, 1H), 3.75 (s, 3H), 2.04 (d, J = 7.2Hz, 3H). The following general intermediates were prepared from the appropriate reagents according to the procedure of I-24. [Table 14-1] [Table 14-2]

[0452] Preparation of common intermediate I-27: [ka] Step 1: Synthesis of 2-bromo-1-ethyl-4-(trifluoromethyl)-1H-imidazole: [ka] To a stirred solution of 1-ethyl-4-(trifluoromethyl)-1H-imidazole 1 (12.0 g, 73.2 mmol) in THF (75 mL) at −78° C., n-BuLi (1.6 M in hexane, 68.5 mL, 110 mmol) was added dropwise. The resulting mixture was stirred at −78° C. for 30 min and then treated with a solution of CBr (36.3 g, 109.75 mmol) in dry THF (75 mL). The reaction mixture was warmed to room temperature and then stirred for 16 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EA (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography eluting with 0–10% EA in hexane to give the title compound (8.00 g). 1 H-NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 4.01 (q, J = 7.34 Hz, 2H), 1.33 (t, J = 7.34 Hz, 3H).

[0453] Step 2: Synthesis of 1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-fluorophenyl)ethan-1-one: [ka] To a stirred solution of 2-bromo-1-ethyl-4-(trifluoromethyl)-1H-imidazole 2 (1.80 g, 7.44 mmol) in dioxane:HO (8:2 mL) was added KPO (3.94 g, 18.6 mmol) and (4-acetyl-2-fluorophenyl)boronic acid 3 (1.48 g, 8.18 mmol). The resulting mixture was degassed with argon for 10 minutes and then treated with X-Phos (0.708 g, 1.49 mmol) and X-Phos-Pd-G (0.292 g, 0.372 mmol) in a sealed tube at room temperature. The reaction mixture was further degassed with argon for 10 minutes and then heated at 100 °C for 2 hours. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography eluting with 0-20% EA in hexane to give the title compound (1.85 g). LC-MS (Method B) (ESI+): m / z 301.15 (M+H) + ; 1 H-NMR (400 MHz, DMSO-d6) δ 8.14-8.20 (m, 1H), 7.93 (d, J = 9.29 Hz, 2H), 7.76 (t, J = 7.34 Hz, 1H), 3.93 (q, J = 7.01 Hz, 2H), 2.66 (s, 3H), 1.29 (t, J = 7.34 Hz, 3H).

[0454] Step 3: Synthesis of (R)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-fluorophenyl)ethan-1-ol: [ka] To a stirred solution of 1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-fluorophenyl)ethan-1-one 4 (2.30 g, 7.67 mmol) in THF (18 mL) was added (S)-2-methyl-CBS-oxazoborolidine (0.42 mL 1.53 mmol) at room temperature. The resulting mixture was then heated at 45° C. for 1 h. To the resulting reaction mixture was added borane-DMS (1.09 mL, 11.5 mmol), and the mixture was heated at 60° C. for 16 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature, quenched with methanol (10 mL), and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography eluting with 0-30% EA in hexane to give the title compound (2.10 g). LC-MS (Method B) (ESI+): m / z 303.00 (M+H) + ; 1 H-NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.50 (t, J = 7.82 Hz, 1H), 7.30-7.37 (m, 2H), 5.43 (d, J = 4.40 Hz, 1H), 4.81 (m, J = 5.87 Hz, 1H), 3.88 (q, J = 7.17 Hz, 2H), 1.37 (d, J = 6.36 Hz, 3H), 1.27 (t, J = 7.09 Hz, 3H).

