WO2024061300A1 - Inhibitors of trex1 and uses thereof - Google Patents
Inhibitors of trex1 and uses thereof Download PDFInfo
- Publication number
- WO2024061300A1 WO2024061300A1 PCT/CN2023/120257 CN2023120257W WO2024061300A1 WO 2024061300 A1 WO2024061300 A1 WO 2024061300A1 CN 2023120257 W CN2023120257 W CN 2023120257W WO 2024061300 A1 WO2024061300 A1 WO 2024061300A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- alkyl
- formula
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 562
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims description 450
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 161
- 229910052736 halogen Inorganic materials 0.000 claims description 89
- 150000002367 halogens Chemical group 0.000 claims description 89
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 74
- 238000000034 method Methods 0.000 claims description 68
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 65
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 61
- 229910052739 hydrogen Inorganic materials 0.000 claims description 59
- 239000001257 hydrogen Substances 0.000 claims description 59
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 52
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 52
- 229910052757 nitrogen Inorganic materials 0.000 claims description 47
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 47
- 150000002431 hydrogen Chemical group 0.000 claims description 34
- 125000004043 oxo group Chemical group O=* 0.000 claims description 33
- 229910052760 oxygen Inorganic materials 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 229910052717 sulfur Inorganic materials 0.000 claims description 25
- 241000124008 Mammalia Species 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 16
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 16
- 201000011510 cancer Diseases 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 12
- 125000004429 atom Chemical group 0.000 claims description 12
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 10
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 206010005003 Bladder cancer Diseases 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010014733 Endometrial cancer Diseases 0.000 claims description 5
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 206010038389 Renal cancer Diseases 0.000 claims description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 5
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 5
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 201000007450 intrahepatic cholangiocarcinoma Diseases 0.000 claims description 5
- 201000010982 kidney cancer Diseases 0.000 claims description 5
- 201000007270 liver cancer Diseases 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- 201000002510 thyroid cancer Diseases 0.000 claims description 5
- 206010044412 transitional cell carcinoma Diseases 0.000 claims description 5
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 5
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 4
- 201000010536 head and neck cancer Diseases 0.000 claims description 4
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 324
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 31
- 201000010099 disease Diseases 0.000 abstract description 26
- 102100024855 Three-prime repair exonuclease 1 Human genes 0.000 abstract description 15
- 238000011282 treatment Methods 0.000 abstract description 12
- 208000035475 disorder Diseases 0.000 abstract description 5
- 101000830956 Homo sapiens Three-prime repair exonuclease 1 Proteins 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 216
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 168
- -1 2-methyl-3-butyl Chemical group 0.000 description 150
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 141
- 239000000243 solution Substances 0.000 description 130
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 117
- 239000012044 organic layer Substances 0.000 description 109
- 239000012071 phase Substances 0.000 description 109
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 103
- 235000019439 ethyl acetate Nutrition 0.000 description 94
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 89
- 239000007832 Na2SO4 Substances 0.000 description 82
- 229910052938 sodium sulfate Inorganic materials 0.000 description 82
- 239000012267 brine Substances 0.000 description 77
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 77
- 238000004440 column chromatography Methods 0.000 description 72
- 238000005160 1H NMR spectroscopy Methods 0.000 description 61
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 54
- 238000000746 purification Methods 0.000 description 43
- 125000004432 carbon atom Chemical group C* 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- 238000004808 supercritical fluid chromatography Methods 0.000 description 37
- 125000000753 cycloalkyl group Chemical group 0.000 description 34
- 125000001072 heteroaryl group Chemical group 0.000 description 34
- 239000011541 reaction mixture Substances 0.000 description 34
- 238000002953 preparative HPLC Methods 0.000 description 33
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 32
- 239000012299 nitrogen atmosphere Substances 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 30
- 125000003118 aryl group Chemical group 0.000 description 29
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
- 125000000217 alkyl group Chemical group 0.000 description 27
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 27
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 24
- 125000003226 pyrazolyl group Chemical group 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 23
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 22
- 239000007858 starting material Substances 0.000 description 22
- 238000010829 isocratic elution Methods 0.000 description 21
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 20
- 239000000543 intermediate Substances 0.000 description 19
- 239000000725 suspension Substances 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 238000009472 formulation Methods 0.000 description 17
- 125000001786 isothiazolyl group Chemical group 0.000 description 17
- 125000000842 isoxazolyl group Chemical group 0.000 description 17
- 125000002971 oxazolyl group Chemical group 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 125000000335 thiazolyl group Chemical group 0.000 description 17
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- CVCYZCBJCQXUCN-UHFFFAOYSA-N 1,2-oxazol-4-amine Chemical compound NC=1C=NOC=1 CVCYZCBJCQXUCN-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 125000003545 alkoxy group Chemical group 0.000 description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- 229910015845 BBr3 Inorganic materials 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 125000001715 oxadiazolyl group Chemical group 0.000 description 13
- 108010036169 three prime repair exonuclease 1 Proteins 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 12
- 125000000304 alkynyl group Chemical group 0.000 description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 12
- 238000010828 elution Methods 0.000 description 12
- 125000004404 heteroalkyl group Chemical group 0.000 description 12
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 12
- 239000001301 oxygen Substances 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- 125000001188 haloalkyl group Chemical group 0.000 description 11
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 125000002098 pyridazinyl group Chemical group 0.000 description 11
- 125000001425 triazolyl group Chemical group 0.000 description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 11
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 description 10
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 10
- 150000002825 nitriles Chemical class 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 9
- 150000007942 carboxylates Chemical class 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 125000000392 cycloalkenyl group Chemical group 0.000 description 9
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 9
- 125000000714 pyrimidinyl group Chemical group 0.000 description 9
- 239000011593 sulfur Substances 0.000 description 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 8
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 8
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Substances BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 239000011701 zinc Substances 0.000 description 8
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 description 7
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 229910052681 coesite Inorganic materials 0.000 description 6
- 229910052906 cristobalite Inorganic materials 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229910052682 stishovite Inorganic materials 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 229910052905 tridymite Inorganic materials 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229910006124 SOCl2 Inorganic materials 0.000 description 5
- 125000002947 alkylene group Chemical group 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- 125000000168 pyrrolyl group Chemical group 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 4
- 102000053602 DNA Human genes 0.000 description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- 239000012448 Lithium borohydride Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
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- 239000002775 capsule Substances 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 229910052805 deuterium Inorganic materials 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 229910010084 LiAlH4 Inorganic materials 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- TREX1 Three-prime repair exonuclease 1
- TREX1 dampens the intrinsic immune response to tumors by preventing activation of the DNA-sensing cGAS/STING pathway in tumor cells, which is required for activation of T cells and cross presentation of tumor antigens by dendritic cells.
- Many advanced cancers exhibit deficient DNA repair, due to mutations in genes encoding proteins involved in various DNA repair pathways, leading to increased tumor virulence.
- TREX1 mutations also result in increased levels of cytosolic DNA and correspondingly increased levels of TREX1, which in turn sufficiently degrades cytosolic DNA and diminishes the extent of activation ofthe cGAS-STING pathway.
- high levels of TREXI expression facilitate evasion of immune recognition, and therapeutic intervention with agents that inhibit TREX I will result in activation of the cGAS-STING pathway and promote systemic antitumor immunity. Consequently, TREX1 inhibition is a promising therapeutic target for treating cancer.
- a compound, or a pharmaceutically acceptable salt thereof having the structure of Formula (Ia-1) :
- a compound, or a pharmaceutically acceptable salt thereof having the structure of Formula (Ia-3) to Formula (Ia-5) :
- a pharmaceutical composition comprising a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof.
- a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, wherein the cancer is a solid tumor.
- a method of treating cancer in a mammal in need thereof comprising administering to the mammal a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, wherein the cancer is head and neck cancer, intra-hepatic cholangiocarcinoma, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.
- the cancer is head and neck cancer, intra-hepatic cholangiocarcinoma, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.
- Carboxyl refers to -COOH.
- Cyano refers to -CN.
- Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopent
- a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
- the alkyl is a C 1- 10 alkyl.
- the alkyl is a C 1-6 alkyl.
- the alkyl is a C 1 - 5 alkyl.
- the alkyl is a C 1-4 alkyl.
- the alkyl is a C 1-3 alkyl.
- an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
- the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
- the alkyl is optionally substituted with halogen.
- Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
- a numerical range such as “C 2 -C 6 alkenyl” or “C 2-6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
- an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
- the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
- the alkenyl is optionally substituted with halogen.
- Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like.
- a numerical range such as “C 2 -C 6 alkynyl” or “C 2-6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
- an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
- the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
- the alkynyl is optionally substituted with halogen.
- Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
- Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
- Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
- the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
- the aryl is a 6-to 10-membered aryl.
- the aryl is a 6-membered aryl (phenyl) .
- Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
- an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
- the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
- Cycloalkyl refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
- Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (e.g., C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (e.g., C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (e.g., C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (e.g., C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four
- the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl.
- Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
- Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
- a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
- a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
- the cycloalkyl is optionally substituted with halogen.
- Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
- Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
- “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
- Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
- Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
- a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
- a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
- heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
- heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH (CH 3 ) OCH 3 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N (CH 3 ) 2 .
- a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
- a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
- Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
- the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
- the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
- heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (e.g., C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (e.g., C 2 -C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (e.g., C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (e.g., C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to five carbon
- heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl
- heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
- heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
- the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl.
- the heterocycloalkyl is a 3-to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl.
- the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl.
- a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
- the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
- Heteroaryl refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
- the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
- the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
- the heteroaryl comprises one to three nitrogens.
- the heteroaryl comprises one or two nitrogens.
- the heteroaryl comprises one nitrogen.
- the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
- the heteroaryl is a 5-to 10-membered heteroaryl.
- the heteroaryl is a 5-to 6-membered heteroaryl.
- the heteroaryl is a 6-membered heteroaryl.
- the heteroaryl is a 5-membered heteroaryl.
- examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl,
- a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
- the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
- an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ) , fully substituted (e.g., -CF 2 CF 3 ) , mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc. ) .
- any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
- an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
- Treatment of an individual (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell.
- treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.
- treat, ” “treating” or “treatment, ” as used herein, can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
- the compounds of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) described herein, or a pharmaceutically acceptable salt thereof, are TREX1 inhibitors and are useful in the treatment of a disease or disorder associated with TREX1.
- the compounds of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof are useful in the treatment of cancer.
- the compounds described herein have superior bioavailability.
- the cancer is selected from intra-hepatic cholangiocarcinoma, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.
- ring A is selected from C 6-10 aryl and C 2-9 heteroaryl
- ring B is selected from C 6-10 aryl and C 2-9 heteroaryl
- X is selected from -O-, -N (R 8 ) -, -C (R 7 ) (R 7a ) -, -O-C (R 7 ) (R 7a ) -, -C (R 7 ) (R 7a ) -O-, -S-C (R 7 ) (R 7a ) -, -C (R 7 ) (R 7a ) -S-, -S (O) 2 -C (R 7 ) (R 7a ) -, -C (R 7 ) (R 7a ) -S (O) 2 -, -N (R 8 ) -C (R 7 ) (R 7a ) -, -C (R 7 ) (R 7a ) -N (R 8 ) -C (O) -, -C (O) -N (R 8 ) -, -S (O) 2 -
- Y is -C (H) -or -N-;
- L is -N (R 3a ) -, -O-, -S-, C 1-6 alkylene, or C 3-6 cycloalkylene, wherein C 1-6 alkylene and C 3- 6 cycloalkylene are optionally substituted with one, two, or three groups selected from R 15a ; wherein when L is -N (R 3a ) -, -O-, or -S-, then Y is -C (H) -;
- R 1 is selected from C 6-10 aryl and C 1-9 heteroaryl, wherein C 6-10 aryl and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from R 15b ;
- R 2 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
- R 3 and R 3a are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from R 15c ; or R 3 and R 3a together with the atoms to which they are attached form a 5 or 6-membered heterocycloalkyl ring, wherein the 5 or 6-membered heterocycloalkyl ring is optionally substituted with one, two, or three groups selected from R 15c ;
- R 4 is selected from hydrogen and C 1-6 alkyl optionally substituted with one, two, or three groups selected from R 15d ;
- each R 5 and each R 6 are independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , - SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11
- each R 7 and each R 7a are independently selected from hydrogen and C 1-6 alkyl optionally substituted with one, two, or three groups selected from R 15f ;
- R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -C (O) OR 10 , -C (O) R 13 , -S (O) R 13 , -C (O) N (R 10 ) (R 11 ) , and -S (O) 2 R 13 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from R 15g ;
- R 8a is selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) , -C (O) C
- each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, -CH 2 -C 6-10 aryl, C 6-10 aryl, C 1-9 heteroaryl, and -CH 2 -C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, -CH 2 -C 6-10 aryl, C 6-10 aryl, C 1-9 heteroaryl, and -CH 2 -C 1-9 heteroaryl
- each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 10 and R 11 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl;
- each R 12 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
- each R 13 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
- each R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , and R 15h are each independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -CH 2 -C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1- 9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 )
- n 0, 1, 2, 3, or 4;
- p 0, 1, 2, 3, or 4.
- the compound has the structure of Formula (Ia-3) , (Ia-4) , or (Ia-5) :
- Z 1 is CH, CR 5 , N, NH, NR 5 , O or S;
- Z 2 is CH, CR 5 , N, NH, NR 5 , O or S ;
- Z 3 is CH, CR 5 , N, NH, NR 5 , O or S;
- Z 4 is CH, CR 5 , N, NH, NR 5 , O or S;
- Z 11 is CH, CR 6 , N, NH, NR 6 , O or S;
- Z 22 is CH, CR 6 , N, NH, NR 6 , O or S;
- Z 33 is CH, CR 6 , N, NH, NR 6 , O or S;
- Z 44 is CH, CR 6 , N, NH, NR 6 , O or S;
- k is 0 or 1
- q 0 or 1.
- Y is -CH-. In some embodiments of a compound of Formula (I) , or (Ia-3) - (Ia-5) , or a pharmaceutically acceptable salt thereof, Y is -N-.
- disclosed herein is a compound of Formula (Ia-3) , or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a compound of Formula (Ia-4) , or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof.
- q is 0. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, q is 1.
- k is 0. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, k is 1.
- Z 1 is CH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 1 is CR 5 . In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 1 is N. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 1 is NH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 1 is NR 5 .
- Z 1 is S. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 1 is O.
- Z 2 is CH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 2 is CR 5 . In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 2 is N. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 2 is NH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 2 is NR 5 .
- Z 2 is S. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 2 is O.
- Z 3 is CH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 3 is CR 5 . In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 3 is N. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 3 is NH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 3 is NR 5 .
- Z 3 is S. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 3 is O.
- Z 4 is CH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 4 is CR 5 . In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 4 is N. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 4 is NH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 4 is NR 5 .
- Z 4 is S. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 4 is O.
- Z 11 is CH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 11 is CR 6 . In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 11 is N. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 11 is NH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 11 is NR 6 . In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 11 is S. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 11 is O.
- Z 22 is CH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 22 is CR 6 . In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 22 is N. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 22 is NH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 22 is NR 6 . In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 22 is S. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 22 is O.
- Z 33 is CH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 33 is CR 6 . In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 33 is N. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 33 is NH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 33 is NR 6 . In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 33 is S. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 33 is O.
- Z 44 is CH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 44 is CR 6 . In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 44 is N. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 44 is NH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 44 is NR 6 . In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 44 is S. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z 44 is O.
- the compound has a structure of Formula (Ia-3) . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt thereof, the compound has a structure of Formula (Ia-4) . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt thereof, the compound has a structure of Formula (Ia-5) .
- ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, L, n, and p have the meaning as defined herein.
- disclosed herein is a compound of Formula (Ia-1) , or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a compound of Formula (Ia-2) , or a pharmaceutically acceptable salt thereof.
- L is -N (R 3a ) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is -O-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is C 1-3 alkylene, which is optionally substituted with one, two, or three groups selected from R 15a .
- L is -S-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is C 1-6 alkylene optionally substituted with one, two, or three groups selected from R 15a . In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is unsubstituted C 1-6 alkylene.
- L is -CH 2 -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, wherein L is -CH 2 CH 2 -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is -C (R 15a ) 2 -.
- L is -CH (R 15a ) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is C 3-6 cycloalkylene optionally substituted with one, two, or three groups selected from R 15a . In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is unsubstituted C 3-6 cycloalkylene. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is unsubstituted cyclopropylene. In some embodiments, L is
- X is selected from -O-C (R 7 ) (R 7a ) -, -C (R 7 ) (R 7a ) -O-, -S-C (R 7 ) (R 7a ) -, -C (R 7 ) (R 7a ) -S-, -S (O) 2 -C (R 7 ) (R 7a ) -, -C (R 7 ) (R 7a ) -S (O) 2 -, -N (R 8 ) -C (R 7 ) (R 7a ) -, -C (R 7 ) (R 7a ) -N (R 8 ) -C (O) -, -C (O) -N (R 8 ) -, -S (O) -N (R 8 ) -, -S (
- X is -O-C (R 7 ) (R 7a ) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -C (R 7 ) (R 7a ) -O-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -S-C (R 7 ) (R 7a ) -.
- X is -C (R 7 ) (R 7a ) -S-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -S (O) 2 -C (R 7 ) (R 7a ) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -C (R 7 ) (R 7a ) -S (O) 2 -.
- X is -N (R 8 ) -C (R 7 ) (R 7a ) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -C (R 7 ) (R 7a ) -N (R 8 ) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -N (R 8 ) -C (O) -.
- X is -C (O) -N (R 8 ) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -S (O) 2 -N (R 8 ) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -N (R 8 ) -S (O) 2 -.
- X is selected from -O-, -N (R 8 ) -, and -C (R 7 ) (R 7a ) -.
- X is selected from -O-C (R 7 ) (R 7a ) -C (R 7 ) (R 7a ) -, -C (R 7 ) (R 7a ) -C (R 7 ) (R 7a ) -O-, -C (R 7 ) (R 7a ) -O-C (R 7 ) (R 7a ) -, -N (R 8 ) -C (R 7 ) (R 7a ) -C (R 7 ) (R 7a ) -, -C (R 7 ) (R 7a ) -C (R 7 ) (R 7a ) -N (R 8 ) -, -C (R 7 ) (R 7a ) -N (R 8 ) -, -C (R 7 ) (R 7a ) -N (R 8 ) -, -C (R 7 ) (R 7a ) -N (R 8 )
- X is -O-CH 2 -or -CH 2 -O-. In some embodiments, X is -O-CH 2 -. In some embodiments, X is -CH 2 -O-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -S-CH 2 -or -CH 2 -S-. In some embodiments, X is -S-CH 2 -. In some embodiments, X is -CH 2 -S-.
- X is -N (R 8 ) -C (R 7 ) (R 7a ) -or -C (R 7 ) (R 7a ) -N (R 8 ) -.
- X is -N (CH 3 ) -CH 2 -.
- X is -CH 2 -N (CH 3 ) -.
- X is In some embodiments, X is
- X is N (R 8 ) -C (O) -or -C (O) -N (R 8 ) -. In some embodiments, X is
- X is -S (O) 2 -N (R 8 ) -or -N (R 8 ) -S (O) 2 -. In some embodiments, X is -S (O) 2 -NH-or -NH-S (O) 2 -.
- X is -S (O) 2 -C (R 7 ) (R 7a ) -or -C (R 7 ) (R 7a ) -S (O) 2 -. In some embodiments, X is-S (O) 2 -CH 2 -or -CH 2 -S (O) 2 -.
- X is -O-. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -S-. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -CH 2 -. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -N (CH 3 ) -.
- each R 7 and each R 7a are independently selected from hydrogen and unsubstituted C 1-6 alkyl. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, R 7 and R 7a are each hydrogen.
- ring A is C 2-9 heteroaryl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is pyridyl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is pyrimidinyl.
- ring A is pyridazinyl, pyrazolyl, triazolyl, or indazolyl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is pyrazolyl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is pyridazinyl.
- ring A is triazolyl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is indazolyl. In some embodiments, ring A is pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl. In some embodiments, ring A is pyrrolyl. In some embodiments, ring A is oxazolyl. In some embodiments, ring A is isoxazolyl. In some embodiments, ring A is isoxazolyl. In some embodiments, ring A is isoxazolyl.
- ring A is thiazolyl. In some embodiments, ring A is isothiazolyl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is C 6-10 aryl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is phenyl.
- ring A is a 5 membered heteroaryl.
- ring A is a 6 membered aryl or heteroaryl.
- ring A comprises 1-3 nitrogen, 0-1 oxygen and 0-1 sulfur. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A comprises 1-2 nitrogen. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A comprises 1 nitrogen. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A comprises 2 nitrogen.
- n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.
- n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
- a compound of Formula (I) , or (Ia-1) , or (Ia-2) , or a pharmaceutically acceptable salt thereof is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is in some embodiments, is
- ring B is C 2-9 heteroaryl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is pyridyl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is pyrimidinyl.
- ring B is pyridazinyl, pyrazolyl, triazolyl, or indazolyl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is pyrazolyl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is pyridazinyl.
- ring B is triazolyl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is indazolyl. In some embodiments, ring B is pyrrolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl. In some embodiments, ring B is pyrrolyl. In some embodiments, ring B is oxazolyl. In some embodiments, ring B is isoxazolyl. In some embodiments, ring B is isoxazolyl. In some embodiments, ring B is isoxazolyl.
- ring B is thiazolyl. In some embodiments, ring B is isothiazolyl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is C 6-10 aryl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is phenyl.
- ring B is a 5 membered heteroaryl.
- ring B is a 6 membered aryl or heteroaryl.
- ring B comprises 1-3 nitrogen, 0-1 oxygen and 0-1 sulfur. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B comprises 1-2 nitrogen. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B comprises 1 nitrogen. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B comprises 2 nitrogen.
- a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is
- a compound of Formula (I) , or (Ia-1) , (Ia-2) , or a pharmaceutically acceptable salt thereof is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodimetns, p is 1. In some embodimetns, p is 2. In some embodimetns, p is 3.
- a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is in some embodiments, is in some embodiments, is
- R 1 , R 2 , R 3 , R 3a , R 4 , R 5 , R 6 , n, and p have the meaning as defined herein.
- R 1 , R 2 , R 3 , R 3a , R 4 , R 5 , R 6 , R 7 , R 7a , R 8 , R 15a , n, and p have the meaning as defined herein
- R 3a is C 1-6 alkyl optionally substituted with one, two, or three groups selected from R 15c .
- R 3a is unsubstituted C 1- 6 alkyl.
- R 3a is -CH 3 .
- R 3a is hydrogen.
- each R 5 is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 , wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 15e .
- each R 5 is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -C 1-6 alkoxyl, wherein C 1-6 alkyl and C 1- 6 alkoxyl are optionally substituted with one, two, or three groups selected from R 15e .
- each R 5 is independently selected from halogen. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, each R 5 is independently selected from C 1-6 alkyl optionally substituted with one, two, or three groups selected from R 15e .
- each R 5 is unsubstituted C 1-6 alkyl.
- each R 5 is C 1-6 haloalkyl.
- at least one R 5 is CN.
- at least one R 5 is halogen.
- at least one R 5 is C 1-6 alkyl.
- At least one R 5 is C 1-6 haloalkyl. In some embodiments, at least one R 5 is C 1-6 alkoxyl, which is optionally subsituted with one or more halogen. In some embodiments, at least one R 5 is -OR 10 .
- n is 1. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, n is 2. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, n is 0.
- each R 6 is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 , wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 15e .
- each R 6 is independently selected from halogen.
- each R 6 is independently selected from C 1-6 alkyl optionally substituted with one, two, or three groups selected from R 15e .
- each R 6 is unsubstituted C 1-6 alkyl.
- each R 6 is C 1-6 haloalkyl.
- p is 1. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, p is 2. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, p is 0.
- R 3 is selected from hydrogen, C 1-6 alkyl, and C 2- 9 heterocycloalkyl, wherein C 1-6 alkyl and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from R 15c .
- R 3 is selected from hydrogen and C 1-6 alkyl optionally substituted with one, two, or three groups selected from R 15c .
- R 3 is C 1-6 alkyl optionally substituted with one, two, or three groups selected from R 15c .
- R 3 is -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH (CH 3 ) 2 , -CH 2 CH 2 OCF 3 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 N (CH 3 ) 2 , In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 3 is -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 3 is -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , In some embodiments of a compound of Formula (I) , (Ia
- R 3 is -CH 2 CH 2 OCH 3 . In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 3 is -CH 2 CH 2 OCH 3 . In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 3 is -CH 2 CH 2 OCH (CH 3 ) 2 .
- R 3 is -CH 2 CH 2 OCF 3 . In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 3 is -CH 2 CH 2 NH 2 .
- R 3 is CH 2 CH 2 N (CH 3 ) 2 .
- R 3 is In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 3 is In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 3 is In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 3 is In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 3 is In some embodiments of a compound of Formula (
- R 3 is -CH 3 .
- R 3 is hydrogen.
- R 4 is hydrogen. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 4 is C 1-6 alkyl optionally substituted with one, two, or three groups selected from R 15d .
- R 4 is unsubstituted C 1-6 alkyl. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 4 is -CH 3 .
- R 1 is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is a 5-membered heteroaryl, optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is a 6-membered heteroaryl, optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is selected from isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl, wherein isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl are optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is selected from isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl, wherein isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl are unsubstituted.
- R 1 is isoxazolyl optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is unsubstituted isoxazolyl.
- R 1 is isothiazolyl optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is unsubstituted isothiazolyl.
- R 1 is oxazolyl optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is unsubstituted oxazolyl.
- R 1 is thiazolyl optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is unsubstituted thiazolyl.
- R 1 is pyrazolyl optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is unsubstituted pyrazolyl.
- R 1 is oxadiazolyl optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is unsubstituted oxadiazolyl.
- R 1 is In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 1 is In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 1 is In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 1 is In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 1 is In some embodiments of a compound of Formula (
- R 1 is phenyl optionally substituted with one, two, or three groups selected from R 15b .
- R 2 is hydrogen. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 2 is C 1-6 alkyl.
- R 2 is C 1-6 haloalkyl.
- L 1 is -N (R 3c ) -, -O-, -S-, C 1-6 alkylene, or C 3-6 cycloalkylene, wherein C 1-6 alkylene and C 3- 6 cycloalkylene are optionally substituted with one, two, or three groups selected from R 15a ;
- R 1 is selected from C 6-10 aryl and C 1-9 heteroaryl, wherein C 6-10 aryl and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from R 15b ;
- R 2 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
- R 3b is selected from C 2-6 alkyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, and -CH 2 -C 6-10 aryl, wherein C 2-6 alkyl and C 3-6 cycloalkyl are substituted with one, two, or three groups selected from -OR 10 , -SR 10 , and -N (R 10 ) (R 11 ) , and wherein -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, and -CH 2 -C 6-10 aryl are optionally substituted with one, two, or three groups selected from R 15c ; or R 3b and R 3c together with the atoms to which they are attached form a 5 or 6-membered heterocycloalkyl ring, where
- R 3c is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl, wherein C 1- 6 alkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl, are optionally substituted with one, two, or three groups selected from R 15c ;
- R 4 is selected from hydrogen and C 1-6 alkyl optionally substituted with one, two, or three groups selected from R 15d ;
- R 9 and R 9a are each independently selected from C 6-10 aryl and C 1-9 heteroaryl, wherein C 6-10 aryl and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from R 15h ;
- each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, -CH 2 -C 6-10 aryl, C 6-10 aryl, C 1-9 heteroaryl, and -CH 2 -C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, -CH 2 -C 6-10 aryl, C 6-10 aryl, C 1-9 heteroaryl, and -CH 2 -C 1-9 heteroaryl
- each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 10 and R 11 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl;
- each R 12 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
- each R 13 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; and
- each R 15a , R 15b , R 15c , R 15d , and R 15h are each independently selected from deuterium, halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (
- L 1 is C 3-6 cycloalkylene optionally substituted with one, two, or three groups selected from R 15a ;
- R 1 is selected from C 6-10 aryl and C 1-9 heteroaryl, wherein C 6-10 aryl and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from R 15b ;
- R 2 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
- R 3b is selected from C 1-6 alkyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, and -CH 2 -C 6-10 aryl, wherein C 2-6 alkyl and C 3-6 cycloalkyl are substituted with one, two, or three groups selected from -OR 10 , -SR 10 , and -N (R 10 ) (R 11 ) , and wherein -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, and -CH 2 -C 6-10 aryl are optionally substituted with one, two, or three groups selected from R 15c ;
- R 4 is selected from hydrogen and C 1-6 alkyl optionally substituted with one, two, or three groups selected from R 15d ;
- R 9 and R 9a are each independently selected from C 6-10 aryl and C 1-9 heteroaryl, wherein C 6-10 aryl and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from R 15h ;
- each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, -CH 2 -C 6-10 aryl, C 6-10 aryl, C 1-9 heteroaryl, and -CH 2 -C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, -CH 2 -C 6-10 aryl, C 6-10 aryl, C 1-9 heteroaryl, and -CH 2 -C 1-9 heteroaryl
- each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 10 and R 11 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl;
- each R 12 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
- each R 13 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; and
- each R 15a , R 15b , R 15c , R 15d , and R 15h are each independently selected from halogen, oxo, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 )
- R 9 and R 9a are each independently selected from 6 membered aryl rings and 6 membered heteroaryl rings, each of which is optionally substituted with one, two, or three groups selected from R 15h .
