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

Description

BACKGROUND OF THE DISCLOSUREField of the Invention

[0001] The present disclosure provides substituted pyrazolopyrimidines and substituted purines as ubiquitin-specific-processing protease 1 (USP1) inhibitors, as further defined in the claims, and provides these compounds for use in treating cancer.Background

[0002] Ubiquitin is a small (76 amino acid) protein that is post-transcriptionally attached to target proteins. The consequence 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 poly-ubiquitin chains are generally targeted to the proteasome for degradation, while mono-ubiquitination or poly-ubiquitin 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 that is required for the deubiquitinase activity. The USP1 IUAF1 complex deubiquitinates mono-ubiquitinated PCNA (proliferating cell nuclear antigen) and mono-ubiquitinated FANCD2 (Fanconi anemia group complementation group D2), which are proteins that play important functions in translesion synthesis (TLS) and the Fanconi anemia (FA) pathway, 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] US 2017 / 145012 describes certain purinone compounds and their use as USP1 inhibitors.

[0005] Safe and effective treatments targeting deubiquitinases are unknown, not yet commercially available, or have not yet been clinically developed.BRIEF SUMMARY OF THE DISCLOSURE

[0006] In one aspect, the present disclosure relates to compounds, or a pharmaceutically acceptable salt or solvate thereof, having Formula I (also referred to herein as Compounds of the Disclosure): wherein: is each of R 1< and R 2< is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 3< is an optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, or optionally substituted pyrazolyl; each of X 11< and X 12< is independently selected from N and CH; R 5'< is independently selected from 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, 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 substituted (C 6 -C 14 ) aryl, optionally substituted (C 6 -C 14 ) ar-(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 ) ar-(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 independently selected from 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, 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 substituted (C 6 -C 14 ) aryl, optionally substituted (C 6 -C 14 ) ar-(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 ) ar-(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; or one of R 5< and one of R 5'< on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted (C 6 -C 14 ) aryl ring; or one of R 5< and one of R 5'< on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted heteroaryl ring; or one of R 5< and one of R 5'< on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted (C 3 -C 8 ) cycloalkyl ring; or one of R 5< and one of R 5'< on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl ring; or one of R 5< and one of R 5'< on adjacent atoms on the same atom to which they are attached are taken together to form an optionally substituted spirocycloalkyl ring; or one of R 5< and one of R 5'< on adjacent atoms on the same atom to which they are attached are taken together to form an optionally substituted spiroheterocycloalkyl ring; each of R 6< and R 7< 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; and each of 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.

[0007] In some embodiments, the Compounds of the Disclosure exhibit improved solubility, e.g., as measured by an ADME solubility assay as disclosed herein.

[0008] In some embodiments, the Compounds of the Disclosure exhibit improved metabolic stability, e.g., as measured by liver microsome and hepatocyte metabolic stability assays as disclosed herein.

[0009] In other embodiments, the Compounds of the Disclosure exhibit improved duration of action and oral exposure in vivo.

[0010] In some embodiments, a Compound of the Disclosure is a compound having Formula I, wherein R 5'< is selected from hydrogen, halo, and optionally substituted (C 1 -C 6 ) alkyl.

[0011] In some embodiments, a Compound of the Disclosure is a compound having Formula I, wherein at least one of X 11< and X 12< is N. In some embodiments, X 11< is N. In some embodiments, X 12< is N.

[0012] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein at least one of X 11< and X 12< is CH. In some embodiments, X 11< is CH. In some embodiments, X 12< is CH.

[0013] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein each of X 11< and X 12< is N.

[0014] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein each of X 11< and X 12< is CH.

[0015] In some embodiments, one of X 11< and X 12< is N and the other of X 11< and X 12< 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.

[0016] In some embodiments, the optional substituents on R 3< are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, 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, (cycloalkylamino)alkyl, (C 1-4 haloalkoxy)alkyl, and (heteroaryl)alkyl; or two of the optional substituents on R 3< are taken together with the carbon or nitrogen atoms to which they are attached to form an optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl group.

[0017] 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.

[0018] In some embodiments, R 3< is an optionally substituted pyrid-3-yl or 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 wherein 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.

[0019] 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.

[0020] 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.

[0021] In some embodiments, R 3< is substituted and the substituents are 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.

[0022] In some embodiments, R 3< is selected from the group consisting of:

[0023] In some embodiments, the optional substituents on R 5< 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, 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(=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 two of the optional substituents on R 5< are taken together with the carbon or nitrogen atoms to which they are attached to form a cycloalkyl, heterocyclo, aryl, or heteroaryl group; and each of R 24< , R 25< , R 26< , R 27< , R 28< , R 29< , R 30< , R 32a< , and R 32b< 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.

[0024] In some embodiments, R 5< is selected from 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, 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< , and -NR 31a< SO 2 R 27< , optionally substituted -O-(C 6 -C 14 ) aryl, optionally substituted -O-(C 6 -C 14 ) ar-(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 -Cs) cycloalkyl)-(C 1 -C 2 ) alkyl, optionally substituted -O-heterocyclo, optionally substituted -O-heterocyclo-(C 1 -C 2 ) alkyl.

[0025] In some embodiments, R 5< is selected from optionally substituted (C 6 -C 14 ) aryl, optionally substituted (C 6 -C 14 ) ar-(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.

[0026] In some embodiments, R 5< is an optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazolyl, or optionally substituted tetrazolyl.

[0027] In some embodiments, R 5< is an optionally substituted imidazolyl.

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

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

[0030] 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.

[0031] In some embodiments, R 5< is selected from the group consisting of:

[0032] In some embodiments, the compound has Formula II: wherein is (i.e., X 1< is CR 2< , and X 2< is N); X 3< is selected from N and CR 10< ; X 4< is selected from N and CR 11< ; X 5< is selected from N and CR 12< ; and each of R 8< , R 9< , R 10< , R 11< , and R 12< is independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, 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, (cycloalkylamino)alkyl, (C 1-4 haloalkoxy)alkyl, or (heteroaryl)alkyl.

[0033] In some embodiments, the Compounds of the Disclosure has Formula III, Formula IV, Formula V, Formula VI, or Formula VIa: wherein each of X 1< , X 2< , R 1< , R 5< , R 6< , R 7< , R 8< , R 9< , and R 11< are as defined above for Formula II.

[0034] In some embodiments, R 5< is: wherein X 6< is selected from NR 13< and CR 18< ; X 7< is selected from NR 14< and CR 19< ; X 8< is selected from NR 15< and CR 20< ; X 9< is selected from NR 16< and CR 21< ; X 10< is selected from NR 17< and CR 22< ; each of R 13< , R 14< , R 15< , R 16< , and R 17< 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; and each of R 18< , R 19< , R 20< , R 21< , and R 22< is independently selected from hydrogen, halo, methyl, ethyl, isopropyl, cyclopropyl, methoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, and methylazetidinyl.

[0035] In some embodiments, the Compounds of the Disclosure has Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, or Formula XII: wherein each of 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< are as defined above for Formula II.

[0036] In some embodiments, the Compound of the Disclosure is one of the specific compounds listed in the detailed description, or a pharmaceutically acceptable salt or solvate thereof.

[0037] In some embodiments, the Compound of the Disclosure inhibits a USP1 protein.

[0038] In some embodiments, the Compound of the Disclosure inhibits a USP1 protein with an IC 50 value of less than about 1 µM in a Ub-Rho deubiquitinating assay.

[0039] In some embodiments, the Ub-Rho deubiquitinating assay is the assay disclosed in Example 26.

[0040] In one aspect, the present disclosure relates to a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, for use in treating cancer in a patient, said use comprising administering to the patient a therapeutically effective amount of the Compound of the Disclosure, or the pharmaceutically acceptable salt or solvate thereof.

[0041] In one aspect, the present disclosure relates to a pharmaceutical composition comprising a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0042] In some embodiments, the present disclosure relates to a pharmaceutical composition for use in the treatment of cancer.

[0043] In some embodiments, the present disclosure relates to a Compound of the Disclosure for use in the treatment of cancer.

[0044] In one aspect, the present disclosure relates to a kit comprising a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a Compound of the Disclosure, and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition to a patient having cancer.

[0045] In one aspect, the present disclosure relates to a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a Compound of the Disclosure, for use in treating cancer in a patient.

[0046] 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.

[0047] In some embodiments, the cancer comprises cancer cells with a mutation in a gene encoding p53. In some embodiments, the mutation in a gene encoding p53 is a germline mutation. In some embodiments, the mutation in a gene encoding p53 is a somatic mutation. In some embodiments, the cancer comprises cancer cells with a loss of function mutation in a gene encoding p53.

[0048] 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.

[0049] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0050] In some embodiments, the cancer is colon cancer.

[0051] In some embodiments, the cancer is bladder cancer.

[0052] In some embodiments, the cancer is ovarian cancer or breast cancer.

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

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

[0055] In some embodiments, the cancer is triple negative breast cancer.

[0056] In some embodiments, the cancer comprises cancer cells with elevated levels of RAD18.

[0057] In some embodiments, the elevated levels of RAD18 are elevated RAD18 protein levels.

[0058] In some embodiments, the elevated levels of RAD18 are elevated RAD18 mRNA levels.

[0059] In some embodiments, the elevated levels of RAD18 have been detected prior to the administration.

[0060] In another aspect, the present disclosure relates to a compound or composition for use as described herein, wherein said use further comprises detecting RAD18 levels in a cancer sample obtained from the subject.

[0061] 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.

[0062] In some embodiments, the cancer is a DNA damage repair pathway deficient cancer.

[0063] In some embodiments, the cancer comprises cancer cells with a mutation in a gene encoding p53. In some embodiments, the mutation in a gene encoding p53 is a germline mutation. In some embodiments, the mutation in a gene encoding p53 is a somatic mutation. In some embodiments, the cancer comprises cancer cells with a loss of function mutation in a gene encoding p53.

[0064] 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 leads to BRCA1 deficiency.

[0065] 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 leads to BRCA2 deficiency.

[0066] In some embodiments, the cancer is a BRCA1 mutant cancer and a BRCA2 mutant cancer.

[0067] In some embodiments, the cancer is a BRCA1 deficient cancer.

[0068] In some embodiments, the cancer is a BRCA2 deficient cancer.

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

[0070] 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.

[0071] 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.

[0072] In some embodiments the cancer has a mutation in the gene encoding at least two of p53, BRCA1, BRCA2, and ATM.

[0073] In another aspect, the present disclosure relates to a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a Compound of the Disclosure, for use in treating a USP1 protein mediated disorder.

[0074] In some embodiments, the USP1 protein comprises the amino acid sequence of SEQ ID NO:1.

[0075] In another aspect, the present disclosure relates to an in vitro method of inhibiting a USP1 protein comprising contacting a USP1 protein with a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a Compound of the Disclosure.

[0076] As explained above, the contacting in said method occurs in vitro.

[0077] In another aspect, the present disclosure relates to a Compound of the Disclosure for use in treating cancer in a patient, wherein the cancer comprises cancer cells with a mutation in a gene encoding p53.

[0078] In some embodiments, the mutation in a gene encoding p53 has been detected prior to the administration.

[0079] In some embodiments, the use described herein further comprises detecting the mutation in the gene encoding p53 in a cancer sample obtained from the patient.

[0080] In another aspect, the present disclosure relates to a USP1 inhibitor which is Compound of the Disclosure for use in the treatment of cancer in a patient, wherein the cancer comprises cancer cells with a mutation in a gene encoding p53.

[0081] In some embodiments, the patient is identified to be responsive to the treatment with the USP1 inhibitor by detecting cancer cells with a mutation in a gene encoding p53 in a cancer sample obtained from the patient, wherein cancer cells with a mutation in a gene encoding p53 in the cancer sample identify the patient to be responsive to the treatment with an USP1 inhibitor.

[0082] In another aspect, the present disclosure relates to a USP1 inhibitor which is a Compound of the Disclosure for use in the treatment of cancer in a subject identified to be responsive to the treatment with the USP1 inhibitor by cancer cells with a mutation in a gene encoding p53 in a cancer sample obtained from the subject, wherein cancer cells with a mutation in a gene encoding p53 in the cancer sample identify the patient to be responsive to the treatment with an USP1 inhibitor.

[0083] In some embodiments, the USP1 inhibitor is not administered to a subject in case a mutation in a gene encoding p53 is not detected in a cancer sample obtained from the subject.

[0084] In another aspect, the present disclosure relates to a Compound of the Disclosure for use in treating cancer in a patient, wherein the cancer comprises cancer cells with a mutation in a gene encoding BRCA1.

[0085] In some embodiments, the mutation in a gene encoding BRCA1 has been detected prior to the administration.

[0086] In some embodiments, the use further comprises detecting the mutation in the gene encoding BRCA1 in a sample (e.g., a cancer sample or blood sample) obtained from the patient.

[0087] In another aspect, the present disclosure relates to a USP1 inhibitor which is a Compound of the Disclosure for use in the treatment of cancer in a patient, wherein the cancer comprises cancer cells with a mutation in a gene encoding BRCA1.

[0088] In some embodiments, the patient is identified to be responsive to the treatment with the USP1 inhibitor by detecting a mutation in a gene encoding BRCA1 in a sample (e.g., a cancer sample or a blood sample) obtained from the patient, wherein a mutation in a gene encoding BRCA1 in the sample identifies the patient to be responsive to the treatment with a USP1 inhibitor.

[0089] In another aspect, the present disclosure relates to a USP1 inhibitor which is a Compound of the Disclosure for use in the treatment of cancer in a subject identified to be responsive to the treatment with the USP1 inhibitor by cancer cells with a mutation in a gene encoding BRCA1 in a sample (e.g., a cancer sample or a blood sample) obtained from the subject, wherein cancer cells with a mutation in a gene encoding BRCA1 in the sample identify the patient to be responsive to the treatment with an USP1 inhibitor.

[0090] In some embodiments, the USP1 inhibitor is not administered to a subject in case a mutation in a gene encoding BRCA1 is not detected in a sample (e.g., a cancer sample or a blood sample) obtained from the subject.

[0091] In another aspect, the present disclosure relates to a Compound of the Disclosure for use in treating cancer in a patient, wherein the cancer comprises cancer cells with a mutation in a gene encoding BRCA2.

[0092] In some embodiments, the mutation in a gene encoding BRCA2 has been detected prior to the administration.

[0093] In some embodiments, the use further comprises detecting the mutation in the gene encoding BRCA2 in a sample (e.g., a cancer sample or a blood sample) obtained from the patient.

[0094] In another aspect, the present disclosure relates to a USP1 inhibitor which is a Compound of the Disclosure for use in the treatment of cancer in a patient, wherein the cancer comprises cancer cells with a mutation in a gene encoding BRCA2.

[0095] In some embodiments, the patient is identified to be responsive to the treatment with the USP1 inhibitor by detecting a mutation in a gene encoding BRCA2 in a sample (e.g., a cancer sample or a blood sample) obtained from the patient, wherein a mutation in a gene encoding BRCA2 in the sample identifies the patient to be responsive to the treatment with an USP1 inhibitor.

[0096] In another aspect, the present disclosure relates to a USP1 inhibitor which is a Compound of the Disclosure for use in the treatment of cancer in a subject identified to be responsive to the treatment with the USP1 inhibitor by cancer cells with a mutation in a gene encoding BRCA2 in a sample (e.g., a cancer sample or a blood sample) obtained from the subject, wherein cancer cells with a mutation in a gene encoding BRCA2 in the sample identify the patient to be responsive to the treatment with an USP1 inhibitor.

[0097] In some embodiments, the USP1 inhibitor is not administered to a subject in case a mutation in a gene encoding BRCA2 is not detected in a sample (e.g., a cancer sample or a blood sample) obtained from the subject.

[0098] In another aspect, the present disclosure relates to a Compound of the Disclosure for use in treating cancer in a patient, wherein the cancer comprises cancer cells with a mutation in a gene encoding ATM.

[0099] In some embodiments, the mutation in a gene encoding ATM has been detected prior to the administration.

[0100] In some embodiments, the use further comprises detecting the mutation in the gene encoding ATM in a sample obtained from the patient.

[0101] In another aspect, the present disclosure relates to a USP1 inhibitor which is a Compound of the Disclosure for use in the treatment of cancer in a patient, wherein the cancer comprises cancer cells with a mutation in a gene encoding ATM.

[0102] In some embodiments, the patient is identified to be responsive to the treatment with the USP1 inhibitor by detecting cancer cells with a mutation in a gene encoding ATM in a cancer sample obtained from the patient, wherein cancer cells with a mutation in a gene encoding ATM in the cancer sample identify the patient to be responsive to the treatment with an USP1 inhibitor.

[0103] In another aspect, the present disclosure relates to a USP1 inhibitor which is a Compound of the Disclosure for use in the treatment of cancer in a subject identified to be responsive to the treatment with the USP1 inhibitor by cancer cells with a mutation in a gene encoding ATM in a cancer sample obtained from the subject, wherein cancer cells with a mutation in a gene encoding ATM in the cancer sample identify the patient to be responsive to the treatment with an USP1 inhibitor.

[0104] In some embodiments, the USP1 inhibitor is not administered to a subject in case a mutation in a gene encoding ATM is not detected in a cancer sample obtained from the subject.

[0105] In one aspect (A1), the present disclosure provides a USP1 inhibitor which is a Compound of the Disclosure for use in treating cancer in a subject, wherein the cancer comprises cancer cells with elevated levels of RAD18.

[0106] In one aspect (A2), the present disclosure provides a USP1 inhibitor which is a Compound of the Disclosure for use in treating a triple negative breast cancerin a subject. In one aspect of A1 (A3), the cancer comprises cancer cells with elevated levels of RAD18.

[0107] In one aspect (A4) of A1 or A3, the elevated levels of RAD18 have been detected prior to the administration. In one aspect (A5) of A4, the use further comprises detecting RAD18 levels in a cancer sample obtained from the subject.

[0108] In one aspect (A6), the present disclosure provides a USP1 inhibitor which is a Compound of the Disclosure for use in the treatment of cancer in a subject, wherein the cancer comprises cancer cells with elevated levels of RAD18.

[0109] In one aspect (A7), the present disclosure provides a USP1 inhibitor which is a Compound of the Disclosure for use in the treatment of triple negative breast cancer in a subject.

[0110] In one aspect (A9) of A7 or A8, the subject is identified to be responsive to the treatment with the 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 to be responsive to the treatment with an USP1 inhibitor.

[0111] In one aspect (A10), the present disclosure provides a USP1 inhibitor which is a Compound of the Disclosure for use in the treatment of cancer in a subject identified to be responsive to the treatment with the USP1 inhibitor by detecting elevated RAD18 levels in a cancer sample obtained from the subject, wherein elevated levels of RAD18 in the cancer sample identify the patient to be responsive to the treatment with an USP1 inhibitor.

[0112] In one aspect (A11), the present disclosure provides a USP1 inhibitor which is a Compound of the Disclosure for use of any of A7-A10, wherein the USP1 inhibitor is not administered to a subject in case non-elevated RAD18 levels are detected in a cancer sample obtained from the subject.

[0113] In one aspect (A14), the present disclosure provides a kit or kit-of-parts, comprising: (a) a pharmaceutical composition comprising a USP1 inhibitor which is a Compound of the Disclosure and one or more pharmaceutically acceptable excipients, and (b) a diagnostic kit comprising at least one agent capable of specifically detecting RAD18.

[0114] In one aspect (A15) of A14, the at least one agent capable of specifically detecting RAD18 is capable of specifically hybridizing to RAD18 mRNA. In one aspect (A16) of A14, the at least one agent capable of specifically detecting RAD18 is capable of specifically binding to RAD18 protein.

[0115] In one aspect (A17) of A10, the cancer is triple negative breast cancer.

[0116] In one aspect (A18) of A10 or A17, the cancer comprises cancer cells with elevated levels of RAD18.

[0117] In one aspect (A20) of any one of A1-A18, the cancer is not a BRCA1 mutant cancer. In one aspect (A21) of any one of A1-A18, the cancer is not a BRCA2 mutant cancer. In one aspect (A22) of any one of A1-A18, the cancer is not a BRCA1 mutant cancer or a BRCA2 mutant cancer.

[0118] In one aspect (A23) of any one of A1-A18, the cancer is not a homologous-recombination deficient cancer. In one aspect (A24) of any one of A1-A18, the cancer is a homologous-recombination deficient cancer.

[0119] In one aspect (A25) of any one of A1-A23, the cancer comprises cancer cells with a mutation in a gene encoding p53, optionally wherein the mutation in the gene encoding p53 is a loss of function mutation.

[0120] In one aspect (A26) of any one of A1, A3-A7, A9-A11, and A18-A25, the elevated levels of RAD18 are elevated RAD18 protein levels. In one aspect (A27) of A26, the detection of elevated RAD18 protein levels is by Western blot. In one aspect (A28) of A26, the detection of elevated RAD18 protein levels is by fluorescenceactivated cell sorting (FACS). In one aspect (A29) of A26, the detection of elevated RAD18 protein levels is by immunohistochemistry.

[0121] In one aspect (A30) of any one of A1, A3-A7, A9-A11, and A18-A25, the elevated levels of RAD18 are elevated RAD18 mRNA levels. In one aspect (A31) of A30, the detection of elevated of RAD18 mRNA levels is by quantitative reverse transcriptase (RT)-polymerase chain reaction (PCR), RNA-Seq, or microarray.

[0122] In one aspect (A32) of any one of A1, A3-A7, A9-A11, and A18-A31, the elevated levels of RAD18 are at least as high as the RAD18 levels in ES2 cells. In one aspect (A33) of any one of A1, A3-A7, A9-A11, and A18-A31, the elevated levels of RAD18 are higher than the RAD18 levels in HEP3B217 cells.

[0123] In one aspect (A34) of any one of A1, A4-A7, A9-A16, and A18-A33, the cancer is an ovarian cancer. In one aspect (A35) of any one of A1, A4-A7, A9-A16, and A18-A33, the cancer is a breast cancer. In one aspect (A36) of A35, the breast cancer is a triple negative breast cancer.

[0124] In one aspect (A37) of any one of A1-A19 and A24-A36, the cancer is a BRCA1 mutant cancer. In one aspect (A38) of any one of A1-A19 and A24-A36, the cancer is a BRCA2 mutant cancer. In one aspect (A39) of any one of A1-A19 and A24-A36, the cancer is a BRCA1 mutant cancer and a BRCA2 mutant cancer.

[0125] In one aspect (A40) of any one of A1-A18 and A20-A39, the USP1 inhibitor specifically binds USP1 protein. In one aspect (A42) of A40, the USP1 protein comprises the amino acid sequence

[0126] In one aspect (A43) of any one of A1-A18 and A20-A42, the USP1 inhibitor inhibits formation and / or activity of the USP1 / UAF1 complex.

[0127] In one aspect (A44) of any one of A1-A18 and A20-A40, the USP1 inhibitor specifically binds to the USP1 / UAF1 complex.

[0128] In one aspect (A45) of any one of A1-A18 and A20-A40, the USP1 inhibitor specifically binds USP1 mRNA.

[0129] In one aspect (A46) of any one of A1-A18 and A20-A45, the USP1 inhibitor increases mono-ubiquitinated PCNA.

[0130] In one aspect (A47) of any one of A1-A18 and A20-A46, the USP1 inhibitor increases mono-ubiquitinated FANCD2.

[0131] In one aspect (A52) of any one of A1-A18 and A20-A51, the subject is human.

[0132] Additional embodiments and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by 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.