[0455] Step 3: Synthesis of (S)-6-chloro-1-(1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-fluorophenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (I-27): [ka] To a stirred solution of (R)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-fluorophenyl)ethan-1-ol 5 (2.10 g, 6.95 mmol) in THF (12 mL) at 0 °C, 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.07 g, 6.95 mmol), DEAD (2.41 g, 13.9 mmol), and TPP (2.25 g, 13.9 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 0-30% EA in hexane to give the title compound (2.20 g). LC-MS (Method B) (ESI+): m / z 439.22 (M+H) + . The following general intermediates were prepared from the appropriate ketone and CBS reducing reagent according to the procedure of I-27. [Table 15-1] [Table 15-2]

[0456] Preparation of common intermediate I-31: [ka] Step 1: Synthesis of 2-(4-(((Tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazole: [ka] To a solution of (4-(4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (1.90 g, 7.85 mmol), DMAP (95.8 mg, 0.79 mmol), and TEA (1.19 g, 11.78 mmol) in THF (40 mL) was added TBSCl (1.42 g, 9.42 mmol) in one portion. After the addition, the reaction mixture was stirred at room temperature for 1.5 h. The reaction was then quenched with water (20 mL) and extracted with EA (150 ml × 3). The combined organic layers were dried over anhydrous NaSO (50 g), filtered, and concentrated in vacuo. The concentrated residue was purified by silica gel chromatography (EA:n-Hex = 1:10 to 1:1) to give 2.69 g of the title compound. LC-MS (Method A) (ESI+): m / z 357 (M+H) + ; 1 H-NMR (300 MHz, CDCl3) δ 9.82 (br s, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.26-7.31 (m, 3H), 4.66 (s, 2H), 0.84 (s, 9H), 0.00 (s, 6H).

[0457] Step 2: Synthesis of 3-(2-(4-(hydroxymethyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)azetidine-1-carboxylate: [ka] To a solution of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazole (2.50 g, 7.02 mmol) in DMF (40 mL) were added tert-butyl 3-iodoazetidine-1-carboxylate (2.58 g, 9.13 mmol) and CsCO (6.87 g, 21.06 mmol). The reaction mixture was stirred at 120 °C for 4 h. The reaction was then quenched with water (80 mL) and extracted with EA (150 ml × 3). The combined organic layers were washed with water (50 mL × 2), dried over anhydrous NaSO (100 g), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM:MeOH = 100:1 to 20:1) to give 917 mg of the title compound. LC-MS (Method A) (ESI+): m / z 398 (M+H) + ; 1 H-NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 7.37-7.44 (m, 4H), 5.06 (m, 1H), 4.74 (s, 2H), 4.37-4.43 (m, 2H), 4.07-4.16 (m, 2H), 2.86 (br s, 1H), 1.46 (s, 9H).

[0458] Step 3: Synthesis of tert-butyl 3-(2-(4-(chloromethyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)azetidine-1-carboxylate: [ka] To a solution of tert-butyl 3-(2-(4-(hydroxymethyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)azetidine-1-carboxylate (0.92 g, 2.32 mmol) in DCE (22 mL) was added pyridine (1.10 g, 13.92 mmol) and SOCl2 (0.83 g, 6.95 mmol). The reaction was then stirred overnight at room temperature before being concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (EA:n-Hex = 1:10 to 1:4) to give 480 mg of the title compound. LC-MS (Method A) (ESI+): m / z 416 (M+H) + ; 1 H-NMR (300 MHz, CDCl3) δ 7.75 (s, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 5.07 (m, 1H), 4.64 (s, 2H), 4.41-4.47 (t, J = 9.0 Hz, 2H), 4.09-4.14 (m, 2H), 4.47 (s, 9H).

[0459] Step 4: Synthesis of tert-butyl 3-(2-(4-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)azetidine-1-carboxylate (I-31): [ka] A solution of tert-butyl 3-(2-(4-(chloromethyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)azetidine-1-carboxylate (0.45 g, 1.07 mmol), 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.18 g, 1.18 mmol), and K2CO3 (0.37 g, 2.68 mmol) in DMF (13 mL) was stirred at room temperature for 3 h. The mixture was then quenched with water (30 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with water (20 mL), dried over anhydrous Na2SO4 (50 g), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EA:Hex = 1:10 to 1:0) to give 280 mg of the title compound. LC-MS (Method A) (ESI+): m / z 534 (M+H) + ; 1 H-NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 8.19 (s, 1H), 7.72 (s, 1H), 7.41-7.49 (m, 4H), 5.70 (s, 2H), 5.01 (m, 1H), 4.36-4.42 (t, J = 8.7 Hz, 2H), 4.06-4.13 (m, 2H), 1.42 (s, 9H).