- R 9 is selected from phenyl and 6 membered heteroaryl rings, each of which is optionally substituted with one, two, or three groups selected from R 15h .
- R 9a is selected from phenyl and 6 membered heteroaryl rings, each of which is optionally substituted with one, two, or three groups selected from R 15h .
- L 1 is -N (R 3c ) -, -O-, -S-, or C 3-6 cycloalkylene. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, L 1 is -N (R 3c ) -. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, L 1 is -O-. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, L 1 is -S-.
- L 1 is C 1-6 alkylene optionally substituted with one, two, or three groups selected from R 15a . In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, L 1 is unsubstituted C 1-6 alkylene. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, wherein L 1 is -CH 2 -. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, wherein L 1 is -CH (R 15a ) -.
- L 1 is C 3-6 cycloalkylene optionally substituted with one, two, or three groups selected from R 15a . In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, L 1 is unsubstituted C 3-6 cycloalkylene. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, L 1 is unsubstituted cyclopropylene. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, L 1 is
- R 9 is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from R 15h . In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 9 is pyridyl optionally substituted with one, two, or three groups selected from R 15h .
- R 9 is selected from pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, and indazolyl, wherein pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, and indazolyl are optionally substituted with one, two, or three groups selected from R 15h .
- R 9 is pyrimidinyl optionally substituted with one, two, or three groups selected from R 15h .
- R 9 is pyridazinyl optionally substituted with one, two, or three groups selected from R 15h .
- R 9 is pyrazolyl optionally substituted with one, two, or three groups selected from R 15h .
- R 9 is triazolyl optionally substituted with one, two, or three groups selected from R 15h .
- R 9 is indazolyl optionally substituted with one, two, or three groups selected from R 15h .
- R 9 is phenyl optionally substituted with one, two, or three groups selected from R 15h .
- R 9a is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from R 15h .
- R 9a is pyridyl optionally substituted with one, two, or three groups selected from R 15h .
- R 9a is selected from pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, and indazolyl, wherein pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, and indazolyl are optionally substituted with one, two, or three groups selected from R 15h .
- R 9a is pyrimidinyl optionally substituted with one, two, or three groups selected from R 15h .
- R 9a is pyridazinyl optionally substituted with one, two, or three groups selected from R 15h .
- R 9a is pyrazolyl optionally substituted with one, two, or three groups selected from R 15h .
- R 9a is triazolyl optionally substituted with one, two, or three groups selected from R 15h .
- R 9a is indazolyl optionally substituted with one, two, or three groups selected from R 15h .
- R 9a is phenyl optionally substituted with one, two, or three groups selected from R 15h .
- R 9a is unsubstituted phenyl.
- R 3b is selected from C 1-6 alkyl, C 2-9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 2-6 alkyl is substituted with one, two, or three groups selected from -OR 10 , -SR 10 , and -N (R 10 ) (R 11 ) , and wherein C 2-9 heterocycloalkyl and -CH 2 -C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from R 15c .
- R 3b is C 2-6 alkyl substituted with one, two, or three groups selected from -OR 10 , -SR 10 , and -N (R 10 ) (R 11 ) .
- R 3b is methyl
- R 3b is selected from C 2-6 alkyl, C 2-9 heterocycloalkyl, and -CH 2 -C 2- 9 heterocycloalkyl, wherein C 2-6 alkyl is substituted with one, two, or three groups selected from -OR 10 , -SR 10 , and -N (R 10 ) (R 11 ) , and wherein C 2-9 heterocycloalkyl and -CH 2 -C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from R 15c .
- R 3b is C 2-6 alkyl substituted with one, two, or three groups selected from -OR 10 , -SR 10 , and -N (R 10 ) (R 11 ) .
- R 3b is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups selected from R 15c .
- R 3b is unsubstituted C 2-9 heterocycloalkyl.
- R 3b is -CH 2 -C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups selected from R 15c .
- R 3b is unsubstituted -CH 2 -C 2-9 heterocycloalkyl.
- R 3b is -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH (CH 3 ) 2 , -CH 2 CH 2 OCF 3 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 N (CH 3 ) 2 ,
- R 3b is -CH 2 CH 2 OCD 3 .
- R 3b is -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 3b is -CH 2 CH 2 OH. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 3b is -CH 2 CH 2 OCH 3 . In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 3b is -CH 2 CH 2 OCH (CH 3 ) 2 .
- R 3b is -CH 2 CH 2 OCF 3 . In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 3b is -CH 2 CH 2 NH 2 . In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 3b is CH 2 CH 2 N (CH 3 ) 2 .
- R 3b is In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 3b is In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 3b is In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 3b is In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 3b is In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 3b is
- R 3c is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl, wherein C 1- 6 alkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl, are optionally substituted with one, two, or three groups selected from R 15c .
- R 3c is hydrogen.
- R 3c is C 1- 6 alkyl.
- R 3c is mehtyl.
- R 3b and R 3c together with the atoms to which they are attached form a 5 or 6-membered heterocycloalkyl ring, wherein the 5 or 6-membered heterocycloalkyl ring is optionally substituted with one, two, or three groups selected from R 15c .
- R 4 is hydrogen. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 4 is C 1-6 alkyl optionally substituted with one, two, or three groups selected from R 15d . In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 4 is unsubstituted C 1-6 alkyl. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 4 is -CH 3 .
- R 1 is C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is selected from isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl, wherein isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl are optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is selected from isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl, wherein isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl are unsubstituted.
- R 1 is isoxazolyl optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is unsubstituted isoxazolyl. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 1 is isothiazolyl optionally substituted with one, two, or three groups selected from R 15b . In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 1 is unsubstituted isothiazolyl.
- R 1 is oxazolyl optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is unsubstituted oxazolyl.
- R 1 is thiazolyl optionally substituted with one, two, or three groups selected from R 15b .
- R 1 is unsubstituted thiazolyl. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 1 is pyrazolyl optionally substituted with one, two, or three groups selected from R 15b . In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 1 is unsubstituted pyrazolyl.
- R 1 is oxadiazolyl optionally substituted with one, two, or three groups selected from R 15b . In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 1 is unsubstituted oxadiazolyl.
- R 1 is In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 1 is In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 1 is In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 1 is In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 1 is In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 1 is In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 1 is In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 1 is In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt
- R 2 is hydrogen. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 2 is C 1-6 alkyl. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R 2 is C 1-6 haloalkyl.
- R 7 is hydrogen. In some embodiments of (I) , (Ia-1) - (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 7 is C 1-6 alkyl optionally substituted with one, two, or three groups selected from R 15f .
- R 7a is hydrogen. In some embodiments of (I) , (Ia-1) - (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R 7a is C 1-6 alkyl optionally substituted with one, two, or three groups selected from R 15f .
- R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, wherein C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from R 15g .
- R 8 is selected from hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl, wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 15g .
- R 8 is hydrogen.
- R 8 is C 1-6 alkyl.
- R 8 is C 1-6 haloalkyl.
- R 8 is C 1-6 hydroxylalkyl.
- R 8a is selected from hydrogen, halogen, -N (R 10 ) (R 11 ) , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl, wherein C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from R 15h .
- R 8a is selected from hydrogen, halogen, -C 1-6 alkyl, C 1- 6 haloalkyl, wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from R 15h .
- R 8a is hydrogen.
- R 8a is halogen.
- R 8a is -C 1-6 alkyl.
- R 8a is C 1-6 haloalkyl.
- R 8a is -N (R 10 ) (R 11 ) .
- R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and -CH 2 -C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloal
- R 10 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl, wherein C 1- 6 alkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
- R 10 is hydrogen.
- R 10 is -C 1-6 alkyl.
- R 10 is C 1-6 haloalkyl.
- R 11 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is C 1-6 alkyl. In some embodiments, R 11 is C 1-6 haloalkyl.
- R 10 and R 11 together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl.
- each R 12 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl.
- R 12 is hydrogen.
- R 12 is C 1-6 alkyl.
- R 12 is C 1-6 haloalkyl.
- R 13 is independently selected from C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3- 6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl.
- R 13 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, and C 3-6 cycloalkyl. In some embodiments, R 13 is C 1-6 alkyl. In some embodiments, R 13 is C 2- 6 alkenyl. In some embodiments, R 13 is C 2-6 alkynyl. In some embodiments, R 13 is C 3-6 cycloalkyl.
- R 15a is C 1-6 alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy, C 1-6 haloalkoxy, and -OR 10 .
- R 15a is unsubstituted C 1-6 alkyl.
- R 15a is C 1-3 alkyl.
- R 15a is -CH 3 .
- R 15a is C 1- 3 haloalkyl.
- R 15b is C 1-6 alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy, C 1-6 haloalkoxy, and -OR 10 .
- R 15b is unsubstituted C 1-6 alkyl.
- R 15b is C 1-3 alkyl.
- R 15b is -CH 3 .
- R 15b is C 1- 3 haloalkyl.
- R 15c is C 1-6 alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy, C 1-6 haloalkoxy, and -OR 10 .
- R 15c is unsubstituted C 1-6 alkyl.
- R 15c is C 1-3 alkyl.
- R 15c is -CH 3 .
- R 15c is C 1- 3 haloalkyl.
- R 15d is C 1-6 alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy, C 1-6 haloalkoxy, and -OR 10 .
- R 15d is unsubstituted C 1-6 alkyl.
- R 15d is C 1-3 alkyl.
- R 15d is -CH 3 .
- R 15d is C 1- 3 haloalkyl.
- R 15e is C 1-6 alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy, C 1-6 haloalkoxy, and -OR 10 .
- R 15e is unsubstituted C 1-6 alkyl.
- R 15e is C 1-3 alkyl.
- R 15e is -CH 3 .
- R 15e is C 1- 3 haloalkyl.
- R 15f is C 1-6 alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy, C 1-6 haloalkoxy, and -OR 10 .
- R 15f is unsubstituted C 1-6 alkyl.
- R 15f is C 1-3 alkyl.
- R 15f is -CH 3 .
- R 15f is C 1- 3 haloalkyl.
- R 15g is C 1-6 alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy, C 1-6 haloalkoxy, and -OR 10 .
- R 15g is unsubstituted C 1-6 alkyl.
- R 15g is C 1-3 alkyl.
- R 15g is -CH 3 .
- R 15g is C 1- 3 haloalkyl.
- each R 15h is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
- each R 15h is independently selected from halogen, -CN, C 1-6 alkyl, and C 1-6 haloalkyl.
- each R 15h is independently selected from halogen.
- the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
- Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
- mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
- the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
- dissociable complexes are preferred.
- the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.
- the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
- the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
- bonds represented by solid wedge lines and dashed wedge lines are are used to indicate absolute configuration of a chiral center
- bonds represented by solid lines and dashed lines are used to indicate relative configuration of a chiral center
- a bond represented by a wavy line is used to indicate (1) a solid wedge line or a dashed wedge line or (2) a solid line or a dashed line
- the compounds described herein exist in their isotopically-labeled forms.
- the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
- the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
- the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2 H (D) , 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
- Compounds described herein, and the pharmaceutically acceptable salts thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
- Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
- the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
- one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium.
- one or more 1 H are replaced with one or more deuteriums in one or more of the substituents disclosed herein.
- the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
- the compounds described herein exist as their pharmaceutically acceptable salts.
- the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
- the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
- the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
- these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
- Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
- the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedis
- those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
- a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
- Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
- bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
- Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
- Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
- Disclosed herein is a method of treating a disease in which inhibition of TREX1 is beneficial, the method comprising administering a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- Disclosed herein is a method of treating a disease or disorder associated with TREX1, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- Disclosed herein is a method of treating cancer in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- a method of treating cancer in a subject comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from head and neck cancer, intra-hepatic cholangiocarcinoma, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.
- the cancer is selected from head and neck cancer, intra-hepatic cholangiocarcinoma, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.
- a method of treating head and neck cancer in a subject comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- a method of treating intra-hepatic cholangiocarcinoma in a subject comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- a method of treating urothelial cancer in a subject comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- a method of treating gastric cancer in a subject comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- a method of treating bladder cancer in a subject comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- a method of treating endometrial cancer in a subject comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- a method of treating kidney cancer in a subject comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- a method of treating liver cancer in a subject comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- a method of treating melanoma in a subject comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- a method of treating pancreatic cancer in a subject comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- a method of treating prostate cancer in a subject comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- a method of treating thyroid cancer in a subject comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
- compositions containing the compound (s) described herein are administered for prophylactic and/or therapeutic treatments.
- the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician.
- Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
- compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
- a patient susceptible to or otherwise at risk of a particular disease, disorder or condition is defined to be a “prophylactically effective amount or dose. ”
- the precise amounts also depend on the patient’s state of health, weight, and the like.
- effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician.
- prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
- the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
- the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
- doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
- the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
- Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 10 and the ED 90 .
- the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD 50 and ED 50 .
- the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
- the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED 50 with minimal toxicity.
- the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
- the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.
- any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
- any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose or multiple doses; (ii) the time between multiple administrations is every 6-12 hours; (iii) the compound is administered to the mammal every 1 to 2 days; or (iv) the compound is administered to the subject every week or every month.
- Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
- parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
- a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
- long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
- the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody.
- the liposomes are targeted to and taken up selectively by the organ.
- the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
- the compound described herein is administered topically.
- the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
- the compounds of this invention may be administered to animals.
- the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
- compositions comprising a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- a pharmaceutical compositions comprising a compound of Formula (I) described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- a pharmaceutical compositions comprising a compound of Formula (Ia) described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- a pharmaceutical compositions comprising a compound of Formula (Ib) described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- a pharmaceutical compositions comprising a compound of Formula (Ic) described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- a pharmaceutical compositions comprising a compound of Formula (Id) described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- a pharmaceutical compositions comprising a compound of Formula (Ie) described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
- a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins1999) , herein incorporated by reference for such disclosure.
- the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
- compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular) , intranasal, buccal, topical, rectal, or transdermal administration routes.
- parenteral e.g., intravenous, subcutaneous, intramuscular
- intranasal e.g., buccal
- topical e.g., topical, rectal, or transdermal administration routes.
- the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
- compositions including compounds described herein, or a pharmaceutically acceptable salt thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.
- compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
- Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
- disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
- dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
- compositions that are administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
- the push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
- suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added.
- compositions for parental use are formulated as infusions or injections.
- the pharmaceutical composition suitable for injection or infusion includes sterile aqueous solutions, or dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition comprises a liquid carrier.
- the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like) , vegetable oils, nontoxic glyceryl esters, and any combinations thereof.
- the pharmaceutical compositions further comprise a preservative to prevent growth of microorganisms.
- Int A8 was synthesized using similar conditions as those described in for Int A3 above along with appropriate starting materials.
- Int A4 was prepared in four steps from Int A4-5 using similar conditions as those described in the synthesis of Int A3 from Int A3-6.
- Int A7 was prepared in four steps from Int A7-3 using similar conditions as those described in the synthesis of Int A3 from Int A3-6.
- Int A9 was prepared in four steps from Int A9-1 using similar conditions as those described in the synthesis of Int A3 from Int A3-6.
- Int B2 and Int B3 were synthesized using similar conditions as those described in the step above along with appropriate starting materials.
- Example 1 2- ( (10-Chloro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) (methyl) amino) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 1)
- Example 3 1- (10, 11-dihydro-5H-dibenzo [a, d] [7] annulen-5-yl) -6-hydroxy-N- (isoxazol-4-yl) -5-oxo-1, 2, 3, 5-tetrahydroimidazo [1, 2-a] pyrimidine-7-carboxamide (Compound 8)
- Example 7 2- ( (10-chloro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) (2-methoxyethyl) amino) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-ihydropyrimidine-4-carboxamide (Compound 13)
- Example 8 2- (1- (4-chlorodibenzo [b, e] [1, 4] oxazepin-5 (11H) -yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 14)
- Compound 15 was prepared in five steps from 15-2 using similar conditions as those described in the synthesis of compound 1 from 1-1.
- Compound 21 was prepared in two steps from 21-1 using similar conditions as those described in the synthesis of compound 18 from 18-3.
- Example 12 2- (1- (4-cyanodibenzo [b, e] [1, 4] oxazepin-5 (11H) -yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 25)
- Example 13 2- (1- (5-cyano-2-methyl-2, 10-dihydro-4H-benzo [b] pyrazolo [4, 3-e] [1, 4] oxazepin-4-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 27)
- Example 14 2- (1- (10-cyano-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 28-P1-1 &28-P1-2)
- Example 15 2- (1- (10-chloro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 29-P1-1 &29-P1-2)
- 29-3-P1 was further seperated by chiral SFC to give 29-3-P1-1 and 29-3-P1-2.
- Example 16 2- (1- (10-chloro-7-fluoro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 30-P1-1, 30-P1-2, 30-P2-1 &30-P2-2)
- Compound 30-P1-1 &30-P1-2 were prepared in four steps from 30-1-P1 using similar conditions as those described in the synthesis of 29-P1 &29-P2 from 29-3.
- Compound 30-P2-1 &30-P2-2 were prepared in four steps from 30-1-P2 using similar conditions as those described in the synthesis of 29-P1 &29-P2 from 29-3.
- Example 17 2- (1- (5-cyano-1-methyl-4, 10-dihydro-1H-benzo [6, 7] oxepino [3, 4-c] pyrazol-4-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 31)
- Example 18 2- (1- (10-cyano-7-fluoro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 33-P1-1, 33-P1-2, 33-P2-1 &33-P2-2)
- 33-4-P1 was further seperated by chiral SFC to give 33-4-P1-1 and 33-4-P1-2.
- Compound 33-4-P2-1 &33-4-P2-2 were prepared in three steps from 33-2-P2 using similar conditions as those described in the synthesis of 33-4-P1-1 &33-4-P1-2 from 33-2-P1.
- Example 19 2- (1- (1-cyano-6, 11-dihydrodibenzo [b, e] oxepin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 38-P1, 38-P2, 38-P3 &38-P4)
- 38-3 was further seperated by chiral SFC to give 38-3-P1, 38-3-P2, 38-3-P3and 38-3-P4.
- Example 20 2- (1- (5-cyano-1- (difluoromethyl) -4, 10-dihydro-1H-benzo [6, 7] oxepino [3, 4-c] pyrazol-4-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 41-P1, 41-P2) and 2- (1- (5-cyano-2- (difluoromethyl) -2, 10-dihydro-4H-benzo [6, 7] oxepino [3, 4-c] pyrazol-4-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 42-P1, 42-P2)
- Example 21 2- (1- (6-cyano-4-fluoro-5, 10-dihydrobenzo [5, 6] oxepino [2, 3-b] pyridin-5-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 43-P1-1 and 43-P1-2)
- Compound 43-3-P1-1 &43-3-P1-2 were prepared in three steps from Int A24 using similar conditions as those described in the synthesis of 29-3-P1-1 &29-3-P1-2 from Int A11.
- Example 22 Compounds 36-P1-1 and 36-P1-2
- the Enzymatic assay for TREX1 was performed by a FRET assay using a custom dsDNA substrate processing a fluorophore-quencher on 3’ end and a 5’ fluorophore. Specifically, ssDNA oligos were resuspended at a concentration of 200 uM in Duplex Buffer to anneal to dsDNA.
- mice Six male SD rats were assigned into 2 groups. Animals in Group 1 were given 1 mg/kg of TA by intravenous injection without fasting, animals in Groups 2 were given 5 mg/kg of TA by oral administration with fasting. Blood samples of Group 1 were collected via submandibular vein at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h, and blood samples of Group 2 were collected via submandibular vein at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h. Blood samples were placed into tubes containing K2-EDTA and centrifuged at 6800 g for 6 minutes at 2 ⁇ 8 °C to separate plasma from the samples. Following centrifugation, the resulting plasma was transferred to clean tubes. The samples were stored frozen at -80 °C until bioanalysis. Pharmacokinetic parameters were calculated by the concentration data of TA in plasma samples using non-compartment model of Phoenix 7.0 software.
Abstract
Described herein are TREX1 inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of a disease or disorder associated with TREX1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
This patent application claims the benefit of International Application No. PCT/CN2022/120419, filed September 22, 2022, International Application No. PCT/CN2022/137271, filed December 7, 2022, International Application No. PCT/CN2023/075901, filed February 14, 2023, and International Application No. PCT/CN2023/096905, filed May 29, 2023, each of which is incorporated herein by reference in its entirety.
Three-prime repair exonuclease 1 (TREX1) is a major 3′–5′ DNA exonuclease and plays an important role in preventing aberrant immune responses to self-DNA in normal cells. TREX1 dampens the intrinsic immune response to tumors by preventing activation of the DNA-sensing cGAS/STING pathway in tumor cells, which is required for activation of T cells and cross presentation of tumor antigens by dendritic cells. Many advanced cancers exhibit deficient DNA repair, due to mutations in genes encoding proteins involved in various DNA repair pathways, leading to increased tumor virulence. These mutations also result in increased levels of cytosolic DNA and correspondingly increased levels of TREX1, which in turn sufficiently degrades cytosolic DNA and diminishes the extent of activation ofthe cGAS-STING pathway. Thus, high levels of TREXI expression facilitate evasion of immune recognition, and therapeutic intervention with agents that inhibit TREX I will result in activation of the cGAS-STING pathway and promote systemic antitumor immunity. Consequently, TREX1 inhibition is a promising therapeutic target for treating cancer.
Disclosed herein is a compound of Formula (I) , or a pharmaceutically acceptable salt thereof:
Formula (I) , as described herein.
In some embodiments, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (Ia-1) :
Formula (Ia-1) , as described herein.
In some embodiments, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (Ia-2) :
Formula (Ia-2) , as described herein.
In some embodiments, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (Ia-3) to Formula (Ia-5) :
Formula (Ia-5) , as described herein.
In some embodiments, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (Ib) :
Formula (Ib) , as described herein.
Disclosed herein is a compound of any of Formula (Ic-1) - (Ic-91) , or a pharmaceutically acceptable salt thereof, as described herein.
Disclosed herein is a compound of Formula (II) , or a pharmaceutically acceptable salt thereof:
Formula (II) , as described herein.
Disclosed herein is a compound of Formula (III) , or a pharmaceutically acceptable salt thereof:
Formula (III) , as described herein.
In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
In some embodiments, disclosed herein is a method of treating cancer in a mammal in need thereof, comprising administering to the mammal a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a method of treating cancer in a mammal in need thereof, comprising administering to the mammal a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, wherein the cancer is a solid tumor. In some embodiments, disclosed herein is a method of treating cancer in a mammal in need thereof, comprising administering to the mammal a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, wherein the cancer is head and neck cancer, intra-hepatic cholangiocarcinoma, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
Definitions
In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to. ” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a, ” “an, ” and “the” include plural referents unless the
content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
The terms below, as used herein, have the following meanings, unless indicated otherwise:
“oxo” refers to =O.
“Carboxyl” refers to -COOH.
“Cyano” refers to -CN.
“Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl” or “C1-6alkyl” , means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-
10alkyl. In some embodiments, the alkyl is a C1-6alkyl. In some embodiments, the alkyl is a C1-5alkyl. In some embodiments, the alkyl is a C1-4alkyl. In some embodiments, the alkyl is a C1-3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.
“Alkenyl” refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond (s) , and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2) , 1-propenyl (-CH2CH=CH2) , isopropenyl [-C (CH3) =CH2] , butenyl, 1, 3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl” , means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally
substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
“Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-6alkynyl” , means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
“Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
“Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
“Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl) . Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene,
fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
“Cycloalkyl” refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl) , from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl) , from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl) , from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl) , from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl) , or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl) . In some embodiments, the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.
“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
“Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
“Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
“Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH (CH3) OCH3, -CH2NHCH3, -CH2N (CH3) 2, -CH2CH2NHCH3, or -CH2CH2N (CH3) 2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
“Heterocycloalkyl” refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one
nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl) , from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl) , from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl) , from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl) , from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl) , from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl) , or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl) . Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, 1, 3-dihydroisobenzofuran-1-yl, 3-oxo-1, 3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1, 3-dioxol-4-yl, and 2-oxo-1, 3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) . In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with
oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
“Heteroaryl” refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5-to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5-to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl) . Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen,
methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3) , fully substituted (e.g., -CF2CF3) , mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc. ) . It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
“Treatment” of an individual (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.
The terms “treat, ” “treating” or “treatment, ” as used herein, can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
Compounds
The compounds of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) described herein, or a pharmaceutically acceptable salt thereof, are TREX1 inhibitors and are useful in the treatment of a disease or disorder associated with TREX1. In some embodiments, the compounds of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, are useful in the treatment of cancer. In some embodiments, the compounds described herein have superior bioavailability. In some embodiments, the cancer is selected from intra-hepatic cholangiocarcinoma, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.