[0133] 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.BRIEF DESCRIPTION OF THE FIGURES

[0134] FIG. 1 provides a USP1 dropout profile across approximately 500 cancer cell lines. A lower dropout score indicates a greater sensitivity to loss of USP1. Breast cancer cell lines are shown in white, and ovarian cancer cell lines are shown in black. Symbols indicate BRCA1 / 2 mutations or triple negative breast cancer (TNBC) status. FIG. 2 provides a schematic of PCNA ubiquitination from Jacquemont C. and Taniguchi T., BMC Biochemistry 8 (Suppl 1):S10 (2007). The E3 ligase Rad18 monoubiquitinates PCNA. USP1 deubiquitnates mono-ubiquitinated PCNA. FIG. 3 shows the distribution of Rad18 mRNA expression across approximately 500 cancer cell lines. The x-axis shows normalized Rad18 mRNA expression values, and y-axis shows the number of cell lines that have the expression value indicated on the x-axis. The 20 cell lines with the lowest USP1 dropout scores are shown in the dark bars reaching to the top of the graph. FIG. 4 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). FIG. 5 shows Rad18 mRNA levels in USP1 sensitive cell lines (59M and ES2) and insensitive cell lines (OVISE, JHH7, and HEP3B217) as measured by qRT-PCT, normalized to GAPDH expression, and normalized to OVISE. FIG. 6 shows RAD18 protein levels in the USP1 sensitive cell lines (59M and ES2) and insensitive cell lines (OVISE, JHH7, and HEP3B217). The top panel shows the protein levels in a Western blot, and the bottom panel provides quantitation of the Western blot protein levels. "HCC1395" in the Western assay (top panel) was determined to be contaminated with another cell line and therefore not used in the quantitation (bottom panel). FIG. 7. provides graphs demonstrating that deletion of Rad18 rescues deletion of USP1. The graphs show the relative cell viability in OR1A1 (negative control) knockout cells (left panel) or Rad18 knockout cells (right panel) with the addition of guides against OR1A1 negative control ("negative control"), EEF2 pan lethal positive control ("lethal control"), or 4 different USP1 guides ("USP1_1," "USP1_2," "USP1_3," and "USP1_4"). DETAILED DESCRIPTION OF THE DISCLOSURE

[0135] One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of a ubiquitin-specific-processing protease 1 (USP1) protein. In view of this property, the Compounds of the Disclosure are useful for inhibiting a USP1 protein and for treating diseases, disorders, or conditions, e.g., cancer, that are responsive to inhibition of a USP1 protein.

[0136] In some embodiments, the Compounds of the Disclosure exhibit improved solubility, e.g., as measured by an ADME solubility assay as disclosed herein.

[0137] In some embodiments, the Compounds of the Disclosure exhibit improved metabolic stability, e.g., as measured by liver microsome metabolic stability assays as disclosed herein.

[0138] In other embodiments, the Compounds of the Disclosure exhibit improved duration of action and oral exposure in vivo.

[0139] In one embodiment, Compounds of the Disclosure are compounds having Formula I: and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein: is each of R 1< and R 2< is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 3< is an optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, or optionally substituted pyrazolyl; R 5'< is selected from 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, 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 substituted (C 6 -C 14 ) aryl, optionally substituted (C 6 -C 14 ) ar-(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 ) ar-(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< is selected from 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, 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 substituted (C 6 -C 14 ) aryl, optionally substituted (C 6 -C 14 ) ar-(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 ) ar-(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 one of R 5< and one of R 5'< on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted (C 6 -C 14 ) aryl ring; or one of R 5< and one of R 5'< on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted heteroaryl ring; or one of R 5< and one of R 5'< on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted (C 3 -C 8 ) cycloalkyl ring; or one of R 5< and one of R 5'< on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl ring; or one of R 5< and one of R 5'< on adjacent atoms on the same atom to which they are attached are taken together to form an optionally substituted spirocycloalkyl ring; or one of R 5< and one of R 5'< on adjacent atoms on the same atom to which they are attached are taken together to form an optionally substituted spiroheterocycloalkyl ring; each of R 6< and R 7< is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; each of X 11< and X 12< is independently selected from N and CH; 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; and each of 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.

[0140] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 5'< is selected from hydrogen, halo, and optionally substituted (C 1 -C 6 ) alkyl.

[0141] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein each of R 1< and R 2< is independently selected from hydrogen, halo, and cyano.

[0142] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein each of R 1< and R 2< is independently selected from optionally substituted (C 1-4 ) alkyl, optionally substituted (C 2-4 ) alkenyl, and optionally substituted (C 2-4 ) alkynyl. In some embodiments, each of R 1< and R 2< is independently selected from optionally substituted (C 1-4 ) alkyl. In some embodiments, each of R 1< and R 2< is independently selected from optionally substituted (C 2-4 ) alkenyl. In some embodiments, each of R 1< and R 2< is independently selected from optionally substituted (C 2-4 ) alkynyl.

[0143] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 3< is an optionally substituted phenyl.

[0144] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 3< is an optionally substituted pyridyl.

[0145] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 3< is an optionally substituted pyrimidinyl.

[0146] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 3< is an optionally substituted pyrazinyl.

[0147] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 3< is an optionally substituted pyridazinyl.

[0148] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 3< is an optionally substituted pyrazolyl.

[0149] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein the optional substituents on R 3< are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, 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, (cycloalkylamino)alkyl, (C 1-4 haloalkoxy)alkyl, and (heteroaryl)alkyl.

[0150] In another embodiment, the optional substituents on R 3< are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, (C 1 -C 4 ) alkylamino, di-(C 1 -C 4 ) alkylamino, halo-(C 1 -C 4 ) alkyl, hydroxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halo-(C 1 -C 4 ) alkoxy, (C 6 -C 10 ) aryloxy, (C 3 -C 6 ) heteroaryloxy, ar-(C 1 -C 4 ) alkyl, ar-(C 1 -C 4 ) alkyloxy, (C 1 -C 4 ) alkylthio, carboxamido, sulfonamido, (C 1 -C 4 ) alkylcarbonyl, (C 6 -C 10 ) arylcarbonyl, (C 1 -C 4 ) alkylsulfonyl, (C 6 -C 10 ) arylsulfonyl, carboxy, carboxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, alkoxy-(C 1 -C 4 ) alkyl, (amino)-(C 1 -C 4 ) alkyl, hydroxy-(C 1 -C 4 ) alkylamino, (alkylamino)-(C 1 -C 4 ) alkyl, (dialkylamino)-(C 1 -C 4 ) alkyl, (cyano)-(C 1 -C 4 ) alkyl, (carboxamido)-(C 1 -C 4 ) alkyl, mercapto-(C 1 -C 4 ) alkyl, (heterocyclo)-(C 1 -C 4 ) alkyl, (cycloalkylamino)-(C 1 -C 4 ) alkyl, (C 1-4 haloalkoxy)-(C 1 -C 4 ) alkyl, and (heteroaryl)-(C 1 -C 4 ) alkyl.

[0151] In another embodiment, the optional substituents on R 3< are independently selected from (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, (C 3 -C 6 ) heteroaryl, and (C 3 -C 8 ) heterocyclo.

[0152] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein two of the optional substituents on R 3< are taken together with the carbon or nitrogen atoms to which they are attached to form an optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl group.

[0153] In another embodiment, two of the optional substituents on R 3< are taken together with the carbon or nitrogen atoms to which they are attached to form an optionally substituted (C 3 -C 8 ) cycloalkyl, optionally substituted (C 3 -C 8 ) heterocyclo, optionally substituted (C 6 -C 10 ) aryl, or optionally substituted (C 3 -C 6 ) heteroaryl group.

[0154] In one embodiment, a Compound of the Disclosure is a compound 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.

[0155] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 3< is an optionally substituted pyrid-3-yl or optionally substituted pyrid-4-yl.

[0156] 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.

[0157] 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.

[0158] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 3< is 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.

[0159] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 3< is an optionally substituted pyrazol-3-yl or optionally substituted pyrazol-5-yl.

[0160] In one embodiment, a Compound of the Disclosure is a compound 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.

[0161] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 3< is substituted and the substituents are 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.

[0162] In one embodiment, R 3< is selected from the group consisting of:

[0163] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein at least one of X 11< and X 12< is N. In some embodiments, X 11< is N. In some embodiments, X 12< is N.

[0164] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein at least one of X 11< and X 12< is CH. In some embodiments, X 11< is CH. In some embodiments, X 12< is CH.

[0165] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein each of X 11< and X 12< is N.

[0166] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein each of X 11< and X 12< is CH.

[0167] In some embodiments, one of X 11< and X 12< is N and the other of X 11< and X 12< 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.

[0168] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 5< is selected from optionally substituted (C 1 -C 4 ) alkyl, optionally substituted (C 2 -C 4 ) alkenyl, optionally substituted (C 2 -C 4 ) alkynyl, optionally substituted (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, (C 1 -C 4 ) hydroxyalkyl.

[0169] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 5< is selected from 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< .

[0170] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 5< is selected from optionally substituted (C 6 -C 10 ) aryl, optionally substituted (C 6 -C 10 ) ar-(C 1 -C 2 ) alkyl, optionally substituted (C 3 -C 6 ) heteroaryl, optionally substituted (C 3 -C 6 ) 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 (C 3 -C 8 ) heterocyclo, optionally substituted (C 3 -C 8 ) heterocyclo-(C 1 -C 2 ) alkyl, optionally substituted -O-(C 6 -C 10 ) aryl, optionally substituted -O-(C 6 -C 10 ) ar-(C 1 -C 2 ) alkyl, optionally substituted -O-(C 3 -C 6 ) heteroaryl, optionally substituted -O-(C 3 -C 6 ) 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-(C 3 -C 8 ) heterocyclo, optionally substituted -O-(C 3 -C 8 ) heterocyclo-(C 1 -C 2 ) alkyl.

[0171] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 5< is an optionally substituted heteroaryl. In another embodiment, R 5< is an optionally substituted 5- or 6-membered heteroaryl containing one or more nitrogens. In another embodiment, R 5< is an optionally substituted 5- or 6-membered heteroaryl containing only nitrogen as the heteroatom or heteroatoms.

[0172] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein one of R 5< and one of R 5'< on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted (C 6 -C 10 ) aryl ring.

[0173] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein one of R 5< and one of R 5'< on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted (C 3 -C 6 ) heteroaryl ring.

[0174] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein one of R 5< and one of R 5'< on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted (C 3 -C 8 ) cycloalkyl ring.

[0175] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein one of R 5< and one of R 5'< on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted (C 3 -C 8 ) heterocycloalkyl ring.

[0176] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein one of R 5< and one of R 5'< on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted spirocycloalkyl ring.

[0177] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein one of R 5< and one of R 5'< on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted spiroheterocycloalkyl ring.

[0178] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein the optional substituents on R 5< 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, 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< 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< .

[0179] In another embodiment, the optional substituents on R 5< are independently selected from hydrogen, halo, nitro, cyano, optionally substituted (C 1 -C 4 ) alkyl, optionally substituted (C 2 -C 4 ) alkenyl, optionally substituted (C 2 -C 4 ) alkynyl, (C 1 -C 4 ) alkoxy, hydroxy, carboxy, carboxy-(C 1 -C 4 ) alkyl, amino, (C 1 -C 4 ) alkylamino, di-(C 1 -C 4 ) alkylamino, (C 3 -C 8 ) cycloalkylamino, heterocycl0-(C 1 -C 4 ) alkylamino, ar-(C 1 -C 4 ) alkylamino, heteroar-(C 1 -C 4 ) alkylamino, (C 1 -C 4 ) alkylthio, halo-(C 1 -C 4 ) alkyl, halo-(C 1 -C 4 ) alkoxy, hydroxy-(C 1 -C 4 ) alkyl, hydroxy-(C 1 -C 4 ) alkylamino, alkoxy-(C 1 -C 4 ) alkyl, (alkoxyalkyl)amino, (amino)-(C 1 -C 4 ) alkyl, (alkylamino)-(C 1 -C 4 ) alkyl, (dialkylamino)-(C 1 -C 4 ) alkyl, (cycloalkylamino)-(C 1 -C 4 ) alkyl, (carboxamido)-(C 1 -C 4 ) alkyl, mercapto-(C 1 -C 4 ) alkyl, (cyano)-(C 1 -C 4 ) alkyl, (cycloalkyl)-(C 1 -C 4 ) alkyl, ar-(C 1 -C 4 ) alkyl, ar-(C 1 -C 4 ) alkyloxy, (C 1 -C 4 ) alkylcarbonyl, arylcarbonyl, (heterocyclo)-(C 1 -C 4 ) alkyl, (heteroaryl)-(C 1 -C 4 ) alkyl, (amino)(hydroxy)-(C 1 -C 4 ) alkyl, (aralkylamino)-(C 1 -C 4 ) alkyl, and (C 1-4 haloalkoxy)-(C 1 -C 4 ) alkyl.

[0180] In another embodiment, the optional substituents on R 5< are independently selected from optionally substituted (C 3 -C 8 ) heterocyclo, optionally substituted (C 3 -C 6 ) heteroaryl, optionally substituted (C 6 -C 10 ) aryl, optionally substituted (C 3 -C 8 ) cycloalkyl.

[0181] In another embodiment, the optional substituents on R 5< are independently selected from carboxamido, sulfonyl, sulfonamido, sulfamido, (C 1 -C 4 ) alkylsulfonyl, (C 1 -C 4 ) alkylsulfonamido, (C 1 -C 4 ) alkylsulfamido, (C 6 -C 10 ) arylsulfonyl, (C 6 -C 10 ) aryloxy, (C 3 -C 6 ) 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< .

[0182] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein two of the optional substituents on R 5< are taken together with the carbon or nitrogen atoms to which they are attached to form an optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl group.

[0183] In another embodiment, two of the optional substituents on R 5< are taken together with the carbon atoms to which they are attached to form an optionally substituted (C 3 -C 8 ) cycloalkyl, optionally substituted (C 3 -C 8 ) heterocyclo, optionally substituted (C 6 -C 10 ) aryl, or optionally substituted (C 3 -C 6 ) heteroaryl group.

[0184] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 5< is selected from 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, and (C 1 -C 6 ) hydroxyalkyl.

[0185] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 5< is selected from 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< , and -NR 31a< SO 2 R 27< .

[0186] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 5< is selected from optionally substituted -O-(C 6 -C 14 ) aryl, optionally substituted -O-(C 6 -C 14 ) ar-(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. In another embodiment, R 5< is selected from optionally substituted -O-(C 6 -C 10 ) aryl, optionally substituted -O-(C 6 -C 10 ) ar-(C 1 -C 2 ) alkyl, optionally substituted - O-(C 3 -C 6 ) heteroaryl, optionally substituted -O-(C 3 -C 6 ) 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-(C 3 -C 8 ) heterocyclo, optionally substituted -O-(C 3 -C 8 ) heterocyclo-(C 1 -C 2 ) alkyl.

[0187] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 5< is selected from optionally substituted (C 6 -C 14 ) aryl, optionally substituted (C 6 -C 14 ) ar-(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. In another embodiment, R 5< is selected from optionally substituted (C 6 -C 10 ) aryl, optionally substituted (C 6 -C 10 ) ar-(C 1 -C 2 ) alkyl, optionally substituted (C 3 -C 6 ) heteroaryl, optionally substituted (C 3 -C 6 ) 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 (C 3 -C 8 ) heterocyclo, optionally substituted (C 3 -C 8 ) heterocyclo-(C 1 -C 2 ) alkyl.

[0188] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 5< is an optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazolyl, or optionally substituted tetrazolyl. In another embodiment, R 5< is an optionally substituted pyrrolyl. In another embodiment, R 5< is an optionally substituted imidazolyl. In another embodiment, R 5< is an optionally substituted pyrazolyl. In another embodiment, R 5< is an optionally substituted triazolyl. In another embodiment, R 5< is an optionally substituted tetrazolyl.

[0189] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 5< is substituted and 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.

[0190] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 5< is selected from the group consisting of:

[0191] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein each of R 6< and R 7< is independently selected from hydrogen, halo, and cyano.

[0192] In another embodiment, a Compound of the Disclosure is a compound having Formula I, wherein each of R 6< and R 7< is independently selected from optionally substituted (C 1 -C 4 ) alkyl, optionally substituted (C 2 -C 4 ) alkenyl, and optionally substituted (C 2 -C 4 ) alkynyl.

[0193] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein R 23< is selected from the group consisting of hydrogen, optionally substituted (C 1 -C 4 ) alkyl, optionally substituted (C 2 -C 4 ) alkenyl, optionally substituted (C 2 -C 4 ) alkynyl, amino, (C 1 -C 4 ) alkylamino, di-(C 1 -C 4 ) alkylamino, cyclo-(C 1 -C 4 ) alkylamino, hydroxy-(C 1 -C 4 ) alkyl, (amino)-(C 1 -C 4 ) alkyl, (alkylamino)-(C 1 -C 4 ) alkyl, (dialkylamino)-(C 1 -C 4 ) alkyl, (cycloalkylamino)-(C 1 -C 4 ) alkyl, (cycloalkyl)-(C 1 -C 4 ) alkyl, ar-(C 6 -C 10 ) alkyl, (heterocyclo)-(C 1 -C 4 ) alkyl, (heteroaryl)-(C 1 -C 4 ) alkyl, (amino)(hydroxy)-(C 1 -C 4 ) alkyl, (aralkylamino)-(C 1 -C 4 ) alkyl, optionally substituted (C 3 -C 8 ) heterocyclo, optionally substituted (C 3 -C 6 ) heteroaryl, optionally substituted (C 6 -C 10 ) aryl, and optionally substituted (C 3 -C 8 ) cycloalkyl.

[0194] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein each of R 31a< and R 31b< is independently selected from the group consisting of hydrogen, optionally substituted (C 1 -C 4 ) alkyl, optionally substituted (C 2 -C 4 ) alkenyl, optionally substituted (C 2 -C 4 ) alkynyl, hydroxy-(C 1 -C 4 ) alkyl, (amino)-(C 1 -C 4 ) alkyl, (alkylamino)-(C 1 -C 4 ) alkyl, (dialkylamino)-(C 1 -C 4 ) alkyl, alkoxy-(C 1 -C 4 ) alkyl, (C 3 -C 8 ) cycloalkyl, (cycloalkyl)-(C 1 -C 4 ) alkyl, (heterocyclo)-(C 1 -C 4 ) alkyl, ar-(C 1 -C 4 ) alkyl, and (heteroaryl)-(C 1 -C 4 ) alkyl.

[0195] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein each of R 24< , R 25< , R 27< , R 32a< , and R 32b< is independently selected from the group consisting of hydrogen, optionally substituted (C 1 -C 4 ) alkyl, optionally substituted (C 2 -C 4 ) alkenyl, optionally substituted (C 2 -C 4 ) alkynyl, amino, (C 1 -C 4 ) alkylamino, di-(C 1 -C 4 ) alkylamino, (C 3 -C 8 ) cycloalkylamino, hydroxy-(C 1 -C 4 )alkyl, (amino)-(C 1 -C 4 ) alkyl, (alkylamino)-(C 1 -C 4 )alkyl, (dialkylamino)-(C 1 -C 4 ) alkyl, (cycloalkylamino)-(C 1 -C 4 ) alkyl, (cycloalkyl)-(C 1 -C 4 ) alkyl, ar-(C 1 -C 4 ) alkyl, (heterocyclo)-(C 1 -C 4 ) alkyl, (heteroaryl)-(C 1 -C 4 ) alkyl, (amino)(hydroxy)-(C 1 -C 4 ) alkyl, (aralkylamino)-(C 1 -C 4 ) alkyl, alkoxy-(C 1 -C 4 ) alkyl, optionally substituted (C 3 -C 8 ) heterocyclo, optionally substituted (C 3 -C 6 ) heteroaryl, optionally substituted (C 6 -C 10 ) aryl, and optionally substituted (C 3 -C 8 ) cycloalkyl.

[0196] In one embodiment, a Compound of the Disclosure is a compound having Formula I, wherein each of R 24< , R 25< , R 26< , R 27< , R 28< , R 29< , R 30< , R 32a< , and R 32b< 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.

[0197] In another embodiment, each of R 24< , R 25< , R 26< , R 27< , R 28< , R 29< , R 30< , R 32a< , and R 32b< is selected from the group consisting of hydrogen, optionally substituted (C 1 -C 4 ) alkyl, optionally substituted (C 2 -C 4 ) alkenyl, optionally substituted (C 2 -C 4 ) alkynyl, amino, (C 1 -C 4 ) alkylamino, di-(C 1 -C 4 ) alkylamino, (C 3 -C 8 ) cycloalkylamino, hydroxy-(C 1 -C 4 ) alkyl, (amino)-(C 1 -C 4 ) alkyl, (alkylamino)-(C 1 -C 4 ) alkyl, (dialkylamino)-(C 1 -C 4 ) alkyl, (cycloalkylamino)-(C 1 -C 4 ) alkyl, (cycloalkyl)-(C 1 -C 4 ) alkyl, ar-(C 1 -C 4 ) alkyl, (heterocyclo)-(C 1 -C 4 ) alkyl, (heteroaryl)-(C 1 -C 4 ) alkyl, (amino)(hydroxy)-(C 1 -C 4 ) alkyl, (aralkylamino)-(C 1 -C 4 ) alkyl, alkoxy-(C 1 -C 4 ) alkyl, optionally substituted (C 3 -C 8 ) heterocyclo, optionally substituted (C 3 -C 6 ) heteroaryl, optionally substituted (C 6 -C 10 ) aryl, and optionally substituted (C 3 -C 8 ) cycloalkyl.

[0198] In another embodiment, Compounds of the Disclosure are compounds having Formula II: and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein: each of X 1< , X 2< , R 1< , R 5< , R 6< , and R 7< are as defined above for Formula I; X 3< is selected from N and CR 10< ; X 4< is selected from N and CR 11< ; and X 5< is selected from N and CR 12< ; and each of R 8< , R 9< , R 10< , R 11< , and R 12< is independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, 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, (cycloalkylamino)alkyl, (C 1-4 haloalkoxy)alkyl, or (heteroaryl)alkyl.

[0199] In another embodiment, each of R 8< , R 9< , R 10< , R 11< , and R 12< is independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, (C 1 -C 4 ) alkylamino, di-(C 1 -C 4 ) alkylamino, halo-(C 1 -C 4 ) alkyl, hydroxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halo-(C 1 -C 4 ) alkoxy, (C 6 -C 10 ) aryloxy, (C 3 -C 6 ) heteroaryloxy, ar-(C 1 -C 4 ) alkyl ar-(C 1 -C 4 ) alkyloxy, (C 1 -C 4 ) alkylthio, carboxamido, sulfonamido, (C 1 -C 4 ) alkylcarbonyl, (C 6 -C 10 ) arylcarbonyl, (C 1 -C 4 ) alkylsulfonyl, (C 6 -C 10 ) arylsulfonyl, carboxy, carboxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, alkoxy-(C 1 -C 4 ) alkyl, (amino)-(C 1 -C 4 ) alkyl, hydroxy-(C 1 -C 4 ) alkylamino, (alkylamino)-(C 1 -C 4 ) alkyl, (dialkylamino)-(C 1 -C 4 ) alkyl, (cyano)-(C 1 -C 4 ) alkyl, (carboxamido)-(C 1 -C 4 ) alkyl, mercapto-(C 1 -C 4 ) alkyl, (heterocyclo)-(C 1 -C 4 ) alkyl, (cycloalkylamino)-(C 1 -C 4 ) alkyl, (C 1-4 haloalkoxy)-(C 1 -C 4 ) alkyl, or (heteroaryl)-(C 1 -C 4 ) alkyl.

[0200] In another embodiment, each of R 8< , R 9< , R 10< , R 11< , and R 12< is independently selected from optionally substituted (C 3 -C 8 ) cycloalkyl, optionally substituted (C 6 -C 10 ) aryl, optionally substituted (C 3 -C 6 ) heteroaryl, and optionally substituted (C 3 -C 8 ) heterocyclo.

[0201] In one embodiment, Compounds of the Disclosure are compounds having Formula III, Formula IV, Formula V, Formula VI, or Formula VIa: wherein each of X 1< , X 2< , R 1< , R 5< , R 6< , R 7< , R 8< , R 9< , and R 11< are as defined above for Formula II.

[0202] In another embodiment, R 5< is: wherein: X 6< is selected from NR 13< and CR 18< ; X 7< is selected from NR 14< and CR 19< ; X 8< is selected from NR 15< and CR 20< ; X 9< is selected from NR 16< and CR 21< ; X 10< is selected from NR 17< and CR 22< ; and each of R 13< , R 14< , R 15< , R 16< , and R 17< 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. each of R 18< , R 19< , R 20< , R 21< , and R 22< is independently selected from hydrogen, halo, methyl, ethyl, isopropyl, cyclopropyl, methoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, and methylazetidinyl.