[0460] Preparation of common intermediate I-32: [ka] Step 1: Synthesis of ethyl 4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)benzoate: [ka] To a solution of 4-hydrazinylbenzoate hydrochloride ethyl salt (300 mg, 1.5 mmol) and 1,1-difluoropentane-2,4-dione (201.5 mg, 1.5 mmol) in HFIP (2 mL) at 0 °C, a solution of TEA (299.6 mg, 3.0 mmol) in HFIP (1 mL) was added dropwise over 2 min. After the addition, the reaction was stirred at room temperature for 2.5 h. The reaction was then quenched with water (10 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with water (10 mL), dried over anhydrous NaSO (20 g), and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA = 15:1 to 3:1) to give 300 mg of the title compound. 1 H-NMR (300 MHz, CDCl3) δ 8.17 (dd, J = 6.9, 1.8Hz, 2H), 7.56 (dd, J = 6.9, 1.8 Hz, 2H), 6.71 (t, J = 54.9 Hz, 1H), 6.48 (s, 1H), 3.96 (s, 3H), 2.42 (s, 3H).

[0461] Step 2: Synthesis of (4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)phenyl)methanol: [ka] The title compound was synthesized according to step 3 of common intermediate I-1. 1 H-NMR (300 MHz, CDCl3) δ 7.49 (dd, J = 6.3, 2.1 Hz, 2H), 7.42 (dd, J = 6.3, 2.1 Hz, 2H), 6.70 (t, J = 55.2 Hz, 1H), 6.44 (s, 1H), 4.78 (d, J = 5.7 Hz, 2H), 2.35 (s, 3H), 1.90 (t, J = 5.7 Hz, 1H).

[0462] Step 3: Synthesis of 1-(4-(chloromethyl)phenyl)-3-(difluoromethyl)-5-methyl-1H-pyrazole: [ka] To a solution of (4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)phenyl)methanol (290 mg, 1.2 mmol) in DCE (10 mL) was added SOCl (426.4 mg, 3.6 mmol) in one portion. After the addition, the reaction was stirred at 60 °C for 1 h and then concentrated in vacuo to give 300 mg of the crude title compound. 1 H-NMR (300 MHz, CDCl3) δ 7.52 (dd, J = 6.3, 2.1 Hz, 2H), 7.44 (dd, J = 6.3, 2.1 Hz, 2H), 6.70 (t, J = 54.9 Hz, 1H), 6.44 (s, 1H), 4.65 (s, 2H), 2.37 (s, 3H).

[0463] Step 4: Synthesis of 6-chloro-1-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-32): [ka] A solution of 1-(4-(chloromethyl)phenyl)-3-(difluoromethyl)-5-methyl-1H-pyrazole (300 mg, 1.2 mmol), 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (270.9 mg, 1.8 mmol), and K2CO3 (484.6 mg, 351 mmol) in DMF (12 mL) was stirred at 90 °C for 1.5 h. The reaction was then quenched with water (25 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with water (20 mL × 2), dried over anhydrous Na2SO4 (30 g), and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA = 5:1 to 3:1) to give 150 mg of the title compound with a minor regioisomer. 1H-NMR (300 MHz, CDCl3) δ 9.06 (s, 1H), 8.19 (s, 1H), 7.50 (dd, J = 6.6, 1.8 Hz, 2H), 7.41 (dd, J = 6.6, 1.8 Hz, 2H), 6.67 (t, J = 54.9 Hz, 1H), 6.42 (s, 1H), 5.69 (s, 2H), 2.33 (s, 3H).