In some embodiments disclosed herein is a compound of Formula (I) , or a pharmaceutically acceptable salt thereof:
wherein:
ring A is selected from C6-10aryl and C2-9heteroaryl;
ring B is selected from C6-10aryl and C2-9heteroaryl;
X is selected from -O-, -N (R8) -, -C (R7) (R7a) -, -O-C (R7) (R7a) -, -C (R7) (R7a) -O-, -S-C (R7) (R7a) -, -C (R7) (R7a) -S-, -S (O) 2-C (R7) (R7a) -, -C (R7) (R7a) -S (O) 2-, -N (R8) -C (R7) (R7a) -, -C (R7) (R7a) -N (R8) -, -N (R8) -C (O) -, -C (O) -N (R8) -, -S (O) 2-N (R8) -, -N (R8) -S (O) 2-, -N=C (R8a) -, -C (R8a) =N-, -C (R7) (R7a) -C (R7) (R7a) -, -O-C (R7) (R7a) -C (R7) (R7a) -, -C (R7) (R7a) -C (R7) (R7a) -O-, -C (R7) (R7a) -O-C (R7) (R7a) -, -N (R8) -C (R7) (R7a) -C (R7) (R7a) -, -C (R7) (R7a) -C (R7) (R7a) -N (R8) -, -C (R7) (R7a) -N (R8) -C (R7) (R7a) -, and -C (R7) (R7a) -C (R7) (R7a) -C (R7) (R7a) -;
Y is -C (H) -or -N-;
L is -N (R3a) -, -O-, -S-, C1-6alkylene, or C3-6cycloalkylene, wherein C1-6alkylene and C3-
6cycloalkylene are optionally substituted with one, two, or three groups selected from R15a; wherein when L is -N (R3a) -, -O-, or -S-, then Y is -C (H) -;
R1 is selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15b;
R2 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R3 and R3a are each independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-
6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15c; or R3 and R3a together with the atoms to which they are attached form a 5 or 6-membered heterocycloalkyl ring, wherein the 5 or 6-membered heterocycloalkyl ring is optionally substituted with one, two, or three groups selected from R15c;
R4 is selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from R15d;
each R5 and each R6 are independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-
6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, -
SR10, -SF5, -N (R10) (R11) , -C (O) OR10, -OC (O) N (R10) (R11) , -N (R12) C (O) N (R10) (R11) , -N (R12) C (O) OR13, -N (R12) S (O) 2R13, -C (O) R13, -S (O) R13, -OC (O) R13, -C (O) N (R10) (R11) , -C (O) C (O) N (R10) (R11) , -N (R12) C (O) R13, -S (O) 2R13, -S (O) 2N (R10) (R11) -, -N=S (=O) (R13) 2, -S (=O) (=NH) N (R10) (R11) , -S (=O) (=NH) (R13) , -S (=O) (=NR13) R13, -CH2C (O) N (R10) (R11) , -CH2N (R12) C (O) R13, -CH2S (O) 2R13, -CH2S (O) 2N (R10) (R11) , -Si (C1-6alkyl) 3, and -P (O) (R10) 2, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15e;
each R7 and each R7a are independently selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from R15f;
R8 is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-
9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -C (O) OR10, -C (O) R13, -S (O) R13, -C (O) N (R10) (R11) , and -S (O) 2R13, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15g;
R8a is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-
6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, -SR10, -N (R10) (R11) , -C (O) OR10, -OC (O) N (R10) (R11) , -N (R12) C (O) N (R10) (R11) , -N (R12) C (O) OR13, -N (R12) S (O) 2R13, -C (O) R13, -S (O) R13, -OC (O) R13, -C (O) N (R10) (R11) , -C (O) C (O) N (R10) (R11) , -N (R12) C (O) R13, -S (O) 2R13, and -S (O) 2N (R10) (R11) -, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15h;
each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-
6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-
9heterocycloalkyl, -CH2-C6-10aryl, C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6-10aryl, C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
each R11 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R10 and R11, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl;
each R12 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
each R13 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-
9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
each R15a, R15b, R15c, R15d, R15e, R15f, R15g, and R15h are each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-
6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-
9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N (R10) (R11) , -C (O) OR10, -OC (O) N (R10) (R11) , -N (R12) C (O) N (R10) (R11) , -N (R12) C (O) OR13, -N (R12) S (O) 2R13, -C (O) R13, -S (O) R13, -OC (O) R13, -C (O) N (R10) (R11) , -C (O) C (O) N (R10) (R11) , -N (R12) C (O) R13, -S (O) 2R13, -S (O) 2N (R10) (R11) -, -N=S (=O) (R13) 2, -S (=O) (=NH) N (R10) (R11) , -S (=O) (=NH) (R13) , -S (=O) (=NR13) R13, -CH2C (O) N (R10) (R11) , -CH2N (R12) C (O) R13, -CH2S (O) 2R13, -CH2S (O) 2N (R10) (R11) , -Si (C1-6alkyl) 3, and -P (O) (R10) 2, wherein C1-6alkyl, C2-6alkenyl, C2-
6alkynyl, C3-6cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-
9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR10, -SR10, -SF5, -N (R10) (R11) , -C (O) OR10, -OC (O) N (R10) (R11) , -N (R12) C (O) N (R10) (R11) , -N (R12) C (O) OR13, -N (R12) S (O) 2R13, -C (O) R13, -S (O) R13, -OC (O) R13, -C (O) N (R10) (R11) , -C (O) C (O) N (R10) (R11) , -N (R12) C (O) R13, -S (O) 2R13, -S (O) 2N (R10) (R11) -, -N=S (=O) (R13) 2, -S (=O) (=NH) N (R10) (R11) , -S (=O) (=NH) (R13) , -S (=O) (=NR13) R13, -CH2C (O) N (R10) (R11) , -CH2N (R12) C (O) R13, -CH2S (O) 2R13, -CH2S (O) 2N (R10) (R11) and -P (O) (R10) 2;
n is 0, 1, 2, 3, or 4; and
p is 0, 1, 2, 3, or 4.
In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt thereof, the compound has the structure of Formula (Ia-3) , (Ia-4) , or (Ia-5) :
wherein:
Z1 is CH, CR5, N, NH, NR5, O or S;
Z2 is CH, CR5, N, NH, NR5, O or S ;
Z3 is CH, CR5, N, NH, NR5, O or S;
Z4 is CH, CR5, N, NH, NR5, O or S;
Z11 is CH, CR6, N, NH, NR6, O or S;
Z22 is CH, CR6, N, NH, NR6, O or S;
Z33 is CH, CR6, N, NH, NR6, O or S;
Z44 is CH, CR6, N, NH, NR6, O or S;
k is 0 or 1; and
q is 0 or 1.
In some embodiments of a compound of Formula (I) , or (Ia-3) - (Ia-5) , or a pharmaceutically acceptable salt thereof, Y is -CH-. In some embodiments of a compound of Formula (I) , or (Ia-3) - (Ia-5) , or a pharmaceutically acceptable salt thereof, Y is -N-.
In some embodiments, disclosed herein is a compound of Formula (Ia-3) , or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a compound of Formula (Ia-4) , or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof.
In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, q is 0. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, q is 1.
In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, k is 0. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, k is 1.
In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z1 is CH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z1 is CR5. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z1 is N. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z1 is NH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z1 is NR5. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z1 is S. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z1 is O.
In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z2 is CH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z2 is CR5. In some embodiments of a compound of
Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z2 is N. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z2 is NH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z2 is NR5. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z2 is S. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z2 is O.
In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z3 is CH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z3 is CR5. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z3 is N. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z3 is NH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z3 is NR5. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z3 is S. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z3 is O.
In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z4 is CH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z4 is CR5. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z4 is N. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z4 is NH. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z4 is NR5. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z4 is S. In some embodiments of a compound of Formula (Ia-4) or (Ia-5) , or a pharmaceutically acceptable salt thereof, Z4 is O.
In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z11 is CH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z11 is CR6. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z11 is N. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z11 is NH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z11 is NR6. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z11 is S. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z11 is O.
In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z22 is CH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z22 is CR6. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z22 is N. In some embodiments of a compound of Formula
(Ia-5) , or a pharmaceutically acceptable salt thereof, Z22 is NH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z22 is NR6. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z22 is S. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z22 is O.
In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z33 is CH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z33 is CR6. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z33 is N. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z33 is NH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z33 is NR6. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z33 is S. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z33 is O.
In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z44 is CH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z44 is CR6. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z44 is N. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z44 is NH. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z44 is NR6. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z44 is S. In some embodiments of a compound of Formula (Ia-5) , or a pharmaceutically acceptable salt thereof, Z44 is O.
In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt thereof, the compound has a structure of Formula (Ia-3) . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt thereof, the compound has a structure of Formula (Ia-4) . In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt thereof, the compound has a structure of Formula (Ia-5) .
In some embodiments disclosed herein is a compound of Formula (Ia-1) or Formula (Ia-2) , or a pharmaceutically acceptable salt thereof:
wherein ring A, ring B, R1, R2, R3, R4, R5, R6, X, L, n, and p have the meaning as defined herein.
In some embodiments, disclosed herein is a compound of Formula (Ia-1) , or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a compound of Formula (Ia-2) , or a pharmaceutically acceptable salt thereof.
In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is -N (R3a) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is -O-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is C1-3alkylene, which is optionally substituted with one, two, or three groups selected from R15a. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is -S-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is C1-6alkylene optionally substituted with one, two, or three groups selected from R15a. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is unsubstituted C1-6alkylene. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is -CH2-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, wherein L is -CH2CH2-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is -C (R15a) 2-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is -CH (R15a) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is C3-6cycloalkylene optionally substituted with one, two, or three groups selected from R15a. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is unsubstituted C3-6cycloalkylene. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, L is unsubstituted cyclopropylene. In some embodiments, L is
In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is selected from -O-C (R7) (R7a) -, -C (R7) (R7a) -O-, -S-C (R7) (R7a) -, -C (R7) (R7a) -S-, -S (O) 2-C (R7) (R7a) -, -C (R7) (R7a) -S (O) 2-, -N (R8) -C (R7) (R7a) -, -C (R7) (R7a) -N (R8) -, -N (R8) -C (O) -, -C (O) -N (R8) -, -S (O) 2-N (R8) -, -N (R8) -S (O) 2-, -N=C (R8a) -, -C (R8a) =N-, and -C (R7) (R7a) -C (R7) (R7a) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -O-C (R7) (R7a) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -C (R7) (R7a) -O-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -S-C (R7) (R7a) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -C (R7) (R7a) -S-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -S (O) 2-C (R7) (R7a) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -C (R7) (R7a) -S (O) 2-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -N (R8) -C (R7) (R7a) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -C (R7) (R7a) -N (R8) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -N (R8) -C (O) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -C (O) -N (R8) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -S (O) 2-N (R8) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -N (R8) -S (O) 2-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -N=C (R8a) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -C (R8a) =N-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -C (R7) (R7a) -C (R7) (R7a) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is selected from -O-, -N (R8) -, and -C (R7) (R7a) -. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is selected from -O-C (R7) (R7a) -C (R7) (R7a) -, -C (R7) (R7a) -C (R7) (R7a) -O-, -C (R7) (R7a) -O-C (R7) (R7a) -, -N (R8) -C (R7) (R7a) -C (R7) (R7a) -, -C (R7) (R7a) -C (R7) (R7a) -N (R8) -, -C (R7) (R7a) -N (R8) -C (R7) (R7a) -, and -C (R7) (R7a) -C (R7) (R7a) -C (R7) (R7a) -.
In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -O-CH2-or -CH2-O-. In some embodiments, X is -O-CH2-. In some embodiments, X is -CH2-O-. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -S-CH2-or -CH2-S-. In some embodiments, X is -S-CH2-. In some embodiments, X is -CH2-S-.
In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -N (R8) -C (R7) (R7a) -or -C (R7) (R7a) -N (R8) -. In some embodiments, X is -N (CH3) -CH2-. In some embodiments, X is -CH2-N (CH3) -. In some embodiments, X isIn some embodiments, X is
In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is N (R8) -C (O) -or -C (O) -N (R8) -. In some embodiments, X is
In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -N=C (R8a) -or -C (R8a) =N-. In some embodiments, X is
In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -S (O) 2-N (R8) -or -N (R8) -S (O) 2-. In some embodiments, X is -S (O) 2-NH-or -NH-S (O) 2-.
In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -S (O) 2-C (R7) (R7a) -or -C (R7) (R7a) -S (O) 2-. In some embodiments, X is-S (O) 2-CH2-or -CH2-S (O) 2-.
In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -O-. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -S-. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -CH2-. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, X is -N (CH3) -.
In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, each R7 and each R7a are independently selected from hydrogen and unsubstituted C1-6alkyl. In some embodiments of a compound of Formula (I) , or (Ia-1) to (Ia-5) , or a pharmaceutically acceptable salt thereof, R7 and R7a are each hydrogen.
In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is C2-9heteroaryl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is pyridyl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a
pharmaceutically acceptable salt thereof, ring A is pyrimidinyl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is pyridazinyl, pyrazolyl, triazolyl, or indazolyl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is pyrazolyl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is pyridazinyl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is triazolyl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is indazolyl. In some embodiments, ring A is pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl. In some embodiments, ring A is pyrrolyl. In some embodiments, ring A is oxazolyl. In some embodiments, ring A is isoxazolyl. In some embodiments, ring A is thiazolyl. In some embodiments, ring A is isothiazolyl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is C6-10aryl. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is phenyl.
In some embodiments of a compound of Formula (I) , or (Ia-1) , (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is a 5 membered heteroaryl.
In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A is a 6 membered aryl or heteroaryl.
In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A comprises 1-3 nitrogen, 0-1 oxygen and 0-1 sulfur. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A comprises 1-2 nitrogen. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A comprises 1 nitrogen. In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring A comprises 2 nitrogen.
In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof,
In some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, is
In some embodiments, isIn some embodiments, is
In some embodiments, isIn some embodiments, is In some embodiments, isIn some embodiments, is In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.
In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, is
In some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
In some embodiments of a compound of Formula (I) , or (Ia-1) , or (Ia-2) , or a pharmaceutically acceptable salt thereof, is
In some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, is
In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is C2-9heteroaryl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is pyridyl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is pyrimidinyl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is pyridazinyl, pyrazolyl, triazolyl, or indazolyl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is pyrazolyl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is pyridazinyl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is triazolyl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is indazolyl. In some embodiments, ring B is pyrrolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl. In some embodiments, ring B is pyrrolyl. In some embodiments, ring B is oxazolyl. In some embodiments, ring B is isoxazolyl. In some embodiments, ring B is thiazolyl. In some embodiments, ring B is isothiazolyl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is C6-10aryl. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is phenyl.
In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is a 5 membered heteroaryl.
In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B is a 6 membered aryl or heteroaryl.
In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B comprises 1-3 nitrogen, 0-1 oxygen and 0-1 sulfur. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B comprises 1-2 nitrogen. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B comprises 1 nitrogen. In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, ring B comprises 2 nitrogen.
In some embodiments of a compound of Formula (I) , (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, is
In some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, is
In some embodiments, isIn some embodiments, is
In some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, is In some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, is In some embodiments, isIn some embodiments, is In some embodimetns, p is 0. In some embodimetns, p is 1. In some embodimetns, p is 2. In some embodimetns, p is 3. In some embodimetns, p is 4.
In some embodiments of a compound of Formula (I) , or (Ia-1) , (Ia-2) , or a pharmaceutically acceptable salt thereof, is
In some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodimetns, p is 1. In some embodimetns, p is 2. In some embodimetns, p is 3.
In some embodiments of a compound of Formula (I) , or (Ia-1) or (Ia-2) , or a pharmaceutically acceptable salt thereof, is
In some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, isIn some embodiments, is
In some embodiments disclosed herein is a compound of Formula (Ib) , or a pharmaceutically acceptable salt thereof:
wherein R1, R2, R3, R3a, R4, R5, R6, n, and p have the meaning as defined herein.
In some embodiments disclosed herein is a compound of Formula (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof:
wherein R1, R2, R3, R3a, R4, R5, R6, R7, R7a, R8, R15a, n, and p have the meaning as defined herein
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3a is C1-6alkyl optionally substituted with one, two, or three groups selected from R15c. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3a is unsubstituted C1-
6alkyl. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3a is -CH3. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3a is hydrogen.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, each R5 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -OR10, wherein C1-6alkyl is optionally substituted with one, two, or three groups selected from R15e. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, each R5 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -C1-6alkoxyl, wherein C1-6alkyl and C1-
6alkoxyl are optionally substituted with one, two, or three groups selected from R15e. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , or (Ib) , (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, each R5 is independently selected from halogen. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, each R5 is independently selected from C1-6alkyl optionally substituted with one, two, or three groups selected from R15e. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, each R5 is unsubstituted C1-6alkyl. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, each R5 is C1-6haloalkyl. In some embodiments, at least one R5 is CN. In some embodiments, at least one R5 is halogen. In some embodiments, at least one R5 is C1-6alkyl. In some embodiments, at least one R5 is C1-6haloalkyl. In some embodiments, at least one R5 is C1-6alkoxyl, which is optionally subsituted with one or more halogen. In some embodiments, at least one R5 is -OR10.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, n is 1. In some embodiments of a compound of
Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, n is 2. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, n is 0.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -OR10, wherein C1-6alkyl is optionally substituted with one, two, or three groups selected from R15e. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, each R6 is independently selected from halogen. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, each R6 is independently selected from C1-6alkyl optionally substituted with one, two, or three groups selected from R15e. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, each R6 is unsubstituted C1-6alkyl. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, each R6 is C1-6haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, p is 1. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, p is 2. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, p is 0.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 is selected from hydrogen, C1-6alkyl, and C2-
9heterocycloalkyl, wherein C1-6alkyl and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from R15c. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 is selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from R15c. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 is C1-6alkyl optionally substituted with one, two, or three groups selected from R15c. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 is -CH2CH2OH, -CH2CH2OCH3, -CH2CH2OCH (CH3) 2, -CH2CH2OCF3, -CH2CH2NH2, -CH2CH2N (CH3) 2,
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3
is -CH2CH2OH, -CH2CH2OCH3, In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 is -CH2CH2OH. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 is -CH2CH2OCH3. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 is -CH2CH2OCH (CH3) 2. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 is -CH2CH2OCF3. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 is -CH2CH2NH2. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 is CH2CH2N (CH3) 2. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 isIn some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 isIn some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 isIn some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 isIn some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 isIn some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 is unsubstituted C1-6alkyl. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 is -CH3. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R3 is hydrogen.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R4 is hydrogen. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R4 is C1-6alkyl optionally substituted with one, two, or three groups selected from R15d. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a
pharmaceutically acceptable salt thereof, R4 is unsubstituted C1-6alkyl. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R4 is -CH3.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is C1-9heteroaryl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is a 5-membered heteroaryl, optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is a 6-membered heteroaryl, optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is selected from isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl, wherein isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl are optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is selected from isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl, wherein isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl are unsubstituted. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is isoxazolyl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is unsubstituted isoxazolyl. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is isothiazolyl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is unsubstituted isothiazolyl. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is oxazolyl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is unsubstituted oxazolyl. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is thiazolyl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is unsubstituted thiazolyl. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is pyrazolyl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) ,
or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is unsubstituted pyrazolyl. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is oxadiazolyl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is unsubstituted oxadiazolyl. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 isIn some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 isIn some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 isIn some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 isIn some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 isIn some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 isIn some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 isIn some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is C6-10aryl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R1 is phenyl optionally substituted with one, two, or three groups selected from R15b.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R2 is hydrogen. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R2 is C1-6alkyl. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R2 is C1-6haloalkyl.
In some embodiments disclosed herein is a compound of Formula (II) , or a pharmaceutically acceptable salt or solvate thereof:
wherein:
L1 is -N (R3c) -, -O-, -S-, C1-6alkylene, or C3-6cycloalkylene, wherein C1-6alkylene and C3-
6cycloalkylene are optionally substituted with one, two, or three groups selected from R15a;
R1 is selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15b;
R2 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R3b is selected from C2-6alkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-
9heterocycloalkyl, and -CH2-C6-10aryl, wherein C2-6alkyl and C3-6cycloalkyl are substituted with one, two, or three groups selected from -OR10, -SR10, and -N (R10) (R11) , and wherein -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, and -CH2-C6-10aryl are optionally substituted with one, two, or three groups selected from R15c; or R3b and R3c together with the atoms to which they are attached form a 5 or 6-membered heterocycloalkyl ring, wherein the 5 or 6-membered heterocycloalkyl ring is optionally substituted with one, two, or three groups selected from R15c;
R3c is selected from hydrogen, C1-6alkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-
6alkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, are optionally substituted with one, two, or three groups selected from R15c;
R4 is selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from R15d;
R9 and R9a are each independently selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15h;
each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-
6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-
9heterocycloalkyl, -CH2-C6-10aryl, C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6-10aryl, C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN,
hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
each R11 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R10 and R11, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl;
each R12 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
each R13 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-
9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and
each R15a, R15b, R15c, R15d, and R15h are each independently selected from deuterium, halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N (R10) (R11) , -C (O) OR10, -OC (O) N (R10) (R11) , -N (R12) C (O) N (R10) (R11) , -N (R12) C (O) OR13, -N (R12) S (O) 2R13, -C (O) R13, -S (O) R13, -OC (O) R13, -C (O) N (R10) (R11) , -C (O) C (O) N (R10) (R11) , -N (R12) C (O) R13, -S (O) 2R13, -S (O) 2N (R10) (R11) -, -N=S (=O) (R13) 2, -S (=O) (=NH) N (R10) (R11) , -S (=O) (=NH) (R13) , -S (=O) (=NR13) R13, -CH2C (O) N (R10) (R11) , -CH2N (R12) C (O) R13, -CH2S (O) 2R13, -CH2S (O) 2N (R10) (R11) , -Si (C1-
6alkyl) 3, and -P (O) (R10) 2, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-
10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-
6haloalkoxy, -OR10, -SR10, -SF5, -N (R10) (R11) , -C (O) OR10, -OC (O) N (R10) (R11) , -N (R12) C (O) N (R10) (R11) , -N (R12) C (O) OR13, -N (R12) S (O) 2R13, -C (O) R13, -S (O) R13, -OC (O) R13, -C (O) N (R10) (R11) , -C (O) C (O) N (R10) (R11) , -N (R12) C (O) R13, -S (O) 2R13, -S (O) 2N (R10) (R11) -, -N=S (=O) (R13) 2, -S (=O) (=NH) N (R10) (R11) , -S (=O) (=NH) (R13) , -S (=O) (=NR13) R13, -CH2C (O) N (R10) (R11) , -CH2N (R12) C (O) R13, -CH2S (O) 2R13, -CH2S (O) 2N (R10) (R11) and -P (O) (R10) 2.
In some embodiments disclosed herein is a compound of Formula (III) , or a pharmaceutically acceptable salt thereof:
wherein:
L1 is C3-6cycloalkylene optionally substituted with one, two, or three groups selected from R15a;
R1 is selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15b;
R2 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R3b is selected from C1-6alkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-
9heterocycloalkyl, and -CH2-C6-10aryl, wherein C2-6alkyl and C3-6cycloalkyl are substituted with one, two, or three groups selected from -OR10, -SR10, and -N (R10) (R11) , and wherein -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, and -CH2-C6-10aryl are optionally substituted with one, two, or three groups selected from R15c;
R4 is selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from R15d;
R9 and R9a are each independently selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15h;
each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-
6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-
9heterocycloalkyl, -CH2-C6-10aryl, C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6-10aryl, C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
each R11 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R10 and R11, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl;
each R12 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
each R13 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-
9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and
each R15a, R15b, R15c, R15d, and R15h are each independently selected from halogen, oxo, -CN, C1-
6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-6cycloalkyl, C2-
9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N (R10) (R11) , -C (O) OR10, -OC (O) N (R10) (R11) , -N (R12) C (O) N (R10) (R11) , -N (R12) C (O) OR13, -N (R12) S (O) 2R13, -C (O) R13, -S (O) R13, -OC (O) R13, -C (O) N (R10) (R11) , -C (O) C (O) N (R10) (R11) , -N (R12) C (O) R13, -S (O) 2R13, -S (O) 2N (R10) (R11) -, -N=S (=O) (R13) 2, -S (=O) (=NH) N (R10) (R11) , -S (=O) (=NH) (R13) , -S (=O) (=NR13) R13, -
CH2C (O) N (R10) (R11) , -CH2N (R12) C (O) R13, -CH2S (O) 2R13, -CH2S (O) 2N (R10) (R11) , -Si (C1-
6alkyl) 3, and -P (O) (R10) 2, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-
10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-
6haloalkoxy, -OR10, -SR10, -SF5, -N (R10) (R11) , -C (O) OR10, -OC (O) N (R10) (R11) , -N (R12) C (O) N (R10) (R11) , -N (R12) C (O) OR13, -N (R12) S (O) 2R13, -C (O) R13, -S (O) R13, -OC (O) R13, -C (O) N (R10) (R11) , -C (O) C (O) N (R10) (R11) , -N (R12) C (O) R13, -S (O) 2R13, -S (O) 2N (R10) (R11) -, -N=S (=O) (R13) 2, -S (=O) (=NH) N (R10) (R11) , -S (=O) (=NH) (R13) , -S (=O) (=NR13) R13, -CH2C (O) N (R10) (R11) , -CH2N (R12) C (O) R13, -CH2S (O) 2R13, -CH2S (O) 2N (R10) (R11) and -P (O) (R10) 2.
In some embodiments, disclosed herein is a compound of Formula (II) , (III) , or a pharmaceutically acceptable salt thereof, R9 and R9a are each independently selected from 6 membered aryl rings and 6 membered heteroaryl rings, each of which is optionally substituted with one, two, or three groups selected from R15h. In some embodiments, disclosed herein is a compound of Formula (II) , (III) , or a pharmaceutically acceptable salt thereof, R9 is selected from phenyl and 6 membered heteroaryl rings, each of which is optionally substituted with one, two, or three groups selected from R15h. In some embodiments, disclosed herein is a compound of Formula (II) , (III) , or a pharmaceutically acceptable salt thereof, R9a is selected from phenyl and 6 membered heteroaryl rings, each of which is optionally substituted with one, two, or three groups selected from R15h.
In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, L1 is -N (R3c) -, -O-, -S-, or C3-6cycloalkylene. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, L1 is -N (R3c) -. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, L1 is -O-. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, L1 is -S-. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, L1 is C1-6alkylene optionally substituted with one, two, or three groups selected from R15a. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, L1 is unsubstituted C1-6alkylene. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, wherein L1 is -CH2-. In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, wherein L1 is -CH (R15a) -.
In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, L1 is C3-6cycloalkylene optionally substituted with one, two, or three groups selected from R15a. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, L1 is unsubstituted C3-6cycloalkylene. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, L1 is
unsubstituted cyclopropylene. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, L1 is
In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R9 is C1-9heteroaryl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R9 is pyridyl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, wherein R9 is selected from pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, and indazolyl, wherein pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, and indazolyl are optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, wherein R9 is pyrimidinyl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, wherein R9 is pyridazinyl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, wherein R9 is pyrazolyl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, wherein R9 is triazolyl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, wherein R9 is indazolyl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R9 is phenyl optionally substituted with one, two, or three groups selected from R15h.
In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R9a is C1-9heteroaryl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R9a is pyridyl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) , (III) , or a pharmaceutically acceptable salt thereof, wherein R9a is selected from pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, and indazolyl, wherein pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, and indazolyl are optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, wherein R9a is pyrimidinyl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, wherein R9a is pyridazinyl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable
salt thereof, wherein R9a is pyrazolyl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, wherein R9a is triazolyl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, wherein R9a is indazolyl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R9a is phenyl optionally substituted with one, two, or three groups selected from R15h. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R9a is unsubstituted phenyl.
In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt thereof, R3b is selected from C1-6alkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C2-6alkyl is substituted with one, two, or three groups selected from -OR10, -SR10, and -N (R10) (R11) , and wherein C2-9heterocycloalkyl and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from R15c. In some embodiments of a compound of Formula (II) , (III) , or a pharmaceutically acceptable salt thereof, R3b is C2-6alkyl substituted with one, two, or three groups selected from -OR10, -SR10, and -N (R10) (R11) .
In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt thereof, R3b is methyl.
In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is selected from C2-6alkyl, C2-9heterocycloalkyl, and -CH2-C2-
9heterocycloalkyl, wherein C2-6alkyl is substituted with one, two, or three groups selected from -OR10, -SR10, and -N (R10) (R11) , and wherein C2-9heterocycloalkyl and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from R15c. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is C2-6alkyl substituted with one, two, or three groups selected from -OR10, -SR10, and -N (R10) (R11) .
In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is C2-9heterocycloalkyl optionally substituted with one, two, or three groups selected from R15c. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is unsubstituted C2-9heterocycloalkyl. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups selected from R15c. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is unsubstituted -CH2-C2-9heterocycloalkyl. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is -CH2CH2OH, -CH2CH2OCH3, -CH2CH2OCH (CH3) 2, -CH2CH2OCF3, -CH2CH2NH2, -CH2CH2N (CH3) 2,
In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is -CH2CH2OCD3. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is -CH2CH2OH, -CH2CH2OCH3, In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is -CH2CH2OH. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is -CH2CH2OCH3. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is -CH2CH2OCH (CH3) 2. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is -CH2CH2OCF3. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is -CH2CH2NH2. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is CH2CH2N (CH3) 2. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b isIn some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b isIn some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b isIn some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b isIn some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R3b is
In some embodiments of a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, R3c is selected from hydrogen, C1-6alkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-
6alkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, are optionally substituted with one, two, or three groups selected from R15c. In some embodiments, R3c is hydrogen. In some embodiments, R3c is C1-
6alkyl. In some embodiments, R3c is mehtyl.
In some embodiments of a compound of Formula (II) , R3b and R3c together with the atoms to which they are attached form a 5 or 6-membered heterocycloalkyl ring, wherein the 5 or 6-membered heterocycloalkyl ring is optionally substituted with one, two, or three groups selected from R15c.
In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R4 is hydrogen. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R4 is C1-6alkyl optionally substituted with one, two, or three groups selected from R15d. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R4 is unsubstituted C1-6alkyl. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R4 is -CH3.
In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is C1-9heteroaryl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is selected from isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl, wherein isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl are optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is selected from isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl, wherein isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, and oxadiazolyl are unsubstituted. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is isoxazolyl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is unsubstituted isoxazolyl. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is isothiazolyl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is unsubstituted isothiazolyl. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is oxazolyl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is unsubstituted oxazolyl. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is thiazolyl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is unsubstituted thiazolyl. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is pyrazolyl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is unsubstituted pyrazolyl. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is oxadiazolyl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is unsubstituted oxadiazolyl. In some embodiments of a compound of Formula (II) or (III) , or a
pharmaceutically acceptable salt thereof, R1 isIn some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 isIn some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 isIn some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 isIn some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 isIn some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 isIn some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 isIn some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is C6-10aryl optionally substituted with one, two, or three groups selected from R15b. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R1 is phenyl optionally substituted with one, two, or three groups selected from R15b.