[0203] In one embodiment, Compounds of the Disclosure are compounds having Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, or Formula XII: wherein each of 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< are as defined above for Formula II.

[0204] In one embodiment, Compounds of the Disclosure are compounds selected from the group consisting of: 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, e.g., hydrate, of any of the above.

[0205] In another embodiment, Compounds of the Disclosure are compounds selected from the group consisting of: 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 pharmaceutically acceptable salt or solvate, e.g., hydrate, of any of the above.

[0206] In another embodiment, Compounds of the Disclosure are compounds selected from the group consisting of: 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. Definitions

[0207] For the purpose of the present disclosure, the term "alkyl" as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms (i.e., C 1-12 alkyl) or the number of carbon atoms designated (i.e., a C 1 alkyl such as methyl, a C 2 alkyl such as ethyl, a C 3 alkyl such as propyl or isopropyl, etc.). The alkyl group can be suitably chosen from a straight chain C 1-10 alkyl group, a branched chain C 3-10 alkyl group, a straight chain C 1-6 alkyl group, a branched chain C 3-6 alkyl group, a straight chain C 1-4 alkyl group, a branched chain C 3-4 alkyl group, a straight or branched chain C 3-4 alkyl group. The alkyl group can be partially or completely 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 -CD 3 ), ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Non-limiting exemplary C 1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.

[0208] For the purpose of the present disclosure, the term "optionally substituted alkyl" as used by itself or as part of another group means that the alkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen 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. The alkyl can be an optionally substituted C 1-4 alkyl. The optionally substituted alkyl can be substituted with two substituents, or one substituent. Non-limiting exemplary optionally substituted alkyl groups include - CH 2 CH 2 NO 2 , -CH 2 CH 2 CO 2 H, -CH 2 CH 2 SO 2 CH 3 , -CH 2 CH 2 COPh, and -CH 2 C 6 H 11 .

[0209] For the purpose of the present disclosure, the term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. The alkylene group may also be a C 1 -C 6 alkylene or a C 1 -C 4 alkylene. Non-limiting exemplary alkylene groups include, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 -.

[0210] For the purpose of the present disclosure, the term "cycloalkyl" as used by itself or as part of another group refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms (i.e., C 3-12 cycloalkyl) or the number of carbons designated. The cycloalkyl group can have two rings, or one ring. The cycloalkyl group can be chosen from a C 3-8 cycloalkyl group and a C 3-6 cycloalkyl group. The cycloalkyl group can 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.

[0211] For the purpose of the present disclosure, the term "optionally substituted cycloalkyl" as used by itself or as part of another group means that the cycloalkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen 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. The optionally substituted cycloalkyl can be substituted with two substituents or one substituent.

[0212] For the purpose of the present disclosure, the term "alkenyl" as 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. The alkenyl group can be chosen from a C 2-6 alkenyl group and a C 2-4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0213] For the purpose of the present disclosure, the term "optionally substituted alkenyl" as used herein by itself or as part of another group means the alkenyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen 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.

[0214] For the purpose of the present disclosure, the term "alkynyl" as 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. The alkynyl can have one carbon-to-carbon triple bond. The alkynyl group can be chosen from a C 2-6 alkynyl group and a C 2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0215] For the purpose of the present disclosure, the term "optionally substituted alkynyl" as used herein by itself or as part of another group means the alkynyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen 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.

[0216] For the purpose of the present disclosure, the term "haloalkyl" as used by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine and / or iodine atoms. The alkyl group can be substituted by one, two, or three fluorine and / or chlorine atoms. The haloalkyl group can be chosen from a C 1-4 haloalkyl group. 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.

[0217] For the purpose of the present disclosure, the term "hydroxyalkyl" as 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. The hydroxyalkyl group can be chosen from a monohydroxyalkyl group, i.e., substituted with one hydroxy group, a dihydroxyalkyl group, i.e., substituted with two hydroxy groups, and a C 1-4 hydroxyalkyl group. Non-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.

[0218] For the purpose of the present disclosure, the term "alkoxy" as 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. The alkoxy group can be chosen from a C 1-4 alkoxy group and a C 1-4 alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, and tert-butoxy.

[0219] For the purpose of the present disclosure, the term "alkylthio" as used by itself or as part of another group refers to a sulfur atom substituted by an optionally substituted alkyl group. The alkylthio group can be chosen from a C 1-4 alkylthio group. Non-limiting exemplary alkylthio groups include -SCH 3 (i.e., methylthio), and -SCH 2 CH 3 .

[0220] For the purpose of the present disclosure, the term "alkoxyalkyl" as 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.

[0221] For the purpose of the present disclosure, the term "halo" as 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.

[0222] For the purpose of the present disclosure, the term "haloalkoxy" as 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.

[0223] For the purpose of the present disclosure, the term "heteroalkyl" as used by itself or 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, which can be the same or different, selected from O, N, or S, wherein: 1) the nitrogen atom(s) and sulfur atom(s) can optionally be oxidized; and / or 2) the nitrogen atom(s) can optionally be quaternized. The heteroatoms can be placed at any interior position of the heteroalkyl group or at a position at which the heteroalkyl group is attached to the remainder of the molecule. The heteroalkyl group can contain two oxygen atoms, one oxygen and one nitrogen atom, or two nitrogen atoms. Non-limiting exemplary heteroalkyl groups include -CH 2 OCH- 2 CH 2 OCH 3 , -OCH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH 2 NHCH 2 CH 2 OCH 2 , -OCH 2 CH 2 NH 2 , -NHCH 2 CH 2 N(H)CH 3 , -NHCH 2 CH 2 OCH 3 and -OCH 2 CH 2 OCH 3 .

[0224] For the purpose of the present disclosure, the term "aryl" as used by itself or as part of another group refers to a monocyclic or bicyclic aromatic ring system having from six to fourteen carbon atoms (i.e., C 6-14 aryl). The aryl group can be chosen from a C 6-14 aryl group and a C 6-10 aryl group. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. The aryl group can be chosen from phenyl or naphthyl. The aryl group can be phenyl.

[0225] For the purpose of the present disclosure, the term "optionally substituted aryl" as used herein by itself or as part of another group means that the aryl as defined above is either unsubstituted or substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, 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, (cycloalkylamino)alkyl, (C 1-4 haloalkoxy)alkyl, (heteroaryl)alkyl. The optionally substituted aryl can be an optionally substituted phenyl. The optionally substituted phenyl can have four substituents, three substituents, two substituents, or one substituent. The optionally substituted phenyl can 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-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylpropan-2-amine. The term optionally substituted aryl is meant to include groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include:

[0226] For the purpose of the present disclosure, the term "aryloxy" as 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-.

[0227] For the purpose of the present disclosure, the term "heteroaryloxy" as used by itself or as part of another group refers to an optionally substituted heteroaryl attached to a terminal oxygen atom.

[0228] For the purpose of the present disclosure, the term "aralkyloxy" or "arylalkyloxy" as used by itself or as part of another group refers to an aralkyl group attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCH 2 O-.

[0229] For the purpose of the present disclosure, the term "heteroaryl" or "heteroaromatic" refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring atoms (i.e., C 5-14 heteroaryl) and 1, 2, 3, or 4 heteroatoms independently chosen from oxygen, nitrogen or sulfur. The heteroaryl group can be chosen from a C 5-14 heteroaryl group and a C 3-6 heteroaryl group. The heteroaryl can have three heteroatoms, two heteroatoms, or one heteroatom. The heteroaryl can be a C 5 heteroaryl, or a C 6 heteroaryl. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, 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, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, triazolyl, tetrazolyl, and phenoxazinyl. The heteroaryl can be chosen from 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, pyrimidin-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-oxide.

[0230] For the purpose of the present disclosure, the term "optionally substituted heteroaryl" as used by itself or as part of another group means that the heteroaryl as defined above is either unsubstituted or substituted with one to four substituents, e.g., one or two substituents, independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkyl aryloxy, 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, (heteroaryl)alkyl, -N(R 33< )(R 34< ), or -N(H)C(=O)-R 35< , wherein R 33< is hydrogen or C 1-4 alkyl; R 34< is alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl; and R 35< is alkyl, optionally substituted aryl, or optionally substituted heteroaryl. The optionally substituted heteroaryl can have one substituent. The substituent can be 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 can be an optionally substituted pyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogen atom can be substituted.

[0231] For the purpose of the present disclosure, the term "heterocycle" or "heterocyclo" as used by itself or as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups containing one, two, or three rings having from three to fourteen ring members (i.e., a 3- to 14-membered heterocyclo) and at least one heteroatom. The heterocyclo group can be chosen from a C 3-14 heterocyclo group and a C 3-8 heterocyclo group. Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and / or nitrogen atoms, which can be quaternized. The term "heterocyclo" is meant 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 meant to include groups having fused optionally substituted aryl groups, e.g., indolinyl, indolinyl-2-one, benzo[d]oxazolyl-2(3H)-one. The term "heterocyclo" is also meant to include groups having fused optionally substituted heteroaryl groups, e.g., 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine. The heterocyclo group can be chosen from a 4-, 5-, 6-, 7- or 8-membered cyclic group containing one ring and one or two oxygen and / or nitrogen atoms, a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms, an 8-, 9-, 10-, 11-, or 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be optionally linked to the rest 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.

[0232] For the purpose of the present disclosure, the term "optionally substituted heterocyclo" as used herein by itself or part of another group means the heterocyclo as 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, aralkyl, aralkyloxy, 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. Substitution may occur on any available carbon or nitrogen atom, and may form a spirocycle.

[0233] For the purpose of the present disclosure, the term "amino" as used by itself or as part of another group refers to -NH 2 .

[0234] For the purpose of the present disclosure, the term "alkylamino" as used by itself or as part of another group refers to -NHR 36< , wherein R 36< is C 1-6 alkyl. R 36< can be C 1-4 alkyl. Non-limiting exemplary alkylamino groups include -N(H)CH 3 and -N(H)CH 2 CH 3 .

[0235] For the purpose of the present disclosure, the term "dialkylamino" as used by itself or as part of another group refers to -NR 37a< R 37b< , wherein R 37a< and R 37b< are each independently C 1-6 alkyl. R 37a< and R 37b< can each independently be C 1-4 alkyl. Non-limiting exemplary dialkylamino groups include -N(CH 3 ) 2 and -N(CH 3 )CH 2 CH(CH 3 ) 2 .

[0236] For the purpose of the present disclosure, the term "hydroxyalkylamino" as used by itself or as part of another group refers to -NHR 38< , wherein R 38< is hydroxyalkyl.

[0237] For the purpose of the present disclosure, the term "cycloalkylamino" as used by itself or as part of another group refers to -NR 39a< R 39b< , wherein R 39a< is optionally substituted cycloalkyl and R 39b< is hydrogen or C 1-4 alkyl.

[0238] For the purpose of the present disclosure, the term "aralkylamino" as used by itself or as part of another group refers to -NR 40a< R 40b< , wherein R 40a< is aralkyl and R 40b< is hydrogen or C 1-4 alkyl. Non-limiting exemplary aralkylamino groups include -N(H)CH 2 Ph and -N(CH 3 )CH 2 Ph.

[0239] For the purpose of the present disclosure, the term "(amino)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with an amino group. The alkyl can be a C 1-4 alkyl. Non-limiting exemplary (amino)alkyl groups include -CH 2 NH 2 , -C(NH 2 )(H)CH 3 , -CH 2 CH 2 NH 2 , -CH 2 C(NH 2 )(H)CH 3 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , and -CH 2 C(CH 3 ) 2 CH 2 NH 2

[0240] For the purpose of the present disclosure, the term "(alkylamino)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with an alkylamino group. The alkyl can be a C 1-4 alkyl. A non-limiting exemplary (alkylamino)alkyl group is -CH 2 CH 2 N(H)CH 3 .

[0241] For the purpose of the present disclosure, the term "(dialkylamino)alkyl" as used by itself or as part of another group refers to an alkyl group substituted by a dialkylamino group. The alkyl can be a C 1-4 alkyl. Non-limiting exemplary (dialkylamino)alkyl groups are -CH 2 CH 2 N(CH 3 ) 2 .

[0242] For the purpose of the present disclosure, the term "(cycloalkylamino)alkyl" as used by itself or as part of another group refers to an alkyl group substituted by a cycloalkylamino group. The alkyl can be a C 1-4 alkyl. Non-limiting exemplary (cycloalkylamino)alkyl groups include -CH 2 N(H)cyclopropyl, -CH 2 N(H)cyclobutyl, and -CH 2 N(H)cyclohexyl.

[0243] For the purpose of the present disclosure, the term "(aralkylamino)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with an aralkylamino group. The alkyl can be a C 1-4 alkyl. A non-limiting exemplary (aralkylamino)alkyl group is -CH 2 CH 2 CH 2 N(H)CH 2 Ph.

[0244] For the purpose of the present disclosure, the term "(cyano)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one or more cyano, e.g., -CN, groups. The alkyl can be a C 1-4 alkyl. Non-limiting exemplary (cyano)alkyl groups include -CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CN, and -CH 2 CH 2 CH 2 CH 2 CN.

[0245] For the purpose of the present disclosure, the term "(amino)(hydroxy)alkyl" as 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. The alkyl is a C 1-6 alkyl or a C 1-4 alkyl.

[0246] For the purpose of the present disclosure, the term "(amino)(aryl)alkyl" as 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. The alkyl can be a C 1-6 alkyl. The optionally substituted aryl group can be an optionally substituted phenyl.

[0247] For the purpose of the present disclosure, the term "(cycloalkyl)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one optionally substituted cycloalkyl group. The alkyl can be a C 1-4 alkyl or a C 3-6 cycloalkyl. The optionally substituted cycloalkyl group can be substituted with an amino or (amino)alkyl group.

[0248] For the purpose of the present disclosure, the term "(hydroxy)(aryl)alkyl" as 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. The alkyl can be a C 1-6 alkyl. The optionally substituted aryl group can be an optionally substituted phenyl. Non-limiting exemplary (hydroxy)(aryl)alkyl groups include:

[0249] For the purpose of the present disclosure, the term "carboxamido" as used by itself or as part of another group refers to a radical of formula -C(=O)NR 41a< R 41b< , wherein 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< taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group. R 41a< and R 41b< can each independently be hydrogen or optionally substituted alkyl. Non-limiting exemplary carboxamido groups include -CONH 2 , -CON(H)CH 3 , -CON(CH 3 ) 2 , and -CON(H)Ph.

[0250] For the purpose of the present disclosure, the term "(carboxamido)alkyl" as 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 -CH 2 CONH 2 , -C(H)CH 3 -CONH 2 , and -CH 2 CON(H)CH 3 .

[0251] For the purpose of the present disclosure, the term "sulfonamido" as used by itself or as part of another group refers to a radical of the formula -SO 2 NR 42a< R 42b< , wherein 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 sulfonamido groups include -SO 2 NH 2 , -SO 2 N(H)CH 3 , and -SO 2 N(H)Ph.

[0252] For the purpose of the present disclosure, the term "alkylcarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C(=O)-, substituted by an alkyl group. A non-limiting exemplary alkylcarbonyl group is -COCH 3 .

[0253] For the purpose of the present disclosure, the term "arylcarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C(=O)-, substituted by an optionally substituted aryl group. A non-limiting exemplary arylcarbonyl group is -COPh.

[0254] For the purpose of the present disclosure, the term "alkylsulfonyl" as used by itself or as part of another group refers to a sulfonyl group, i.e., -SO 2 -, substituted by any of the above-mentioned optionally substituted alkyl groups. Non-limiting exemplary alkylsulfonyl groups are -SO 2 CH 3 (i.e., methylsulfonyl) and -SO 2 CH 2 CH 3 (i.e., ethylsulfonyl).

[0255] For the purpose of the present disclosure, the term "arylsulfonyl" as used by itself or as part of another group refers to a sulfonyl group, i.e., -SO 2 -, substituted by any of the above-mentioned optionally substituted aryl groups. A non-limiting exemplary arylsulfonyl group is -SO 2 Ph.

[0256] For the purpose of the present disclosure, the term "mercaptoalkyl" as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted by a -SH group.

[0257] For the purpose of the present disclosure, the term "carboxy" as used by itself or as part of another group refers to a radical of the formula -COOH.

[0258] For the purpose of the present disclosure, the term "carboxyalkyl" as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted with a -COOH. A non-limiting exemplary carboxyalkyl group is -CH 2 CO 2 H.

[0259] For the purpose of the present disclosure, the term "alkoxycarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C(=O)-, substituted by an alkoxy group. Non-limiting exemplary alkoxycarbonyl groups are -CO 2 Me and -CO 2 Et.

[0260] For the purpose of the present disclosure, the term "aralkyl" or "arylalkyl" as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups. The aralkyl group can be a C 1-4 alkyl substituted with one optionally substituted aryl group. Non-limiting exemplary aralkyl groups include benzyl, phenethyl, -CHPh 2 , -CH 2 (4-OH-Ph), and -CH(4-F-Ph) 2 .

[0261] For the purpose of the present disclosure, the term "(heterocyclo)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heterocyclo groups. The (heterocyclo)alkyl can be a C 1-4 alkyl substituted with one optionally substituted heterocyclo group. The heterocyclo can be linked to the alkyl group through a carbon or nitrogen atom. Non-limiting exemplary (heterocyclo)alkyl groups include:

[0262] For the purpose of the present disclosure, the term "heteroaralkyl" or "(heteroaryl)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heteroaryl groups. The (heteroaryl)alkyl group can be a C 1-4 alkyl substituted with one optionally substituted heteroaryl group. Non-limiting exemplary (heteroaryl)alkyl groups include:

[0263] For the purpose of the present disclosure, the term "alkylcarbonylamino" as 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 -NHCOCH 3 .

[0264] The present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (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 include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 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 36< Cl, respectively, e.g., 3< H, 11< C, and 14< C. The present disclosure also provides a composition wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number. The present disclosure also provides a composition wherein a portion of the atoms at a position within the Compound of the disclosure are replaced, i.e., the Compound of the Disclosure is enriched at a position with an atom having a different atomic mass or mass number. In one embodiment, the present disclosure provides a composition wherein a Compound of the Disclosure has from 1 to 8 hydrogens replaced with deuterium. Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art.

[0265] Compounds of the Disclosure may contain one or more asymmetric centers and may thus 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. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present disclosure as well.

[0266] As used herein, the term "stereoisomers" 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 more than one chiral center that are not mirror images of one another (diastereomers).

[0267] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

[0268] The terms "enantiomer" and "enantiomeric" refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.

[0269] The term "racemic" refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.

[0270] The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

[0271] The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated.

[0272] The term "enantiomeric excess" or "ee" refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as |R - S|*100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R + S = 1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined 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.

[0273] The terms "enantiomerically pure" or "enantiopure" refer to a sample of a chiral substance all of whose molecules (within the limits of detection) have the same chirality sense.

[0274] The terms "enantiomerically enriched" or "enantioenriched" refer to a sample of a chiral substance whose enantiomeric ratio is greater than 50:50. Enantiomerically enriched compounds may be enantiomerically pure.

[0275] It is understood that embodiments of the invention described herein include "consisting" and / or "consisting essentially of" embodiments. As used herein, the singular form "a," "an," and "the" includes plural references unless indicated otherwise. Use of the term "or" herein is not meant to imply that alternatives are mutually exclusive.

[0276] In this application, the use of "or" means "and / or" unless expressly stated or understood by one skilled in the art. In the context of a multiple dependent claim, the use of "or" refers back to more than one preceding independent or dependent claim.

[0277] The term "about," as used herein, includes the recited number ± 10%. Thus, "about 10" means 9 to 11. As is understood by one skilled in the art, reference to "about" a value or parameter herein includes (and describes) instances that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X."

[0278] The present disclosure encompasses the preparation and use of salts of the Compounds of the Disclosure, including non-toxic pharmaceutically acceptable salts. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts. The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; and amino acid salts such as arginate, asparginate, glutamate and the like. The term "pharmaceutically acceptable salt" as used herein, refers to any salt, e.g., obtained by reaction with an acid or a base, of a Compound of the Disclosure that is physiologically tolerated in the target patient (e.g., a mammal, e.g., a human).

[0279] Acid addition salts can be formed by mixing a solution of the particular Compound of the Disclosure 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, or the like. Basic salts can be formed by mixing a solution of the compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.

[0280] The present disclosure encompasses the preparation and use of solvates of Compounds of the Disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term "solvate" as used herein is a combination, physical association and / or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to 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, the solvate can 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. Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure. One type of solvate is a hydrate. A "hydrate" relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. 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 solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E.C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004), and A.L. Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures 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, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.

[0281] Since Compounds of the Disclosure are inhibitors of USP1 proteins, the present disclosure provides an in vitro method for inhibiting a USP1 protein comprising contacting a USP1 protein or a composition comprising a USP1 protein with one or more Compounds of the Disclosure.

[0282] Since Compounds of the Disclosure are inhibitors of USP1 proteins, a number of diseases, conditions, or disorders mediated by USP1 proteins can be treated by employing these compounds. The present disclosure is thus directed generally to a Compound of the Disclosure for use in treating a disease, condition, or disorder responsive to the inhibition of USP1 proteins in an animal suffering from, or at risk of suffering from, the disorder.

[0283] As used herein, "treatment" is an approach for obtaining beneficial or desired clinical results. "Treatment" as used herein, covers any administration or application of a therapeutic for 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: alleviation of one or more symptoms, diminishment of extent of disease, preventing or delaying spread (for example, metastasis) of disease, preventing or delaying recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, inhibiting the disease or progression of the disease, inhibiting or slowing the disease or its progression, arresting its development, and remission (whether partial or total). Also encompassed by "treatment" is a reduction of pathological consequence of a proliferative disease. The uses provided herein contemplate any one or more of these aspects of treatment. In-line with the above, the term treatment does not require one-hundred percent removal of all aspects of the disorder.

[0284] In the context of cancer, the term "treating" includes, but is not limited to, inhibiting growth of cancer cells, inhibiting replication of cancer cells, lessening of overall tumor burden, and delaying, halting, or slowing tumor growth, progression, or metastasis.

[0285] As used herein, "delaying" means to defer, hinder, slow, retard, stabilize, suppress and / or postpone development or progression of the 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.

[0286] A "therapeutically effective amount" of a substance can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the substance are outweighed by the therapeutically beneficial effects. 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.

[0287] The terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of the therapeutic agent to the desired site of biological action. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0288] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a preparation which is in such form as to permit the biological activity of the active ingredient(s) to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations may be sterile.

[0289] A "pharmaceutically acceptable carrier" refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with a therapeutic agent that together comprise a "pharmaceutical composition" for administration to a subject. A pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. The pharmaceutically acceptable carrier is appropriate for the formulation employed.

[0290] A "sterile" formulation is aseptic or essentially free from living microorganisms and their spores.

[0291] The term "container" means any receptacle and closure therefore suitable for storing, shipping, dispensing, and / or handling a pharmaceutical product.

[0292] The term "insert" or "package insert" means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product. The package insert generally is regarded as the "label" for a pharmaceutical product.

[0293] The term "disease" or "condition" or "disorder" as used herein refers to a condition where treatment is needed and / or desired and denotes disturbances and / or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and / or malfunctions. As demonstrated below, Compounds of the Disclosure inhibit USP1 proteins and can be used in treating diseases and conditions such as proliferative diseases, wherein inhibition of USP1 proteins provides a benefit.

[0294] The terms "polypeptide" and "protein" are used interchangeably to refer to a polymer of amino acid residues and are not limited to a minimum length. Such polymers of amino acid residues may contain natural or non-natural 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 terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of the present disclosure, a "polypeptide" refers to a protein which includes modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, as 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 mutations of hosts which produce the proteins or errors due to PCR amplification.

[0295] "USP1" and "ubiquitin-specific-processing protease 1" as used herein refer to any native polypeptide or USP1-encoding polynucleotide. The term "USP1" encompasses "full-length," unprocessed USP1 polypeptide as well as any forms of USP1 that result from processing within the cell (e.g., removal of the signal peptide). The term also encompasses naturally occurring variants of USP1, e.g., 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 sequences publicly available as UniProt No. O94782 (including isoforms). As used herein, the term "human USP1 protein" refers to USP1 protein comprising the amino acid sequence as set forth in SEQ ID NO: 1 in U.S. provisional patent application no. 62 / 857,986 filed June 6, 2019.