[0464] Preparation of common intermediates I-33 and I-34: [ka] Step 1: Synthesis of 4-bromobenzimidate hydrochloride ethyl salt: [ka] Gaseous HCl was bubbled through a vigorously stirred solution of 4-bromobenzonitrile (4.2 g, 23.07 mmol) in anhydrous MeOH (40 mL) at 0° C. for 3 hours. The mixture was then stirred at room temperature overnight. The resulting reaction mixture was poured into EtO (40 mL), and the resulting solid precipitate was collected by filtration. The solid was suspended in cold DCM (80 mL) and neutralized with saturated aqueous NaHCO (80 mL). After separating the organic phase, the aqueous phase was extracted with DCM (40 mL×2). The combined organic phases were dried over sodium sulfate (40 g), filtered, and concentrated to give 5.0 g of the title compound. LC-MS (Method A) (ESI+): m / z 214 (M+H) + ; 1 H-NMR (300 MHz, CDCl3) δ 7.81 (br s, 1H), 7.51-7.68 (m, 4H)...

Claims

1. Compounds having formula I: 【Chemical 446】 or a pharma- ceutically acceptable salt or solvate thereof, wherein: 【Chemical 447】 but 【Chemistry 448】 and R １ and R ２ each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R ３ is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, or optionally substituted pyrazolyl; X １１ and X １２ each is independently selected from N and CH; R ５’ is hydrogen, optionally substituted (C １ -C ６ ) alkyl, optionally substituted (C ２ -C ６ ) alkenyl, optionally substituted (C ２ -C ６ ) alkynyl, optionally substituted (C １ -C ６ ) alkoxy, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) haloalkoxy, (C １ -C ６ ) hydroxyalkyl, cyano, halo, sulfonamide, -C(=O)R ２３ , -C(=O)OR ２４ , -NR ３２ａ R ３２ｂ , -NR ３１ａ C(=O)R ２５ , -NR ３１ａ C(=O)NR ３１ａ R ３１ｂ , -C(=O)NR ３１ａ R ３１ｂ , -S(O) ２ R ２７ , -NR ３１ａ SO ２ R ２７ , optionally substituted (C ６ -C １４ ) aryl, optionally substituted (C ６ -C １４ ) Al-(C １ -C ２ ) alkyl, optionally substituted heteroaryl, optionally substituted heteroar-(C １ -C ２ ) alkyl, optionally substituted (C ３ -C ８ ) cycloalkyl, optionally substituted ((C ３ -C ８ ) cycloalkyl)-(C １ -C ２ ) alkyl, optionally substituted heterocyclo, optionally substituted heterocyclo-(C １ -C ２ ) alkyl, optionally substituted —O—(C ６ -C １４ ) aryl, optionally substituted —O—(C ６ -C １４ ) Al-(C １ -C ２ ) alkyl, optionally substituted —O-heteroaryl, optionally substituted —O-heteroar-(C １ -C ２ ) alkyl, optionally substituted —O—(C ３ -C ８ ) cycloalkyl, optionally substituted —O—((C ３ -C ８ ) cycloalkyl)-(C １ -C ２ ) alkyl, optionally substituted —O-heterocyclo, and optionally substituted —O-heterocyclo-(C １ -C ２ ) alkyl; R ５ is optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazolyl, or optionally substituted tetrazolyl; R ６ and R ７ each is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R ２３ is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl; R ３１ａ and R ３１ｂ are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, alkoxyalkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, aralkyl, and (heteroaryl)alkyl; R ２４ , R ２５ , R ２７ , R ３２ａ , and R ３２ｂ each is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl; The compound or a pharma- ceutically acceptable salt or solvate thereof.

2. R ３ The above optional substituents are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkylaralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (C １－４ (haloalkoxy)alkyl, and (heteroaryl)alkyl; or R ３ The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein two of the above optional substituents, together with the carbon or nitrogen atom to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted heterocyclo, an optionally substituted aryl, or an optionally substituted heteroaryl group.