In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R2 is hydrogen. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R2 is C1-6alkyl. In some embodiments of a compound of Formula (II) or (III) , or a pharmaceutically acceptable salt thereof, R2 is C1-6haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) - (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R7 is hydrogen. In some embodiments of (I) , (Ia-1) - (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R7 is C1-6alkyl optionally substituted with one, two, or three groups selected from R15f.
In some embodiments of a compound of Formula (I) , (Ia-1) - (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R7a is hydrogen. In some embodiments of (I) , (Ia-1) - (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R7a is C1-6alkyl optionally substituted with one, two, or three groups selected from R15f.
In some embodiments of a compound of Formula (I) , (Ia-1) - (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R8 is selected from hydrogen, C1-6alkyl, C1-6haloalkyl,
C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, wherein C1-
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15g. In some embodiments, R8 is selected from hydrogen, C1-6alkyl, or C1-6haloalkyl, wherein C1-6alkyl is optionally substituted with one, two, or three groups selected from R15g. In some embodiments, R8 is hydrogen. In some embodiments, R8 is C1-6alkyl. In some embodiments, R8 is C1-6haloalkyl. In some embodiments, R8 is C1-6hydroxylalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) - (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R8a is selected from hydrogen, halogen, -N (R10) (R11) , -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, or C3-6cycloalkyl, wherein C1-6alkyl, C2-
6alkenyl, C2-6alkynyl, and C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from R15h. In some embodiments, R8a is selected from hydrogen, halogen, -C1-6alkyl, C1-
6haloalkyl, wherein C1-6alkyl is optionally substituted with one, two, or three groups selected from R15h. In some embodiments, R8a is hydrogen. In some embodiments, R8a is halogen. In some embodiments, R8a is -C1-6alkyl. In some embodiments, R8a is C1-6haloalkyl. In some embodiments, R8a is -N (R10) (R11) .
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-
6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl. In some embodiments, R10 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl, wherein C1-
6alkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl. In some embodiments, R10 is hydrogen. In some embodiments, R10 is -C1-6alkyl. In some embodiments, R10 is C1-6haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, R11 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R11 is hydrogen. In some embodiments, R11 is C1-6alkyl. In some embodiments, R11 is C1-6haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, R10 and R11, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, each R12 is independently selected from
hydrogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R12 is hydrogen. In some embodiments, R12 is C1-6alkyl. In some embodiments, R12 is C1-6haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, R13 is independently selected from C1-
6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-
6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-
9heteroaryl. In some embodiments, R13 is independently selected from C1-6alkyl, C2-6alkenyl, C2-
6alkynyl, and C3-6cycloalkyl. In some embodiments, R13 is C1-6alkyl. In some embodiments, R13 is C2-
6alkenyl. In some embodiments, R13 is C2-6alkynyl. In some embodiments, R13 is C3-6cycloalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, R15a is C1-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-
6alkoxy, C1-6haloalkoxy, and -OR10. In some embodiments, R15a is unsubstituted C1-6alkyl. In some embodiments, R15a is C1-3alkyl. In some embodiments, R15a is -CH3. In some embodiments, R15a is C1-
3haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, R15b is C1-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-
6alkoxy, C1-6haloalkoxy, and -OR10. In some embodiments, R15b is unsubstituted C1-6alkyl. In some embodiments, R15b is C1-3alkyl. In some embodiments, R15b is -CH3. In some embodiments, R15b is C1-
3haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, R15c is C1-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-
6alkoxy, C1-6haloalkoxy, and -OR10. In some embodiments, R15c is unsubstituted C1-6alkyl. In some embodiments, R15c is C1-3alkyl. In some embodiments, R15c is -CH3. In some embodiments, R15c is C1-
3haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, R15d is C1-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-
6alkoxy, C1-6haloalkoxy, and -OR10. In some embodiments, R15d is unsubstituted C1-6alkyl. In some embodiments, R15d is C1-3alkyl. In some embodiments, R15d is -CH3. In some embodiments, R15d is C1-
3haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R15e is C1-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-
6alkoxy, C1-6haloalkoxy, and -OR10. In some embodiments, R15e is unsubstituted C1-6alkyl. In some embodiments, R15e is C1-3alkyl. In some embodiments, R15e is -CH3. In some embodiments, R15e is C1-
3haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R15f is C1-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-
6alkoxy, C1-6haloalkoxy, and -OR10. In some embodiments, R15f is unsubstituted C1-6alkyl. In some embodiments, R15f is C1-3alkyl. In some embodiments, R15f is -CH3. In some embodiments, R15f is C1-
3haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , or (Ic-1) to (Ic-91) , or a pharmaceutically acceptable salt thereof, R15g is C1-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-
6alkoxy, C1-6haloalkoxy, and -OR10. In some embodiments, R15g is unsubstituted C1-6alkyl. In some embodiments, R15g is C1-3alkyl. In some embodiments, R15g is -CH3. In some embodiments, R15g is C1-
3haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, each R15h is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -OR10. In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt thereof, each R15h is independently selected from halogen, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments of a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) , or a pharmaceutically acceptable salt thereof, each R15h is independently selected from halogen.
Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. In some embodiments, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
In some embodiments, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
In some embodiments, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
In some embodiments, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
In some embodiments, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
Further Forms of Compounds Disclosed Herein
Isomers/Stereoisomers
In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E) , and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities,
reactivity, etc. ) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
Unless explained otherwise, in the present disclosure, bonds represented by solid wedge linesand dashed wedge linesare are used to indicate absolute configuration of a chiral center, bonds represented by solid linesand dashed linesare used to indicate relative configuration of a chiral center, and a bond represented by a wavy lineis used to indicate (1) a solid wedge lineor a dashed wedge lineor (2) a solid lineor a dashed line
Labeled compounds
In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2H (D) , 3H, 13C, 14C, l5N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability.
In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar. In some embodiments, one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, one or more 1H are replaced with one or more deuteriums in one or more of the substituents disclosed herein.
In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
Pharmaceutically acceptable salts
In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate and xylenesulfonate.
Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-
naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4, 4’-methylenebis- (3-hydroxy-2-ene-1 -carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein.
In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+ (C1-4 alkyl) 4, and the like.
Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
Tautomers
In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
Method of Treatment
Disclosed herein is a method of treating a disease in which inhibition of TREX1 is beneficial, the method comprising administering a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
Disclosed herein is a method of treating a disease or disorder associated with TREX1, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
Disclosed herein is a method of treating cancer in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating cancer in a subject, the method comprising administering to the subject a
compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from head and neck cancer, intra-hepatic cholangiocarcinoma, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer. In some embodiments of a method of treating head and neck cancer in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating intra-hepatic cholangiocarcinoma in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating urothelial cancer in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating gastric cancer in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating bladder cancer in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating breast cancer in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating endometrial cancer in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments is a method of treating kidney cancer in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating liver cancer in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating lung cancer in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating melanoma in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating pancreatic cancer in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In some
embodiments of a method of treating prostate cancer in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating thyroid cancer in a subject, the method comprising administering to the subject a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) disclosed herein, or a pharmaceutically acceptable salt thereof.
Dosing
In certain embodiments, the compositions containing the compound (s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose. ” In this use, the precise amounts also depend on the patient’s state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1
mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD10 and the ED90. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.
In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose or multiple doses; (ii) the time between multiple administrations is every 6-12 hours; (iii) the compound is administered to the mammal every 1 to 2 days; or (iv) the compound is administered to the subject every week or every month.
Routes of Administration
Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically.
Pharmaceutical Compositions/Formulations
The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds of this invention may be administered to animals. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
In another aspect, provided herein are pharmaceutical compositions comprising a compound of Formula (I) , (Ia-1) to (Ia-5) , (Ib) , (Ic-1) to (Ic-91) , (II) , or (III) described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments of a pharmaceutical compositions comprising a compound of Formula (I) described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments of a pharmaceutical compositions comprising a compound of Formula (Ia) described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments of a pharmaceutical compositions comprising a compound of Formula (Ib) described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments of a pharmaceutical compositions comprising a compound of Formula (Ic) described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments of a pharmaceutical compositions comprising a compound of Formula (Id) described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically
acceptable excipient. In some embodiments of a pharmaceutical compositions comprising a compound of Formula (Ie) described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins1999) , herein incorporated by reference for such disclosure.
In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
The pharmaceutical compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular) , intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
Pharmaceutical compositions including compounds described herein, or a pharmaceutically acceptable salt thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.
Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch,
wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical compositions that are administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added.
Pharmaceutical compositions for parental use are formulated as infusions or injections. In some embodiments, the pharmaceutical composition suitable for injection or infusion includes sterile aqueous solutions, or dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like) , vegetable oils, nontoxic glyceryl esters, and any combinations thereof. In some embodiments, the pharmaceutical compositions further comprise a preservative to prevent growth of microorganisms.
EXAMPLES
The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:
ACN or MeCN acetonitrile
AcOH acetic acid
Ac acetyl
Bn benzyl
BOC or Boc tert-butyl carbamate
i-Bu iso-butyl
t-Bu tert-butyl
CDI 1, 1-carbonyldiimidazole
DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene
DCE dichloroethane (ClCH2CH2Cl)
DCM dichloromethane (CH2Cl2)
DIBAL-H diisobutylaluminum hydride
DIPEA or DIEA diisopropylethylamine
DMAP 4- (N, N-dimethylamino) pyridine
DME 1, 2-dimethoxyethane
DMF N, N-dimethylformamide
DMA N, N-dimethylacetamide
DMPU N, N′-dimethylpropyleneurea
DMSO dimethylsulfoxide
DPPA diphenyl phosphoryl azide
Dppf or dppf 1, 1'-bis (diphenylphosphino) ferrocene
EDC or EDCI N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide
ACN or MeCN acetonitrile
AcOH acetic acid
Ac acetyl
Bn benzyl
BOC or Boc tert-butyl carbamate
i-Bu iso-butyl
t-Bu tert-butyl
CDI 1, 1-carbonyldiimidazole
DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene
DCE dichloroethane (ClCH2CH2Cl)
DCM dichloromethane (CH2Cl2)
DIBAL-H diisobutylaluminum hydride
DIPEA or DIEA diisopropylethylamine
DMAP 4- (N, N-dimethylamino) pyridine
DME 1, 2-dimethoxyethane
DMF N, N-dimethylformamide
DMA N, N-dimethylacetamide
DMPU N, N′-dimethylpropyleneurea
DMSO dimethylsulfoxide
DPPA diphenyl phosphoryl azide
Dppf or dppf 1, 1'-bis (diphenylphosphino) ferrocene
EDC or EDCI N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide
hydrochloride
eq equivalent (s)
Et ethyl
Et2O diethyl ether
EtOH ethanol
EA or EtOAc ethyl acetate
HATU 1- [bis (dimethylamino) methylene] -1H-1, 2, 3-triazolo [4, 5-
b] pyridinium 3-oxid hexafluorophosphate
HOBt 1-hydroxybenzotriazole
HPLC high performance liquid chromatography
KOAc potassium acetate
KOtBu potassium tert-butoxide
KHMDS potassium bis (trimethylsilyl) amide
NaHMDS sodium bis (trimethylsilyl) amide
LiHMDS lithium bis (trimethylsilyl) amide
LAH/LiAlH4 lithium aluminum anhydride
LCMS liquid chromatography mass spectrometry
Me methyl
MeOH methanol
MS mass spectroscopy
MTBE methyl tert-butyl ether
NBS N-bromosuccinimide
NMP N-methyl-pyrrolidin-2-one
NMR nuclear magnetic resonance
PE petroleum ether
Ph phenyl
iPr/i-Pr iso-propyl
PyAOP 7-Azabenzotriazol-1-yloxy) tripyrrolidinophosphonium
hexafluorophosphate
RP-HPLC reverse-phase high-pressure liquid chromatography
rt room temperature
SEM 2- (trimethylsilyl) ethoxymethyl
TBS tert-butyldimethylsilyl
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl
eq equivalent (s)
Et ethyl
Et2O diethyl ether
EtOH ethanol
EA or EtOAc ethyl acetate
HATU 1- [bis (dimethylamino) methylene] -1H-1, 2, 3-triazolo [4, 5-
b] pyridinium 3-oxid hexafluorophosphate
HOBt 1-hydroxybenzotriazole
HPLC high performance liquid chromatography
KOAc potassium acetate
KOtBu potassium tert-butoxide
KHMDS potassium bis (trimethylsilyl) amide
NaHMDS sodium bis (trimethylsilyl) amide
LiHMDS lithium bis (trimethylsilyl) amide
LAH/LiAlH4 lithium aluminum anhydride
LCMS liquid chromatography mass spectrometry
Me methyl
MeOH methanol
MS mass spectroscopy
MTBE methyl tert-butyl ether
NBS N-bromosuccinimide
NMP N-methyl-pyrrolidin-2-one
NMR nuclear magnetic resonance
PE petroleum ether
Ph phenyl
iPr/i-Pr iso-propyl
PyAOP 7-Azabenzotriazol-1-yloxy) tripyrrolidinophosphonium
hexafluorophosphate
RP-HPLC reverse-phase high-pressure liquid chromatography
rt room temperature
SEM 2- (trimethylsilyl) ethoxymethyl
TBS tert-butyldimethylsilyl
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl
Intermediate A1: Synthesis of 10-chloro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-amine (Int A1)
To a solution of Int A1-1 (50.0 g, 423 mmol) and AIBN (6.95 g, 42.3 mmol) in DCE (500 mL) was added NBS (90.4 g, 508 mmol) . The mixture was stirred at 85 ℃ for 12 hrs. The mixture was poured into water (1000 mL) and extracted with DCM (400 mL × 3) . The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give compound Int A1-2. MS m/z (ESI) : 199.1 [M+H] +.
To a solution of Int A1-2 (38.0 g, 129 mmol) and 3-chlorophenol (19.9 g, 155 mmol) in DMF (600 mL) was added Cs2CO3 (84.2 g, 258 mmol) . The mixture was stirred at 20 ℃ for 12 hrs. The mixture was poured into water (1000 mL) . The precipitate was filtered to give Int A1-3, which was used in the next step without further purification. MS m/z (ESI) : 245.1 [M+H] +.
A mixture of Int A1-3 (20.0 g, 81.7 mmol) in TfOH (120 mL) was stirred at 20 ℃ for 16 hrs. The mixture was quenched with water and conc. HCl, extracted with EtOAc (100 mL × 3) , washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by C18 silica gel column chromatography to give compound Int A1-4. MS m/z (ESI) : 245.2 [M+H] +; 1H NMR (400 MHz, CDCl3) δ 8.79 -8.78 (m, 1H) , 7.65 -7.63 (m, 1H) , 7.48 -7.47 (m, 1H) , 7.36 -7.34 (m, 1H) , 7.28 -7.26 (m, 1H) , 7.08 -7.06 (m, 1H) , 5.29 (s, 2H) .
A mixture of Int A1-4 (4.5 g, 18.3 mmol) and hydroxylamine hydrochloride (6.36 g, 91.6 mmol) in pyridine (50 mL) was stirred at 120 ℃ for 2 hrs. The mixture was concentrated to remove the pyridine. The residue was poured into water (30 mL) and extracted with EtOAc (50 mL × 3) . The combined organic extracts were washed with brine (20 mL × 2) , dried over Na2SO4, filtered and concentrated to give compound Int A1-5, which was used in the next step without further purification. MS m/z (ESI) : 261.1 [M+H] +.
To a solution of Int A1-5 (5.0 g, 19.2 mmol) , CH3COONH4 (13.4 g, 384 mmol) and NH3·H2O (0.74 g, 9.59 mmol) in EtOH (2 mL) was added Zn dust (6.27 g, 95.9 mmol) . The mixture was stirred at 80 ℃ for 6 hrs. The mixture was concentrated. Water was added to the residue and the mixture was extracted with EtOAc (20 mL × 3) . The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give compound Int A1, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.55 -8.54 (m, 1H) , 7.51 -7.49 (m, 1H) , 7.29 -7.28 (m, 1H) , 7.19 -7.18 (m, 2H) , 7.01 -6.99 (m, 1H) , 5.85 (s, 1H) , 5.72 (d, J = 14.4 Hz, 1H) , 5.00 (d, J = 14.4 Hz, 1H) .
The following intermediates were synthesized using similar conditions as those described in for Int A1 above along with appropriate starting materials.
Intermediate A3: Synthesis of 10-chloro-6, 11-dihydrodibenzo [b, e] oxepin-11-amine (Int A3)
A mixture of Int A3-1 (20.0 g, 118.6 mmol) in SOCl2 (150 mL) was stirred at 70 ℃ for 2 hrs. The mixture was quenched with MeOH (200 mL) at 0 ℃, The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A3-2. 1HNMR: (400 MHz, CDCl3) δ = 7.24 -7.18 (m, 2H) , 7.10 -7.08 (m, 1H) , 3.93 (s, 3H) , 2.30 (s, 3H) .
To a suspension of Int A3-2 (16 g, 87.2 mmol) in CCl4 (200 mL) was added NBS (18.6 g, 104.2 mmol) and AIBN (1.42 g, 8.72 mmol) . The mixture was stirred at 80 ℃ for 16 hrs. The mixture was cooled to room temperature, quenched with water (200 mL) , and extracted with dichloromethane (200 mL × 3) . The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A3-3. 1HNMR: (400 MHz, CDCl3) , δ = 7.35 -7.24 (m, 3H) , 4.48 (s, 2H) , 3.98 (s, 3H) .
To a suspension of Int A3-3 (14 g, 75.2 mmol) in DMF (200 mL) was added phenol (7.8 g, 82.8 mmol) and K2CO3 (20.8 g, 150.4 mmol) . The mixture was stirred at 80 ℃ for 2 hrs. The resultant mixture was cooled to room temperature. The mixture was quenched with water (300 mL) and extracted with dichloromethane (300 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A3-4. MS m/z (ESI) : 457.3 [M+H] +; 1HNMR: (400 MHz, CDCl3) , δ = 7.40 -7.34 (m, 3H) , 7.29 -7.24 (m, 2H) , 6.98 -6.90 (m, 3H) , 5.07 (s, 2H) , 3.87 (s, 3H) .
To a suspension of Int A3-4 (12.0 g, 1.0 mmol) in MeOH (100 mL) was added 5N NaOH (100 mL) . The mixture was stirred at 70 ℃ for 16 hrs. The mixture was adjusted to pH = 3 with aq. HCl and extracted with dichloromethane (200 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A3-5. MS m/z (ESI) : 261.1 [M-H] -.
A mixture of Int A3-5 (10.0 g) and PPA (50 mL) was stirred at 120 ℃ for 4 hrs. The mixture was cooled to room temperature, quenched with water (200 mL) , and extracted with dichloromethane (200 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by
column chromatography to give Int A3-6. 1HNMR: (400 MHz, CDCl3) , δ = 7.96 -7.93 (dd, J = 1.6 Hz, 3.2 Hz, 1H) , 7.48 -7.44 (m, 2H) , 7.42 -7.38 (m, 1H) , 7.30 -7.28 (dd, J = 1.6 Hz, 3.2 Hz, 1H) , 7.11 -7.07 (m, 1H) , 6.99 -6.97 (dd, J = 1.6 Hz, 3.2 Hz, 1H) , 5.13 (s, 2H) .
To a suspension of Int A3-6 (2.46 g, 10 mmol) in THF (30 mL) was added LiAlH4 (8 mL, 2.5 N, 20 mmol) at 0 ℃. The mixture was stirred at rt for 0.5 hr. The mixture was quenched with water (30 mL) and extracted with dichloromethane (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A3-7. 1HNMR: (400 MHz, CDCl3) , δ =7.44 -7.39 (m, 2H) , 7.35 -7.28 (m, 2H) , 7.23 -7.19 (m, 1H) , 6.91 -6.87 (m, 1H) , 6.79 -6.76 (m, 1H) , 6.32 (d, J = 3.6 Hz, 1H) , 6.16 (d, J = 12 Hz, 1H) , 6.99 (d, J = 3.2 Hz, 1H) , 4.90 (d, J = 12 Hz, 1H) .
To a suspension of Int A3-7 (2.4 g, 9.76 mmol) in DCM (30 mL) was added SOCl2 (2 mL) , The mixture was stirred at rt for 1 hr. The mixture concentrated under reduced pressure to give Int A3-8, which was used in the next step without further purification.
To a suspension of Int A3-8 (2.6 g, 10 mmol) in DMF (30 mL) was added NaN3 (1.6 g, 25 mmol) and TEA (2.0 g, 20 mmol) at 0 ℃. The mixture was stirred at rt for 1 hr. The mixture was quenched with water (30 mL) and extracted with dichloromethane (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A3-9. 1HNMR: (400 MHz, CDCl3) , δ = 7.59 -7.53 (m, 2H) , 7.49 -7.42 (m, 2H) , 7.34 -7.30 (m, 1H) , 7.01 -6.97 (m, 1H) , 6.90 -6.88 (m, 1H) , 6.43 (s, 1H) , 5.78 (d, J = 12.8 Hz, 1H) , 5.04 (d, J = 12.8 Hz, 1H) .
To a suspension of Int A3-9 (500 mg, 1.84 mmol) in THF (30 mL) was added LiAlH4 (1.84 mL, 2.5 N, 4.6 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 hr. The mixture was quenched with water (30 mL) and extracted with dichloromethane (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A3. 1HNMR: (400 MHz, CDCl3) , δ = 7.43 (dd, J = 1.2 Hz, 7.6 Hz, 1H) , 7.35 (d, J = 7.2 Hz, 1H) , 7.30 -7.27 (m, 2H) , 7.16 -6.13 (m, 1H) , 6.91 -6.87 (m, 1H) , 6.79 -6.77 (m, 1H) , 6.38 (d, J = 12.4 Hz, 1H) , 5.53 (s, 1H) , 4.87 (d, J = 12.4 Hz, 1H) .
Int A8 was synthesized using similar conditions as those described in for Int A3 above along with appropriate starting materials.
Intermediate A4: Synthesis of 2, 3-difluoro-6, 11-dihydrodibenzo [b, e] oxepin-11-amine (Int A4)
To a solution of Int A4-1 (10.0 g, 56.8 mmol) in DMI (120 mL) was added NaOH (9.09 g, 227 mmol) . The mixture was stirred at 130 ℃ for 1.5 hrs. The mixture was poured into ice water (500 mL) and the pH was adjusted to 2 -3 by conc. HCl. The mixture was filtered and the filter cake was washed with water (50 mL × 3) . The solid was dried under vacuum to give Int A4-2, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.76 -7.71 (m, 1H) , 7.10 -7.06 (m, 1H) .
To a solution of Int A4-2 (6.40 g, 25.7 mmol) in DCM (60 mL) was added Et3N (2.34 g, 23.2 mmol) and N-methoxymethanamine hydrochloride (3.01 g, 30.8 mmol) . The mixture was stirred for 15 min, followed by the addition of EDCI (7.40 g, 38.6 mmol) . The mixture was stirred at 20 ℃for another 15 min. The mixture was poured into water (100 mL) and extracted with DCM (120 mL ×3) . The combined organic layers were washed with brine (200 mL × 2) , dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give Int A4-3. MS m/z (ESI) : 218.1 [M+H] +.
To a solution of Int A4-3 (4.0 g, 16.6 mmol) and 1-bromo-2- (bromomethyl) benzene (6.22 g, 24.9 mmol) in DMF (20 mL) was added K2CO3 (4.59 g, 33.2 mmol) . The mixture was stirred at 60 ℃ for 6 hrs. The mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 3) . The combined organic layers were washed with brine (200 mL × 2) , dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give Int A4-4. MS m/z (ESI) : 388.0 [M+H] +.
To the solution of Int A4-4 (2.90 g, 7.25 mmol) and TMEDA (2.11 g, 18.1 mmol) in THF (150 mL) was added n-BuLi (2.5 M, 7.3 mL) . The mixture was stirred at -60 ℃ for 3 hrs. The mixture was quenched by NH4Cl (50 mL) and extracted with EtOAc (50 mL × 3) . The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by column chromatography to give Int A4-5. MS m/z (ESI) : 247.1 [M+H] +.
Int A4 was prepared in four steps from Int A4-5 using similar conditions as those described in the synthesis of Int A3 from Int A3-6.
Int A4: 1H NMR (400 MHz, CDCl3) δ 7.45 -7.39 (m, 2H) , 7.39 -7.30 (m, 3H) , 6.85 -6.82 (m, 1H) , 5.73 (d, J = 12.0 Hz, 1H) , 5.29 (d, J = 12.0 Hz, 1H) , 4.10 (d, J = 1.2 Hz, 1H) , 3.18 (d, J = 4.4 Hz, 2H) .
Intermediate A7: Synthesis of 2, 3-difluoro-6, 11-dihydrodibenzo [b, e] oxepin-11-amine (Int A7)
The mixture of Int A7-1 (45.0 g, 260 mmol) , Int A1-2 (51.3 g, 260 mmol) and Cs2CO3 (127 g, 390 mmol) in DMF (900 mL) was stirred at 20 ℃ for 6 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (500 mL × 3) . The combined organic layers were washed with brine (300 mL × 3) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int A7-2, which was used in the next step without further purification. MS m/z (ESI) : 290.8 [M+H] +.
The mixture of Int A7-2 (125 g, 431 mmol) in TfOH (720 mL) was stirred at 20 ℃ for 8 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (2 L) and HCl (20 mL) , the mixture was stirred for 0.5 hr, The system was adjusted to pH = 10 with NaOH, the mixture was extracted with DCM (700 mL × 3) . The combined organic layers were washed with brine (500 mL ×3) , dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC to give Int A7-3. MS m/z (ESI) : 290.2 [M+H] +.
Int A7 was prepared in four steps from Int A7-3 using similar conditions as those described in the synthesis of Int A3 from Int A3-6.
Int A7: 1H NMR (400 MHz, CDCl3) δ 8.51 (dd, J = 4.8, 1.7 Hz, 1H) , 7.46 (dd, J = 7.7, 1.8 Hz, 1H) , 7.35 (dd, J = 7.9, 1.4 Hz, 1H) , 7.23 (dd, J = 7.7, 4.8 Hz, 1H) , 7.09 (t, J = 8.0 Hz, 1H) , 7.01 (dd, J = 8.1, 1.4 Hz, 1H) , 5.80 (d, J = 14.4 Hz, 1H) , 5.77 (s, 1H) , 4.95 (d, J = 14.4 Hz, 1H) .
The following intermediates were synthesized using similar conditions as those described in for Int A7 above along with appropriate starting materials.
Intermediate A9: Synthesis of 10- (trifluoromethyl) -5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-amine (Int A9)
The mixture of Int A7-3 (3.20 g, 11.0 mmol) , CuI (2.10 g, 11.0 mmol) , methyl 2, 2-difluoro-2-fluorosulfonyl-acetate (4.24 g, 22.0 mmol) in NMP (30 mL) was stirred at 120 ℃ for 4 hrs under N2 atmosphere. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (30 mL × 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give Int A9-1. MS m/z (ESI) : 280.1 [M+H] +.
Int A9 was prepared in four steps from Int A9-1 using similar conditions as those described in the synthesis of Int A3 from Int A3-6.
Int A9: MS m/z (ESI) : 264.3 [M-NH3+H] +.
Intermediate A11: 10-chloro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridine (Int A11)
To a solution of Int A1-4 (1.60 g, 6.51 mmol) in MeOH (8 mL) and THF (8 mL) was added NaBH4 (295 mg, 7.81 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 1 hr. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL × 3) . The combined organic layers were washed with brine (100 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give Int A11-1, which was used in the next step without further purification. MS m/z (ESI) : 248.3 [M+H] +.