[0296] USP1 is a deubiquitinating enzyme that acts as part of a complex with UAF1. USP1's "deubiquitinase activity" includes its ability to deubiquitinate as part of the USP1-UAF1 complex.

[0297] The term "specifically binds" to a protein or domain of a protein is a term that is well understood in the art, and methods to determine 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 more frequently, more rapidly, with greater duration and / or with greater affinity with a particular protein or domain of a protein than it does 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. As such, "specific binding" or "preferential binding" does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means 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 a reduced affinity as compared to binding to USP1.

[0298] The terms "reduction" or "reduce" or "inhibition" or "inhibit" refer to a decrease or cessation of any phenotypic characteristic or to the decrease or cessation in the incidence, degree, or likelihood of that characteristic. To "reduce" or "inhibit" is to decrease, reduce or arrest an activity, function, and / or amount as compared to a reference. In some embodiments, by "reduce" or "inhibit" is meant the ability to cause an overall decrease of 20% or greater. In some embodiments, by "reduce" or "inhibit" is meant the ability to cause an overall decrease of 50% or greater. In some embodiments, by "reduce" or "inhibit" is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater. In some embodiments, the amount noted above is inhibited or decreased over a period of time, relative to a control over the same period of time.

[0299] In some embodiments inhibiting USP1 proteins is the inhibition of one or more activities or functions of USP1 proteins. It should be appreciated that the activity or function of the one or more USP1 proteins may be inhibited in vitro or in vivo. Non-limiting examples of activities and functions of USP1 include deubiquitinase activity, and formation of a complex with UAF1 and are described herein. Examplary levels of inhibition of the activity of one or more USP1 proteins include at least 10% inhibiton, 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.

[0300] The terms "individual" or "subject" are used interchangeably herein to refer to an animal; for example, a mammal, such as a human. In some instances, mammals, including, but not limited to, humans, rodents, simians, felines, canines, equines, bovines, porcines, ovines, caprines, mammalian laboratory animals, mammalian farm animals, mammalian sport animals, and mammalian pets, are treated. In some examples, an "individual" or "subject" refers to an individual or subject in need of treatment for a disease or disorder. In some instances, the subject to receive the treatment can be a patient, designating the fact that the subject has been identified as having a disorder of relevance to the treatment, or being at particular risk of contracting the disorder.

[0301] As used herein, the terms "cancer" and "tumor" refer to or describe the physiological condition in mammals in which a population of cells are 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 can be BRCA1 or BRCA2 wildtype. The cancer can also be BRCA1 or BRCA2 mutant. The cancer can further be a PARP inhibitor resistant or refractory cancer, or a PARP inhibitor resistant or refractory BRCA1 or BRCA2-mutant cancer.

[0302] As used herein, the term "loss of function" mutation refers to a mutation that that results in the absence of a gene, decreased expression of a gene, or the production of a gene product (e.g. protein) having decreased activity 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 a gene encoding p53 include cancer cells that contain missense mutations in a gene encoding p53 as well as cancer cells that lack a gene encoding p53.USP1 Inhibitors

[0303] In various embodiments, the Compounds of the Disclosure are USP1 inhibitors that reduce the level of USP1 protein and / or inhibit or reduce at least one biological activity of USP1 protein.

[0304] In some embodiments, the Compounds of the Disclosure specifically bind to USP1 protein. In some embodiments, the Compounds of the Disclosure specifically bind to USP1 protein in a USP1-UAF1 complex. In some embodiments, the Compounds of the Disclosure specifically bind to USP1 mRNA. In some embodiments, the Compounds of the Disclosure specifically bind to USP1 protein (alone or in a USP1-UAF1 complex) or USP1 mRNA. In some embodiments, the Compounds of the Disclosure specifically bind to UAF1 (alone or in a USP1-UAF1 complex) and inhibit or reduces formation or activity of the USP1-UAF1 complex.

[0305] In some embodiments, the Compounds of the Disclosure decrease the formation of the USP1-UAF1 complex. In some embodiments, the Compounds of the Disclosure decrease the activity of the USP1-UAF1 complex. In some embodiments, the Compounds of the Disclosure decrease the deubiquitinase activity of USP1. In some embodiments, the Compounds of the Disclosure increase mono-ubiquitinated PCNA. In some embodiments, the Compounds of the Disclosure increase mono-ubiquitinated FANCD2. In some embodiments, the Compounds of the Disclosure increase mono-ubiquitinated FANCI.

[0306] In some embodiments, the Compounds of the Disclosure do not bind to other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) or bind deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) with at least 5-fold, at least 10-fold, at least 20-fold, or at least 100-fold reduced affinity compared to the affinity for USP1 (i.e., the K D of the USP1 inhibitor for other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) is at least 5-fold, at least 10-fold, at least 20-fold, or at least 100-fold higher than the K D for USP1).

[0307] In some embodiments, the Compounds of the Disclosure inhibit USP1 deubiquitinase activity with an IC50 of less than about 50 nM, between about 50 nM and about 200 nM, between about 200 nM and about 2 pM, or greater than 2 pM, e.g., as measured using the assay disclosed in US Patent Application Publication No. 2017 / 0145012 or IC50 of 50 nM to 1000 nM, e.g., as measured using the assay disclosed in Liang et al., Nat Chem Biol 10: 289-304 (2014). In some embodiments, the Compounds of the Disclosure inhibit USP1 deubiquitinase activity with an IC50 as measured using the assay disclosed in Chen, et al., Chem Biol., 18(11):1390-1400 (2011). In some embodiments, the Compounds of the Disclosure 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 at least 5-fold, at least 10-fold, at least 20-fold, or at least 100-fold higher IC50 compared to the IC50 for inhibition of USP1 deubiquitinase activity.

[0308] In some embodiments, the Compounds of the Disclosure bind to a USP1 protein with an affinity in the range of 1 pM to 100 µM, or 1 pM to 1 µM, or 1 pM to 500 nM, or 1 pM to 100 nM. In some embodiment, the Compounds of the Disclosure bind to a 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 embodiment, the Compounds of the Disclosure bind to a USP1 protein with an affinity 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 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. In some embodiment, the Compounds of the Disclosure bind to a USP1 protein with an affinity 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, about 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. In some embodiment, the Compounds of the Disclosure bind to a 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 Compounds of the Disclosure bind to a USP1 protein with an affinity of less than 1 nM.

[0309] In some embodiments, the Compounds of the Disclosure inhibit USP1 activity with an IC 50 of 1 pM to 100 µM, or 1 pM to 1 µM, or 1 pM to 500 nM, or 1 pM to 100 nM. In some embodiments, the Compounds of the Disclosure inhibit USP1 activity with an IC 50 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 embodiment, the Compounds of the Disclosure inhibit USP1activity with an IC 50 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 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. In some embodiment, the Compounds of the Disclosure inhibit USP1 activity with an IC 50 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, about 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. In some embodiments, the Compounds of the Disclosure inhibit USP1 activity with an IC 50 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 Compounds of the Disclosure inhibit USP1 activity with an IC 50 of less than 1 nM.Exemplary Assays

[0310] Any suitable assay in the art can be used to determine an activity, detect an outcome or effect, determine efficacy, etc. Certain non-limiting exemplary assays that can be used herein are described.

[0311] In some instances, a method of determining whether a Compound of the Disclosure inhibits USP1 deubiquitinase activity measure a change in mass upon di-ubiquitin cleavage of deubiquitinase binding. For example, ubiquitin aldehyde and ubiquitin vinyl sulfone form covalent irreversible linkages to deubiquitinases that result in observable mass changes to the deubiquitinases. Similarly, cleavage of di-ubiquitins results in an observable mass change.

[0312] In some instances, a method of determining whether a Compound of the Disclosure inhibits USP1 deubiquitinase activity involves an increase in luminescence or fluorescence upon cleavage, e.g., that can be monitored on a plate reader. Such assays can use ubiquitin linked to a flurophore through a linker linkage, such as ubiquitin-7-amino-4-methylcoumarin (Ub-AMC) or ubiquitin-Rhodamine110. Such assays can also use a di-ubiquitin containing an isopeptide linkage. Exemplary di-ubiquitins can comprise a flurophore on one ubiquitin and a quencher on the other ubiquitin such that fluorescence increases with then di-ubiquitin is cleaved. Such assays can also use enzyme coupled systems wherein ubiquitin is coupled to an enzyme that is only active in producing a fluorescence enzyme product when released from the ubiquitin.

[0313] 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 yields an increase in fluorescence signal. The assay can be conducted in 20ul total volume of assay buffer (50mM Tris-HCl, pH 7.8, 0.5mM EDTA, 0.01% Bovine Serum Albumin, 1mM DTT, 0.01% Tween-20), and 0.05nM USP1 / UAF1 enzyme. Reaction can be initiated by addition of 150nM Ubiquitin-rhodamine (Boston Biochem) substrate.

[0314] Compounds of the Disclosure can be dissolved in DMSO and tested in dose response format, beginning at 10µM.

[0315] Compounds of the Disclosure can be added to enzyme / assay buffer mix and incubated 10 min. Substrate mix can be added, and reaction mix can be read in kinetic mode for 30 min at Ex480 / Em540 and IC50 response curves can be plotted. See, e.g., Chen, et al., Chem Biol., 18(11):1390-1400 (2011).Use

[0316] In some embodiments, the Compounds of the Disclosure can be used to inhibit the activity of a USP1 protein. For example, in some embodiments, an in vitro method of inhibiting a USP1 protein comprises contacting the USP1 protein with a Compound of the Disclosure. The contacting occurs in vitro.

[0317] In some embodiments, the Compounds of the Disclosure can be used to treat a "USP1 protein mediated disorder." A USP1 protein mediated disorder is any pathological condition in which a USP1 protein is known to play a role. In some embodiments, a USP1 protein mediated disorder is a proliferative disease such as cancer.

[0318] The Compounds of the Disclosure are provided herein for use in treating diseases and disorders. Exemplary diseases and disorders that may be treated with the Compounds of the Disclosure include, but are not limited to, cancer.

[0319] In some embodiments, Compounds of the Disclosure are provided for use in treating cancer. Such uses comprise administering to a subject with cancer a therapeutically effective amount of a Compound of the Disclosure.

[0320] In some embodiments, the cancer to be treated with a Compound of the Disclosure is selected from a hematological cancer, a lymphatic cancer, and a DNA damage repair pathway deficient cancer. In some embodiments, the cancer to be treated with a Compound of the Disclosure is a cancer that comprises cancer cells with a mutation in a gene encoding p53. In some embodiments, the cancer to be treated with a Compound of the Disclosure is a cancer that comprises cancer cells with a loss of function mutation in a gene encoding p53. In some embodiments, the cancer to be treated with a Compound of the Disclosure is a cancer that comprises cancer cells with a mutation in a gene encoding BRCA1. In some embodiments, the cancer to be treated with a Compound of the Disclosure is a cancer that comprises cancer cells with a mutation in a gene encoding BRCA2. In some embodiments, the cancer to be treated with a Compound of the Disclosure is a cancer that comprises cancer cells with a loss of function mutation in a gene encoding ATM.

[0321] In some embodiments, the cancer to be treated with a Compound of the Disclosure 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 a triple negative breast cancer.

[0322] In some embodiments, the cancer to be treated with a Compound of the Disclosure 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.

[0323] The Compounds of the Disclosure are provided herein for use in treating cancer. In some embodiments, a therapeutically effective amount of a Compound of the Disclosure is administered to a subject with cancer, wherein the cancer comprises cancer cells with elevated levels of RAD18. In some embodiments, the elevated levels of RAD18 are elevated RAD18 protein levels. In some embodiments, the elevated levels of RAD18 are elevated RAD18 mRNA levels. In some embodiments, elevated levels of RAD18 (e.g., RAD18 protein and / or RAD18 mRNA) have been detected (e.g., in a cancer sample obtained from the subject) prior to the administration. That is, in some embodiments, a subject's cancer has been tested for RAD18 protein or mRNA prior to beginning treatment with a USP1 inhibitor.

[0324] In some embodiments, such uses comprise (a) identifying a cancer in a subject as a USP1 inhibitor-sensitive cancer and then (b) administering a therapeutically effective amount of a Compound of the Disclosure to the subject.

[0325] In some embodiments, such uses comprise (a) detecting levels of RAD18 (e.g., RAD18 protein and / or RAD18 mRNA) in cancer cells (e.g., in a cancer sample obtained from the subject) and then (b) administering a therapeutically effective amount of a Compound of the Disclosure to a subject having a cancer comprising cells with elevated levels of RAD18.

[0326] In some embodiments, such uses comprise administering to a subject with triple negative breast cancer a therapeutically effective amount of a Compound of the Disclosure.

[0327] In some embodiments, a Compound of the Disclosure is used to treat a cancer, wherein the cancer is a homologous-recombination deficient cancer. In some embodiments, a Compound of the Disclosure is used to treat a cancer, wherein the cancer comprises cancer cells with a mutation in a gene encoding p53. In some embodiments, a Compound of the Disclosure is used to treat a cancer, wherein the cancer comprises cancer cells with a loss of function mutation in a gene encoding p53. In some embodiments, a Compound of the Disclosure is used to treat a cancer that does not have a defect in the homologous recombination pathway.

[0328] In some embodiments, a Compound of the Disclosure is used to treat a cancer, wherein the cancer is a BRCA1 mutant cancer. In some embodiments, a Compound of the Disclosure is used to treat a cancer, wherein the cancer is a BRCA2 mutant cancer. In some embodiments, a Compound of the Disclosure is used to treat a 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 mutant cancer.

[0329] In some embodiments, a Compound of the Disclosure is used to treat a cancer, wherein 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.

[0330] In some embodiments, a Compound of the Disclosure is used to treat a cancer, wherein the cancer is a PARP inhibitor resistant or refractory cancer. In some embodiments, a Compound of the Disclosure is used to treat a cancer, wherein the cancer is a PARP inhibitor resistant or refractory BRCA1-deficient cancer.

[0331] In some embodiments, the cancer is a BRCA1 and / or BRCA2 mutant cancer, wherein the cancer comprises cells with elevated levels of RAD18, e.g., wherein the elevated levels of RAD18 are at least as high as the RAD18 protein and / or mRNA levels in ES2 cells or wherein the elevated levels of RAD18 are higher than the RAD18 protein and / or mRNA levels in HEP3B217 cells. In some embodiments, a triple negative breast cancer is a BRCA1 and / or BRCA2 mutant cancer.

[0332] In some instances, the cancer is a solid cancer. In some instances, the cancer is a hematological / lymphatic cancer. In some instances, the cancer is a DNA damage repair pathway deficient cancer. In some instances, the cancer is a homolgous-recombination deficient cancer. In some instances, the cancer comprises cancer cells with a mutation in a gene encoding p53. In some instances, the cancer comprises cancer cells with a loss of function mutation in a gene encoding p53. In some instances, 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 instances, the cancer is ovarian cancer or breast cancer (including triple negative breast cancer). In some instances, the cancer is ovarian cancer. In some instances, the cancer is breast cancer (including triple negative breast cancer.)

[0333] In some embodiments, a Compound of the Disclosure is used in combination with one or more additional therapeutic agents to treat cancer. It has been reported that p53 status determines PARP inhibitor sensitization (Sa et al. Genome Biology, (2019) 20:253) and that BRCA1 / 2 status predicts the efficacy of PARP inhibitors in the clinic (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. Accordingly, in some embodiments, a Compound of the Disclosure is used in combination with a PARP inhibitor to treat cancer.

[0334] In some embodiments, provided herein are Compounds of the Disclosure for use as a medicament, e.g., for the treatment of cancer. In some embodiments, provided herein are Compounds of the Disclosure for use in the treatment of cancer.Pharmaceutical Compositions

[0335] Compounds of the Disclosure can be administered to a mammal in the form of a raw chemical without any other components present, or Compounds of the Disclosure can also be administered to a mammal 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 a carrier can be selected from pharmaceutically acceptable excipients and auxiliaries. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" encompasses any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.

[0336] A pharmaceutical composition of the present disclosure may be prepared as liquid suspensions or solutions using a liquid, such as an oil, water, an alcohol, and combinations of these.

[0337] A pharmaceutical composition of the present disclosure may be prepared as a sterile injectable, which may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art.

[0338] A pharmaceutical composition of the present disclosure may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions.

[0339] A pharmaceutical composition of the present disclosure may be administered in the form of suppositories for rectal administration.

[0340] A pharmaceutical composition of the present disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment, lotion, or cream containing the active component suspended or dissolved in one or more carriers.

[0341] A pharmaceutical composition of the present disclosure may also be administered ophthalmically and formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

[0342] A pharmaceutical composition of the present disclosure may also 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, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0343] The pharmaceutical compositions to be used for in vivo administration can be sterile. This is readily accomplished by filtration through, e.g., sterile filtration membranes.

[0344] Pharmaceutical compositions within the scope of the present disclosure include all compositions where a Compound of the Disclosure is combined with one or more pharmaceutically acceptable carriers. In one embodiment, the Compound of the Disclosure is present in the composition in an amount that is effective to achieve its intended therapeutic purpose.

[0345] A pharmaceutical composition of the present disclosure can be administered to any patient that may experience the beneficial effects of a Compound of the Disclosure. Foremost among such patients are mammals, e.g., 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, a pharmaceutical composition of the present disclosure can be administered to a patient having PARP inhibitor resistant or refractory cancer. In another embodiment, a pharmaceutical composition of the present disclosure can be administered to a patient having PARP inhibitor resistant or refractory BRCA1-deficient cancer. In another embodiment, a pharmaceutical composition of the present disclosure can be administered to a patient in combination with a PARP inhibitor.

[0346] In another embodiment, the present disclosure provides kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure. In one embodiment, the kit includes a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) 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 use of the compound or composition to practice the method of the disclosure. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit further can include a device suitable for administering the composition according to the intended route of administration. In some embodiments, the present disclosure provides a kit which comprise a Compound of the Disclosure, 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 having cancer.

[0347] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0348] 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.

[0349] 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.

[0350] 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.

[0351] 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.

[0352] 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.

[0353] 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.

[0354] 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.

[0355] 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.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure, 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.

[0362] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is for use in treating cancer.EXAMPLESGeneral Synthetic Methods

[0363] Compounds of the Disclosure are prepared using methods known to those skilled in the art in view of this disclosure, or by the illustrative methods shown in the General Schemes below. In any of the General Schemes, suitable protecting groups can be employed in the synthesis. (See, Wuts, P. G. M.; Greene, T. W., "Greene's Protective Groups in Organic Synthesis", 4th Ed., J. Wiley & Sons, NY, 2007).

[0364] Unless otherwise noted, all reagents were used without further purification. 1< H-NMR spectra were obtained in DMSO-d 6 or CD 3 OD at room temperature on a Bruker 300 MHz instrument. When more than one conformer was detected, the chemical shifts for the most abundant one is reported. Chemical shifts of 1< H NMR spectra were recorded in parts per million (ppm) on the δ scale from an internal standard of residual solvent. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. LC-MS and prep-HPLC conditions are described below: LCMS Method A LCMS Column:Agilent Zorbax XDB C18 4.6×50 mm, 3.5µmMobile phase:Solvent A: Water (with 0.1% Formic acid)Solvent B: MeOHFlow rate:1.0 mL / min,Run time:2 min gradient (20%-90% B), then 3 min @90% B,Temperature:30 °C LCMS Method B LCMS Column:X-Select CSH C18 3.0×50 mm, 2.5µmMobile phase:Solvent A: Water (with 0.05% Formic acid) / MeCN (95:5)Solvent B: 0.05% Formic acid in MeCNFlow rate:1.2 mL / min,Run time:2 min gradient (0%-98% B), hold 1 min, then 0% B up to 4 minTemperature:50 °C LCMS Method C LCMS Column:X-Select CSH C18 3.0×50 mm, 2.5µmMobile phase:Solvent A: 5 mM Ammonium BicarbonateSolvent B: MeCNFlow rate:1.2 mL / min,Run time:2 min gradient (0%-98% B), hold 1 min, then 0% B up to 4 minTemperature:50 °C HPLC Column A:Agilent SB-C18 4.6×150 mm, 3.5µmMobile phase:Solvent A: water (with 0.02% TFA)Solvent B: MeOHFlow rate:1.0 mL / min,Run time:0.5 min @10% B, 9.5 min gradient (10%-90% B), then 10 min @90% B,Temperature:30 °C Preparative Column A:Phenomenex Luna 5u 100A, 21.2×250 mm, 5µmMobile phase:Solvent A: WaterSolvent B: MeOHFlow rate:10 mL / min,Run time:1 min @20% B, 30 min gradient (20%-80% B), then 10 min @90% B,Temperature:Ambient Preparative Column B:X-Select C18, 30 x 250 mm, 5µmMobile phase:Solvent A: 10 mm Formic acid in WaterSolvent B: MeCNFlow rate:30 mL / min,Run time:50 min, isocratic 5% A:95% BTemperature:Ambient Preparative Column C :Nucleodur C18, 30 x 250 mm, 5µmMobile phase:Solvent A: 10 mM Ammonium bicarbonate in WaterSolvent B: MeCNFlow rate:30 mL / min,Run time:50 min, isocratic 5% A:95% BTemperature:Ambient Preparative Column D:X-Select C18, 30 x 250 mm, 5µmMobile phase:Solvent A: 10 mM Ammonium bicarbonate in WaterSolvent B: MeCNFlow rate:30 mL / min,Run time:50 min, isocratic 5% A:95% BTemperature:Ambient Preparative Column E:Nucleodur C18, 30 x 250 mm, 5µmMobile phase:Solvent A: 10 mM NH 3 in WaterSolvent B: MeCNFlow rate:30 mL / min,Run time:50 min, isocratic 5% A:95% BTemperature:Ambient SFC Method:Green Sep ES Diol, 250 x 4.6mm, 5 µmMobile PhaseSolvent A: CO 2 Solvent B: MeCNFlow rate:80 mL / min; Diluent: MeCNRun Time:10-20% B 3min, 20-25% B 9min, 25-30%B 3 min, 30-50%B 6 min, 50%B 50 min Chiral Method A:DIACEL CHIRAL PAK- IC (250 x 4.6mm, 5 µ); Wavelength: 260 nmMobile PhaseSolvent A: CO 2 Solvent B: MeOH + DCM (80:20)Flow rate:3 mL / min.Run Time:25-50% B in 5 min, hold 50% B 4 min, 50-25% B at 10 min, hold 25% B 2 min Chiral Method B:DIACEL CHIRAL PAK- IG (250 x 4.6mm, 5 µ); Wavelength: 280 nmMobile PhaseSolvent A: CO 2 Solvent B: MeOH + 0.1% NH 3 Flow rate:3 mL / min.Run Time:10-40% B 5.0 min, hold 40% B till 4 min, 40-10% B at 10 min, hold 10% B 2 min

[0365] 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 Tf 2 O = 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 = Diethylazodicarboxylate DIAD = Diisopropyl azodicarboxylate PS-TPP = Polystyrene supported triphenylphosphine NBS = N-Bromosuccinimide. Preparation of Common Intermediate I-1 :

[0366] Step 1: Synthesis of Methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl) benzoate:

[0367]

[0368] 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 hour, then cooled to room temperature. A solution of methyl 4-formylbenzoate (1.7 g, 10.34 mmol) in MeOH (47 ml) and NH 4 OH (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 hours. The mixture was quenched with water (50 mL), and then extracted with EA (100 mL x 2). The organic layer was dried over Na 2 SO 4 (30 g), filtered and concentrated. The concentrated residue was purified by silica gel chromatography (PE:EA = 20:1 to 5:1) to afford 1.9 g of the title compound. LC-MS (Method A) (ESI+): m / z 271 (M+H) +< ; 1< H-NMR (300 MHz, CD 3 OD) 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).Step 2: Synthesis of Methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate:

[0369]

[0370] To a solution of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (1.9 g, 7.03 mmol) in THF at 0 °C (50 ml), was added NaH (60% dispersion) (338 mg, 8.44 mmol) portion-wise over 5 min. After the mixture was stirred at 0 °C for 30 min, MeI (1.2 g, 8.44 mmol) was added to the reaction mixture dropwise over 2 min. The reaction was warmed to room temperature over 3 hours, then quenched with ice-water (30 g). The resulting solution was extracted with EA (50 mL x 3), and the combined organic layer was dried over Na 2 SO 4 (30 g), filtered and concentrated. The resulting residue was purified by silica gel chromatography (PE:EA = 20:1 to 5:1) to yield 1.4 g of the title compound. LC-MS (Method A) (ESI+): m / z 285 (M+H) +< ; 1< H-NMR (300 MHz, CD 3 OD) 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).Step 3: Synthesis of (4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol:

[0371]

[0372] 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, was DIBAL-H (24 ml, 24.6 mmol, 1 M in toluene) 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 a 1N HCl solution. The resulting mixture was extracted with EA (50 mL x 2), and the combined organic layer was washed with brine (30 mL), dried over Na 2 SO 4 (30 g), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE:EA = 20:1 to 5:1) to afford 1.2 g of the title compound. LC-MS (Method A) (ESI+): m / z 257 (M+H) +< ; 1< H-NMR (300 MHz, CD 3 OD) 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).Step 4: Synthesis of 2-(4-(Chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole:

[0373]

[0374] 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 2 (1.7 g, 14.1 mmol) in one portion. After the addition, the reaction was stirred at 50 °C for 20 min, then concentrated to dryness to afford 1.28 g of the crude title compound. LC-MS (Method A) (ESI+): m / z 275, 277 (M+H) +< ; 1< H-NMR (300 MHz, CD 3 OD) 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).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):

[0375]

[0376] To a solution of 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (1 g, 3.64 mmol) in DMF (25 ml), was added 6-chloro-1H-pyrazolo[3,4-d]pyrimidine ( 675 mg, 4.37 mmol) and K 2 CO 3 (1.26 g, 9.10 mmol). The resulting mixture was stirred at 35 °C for 20 hours, then quenched with water (50 mL) and extracted with EA (100 mL x 2). The combined organic phase was washed with water and brine, dried over Na 2 SO 4 (50 g), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE:EA = 20:1 to 10:1) to afford 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, CDCl 3 ) 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).