3. a) R ３ is optionally substituted phenyl, said phenyl being optionally substituted at the 2-position, optionally substituted at the 6-position, optionally disubstituted at said 2-position and said 6-position, or optionally disubstituted at the 2-position and said 3-position; or b) R ３ is an optionally substituted pyrid-3-yl or an optionally substituted pyrid-4-yl, said pyrid-3-yl being optionally substituted at the 2-position, optionally substituted at the 4-position or optionally disubstituted at the 2- and 4-positions; said pyrid-4-yl being optionally substituted at the 3-position, optionally substituted at the 5-position or optionally disubstituted at the 3- and 5-positions, or c) R ３ is an optionally substituted pyrimidin-5-yl, said pyrimidin-5-yl being optionally substituted at the 4-position, optionally substituted at the 6-position, optionally disubstituted at the 4-position and at the 6-position, or optionally trisubstituted at the 2-position, the 4-position, and the 6-position; or d) R ３ is an optionally substituted pyrazol-5-yl, said pyrazol-5-yl being optionally substituted at the 1-position, optionally substituted at the 4-position, or optionally disubstituted at said 1-position and said 4-position; 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt or solvate thereof.

4. R ３ but, 【Chemistry 449-1】 【Chemistry 449-2】 3. The compound of claim 1 or 2, selected from the group consisting of: or a pharma- ceutically acceptable salt or solvate thereof.

5. R ３ is substituted, said substituents being independently selected from methoxy, deuterium methoxy, ethoxy, isopropoxy, t-butoxy, difluoromethoxy, 2-fluoroethoxy, 2-methoxyethoxy, cyclopropoxy, cyclobutoxy, (tetrahydrofuran-3-yl)oxy, benzyloxy, methyl, ethyl, isopropyl, 2-fluoroisopropyl, t-butyl, cyclopropyl, cyclobutyl, methylcyclopropyl, pyrrolidin-1-yl, azetidin-1-yl, methylamino, dimethylamino, cyano, halo, methylthio, methylsulfonyl, and ethylsulfonyl, or a pharma- ceutically acceptable salt or solvate thereof.

6. X １１ and X １２ or a pharma- ceutically acceptable salt or solvate thereof.

2. The compound of claim 1, wherein at least one of:

7. R ５ The above optional substituents are independently selected from hydrogen, halo, nitro, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, hydroxy, carboxy, carboxyalkyl, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, aralkylamino, heteroaralkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkylamino, alkoxyalkyl, (alkoxyalkyl)amino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (carboxamido)alkyl, mercaptoalkyl, (cyano)alkyl, (cycloalkyl)alkyl, aralkyl, aralkyloxy, alkylcarbonyl, arylcarbonyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, (C １－４ haloalkoxy)alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, carboxamide, sulfonyl, sulfonamido, sulfamido, alkylsulfonyl, alkylsulfonamido, alkylsulfamido, arylsulfonyl, aryloxy, heteroaryloxy, -C(=O)R ２３ , -C(=O)OR ２４ , -C(=O)NR ３１ａ R ３１ｂ , -NR ３１ａ C(=O)R ２５ , -NR ３１ａ C(=O)OR ２６ , -NR ３１ａ C(=O)NR ３１ａ R ３１ｂ , -NR ３１ａ SO ２ R ２７ , -OC(=O)R ２８ , -OC(=O)OR ２９ , -OC(=O)NR ３１ａ R ３１ｂ , -OSO ２ R ３０ , and -NR ３２ａ R ３２ｂ or R ５ two of the above optional substituents taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl, an optionally substituted heterocyclo, an optionally substituted aryl, or an optionally substituted heteroaryl group; and R ２４ , R ２５ , R ２６ , R ２７ , R ２８ , R ２９ , R ３０ , R ３２ａ , and R ３２ｂ each is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, amino, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (cycloalkyl)alkyl, aralkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, (amino)(hydroxy)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted cycloalkyl; 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

8. R ５ 8. The compound of claim 1 or 7, or a pharma- ceutically acceptable salt or solvate thereof, wherein: is an optionally substituted imidazolyl.

9. The compound of claim 1 or 7, or a pharma- ceutically acceptable salt or solvate thereof, wherein R5 is optionally substituted pyrazolyl.

10. R ５ 8. The compound of claim 1 or 7, or a pharma- ceutically acceptable salt or solvate thereof, wherein: is an optionally substituted triazolyl.