To a solution of Int A11-1 (1.50 g, 6.06 mmol) and 2, 2, 2-trifluoroacetic acid (4.14 g, 36.3 mmol) in DCE (7.5 mL) was added triethylsilane (4.23 g, 36.3 mmol) . The mixture was stirred at 60
℃ for 12 hrs. The mixture was quenched with KOH (12 N, 20 mL) at 0 ℃, the mixture was diluted with H2O (50 mL) and extracted with DCM (20 mL × 3) . The combined organic layers were washed with brine (30 mL × 2) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A11. MS m/z (ESI) : 232.2 [M+H] +; 1H NMR (400 MHz, CDCl3) δ 8.48 -8.46 (m, 1H) , 7.41 -7.39 (m, 1H) , 7.19 -7.16 (m, 1H) , 7.14 -7.12 (m, 1H) , 7.11 -7.09 (m, 1H) , 6.94 -6.91 (m, 1H) , 5.26 (s, 2H) , 4.69 (s, 2H) .
The following intermediates were synthesized using similar conditions as those described in for Int A11 above along with appropriate starting materials.
Intermediate A14: 1-methyl-4, 10-dihydro-1H-benzo [6, 7] oxepino [3, 4-c] pyrazole-5-carbonitrile (Int A14)
To a solution of Int A14-1 (50.0 g, 267 mmol) in THF (500 mL) were added NaH (12.8 g, 321 mmol) and chloro (methoxy) methane (23.7 g, 294 mmol) . The mixture was stirred at 20 ℃ for 2 hrs. The reaction was diluted with water (800 mL) and extracted with EtOAc (400 mL) . The organic layer was washed with brine (100 mL) and concentrated under reduced pressure to give Int A14-2, which was used in the next step without further purification.
To a solution of Int A14-2 (45.0 g, 195 mmol) in DMF (190 mL) were added CuCN (34.9 g, 389 mmol) . The mixture was stirred at 140 ℃ for 16 hrs. The reaction was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give Int A14-3, which was used in the next step without further purification.
To a solution of Int A14-3 (23.0 g, 130 mmol) in DCE (300 mL) were added NBS (25.4 g, 143 mmol) and AIBN (2.10 g, 13.0 mmol) . The mixture was stirred at 80 ℃ for 16 hrs. The reaction was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A14-4. 1H NMR (400 MHz, CDCl3) δ 7.29 -7.30 (m, 2H) , 7.24 -7.27 (m, 1H) , 5.25 (s, 2H) , 4.65 (s, 2H) , 3.46 (s, 3H) .
To a solution of Int A14-5 (10.0 g, 48.8 mmol) in DMF (100 mL) were added K2CO3 (13.5 g, 97.6 mmol) and iodomethane (7.60 g, 53.7 mmol) . The mixture was stirred at 20 ℃ for 2 hrs. The reaction was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A14-6. MS m/z (ESI) : 219.1 [M+H] +.
To a solution of Int A14-6 (20.0 g, 91.3 mmol) in dioxane (200 mL) were added Pd (dppf) Cl2 (25.5 g, 100 mmol) , potassium acetate (26.9 g, 274 mmol) , and bis [5- (diphenylphosphanyl) cyclopenta-1, 3-dienyl] -λ2-iron (II) palladium chloride (6.70 g, 9.13 mmol) . The
mixture was stirred at 55 ℃ for 12 hrs. The reaction was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A14-7.
To a solution of Int A14-7 (4.00 g, 15.0 mmol) in DME (40 mL) EtOH (10 mL) and H2O (10 mL) were added Int A14-4 (3.80 g, 15.0 mmol) , K3PO4 (9.60 g, 45.1 mmol) and palladium (0) tetrakis (triphenylphosphane) (1.70 g, 1.50 mmol) . The mixture was stirred at 100 ℃ for 2 hrs. The reaction was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A14-8. MS m/z (ESI) : 316.2 [M+H] +.
To a solution of Int A14-8 (2.80 g, 8.88 mmol) in THF (28 mL) were added LiBH4 (17.8 mL, 35.5 mmol) . The mixture was stirred at 70 ℃ for 16 hrs. The reaction was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give Int A14-9, which was used in the next step without further purification. MS m/z (ESI) : 288.3 [M+H] +.
The mixture of Int A14-9 (2.10 g, 7.31 mmol) in SOCl2 (20 mL) was stirred at 20 ℃ for 2 hrs. The mixture was concentrated under reduced pressure to give Int A14-10, which was used in the next step without further purification.
To a solution of Int A14-10 (1.80 g, 6.88 mmol) in DMF (20 mL) was added K2CO3 (1.90 g, 13.8 mmol) . The mixture was stirred at 80 ℃ for 2 hrs. The reaction was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A14. MS m/z (ESI) : 226.2 [M+H] +. 1H NMR (400 MHz, CDCl3) δ 7.39 -7.43 (m, 3H) , 7.30 -7.39 (m, 1H) , 5.13 (s, 2H) , 4.11 (s, 2H) , 3.66 (s, 3H) .
The following intermediates were synthesized using similar conditions as those described in for Int A14 above along with appropriate starting materials.
Intermediate A17: 5, 11-dihydrobenzo [6, 7] oxepino [3, 4-b] pyrazine-10-carbonitrile (Int A17)
The mixture of Int A17-4 (20.0 g, 131 mmol) , NBS (25.7 g, 145 mmol) and AIBN (2.16 g, 13.1 mmol) in 1, 2-dichloroethane (200 mL) was stirred at 80 ℃ for 4 hrs under N2 atmosphere. The mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 3) . The combined organic layers were washed with brine (100 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give Int A17-5. MS m/z (ESI) : 231.0 [M+H] +.
To a solution of Int A17-1 (70.0 g, 587 mmol) and t-BuOK (98.9 g, 881 mmol) in DMF (700 mL) was added MOMCl (88.3 g, 1.10 mol) at 0 ℃ under N2 atmosphere. The mixture was stirred at 0 ℃ for 4 hrs under N2 atmosphere. The mixture was quenched with water (300 mL) at 0 ℃ and extracted with EtOAc (300 mL × 3) . The combined organic layers were washed with brine (300 mL × 3) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A17-2. MS m/z (ESI) : 164.2 [M+H] +.
To a solution of Int A17-2 (50.0 g, 306 mmol) in THF (500 mL) was added LDA (2.00 M, 230 mL, 1.50 eq) at -70 ℃ for 2 hrs under N2 atmosphere, followed by the addition of 2-isopropoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (85.5 g, 460 mmol) . The mixture was stirred at -70 ℃ for 2 hrs under N2 atmosphere. The mixture was quenched with water (400 mL) at -70 ℃ and then extracted with EtOAc (300 mL × 3) . The combined organic layers were washed with brine (300 mL ×3) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A17-3. MS m/z (ESI) : 289.9 [M+H] +.
To a solution of Int A17-3 (30.0 g, 104 mmol) , Int A17-5 (16.0 g, 69.2 mmol) , K3PO4 (29.4 g, 138 mmol) and Ag2O (24.1 g, 104 mmol) in dioxane (200 mL) was added cataCxiumAPdG3 (5.04 g, 6.93 mmol) under N2 atmosphere. The mixture was stirred at 100 ℃ for 2 hrs. The mixture was quenched with water (200 mL) at 25 ℃ and then extracted with EtOAc (200 mL × 3) . The combined organic layers were washed with brine (200 mL × 2) , dried over Na2SO4, filtered and
concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give Int A17-6. MS m/z (ESI) : 314.4 [M+H] +. 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 2.4 Hz, 1H) , 8.43 (d, J = 2.4 Hz, 1H) , 7.29 -7.23 (m, 3H) , 4.97 (s, 2H) , 4.77 (s, 2H) , 4.00 (s, 3H) , 3.15 (s, 3H) .
To a solution of Int A17-6 (4.20 g, 11.1 mmol) in THF (40 mL) was added LiBH4 (2.0 M in THF, 14 mL) at 0 ℃ under N2 atmosphere. The mixture was stirred at 0 ℃ for 2 hrs. The mixture was quenched with water (30 mL) at -10 ℃ and then extracted with EtOAc (30 mL × 3) . The combined organic layers were washed with brine (30 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A17-7. MS m/z (ESI) : 286.1 [M+H] +.
To a solution of Int A17-7 (900 mg, 3.15 mmol) in dioxane (10 mL) was added HCl/dioxane (4.0 M, 12 mL) . The mixture was stirred at 20 ℃ for 1 hr. The mixture was concentrated under reduced pressure to give Int A17-8, which was used in the next step without further purification. MS m/z (ESI) : 242.0 [M+H] +.
To a solution of PPh3 (1.96 g, 7.46 mmol) and DEAD (975 mg, 5.60 mmol) in THF (80 mL) was added Int A17-8 (450 mg, 1.87 mmol, 1.00 eq) at 0 ℃ under N2 atmosphere. The mixture was stirred at 25 ℃ for 2.5 hrs under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give Int A17. MS m/z (ESI) : 224.0 [M+H] +; 1H NMR (400 MHz, CDCl3) δ 8.44 -8.41 (m, 2H) , 7.47 -7.34 (m, 3H) , 5.32 (s, 2H) , 4.70 (s, 2H) .
The following intermediates were synthesized using similar conditions as those described in for Int A17 above along with appropriate starting materials.
Intermediate A19: 10- ( (trimethylsilyl) ethynyl) -5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridine (Int A19)
To a solution of Int A12 (300 mg, 1.08 mmol) and ethynyltrimethylsilane (213 mg, 2.17 mmol) in piperidine (2 mL) was added Pd (PPh3) 2Cl2 (152 mg, 0.22 mmol) . The mixture was stirred at 80 ℃ for 2 hrs. The mixture was diluted with sat. NH4Cl (2 mL) , extracted with EtOAc (2 mL × 3) , the combined organic layers were washed with sat. NH4Cl (2 mL) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give Int A19. MS m/z (ESI) : 294.1 [M+H] +.
Intermediate A24: 4-fluoro-5, 10-dihydrobenzo [5, 6] oxepino [2, 3-b] pyridine-6-carbonitrile (Int A24)
To a mixture of Int A24-1 (9.00 g, 70.8 mmol) in dry THF (180 mL) was added LDA (53 mL, 2 M in THF) at -72 ℃ under nitrogen atmosphere. The mixture was stirred at -72 ℃ for 1 hr. To the mixture was added 4, 4, 5, 5-tetramethyl-2- (prop-2-yloxy) -1, 3, 2-dioxaborolane (19.8 g, 106 mmol) at -72 ℃ under nitrogen atmosphere. The mixture was stirred at -72 ℃ for 2 hrs. The mixture was diluted with aq. NH4Cl (200 mL) extracted with EtOAc (200 mL × 2) , The combined organic layers were washed with brine (150 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A24-2. 1H NMR (400 MHz, CDCl3) δ 8.12 (dd, J = 9.2, 5.6 Hz, 1H) , 6.61 (dd, J = 7.6, 6.0 Hz, 1H) , 3.94 (s, 3H) , 1.38 (s, 12H) .
To a mixture of Int A24-2 (6.25 g, 24.7 mmol) and Int A24-3 (7.50 g, 29.6 mmol) in toluene (100 mL) and H2O (10 mL) were added Cs2CO3 (16.1 g, 49.4 mmol) and SPhos Pd G2 (92.5 mg, 0.128
mmol) at 20 ℃ under nitrogen atmosphere. The mixture was stirred at 90 ℃ for 18 hrs. The reaction mixture was diluted with EtOAc (50 mL) and H2O (50 mL) , the aqueous phase was extracted with EtOAc (25 mL) , the combined organics were washed with brine (25 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A24-4. MS m/z (ESI) : 301.0 [M+H] +.
To a mixture of Int A24-4 (2.07 g, 6.89 mmol) in DMF (20 mL) were added LiCl (1.46 g, 34.4 mmol) and 4-methylbenzenesulfonic acid (5.93 g, 34.4 mmol) at 20 ℃ under nitrogen atmosphere. The mixture was stirred at 120 ℃ for 0.5 hr. The mixture was poured into water (50 mL) and extracted with EtOAc (30 mL × 3) . The combined organics were washed with brine (30 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A24-5. MS m/z (ESI) : 287.0 [M+H] +.
To a mixture of Int A24-5 (1.55 g, 5.41 mmol) in THF (40 mL) was added LiBH4 (16.4 mL, 1 M in THF) at 0 ℃ under nitrogen atmosphere. The mixture was stirred at 20 ℃ for 36 hrs. The mixture was poured into water (100 mL) and extracted with EA (100 mL × 4) . The combined organics were washed with brine (100 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int A24-6. MS m/z (ESI) : 259.0 [M+H] +.
To a solution of Int A24-6 (310 mg, 1.20 mmol) and PPh3 (629 mg, 2.40 mmol) in THF (40 mL) was added DIAD (485 mg, 2.40 mmol) at 0 ℃ under nitrogen atmosphere. The mixture was stirred at 20 ℃ for 18 hrs. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give the crude product, the crude product was further purified by prep-HPLC to give Int A24. 1H NMR (400 MHz, CDCl3) : δ 8.06 (dd, J = 8.4, 5.6 Hz, 1H) , 7.69 (dd, J = 7.6, 1.2 Hz, 1H) , 7.62 (d, J = 7.6 Hz, 1H) , 7.43 (t, J = 7.6 Hz, 1H) , 6.75 (dd, J = 8.0, 5.6 Hz, 1H) , 5.46 (s, 2H) , 4.53 (s, 2H) .
Intermediate B1: Synthesis of ethyl 2-chloro-5-methoxy-1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxylate (Int B1)
Na (35.25 g, 1.53 mol) was added to EtOH (600 mL) at 25 ℃ in 10 portions under N2, followed by the addition of ethyl methoxyacetate (100 g, 684 mmol) and a solution of diethyl oxalate (80.8 g, 684 mmol) in EtOH (200 mL) . The reaction mixture was stirred at 35 ℃ for 16 hrs. The reaction was quenched with H2O (600 mL) at 0 ℃. The pH of the solution was adjusted to 3 with HCl (1M) at 0 ℃. The mixture was partly concentrated under vacuum and the mixture was extracted with ethyl acetate (1000 mL × 3) . The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give Int B1-1. MS m/z (ESI) : 218.8 [M+H] +.
A solution of N-methyl urea (45.4 g, 614 mmol) and Int B1-1 (134 g, 614 mmol) in AcOH (850 mL) and HCl/dioxane (275 mL) was stirred at 105 ℃ for 3 hrs. The reaction mixture was filtered and the filter cake was collected. The crude product was triturated with hexane/ethyl acetate (500 mL, 5: 1) at 25 ℃ for 1 hr and filtered. The filter cake was collected to give Int B1-2. MS m/z (ESI) : 229.4 [M+H] +; 1HNMR: (400 MHz, DMSO-d6) δ = 10.07 (s, 1H) , 4.29 (q, J = 7.20 Hz, 2H) , 3.64 (s, 3H) , 2.91 (s, 3H) , 1.27 (t, J = 7.20 Hz, 3H) .
A solution of Int B1-2 (100 g, 418 mmol) in KOH (1 M, 627 mL) was stirred at 105 ℃ for 3 hrs. The reaction mixture was acidified with HCl (12 M) to pH~3 at 0 ℃ and lyophilized to give Int B1-3, which was used in the next step without further purification. MS m/z (ESI) : 201.0 [M+H] +.
To the solution of Int B1-3 (30.0 g, 150 mmol) in EtOH (600 mL) was added acetyl chloride (198 g, 2.52 mol, 180 mL) dropwise at 0 ℃ under N2. The mixture was stirred at 80 ℃ for 16 hrs. The resulting mixture was concentrated under vacuum to remove most of the solvent. The mixture was filtered and the filter cake was collected and the crude product was triturated with EtOH (400 mL) at 25 ℃ for 2 hrs. The solid was filtered and the filter cake was collected to give a residue. The residue was dispersed into DCM (1000 mL) , filtered and the filtrate was concentrated under reduced pressure to give Int B1-4. MS m/z (ESI) : 229.1 [M+H] +; 1HNMR: (400 MHz, DMSO-d6) δ = 11.12 (s, 1H) , 4.30 (q, J = 7.20 Hz, 2H) , 3.69 (s, 3H) , 3.14 (s, 3H) , 1.30 (t, J = 7.20 Hz, 3H) .
To the solution of Int B1-4 (5.00 g, 21.9 mmol) in POCl3 (82.5 g, 538 mmol, 50.0 mL) was added dimethyl aniline (3.75 g, 30.7 mmol) at 25 ℃. The mixture was stirred at 100 ℃ for 12 hrs. The reaction mixture was distilled at 90 ℃. The mixture was cooled to 20 ℃ and diluted with ethyl acetate (50.0 mL) , and then poured slowly into the stirring ice water (150 mL) . The mixture was neutralized with sat. aq NaHCO3 and extracted with ethyl acetate (200 mL × 3) . The combined organic phase was washed with brine (150 mL) and dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography to give Int B1. MS m/z (ESI) : 246.7 [M+H] +; 1H NMR: (400 MHz, DMSO-d6) δ = 4.30 (q, J = 7.20 Hz, 2H) , 3.82 (s, 3H) , 3.53 (s, 3H) , 1.29 (t, J = 7.00 Hz, 3H) .
Int B2 and Int B3 were synthesized using similar conditions as those described in the step above along with appropriate starting materials.
Intermediate B4: Synthesis of ethyl 2-chloro-5-methoxy-1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxylate (Int B4)
To a mixture of Int B1 (30.0 g, 122 mmol) , potassium ethyltrifluoroborate (41.4 g, 304 mmol) and K2CO3 (50.4 g, 365 mmol, 3.00 eq) in THF (15 mL) and dioxane (100 mL) was added Ag2O (70.5 g, 304 mmol) and Pd (dppf) Cl2 (9.90 g, 12.2 mmol) under N2 atmosphere. The mixture was stirred at 110 ℃ for 16 hrs. The combined organic layers were washed with brine (100 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int B4-1. MS m/z (ESI) : 241.3 [M+H] +.
To a solution of Int B4-1 (10.0 g, 40.5 mmol) in DCE (100 mL) was added AIBN (0.70 g, 4.05 mmol) and NBS (8.70 g, 48.6 mmol) . The mixture was stirred at 80 ℃ for 16 hrs. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give Int B4. MS m/z (ESI) : 321.2 [M+H] +; 1H NMR (400 MHz, CDCl3) δ 4.94 (q, J = 6.8 Hz, 1H) , 4.41 (q, J = 7.2 Hz, 2H) , 4.01 (s, 3H) , 3.67 (s, 3H) , 2.10 (d, J = 6.8 Hz, 3H) , 1.40 (t, J = 7.2 Hz, 3H) .
Example 1: 2- ( (10-Chloro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) (methyl) amino) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 1)
To a solution of Int B1 (3.0 g, 12.2 mmol) and Int A1 (3.3 g, 13.4 mmol) in DMSO (30 mL) was added CsF (3.7 g, 24.3 mmol, 897 uL) . The mixture was stirred at 80 ℃ for 1 hr. The reaction mixture was quenched by water (100 mL) at 20 ℃, and then extracted with EtOAc (40 mL ×3) . The combined organic layers were washed with brine (50 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give compound 1-1. MS m/z (ESI) : 457.3 [M+H] +; 1H NMR (400 MHz, CDCl3) δ 8.52 -8.51 (m, 1H) , 7.37 -7.27 (m, 1H) , 7.26 -7.25 (m, 1H) , 7.25 -7.23 (m, 1H) , 7.23 -7.21 (m, 1H) , 7.18 -7.10 (m, 1H) , 6.43 (d, J = 9.2 Hz, 1H) , 5.51 (d, J = 16 Hz, 1H) , 5.13 (d, J = 16 Hz, 1H) . 4.37 (q, J = 6.8 Hz, 2H) , 3.81 (s, 3H) , 3.38 (s, 3H) , 1.25 (t, J = 6.8 Hz, 3H) .
To a solution of 1-1 (1.60 g, 3.50 mmol) in DCM (15 mL) was added tribromoborane (1.32 g, 5.25 mmol) . The mixture was stirred at 0 ℃ for 2 hrs. The mixture was quenched with MeOH (5 mL) , poured into NaHCO3 (5 mL) , and extracted with EtOAc (20 mL × 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give compound 1-2, which was used in the next step without further purification. MS m/z (ESI) : 443.3 [M+H] +.
To a solution of 1-2 (740 mg, 1.67 mmol) and chloro [tri (prop-2-yl) ] silane (965 mg, 5.01 mmol) in DMF (10 mL) was added TEA (0.7 mL, 5.01 mmol) . The mixture was stirred at 80 ℃ for 12 hrs. The mixture was poured into water (10 mL) and extracted with EtOAc (100 mL × 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 1-3, which was used in the next step without further purification. MS m/z (ESI) : 600.8 [M+H] +.
To a solution of 1-3 (1.50 g, 2.50 mmol) and Cs2CO3 (2.45 g, 7.51 mmol) in DMF (15 mL) was added iodomethane (1.07 g, 7.51 mmol) . The mixture was stirred at 20 ℃ for 2 hrs. The mixture was poured into water and extracted with EtOAc (40 mL × 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by prep-HPLC to give 1-4. MS m/z (ESI) : 613.8 [M+H] +.
To a solution of 1-4 (700 mg, 1.14 mmol) in THF (7 mL) and H2O (3 mL) was added LiOH (192 mg, 4.57 mmol) . The mixture was stirred at 70 ℃ for 4 hrs. The mixture was poured into water, filtered and concentrated to give 1-5, which was used in the next step without further purification. MS m/z (ESI) : 427.0 [M-H] -.
To a solution of 1-5 (400 mg, 0.93 mmol) and isoxazol-4-amine (235 mg, 2.80 mmol) in DMF (5 mL) was added N, N-diisopropylethylamine (0.46 mL, 2.80 mmol) and HBTU (1.06 g, 2.80 mmol) . The mixture was stirred at 20 ℃ for 3 hrs. The mixture was poured into water and extracted with EtOAc (20 mL × 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give 2- ( (10-chloro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) (methyl) amino) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 1) . MS m/z (ESI) : 492.8 [M-H] -; 1H NMR (400 MHz, CDCl3) δ 10.87 (s, 1H) , 10.20 (s, 1H) , 9.15 (s, 1H) , 8.74 (s, 1H) , 8.38 -8.37 (m, 1H) , 7.44 -7.27 (m, 1H) , 7.24 -7.14 (m, 3H) , 6.94 -6.92 (m, 1H) , 6.59 (s, 1H) , 5.90 (d, J = 14.0 Hz, 1H) , 5.00 (d, J = 14.0 Hz, 1H) , 3.58 (s, 3H) , 2.71 (s, 3H) .
The following compounds were synthesized using similar conditions as those described in Example 1 above along with appropriate starting materials.
Example 2: 2- ( (5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) (methyl) amino) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 2)
To a suspension of Int A2 (1.3 g, 6.13 mmol) in DMSO (20 mL) was added Int B1 (2.1 g, 8.58 mmol) and CsF (1.85 g, 12.3 mmol) at 0 ℃, The mixture was stirred at 100 ℃ for 2 hrs. The mixture was quenched with water (30 mL) and extracted with dichloromethane (30 mL × 3) . The organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography to give 2-1. MS m/z (ESI) : 423.1 [M+H] +.
To a suspension of 2-1 (1.6 g, 3.79 mmol) in DMF (20 mL) was added MeI (1.6 g, 11.37 mmol) and Cs2CO3 (2.47 g, 7.58 mmol) at 0 ℃. The mixture was stirred at rt for 16 hrs. The mixture was quenched with water (30 mL) and extracted with dichloromethane (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography to give 2-2. MS m/z (ESI) : 437.2 [M+H] +.
To a suspension of 2-2 (250 mg, 0.57 mmol) in THF (10 mL) was added LiOH (69 mg, 2.86 mmol) in H2O (5 mL) . The mixture was stirred at rt for 1 hr. The mixture was quenched with water (20 mL) . The mixture was adjusted to pH = 3 with 2N HCl and extracted with dichloromethane (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered and
concentrated under vacuum. The residue was purified by column chromatography to give 2-3. MS m/z (ESI) : 407.1 [M-H] -.
To a suspension of 2-3 (250 mg, 0.62 mmol) in DMF (10 mL) was added isoxazol-4-amine (90 mg, 0.74 mmol) , HATU (282 mg, 0.74 mmol) and DIEA (237 mg, 1.86 mmol) at 0 ℃, the mixture was stirred at rt for 1 hr. The mixture was quenched with water (30 mL) and extracted with dichloromethane (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography to give 2-4. MS m/z (ESI) : 473.1 [M-H] -.
To a suspension of 2-4 (50 mg, 0.11 mmol) in DCM (10 mL) was added BBr3 (1N, 0.21 mL) at 0 ℃. The mixture was stirred at 0 ℃ for 1 hr. The mixture was quenched with MeOH (5 mL) , diluted with water (20 mL) , and extracted with dichloromethane (20 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by prep-HPLC to give 2- ( (5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) (methyl) amino) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 2) . MS m/z (ESI) : 461.2 [M+H] +; 1HNMR: (400 MHz, CDCl3) , δ = 10.67 (s, 1H) , 10.58 (s, 1H) , 9.16 (s, 1H) , 8.76 (s, 1H) , 8.26 (d, J = 5.2 Hz, 1H) , 7.55 (s, 1H) , 7.44 (d, J = 5.2 Hz, 1H) , 7.33 -7.29 (m, 1H) , 7.17 (s, 1H) , 6.99 -6.96 (m, 1H) , 6.92 (d, J = 5.2 Hz, 1H) , 6.19 (d, J = 12.8 Hz, 1H) , 5.79 (s, 1H) , 4.90 (d, J = 12.8 Hz , 1H) , 3.55 (s, 3H) , 2.68 (s, 3H) .
The following compounds were synthesized using similar conditions as those described in Example 2 above along with appropriate starting materials.
Example 3: 1- (10, 11-dihydro-5H-dibenzo [a, d] [7] annulen-5-yl) -6-hydroxy-N- (isoxazol-4-yl) -5-oxo-1, 2, 3, 5-tetrahydroimidazo [1, 2-a] pyrimidine-7-carboxamide (Compound 8)
To a solution of 8-1 (1.65 g, 7.85 mmol) in CH2Cl2 (16.0 mL) was added thionyl chloride (5.69 mL, 78.4 mmol) . The mixture was stirred at 20 ℃ for 4 hrs. The solvent was removed by distillation under vacuum to give 8-2, which was used in the next step without further purification.
To a flask containing ethane-1, 2-diamine (10 mL, 150 mmol) was added K2CO3 (3.23 g, 23.3 mmol) , followed by the addition of 8-2 (1.78 g, 7.78 mmol) at 10 ℃. The mixture was stirred at 20 ℃ for 2 hrs. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3) . The combined organic layers were washed with brine (10 mL × 2) , dried over Na2SO4, filtered and concentrated under vacuum to give 8-3, which was used in the next step without further purification.
To a solution of 8-3 (1.72 g, 6.52 mmol) in absolute EtOH (20 mL) was added cyanogen bromide (0.97 g, 9.12 mmol) . The reaction mixture was stirred at ambient temperature for 1 hr. The reaction mixture was cooled in an ice water bath. The solution was adjusted to pH 10 by the dropwise addition of 1 M sodium hydroxide. The solvent was concentrated in vacuum. The residue was diluted with ethyl acetate (40 mL) , washed with water (40 mL) and brine (30 mL) . The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 8-4, which was used in the next step without further purification. MS m/z (ESI) : 278.4 [M+H] +.
To a solution of NaH (2.88 g, 72.0 mmol) in DMF (50 mL) was added a solution of 8-5 (5.0 g, 48.0 mmol) in DMF (50 mL) at 0 ℃. After the mixture was stirred at 0 ℃ for 1 hr, 4- (chloromethyl) -1-methoxybenzene (11.3 g, 72.0 mmol) was slowly added and the mixture was stirred at 20 ℃ for 9 hrs. The mixture was quenched with NH4Cl (30 mL) slowly at 0 ℃ and extracted with EtOAc (50 mL × 3) . The combined organic layers were washed with brine (80 mL) , dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography to give 8-6.
A solution of 8-6 (1.4 g, 6.24 mmol) , diethyl oxalate (0.91 g, 6.24 mmol) and NaH (0.37 g, 9.36 mmol) in THF/MeOH (14.0 mL/0.01 mL) was stirred at 20 ℃ for 5 hrs. To the mixture were added 8-4 (1.80 g, 6.17 mmol) , NaH (0.07 g, 3.08 mmol) , and EtOH (14.0 mL) . The mixture was stirred at rt for 12 hrs, diluted with ethyl acetate (40.0 mL) , and washed with water (40 mL) and brine (30 mL) . The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 8-7, which was used in the next step without further purification. MS m/z (ESI) : 538.1 [M+H] +.
