Substituted pyrazolopyrimidines and substituted purines and their use as ubiquitin-specific-processing protease 1 (USP1) inhibitors
The present disclosure provides compounds having Formula I: and the pharmaceutically acceptable salts and solvates thereof, wherein X 1 , X 2 , X 11 , X 12 , R 1 , R 3 , R 5 , R 5′ , R 6 , and R 7 are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to inhibit a USP1 protein and/or to treat a disorder responsive to the inhibition of USP1 proteins and USP1 activity. Compounds of the present disclosure are especially useful for treating cancer.
1. A method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound having Formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
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 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 31a (═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;
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.
2. The method of claim 1 , 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.
3. The method of claim 1 , wherein the cancer is a triple negative breast cancer.
4. The method of claim 1 , wherein the cancer comprises cancer cells with a mutation in a gene encoding p53, wherein the mutation in the gene encoding p53 is a loss of function mutation.
5. The method of claim 1 , wherein the cancer is a BRCA1 mutant cancer, a BRCA2 mutant cancer, a BRCA1 mutant cancer and a BRCA2 mutant cancer, a PARP inhibitor resistant or refractory cancer, a PARP inhibitor resistant or refractory BRCA1 or BRCA2 mutant cancer, a DNA damage repair pathway deficient cancer, or a homologous-recombination deficient cancer.
6. The method of claim 1 , wherein the cancer is ovarian cancer.
7. The method of claim 1 , wherein the cancer is breast cancer.
8. The method of claim 1 , wherein the cancer is a BRCA1 mutant cancer, a BRCA2 mutant cancer, or a BRCA1 mutant cancer and a BRCA2 mutant cancer.
9. The method of claim 1 , wherein the cancer is a PARP inhibitor resistant or refractory cancer.
10. The method of claim 1 , a PARP inhibitor resistant or refractory BRCA1 or BRCA2 mutant cancer.
11. The method of claim 1 , wherein R 3 is an optionally substituted phenyl, an optionally substituted pyrid-3-yl, an optionally substituted pyrid-4-yl, an optionally substituted pyrimidin-5-yl, or an optionally substituted pyrazol-5-yl; and
when R 3 is substituted, 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.
12. The method of claim 1 , wherein R 3 is selected from the group consisting of:
13. The method of claim 1 , wherein R 5 is an optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazolyl, or optionally substituted tetrazolyl; and
when R 5 is substituted, the substituents are independently selected from halo, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, triazolyl, cyano, optionally substituted alkyl, amino, alkylamino, dialkylamino, difluoromethyl, trifluoromethyl, methyl sulfonyl, oxetan-3-yl, and methylazetidinyl.
14. The method of claim 1 , wherein R 5 is selected from the group consisting of:
15. The method of claim 1 , wherein the compound has a Formula II:
wherein:
X 1 is CR 2 ;
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, alkyl sulfonyl, 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.
16. The method of claim 11 , wherein the compound has a Formula III, Formula IV, Formula V, Formula VI, Formula Via, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, or Formula XII:
17. A method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound 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-(methyl sulfonyl)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-(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-(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;
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;
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-(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-(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-(benzyl oxy)-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.
18. The method of claim 17 , 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.
19. The method of claim 18 , 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.
20. The method of claim 18 , wherein the cancer is ovarian cancer.
21. The method of claim 18 , wherein the cancer is breast cancer.
22. The method of claim 18 , wherein the cancer is a triple negative breast cancer.
23. The method of claim 18 , wherein the cancer comprises cancer cells with a mutation in a gene encoding p53.
24. The method of claim 18 , wherein the cancer is a BRCA1 mutant cancer, a BRCA2 mutant cancer, a BRCA1 mutant cancer and a BRCA2 mutant cancer, a PARP inhibitor resistant or refractory cancer, a PARP inhibitor resistant or refractory BRCA1 or BRCA2 mutant cancer, a DNA damage repair pathway deficient cancer, or a homologous-recombination deficient cancer.
25. The method of claim 16 , wherein the cancer is a BRCA1 mutant cancer, a BRCA2 mutant cancer, or a BRCA1 mutant cancer and a BRCA2 mutant cancer.
26. The method of claim 16 , wherein the cancer is a PARP inhibitor resistant or refractory cancer.
27. The method of claim 16 , wherein the cancer is a PARP inhibitor resistant or refractory BRCA1 or BRCA2 mutant cancer.
28. The method of claim 1 , wherein the compound has a Formula VIa:
wherein R 8 is optionally substituted cycloalkyl, R 9 is alkoxy, and R 11 is hydrogen; or
wherein the compound has a Formula IX:
wherein R 17 is optionally substituted alkyl, R 20 is optionally substituted alkyl, and R 21 is hydrogen.
29. A method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound having Formula I:
or a pharmaceutically acceptable salt or solvate thereof
each of X 1 and X 2 is independently selected from N and CR 2 ;
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 selected from the group consisting of:
each of X 11 and X 12 is independently selected from N and CH;
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;
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.
30. A method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound having Formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
each of X 1 and X 2 is independently selected from N and CR 2 ;
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 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 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;
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.