11. R 5 is 【Chemical 450-1】 【Chemical 450-2】 2. The compound of claim 1, selected from the group consisting of: or a pharma- ceutically acceptable salt or solvate thereof.

12. R ５ is substituted, said substituents being independently selected from halo, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, oxetan-3-yl, and methylazetidinyl, or a pharma- ceutically acceptable salt or solvate thereof.

13. 10. The compound of claim 1 having formula II, or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 451】 During the ceremony, X １ But, CR ２ and X ２ is N, X ３ But N and CR １０ is selected from X ４ But N and CR １１ is selected from X ５ But N and CR １２ is selected from R ８ , R ９ , R １０ , R １１ , and R １２ each of which is independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkylaralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (C １－４ (haloalkoxy)alkyl, and (heteroaryl)alkyl; The compound, or a pharma- ceutically acceptable salt or solvate thereof.

14. 14. The compound of claim 13 having formula III, IV, V, VI, or VIa, or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 452-1】 【Chemistry 452-2】 。

15. R ５ but, 【Chemistry 453】 and During the ceremony, X ６ But, N.R. １３ and C.R. １８ is selected from X ７ But, N.R. １４ and C.R. １９ is selected from X ８ But, N.R. １５ and C.R. ２０ is selected from X ９ But, N.R. １６ and C.R. ２１ is selected from X １０ But, N.R. １７ and C.R. ２２ is selected from wherein X 6 , X 7 , X 8 , X 9 , and X 10 are selected such that R 5 is optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazolyl, or optionally substituted tetrazolyl; R １３ , R １４ , R １５ , R １６ , and R １７ each is absent or independently selected from hydrogen, halo, methyl, ethyl, isopropyl, cyclopropyl, methoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, and methylazetidinyl; R １８ , R １９ , R ２０ , R ２１ , and R ２２ each is independently selected from hydrogen, halo, methyl, ethyl, isopropyl, cyclopropyl, methoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, and methylazetidinyl; 15. The compound according to claim 13 or 14, or a pharma- ceutically acceptable salt or solvate thereof.

16. 16. The compound of claim 15 having formula VII, VIII, IX, X, XI, or XII, or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 454-1】 【Chemistry 454-2】 【Chemistry 454-3】 。

17. 6-(3-methoxypyridin-4-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-(methylsulfonyl)-phenyl)-1H-pyrazolo[3,4-d]pyrimidine, 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-methyl-6-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2-(ethylsulfonyl)phenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 1-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)benzyl)-6-(2-isopropylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2-methoxy-4-methylpyridin-3-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-methoxy-6-methylpyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2-isopropylpyridin-3-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2,6-dimethoxyphenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2-methoxyphenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2-isopropylphenyl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2-methoxy-6-methylphenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 2-methoxy-3-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)isonicotinonitrile, 2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2-isopropylpyridin-3-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(2-methyl-6-(methylthio)phenyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2-cyclopropyl-6-methoxyphenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2-isopropylphenyl)-1-(4-(1-(1-methylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2-isopropylphenyl)-1-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2-isopropylphenyl)-4-methyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(3-fluoro-2-isopropylphenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2-isopropylphenyl)-3-methyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2-isopropylphenyl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(tert-butyl)-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(2-fluoropropan-2-yl)-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-methoxy-6-(1-methylcyclopropyl)pyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclobutyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, (S)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, (R)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-ethoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-isopropoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-cyclopropyl-5-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidine-4-carbonitrile, 6-cyclopropyl-N,N-dimethyl-5-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidin-4-amine, 6-(4,6-dimethoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-isopropyl-6-methylpyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6-(4-methyl-6-(methylthio)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-methyl-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-9H-purine, 1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6-(4-methyl-6-(methylsulfonyl)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(2-methoxyethoxy)-6-methylpyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(1-isopropyl-4-methoxy-1H-pyrazol-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-1-isopropyl-1H-pyrazol-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine, and 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine, or a pharma- ceutically acceptable salt or solvate thereof.