To a solution of 8-7 (500 mg, 0.93 mmol) in THF (3.0 mL) and H2O (1.5 mL) was added LiOH (78.1 mg, 1.86 mmol) . The mixture was stirred at 70 ℃ for 2 hrs. To the reaction mixture was added H2O (10 mL) and the mixture was filtered. The filter cake was washed with H2O (1.0 mL) and dried under vacuum to give 8-8, which was used in the next step without further purification. MS m/z (ESI) : 510.4 [M+H] +;
To a solution of 8-8 (460 mg, 0.9 mmol) in ACN (3.0 mL) was added 1-methylimidazole (259 mg, 3.16 mmol) , [chloro (dimethylamino) methylidene] dimethylammonium hexafluoro-λ5-phosphanuide (886 mg, 3.16 mmol) , and isoxazol-4-amine (76 mg, 0.9 mmol) . The reaction mixture
was stirred at 20 ℃ for 2 hrs and then diluted with ethyl acetate (30 mL) . The organic solution was washed with water (10 mL) and brine (20 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 8-9, which was used in the next step without further purification. MS m/z (ESI) : 576.3 [M+H] +.
To a solution of 8-9 (30 mg, 0.052 mmol) in DCM (3.0 mL) was added trichloroborane (78 μL, 0.078 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 5 min and then diluted with DCM (30 mL) . The organic solution was washed with water (10.0 mL) and brine (20.0 mL) . The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by prep-HPLC to give 1- (10, 11-dihydro-5H-dibenzo [a, d] [7] annulen-5-yl) -6-hydroxy-N- (isoxazol-4-yl) -5-oxo-1, 2, 3, 5-tetrahydroimidazo [1, 2-a] pyrimidine-7-carboxamide (Compound 8) . MS m/z (ESI) : 454.1 [M-H] -; 1H NMR: (400 MHz, DMSO-d6) δ 9.90 (s, 1H) , 9.31 (s, 1H) , 8.92 (s, 1H) , 7.61 -7.60 (m, 2H) , 7.27 -7.21 (m, 6H) , 6.33 (s, 1H) , 3.93 (m, 2H) , 3.62 -3.47 (m, 2H) , 3.41 -3.37 (m, 2H) , 2.90 -2.89 (m, 2H) .
Example 4: 2- ( ( (3-chloropyridin-2-yl) (phenyl) methyl) (methyl) amino) -5-hydroxy-N- (isoxazol-4-yl) -1- (2-methoxyethyl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 9)
To a suspension of Int B2 (210 mg, 0.72 mmol) in DMSO (2 mL) was added 9-1 (158 mg, 0.72 mmol) and DIPEA (374 mg, 2.88 mmol) at rt. The mixture was stirred at 80 ℃ for 4 hrs. The mixture was diluted with EA and water. The organic layer was concentrated under vacuum. The residue was purified by column chromatography to give 9-2. MS m/z (ESI) : 473.4 [M+H] +.
To a suspension of 9-2 (185 mg, 0.39 mmol) in DMF (2 mL) was added Cs2CO3 (255 mg, 0.78 mmol) and MeI (167 mg, 1.17 mmol) at rt. The mixture was stirred at rt for 16 hrs. The mixture was diluted with EA and water. The organic layer was washed with brine, and concentrated under vacuum. The residue was purified by column chromatography to give 9-3. MS m/z (ESI) : 487.2 [M+H] +.
To a suspension of 9-3 (150 mg, 0.31 mmol) in THF (2 mL) was added LiOH (in H2O) (1M) (0.46 mL, 0.46 mmol) at rt. The mixture was stirred at rt for 16 hrs. The reaction mixture was
cooled to 0 ℃, and was adjusted to pH = 3 with HCl (1M) . The reaction mixture was diluted with EA and water. The organic layer was washed with brine and concentrated under vacuum to give 9-4, which was used in the next step without further purification. MS m/z (ESI) : 459.2 [M+H] +.
To a suspension of 9-4 (100 mg, 0.22 mmol) in DMF (2 mL) was added isoxazol-4-amine (31.6 mg, 0.26 mmol) , DIEA (84.5 mg, 0.66 mmol) , and HATU (165.9 mg, 0.44 mmol) at rt. The mixture was stirred at rt for 16 hrs. The mixture was diluted with EA and water. The organic layer was washed with brine and concentrated under vacuum. The residue was purified by column chromatography to give 9-5. MS m/z (ESI) : 525.3 [M+H] +.
To a suspension of 9-5 (82 mg, 0.14 mmol) in DCM (5 mL) was added tribromoborane (0.56 mL, 0.562 mmol) at 0 ℃ under N2. The mixture was stirred at 0 ℃ for 3 hrs. The reaction mixture was quenched with MeOH and then diluted with EA and water. The organic layer was washed with brine and concentrated under vacuum. The residue was purified by prep-HPLC to give 2- ( ( (3-chloropyridin-2-yl) (phenyl) methyl) (methyl) amino) -5-hydroxy-N- (isoxazol-4-yl) -1- (2-methoxyethyl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 9) . MS m/z (ESI) : 511.3 [M+H] +; 1H NMR: (400 MHz, DMSO-d6) δ = 10.94 (s, 1H) , 10.16 (s, 1H) , 9.26 (s, 1H) , 8.88 (s, 1H) , 8.37 (dd, J = 4.4, 1.6 Hz, 1H) , 7.74 (dd, J = 8.0, 1.6 Hz, 1H) , 7.63 -7.57 (m, 2H) , 7.38 -7.32 (m, 2H) , 7.29 -7.24 (m, 1H) , 7.16 -7.11 (m, 1H) , 6.19 (s, 1H) , 4.69 -4.60 (m, 1H) , 4.23 -4.16 (m, 1H) , 3.88 -3.84 (m, 2H) , 3.30 (s, 3H) , 2.62 (s, 3H) .
Example 5: 2- ( ( (3-chloropyridin-2-yl) (phenyl) methyl) (methyl) amino) -5-hydroxy-1- (2-hydroxyethyl) -N- (isoxazol-4-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 10)
To a solution of Compound 9 (100 mg, 0.19 mmol) in DCM (5 mL) was added tribromoborane (143 mg, 0.57 mmol) at 0 ℃ and the reaction was stirred at 25 ℃ for 4 hrs. The reaction mixture was quenched with MeOH (1 mL) and diluted with water (10 mL) and DCM (10 mL) . The organic layer was separated, washed with brine (10 mL) , and concentrated in vacuo. The crude product was purified by prep-HPLC to give 2- ( ( (3-chloropyridin-2-yl) (phenyl) methyl) (methyl) amino) -5-hydroxy-1- (2-hydroxyethyl) -N- (isoxazol-4-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 10) . MS m/z (ESI) : 497.1 [M+H] +; 1H NMR: (400 MHz, CDCl3) δ 11.05 (s, 1H) , 9.07 (s, 1H) , 8.89 (s, 1H) , 8.58 (s, 1H) , 8.33 -8.32 (m, 1H) , 7.77 -7.75 (m, 2H) , 7.66 -7.64 (m, 1H) , 7.41 -7.39 (m, 2H) , 7.36 -7.34 (m, 1H) , 7.24 -7.10 (m, 1H) , 6.12 (s, 1H) , 4.75 -4.71 (m, 1H) , 4.48 -4.46 (m, 1H) , 4.11 -4.04 (m, 2H) , 2.67 (s, 3H) .
Example 6: 2- ( (10-chloro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) (methyl) amino) -5-hydroxy-1- (2-hydroxyethyl) -N- (isoxazol-4-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 12)
2- ( (10-Chloro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) (methyl) amino) -5-hydroxy-1- (2-hydroxyethyl) -N- (isoxazol-4-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 12) was synthesized from Compound 11 using similar conditions as those described in Example 5. 1H NMR: (400 MHz, CDCl3) δ 10.97 (s, 1H) , 10.10 (s, 1H) , 9.15 (s, 1H) , 8.71 (s, 1H) , 8.42 (d, J = 4.7 Hz, 1H) , 7.46 (d, J = 7.7 Hz, 1H) , 7.28 -7.20 (m, 2H) , 7.16 (d, J = 7.9 Hz, 1H) , 7.00 (d, J = 8.0 Hz, 1H) , 6.58 (s, 1H) , 5.92 (d, J = 14.5 Hz, 1H) , 4.99 (d, J = 14.5 Hz, 1H) , 4.56 -4.24 (m, 2H) , 4.10 -3.85 (m, 2H) .
Example 7: 2- ( (10-chloro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) (2-methoxyethyl) amino) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-ihydropyrimidine-4-carboxamide (Compound 13)
To a solution of 1-1 (600 mg, 1.31 mmol) in DMF (5.00 mL) were added 2-iodo-1-methoxyethane (1.22 g, 6.57 mmol) and Cs2CO3 (2.14 g, 6.57 mmol) . The mixture was stirred at 80 ℃ for 2 hrs. The reaction mixture was diluted with water and EtOAc. The organic layer was
concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give compound 13-1. MS m/z (ESI) : 515.3 [M+H] +.
To a solution of 13-1 (300 mg, 0.58 mmol) in THF (3 mL) and H2O (3 mL) was added LiOH (48.9 mg, 1.17 mmol) . The mixture was stirred at 20 ℃ for 4 hrs. The system was adjusted to pH = 2 with HCl (1M) , the mixture was extracted with EtOAc, The organic layer was washed with brine and concentrated under vacuum to give 13-2, which was used in the next step without further purification. MS m/z (ESI) : 487.3 [M+H] +.
To a solution of 13-2 (180 mg, 0.370 mmol) in ACN (2 mL) were added isoxazol-4-amine (31.1 mg, 0.37 mmol) , TCFH (311 mg, 1.11 mmol) and NMI (91.1 mg, 1.11 mmol) . The mixture was stirred at 20 ℃ for 4 hrs. The reaction was diluted with water (10 mL) and EtOAc (10 mL) . The organic layer was washed with brine and concentrated under vacuum to give 13-3, which was used in the next step without further purification. MS m/z (ESI) : 553.4 [M+H] +.
To a solution of 13-3 (20.0 mg, 0.036 mmol) in DCM (1 mL) was added BCl3 (72 μL, 0.072 mmol) at -20 ℃. The mixture was stirred at -20 ℃ for 6 hrs. The mixture was diluted with MeOH (10 mL) and aq. NaHCO3 (10 mL) . The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 2- ( (10-chloro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) (2-methoxyethyl) amino) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-ihydropyrimidine-4-carboxamide (Compound 13) . MS m/z (ESI) : 539.4 [M+H] -; 1H NMR: (400 MHz, CDCl3) δ 10.90 (s, 1H) , 9.14 (s, 1H) , 8.71 (s, 1H) , 8.54 (d, J = 2.0 Hz, 1H) , 7.39 (d, J = 8.0 Hz, 1H) , 7.21 -7.27 (m, 2H) , 7.17 -7.179 (m, 1H) , 6.94 -7.13 (m, 1H) , 6.59 (s, 1H) , 5.77 (d, J = 14.4 Hz, 1H) , 5.00 (d, J = 14.4 Hz, 1H) , 3.62 (s, 3H) , 3.52 -3.54 (m, 2H) , 3.44 -3.45 (m, 1H) , 3.17 -3.21 (m, 1H) , 3.13 (s, 3H) .
Example 8: 2- (1- (4-chlorodibenzo [b, e] [1, 4] oxazepin-5 (11H) -yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 14)
To a solution of 14-1 (25.0 g, 120 mmol) in ACN (250 mL) were added NBS (23.8 g, 133 mmol) and AIBN (1.25 g, 7.61 mmol) . The mixture was stirred at 80 ℃ for 12 hrs. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 14-2. 1HNMR: (400 MHz, CDCl3) δ = 7.43 (br d, J = 8.00 Hz, 1H) , 7.37 (d, J = 7.60 Hz, 1H) , 7.27 -7.22 (m, 1H) , 4.65 (s, 2H) .
To a solution of 14-2 (30.0 g, 105 mmol) in ACN (300 mL) were added K2CO3 (29.1 g, 210 mmol) and 2-nitrophenol (16.1 g, 116 mmol) . The mixture was stirred at 50 ℃ for 2 hrs. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (1000 mL × 2) . The combined organic layers were washed with brine (50 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether/ethyl acetate = 20/1 (100 mL) at 25 ℃ for 30 min, the mixture was filtered to give 14-3. 1HNMR: (400 MHz, DMSO-d6) δ = 7.93 (dd, J = 1.60, 8.40 Hz, 1H) , 7.75 -7.64 (m, 2H) , 7.61 -7.55 (m, 1H) , 7.48 (dd, J = 7.60, 13.6 Hz, 2H) , 7.23 -7.14 (m, 1H) , 5.36 (s, 2H) .
To a solution of 14-3 (31.0 g, 90.4 mmol) in MeOH (750 mL) was added Pt/V/C (15.0 g) under N2 atmosphere. The mixture was stirred at 25 ℃ for 4 hrs under H2 (50 psi) atmosphere. The reaction mixture was filtered through a pad of celite, the cake was washed with MeOH (3000 mL) , the filtrate was concentrated under reduced pressure to give 14-4. MS m/z (ESI) : 314.0 [M+H] +.
The mixture of 14-4 (26.0 g, 83.1 mmol) , t-Bu3P (8.41 g, 41.5 mmol) , Pd2 (dba) 3 (7.62 g, 8.32 mmol) , K2CO3 (22.9 g, 166 mmol) and t-BuONa (15.9 g, 166 mmol) in toluene (300 mL) was stirred at 95 ℃ for 5 hrs under N2 atmosphere. The reaction mixture was filtered through a pad of celite, the cake was washed with EtOAc (2000 mL) , the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography to give compound 14-5. MS m/z (ESI) : 232.0 [M+H] +; 1H NMR: (400 MHz, DMSO-d6) δ = 7.48 (s, 1H) , 7.41 -7.29 (m, 2H) , 7.15 (d, J = 7.20 Hz, 1H) , 6.95 -6.84 (m, 2H) , 6.79 (t, J = 7.60 Hz, 1H) , 6.74 -6.66 (m, 1H) , 5.02 (s, 2H) .
To a solution of 14-5 (1.0 g, 4.31 mmol) in DMF (12 mL) was added NaH (0.52 g, 12.9 mmol, 60%wt. in mineral oil) at 0 ℃, The mixture was stirred at 0 ℃ for 0.5 hr. To the mixture was added 2-bromopropanenitrile (1.73 g, 12.9 mmol) , the reaction was stirred at 80 ℃ for 16 hrs. The mixture was diluted with EA (100 mL) and brine. The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 14-6. MS m/z (ESI) : 285.0 [M+H] +.
To a solution of 14-6 (700 mg, 2.45 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (512 mg, 7.37 mmol) at 0 ℃, TEA (746 mg, 7.37 mmol) was added thereafter. The mixture was stirred at 78 ℃ for 16 hrs. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 14-7. MS m/z (ESI) : 317.8 [M+H] +.
To a solution of 14-7 (560 mg, 1.76 mmol) in CH3CN (8 mL) was added dimethyl but-2-ynedioate (300 mg, 2.11 mmol) . The mixture was stirred at 25 ℃ for 16 hrs. The mixture was concentrated under reduced pressure to give a residue, the crude product was extracted with EA (100 mL × 2) . The combined organic layers were washed with brine (100 mL) , dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography to give 14-8. MS m/z (ESI) : 460.2 [M+H] +.
The solution of 14-8 (340 mg, 0.73 mmol) in xylene (8 mL) was stirred at 140 ℃ for 12 hrs. The mixture was concentrated to give a residue. The residue was purified by column chromatography to give 14-9. MS m/z (ESI) : 428.1 [M+H] +.
To a solution of 14-9 (100 mg, 0.19 mmol) in pyridine (3 mL) was added benzoyl chloride (52.5 mg, 0.37 mmol) . The mixture was stirred at 25 ℃ for 16 hrs. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with EA (60 mL) and brine. The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 14-10. MS m/z (ESI) : 532.0 [M+H] +.
To a solution of 14-10 (55 mg, 0.10 mmol) in DMSO (2 mL) was added Mg (OMe) 2 (223 mg, 0.21 mmol) at 0 ℃. The mixture was stirred at room temperature for 1 hr. The mixture was cooled to 0 ℃ and CH3I (58.7 mg, 0.41 mmol) was added. The mixture was stirred at 25 ℃ for 16 hrs. The mixture was adjusted to pH = 6 with 1N HCl and extracted with EtOAc (15 mL × 2) . The
organic layer was washed with brine and concentrated under vacuum to give 14-11, which was used in the next step without further purification. MS m/z (ESI) : 441.8 [M+H] +.
To a solution of 14-11 (70 mg, 0.16 mmol) in H2O (1 mL) , THF (1 mL) and MeOH (1 mL) was added LiOH·H2O (33.3 mg, 0.79 mmol) . The mixture was stirred at 25 ℃ for 5 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with ice water (10 mL) and extracted with ethyl acetate (20 mL × 2) . The combined aqueous layer was acidified with 1N HCl at 0 ℃ and extracted with methanol/dichloromethane (30 mL × 2, 1: 10) . The combined organic layers were washed with brine and concentrated under vacuum to give 14-12, which was used in the next step without further purification. MS m/z (ESI) : 428.2 [M+H] +.
To a solution of 14-12 (70 mg, 0.14 mmol) and isoxazole-4-amine (24 mg, 0.28) in DMF (3 mL) were added HBTU (158 mg, 0.42 mmol) and DIEA (70 μL, 0.42 mmol) . The mixture was stirred at 25 ℃ for 16 hrs. The mixture was purified by prep-HPLC to give 2- (1- (4-chlorodibenzo [b, e] [1, 4] oxazepin-5 (11H) -yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 14) . MS m/z (ESI) : 494.0 [M+H] +; 1H NMR (400 MHz, CDCl3) : δ 11.41 -11.02 (m, 1H) , 9.76 -8.07 (m, 3H) , 7.48 -7.38 (m, 2H) , 7.29 -7.23 (m, 1H) , 7.21 -7.05 (m, 1H) , 6.95 -6.90 (m, 1H) , 6.89 -6.68 (m, 3H) , 5.89 -5.08 (m, 1H) , 5.08 -4.68 (m, 1H) , 3.86 -3.16 (m, 3H) , 1.76 -1.34 (m, 3H) .
The following compounds were synthesized using similar conditions as those described in Example 8 above along with appropriate starting materials.
Example 9: 2- ( (1-cyano-6, 11-dihydrodibenzo [b, e] oxepin-11-yl) (methyl) amino) -5-hydroxy-N- (isoxazol-4-yl) -1- (2-methoxyethyl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 15)
To a solution of Int B2 (2.84 g, 9.78 mmol) and Int A8 (2.76 g, 8.15 mmol) in DMSO (40 mL) was added CsF (2.48 g, 16.3 mmol) . The mixture was stirred at 80 ℃ for 2 hrs. The reaction mixture was diluted with water (100 mL) at 20 ℃. The solution was extracted with EtOAc (50 mL ×3) , the combined organic layers were washed with brine (100 mL × 3) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 15-1. MS m/z (ESI) : 544.2 [M+H] +.
To a solution of 15-1 (1.05 g, 1.93 mmol) in NMP (12 mL) was added zinc powder (12.6 mg, 0.19 mmol) , Zn (CN) 2 (453 mg, 3.86 mmol) and palladium bis [tris (2-methylprop-2-yl) phosphane] (98.6 mg, 0.19 mmol) . The mixture was stirred at 80 ℃ for 1 hr under N2 atmosphere. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 3) . The combined organic layers were washed with brine (30 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 15-2. MS m/z (ESI) : 491.3 [M+H] +.
Compound 15 was prepared in five steps from 15-2 using similar conditions as those described in the synthesis of compound 1 from 1-1.
Compound 15: MS m/z (ESI) : 527.1 [M-H] -; 1H NMR (400 MHz, CDCl3) δ 11.93 (brs, 1H) , 9.87 (s, 1H) , 9.19 (s, 1H) , 8.81 (s, 1H) , 7.64 -7.50 (m, 2H) , 7.47 -7.39 (m, 2H) , 7.38 -7.28 (m, 1H) , 7.02 -6.95 (m, 1H) , 6.92 (dd, J = 8.3, 1.3 Hz, 1H) , 6.59 -6.33 (m, 1H) , 6.11 (s, 1H) , 4.90 (d, J = 12.8 Hz, 1H) , 4.51 -4.21 (m, 2H) , 3.80 -3.40 (m, 2H) , 3.12 (s, 3H) , 2.62 (s, 3H) .
Example 10: 2- ( (10-cyano-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) (methyl) amino) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 18)
Compound 18-2 was prepared in two steps from Int A7 using similar conditions as those described in the synthesis of 2-2 from Int A2.18-2: MS m/z (ESI) : 517.2 [M+H] +.
To a solution of 18-2 (500 mg, 0.97 mmol) in NMP (20 mL) were added Zn (CN) 2 (227 mg, 1.94 mmol) , Zn (6.30 mg, 0.097 mmol) , and Pd (t-Bu3P) 2 (248 mg, 0.49 mmol) . The mixture was stirred at 90 ℃ for 2 hrs. The reaction was diluted with EtOAc and water. The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 18-3. MS m/z (ESI) : 462.3 [M+H] +.
To a solution of 18-3 (300 mg, 0.65 mmol) and isoxazol-4-amine (109 mg, 1.3 mmol) in toluene (3 mL) was added LiHMDS (1.3 mL, 1.30 mmol) at -70 ℃. The mixture was stirred at 20 ℃ for 2 hrs. The mixture was diluted with aq. NH4Cl and EtOAc. The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 18-4. MS m/z (ESI) : 500.4 [M+H] +.
To a solution of 18-4 (120 mg, 0.24 mmol) in DCM (2 mL) was added BCl3 (0.5 mL, 0.48 mmol) , the reaction was stirred at 0 ℃ for 3 hrs. The reaction was diluted with MeOH and aq. NaHCO3. The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 2- ( (10-cyano-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) (methyl) amino) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 18) . MS m/z (ESI) : 486.3 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 11.42 (s, 1H) , 10.06 (s, 1H) , 9.17 (s, 1H) , 8.81 (s, 1H) , 8.49 (d, J = 4.8 Hz, 1H) , 7.54 (d, J = 7.5 Hz, 1H) , 7.37 (d, J = 4.8 Hz, 2H) , 7.33 (dd, J = 7.7, 4.9 Hz, 1H) , 7.27 -7.21 (m, 1H) , 6.41 (s, 1H) , 6.05 (d, J = 13.8 Hz, 1H) , 5.07 (d, J = 13.8 Hz, 1H) , 3.61 (s, 3H) , 2.69 (s, 3H) .
The following compounds were synthesized using similar conditions as those described in Example 10 above along with appropriate starting materials.
Example 11: 5-hydroxy-N- (isoxazol-4-yl) -1-methyl-2- (methyl (10-methyl-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) amino) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 21)
To a solution of 18-2 (400 mg, 0.78 mmol) in DMF (5 mL) were added 2, 4, 6-trimethyl-1, 3, 5, 2, 4, 6-trioxatriborinane (3.3 mL, 11.6 mmol) , Cs2CO3 (759 mg, 2.33 mmol) , and Pd (PPh3) 4 (89.7 mg, 0.078 mmol) . The mixture was stirred at 100 ℃ for 2 hrs. The reaction was diluted with water (10 mL) and EtOAc (10 mL × 3) . The combined organic layers were washed with brine (30 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 21-1. MS m/z (ESI) : 451.4 [M+H] +.
Compound 21 was prepared in two steps from 21-1 using similar conditions as those described in the synthesis of compound 18 from 18-3.
21: MS m/z (ESI) : 475.5 [M+H] +; 1H NMR (400 MHz, CDCl3) δ 10.6 (s, 1H) , 10.5 (s, 1H) , 9.17 (s, 1H) , 8.74 (s, 1H) , 8.23 (s, 1H) , 7.27 -7.33 (m, 1H) , 7.21 -7.23 (m, 1H) , 7.11 -7.12 (m, 1H) , 6.91 -6.96 (m, 2H) , 6.24 (s, 1H) , 5.70 (d, J = 14.8 Hz 1H) , 5.00 (d, J = 14.8 Hz 1H) , 3.62 (s, 3H) , 2.68 (s, 3H) , 2.61 (s, 3H) .
The following compounds were synthesized using similar conditions as those described in Example 11 above along with appropriate starting materials.
Example 12: 2- (1- (4-cyanodibenzo [b, e] [1, 4] oxazepin-5 (11H) -yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 25)
To a solution of 25-1 (100 g, 462 mmol) in DCE (1 L) were added NBS (82.4 g, 462 mmol) and AIBN (30.4 g, 185 mmol) . The mixture was stirred at 80 ℃ for 16 hrs. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 25-2.
To a solution of 25-2 (90.0 g, 137 mmol) in ACN (1 L) was added 2-iodophenol (33.2 g, 151 mmol) and K2CO3 (38.0 g, 274 mmol) . The mixture was stirred at 50 ℃ for 2 hrs under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was triturated in EtOH (200 mL) at 20 ℃ for 1 hr to give 25-3, which was used in the next step without further purification.
To a solution of 25-3 (50.0 g, 115 mmol) in EtOH (500 mL) and H2O (250 mL) were added Fe (32.1 g, 576 mmol) and NH4Cl (30.8 g, 576 mmol) . The mixture was stirred at 80 ℃ for 2 hrs under N2 atmosphere. The mixture was filtered and concentrated under reduced pressure to give 25-4, which was used in the next step without further purification. MS m/z (ESI) : 405.9 [M+H] +.
To a solution of 25-4 (200 mg, 0.50 mmol) in toluene (4 mL) was added Pd2 (dba) 3 (45.3 mg, 0.05 mmol) , t-Bu3P (500.7 mg, 0.25 mmol) , K2CO3 (137 mg, 0.99 mmol) and t-BuONa (95.1 mg, 0.99 mmol) . The mixture was stirred at 95 ℃ for 16 hrs under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 25-5. MS m/z (ESI) : 277.9 [M+H] +.
25-10 was prepared in four steps from 25-5 using similar conditions as those described in the synthesis of compound 14-9 from 14-5. MS m/z (ESI) : 474.0 [M+H] +.
To a solution of 25-10 (100 mg, 0.201 mmol) in DMF (1 mL) were added iodomethane (58.4 mg, 0.41 mmol) and Cs2CO3 (134 mg, 0.41 mmol) . The mixture was stirred at 20 ℃ for 16 hrs. The mixture was quenched with H2O (2 mL) and extracted with EtOAc (2 mL × 3) . The combined organic layers were washed with brine (2 mL × 3) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 25-11. MS m/z (ESI) : 502.0 [M+H] +.
To a solution of 25-11 (300 mg, 0.6 mmol) in DMF (2 mL) was added CuCN (322 mg, 3.59 mmol) . The mixture was stirred at 140 ℃ for 16 hrs. The mixture was filtered and concentrated under reduced pressure to give 25-12, which was used in the next step without further purification. MS m/z (ESI) : 447.5 [M+H] +.
To a solution of 25-12 (30.0 mg, 0.067 mmol) and isoxazol-4-amine (17.0 mg, 0.20 mmol) in toluene (500 uL) and THF (500 uL) was added LiHMDS (201 uL, 0.202 mmol) at -70 ℃. The mixture was stirred at 20 ℃ for 3 hrs. The mixture was quenched with aq. NH4Cl (2 mL) and extracted with EtOAc (2 mL × 3) , the combined organic layers were washed with brine (2 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 25-13. MS m/z (ESI) : 499.3 [M+H] +.
To a solution of 25-13 (20.0 mg, 0.04 mmol) in DCM (2 mL) was added BBr3 (120 μL, 0.12 mmol) . The mixture was stirred at -10 ℃ for 2 hrs. The mixture was quenched with MeOH (500 uL) , the mixture was adjusted to pH = 8 with aq. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 2- (1- (4-cyanodibenzo [b, e] [1, 4] oxazepin-5 (11H) -yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -
1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 25) . MS m/z (ESI) : 485.1 [M+H] +; 1H NMR (400 MHz, CDCl3) δ 11.5 (s, 1H) , 10.0 (s, 1H) , 9.14 (s, 1H) , 8.67 (s, 1H) , 7.69 -7.68 (d, J = 4.0 Hz, 1H) , 7.38 -7.32 (m, 2H) , 7.24 -7.20 (m, 1H) , 7.08 -7.04 (m, 2H) , 6.98 -6.94 (m, 1H) , 5.52 (d, J = 16.0 Hz, 1H) , 5.23 (q, J = 6.4 Hz, 1H) , 4.98 (d, J = 16.0 Hz, 1H) , 3.22 (s, 3H) , 1.47 (d, J = 6.4 Hz, 3H) .