[0377] The following intermediates were prepared from the appropriate heterocycles and alkylating reagents according to the method of preparation for I-1. IntermediateStructureAnalyticsI-2 LC-MS (Method A) (ESI+): m / z 407, 409 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 8.16 (s, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.29 (s, 1H), 5.66 (s, 2H), 3.74 (s, 3H), 2.81 (s, 3H).I-3 LC-MS (Method B) (ESI+): m / z 421.00 (M+H) +< .I-4 LC-MS (Method A) (ESI+): m / z 407 (M+H); 1< H-NMR (300 MHz, CDCl 3 ) δ 8.95 (s, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.29 (s, 1H), 5.60 (s, 2H), 3.74 (s, 3H), 2.61 (s, 3H).I-5 LC-MS (Method A) (ESI+): m / z 407 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 9.07 (s, 1H), 8.20 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.38 (s, 1H), 5.70 (s, 2H), 4.04 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).I-6 LCMS (Method B) (ESI+): m / z 421.00 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) δ 9.32 (s, 1H), 8.53 (s, 1H), 8.13-8.21 (m, 1H), 7.54 (d, J = 7.48 Hz, 2H), 7.39 (d, J = 7.98 Hz, 2H), 5.74 (s, 2H), 4.44 (td, J = 6.48, 12.96 Hz, 1H), 1.38 (d, J = 6.48 Hz, 6H).I-7 LC-MS (Method A) (ESI+): m / z 408 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 9.07 (s, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H), 8.20 (s, 1H), 7.81 (dd, J = 8.1, 2.1 Hz, 1H), 7.34 (s, 1H), 5.68 (s, 2H), 4.63 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H). Preparation of Common Intermediate I-8:

[0378] Step 1: Synthesis of 3-Fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde:

[0379]

[0380] 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 K 3 PO 4 (3.40 g, 16.30 mmol) in dioxane (20 mL) and H 2 O (5 mL), was degassed with argon for 5 min. To the resulting reaction mixture were added Xphos-Pd-G 2 (0.42 g, 0.54 mmol) and X-Phos (1.03 g, 2.10 mmol) sequentially, and the reaction mixture was heated in a sealed tube at 100 °C for 16 h. Progress of the reaction was monitored by TLC. After 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 afford 1.40 g the title compound. LC-MS (Method B) (ESI+): m / z 272.90 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) δ 10.09 (s, 1H), 8.08 (s, 1H), 7.83-7.94 (m, 3H), 3.66 (s, 3H).Step 2: Synthesis of (3-Fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol:

[0381]

[0382] To an ice cooled 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 NaBH 4 (0.293 g 7.70 mmol), and the reaction mixture was stirred at room temperature for 2h. 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 afford 1.40 g of the title compound that was used without further purification. LC-MS (Method B) (ESI+): m / z 274.85 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) 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).Step 3: Synthesis of 2-(4-(Chloromethyl)-2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole:

[0383]

[0384] To an ice-cooled 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 2 (1.80 g, 15.0 mmol) and the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated NaHCO 3 solution and extracted with DCM. Organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1.42 g of the title compound, which was used without further purification. LC-MS (Method B) (ESI+): m / z 292.85 (M+H) +< .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):

[0385]

[0386] 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 K 2 CO 3 (1.45 g, 10.50 mmol) in DMF (12 mL), was stirred at 35 °C for 16h. Progress of the reaction 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 afford 0.70 g of the title compound. LC-MS (Method B) (ESI+): m / z 410.85 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) 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 intermediate was made from the appropriate aldehyde and alkylating reagents according to the procedure for Intermediate I-8. IntermediateStructureAnalyticsI-9 LC-MS (Method C) (ESI+): m / z 410.90 (M+H) +< .I-10 LC-MS (Method B) (ESI+): m / z 424.90 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) δ 9.33 (s, 1H), 8.54 (s, 1H), 8.10 (s, 1H), 7.51-7.57 (m, 1H), 7.31 (d, J = 10.97 Hz, 1H), 7.19 (d, J = 7.98 Hz, 1H), 5.77 (s, 2H), 3.86 (q, J = 7.15 Hz, 2H), 1.25 (t, J = 6.98 Hz, 3H).I-11 LC-MS (Method B) (ESI+): m / z 439.10 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 8.86 (s, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.44 (s, 1H), 7.19 (s, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 10.2 Hz, 1H), 6.65 (d, J = 3.6 Hz, 1H), 5.49 (s, 2H), 4.23 (m, 1H), 1.41 (d, J = 6.6 Hz, 6H).I-12 LC-MS (Method B) (ESI+): m / z 437.10 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) δ 9.32 (s, 1H), 8.53 (s, 1H), 7.98 (s, 1H), 7.29 (d, J = 7.98 Hz, 1H), 7.19 (s, 1H), 6.81 (d, J = 7.48 Hz, 1H), 5.73 (s, 2H), 3.77 (s, 3H), 3.70-3.76 (m, 2H), 1.21 (t, J = 6.98 Hz, 3H).I-13 LC-MS (Method B) (ESI+): m / z 455.09 (M+H) +< .I-14 LC-MS (Method C) (ESI+): m / z 450.85 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) δ 9.31-9.34 (m, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 7.28 (d, J = 7.48 Hz, 1H), 7.19 (s, 1H), 6.80 (d, J = 7.48 Hz, 1H), 5.73 (s, 2H), 4.10 (q, J = 4.99 Hz, 1H), 3.76 (s, 3H), 1.30 (d, J = 6.48 Hz, 6H). Preparation of Common Intermediate I-15:

[0387] Step 1: Synthesis of 1-(Methyl-d3)-4-(trifluoromethyl)-1H-imidazole:

[0388]

[0389] 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 allowed to warm 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 x 50 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered, and dried under vacuum. The crude product was purified by silica gel chromatography (50-100% EA in n-hexane) to afford 3.0 g of the title compound. LC-MS (Method B) (ESI+): m / z 154.45 (M+H) +< ; 1< H-NMR (400 MHz, CDCl 3 ) δ 7.48 (s, 1H), 7.27 (s, 1H)Step 2: Synthesis of 2-Chloro-1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazole:

[0390]

[0391] 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 2.5M solution of n-butyl lithium 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 an additional 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 x 50 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum. The crude compound was purified by silica gel chromatography (30-100% EA in n-hexane) to afford 1.30 g of the title compound. LC-MS (Method B) (ESI+): m / z 188.30 (M+H) +< .Step 3: Synthesis of 4-(1-(Methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde:

[0392]

[0393] To the 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 min, whereupon solid K 3 PO 4 (4.76 g, 22.5 mmol) and (4-formylphenyl)boronic acid (2.24 g, 14.97 mmol) were added, followed by additional purging with argon gas for another 5 min. The reaction mixture was then heated at 90 °C for 16 h. 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 x 50 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (0-30% EA in n-hexane) to afford 1.62 g of the title compound. LC-MS (Method B) (ESI+): m / z 258.00 (M+H) +< ; 1< H-NMR (400 MHz, CDCl 3 ) 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).Step 4: Synthesis of (4-(1-(Methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol:

[0394]

[0395] 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 NaBH 4 (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 x 50 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under vacuum. The crude compound was purified by silica gel chromatography (0-60% EA in n-hexane) to afford 1.30 g of the title compound. LC-MS (Method B) (ESI+): m / z 259.80 (M+H) +< ; 1< H-NMR (400 MHz, CDCl 3 ) 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).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):

[0396]

[0397] 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 with diethyl azodicarboxylate (0.434 g, 2.509 mmol) dropwise. 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 x 30 mL). The combined organic layer was washed with brine (3 x 30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum. The crude compound was purified by silica gel chromatography (0-3% methanol in DCM) to afford 0.400 g of the title compound. LC-MS (Method B) (ESI+): m / z 396.00 (M+H) +< ; 1< H-NMR (400 MHz, CDCl 3 ) 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).Preparation of Common Intermediate I-16:

[0398] Step 1: Synthesis of Methyl 4-(2-bromoacetyl)benzoate:

[0399]

[0400] To a stirred solution of methyl 4-acetylbenzoate (5.00 g, 28.0 mmol) in AcOH (40 mL), was added Br 2 (1.00 mL, 19.6 mmol) in AcOH (10 mL) dropwise, and the reaction mixture was stirred at room temperature for 6 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured onto ice water (100 mL), and the solid obtained was filtered and dried. The crude compound was purified by silica gel chromatography using 5-7% EA in hexane to afford 3.50 g of the title compound. LC-MS (Method C) (ESI+): m / z 278.95 (M+Na) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) δ 8.04 - 8.15 (m, 4H), 5.00 (s, 2H), 3.89 (s, 3H).Step 2: Synthesis of Methyl 4-(2-(trifluoromethyl)-1H-imidazol-4-yl)benzoate:

[0401]

[0402] To a stirred solution of 2,2,2-trifluoroacetimidamide (4.37 g, 39.0 mmol) in THF (30 mL), was added methyl 4-(2-bromoacetyl)benzoate (2.00 g, 7.80 mmol), and the reaction mixture was stirred at room temperature for 5h. 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 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 to afford 0.81 g of the title compound. LC-MS (Method B) (ESI+): m / z 270.90 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) δ 13.89 (s, 1H), 8.14 (s, 1H), 7.98 (s, 4H), 3.86 (s, 3H).Step 3: Synthesis of Methyl 4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)benzoate:

[0403]

[0404] 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, was added NaH (60% dispersion in mineral oil, 0.178 g, 4.40 mmol) portion wise, and the reaction mixture was stirred at 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. 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 x 30 mL). The combined organic layer was washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 0.80 g of the title compound. LC-MS (Method B) (ESI+): m / z 284.95 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) δ 8.12-8.17 (m, 1H), 7.96-8.02 (m, 2H), 7.88-7.94 (m, 2H), 3.86 (s, 6H).Step 4: Synthesis of (4-(1-Methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)phenyl)methanol:

[0405]

[0406] 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, was added DIBAL-H (1M in toluene, 5.63 mL, 5.63 mmol) dropwise, and the reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with 2N HCl (20 mL) and extracted with EA (2 x 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 0.65 g of the title compound, which was used in subsequent reactions without further purification. LC-MS (Method B) (ESI+): m / z 256.85 (M+H) +< .Step 5: Synthesis of 4-(4-(Chloromethyl)phenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazole:

[0407]

[0408] 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, was added SOCl 2 (0.27 mL, 3.80 mmol), and the reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with DCM (50 mL) and washed with saturated NaHCO 3 solution (3 x 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 0.65 g of the title compound, which was used in subsequent reactions without further purification. LC-MS (Method B) (ESI+): m / z 274.90 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) 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).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):

[0409]

[0410] 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 K 2 CO 3 (0.517 g, 3.70 mmol) in one portion. After stirring for 10 minutes at room temperature, 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 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured onto ice water (50 mL) and extracted with EA (2 x 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 0-50% EA in hexane to afford 0.15 g of the title compound. LC-MS (Method B) (ESI+): m / z 392.95 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) 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 intermediate was made from the appropriate reagents according to the procedure for Intermediate 1-16. IntermediateStructureAnalyticsI-17 LC-MS (Method B) (ESI+): m / z 421.00 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) δ 9.30 (s, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 7.76 (d, J = 7.98 Hz, 2H), 7.30 (d, J = 7.98 Hz, 2H), 5.63 (s, 2H), 4.56 (td, J = 6.48, 12.96 Hz, 1H), 1.48 (d, J = 6.48 Hz, 6H). Preparation of Common Intermediate I-18:

[0411] Step 1: Synthesis of ethyl 4-acetyl-3-methoxybenzoate:

[0412]

[0413] To a stirred solution of 1-(4-bromo-2-methoxyphenyl) ethan-1-one 1 (3.00 g, 13.1 mmol) in ethanol (60 mL), was added triethylamine (3.67 mL, 26.2 mmol) and the mixture was degassed with argon for 10 min. To the reaction mixture was added PdCl 2 (dppf) (0.957 g, 0.131 mmol) at room temperature, and the resulting mixture was heated at 80 °C under carbon monoxide (20 psi pressure) for 3h. Progress of the reaction was monitored by TLC. After 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 eluent to afford the title compound (2.50 g). LC-MS (Method B) (ESI+): m / z 223.00 (M+H) +< ; 1< H-NMR (400 MHz, CDCl 3 ) 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).Step 2: Synthesis of ethyl 4-(2,2-dibromoacetyl)-3-methoxybenzoate:

[0414]

[0415] 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 h, and 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 Na 2 CO 3 solution. The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (1.20 g). 1< H-NMR (400 MHz, CDCl 3 ) 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).Step 3: Synthesis of ethyl 4-(2-bromoacetyl)-3-methoxybenzoate:

[0416]

[0417] 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 triethyl amine (0.44 mL, 3.17 mmol) and diethylphosphite (0.433 g, 3.166 mmol) at room temperature. The resulting mixture was stirred for 3 h, and progress of the reaction was monitored by TLC. After completion, the reaction mixture diluted with EA (30 mL) and washed with brine (3 x 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 eluent to afford the title compound (0.900 g). LC-MS (Method B) (ESI+): m / z 300.80 (M) +< ; 1< H-NMR (400 MHz, CDCl 3 ) 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).Step 4: Synthesis of ethyl 3-methoxy-4-(2-(trifluoromethyl)-1H-imidazol-4-yl)benzoate:

[0418]

[0419] 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. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with EA (50 mL) and washed with saturated NaHCO 3 solution (2 x 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 eluent to afford the title compound (0.300 g). LC-MS (Method B) (ESI+): m / z 315.10 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) 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).Step 5: Synthesis of ethyl 3-methoxy-4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)benzoate:

[0420] 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 60% dispersion of sodium hydride in oil (0.057 g, 1.43 mmol) and methyl iodide (0.089 mL, 1.43 mmol). The reaction mixture was allowed to warm to room temperature, and then stirred for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured over ice cold water (50 mL) and extracted with EA (2 x 30 mL). The combined 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 as eluent to afford the title compound (0.240 g). LC-MS (Method B) (ESI+); m / z 328.90 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) 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).Step 6: Synthesis of (3-methoxy-4-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)phenyl)methanol:

[0421]

[0422] 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 (1M solution in toluene, 1.46 mL, 1.46 mmol). The reaction mixture was allowed to warm to room temperature, and then stirred for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with 1N HCl (20 mL) and extracted with EA (3 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude title compound (0.260 g). LC-MS (Method B) (ESI+): m / z 287.30 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) 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).Step 7: Synthesis of 4-(4-(chloromethyl)-2-methoxyphenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazole:

[0423]

[0424] 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 1h, and progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with DCM (20 mL) and washed with saturated Na 2 CO 3 solution (3 x 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude title compound (0.260 g). LC-MS (Method B) (ESI+): m / z 304.80 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) 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).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):

[0425]

[0426] 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 progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured over ice cold water (30 mL) and extracted with EA (2 x 30 mL). The combined organic layer was washed with brine (2 x 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 eluent to afford the title compound (0.150 g). LC-MS (Method B) (ESI+): m / z 423.00 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) 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).Preparation of Common Intermediate I-19:

[0427] Step 1: Synthesis of Methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate:

[0428]

[0429] 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, was added a solution of TEA (994 mg, 9.84 mmol) in HFIP (3 mL) dropwise over 5 min. After addition, the resulting mixture was stirred at room temperature for 1 hour, then quenched with water (20 mL) and extracted with DCM (100 mL x 3). The combined organics were dried with anhydrous Na 2 SO 4 (30 g), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EA:n-Hex = 1:20) to provide 1.1 g of the title compound. LC-MS (Method A) (ESI+): m / z 285 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) 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).Step 2: Synthesis of (4-(5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol:

[0430]

[0431] 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, was added DIBAL-H (10.5 mL, 10.56 mmol, 1 M in toluene) over 10 min. After the addition, the reaction mixture was warmed to rt. After the reaction was complete as indicated by TLC analysis, the reaction was quenched with a saturated NH 4 Cl solution (20 mL), extracted with EA (100 ml x 3). The combined organic layers were dried with anhydrous Na 2 SO 4 (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, CDCl 3 ) δ 7.40-7.49 (m, 4H), 6.46 (s, 1H), 4.76 (s, 2H), 2.34 (s, 3H), 2.17 (br s, 1H).Step 3: Synthesis of 1-(4-(Chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole:

[0432]

[0433] 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 in SOCl 2 (1.14 g, 9.61 mmol) in one portion. After the reaction was stirred 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 3 (aq) solution and extracted with DCM (3 x 100 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 (50 g), filtered and concentrated to dryness to afford 480 mg of crude product, which was used for the next step directly. LC-MS (Method A) (ESI+): m / z 275 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) 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).Step 4: Synthesis of 6-Chloro-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (1-19):

[0434]

[0435] 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 K 2 CO 3 (0.60 g, 4.38 mmol). The reaction was stirred at room temperature for 2 hours, and then quenched by water (20 mL) and extracted with EA (50 mL x 3). The combined organic layer was dried over anhydrous Na 2 SO 4 (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, CDCl 3 ) 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 common intermediates were prepared according the procedure of I-19 from the appropriate reagents: IntermediateStructureAnalyticsI-20 LC-MS (Method B) (ESI+): m / z 421.00 (M+H) +< ; 1< H-NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.53 (s, 1H), 7.41-7.53 (m, 4H), 6.81 (s, 1H), 5.76 (s, 2H), 2.94 (td, J = 6.73, 13.46 Hz, 1H), 1.12 (d, J = 6.98 Hz, 6H).I-21 LC-MS (Method B) (ESI+): m / z 445.00 (M+H) +< ; 1< H-NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.54 (s, 1H), 7.76 (s, 1H), 7.45-7.49 (m, 2H), 7.38-7.42 (m, 2H), 7.21-7.27 (m, 1H), 6.52-6.56 (m, 1H), 6.28 (d, J = 3.49 Hz, 1H), 5.77 (s, 2H). Preparation of Common Intermediate I-22:

[0436] Step 1: Synthesis of 6-chloro-4-methoxy-1H-pyrazolo[3,4-d]pyrimidine:

[0437]

[0438] 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 the mixture was stirred at rt for 24 h, the reaction was quenched with saturated ammonium chloride (30 mL) solution and extracted with EA (20 mL x 3). The combined organic layer was dried over sodium sulfate (30 g), filtered and concentrated. The residue was purified by silica gel chromatography (eluent: EA / n-Hex = 1 / 10) to afford 120 mg of the title compound. LC-MS (Method A) (ESI+): m / z 185 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 10.69 (br s, 1H), 8.09 (s, 1H), 4.19 (s, 3H).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):

[0439]

[0440] 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, CDCl 3 ) 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 common intermediate was prepared according the procedure of I-22 from the appropriate reagents: IntermediateStructureAnalyticsI-22b LC-MS (Method A) (ESI+): m / z 437 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.97 (s, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.28 (s, 1H), 5.56 (s, 2H), 4.11 (s, 3H), 3.96 (q, J = 7.5 Hz, 2H), 1.34 (t, J = 7.5 Hz, 3H). Preparation of Common Intermediate I-23:

[0441] Step 1: Synthesis of methyl 4-hydrazineyl-3-methoxybenzoate:

[0442]

[0443] To a stirred solution of methyl 4-amino-3-methoxybenzoate 1 (5.0 g, 27.6 mmol) in conc. HCl (55 mL) at -10 °C, was added dropwise an aqueous solution of NaNO 2 (1.99 g, 29.0 mmol) in water (5 mL). To the resulting reaction mixture was added dropwise a solution of SnCl 2 (26.0 g, 138 mmol) in conc. HCl (35 mL), and the reaction was stirred for 2h. Progress of the reaction was monitored by TLC. After completion, the solid obtained was filtered and dried under reduced pressure. The crude compound was washed with diethyl ether (50 mL), filtered and dried under reduced pressure to afford the crude title compound (8.0 g) that was used in the next step without purification. 1< H-NMR (400 MHz, DMSO-d 6 ) 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).Step 2: Synthesis of methyl 3-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate:

[0444]

[0445] 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 16h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude compound was purified by size silica gel chromatography using 0-30% EA in hexane to afford the title compound (2.5 g). LC-MS (Method B) (ESI+): m / z 315.05 (M+H) +< .Step 3: Synthesis of (3-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl) methanol:

[0446]

[0447] 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, was added dropwise DIBAL-H (16 mL, 15.9 mmol, 1.0 M solution in THF). The resulting mixture was stirred for 2h at 0 °C, and progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with 1N HCl (4 mL) at 0 °C and extracted with EA (100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude 4 (1.5 g). The crude product was used as is without purification. LC-MS (Method B) (ESI+): m / z 287.45 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) 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).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):

[0448]

[0449] To an ice cooled 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 2h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (30 mL) and extracted with EA (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by size silica gel chromatography using 0-40% EA in hexane as eluent to afford the title compound (1.0 g). LC-MS (Method B) (ESI+): m / z 423 (M+H) +< .Preparation of Common Intermediate 1-24:

[0450] Step 1: Synthesis of (4-(4-(Trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol:

[0451]

[0452] 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 H 2 O (7.3 mL), was stirred at 100 °C for 1 hour. The reaction mixture was then cooled to 0 °C and the solution of 4-(hydroxymethyl)benzaldehyde (2.18 g, 8.08 mmol) and NH 4 OH (9.3 mL) in MeOH (37 mL), was added over 10 min. After addition, the reaction mixture was stirred at ambient temperature overnight. The resulting mixture was concentrated under reduced pressure to remove most of the solvent. To the concentrated residue was added water (20 mL) and the mixture was extracted with EA (100 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 (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 afford 1.1 g of the title compound. 1< H-NMR (300 MHz, CD 3 OD) 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).Step 2: Synthesis of 4-(4-(Trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde:

[0453]

[0454] 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) portion-wise at 0 °C over 5 min. After 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 NH 4 Cl solution (20 mL), dried with anhydrous Na 2 SO 4 (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. 1< H-NMR (300 MHz, CD 3 OD) 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).Step 3: Synthesis of 4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde:

[0455]