18. 6-(4,6-diethoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(1-cyclopropyl-4-methoxy-1H-pyrazol-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-((6-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine, (R)-6-(4-cyclobutyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, (S)-6-(4-cyclobutyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, (R)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, (S)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(2-fluoropropan-2-yl)-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-ethoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-((6-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine, 1-(4-((6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)-5-methyl-1H-pyrazole-3-carbonitrile, 6-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-(methoxy-d ３ )pyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-cyclopropyl-5-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidine-4-carbonitrile, 6-(4-cyclopropoxy-6-cyclopropylpyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclobutoxy-6-cyclopropylpyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxy-2-methylpyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(tert-butyl)-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(tert-butoxy)-6-cyclopropylpyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-(2-fluoroethoxy)pyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 1-(4-(1-cyclobutyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4,6-dimethoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 1-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-(2-fluoroethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(2,4-dimethoxy-6-methylpyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-(2-methoxyethoxy)pyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-(2-methoxyethoxy)pyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-methoxy-6-(1-methylcyclopropyl)pyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, (S)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, (R)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclobutyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-isopropoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-isopropyl-6-methylpyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-ethoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, N,N,6-trimethyl-5-(1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidin-4-amine, 1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6-(4-methyl-6-(methylthio)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4,6-dimethoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(2-methoxyethoxy)-6-methylpyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-(1-methylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-methoxy-6-methylpyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 3-(1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)picolinonitrile, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-cyclopropyl-N-methyl-5-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidin-4-amine, 1-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6-(4-methoxy-6-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(benzyloxy)-6-cyclopropylpyrimidin-5-yl)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(3-(difluoromethyl)-1-methyl-1H-1,2,4-triazol-5-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(benzyloxy)-6-cyclopropylpyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 2-(2-(4-((6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)-N,N-dimethylacetamide, 6-cyclopropyl-N,N-dimethyl-5-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidin-4-amine, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-(difluoromethyl)-1-methyl-1H-1,2,4-triazol-3-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-cyclopropyl-6-(pyrrolidin-1-yl)pyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, 6-(4-(azetidin-1-yl)-6-cyclopropylpyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, and 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine, or a pharma- ceutically acceptable salt or solvate thereof.

19. 19. The compound of claim 18, which is 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, or a pharma- ceutically acceptable salt or solvate thereof.

20. The compound of claim 19 which is 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt or solvate thereof, or a compound according to claim 20, and a pharma- ceutically acceptable carrier.

22. 22. The pharmaceutical composition of claim 21 for the treatment of cancer.

23. 20. A kit for the treatment of cancer comprising a compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt or solvate thereof, or a compound according to claim 20, or a pharmaceutical composition according to claim 21, and instructions for administering said compound or a pharma- ceutically acceptable salt or solvate thereof, or said pharmaceutical composition to a patient having cancer.

24. the cancer is selected from the group consisting of hematological cancer, lymphatic cancer, DNA damage repair pathway deficient cancer, homologous recombination deficient cancer, cancer comprising cancer cells with a mutation in the gene encoding p53, and cancer comprising cancer cells with a loss-of-function mutation in the gene encoding p53; or the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer; A pharmaceutical composition according to claim 22 or a kit according to claim 23.

25. An in vitro method for inhibiting USP1 protein, comprising contacting USP1 protein with a compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt or solvate thereof, a compound according to claim 20, or a pharmaceutical composition according to claim 21.

26. 22. A pharmaceutical composition according to claim 21 for the treatment of cancer in a patient, comprising: the cancer comprises cancer cells that have a mutation in the gene encoding p53; or the cancer comprises cancer cells that have a mutation in the gene encoding BRCA1; or the cancer comprises cancer cells that have a mutation in the gene encoding BRCA2; or the cancer comprises cancer cells having a mutation in the gene encoding ATM; or the cancer comprises cancer cells with mutations in one or more genes encoding at least two of P53, BRCA1, BRCA2, and ATM; or The cancer is triple-negative breast cancer. The pharmaceutical composition.

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