The following compounds were synthesized using similar conditions as those described in Example 12 above along with appropriate starting materials.
Example 13: 2- (1- (5-cyano-2-methyl-2, 10-dihydro-4H-benzo [b] pyrazolo [4, 3-e] [1, 4] oxazepin-4-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 27)
To a solution of 27-1 (1.00 g, 5.40 mmol) in DMF (10 mL) , was added K2CO3 (1.49 g, 10.8 mmol) and iodomethane (369 uL, 5.94 mmol) . The mixture was stirred at 20 ℃ for 16 hrs. The mixture was quenched with H2O (10 mL) and extracted with EtOAc (10 mL × 3) . The combined organic layers were washed with brine (10 mL × 3) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 27-2. MS m/z (ESI) : 200.2 [M+H] +.
To a solution of 27-2 (400 mg, 2.00 mmol) in THF (5 mL) was added DIBAL-H (6 mL, 6.02 mmol) dropwise at -30 ℃. The mixture was stirred at -30 ℃ for 4 hrs. The mixture was quenched with aq. NH4Cl (5 mL) and extracted with ethyl acetate (10 mL × 3) . The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 27-3, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H) , 4.98 (s, 2H) , 3.99 (s, 3H) .
The mixture of 27-3 (23.0 g, 146 mmol) in SOCl2 (230 mL) was stirred at 80 ℃ for 16 hrs. The mixture was concentrated under reduced pressure to give 27-4, which was used in the next step without further purification. MS m/z (ESI) : 176.2 [M+H] +.
To a solution of 27-4 (21.0 g, 119 mmol) in DMF (200 mL) was added 3-bromo-2-iodophenol (35.7 g, 120 mmol) . The mixture was stirred at 60 ℃ for 16 hrs. To the mixture was added H2O (500 mL) , the mixture was stirred at 0 ℃ for 30 min, filtered and the filter cake was dried under reduced pressure to give 27-5, which was used in the next step without further purification. MS m/z (ESI) : 439.8 [M+H] +.
To a solution of 27-5 (38.0 g, 86.8 mmol) in EtOH (400 mL) and H2O (200 mL) was added Fe (25.6 g, 458 mmol) and NH4Cl (24.5 g, 458 mmol) . The mixture was stirred at 70 ℃ for 2 hrs. The mixture was filtered, the filtrate was concentrated under reduced pressure to give 27-6, which was used in the next step without further purification.
To a solution of 27-6 (1.00 g, 2.45 mmol) in toluene (3 mL) was added Cs2CO3 (1.59 mg, 4.90 mmol) , Xantphos (141 mg, 0.25 mmol) and Pd (OAc) 2 (55.0 mg, 0.25mmol) . The mixture was stirred at 90 ℃ for 16 hrs under N2 atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography to give compound 27-7. 1H NMR: (400 MHz, DMSO-d6) δ = 7.45 (s, 1H) , 7.40 (s, 1H) , 7.31 -7.28 (m, 1H) , 6.99 -6.97 (m, 1H) , 6.62 (t, J = 8.0 Hz, 1H) , 4.96 (s, 2H) , 3.71 (s, 3H) .
Compound 27-13 was prepared in six steps from 27-7 using similar conditions as those described in the synthesis of 25-12 from 25-5. MS m/z (ESI) : 451.1 [M+H] +. To a solution of 27-13 (20.0 mg, 0.044 mmol) in THF (500 uL) , MeOH (500 uL) and H2O (500 uL) was added LiOH (5.60 mg, 0.13 mmol) . The mixture was stirred at 40 ℃ for 2 hrs. The mixture was acidified with HCl (2M) to pH = 2 and extracted with EtOAc (1 mL × 3) , the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 27-14, which was used in the next step without further purification. MS m/z (ESI) : 437.2 [M+H] +.
To a solution of 27-14 (20.0 mg, 0.046 mmol) and ACN (2 mL) were added TCFH (38.6 mg, 0.14 mmol) , isoxazole-4-amine (11.6 mg, 0.14 mmol) and NMI (11.3 mg, 0.14 mmol) . The mixture was stirred at 20 ℃ for 2 hrs. The mixture was concentrated under reduced pressure to give a residue, the residue was suspended in H2O (1 mL) and extracted with EtOAc (1 mL × 3) , the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 27-15, which was used in the next step without further purification. MS m/z (ESI) : 503.5 [M+H] +.
To a solution of 27-15 (23.0 mg, 0.046 mmol) in DCM (1 mL) was added BBr3 (137 uL, 0.14 mmol) . The mixture was stirred at -10 ℃ for 2 hrs. The mixture was quenched with MeOH (200 uL) , adjusted to pH = 8 with NaHCO3 and washed with H2O (2 mL) , the organic layer was dried under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 2- (1- (5-cyano-2-methyl-2, 10-dihydro-4H-benzo [b] pyrazolo [4, 3-e] [1, 4] oxazepin-4-yl) ethyl) -5-hydroxy-N-
(isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 27) . MS m/z (ESI) : 489.1 [M+H] +. 1H NMR (400 MHz, CDCl3) δ 10.2 (s, 1H) , 9.17 (s, 1H) , 8.76 (s, 1H) , 7.52 -7.40 (m, 3H) , 6.78 (s, 1H) , 5.46 (d, J = 16.0 Hz, 1H) , 4.98 (q, J = 8.0 Hz, 1H) , 4.84 (d, J = 16.0 Hz, 1H) , 3.72 (s, 3H) , 3.46 (s, 3H) , 1.27 (d, J = 8.0 Hz, 3H) .
Example 14: 2- (1- (10-cyano-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 28-P1-1 &28-P1-2)
To a solution of Int A12 (1.02 g, 3.19 mmol) in THF (2 mL) was added LiHMDS (5.8 mL, 5.80 mmol) at 0 ℃. The mixture was stirred at -78 ℃ for 1 hr. To the mixture was added Int B4 (1.02 g, 3.19 mmol) in THF (2 mL) . The mixture was stirred at -78 ℃ for 1 hr. The mixture was quenched with aq. NH4Cl (20 mL) at 0 ℃ and extracted with EtOAc (20 mL × 3) . The combined organic layers were washed with brine (20 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 28-1. MS m/z (ESI) : 516.3 [M+H] +; 1H NMR (400 MHz, CDCl3) δ 8.56 -8.55 (m, 1H) , 7.32 (d, J = 8.0 Hz, 1H) , 7.27 -7.25 (m, 1H) , 7.23 -7.20 (m, 1H) , 7.03 -6.98 (m, 2H) , 5.51 (d, J = 16.0 Hz, 1H) , 5.30 (d, J = 10.0 Hz, 1H) , 5.00 (d, J = 16.0 Hz, 1H) , 4.53 -4.46 (m, 1H) , 4.40 (q, J = 7.2 Hz, 2H) , 3.87 (s, 3H) , 3.42 (s, 3H) , 1.42 (t, J = 7.2 Hz, 3H) , 1.28 (d, J = 7.2 Hz, 3H) .
To a solution of 28-1 (500 mg, 0.94 mmol) in NMP (5 mL) were added Zn (6.10 mg, 0.094 mmol) , Zn (CN) 2 (220 mg, 1.87 mmol) and Pd (t-Bu3P) 2 (239 mg, 0.47 mmol) . The mixture was stirred at 110 ℃ for 1.5 hrs. The mixture was filtered, the filtrate was diluted with H2O (100 mL) and extracted with EtOAc (100 mL × 3) . The combined organic layers were washed with brine (100 mL × 4) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 28-2. MS m/z (ESI) : 516.3 [M+H] +.
To a solution of 28-2 (1.05 g, 2.17 mmol) in THF (3 mL) , MeOH (3 mL) and H2O (3 mL) was added LiOH·H2O (0.3 g, 6.49 mmol) . The mixture was stirred at 40 ℃ for 2 hrs. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (2 mL) and extracted with EtOAc (20 mL × 2) . The aqueous phase was adjusted to pH = 8 with aq. HCl (2 M) and extracted with DCM/MeOH (10: 1, 20.0 mL × 8) . The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 28-3, which was used in the next step without further purification. MS m/z (ESI) : 433.3 [M+H] +.
To a solution of 28-3 (480 mg, 1.06 mmol) in ACN (5 mL) were added isoxazole-4-amine (268 mg, 3.18 mmol) , NMI (261 mg, 3.18 mmol) and TCFH (893 mg, 3.18 mmol) . The mixture was stirred at 25 ℃ for 1.5 hrs. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL × 3) . The combined organic layers were washed with brine (50 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 28-4-P1 and 28-4-P2.
28-4-P1: MS m/z (ESI) : 499.4 [M+H] +, Rt = 0.33 min (column: EVO C18 2.1 mm × 30 mm, 5 um; mobile phase: ACN (0.01875%TFA) -water (0.0375%TFA) ; ACN: 5%to 95%in 0.60 min, then 95%for 0.18 min, then 5%for 0.02 min; flow rate: 2.0 mL/min.
28-4-P2: MS m/z (ESI) : 499.4 [M+H] +, Rt = 0.37 min (column: EVO C18 2.1 mm × 30 mm, 5 um; mobile phase: ACN (0.01875%TFA) -water (0.0375%TFA) ; ACN: 5%to 95%in 0.60 min, then 95%for 0.18 min, then 5%for 0.02 min; flow rate: 2.0 mL/min. 28-4-P1 was further seperated by chiral SFC to give 28-4-P1-1 and 28-4-P1-2.
28-4-P1-1: MS m/z (ESI) : 499.3 [M+H] +; SFC: 99.6%ee, Rt = 1.57 min (column: Cellulose-2 50 × 4.6 mm I.D., 3 um; mobile phase: phase A for CO2, and phase B for MeOH (0.05%DEA) ; isocratic elution: 40%B in A; flow rate: 3 mL/min; column temp: 35 ℃) . 28-4-P1-2: MS m/z (ESI) : 499.3 [M+H] +; SFC: 99.7%ee, Rt = 2.33 min (column: Cellulose-2 50 × 4.6 mm I.D., 3 um; mobile phase: phase A for CO2, and phase B for MeOH (0.05%DEA) ; isocratic elution: 40%B in A; flow rate: 3 mL/min; column temp: 35 ℃) .
To a solution of 28-4-P1-1 (110 mg, 0.22 mmol) in DCM (2 mL) was added BBr3 (0.7 mL, 0.66 mmol) . The mixture was stirred at -10 ℃ for 1 hr. The mixture was quenched with MeOH (0.5 mL) at -10 ℃, the mixture was diluted with H2O (10 mL) , adjusted pH = 8 with aq. NaHCO3, and extracted with DCM (10 mL × 3) . The combined organic layers were dried over Na2SO4, filtered and
concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 2- (1- (10-cyano-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 28-P1-1) . MS m/z (ESI) : 485.2 [M+H] +; SFC: 100%ee, Rt = 1.01 min (column: Chiralpak IG-3 50 × 4.6 mm I.D., 3 um; mobile phase: phase A for CO2, and phase B for EtOH (0.05%DEA) ; isocratic elution: 40%B in A, flow rate: 3 mL/min; column temp: 35 ℃) ; 1H NMR (400 MHz, CDCl3) δ 11.8 (s, 1H) , 9.77 (s, 1H) , 9.14 (s, 1H) , 8.77 (s, 1H) , 8.61 -8.60 (m, 1H) , 7.39 -7.28 (m, 5H) , 5.62 (d, J = 16.0 Hz, 1H) , 5.22 (d, J = 10.0 Hz, 1H) , 5.05 (d, J = 16.0 Hz, 1H) , 4.67 -4.60 (m, 1H) , 3.61 (s, 3H) , 1.29 (d, J = 7.2 Hz, 3H) .
To a solution of 28-4-P1-2 (120 mg, 0.23 mmol) in DCM (2 mL) were added BBr3 (0.7 mL, 0.70 mmol) . The mixture was stirred at -10 ℃ for 1 hr. The mixture was quenched with MeOH (0.5 mL) at -10 ℃, the mixture was diluted with H2O (10 mL) , adjusted pH = 8 with aq. NaHCO3, and extracted with DCM (10 mL × 3) . The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 2- (1- (10-cyano-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 28-P1-2) . MS m/z (ESI) : 485.3 [M+H] +; SFC: 100%ee, Rt = 1.51 min (column: Chiralpak IG-3 50 × 4.6 mm I.D., 3 um; mobile phase: phase A for CO2, and phase B for EtOH (0.05%DEA) ; isocratic elution: 40%B in A, flow rate: 3 mL/min; column temp: 35 ℃) ; 1H NMR (400 MHz, CDCl3) δ 11.8 (s, 1H) , 9.77 (s, 1H) , 9.14 (s, 1H) , 8.77 (s, 1H) , 8.61 (d, J = 4.0 Hz, 1H) , 7.39 -7.28 (m, 5H) , 5.62 (d, J = 16.0 Hz, 1H) , 5.23 (d, J = 10.0 Hz, 1H) , 5.05 (d, J = 16.0 Hz, 1H) , 4.67 -4.60 (m, 1H) , 3.61 (s, 3H) , 1.29 (d, J = 7.2 Hz, 3H) .
The following compounds were synthesized using similar conditions as those described in Example 14 above along with appropriate starting materials.
Example 15: 2- (1- (10-chloro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 29-P1-1 &29-P1-2)
To a solution of Int A11 (1.00 g, 4.32 mmol) and Int B4 (1.65 g, 5.18 mmol) in DMF (20 mL) was added NaHMDS (1 M, 5.2 mL, 5.20 mmol) at -40 ℃. The mixture was stirred at 25 ℃ for 3 hrs. The mixture was quenched with H2O (100 mL) at 0 ℃ and extracted with EtOAc (100 mL × 3) . The combined organic layers were washed with brine (200 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 29-1-P1 and 29-1-P2.
29-1-P1: MS m/z (ESI) : 471.8 [M+H] +, Rt = 0.58 min (column: XBridge C18 2.1 mm × 50 mm, 5 um; mobile phase: ACN -water (0.025%NH3·H2O) ; ACN: 5%to 95%in 0.70 min, then 95%for 0.20 min, then 5%for 0.10 min; flow rate: 1.7 mL/min. 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 4.0 Hz, 1H) , 7.31 (d, J = 7.6 Hz, 1H) , 7.22 -7.19 (m, 1H) , 7.08 -7.06 (m, 2H) , 6.98 -6.95 (m, 1H) , 5.50 (d, J = 16.0 Hz, 1H) , 5.31 (d, J = 10.0 Hz, 1H) , 4.99 (d, J = 16.0 Hz, 1H) , 4.50 -4.45 (m, 1H) , 4.40 (q, J = 7.2 Hz, 2H) , 3.87 (s, 3H) , 3.43 (s, 3H) , 1.42 (t, J = 7.2 Hz, 3H) , 1.27 (d, J = 7.2 Hz, 3H) .
29-1-P2: MS m/z (ESI) : 472.1 [M+H] +, Rt = 0.62 min (column: XBridge C18 2.1 mm × 50 mm, 5 um; mobile phase: ACN -water (0.025%NH3·H2O) ; ACN: 5%to 95%in 0.70 min, then 95%for 0.20 min, then 5%for 0.10 min; flow rate: 1.7 mL/min.
To a solution of 29-1-P1 (900 mg, 1.92 mmol) in THF (9 mL) , MeOH (9 mL) and H2O (9 mL) was added LiOH·H2O (345 mg, 5.75 mmol) . The mixture was stirred at 45 ℃ for 3 hrs. The mixture was adjusted to pH = 2 with aq. HCl (2 N) and extracted with DCM/MeOH (10: 1, 10 mL × 5) . The combined organic layers were washed with brine (10 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give 29-2-P1, which was used in the next step without further purification. MS m/z (ESI) : 442.1 [M+H] +.
To a solution of 29-2-P1 (790 mg, 1.63 mmol) and isoxazol-4-amine (411 mg, 4.89 mmol) in ACN (8 mL) were added [chloro (dimethylamino) methylidene] dimethylammonium hexafluoro-λ5-phosphanuide (1.37 g, 4.89 mmol) and 1-methylimidazole (402 mg, 4.89 mmol) . The mixture was stirred at 25 ℃ for 2 hrs. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (10 mL) and extracted with EtOAc (20 mL × 3) . The combined organic layers were washed with brine (20 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 29-3-P1. MS m/z (ESI) : 508.4 [M+H] +.
29-3-P1 was further seperated by chiral SFC to give 29-3-P1-1 and 29-3-P1-2.
29-3-P1-1: MS m/z (ESI) : 508.1 [M+H] +; SFC: 100%ee, Rt = 1.22 min (column: Chiralcel OJ-3 50 × 4.6mm I.D., 3um; mobile phase: phase A for CO2, and phase B for MeOH (0.05%DEA) ; gradient elution: 5%to 40%B in A; flow rate: 3 mL/min; column temp: 35 ℃) .
29-3-P1-2: MS m/z (ESI) : 508.5 [M+H] +; SFC: 99.6%ee, Rt = 1.67 min (column: Chiralcel OJ-3 50 × 4.6mm I.D., 3um; mobile phase: phase A for CO2, and phase B for MeOH (0.05%DEA) ; gradient elution: 5%to 40%B in A; flow rate: 3 mL/min; column temp: 35 ℃) .
To a solution of 29-3-P1-1 (15.0 mg, 0.030 mmol) in DCM (0.5 mL) was added BBr3 (0.2 mL, 0.2 mmol) . The mixture was stirred at 0 ℃ for 3 hrs. The mixture was quenched and adjusted to pH = 8 with aq. NaHCO3 at 0 ℃, the mixture was extracted with DCM (10 mL × 3) . The combined organic layers were washed with brine (10 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 2- (1- (10-chloro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 29-P1-1) . MS m/z (ESI) : 494.1 [M+H] +; SFC: 100%ee, Rt = 0.51 min (column: Chiralcel OD-3 50 × 4.6mm I.D., 3um; mobile phase: phase A for CO2, and phase B for MeOH + ACN (0.05%DEA) ; isocratic elution: 40%B in A, flow rate: 3 mL/min; column temp: 35 ℃) ; 1H NMR (400 MHz, CDCl3) δ 11.40 (s, 1H) , 9.69 (s, 1H) , 9.12 (s, 1H) , 8.68 (s, 1H) , 8.56 (d, J = 3.6 Hz, 1H) , 7.37 (d, J = 7.2 Hz, 1H) , 7.29 (d, J = 4.8 Hz, 1H) , 7.13 -7.01 (m, 3H) , 5.56 (d, J = 16.0 Hz, 1H) , 5.28 (d, J = 10.8 Hz, 1H) , 5.02 (d, J = 16.0 Hz, 1H) , 4.60 -4.56 (m, 1H) , 3.57 (s, 3H) , 1.29 (d, J = 6.4 Hz, 3H) .
To a solution of 29-3-P1-2 (16.0 mg, 0.032 mmol) in DCM (0.5 mL) was added BBr3 (0.2 mL, 0.2 mmol) . The mixture was stirred at 0 ℃ for 3 hrs. The mixture was quenched and adjusted to pH = 8 with aq. NaHCO3 at 0 ℃, the mixture was extracted with DCM (10 mL × 3) . The combined organic layers were washed with brine (10 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 2- (1- (10-chloro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 29-P1-2) . MS m/z (ESI) : 494.1 [M+H] +; SFC: 100%ee, Rt = 0.48 min (column: Chiralcel OD-3 50 × 4.6mm I.D., 3um; mobile phase: phase A for CO2, and phase B for MeOH + ACN (0.05%DEA) ; isocratic elution: 40%B in A, flow rate: 3 mL/min; column temp: 35 ℃) ; 1H NMR (400 MHz, CDCl3) δ 11.40 (s, 1H) , 9.71 (s, 1H) , 9.13 (s, 1H) , 8.68 (s, 1H) , 8.56 (d, J = 4.4 Hz, 1H) , 7.37 (d, J = 8.4 Hz, 1H) , 7.29 (d, J = 4.8 Hz, 1H) , 7.13 -6.98 (m, 3H) , 5.56 (d, J = 16.4 Hz, 1H) , 5.29 (d, J = 9.2 Hz, 1H) , 5.02 (d, J = 16.4 Hz, 1H) , 4.60 -4.55 (m, 1H) , 3.56 (s, 3H) , 1.29 (d, J = 7.2 Hz, 3H) .
The following compounds were synthesized using similar conditions as those described in Example 15 above along with appropriate starting materials.
Example 16: 2- (1- (10-chloro-7-fluoro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 30-P1-1, 30-P1-2, 30-P2-1 &30-P2-2)
To a solution of Int A13 (486 mg, 1.95mmol) and Int B4 (745 mg, 2.34 mmol) in DMF (8 mL) was added [bis (trimethylsilyl) amino] sodium (3.9 mL, 3.89 mmol) at -40 ℃. The mixture was stirred at -40 ℃ for 2 hrs. The mixture was quenched with water (10 mL) at 0 ℃ and extracted with EtOAc (10 mL × 3) . The combined organic layers were washed with brine (10 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 30-1-P1 and 30-1-P2.
30-1-P1: MS m/z (ESI) : 488.4 [M+H] +; Rt = 0.361 min (column: EVO C18 2.1 × 30mm 5um, 5 um; mobile phase: ACN (0.01875%TFA) -water (0.0375%TFA) ; ACN: 5%to 95%in 0.60 min, then 95%for 0.18 min, then 5%for 0.02 min; flow rate: 2.00 mL/min. 1H NMR (400 MHz, CDCl3) δ 8.55 (dd, J = 4.7, 1.7 Hz, 1H) , 7.38 -7.32 (m, 1H) , 7.26 -7.21 (m, 1H) , 7.02 (dd, J = 9.0, 4.6 Hz, 1H) , 6.90 (t, J = 9.0 Hz, 1H) , 5.55 (d, J = 16.0 Hz, 1H) , 5.30 (dd, J = 10.2, 1.7 Hz, 1H) , 5.05 (d, J = 16.0 Hz, 1H) , 4.51 -4.43 (m, 1H) , 4.39 (q, J = 7.1 Hz, 2H) , 3.88 (s, 3H) , 3.45 (s, 3H) , 1.40 (t, J = 7.1 Hz, 3H) , 1.27 (d, J = 6.8 Hz, 3H) .
30-1-P2: MS m/z (ESI) : 488.4 [M+H] +; Rt = 0.373 min (column: EVO C18 2.1 × 30mm 5um, 5 um; mobile phase: ACN (0.01875%TFA) -water (0.0375%TFA) ; ACN: 5%to 95%in 0.60 min, then 95%for 0.18 min, then 5%for 0.02 min; flow rate: 2.00 mL/min. 1H NMR (400 MHz, CDCl3) δ 8.35 -8.34 (m, 1H) , 7.46 -7.45 (m, 1H) , 7.26 -7.25 (m, 1H) , 7.23 -7.19 (m, 1H) , 7.11 -7.06 (m, 1H) , 5.78 -5.54 (m, 1H) , 5.31 -5.28 (m, 1H) , 5.10 -5.03 (m, 1H) , 4.46 -4.39 (m, 2H) , 4.27 -4.26 (m, 1H) , 3.94 (s, 3H) , 3.28 (s, 3H) , 1.44 -1.41 (m, 3H) , 1.29 -1.25 (m, 3H) .
Compound 30-P1-1 &30-P1-2 were prepared in four steps from 30-1-P1 using similar conditions as those described in the synthesis of 29-P1 &29-P2 from 29-3.
30-P1-1: MS m/z (ESI) : 512.3 [M+H] +; SFC: 98.5%ee, Rt = 2.01 min (column: Chiralcel OD-3 50 × 4.6mm I.D., 3um; mobile phase: phase A for CO2, and phase B for IPA (0.05%DEA) ; gradient elution: 5%to 40%B in A, flow rate: 3 mL/min; column temp: 35 ℃) ; 1H NMR (400 MHz, CDCl3) δ 11.40 (s, 1H) , 9.67 (s, 1H) , 9.12 (s, 1H) , 8.67 (s, 1H) , 8.57 -8.56 (m, 1H) , 7.41 -7.39 (m, 1H) , 7.32 -7.29 (m, 1H) , 7.04 -7.01 (m, 1H) , 6.97 -6.93 (m, 1H) , 5.63 (d, J = 16.00 Hz, 1H) , 5.28 -5.25 (m, 1H) , 5.09 (d, J = 16.00 Hz, 1H) , 4.61 -4.54 (m, 1H) , 3.59 (s, 3H) , 1.30 (d, J = 6.80 Hz, 3H) .
30-P1-2: MS m/z (ESI) : 512.3 [M+H] +; SFC: 98.4%ee, Rt = 2.39 min (column: Chiralcel OD-3 50 × 4.6mm I.D., 3um; mobile phase: phase A for CO2, and phase B for IPA (0.05%DEA) ; gradient elution: 5%to 40%B in A, flow rate: 3 mL/min; column temp: 35 ℃) ; 1H NMR (400 MHz, CDCl3) δ 11.43 (s, 1H) , 9.65 (s, 1H) , 9.11 (s, 1H) , 8.66 (s, 1H) , 8.56 (d, J = 4.7 Hz, 1H) , 7.44 –7.34 (m, 1H) , 7.33 –7.28 (m, 1H) , 7.02 (dd, J = 9.0, 4.5 Hz, 1H) , 6.94 (t, J = 8.9 Hz, 1H) , 5.62 (d, J = 16.0 Hz, 1H) , 5.25 (d, J = 10.7
Hz, 1H) , 5.08 (d, J = 16.0 Hz, 1H) , 4.57 (dq, J = 10.4, 6.8 Hz, 1H) , 3.58 (s, 3H) , 1.29 (d, J = 6.8 Hz, 3H) .
Compound 30-P2-1 &30-P2-2 were prepared in four steps from 30-1-P2 using similar conditions as those described in the synthesis of 29-P1 &29-P2 from 29-3.
30-P2-1: MS m/z (ESI) : 512.3 [M+H] +; SFC: 100%ee, Rt = 1.99 min (column: Chiralcel OD-3 50 × 4.6mm I.D., 3um; mobile phase: phase A for CO2, and phase B for MeOH (0.05%DEA) ; gradient elution: 5%to 40%B in A, flow rate: 3 mL/min; column temp: 35 ℃) ; 1H NMR (400 MHz, CDCl3) δ 10.73 (s, 1H) , 9.17 (s, 1H) , 8.67 (s, 1H) , 8.21 -8.20 (m, 1H) , 7.30 -7.28 (m, 1H) , 7.25 -7.22 (m, 1H) , 7.15 -7.07 (m, 2H) , 5.60 -5.59 (m, 2H) , 5.11 (d, J = 16.00 Hz, 1H) , 4.48 -4.41 (m, 1H) , 3.49 (s, 3H) , 1.23 (d, J = 3.40 Hz, 3H) .
30-P2-2: MS m/z (ESI) : 512.4 [M+H] +; SFC: 99.1%ee, Rt = 2.39 min (column: Chiralcel OD-3 50 × 4.6mm I.D., 3um; mobile phase: phase A for CO2, and phase B for MeOH (0.05%DEA) ; gradient elution: 5%to 40%B in A, flow rate: 3 mL/min; column temp: 35 ℃) ; 1H NMR (400 MHz, CDCl3) δ 10.90 (s, 1H) , 10.74 (s, 1H) , 9.18 (s, 1H) , 8.67 (s, 1H) , 8.21 -8.20 (m, 1H) , 7.27 -7.22 (m, 2H) , 7.15 -7.07 (m, 2H) , 5.59 -5.56 (m, 2H) , 5.11 (d, J = 16.00 Hz, 1H) , 4.48 -4.41 (m, 1H) , 3.49 (s, 3H) , 1.23 (d, J = 6.80 Hz, 3H) .
The following compounds were synthesized using similar conditions as those described in Example 16 above along with appropriate starting materials.