[0456] To a solution of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (0.9 g, 3.8 mmol) in DMF (40 mL) at room temperature, was added Cs 2 CO 3 (3.7 g, 11.2 mmol) and MeI (1.1 g, 7.5 mmol) in one portion. After the reaction was stirred at ambient temperature for 1 hour, the reaction was quenched with water (100 mL) and extracted with EA (100 mL x 2). The combined organic layer was washed with water (50 mL x 2), dried with anhydrous Na 2 SO 4 (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, CDCl 3 ) 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).Step 4: Synthesis of 1-(4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan-1-ol:

[0457]

[0458] 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 CH 3 MgBr (4.7 mL, 4.7 mmol, 1 M in THF) dropwise over 10 min at 0 °C. After addition, the reaction was stirred at 0 °C for 1.5 hr, and then quenched by addition of a saturated aqueous NH 4 Cl (20 mL) solution. The resulting mixture was extracted with EA (100 mL x 2), and the combined organic layer was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 (30 g) and concentrated in vacuo to give 0.9 g of the crude title compound. 1< H-NMR (300 MHz, CDCl 3 ) 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 = 6.3 Hz, 3H).Step 5: Synthesis of 2-(4-(1-Chloroethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole:

[0459]

[0460] 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 2 (753.8 mg, 6.3 mmol) in one portion. After addition, the reaction was stirred at 60 °C for 1 hour, and then concentrated to dryness in vacuo. The residue was dissolved in EA (100 mL), and then treated with a saturated NaHCO 3 solution. After separation, the organic layer was dried with anhydrous Na 2 SO 4 (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. 1< H-NMR (300 MHz, CDCl 3 ) 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).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):

[0461]

[0462] To a solution of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (321.2 mg, 2.1 mmol) in DMF (14 mL), was added 2-(4-(1-chloroethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (400 mg, 1.4 mmol) and K 2 CO 3 (574.5 mg, 4.2 mmol). After addition, the reaction mixture was stirred at 65 °C overnight, then quenched with water (30 mL) and extracted with EA (50 mL x 2). The combined organic layer was washed with water (20 mL x 2), dried over anhydrous Na 2 SO 4 (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. Its regioisomer was obtained as the major product after purification. 1< H-NMR (300 MHz, CDCl 3 ) 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 = 7.2 Hz, 3H). The following common intermediates were prepared according the procedure of I-24 from the appropriate reagents: IntermediateStructureAnalyticsI-25 1< H-NMR (300 MHz, CDCl 3 ) δ 9.05 (s, 1H), 8.17 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 5.90 (s, 1H), 5.67 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H).I-26 LC-MS (Method C) (ESI+): m / z 439.29 (M+H) +< ; 1< H-NMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.56 (s, 1H), 8.10 (d, J = 0.98 Hz, 1H), 7.53 (t, J = 7.83 Hz, 1H), 7.39 (dd, J = 0.98, 11.25 Hz, 1H), 7.27 (dd, J = 1.47, 7.83 Hz, 1H), 6.30 (q, J = 7.17 Hz, 1H), 3.85 (q, J = 7.17 Hz, 2H), 1.95 (d, J = 6.85 Hz, 3H), 1.25 (t, J = 7.34 Hz, 3H). Preparation of Common Intermediate I-27:

[0463] Step 1: Synthesis of 2-bromo-1-ethyl-4-(trifluoromethyl)-1H-imidazole:

[0464]

[0465] 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, was added n-BuLi (1.6M in hexane, 68.5 mL, 110 mmol) dropwise. The resulting mixture was stirred for 30 min at -78 °C and was then treated with a solution of CBr 4 (36.3 g, 109.75 mmol) in dry THF (75 mL). The reaction mixture was allowed to warm room temperature and then stirred for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated NH 4 Cl solution and extracted with EA (3 x 50 mL). The combined organic layer was 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 afford the title compound (8.00 g). 1< H-NMR (400 MHz, DMSO-d 6 ) δ 8.09 (s, 1H), 4.01 (q, J = 7.34 Hz, 2H), 1.33 (t, J = 7.34 Hz, 3H).Step 2: Synthesis of 1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-fluorophenyl)ethan-1-one:

[0466]

[0467] To a stirred solution of 2-bromo-1-ethyl-4-(trifluoromethyl)-1H-imidazole 2 (1.80 g, 7.44 mmol) in dioxane:H 2 O (8:2 mL) was added K 3 PO 4 (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 min, and then treated with X-Phos (0.708 g, 1.49 mmol) and X-Phos-Pd-G 2 (0.292 g, 0.372 mmol) in a sealed tube at room temperature. The reaction mixture was further degassed with argon for 10 min and then heated at 100 °C for 2 h. Progress of the reaction was monitored by TLC. After 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 afford the title compound (1.85 g). LC-MS (Method B) (ESI+): m / z 301.15 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) 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).Step 3: Synthesis of (R)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-fluorophenyl)ethan-1-ol:

[0468]

[0469] 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. Progress of the reaction was monitored by TLC. After 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 afford the title compound (2.10 g). LC-MS (Method B) (ESI+): m / z 303.00 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) 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).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):

[0470]

[0471] 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, was added 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). The reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined organic layer was 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 afford the title compound (2.20 g). LC-MS (Method B) (ESI+): m / z 439.22 (M+H) +< . The following common intermediates were prepared according the procedure of I-27 from the appropriate ketones and CBS reducing reagents: IntermediateStructureAnalyticsI-28 1< H-NMR (400 MHz, DMSO-d 6 ) δ 9.30 (s, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.60 (d, J = 8.31 Hz, 2H), 7.46 (d, J = 8.31 Hz, 2H), 6.27 (q, J = 7.01 Hz, 1H), 4.05 (q, J = 7.34 Hz, 2H), 1.95 (d, J = 7.34 Hz, 3H), 1.30 (t, J = 7.34 Hz, 3H).I-29 LC-MS (Method C) (ESI+): m / z 435.00 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) δ 9.30 (s, 1H), 8.54 (s, 1H), 8.16 (s, 1H), 7.53-7.59 (m, 1H), 7.52-7.56 (m, 1H), 7.45-7.49 (m, 2H), 6.23-6.31 (m, 1H), 4.43 (td, J = 6.55, 13.34 Hz, 1H), 1.96 (d, J = 6.98 Hz, 3H), 1.38 (d, J = 6.48 Hz, 6H).I-30 LC-MS (Method C) (ESI+): m / z 435.00 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.55 (s, 1H), 8.17 (s, 1H), 7.52-7.55 (m, 2H), 7.45-7.50 (m, 2H), 6.27 (q, J = 6.65 Hz, 1H), 4.40-4.48 (m, 1H), 1.96 (d, J = 6.98 Hz, 3H), 1.38 (d, J = 6.48 Hz, 6H). Preparation of Common Intermediate 1-31:

[0472] Step 1: Synthesis of 2-(4-(((Tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazole:

[0473]

[0474] 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) at room temperature, was added TBSCl (1.42 g, 9.42 mmol) in one portion. After addition, the reaction mixture was stirred at room temperature for 1.5 hours. The reaction was then quenched with water (20 mL) and extracted with EA (150 ml x 3). The combined organic layer was dried over anhydrous Na 2 SO 4 (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, CDCl 3 ) 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).Step 2: Synthesis of 3-(2-(4-(Hydroxymethyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)azetidine-1-carboxylate:

[0475]

[0476] 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), was added tert-butyl 3-iodoazetidine-1-carboxylate (2.58 g, 9.13 mmol) and Cs 2 CO 3 (6.87 g, 21.06 mmol). The reaction mixture was stirred at 120 °C for 4 hours. The reaction was then quenched with water (80 mL) and extracted with EA (150 mL x 3). The combined organic layer was washed with water (50 mL x 2), dried with anhydrous Na 2 SO 4 (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, CDCl 3 ) 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).Step 3: Synthesis of tert-Butyl 3-(2-(4-(Chloromethyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)azetidine-1-carboxylate:

[0477]

[0478] 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 SOCl 2 (0.83 g, 6.95 mmol). The reaction was then stirred at room temperature overnight before concentration 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, CDCl 3 ) 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).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):

[0479]

[0480] 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 K 2 CO 3 (0.37 g, 2.68 mmol) in DMF (13 mL) was stirred at room temperature for 3 hours. The mixture was then quenched with water (30 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with water (20 mL) and dried over anhydrous Na 2 SO 4 (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, CDCl 3 ) 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).Preparation of Common Intermediate I-32:

[0481] Step 1: Synthesis of Ethyl 4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)benzoate:

[0482]

[0483] To a solution of ethyl 4-hydrazinylbenzoate hydrochloride 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, was added a solution of TEA (299.6 mg, 3.0 mmol) in HFIP (1 mL) dropwise over 2 min. After addition, the reaction was stirred at room temperature for 2.5 hours. The reaction was then quenched with water (10 mL) and extracted with DCM (20 mL x 2). The combined organic layer was washed with water (10 mL), dried over anhydrous Na 2 SO 4 (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, CDCl 3 ) 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).Step 2: Synthesis of (4-(3-(Difluoromethyl)-5-methyl-1H-pyrazol-1-yl)phenyl)methanol:

[0484]

[0485] The title compound was synthesized according to the step 3 of common intermediate I-1. 1< H-NMR (300 MHz, CDCl 3 ) 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).Step 3: Synthesis of 1-(4-(Chloromethyl)phenyl)-3-(difluoromethyl)-5-methyl-1H-pyrazole:

[0486]

[0487] 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 2 (426.4 mg, 3.6 mmol) in one portion. After addition, the reaction was stirred at 60 °C for 1 hour, then concentrated in vacuo to give 300 mg of the crude title compound. 1< H-NMR (300 MHz, CDCl 3 ) 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).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):

[0488]

[0489] 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 K 2 CO 3 (484.6 mg, 351 mmol) in DMF (12 mL) was stirred at 90 °C for 1.5 hours. The reaction was then quenched with water (25 mL) and extracted with EA (50 mL x 2). The combined organic layer was washed with water (20 mL x 2), dried over anhydrous Na 2 SO 4 (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 title compound with a small amount of the regioisomer. 1< H-NMR (300 MHz, CDCl 3 ) 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).Preparation of Common Intermediate I-33 and 1-34:

[0490] Step 1: Synthesis of Ethyl 4-bromobenzimidate hydrochloride salt:

[0491]

[0492] 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 3h. The mixture was then stirred at rt overnight. The resulting reaction mixture was poured into Et 2 O (40 mL), and the resulting solid precipitate was collected by filtration. The solid was suspended in cold DCM (80 mL) and neutralized by a saturated aqueous NaHCO 3 solution (80 mL). After the organic phase was separated, the aqueous phase was extracted with DCM (40 mL x 2). The combined organic phase was dried with sodium sulfate (40 g), filtered and concentrated to afford 5.0 g of the title compound. LC-MS (Method A) (ESI+): m / z 214 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.81 (br s, 1H), 7.51-7.68 (m, 4H), 3.92 (s, 3H).Step 2: Synthesis of 4-Bromobenzohydrazonamide:

[0493]

[0494] To a solution of methyl 4-bromobenzimidate (4.6 g, 21.6 mmol) in IPA (80 mL) at 0 °C, was added hydrazine hydrate (1.6 g, 25.9 mmol) in IPA (20 mL) dropwise over 30 min. The reaction mixture was stirred in an ice-water bath for 1 h and then warmed to rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was concentrated to dryness. The residue was diluted with Et 2 O (35 mL) and a large amount of solid was precipitated. The suspension was stirred at rt for 1 h, then the solid was collected by filtration to afford 3.8 g of the crude title compound. LC-MS (Method A) (ESI+): m / z 214 (M+H) +< ; 1< H-NMR (300 MHz, DMSO) δ 7.63 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 5.66 (br s, 2H), 5.08 (br s, 2H).Step 3: Synthesis of 3-(4-Bromophenyl)-5-(difluoromethyl)-1H-1,2,4-triazole:

[0495]

[0496] A solution of 2,2-difluoroacetic anhydride (1.63 g, 9.38) in DCM (20 mL) was added dropwise over 5 min to a mixture of 4-bromobenzohydrazonamide (2.0 g, 9.38 mmol) and TEA (2.84 g, 28.14 mmol) in DCM (70 mL) at 0 °C. After the addition, the reaction mixture was warmed to rt and stirred overnight. After the reaction was completed as indicated by TLC analysis, the mixture was quenched with brine (80 mL) and extracted with DCM (80 mL x 2). The combined organic layer was dried with sodium sulfate (30 g), filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 8:1 to 4:1) to yield 1.2 g of the title compound. LC-MS (Method A) (ESI+): m / z 274 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.85 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 6.81 (t, J = 53.4 Hz, 1H).Step 4: Synthesis of 5-(4-Bromophenyl)-3-(difluoromethyl)-1-methyl-1H-1,2,4-triazole and 3-(4-bromophenyl)-5- (difluoromethyl)-1-methyl-1H-1,2,4-triazole:

[0497]

[0498] To a solution of 3-(4-bromophenyl)-5-(difluoromethyl)-1H-1,2,4-triazole (1.05 g, 3.85 mmol) in DMF (25 mL) at 0 °C, was added sodium hydride (200 mg, 5.0 mmol) portion-wise over 5 min. After the resulting mixture was stirred at 0 °C for 20 min, MeI (1.09 g, 7.69 mmol) was added dropwise over 1 min. The reaction was warmed to rt and stirred for 1 h. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with ice-water (50 mL) and extracted with EA (70 mL x 2). The combined organic layer was washed with water (60 mL x 2), dried with sodium sulfate (30 g), filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 20:1 to 15:1) to yield 260 mg of 5-(4-bromophenyl)-3-(difluoromethyl)-1-methyl-1H-1,2,4-triazole and 750 mg of 3-(4-bromophenyl)-5-(difluoromethyl)-1-methyl-1H-1,2,4-triazole. 5-(4-bromophenyl)-3-(difluoromethyl)-1-methyl-1H-1,2,4-triazole: LC-MS (Method A) (ESI+): m / z 288 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.70 (d, J = 6.6, 1.8 Hz, 2H), 7.59 (d, J = 6.6, 1.8 Hz, 2H), 6.73 (t, J = 53.7 Hz, 1H), 4.03 (s, 3H). 3-(4-bromophenyl)-5-(difluoromethyl)-1-methyl-1H-1,2,4-triazole: LC-MS (Method A) (ESI+): m / z 288 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.93 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 6.87 (t, J = 53.7 Hz, 1H), 4.09 (s, 3H).Step 5: Synthesis of 3-(Difluoromethyl)-1-methyl-5-(4-vinylphenyl)-1H-1,2,4-triazole:

[0499]

[0500] Under nitrogen protection, a solution of 5-(4-bromophenyl)-3-(difluoromethyl)-1-methyl-1H-1,2,4-triazole (1.6 g, 5.57 mmol) in toluene (50 ml) was treated with tributylvinylstannane (2.65g, 8.36 mmol) and Pd(PPh 3 ) 4 (644 mg, 0.56 mmol) in one portion. The reaction was stirred at 90 °C for 5 hours, then quenched with water (50 mL) and extracted with EA (50 mL x 2). The combined organic layer was washed with brine (60 mL), dried over sodium sulfate (30 g), filtered and concentrated. The residue was purified by flash silica chromatography (PE:EA = 10:1) to yield 1.2 g of the title compound. LC-MS (Method A) (ESI+): m / z 236 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.68 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 6.74 (t, J = 53.7 Hz, 1H), 6.73 (m, 1H), 5.88 (d, J = 17.4 Hz, 1H), 5.40 (d, J = 11.1 Hz, 1H), 4.05 (s, 3H).Step 6: Synthesis of 5-(Difluoromethyl)-1-methyl-3-(4-vinylphenyl)-1H-1,2,4-triazole:

[0501]

[0502] The compound was synthesized according to the procedure of step 5 of common intermediate I-33. LC-MS (Method A) (ESI+): m / z 236 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 8.02 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 6.90 (t, J = 53.7 Hz, 1H), 6.78 (m, 1H), 5.83 (d, J = 17.2 Hz, 1H), 5.31 (d, J = 10.8 Hz, 1H), 4.10 (s, 3H).Step 7: Synthesis of 4-(3-(Difluoromethyl)-1-methyl-1H-1,2,4-triazol-5-yl)benzaldehyde:

[0503]

[0504] To a solution of 3-(difluoromethyl)-1-methyl-5-(4-vinylphenyl)-1H-1,2,4-triazole (450 mg, 1.91mmol) in THF (15 mL) and water (8 mL) at rt, was added NaIO 4 (1.23g, 5.75 mmol) and OsO 4 (4.2 mg, 1 mol%) in one portion. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched by a saturated ammonium chloride solution (20 mL) and extracted with EA (30 mL x 2). The combined organic layer was washed with brine (40 mL), dried over sodium sulfate (20 g), filtered and concentrated to afford 450 mg of the crude title compound. LC-MS (Method A) (ESI+): m / z 238 (M+H) +< .Step 8: Synthesis of 4-(5-(Difluoromethyl)-1-methyl-1H-1,2,4-triazol-3-yl)benzaldehyde:

[0505]

[0506] The compound was synthesized according to the procedure of step 7 of common intermediate I-33 . LC-MS (Method A) (ESI+): m / z 238 (M+H) +< . 1< H-NMR (300 MHz, CDCl 3 ) δ 9.99 (s, 1H), 8.17 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 8.1 Hz, 2H), 6.84 (t, J = 52.5 Hz, 1H), 4.06 (s, 3H).Step 9: Synthesis of (4-(3-(Difluoromethyl)-1-methyl-1H-1,2,4-triazol-5-yl)phenyl)methanol:

[0507]

[0508] To a solution of 4-(3-(difluoromethyl)-1-methyl-1H-1,2,4-triazol-5-yl)benzaldehyde (450 mg, 1.90 mmol) in THF (15 mL), was added NaBH 4 (94 mg, 2.47 mmol) in one portion. After the reaction was completed as indicated by TLC analysis, the reaction was quenched by ice-water (20 mL) and extracted with EA (40 mL x 2). The combined organic layer was washed with brine (40 mL), dried over sodium sulfate (30 g), filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 3:2) to yield 340 mg of the title compound. LC-MS (Method A) (ESI+): m / z 240 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.71 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 6.74 (t, J = 53.7 Hz, 1H), 4.81 (d, J = 5.7 Hz, 2H) 4.04 (s, 3H).Step 10: Synthesis of (4-(5-(Difluoromethyl)-1-methyl-1H-1,2,4-triazol-3-yl)phenyl)methanol:

[0509]

[0510] The compound was synthesized according to the procedure of step 9 of common intermediate I-14. LC-MS (Method A) (ESI+): m / z 240 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 8.06 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.89 (t, J = 52.5 Hz, 1H), 4.75(d, J = 6.0 Hz, 2H) 4.13 (s, 3H).Step 11: Synthesis of 5-(4-(Chloromethyl)phenyl)-3-(difluoromethyl)-1-methyl-1H-1,2,4-triazole:

[0511]

[0512] To a solution of (4-(3-(difluoromethyl)-1-methyl-1H-1,2,4-triazol-5-yl)phenyl)methanol (320 mg, 1.34 mmol) in DCE (15 mL), was added SOCl 2 (318 mg, 2.68 mmol) in one portion. The reaction was stirred at 60 °C for 1 h. After the reaction was completed as indicated by TLC analysis, the reaction mixture was concentrated to dryness to afford 340 mg of the crude title compound. LC-MS (Method A) (ESI+): m / z 258 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.72 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 6.74 (t, J = 53.7 Hz, 1H), 4.66 (s, 2H), 4.05 (s, 3H).Step 12: Synthesis of 3-(4-(Chloromethyl)phenyl)-5-(difluoromethyl)-1-methyl-1H-1,2,4-triazole:

[0513]

[0514] The compound was synthesized according to the procedure of step 11 of common intermediate I-33. LC-MS (Method A) (ESI+): m / z 258 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 8.06 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 6.89 (t, J = 52.5 Hz, 1H), 4.63 (s, 2H), 4.10 (s, 3H).Step 13: Synthesis of 6-Chloro-1-(4-(3-(difluoromethyl)-1-methyl-1H-1,2,4-triazol-5-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-33):

[0515]

[0516] To a solution of 5-(4-(chloromethyl)phenyl)-3-(difluoromethyl)-1-methyl-1H-1,2,4-triazole (340 mg, 1.32 mmol) and 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (244 mg, 1.58 mmol) in DMF (15 mL), was added Cs 2 CO 3 (474 mg, 1.45 mmol) in one portion. The reaction was stirred at 80 °C for 1 h, then cooled to rt. The reaction was then quenched by ice-water (40 mL), and then extracted with EA (50 mL x 2). The combined organic layer was washed with water (40 mL x 3), dried over sodium sulfate (30 g), filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 1:1 to 1:3) to yield 180 mg of the title compound. LC-MS (Method A) (ESI+): m / z 376 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 9.07 (s, 1H), 8.20 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 6.71 (t, J = 53.7 Hz, 1H), 5.72 (s, 2H), 4.00 (s, 3H).Step 14: Synthesis of 6-Chloro-1-(4-(5-(difluoromethyl)-1-methyl-1H-1,2,4-triazol-3-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-34):

[0517]

[0518] The compound was synthesized according to the procedure of step 13 of common intermediate I-33 . LC-MS (Method A) (ESI+): m / z 376 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 9.05 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.86 (t, J = 58.2 Hz, 1H), 5.67 (s, 2H), 4.10 (s, 3H).Preparation of Common Intermediate I-35:

[0519] Step 1: Synthesis of 5-bromo-1-ethyl-3-(trifluoromethyl)-1H-1,2,4-triazole:

[0520]

[0521] To an ice cooled solution of 5-bromo-3-(trifluoromethyl)-1H-1,2,4-triazole 1 (0.500 g, 2.31 mmol) in DMF (10 mL), was added sodium hydride (0.138 g, 3.47 mmol) portion-wise. The resulting mixture was stirred for 15 min, and then ethyl iodide (0.360 mL, 0.708 g, 0.462 mmol) was added. The reaction mixture was allowed to warm to room temperature and then stirred for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (20 mL) and extracted with EA (2 × 30 mL). The combined organic layer was washed with water (20 mL), and brine (20 mL), then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 0-5% EA in n-hexane to afford the title compound (0.280 g). 1< H-NMR (400 MHz, DMSO-d 6 ) δ 4.28 (q, J = 7.01 Hz, 2H), 1.40 (t, J = 7.09 Hz, 3H).Step 2: Synthesis of 4-(1-ethyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)benzaldehyde:

[0522]

[0523] To a stirred solution of 5-bromo-1-ethyl-3-(trifluoromethyl)-1H-1,2,4-triazole 2 (0.250 g, 1.03 mmol) in dioxane:H 2 O (10:4 mL) in a sealed tube were added K 3 PO 4 (0.436 g, 2.07 mmol) and (4-formylphenyl)boronic acid 3 (0.200 g, 1.34 mmol). The resulting mixture was degassed with argon for 10 min, and then X-Phos (0.049 g, 0.102 mmol) and X-Phos-Pd-G 2 (0.040 g, 0.051 mmol) were added at room temperature. The reaction mixture was further degassed with argon for 10 min and then heated at 100 °C for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, quenched with water (20 mL) and extracted with EA (3 × 30 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 eluting with 0-25% EA in hexane to afford the title compound (0.220 g). 1< H-NMR (400 MHz, DMSO-d 6 ) δ 10.13 (s, 1H), 8.11 (d, J = 6.85 Hz, 2H), 8.00 (d, J = 7.34 Hz, 2H), 4.38 (q, J = 6.85 Hz, 2H), 1.44 (t, J = 6.85 Hz, 3H).Step 3: Synthesis of (4-(1-ethyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)phenyl)methanol:

[0524]

[0525] To a stirred solution of 4-(1-ethyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl) benzaldehyde 4 (0.200 g, 0.743 mmol) in methanol (5 mL) was added sodium borohydride (0.056 g, 1.49 mmol) portion-wise. The reaction mixture was allowed to warm to room temperature and was further stirred for 2h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, quenched with water (20 mL) and extracted with EA (3 x 30 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 eluting with 0-40% EA in hexane to afford the title compound (0.150 g). LC-MS (Method B) (ESI+): m / z 271.40 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) δ 7.72 (d, J = 8.31 Hz, 2H), 7.53 (d, J = 7.82 Hz, 2H), 5.38 (t, J = 5.62 Hz, 1H), 4.61 (d, J = 5.87 Hz, 2H), 4.34 (q, J = 7.34 Hz, 2H), 1.42 (t, J = 7.34 Hz, 3H).Step 4: Synthesis of 6-chloro-1-(4-(1-ethyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-35):

[0526]

[0527] To a stirred solution of (4-(1-ethyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)phenyl)methanol 5 (0.130 g, 0.479 mmol) in THF (5 mL) at 0 °C, was added 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.066 g, 0.43 mmol), DEAD (0.163 g, 0.959 mmol) and TPP (0.246 g, 0.959 mmol). The reaction mixture was allowed to warm to room temperature and was then stirred for 6 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 0-30% EA in hexane as eluent to afford the title compound (0.100 g). 1< H-NMR (400 MHz, DMSO-d 6 ) δ 9.33 (s, 1H), 8.53 (s, 1H), 7.73 (d, J = 8.31 Hz, 2H), 7.45 (d, J = 7.83 Hz, 2H), 5.77 (s, 2H), 4.30 (q, J = 7.17 Hz, 2H), 1.39 (t, J = 7.34 Hz, 3H). The following intermediates were prepared from the appropriate heterocycles and alkylating reagents according to the method of preparation for 1-35: IntermediateStructureAnalyticsI-36 LC-MS (Method A) (ESI+): m / z 394 (M+H) +< ; 1< HNMR (300 MHz, CDCl 3 ) δ 9.07 (s, 1H), 8.20 (s, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 5.72 (s, 2H), 4.03 (s, 3H).I-37 LC-MS (Method B) (ESI+): m / z 412 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) δ 9.33 (s, 1H), 8.54 (s, 1H), 7.70 (t, J = 7.83 Hz, 1H), 7.38 (d, J= 10.76 Hz, 1H), 7.26 (d, J= 8.31 Hz, 1H), 5.79 (s, 2H), 3.88 (s, 3H).I-38 LC-MS (Method B) (ESI+): m / z 422.13 (M+H) +< . Preparation of Common Intermediate I-39:

[0528] Step 1: Synthesis of 1-(4-Bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ol:

[0529]

[0530] To a solution of (4-bromophenyl)hydrazine hydrochloride (4.9 g, 22 mmol) in ethanol (60 mL) at rt, was added sodium hydroxide (898 mg, 22.5 mmol) in one portion. The resulting mixture was stirred at rt for 30 min, a then a solution of ethyl 4,4,4-trifluoro-3-oxobutanoate (4.9 g, 27 mmol) in ethanol (10 mL) was added in one portion to the reaction mixture. The reaction was heated to reflux and stirred overnight. After the reaction was completed as indicated by TLC analysis, the reaction was cooled to rt and quenched with water (150 mL). The resulting mixture was acidified to pH 5 with diluted HCl solution (1 N) and extracted with EA (100 mL x 3). The combined organic layer was dried over sodium sulfate (50 g), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA = 30: 1 to 6:1) to afford 6.2 g of the title compound. LC-MS (Method A) (ESI+): m / z 307 (M+H) +< ; 1< H-NMR (300 MHz, CD 3 OD) δ 7.62-7.74 (m, 4H), 5.84 (s, 1H).Step 2: Synthesis of 1-(4-Bromophenyl)-5-methoxy-3-(trifluoromethyl)-1H-pyrazole:

[0531]

[0532] To a solution of methyl 1-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ol (6.2 g, 20 mmol) in DMF (65 ml) at 0 °C, was added sodium hydride (60% dispersion, 973 mg, 0.024 mmol) portion-wise over 5 min. After the mixture was stirred at 0 °C for 30 min, iodomethane (4.26 g, 0.03 mmol) was added dropwise to the reaction mixture over 2 min. The reaction was stirred at rt for 3 h, and then quenched with ice-water (200 mL) and extracted with EA (100 mL x 3). The organic phase was washed with water (100 mL x 2), dried over sodium sulfate (40 g), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE to PE:EA = 100:1) to yield 4.4 g of the title compound. LC-MS (Method A) (ESI+): m / z 321 (M+H) +< ; 1< H-NMR (300 MHz, CD 3 OD) δ 7.55-7.63 (m, 4H), 5.95 (s, 1H), 4.00 (s, 3H).Step 3: Synthesis of 4-(5-Methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzaldehyde:

[0533]

[0534] To solution of 1-(4-bromophenyl)-5-methoxy-3-(trifluoromethyl)-1H-pyrazole (1 g, 3.13 mmol) in THF (10 mL) at -78 °C, was added n-BuLi (1.5 mL, 3.76 mmol) dropwise over 15 min. After the reaction was stirred at -78 °C for 1 h, anhydrous DMF (0.48 mL, 6.26 mmol) was added dropwise to the reaction mixture over 5 min. After addition, the reaction mixture was stirred at -78 °C for additional 30 min and then warmed to rt. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with ice-water (20 mL). The resulting mixture was extracted with EA (30 mL x 2), dried over sodium sulfate (30 g), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA = 30:1 to 20:1) to yield 570 mg of the title compound. LC-MS (Method A) (ESI+): m / z 271 (M+H) +< ; 1< H-NMR (300 MHz, CD 3 OD) δ 10.04 (s, 1H), 7.97 (d, J = 6.6 Hz, 4H), 3.99 (s, 1H), 4.05 (s, 3H).Step 4: Synthesis of (4-(5-Methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol:

[0535]

[0536] To a solution of 4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzaldehyde (570 mg, 2.11 mmol) in THF (10 mL) at rt, was added NaBH 4 (80 mg, 2.11 mmol) in one portion. The reaction was stirred at rt for 1h. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (20 mL) and extracted with EA (20 mL x 2). The combined organic layer was dried over sodium sulfate (20 g), filtered and concentrated in vacuo to afford 620 mg of the title compound that was used without purification in subsequent steps. LC-MS (Method A) (ESI+): m / z 273 (M+H) +< ; 1< H-NMR (300 MHz, CD 3 OD) δ 7.68 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 5.96 (s, 1H), 4.75 (d, J = 5.1 Hz, 2H), 3.99 (s, 3H), 1.58 (s, 1H).Step 5: Synthesis of 1-(4-(Chloromethyl)phenyl)-5-methoxy-3-(trifluoromethyl)-1H-pyrazole:

[0537]

[0538] To a solution of (4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (570 mg, 2.10 mmol) in DCE (20 ml), was added SOCl 2 (748 mg, 6.29 mmol) in one portion. After the addition, the reaction was stirred at 50 °C for 20 min. After the reaction mixture was completed as indicated by TLC analysis, the reaction mixture was concentrated to dryness in vacuo to afford 500 mg of the crude title compound that was used without purification in subsequent steps. LC-MS (Method A) (ESI+): m / z 291 (M+H) +< .Step 6: Synthesis of 6-Chloro-1-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-39):

[0539]

[0540] To a solution of 1-(4-(chloromethyl)phenyl)-5-methoxy-3-(trifluoromethyl)-1H-pyrazole (520 mg, 1.79 mmol) in DMF (25 mL), was added 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (276 mg, 1.79 mmol) and potassium carbonate (741 mg, 5.37 mmol). After the addition, the reaction was stirred at 70 °C for 1 h. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (30 mL) and extracted with EA (30 mL x 2). The combined organic phase was washed with water and brine, dried over sodium sulfate (20 g), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA = 10:1 to 5:1) to afford 330 mg of the title compound. LC-MS (Method A) (ESI+): m / z 409 (M+H) +< ; 1< H -NMR (300 MHz, CD 3 OD) δ 9.05 (s, 1H), 8.17 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 5.93 (s, 1H), 5.66 (s, 2H), 3.99 (s, 3H). The following intermediates were prepared from the appropriate heterocycles and alkylating reagents according to the method of preparation for I-39: IntermediateStructureAnalyticsI-40 LC-MS (Method A) (ESI+): m / z 423 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 9.05 (s, 1H), 8.17 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 5.90 (s, 1H), 5.67 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H).I-41 1< H-NMR (300 MHz, CDCl 3 ) δ 9.05 (s, 1H), 8.17 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 5.94 (s, 1H), 5.66 (s, 2H), 4.27(d, J = 4.5 Hz, 2H), 3.73 (d, J = 4.5 Hz, 2H), 3.73 (s, 1H).I-42 LC-MS (Method A) (ESI+): m / z 595 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 9.05 (s, 1H), 8.17 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 5.94 (s, 1H), 5.66 (s, 2H), 4.21 (t, J = 4.8 Hz, 2H), 4.01 (t, J = 4.8 Hz, 2H), 1.08-1.02 (m, 3H), 0.98 (d, J = 5.4 Hz, 18H).I-43 LC-MS (Method A) (ESI+): m / z 410 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 9.06 (s, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.17 (s, 1H), 7.90 (dd, J= 8.4, 2.1 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 5.96 (s, 1H), 5.69 (s, 2H), 4.02 (s, 3H).I-44 LC-MS (Method A) (ESI+): m / z 511.24 (M+H) +< . Preparation of Common Intermediate I-45:

[0541] Step 1: Synthesis of ethyl 1-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate:

[0542]

[0543] To a solution of (4-bromophenyl)hydrazine hydrochloride (1.0 g, 4.5 mmol) in ethanol (40 mL) was added potassium carbonate (1.23 g, 8.94 mmol). After the reaction was stirred at rt for 30 min, diethyl but-2-ynedioate (761 mg, 4.47 mmol) in ethanol (10 mL) was added to the reaction dropwise over 5 min. After the reaction was stirred under reflux for 4 h, the reaction was quenched with water (50 mL) and adjusted to pH 5 with a dilute hydrochloric acid solution. The resulting mixture was extracted with EA (40 mL x 3). The combined organic layer was dried over sodium sulfate (30 g), filtered and concentrated. The residue was purified by silica gel chromatography (eluent: PE / EA= 10 / 1 to 5:1) to afford 320 mg of the title compound. LC-MS (Method A) (ESI+): m / z 311, 313 (M+H) +< ; 1< H-NMR (300 MHz, CD 3 OD) δ 7.74 (d, J = 9.0 Hz, 2H), 7.71 (d, J = 9.0 Hz, 2H), 6.01 (s, 1H), 4.30-4.38 (q, J = 6.9 Hz, 2H), 1.32-1.38 (t, J = 6.9 Hz, 3H).Step 2: Synthesis of ethyl 1-(4-bromophenyl)-5-methoxy-1H-pyrazole-3-carboxylate:

[0544]

[0545] To a mixture of ethyl 1-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate (720 mg, 2.32 mmol), triphenylphosphine (913 mg, 3.48 mmol) and methanol (96 mg, 3.02 mmol) in toluene (40 mL) at 0 °C, was added DIAD (704 mg, 3.48 mmol) dropwise over 5 min. After the mixture was stirred at 0 °C for 30 min, the reaction was warmed to rt slowly and stirred overnight. After the reaction was complete as indicated by TLC analysis, the mixture was quenched with water (20 mL) and extracted with EA (30 mL x 3). The combined organic layer was dried over sodium sulfate (30 g), filtered and concentrated. The residue was purified by silica gel chromatography (eluent: PE / EA= 20 / 1 to 10 / 1) to yield 650 mg of the title compound. LC-MS (Method A) (ESI+): m / z 325, 327 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.65 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H), 6.22 (s, 1H), 4.39-4.46 (q, J = 7.2 Hz, 2H), 3.98 (s, 3H), 1.39-1.44 (t, J = 7.2 Hz, 3H).Step 3: Synthesis of methyl 1-(4-bromophenyl)-5-methoxy-1H-pyrazole-3 - carboxamide:

[0546]

[0547] In a seal tube, a solution of ethyl 1-(4-bromophenyl)-5-methoxy-1H-pyrazole-3-carboxylate (650 mg, 2.01 mmol) in a saturated methanolic ammonia solution (30 mL) was stirred at 60 °C for 7 h, After the reaction was complete as indicated by TLC analysis, the mixture was quenched with water (30 mL), and extracted with EA (20 mL x 3) . The combined organic layer was dried over sodium sulfate (30 g), filtered and concentrated. The residue was purified by silica gel chromatography (eluent: PE / EA= 5 / 1 to 0 / 1) to yield 405 mg of the title compound. LC-MS (Method A) (ESI+): m / z 296, 298 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.55-7.65 (m, 4H), 6.82 (s, 1H), 6.26 (s, 1H), 5.40 (s, 1H), 3.99 (s, 3H).Step 4: Synthesis of 1-(4-bromophenyl)-5-methoxy-1H-pyrazole-3-carbonitrile:

[0548]

[0549] To a solution of methyl 1-(4-bromophenyl)-5-methoxy-1H-pyrazole-3-carboxamide (400 mg, 1.36 mmol) in DCM (40 mL) and pyridine (2 mL) at 0°C was added trifluoroacetic anhydride (1.6 mL) dropwise over 5 min. The reaction was stirred at 0°C for 1h. After the reaction was complete as indicated by TLC analysis, the mixture was quenched with a saturated aqueous NH 4 Cl solution (40 mL) and extracted with DCM (40 mL x 3). The organic layer was washed with water (20 mL) and brine (20 mL), and dried over sodium sulfate (40 g), filtered and concentrated. The resulting residue was purified by silica gel chromatography (eluent: PE / EA= 20 / 1 to 10 / 1) to yield 295 mg of the title compound. LC-MS (Method A) (ESI+): m / z 278, 280 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.59 (s, 4H), 6.06 (s, 1H), 4.00 (s, 3H).Step 5: Synthesis of 5-methoxy-1-(4-vinylphenyl)-1H-pyrazole-3-carbonitrile:

[0550]

[0551] To a solution of 1-(4-bromophenyl)-5-methoxy-1H-pyrazole-3-carbonitrile (290 mg, 1.05 mmol) in toluene (8 mL) was added tributyl(vinyl)stannane (498 mg, 1.57 mmol) and Pd(Ph 3 ) 4 (121 mg, 0.11 mmol). The reaction was stirred at 90 °C for 6 h. After the reaction was complete as indicated by LC-MS analysis, the mixture was quenched with water (10 mL) and extracted with EA (10 mL x 2). The combined organic layer was dried over sodium sulfate (20 g), filtered and concentrated. The resulting residue was purified by silica gel chromatography (eluent: PE / EA= 20 / 1 to 10 / 1) to yield 200 mg of the title compound. LC-MS (Method A) (ESI+): m / z 226 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.64 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 6.74 (dd, J = 17.7 Hz, J= 10.8Hz, 1H), 6.06 (s, 1H), 5.80 (d, J = 17.7 Hz, 1H), 5.33 (d, J = 10.8 Hz, 1H), 3.99 (s, 3H).Step 6: Synthesis of 1-(4-formylphenyl)-5-methoxy-1H-pyrazole-3-carbonitrile:

[0552]

[0553] To a solution of 5-methoxy-1-(4-vinylphenyl)-1H-pyrazole-3-carbonitrile (20 mg, 0.89 mmol) in THF / H 2 O (10 mL / 5 mL) and was added NaIO 4 (570 mg, 2.67 mmol) and OsO 4 (22 mg, 0.09 mmol) in one portion. The reaction was stirred at room temperature for 30 min. After the reaction was complete as indicated by TLC analysis, the mixture was quenched with an aqueous NH 4 Cl solution (10 mL) and extracted with EA (20 mL x2). The combined organic was dried over sodium sulfate (20 g), filtered and concentrated to afford 210 mg of the crude title compound. LC-MS (Method A) (ESI+): m / z 228 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 10.05 (s, 1H), 7.84-8.05 (m, 4H), 6.01 (s, 1H), 3.99 (s, 3H).Step 7: Synthesis of 1-(4-(hydroxymethyl)phenyl)-5-methoxy-1H-pyrazole-3-carbonitrile:

[0554]

[0555] To a solution of 1-(4-formylphenyl)-5-methoxy-1H-pyrazole-3-carbonitrile (210 mg, 0.93 mmol) in THF (30 mL) was added NaBH 4 (46 mg, 1.2 mmol) portion-wise over 5 min. The reaction was stirred at room temperature for 1h. After the reaction was complete as indicated by TLC analysis, the mixture was quenched with water (20 mL) and extracted with EA (30 mL x 2). The combined organic layer was dried over sodium sulfate (20 g) and concentrated. The residue was purified by silica gel chromatography (eluent: PE / EA= 5 / 1 to 2 / 1) to yield 170 mg of the title compound. LC-MS (Method A) (ESI+): m / z 230 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.67 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 6.07 (s, 1H), 4.76 (d, J = 6 Hz, 2H), 3.99 (s, 3H), 1.75 (t, J = 6 Hz, 1H).Step 8: Synthesis of 1-(4-(chloromethyl)phenyl)-5-methoxy-1H-pyrazole-3-carbonitrile:

[0556]

[0557] To a solution of 1-(4-(hydroxymethyl)phenyl)-5-methoxy-1H-pyrazole-3-carbonitrile (170 mg, 0.74 mmol) in DCE (10 mL) was added SOCl 2 (176 mg, 1.48 mmol) in one portion, and the reaction was stirred at 50 °C for 1 h. After the reaction mixture was complete as indicated by TLC analysis, the reaction mixture was concentrated to dryness to afford 205 mg of the crude title compound. LC-MS (Method A) (ESI+): m / z 248 (M+H) +.< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.70 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 6.07 (s, 1H), 4.62 (s, 2H), 4.00 (s, 3H).Step 9: Synthesis of 1-(4-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)-5-methoxy-1H-pyrazole-3-carbonitrile (I-45):

[0558]

[0559] To a solution of 1-(4-(chloromethyl)phenyl)-5-methoxy-1H-pyrazole-3-carbonitrile (205 mg, 0.83 mmol) in DMF (5 mL) was added 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (153 mg, 1.0 mmol) and potassium carbonate (812 mg, 2.49 mmol) in one portion. After the addition, the reaction was stirred at 70 °C for 1 h. After the reaction mixture was complete as indicated by TLC analysis, the mixture was quenched with water (10 mL) and extracted with EA (30 mL x 2). The combined organic layer was washed with water (20 mL) and brine (10 mL), dried over sodium sulfate (30 g), filtered and concentrated. The residue was purified by silica gel chromatography (eluent: PE / EA= 10 / 1 to 5 / 1) to afford 57 mg of the title compound. LC-MS (Method A) (ESI+): m / z 366 (M+H) +< ; 1< H -NMR (300 MHz, CDCl 3 ) δ 9.05 (s, 1H), 8.18 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 6.04 (s, 1H), 5.67 (s, 2H), 3.97 (s, 3H).Preparation of Common Intermediate I-46:

[0560] Step 1: Synthesis of 4,4,4-trifluoro-3-oxobutanenitrile:

[0561]

[0562] To a stirred suspension of NaH (10.5 g, 264 mmol) in THF (150 mL) at 0 °C, were simultaneously added ethyl 2,2,2-trifluoroacetate 1 (15.0 g, 106 mmol) and MeCN (12.4 g, 159 mmol) under argon atmosphere. The resulting mixture was stirred was at room temperature for 10 min, and then heated to 70 °C for 16h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice cold water (50 mL) and concentrated under reduced pressure to remove the organic phase. The remaining aqueous layer was extracted with diethyl ether (2 x 30 mL). The aqueous layer was then adjusted to pH 2 using conc. HCl, then extracted with diethyl ether (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude title compound 2 (18.0 g) that was used in subsequent steps without further purification.Step 2: Synthesis of ethyl 4-(5-amino-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate:

[0563]

[0564] To a stirred solution of 4,4,4-trifluoro-3-oxobutanenitrile 2 (3.39 g, 24.8 mmol) in methanol (30 mL), was added methyl 4-hydrazineylbenzoate hydrochloride 3 (2.50 g, 12.47 mmol) at room temperature. The reaction mixture was heated to 80 °C for 16h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 20-25% EA in hexane as eluent to afford the title compound (2.00 g). 1< H-NMR (400 MHz, DMSO-d 6 ) δ 8.09 (d, J = 8.48 Hz, 2H), 7.79 (d, J = 8.48 Hz, 2H), 5.98 (br s, 2H), 5.84 (s, 1H), 3.89 (s, 3H).Step 3: Synthesis of methyl 4-(5-acetamido-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate:

[0565]

[0566] To an ice cooled solution of ethyl 4-(5-amino-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate 4 (1.00 g, 3.51 mmol) in pyridine (10 mL), was added CH 3 COCl (0.37 mL, 5.3 mmol) dropwise. The resulting mixture was stirred for 30 min, and progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated CuSO 4 solution (30 mL) and extracted with EA (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 0-40% EA in hexane as eluent to afford the title compound (0.800 g). LC-MS (Method B) (ESI+): Obs.: 328.05 (M+H) +< ; 1< H-NMR (400 MHz, CDCl 3 ) δ 8.21 (d, J = 8.48 Hz, 2H), 7.59 (d, J = 8.48 Hz, 2H), 6.95-7.00 (m, 1H), 3.96 (s, 3H), 2.17 (s, 3H).Step 3: Synthesis of methyl 4-(5-(N-methylacetamido)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate:

[0567]

[0568] To a stirred solution of methyl 4-(5-acetamido-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate 5 (0.800 g, 2.45 mmol) in CH 3 CN (15 mL), was added potassium carbonate (0.506 g, 3.67 mmol) and methyl iodide (0.45 mL, 7.34 mmol) at room temperature. The reaction mixture was then heated in a sealed tube at 85 °C for 16h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with EA (100 mL) and washed with water (2 x 25 mL) followed by brine (20 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 0-30% EA in hexane as eluent to afford the title compound (0.650 g). LC-MS (Method B) (ESI+): Obs.: 342.10 (M+H) +< ; 1< H-NMR (400 MHz, CDCl 3 ) δ 8.19 (d, J = 8.48 Hz, 2H), 7.57 (d, J = 8.48 Hz, 2H), 6.62 (s, 1H), 3.96 (s, 3H), 3.15 (s, 3H), 1.85 (s, 3H).Step 5: Synthesis of methyl 4-(5-(methylamino)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate:

[0569]

[0570] To a stirred solution of methyl 4-(5-(N-methylacetamido)-3-(trifluoromethyl)-1H-pyrazol-1-yl) benzoate 6 (0.650 g, 1.91 mmol) in methanol (10 mL), was added conc. HCl (7 mL) at room temperature. The reaction mixture was then heated at 90 °C for 4 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with EA (3 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 0-30% EA in hexane as eluent to afford the title compound (0.500 g). LC-MS (Method C) (ESI+): m / z 299.98 (M+H) +< ; 1< H-NMR (400 MHz, CDCl 3 ) δ 8.16 (d, J = 8.48 Hz, 2H), 7.68 (d, J = 8.48 Hz, 2H), 5.80 (s, 1H), 3.95 (s, 3H), 2.89 (s, 3H).Step 6: Synthesis of (4-(5-(methylamino)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol:

[0571]

[0572] To a stirred solution of methyl 4-(5-(methylamino)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate 7 (0.500 g, 1.67 mmol) in THF (15 mL) at 0 °C, was added DIBAL-H (1M in toluene, 5.00 mL, 5.02 mmol). The resulting mixture was stirred for 30 min, and progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with aqueous NH 4 Cl (10 mL). The resulting solution was diluted with EA (20 mL) and filtered through a pad of Celite. The aqueous layer was separated and re-extracted with EA (3 x 15 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 50-80% EA in hexane as eluent to afford the title compound (0.400 g). 1< H-NMR (400 MHz, DMSO-d 6 ) δ 7.42-7.51 (m, 4H), 5.89 (s, 1H), 5.83 (d, J = 4.40 Hz, 1H), 5.33 (t, J = 5.62 Hz, 1H), 4.56 (d, J = 5.87 Hz, 2H), 2.69 (d, J = 4.89 Hz, 3H).Step 7: Synthesis of 1-(4-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)-N-methyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (I-46):

[0573]

[0574] To a stirred solution of (4-(5-(methylamino)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol 8 (0.200 g, 0.738 mmol) in THF (10 mL), was added 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.102 g, 0.664 mmol), DIAD (0.336 g, 1.48 mmol) and TPP (0.382 g, 1.48 mmol). The reaction mixture was stirred at room temperature for 1 h, and progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 0-40% EA in hexane as eluent to get the title compound (0.160 g). LC-MS (Method C) (ESI+): m / z 407.86 (M+H) +< .Preparation of Common Intermediate I-47:

[0575] Step 1: Synthesis of ethyl 4-(5-amino-3-(trifluoromethyl)-1H-pyrazol-1-yl)-3-fluorobenzoate:

[0576]

[0577] To a stirred solution of 4,4,4-trifluoro-3-oxobutanenitrile 1 (0.500 g, 2.136 mmol) in methanol (20 mL), was added ethyl 3-fluoro-4-hydrazineylbenzoate hydrochloride 2 (0.731 g, 5.341 mmol) at room temperature. The reaction mixture was then heated to 80 °C for 16h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 15-25% EA in hexane as eluent to afford the title compound (0.070 g). 1< H-NMR (400 MHz, DMSO-d 6 ) δ 7.92 (d, J = 9.29 Hz, 2H), 7.72 (t, J = 7.83 Hz, 1H), 5.91 (s, 2H), 5.75 (s, 1H), 4.37 (q, J = 6.85 Hz, 2H), 1.35 (t, J = 7.09 Hz, 3H).Step 2: Synthesis of ethyl 4-(5-(dimethylamino)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-3-fluorobenzoate:

[0578]

[0579] To a stirred solution of ethyl 4-(5-amino-3-(trifluoromethyl)-1H-pyrazol-1-yl)-3-fluorobenzoate 3 (0.250 g, 0.788 mmol) in DMF (10 mL) at 0 °C, was added 60% dispersion of sodium hydride in oil (0.063 g, 1.577 mmol) and methyl iodide (0.145 mL, 2.365 mmol). The resulting mixture was stirred for 16h, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice cold water (10 mL) and extracted with EA (2 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 0-10% EA in hexane as eluent to afford the title compound (0.070 g). 1< H-NMR (400 MHz, DMSO-d 6 ) δ 7.94-8.00 (m, 2H), 7.79-7.85 (m, 1H), 6.40 (s, 1H), 4.37 (q, J = 6.85 Hz, 2H), 2.56 (s, 6H), 1.35 (t, J = 7.09 Hz, 3H).Step 3: Synthesis of (4-(5-(dimethylamino)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-3-fluorophenyl)methanol:

[0580]

[0581] To an ice cooled solution of ethyl 4-(5-(dimethylamino)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-3-fluorobenzoate 4 (0.150 g, 0.434 mmol) in methanol (10 mL), was added sodium borohydride (0.066 g, 1.739 mmol) portion-wise. Upon complete addition, the reaction mixture was stirred for 5h and progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with aqueous NH 4 Cl solution (10 mL) and extracted with EA (3 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography eluting with 40-50% EA in hexane to afford the title compound (0.090 g). LC-MS (Method B) (ESI+): m / z 304.00 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) δ 7.56 (t, J = 7.98 Hz, 1H), 7.38 (d, J = 11.47 Hz, 1H), 7.32 (d, J = 7.98 Hz, 1H), 6.35 (s, 1H), 5.49 (t, J = 5.73 Hz, 1H), 4.59 (d, J = 5.49 Hz, 2H), 2.54 (s, 6H).Step 4: Synthesis of 1-(4-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-fluorophenyl)-N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (I-47):

[0582]

[0583] To a stirred solution of (4-(5-(dimethylamino)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-3-fluorophenyl)-methanol 5 (0.080 g, 0.264 mmol) in THF (5 mL), was added 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.036 g, 0.237 mmol), DTAD (0.119 g, 0.528 mmol) and TPP (0.136 g, 0.528 mmol) at room temperature. The resulting mixture was stirred for 1h, and progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by silica gel chromatography eluting with 0-60% EA in hexane to afford the title compound (0.060 g). LC-MS (Method B) (ESI+): m / z 440.00 (M+H) +< ; 1< H-NMR (400 MHz, DMSO-d 6 ) δ 9.33 (s, 1H), 8.54 (s, 1H), 7.60 (t, J = 8.07 Hz, 1H), 7.38 (d, J = 10.76 Hz, 1H), 7.21 (d, J = 8.31 Hz, 1H), 6.35 (s, 1H), 5.77 (s, 2H), 2.52 (s, 6H). The following intermediates were prepared from the appropriate heterocycles and alkylating reagents according to the method of preparation for I-47: IntermediateStructureAnalyticsI-48 LC-MS (Method A) (ESI+): m / z 422 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 9.19 (s, 1H), 8.12 (s, 1H) 7.80 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 6.08 (s, 1H), 5.87 (s, 2H), 2.62 (s, 6H).I-49 LC-MS (Method B) (ESI+): m / z 404.00 (M+H) +< . Preparation of Common Intermediate I-50:

[0584] Step 1: Synthesis of 1-(4-bromophenyl)-3-(trifluoromethyl) -1H-pyrazole-5-thiol:

[0585]

[0586] To a solution of 1-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ol (900 mg, 2.94 mmol) in toluene (40 mL), was added Lawesson's Reagent (2.38 g, 5.88 mmol). The reaction was then stirred under reflux for 4 h. After the reaction was completed as indicated by TLC analysis, the suspension was filtered, and the filtrate was concentrated to dryness to afford 2.6 g of the crude title compound. LC-MS (Method A) (ESI+): m / z 323, 325 (M+H) +< .Step 2: Synthesis of 1-(4-bromophenyl)-5-(methylthio)-3-(trifluoromethyl) -1H-pyrazole:

[0587]

[0588] To a solution of crude methyl 1-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-thiol (2.6 g, 8.1 mol) in DMF (20 mL) at 0 °C, was added NaH (388 mg, 9.69 mmol) portion-wise over 5 min. After the mixture was stirred at 0 °C for 30 min, MeI (1.72 g, 12.1 mmol) was added dropwise over 2 min. The reaction was stirred at 0 °C initially, and then warmed to room temperature over 3 h. After the reaction was completed as indicated by TLC analysis, the mixture was quenched with ice-water (20 mL) and extracted with EA (20 mL x 3). The organic layer was washed with water (20 mL x 2) and brine (20 mL), dried over sodium sulfate (20 g), filtered and concentrated. The residue was purified by silica gel chromatography (eluent: PE / EA=50 / 0 to 50 / 1) to yield 650 mg of the title compound. LC-MS (Method A) (ESI+): m / z 337, 339 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.63 (d, J = 6.9 Hz, 2H), 7.48 (d, J = 6.9 Hz, 2H), 6.57 (s, 1H), 2.44 (s, 3H).Step 3: Synthesis of 4-(5-(methylthio)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzaldehyde:

[0589]

[0590] To a solution of 1-(4-bromophenyl)-5-(methylthio)-3-(trifluoromethyl)-1H-pyrazole 3 (550 mg, 1.64 mmol) in anhydrous THF (10 mL) at -78 °C, was added n-BuLi (0.98 mL, 2.46 mmol) dropwise over 5 min. After stirring for 1h at -78 °C, DMF (240 mg, 3.28 mmol) was added dropwise over 5 min, and the mixture was warmed to rt slowly over 2 h. After the reaction was complete as indicated by TLC analysis, the mixture was quenched with ice water (20 mL). The resulting mixture was extracted with EA (30 mL x 2). The organic layer was dried over sodium sulfate (30 g), filtered and concentrated. The resulting residue was purified by silica gel chromatography (eluent: PE / EA=100 / 1 to 50 / 1) to yield 100 mg of the title compound. LC-MS (Method A) (ESI+): m / z 287 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 10.08 (s, 1H), 8.02 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H), 6.61 (s, 1H), 2.48 (s, 3H).Step 4: Synthesis of (4-(5-(methylthio)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol:

[0591]

[0592] Prepared according to the reduction procedure of I-8. LC-MS (Method A) (ESI+): m / z 289 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 7.57 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 6.57 (s. 1H), 4.78 (s, 2H), 2.43 (s, 3H), 1.83 (br s, 1H).Step 5: Synthesis of 6-chloro-1-(4-(5-(methylthio)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-50):

[0593]

[0594] To a suspension of 5 (130 mg, 0.45 mol), 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (90 mg, 0.59 mmol) and PS-TPP (300 mg, 0.9 mmol) in anhydrous THF (10 mL) at 0 °C, was added DIAD ( 136 mg, 0.68 mmol) dropwise over 5 min. The reaction was stirred in an ice-water bath for 30 min and then warmed to rt slowly overnight. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (20 mL) and extracted with EA (20 mL x 2). The combined organic layer was dried and concentrated. The residue was purified by silica gel chromatography (eluent: PE / EA=10 / 1 to 1 / 0) to afford 160 mg of the crude product. The crude product was further purified by preparative HPLC (Method A) to give 30 mg of the title compound. LC-MS (Method A) (ESI+): m / z 425 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 9.06 (s. 1H), 8.19 (s, 1H), 7.59-7.45 (m, 4H), 6.55 (s. 1H), 5.70 (s, 2H), 2.42 (s, 3H).Preparation of Common Intermediate I-51:

[0595] Step 1: Synthesis of Methyl 4-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)benzoate:

[0596]

[0597] To a mixture of 3-bromo-5-methoxy-1-methyl-1H-1,2,4-triazole (500 mg, 2.60 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.02 g, 3.91 mmol), tricyclohexylphosphine (219.07 mg, 0.78 mmol), K 3 PO 4 -3H 2 O (2.08 g, 7.81 mmol) in dioxane (26 mL) and H 2 O (1.3 mL) was added Pd 2 (dba) 3 (238.45 mg, 0.26 mmol) under nitrogen. The resulting mixture was stirred at 90 °C for 1 hr. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (30 mL) and extracted with EA (25 mL x 3). The combined organic layer was dried over anhydrous Na 2 SO 4 (30 g), filtered, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (PE:EA = 10:1) to provide 650 mg of the title compound. 1< H-NMR (300 MHz, CDCl 3 ) δ 8.08 (s, .4H), 4.17 (s, 3H), 3.93 (s, 3H), 3.68 (s, 3H).Step 2: Synthesis of (4-(5-Methoxy-1-methyl-1H-1,2,4-triazol-3-yl)phenyl)methanol:

[0598]

[0599] To a solution of methyl 4-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl) benzoate (650 mg, 2.63 mmol) in THF (26 mL) at 0 °C, was added DIBAL-H (1.5 M, 7.9 mL, 11.9 mmol) dropwise over 15 min. The resulting mixture was stirred at 0 °C for 1 h, then slowly diluted with a saturated aqueous NH 4 Cl solution (10 mL). The resulting suspension was stirred in an ice-water bath for additional 30 min and then filtered to remove the solids. The filter cake was washed with EA (30 mL x 4), and the resulting filtrate was washed with brine (50 mL). After separation, the organic layer was dried over anhydrous Na 2 SO 4 (30 g), filtered, and concentrated to give a crude residue that was purified by silica gel chromatography (PE:EA = 3:1 to 2:1) to give 500 mg of the title compound. 1< H-NMR (300 MHz, CDCl 3 ) δ 8.00 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 4.73 (d, J = 6.0 Hz, 2H), 4.16 (s, 3H), 3.67 (s, 3H), 1.70 (t, J = 6.0 Hz, 1H).Step 3: Synthesis of 3-(4-(Chloromethyl)phenyl)-5-methoxy-1-methyl-1H-1,2,4-triazole:

[0600]

[0601] To a solution of (4-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)phenyl)methanol (450 mg, 2.05 mmol) in DCM (25 mL) at rt, was added PPh 3 (592 mg, 2.26 mmol) and NBS (438 mg, 2.05 mmol) in one portion. The reaction mixture was stirred at rt for 1.5 h. After the reaction was completed, as indicated by TLC analysis, the reaction mixture was concentrated in vacuo and the crude residue was purified by silica gel chromatography (PE:EA = 5:1 to 3:1) to give 480 mg of the title compound. 1< H-NMR (300 MHz, CDCl 3 ) δ 7.98 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.53 (s, 2H), 4.16 (s, 3H), 3.66 (s, 3H).Step 4: Synthesis of 6-Chloro-1-(4-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (I-51):

[0602]

[0603] To a solution of 3-(4-(chloromethyl)phenyl)-5-methoxy-1-methyl-1H-1,2,4-triazole (480 mg, 1.70 mmol) and 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (316 mg, 2.04 mmol) in DMF (17 mL), was added Cs 2 CO 3 (1.66 g, 5.10 mmol) in one portion and the reaction was stirred at 80 °C for 1 h. After the reaction was completed (as indicated by TLC analysis), the mixture was cooled to rt. The reaction was then quenched by ice-water (30 mL) and extracted with EA (50 mL x 2). The combined organic layer was washed with water (40 mL x 3), dried over sodium sulfate (30 g), filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 1:1 to 1:3) to yield 220 mg of the title compound. LC-MS (Method A) (ESI+): m / z 356 (M+H) +< ; 1< H-NMR (300 MHz, CDCl 3 ) δ 9.03 (s, 1H), 8.16 (s, 1H), 7.95 (d, J = 81 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 5.65 (s, 2H), 4.13 (s, 3H), 3.64 (s, 3H). The following intermediate was prepared from the appropriate heterocycle and alkylating reagent according to the method of preparation for I-51: IntermediateStructureAnalyticsI-52 1< H-NMR (300 MHz, CDCl 3 ) δ 9.05 (s, 1H), 8.18 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 5.67 (s, 2H), 4.08 (s, 3H). Preparation of Common Intermediate I-53

[0604] Step 1: Synthesis of (4-(Acetoxymethyl)phenyl)boronic acid:

[0605]

[0606] A mixture of (4-(hydroxymethyl)phenyl)boronic acid (3 g, 0.02 mol) and acetic anhydride (4.08 g, 0.04 mol) in pyridine (5 mL, 0.062 mol), was a stirred at rt for 4 h. After the reaction was complete as indicated by TLC analysis, the mixture was poured into dilute aqueous HCl solution (2 N, 20 mL) and extracted with EA (30 mL x 2). The combined organic phase was washed with saturated sodium bicarbonate solution (50 mL), dried over sodium sulfate (30 g), filtered, and concentrated in vacuo to afford 4.5 g of the crude title compound. 1< H-NMR (300 MHz, CD 3 OD) δ 8.04 (d, J = 7.8 Hz, 2H), 7.38 (d, J = 7.8 Hz, 2H), 5.13 (s, 2H), 2.11 (s, 3H).Step 2: Synthesis of 4-(3-Cyano-5-methyl-1H-pyrazol-1-yl)benzyl acetate:

[0607]

[0608] To a mixture of (4-(acetoxymethyl)phenyl)boronic acid (1.087 g, 5.60 mmol), 5-methyl-1H-pyrazole- 3-carbonitrile (500 mg, 11.60 mmol), triethylamine (709 mg, 4.67 mmol), pyridine (1.11 g, 14.07 mmol) in DCM (20 mL), was added cupric acetate monohydrate (1.14 g, 6.26 mmol) and the resulting mixture was stirred at 40 °C overnight. After the reaction was complete as indicated by TLC analysis, the reaction was quenched by addition of water (20 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with water (20 mL), dried over sodium sulfate (30 g), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography on silica (PE:EA =30:1 to 6:1) to afford 390 mg of the title compound. LC-MS (Method A) (ESI+): m / z 256 (M+H) +< ; 1< H-NMR (300 MHz, CD 3 OD) δ 7.51 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 8.7 Hz, 2H), 6.60 (s, 1H), 5.18 (s, 2H), 2.36 (s, 3H), 2.15 (s, 3H).Step 3 Synthesis of 1-(4-(Hydroxymethyl)phenyl)-5-methyl-1H-pyrazole-3-carbonitrile:

[0609]

[0610] To a solution of 4-(3-cyano-5-methyl-1H-pyrazol-1-yl)benzyl acetate (390 mg, 1.53 mmol) in THF (40 mL) and water (5 mL), was added lithium hydroxide (128 mg, 3.06 mmol) in one portion. The reaction was stirred at rt for 3 h. After the reaction was complete as indicated by TLC analysis, the reaction was quenched with ice-water (10 mL). The resulting mixture was extracted with EA (10 mL x 2) and the layers separated. The combined organic layer was dried over sodium sulfate (10 g), filtered, and concentrated to afford 300 mg of the crude title compound. LC-MS (Method A) (ESI+): m / z 214 (M+H) +< ; 1< H-NMR (300 MHz, CD 3 OD) δ 7.56 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 6.75 (s, 1H), 4.70 (s, 2H), 2.37 (s, 3H).Step 4: Synthesis of 1-(4-(Chloromethyl)phenyl)-5-methyl-1H-pyrazole-3-carbonitrile:

[0611]

[0612] To a solution of 1-(4-(hydroxymethyl)phenyl)-5-methyl-1H-pyrazole-3-carbonitrile (300 mg, 0.96 mmol) in DCE (6 mL), was added SOCl 2 (341 mg, 2.87 mmol) in one portion. After the addition, the reaction was stirred at 60 °C for 1 h. After the reaction mixture was complete as indicated by TLC analysis, the reaction mixture was concentrated to dryness in vacuo to afford 330 mg of the crude title compound. LC-MS (Method A) (ESI+): m / z 232 (M+H) +< ; 1< H-NMR (300 MHz, CD 3 OD) δ 7.55 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 6.10 (s, 1H), 4.65 (s, 2H), 2.38 (s, 3H).Step 5: Synthesis of 1-(4-((6-Chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)-5-methyl-1H-pyrazole-3-carbonitrile (I-53):

[0613]

[0614] To a solution of 1-(4-(chloromethyl)phenyl)-5-methyl-1H-pyrazole-3-carbonitrile (330 mg, 1.43 mmol) in DMF (5 mL), was added 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (220 mg, 1.43 mmol) and potassium carbonate (590 mg, 4.29 mmol). After the addition, the reaction was stirred at 70 °C for 1 h. After the reaction was complete as indicated by TLC analysis, the reaction was quenched with water (10 mL) and extracted with EA (10 mL x 2). The combined organic phase was washed with water, dried over sodium sulfate (10 g), filtered, and concentrated in vacuo. The residu...

Claims

1. A compound having Formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein: is each of R1 and R2 is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R3 is an optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, or optionally substituted pyrazolyl; each of X11 and X12 is independently selected from N and CH; R5' is selected from hydrogen, 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)R23, -C(=O)OR24, -NR32aR32b, -NR31aC(=O)R25, -NR31aC(=O)NR31aR31b, -C(=O)NR31a R31b, -S(O)2R27, -NR31aSO2R27, optionally substituted (C6-C14) aryl, optionally substituted (C6-C14) 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-C14) aryl, optionally substituted -O-(C6-C14) 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; R5 is selected from 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)R23, -C(=O)OR24, -NR32aR32b, -NR31aC(=O)R25, -NR31aC(=O)NR31aR31b, -C(=O)NR31a R31b, -S(O)2R27, -NR31aSO2R27, optionally substituted (C6-C14) aryl, optionally substituted (C6-C14) 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-C14) aryl, optionally substituted -O-(C6-C14) 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; or one of R5 and one of R5' on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted (C6-C14) aryl ring; or one of R5 and one of R5' on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted heteroaryl ring; or one of R5 and one of R5' on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted (C3-C8) cycloalkyl ring; or one of R5 and one of R5' on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl ring; or one of R5 and one of R5' on adjacent atoms on the same atom to which they are attached are taken together to form an optionally substituted spirocycloalkyl ring; or one of R5 and one of R5' on adjacent atoms on the same atom to which they are attached are taken together to form an optionally substituted spiroheterocycloalkyl ring; each of R5 and R7 is independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R23 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; R31a and R31b 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; and each of R24, R25, R27, R32a, and R32b 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.

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the optional substituents on R3 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, 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, (cycloalkylamino)alkyl, (C1-4 haloalkoxy)alkyl, and (heteroaryl)alkyl; or wherein two of the optional substituents on R3 are taken together with the carbon or nitrogen atoms to which they are attached to form an optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl group.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, a) wherein R3 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, or b) wherein R3 is an optionally substituted pyrid-3-yl or 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 wherein 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, or c) wherein R3 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, or d) wherein R3 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, or e) wherein R3 is selected from the group consisting of:

4. The compound of any one of claims 3 option a), 3 option b), 3 option c), or 3 option d), wherein R3 is substituted and the substituents are 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.

5. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, a) wherein at least one of X11 and X12 is N, or b) wherein the optional substituents on R5 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, (C1-4 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)R23, - C(=O)OR24, -C(=O)NR31a R31b, -NR31aC(=O)R25, -NR31aC(=O)OR26, -NR31aC(=O)NR31aR31b, -NR31aSO2R27, -OC(=O)R28, -OC(=O)OR29, -OC(=O)NR31a R31b, -OSO2R30, and -NR32aR32b; or wherein two of the optional substituents on R5 are taken together with the carbon atoms to which they are attached to form an optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl group; and each of R24, R25, R26, R27, R28, R29, R30, R32a, and R32b 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.

6. The compound of claim 1 or 5 option b), or a pharmaceutically acceptable salt or solvate thereof, a) wherein R5 is selected from 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)R23, -C(=O)OR24, -NR32aR32b, -NR31aC(=O)R25, -NR31aC(=O)NR31aR31b, -C(=O)NR31a R31b, -S(O)2R27, -NR31aSO2R27, optionally substituted -O-(C6-C14) aryl, optionally substituted -O-(C6-C14) 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, or b) wherein R5 is selected from optionally substituted (C6-C14) aryl, optionally substituted (C6-C14) 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.

7. The compound of claim 1, 5 option b), or 6 option b), or a pharmaceutically acceptable salt or solvate thereof, a) wherein R5 is an optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazolyl, or optionally substituted tetrazolyl, and / or b) wherein R5 is an optionally substituted imidazolyl, or c) wherein R5 is an optionally substituted pyrazolyl, or d) wherein R5 is an optionally substituted triazolyl, or e) wherein R5 is selected from the group consisting of:

8. The compound of any one of claims 7 option a), 7 option b), or 7 option c), wherein R5 is substituted and 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.

9. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, having a Formula II: wherein: X1 is CR2; X2 is N; X3 is selected from N and CR10; X4 is selected from N and CR11; X5 is selected from N and CR12; and each of R8, R9, R10, R11, and R12 is independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, 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, (cycloalkylamino)alkyl, (C1-4 haloalkoxy)alkyl, or (heteroaryl)alkyl, preferably having Formula III, Formula IV, Formula V, Formula VI, or Formula Vla: and / or wherein R5 is: wherein: X6 is selected from NR13 and CR18; X7 is selected from NR14 and CR19; X8 is selected from NR15 and CR20; X9 is selected from NR16 and CR21; X10 is selected from NR17 and CR22; each of R13, R14, R15, R16, and R17 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; and each of R18, R19, R20, R21, and R22 is independently selected from hydrogen, halo, methyl, ethyl, isopropyl, cyclopropyl, methoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methylsulfonyl, and methylazetidinyl, preferably having Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, or Formula XII:

10. A compound a) selected from the group consisting of: 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 pharmaceutically acceptable salt or solvate thereof, or b) selected from the group consisting of: 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 thereof.

11. The compound of claim 10 option b), wherein the compound 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 pharmaceutically acceptable salt or solvate thereof.

12. A pharmaceutical composition comprising the compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, preferably for use in the treatment of cancer.

13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer.

14. A kit comprising the compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 12 and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition to a patient having cancer.

15. The pharmaceutical composition of claim 12, the compound for use of claim 13, or the kit of claim 14, wherein the cancer is selected from the group consisting of a hematological cancer, a lymphatic cancer, a DNA damage repair pathway deficient cancer, a homologous-recombination deficient cancer, a cancer comprising cancer cells with a mutation in a gene encoding p53, and a cancer comprising cancer cells with a loss of function mutation in a gene encoding p53, or wherein 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.

16. An in vitro method of inhibiting a USP1 protein comprising contacting a USP1 protein with the compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound of any one of claims 1-11 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

17. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 12 for use in the treatment of cancer in a patient, wherein the cancer comprises cancer cells with a mutation in a gene encoding p53, or wherein the cancer comprises cancer cells with a mutation in a gene encoding BRCA1, or wherein the cancer comprises cancer cells with a mutation in a gene encoding BRCA2, or wherein the cancer comprises cancer cells with a mutation in a gene encoding ATM, or wherein the cancer comprises cancer cells with a mutation in one or more genes encoding at least two of p53, BRCA1, BRCA2, and ATM, or wherein the cancer is triple negative breast cancer.