Example 17: 2- (1- (5-cyano-1-methyl-4, 10-dihydro-1H-benzo [6, 7] oxepino [3, 4-c] pyrazol-4-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 31)
To a solution of Int A14 (500 mg, 2.22 mmol) and Int B4 (708 mg, 2.22 mmol) in DMF (5 mL) was added LiHMDS (4.4 mL) . The mixture was stirred at -70 ℃ for 2 hrs. The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 31-1. MS m/z (ESI) : 464.4 [M+H] +.
To a solution of 31-1 (50 mg, 0.11 mmol) in THF (2 mL) , H2O (1 mL) and MeOH (1 mL) was added LiOH (18.7 mg, 0.45 mmol) . The mixture was stirred at 20 ℃ for 6 hrs. The mixture was diluted with water, adjusted pH = 2 with HCl (1 M) and extracted with EtOAc (50 mL + 20 mL) . The organic layer was washed with brine and concentrated under reduced pressure to give 31-2, which was used in the next step without further purification. MS m/z (ESI) : 436.1 [M+H] +.
To a solution of 31-2 (40.0 mg, 0.092 mmol) in ACN (1 mL) were added isoxazol-4-amine (7.70mg, 0.092 mmol) , 1-methylimidazole (7.50 mg, 0.092 mmol) , [chloro (dimethylamino) methylidene] dimethylammonium hexafluoro-λ5-phosphanuide (25.8 mg, 0.092 mmol) and 1-methylimidazole (7.50 mg, 0.092 mmol) . The mixture was stirred at 20 ℃ for 2 hrs. The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 31-3. MS m/z (ESI) : 502.3 [M+H] +.
To a solution of 31-3 (10.0 mg, 0.019 mmol) ) in DCM (1 mL) was added BBr3 (0.04 mL, 0.039 mmol) at -5 ℃ The mixture was stirred at -5 ℃ for 2 hrs. The mixture was diluted with MeOH and aq. NaHCO3. The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 2- (1- (5-cyano-1-methyl-4, 10-dihydro-1H-benzo [6, 7] oxepino [3, 4-c] pyrazol-4-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 31) . MS m/z (ESI) : 488.3 [M+H] +. 1H NMR (400 MHz, CDCl3) δ 11.77 (s, 1H) , 9.69 (s, 1H) , 9.12 (s, 1H) , 8.71 (s, 1H) , 7.58 (s, 1H) , 7.31 -7.38 (m, 1H) ,
7.28 -7.30 (m, 2H) , 5.50 (d, J = 14.8 Hz, 1H) , 4.84 (d, J = 14.8 Hz, 1H) , 4.64 (d, J = 10.0 Hz, 1H) , 4.13 (dq, J = 10.0 Hz, J = 4.0 Hz, 1H) , 3.71 (s, 3H) , 3.56 (s, 3H) , 1.37 (d, J = 4.0 Hz, 3H) .
The following compounds were synthesized using similar conditions as those described in Example 17 above along with appropriate starting materials.
Example 18: 2- (1- (10-cyano-7-fluoro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 33-P1-1, 33-P1-2, 33-P2-1 &33-P2-2)
To a solution of Int A16 (1.80 g, 6.12 mmol) in NMP (20 mL) were added Zn (20.0 mg, 0.31 mmol) , Zn (CN) 2 (1.44 g, 12.24 mmol) and Pd (t-Bu3P) 2 (313 mg, 0.61 mmol) . The mixture was stirred at 100 ℃ for 2 hrs. The mixture was filtered, the filtrate was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3) . The combined organic layers were washed with brine (30 mL × 2) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 33-1. MS m/z (ESI) : 241.2 [M+H] +. 1H NMR (400 MHz, CDCl3) δ 8.54 (dd, J = 4.8 Hz, 1.2 Hz, 1H) , 7.56 (d, J = 7.6 Hz, 1H) , 7.33 -7.29 (m, 1H) , 7.26 -7.24 (m, 1H) , 7.06 (t, J = 9.6 Hz, 1H) , 5.39 (s, 2H) , 4.81 (s, 2H) .
To a solution of 33-1 (680 mg, 2.79 mmol) in THF (2 mL) was added LiHMDS (3.3 mL, 3.34 mmol) . The mixture was stirred at -78 ℃ for 0.5 hr. To the mixture was added a solution of Int B4 (978 mg, 3.06 mmol) in THF (2 mL) . The mixture was stirred at -78 ℃ for 1 hr. The mixture was
quenched with sat. NH4Cl (5 mL) at 0 ℃, diluted with water (10 mL) and extracted with EtOAc (20 mL × 3) . The combined organic layers were washed with brine (30 mL × 2) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 33-2-P1 and 33-2-P2.
33-2-P1: 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 3.6 Hz, 1H) , 7.35 -7.31 (m, 2H) , 7.26 -7.24 (m, 1H) , 7.05 (t, J = 8.8 Hz, 1H) , 5.56 (d, J = 16.0 Hz, 1H) , 5.17 (dd, J = 1.2 Hz, 9.6 Hz, 1H) , 5.05 (d, J = 16.0 Hz, 1H) , 4.47 -4.39 (m, 3H) , 3.89 (s, 3H) , 3.49 (s, 3H) , 1.43 (t, J = 7.2 Hz, 3H) , 1.34 (d, J = 6.8 Hz, 3H) .
33-2-P2: 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 4.0 Hz, 1H) , 7.46 -7.43 (m, 1H) , 7.36 (d, J = 8.0 Hz, 1H) , 7.24 -7.19 (m, 2H) , 5.46 (d, J = 15.6 Hz, 1H) , 5.10 -5.08 (m, 1H) , 5.05 (d, J = 15.6 Hz, 1H) , 4.40 -4.35 (m, 2H) , 4.24 -4.17 (m, 1H) , 4.00 (s, 3H) , 3.49 (s, 3H) , 1.39 (t, J = 6.8 Hz, 3H) , 1.28 (d, J = 6.8 Hz, 3H) .
To a solution of 33-2-P1 (500 mg, 1.03 mmol) in THF (5 mL) and H2O (5 mL) was added LiOH·H2O (130 mg, 3.10 mmol) . The mixture was stirred at 25 ℃ for 2 hrs. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (10 mL) , adjusted to pH = 8 with 2 M HCl and extracted with DCM/MeOH (10: 1, 10.0 mL × 5) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 33-3-P1, which was used in the next step without further purification. MS m/z (ESI) : 451.3 [M+H] +.
To a solution of 33-3-P1 (750 mg, 1.66 mmol) in ACN (10 mL) were added isoxazol-4-amine (419 mg, 4.98 mmol) , NMI (409 mg, 4.98 mmol) and TCFH (1.40 g, 4.98 mmol) . The mixture was stirred at 25 ℃ for 2 hrs. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3) . The combined organic layers were washed with brine (30 mL × 2) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 33-4-P1. MS m/z (ESI) : 517.4 [M+H] +.
33-4-P1 was further seperated by chiral SFC to give 33-4-P1-1 and 33-4-P1-2. 33-4-P1-1: MS m/z (ESI) : 517.4 [M+H] +; SFC: 100%ee, Rt = 0.80 min (column: Chiralpak IC-3 50 ×4.6mm I.D., 3 um; mobile phase: phase A for CO2, and phase B for MeOH + ACN (0.05%DEA) ; isocratic elution: 40%B in A; flow rate: 3 mL/min; column temp: 35 ℃) .
33-4-P1-2: MS m/z (ESI) : 517.4 [M+H] +; SFC: 98.1%ee, Rt = 0.97 min (column: Chiralpak IC-3 50 × 4.6mm I.D., 3 um; mobile phase: phase A for CO2, and phase B for MeOH + ACN (0.05%DEA) ; isocratic elution: 40%B in A; flow rate: 3 mL/min; column temp: 35 ℃) .
Compound 33-4-P2-1 &33-4-P2-2 were prepared in three steps from 33-2-P2 using similar conditions as those described in the synthesis of 33-4-P1-1 &33-4-P1-2 from 33-2-P1.
33-4-P2-1: MS m/z (ESI) : 517.3 [M+H] +; SFC: 100%ee, Rt = 0.84 min (column: Chiralcel OX-3 50 × 4.6mm I.D., 3 um; mobile phase: phase A for CO2, and phase B for MeOH + ACN (0.05%DEA) ; isocratic elution: 40%B in A; flow rate: 3 mL/min; column temp: 35 ℃) .
33-4-P2-2: MS m/z (ESI) : 517.4 [M+H] +; SFC: 99.9%ee, Rt = 2.07 min (column: Chiralcel OX-3 50 × 4.6mm I.D., 3 um; mobile phase: phase A for CO2, and phase B for MeOH + ACN (0.05%DEA) ; isocratic elution: 40%B in A; flow rate: 3 mL/min; column temp: 35 ℃) .
To a solution of 33-4-P1-1 (200 mg, 0.39 mmol) in DCM (2 mL) was added BBr3 (297 mg, 1.16 mmol) . The mixture was stirred at -10 ℃ for 1 hr. The mixture was quenched with MeOH (0.5 mL) at -10 ℃, diluted with water (10 mL) , adjusted to pH = 8 with aq. NaHCO3, and extracted with DCM (10 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 2- (1- (10-cyano-7-fluoro-5, 11-dihydrobenzo [6, 7] oxepino [4, 3-b] pyridin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 33-P1-1) .
All the four isomers were prepared using similar conditions as those described in the synthesis of compound 33-P1-1 from corresponding starting materials.
Example 19: 2- (1- (1-cyano-6, 11-dihydrodibenzo [b, e] oxepin-11-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 38-P1, 38-P2, 38-P3 &38-P4)
The solution of Int A20 (700 mg, 3.20 mmol) in DMF (5 mL) was added into LiHMDS (4.8 mL, 1 M in THF) at -50 ℃. The mixture was stirred at -50 ℃ for 0.5 hr under N2 atmosphere. To the mixture was added Int B4 (1.02 g, 3.50 mmol) in DMF (8 mL) . The mixture was stirred at -50 ℃ for 2 hrs. The mixture was quenched with sat. NH4Cl (50 mL) and then diluted with EtOAc (200 mL) . The mixture was washed with H2O (200 mL) , the organic phase was concentrated reduced pressure to give a residue. The residue was purified by column chromatography to give 38-1. MS m/z (ESI) : 460.2 [M+H] +.
To a solution of 38-1 (600 mg, 1.30 mmol) in THF/MeOH/H2O (4: 1: 1, 7 mL) was added LiOH·H2O (273 mg, 6.50 mmol) . The mixture was stirred at 25 ℃ for 2 hrs under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue, the crude product was adjusted to pH = 2 with 1 N HCl solution (15 mL) , the suspension was filtered to give 38-2, which was used in the next step without further purification. MS m/z (ESI) : 432.2 [M+H] +.
To a solution of 38-2 (350 mg, 0.80 mmol) and isoxazol-4-amine (205 mg, 2.40 mmol) in DMF/CAN (1: 1) (5 mL) was added NMI (200 mg, 2.40 mmol) at 0 ℃. The mixture was stirred at 0 ℃for 5 min under N2 atmosphere, then TCFH (683 mg, 2.40 mmol) was added to the mixture. The mixture was stirred at 25 ℃ for 3 hrs. The mixture was quenched with sat. NaHCO3 (20 mL) and extracted with EA (20 mL) , the organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 38-3.
38-3 was further seperated by chiral SFC to give 38-3-P1, 38-3-P2, 38-3-P3and 38-3-P4.
38-3-P1: MS m/z (ESI) : 498.2 [M+H] +; SFC: 100%ee, Rt = 1.10 min (column: Daicel_ChiralPAK-OJ_100 × 0.3 mm_3 μm; mobile phase: phase A for CO2, and phase B for MeOH (0.1%DEA) ; isocratic elution: 15%B in A; flow rate: 2 mL/min, 5 min; column temp: 35 ℃) .
38-3-P2: MS m/z (ESI) : 498.2 [M+H] +; SFC: 99.99%ee, Rt = 0.99 min (column: Daicel_ChiralPAK-IJ_100 × 0.3 mm_3 μm; mobile phase: phase A for CO2, and phase B for MeOH; isocratic elution: 40%B in A; flow rate: 2 mL/min, 4 min; column temp: 35 ℃)
38-3-P3: MS m/z (ESI) : 498.2 [M+H] +; SFC: 99.99%ee, Rt = 2.11 min (column: Daicel_ChiralPAK-IJ_100 × 0.3 mm_3 μm; mobile phase: phase A for CO2, and phase B for MeOH; isocratic elution: 40%B in A; flow rate: 2 mL/min, 4 min; column temp: 35 ℃) .
38-3-P4: MS m/z (ESI) : 498.2 [M+H] +; SFC: 100%ee, Rt = 2.07 min (column: Daicel_ChiralPAK-OJ_100 × 0.3 mm_3 μm; mobile phase: phase A for CO2, and phase B for MeOH (0.1%diethylamine) ; isocratic elution: 15%B in A; flow rate: 2 mL/min, 5 min; column temp: 35 ℃) .
All the four isomers were prepared using similar conditions as those described in the synthesis of compound 33-P1-1 from corresponding starting materials.
The following compounds were synthesized using similar conditions as those described in Example 19 above along with appropriate starting materials.
Example 20: 2- (1- (5-cyano-1- (difluoromethyl) -4, 10-dihydro-1H-benzo [6, 7] oxepino [3, 4-c] pyrazol-4-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 41-P1, 41-P2) and 2- (1- (5-cyano-2- (difluoromethyl) -2, 10-dihydro-4H-benzo [6, 7] oxepino [3, 4-c] pyrazol-4-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 42-P1, 42-P2)
To a solution of LiHMDS (2.9 mL, 2.9 mmol, 1 M in THF) was added a solution of Int A23 (500 mg, 1.46 mmol) in dry DMF (5 mL) at -70 ℃ under nitrogen. The mixture was stirred at -70 ℃for 0.5 hr. To the mixture was added Int B4 (514 mg, 1.61 mmol) in dry DMF (5 mL) at -70 ℃ under nitrogen. The mixture was stirred at 20 ℃ for 18 hrs. The mixture was quenched with sat. NH4Cl (30 mL) and extracted with EtOAc (50 mL × 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 41-1-P1 and 41-1-P2.
41-1-P1: MS m/z (ESI) : 580.4 [M+H] +; LCMS: Rt = 2.58 min (column: Xbridge C18, 3.5um, 4.6 × 50mm, A-RP-933; mobile phase: phase A for water (0.01%TFA) , and phase B for ACN (0.01%TFA) ; gradient elution: 5%to 95%B in A within 3.0 min; flow rate: 1.8 mL/min; column temp: 45 ℃) .
41-1-P2: MS m/z (ESI) : 580.4 [M+H] +; LCMS: Rt = 2.68 min (column: Xbridge C18, 3.5um, 4.6 × 50mm, A-RP-933; mobile phase: phase A for water (0.01%TFA) , and phase B for ACN (0.01%TFA) ; gradient elution: 5%to 95%B in A within 3.0 min; flow rate: 1.8 mL/min; column temp: 45 ℃) .
The solution of 41-1-P1 (1.50 g, 2.59 mmol) in TFA (5 mL) was stirred at 20 ℃ for 1 hr. The mixture was concentrated under reduced pressure to give a residue, the crude product was diluted with aq. NaHCO3 (50 mL) and extracted with EtOAc (50 mL × 3) . The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 41-2-P1, which was used in the next step without further purification. MS m/z (ESI) : 450.1 [M+H] +.
To a mixture of 41-2-P1 (320 mg, 0.71 mmol) in CH3CN (5 mL) were added KF (161 mg, 2.78 mmol) and diethyl (bromodifluoromethyl) phosphonate (0.74 g, 2.78 mmol) at 20 ℃ under nitrogen atmosphere. The mixture was stirred at 50 ℃ for 15 hrs. The mixture was poured into water (20 mL) and extracted with EtOAc (30 mL × 3) . The combined organics were washed with brine (20 mL) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give the crude product. The crude product was further seperated by chiral SFC to give 41-3-P1-1, 41-3-P1-2, 42-1-P1-1 and 42-1-P1-2.
41-3-P1-1: MS m/z (ESI) : 500.2 [M+H] +; SFC: 99.02%ee, Rt = 4.08 min (column: Daicel_ChiralPAK-IE_100 × 3.0 mm_3 μm; mobile phase: phase A for CO2, and phase B for MeOH (0.1%DEA) ; isocratic elution: 10%B in A; flow rate: 2 mL/min, 10 min; column temp: 35 ℃) .
41-3-P1-2: MS m/z (ESI) : 500.2 [M+H] +; SFC: 98.94%ee, Rt = 5.17 min (column: Daicel_ChiralPAK-IE_100 × 3.0 mm_3 μm; mobile phase: phase A for CO2, and phase B for MeOH (0.1%DEA) ; isocratic elution: 10%B in A; flow rate: 2 mL/min, 10 min; column temp: 35 ℃) .
42-1-P1-1: MS m/z (ESI) : 500.2 [M+H] +; SFC: 99.76%ee, Rt = 3.02 min (column: Daicel_ChiralPAK-IE_100 × 3.0 mm_3 μm; mobile phase: phase A for CO2, and phase B for MeOH (0.1%DEA) ; isocratic elution: 10%B in A; flow rate: 2 mL/min, 10 min; column temp: 35 ℃) .
42-1-P1-2: MS m/z (ESI) : 500.2 [M+H] +; SFC: 98.06%ee, Rt = 3.50 min (column: Daicel_ChiralPAK-IE_100 × 3.0 mm_3 μm; mobile phase: phase A for CO2, and phase B for MeOH (0.1%DEA) ; isocratic elution: 10%B in A; flow rate: 2 mL/min, 10 min; column temp: 35 ℃) .
All the following compounds were prepared using similar conditions as those described in the synthesis of compound 38-P1 from corresponding starting materials.
Example 21: 2- (1- (6-cyano-4-fluoro-5, 10-dihydrobenzo [5, 6] oxepino [2, 3-b] pyridin-5-yl) ethyl) -5-hydroxy-N- (isoxazol-4-yl) -1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Compound 43-P1-1 and 43-P1-2)
Compound 43-3-P1-1 &43-3-P1-2 were prepared in three steps from Int A24 using similar conditions as those described in the synthesis of 29-3-P1-1 &29-3-P1-2 from Int A11.
43-3-P1-1: MS m/z (ESI) : 517.0 [M+H] +; SFC: 100%ee, Rt = 1.57 min (column: Daicel_ChiralPAK-IJ_100 × 3.0 mm_3 μm; mobile phase: phase A for CO2, and phase B for MeOH; isocratic elution: 15%B in A; flow rate: 2 mL/min, 5 min; column temp: 35 ℃) .
43-3-P1-2: MS m/z (ESI) : 517.0 [M+H] +; SFC: 99.40%ee, Rt = 2.35 min (column: Daicel_ChiralPAK-IJ_100 × 3.0 mm_3 μm; mobile phase: phase A for CO2, and phase B for MeOH; gradient elution: 15%B in A; flow rate: 2 mL/min, 5 min; column temp: 35 ℃) .
The following isomers were prepared using similar conditions as those described in the synthesis of compound 29-P1-1 from corresponding starting materials.
Example 22: Compounds 36-P1-1 and 36-P1-2
General procedure for preparation of compound 36-2
To a solution of 36-1 (10.0 g, 64.9 mmol) and K2CO3 (17.9 g, 130 mmol) in DMF (100 mL) was added CH3I (11.1 g, 77.9 mmol) . The mixture was stirred at 25 ℃ for 6 hrs. LCMS showed 36-1 was consumed completely. The reaction mixture was quenched by ice water 400 mL at 0 ℃, and extracted with Ethyl acetate (100 mL × 3) . The combined organic layers were washed with brine (200 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 10/1, Petroleum ether/Ethyl acetate = 10/1, Rf = 0.67) . 36-2 (10.1 g, 60.048 mmol, 92.5%yield) was obtained as a yellow oil which was checked by LCMS (Rt = 0.378 min, MS m/z (ESI) = 169.0 [M+H] +) .
General procedure for preparation of compound 36-3
To a solution of 36-2 (10.1 g, 60.1 mmol) and AIBN (1.00 g, 6.01 mmol) in DCE (100 mL) was added NBS (12.8 g, 72.1 mmol) . The mixture was stirred at 80 ℃ for 3 hrs. LCMS showed 36-2 was consumed completely. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 10/1, Petroleum ether/Ethyl acetate = 10/1, Rf = 0.45) . 36-3 (15.0 g, 58.8 mmol, 97.9%yield) was obtained as a white solid which was checked by LCMS (Rt = 0.473 min, MS m/z (ESI) = 248.1 [M+H] +) .
General procedure for preparation of compound 36-4
To a solution of 36-3 (5.00 g, 20.2 mmol) and 3- (methoxymethoxy) -2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile (5.80 g, 20.2 mmol) in dioxane (50.0 mL) was added K2CO3 (8.40 g, 60.7 mmol) , Ag2O (9.40 g, 40.5 mmol) and Pd (dppf) Cl2 (1.50 g, 2.02 mmol) under N2 atmosphere. The mixture was stirred at 100 ℃ for 12 hrs. LCMS (Rt = 0.431 min, MS m/z (ESI) = 330.1 [M+H] +) showed 36-3 was consumed completely. The reaction mixture was quenched by addition H2O 200 mL at 20 ℃, and extracted with Ethyl acetate (80.0 mL × 3) . The combined organic layers were washed with brine (100 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced
pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 5/1, Petroleum ether/Ethyl acetate = 2/1, Rf = 0.56) . 36-4 (2.40 g, 7.12 mmol, 35.2%yield) was obtained as a white solid which was checked by LCMS (Rt = 0.466 min, MS m/z (ESI) = 330.1 [M+H] +) .
General procedure for preparation of compound 36-5
To a solution of 36-4 (2.40 g, 7.12 mmol) in THF (30.0 mL) was dropwise added LiBH4·THF (8.90 mL, 17.8 mmol) at 0 ℃ under N2 atmosphere. The mixture was stirred at 66 ℃ for 12 hrs. LCMS (Rt = 0.405 min) showed 36-4 was consumed completely. The reaction mixture was quenched by ice water 100 mL at 0 ℃, and extracted with Ethyl acetate (50.0 mL × 3) . The combined organic layers were washed with brine (100 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1, Petroleum ether/Ethyl acetate = 1/1, Rf = 0.20) . 36-5 (650 mg, 1.97 mmol, 27.6%yield) was obtained as a yellow solid which was checked by LCMS (Rt = 0.440 min, MS m/z (ESI) = 302.1 [M+H] +) . 1H NMR: (400 MHz, CDCl3) . δ 7.33-7.31 (m, 1H) , 7.29-7.27 (m, 1H) , 7.26-7.25 (m, 1H) , 7.24-7.19 (m, 2H) , 6.96-6.91 (m, 1H) , 5.04 (s, 2H) , 4.83 (d, J = 2.4 Hz, 2H) , 4.32 (s, 2H) , 3.13 (s, 3H) . 19F NMR: (400 MHz, CDCl3) . δ -113.54.
General procedure for preparation of compound 36-6
To a solution of 36-5 (1.30 g, 4.31 mmol) in dioxane (10.0 mL) was dropwise added HCl/dioxane (15.0 mL) . The mixture was stirred at 25 ℃ for 6 hrs. LCMS (Rt = 0.323 min, MS m/z (ESI) = 258.3 [M+H] +) showed 36-5 was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue. 36-6 (1.10 g, 3.93 mmol) was obtained as a light yellow solid which was checked by LCMS (Rt = 0.358 min) .
General procedure for preparation of compound 36-7
To a solution of 36-6 (1.10 g, 4.28 mmol) in SOCl2 (15.0 mL) was stirred at 25 ℃ for 8 hrs. LCMS (Rt = 0.435 min) showed 36-6 was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue. 36-7 (1.10 g, 3.99 mmol) was obtained as a yellow oil which was checked by LCMS (Rt = 0.440 min) .
General procedure for preparation of compound 36-8
To a solution of 36-7 (1.10 g, 3.99 mmol) in DMF (15.0 mL) was added K2CO3 (1.10 g, 7.98 mmol) . The mixture was stirred at 80 ℃ for 2 hrs. LCMS (Rt = 0.464 min, MS m/z (ESI) : 240.1 [M+H] +) showed 36-7 was consumed completely. The reaction mixture was quenched by addition H2O 100 mL at 0 ℃, and extracted with Ethyl acetate (50.0 mL × 3) . The combined organic layers were washed with brine (50.0 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1, Petroleum ether/Ethyl acetate = 1/1, Rf = 0.46) . 36-8 (930 mg, 3.53 mmol) was obtained as a yellow solid which was checked by LCMS (Rt = 0.469 min, MS m/z (ESI) : 240.1 [M+H] +) .
General procedure for preparation of compound 36-9
A solution of 36-8 (930 mg, 3.89 mmol) in DMF (6.00 mL) was added into LiHMDS (4.67 mL, 4.67 mmol) at -40 ℃. The mixture was stirred at -40 ℃ for 0.5 hr. A solution of ethyl 2- (1-bromoethyl) -5-methoxy-1-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxylate (1.27 g, 3.97 mmol) in DMF (6.00 mL) was added into the reaction mixture at -40 ℃ and then was stirred at -40
℃ for 2.5 hrs. LCMS (Rt = 0.463 min, MS m/z (ESI) : 478.2 [M+H] +, ) showed 36-8 was consumed completely. The reaction mixture was quenched with water 50.0 mL at 0 ℃ and extracted with Ethyl acetate (20.0 mL × 3) . The combined organic layers were washed with brine (20.0 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 1/1, Petroleum ether/Ethyl acetate = 1/2, Rf = 0.42) . 36-9 (450 mg, 1.08 mmol, 27.7%yield) was obtained as a light yellow solid which was checked by LCMS (Rt = 0.501 min, MS m/z (ESI) : 478.1 [M+H] +, Column: EVO C18 2.1x30mm 5um; 50 ℃; Mobile phase: Ramp from 5%ACN (0.01875%TFA) in water (0.0375%TFA) to 95%ACN in water in 0.60 min, Flow rate is set at 2.0mL/min; then hold at 95%ACN for 0.18 minutes Flow rate is set at 2.0mL/min; return back to 5%ACN in water and hold for 0.02 min. Flow rate is set at 2.0mL/min. ) .
General procedure for preparation of compound 36-10
To a solution of 36-9 (410 mg, 0.859 mmol) in THF (4.00 mL) , MeOH (4.00 mL) and H2O (4.00 mL) was added LiOH·H2O (22.6 mg, 0.377 mmol) . The mixture was stirred at 45 ℃ for 3 hrs. LCMS (Rt = 0.413 min) showed 36-9 was consumed completely. The reaction mixture was adjusted with 2N aq. HCl to pH = 2, and extracted with DCM/MeOH (10/1, 30.0 mL × 3) . The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. 36-10 (380 mg, 0.840 mmol, 97.9%yield) was obtained as a light yellow solid which was checked by LCMS (Rt = 0.441 min, MS m/z (ESI) : 450.1 [M+H] +) .
General procedure for preparation of compound 36-11
To a solution of 36-10 (380 mg, 0.846 mmol) and NMI (208.3 mg, 2.54 mmol) in ACN (4.00 mL) was added isoxazol-4-amine (213 mg, 2.54 mmol) and TCFH (712 mg, 2.54 mmol) . The mixture was stirred at 25 ℃ for 4 hrs. LCMS (Rt = 0.488 min, MS m/z (ESI) : 516.1 [M+H] +) showed 36-10 was consumed completely. The reaction mixture was concentrated under reduced pressure to give a
residue. Then the residue was dissolved with 10.0 mL and extracted with Ethyl acetate (20.0 mL × 3) . The combined organic layers were washed with brine (20.0 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed column chromatography (FA condition) . 36-11 (250 mg, 0.485 mmol, 57.4%yield) was obtained as a yellow solid which was checked by LCMS (Rt = 0.455 min, MS m/z (ESI) : 516.1 [M+H] +) .
General procedure for preparation of Compound 36-12
36-12-P1 and 36-12-P2 (SFC: P1: Rt = 1.107 min, 50.5%; P2: Rt = 1.899 min, 49.5%) was purified by SFC (Basic condition, Column: Phenomenex-Cellulose-2 (250mm*30mm, 10um) ; Mobile phase: CO2-ACN/i-PrOH (0.1%NH3H2O) ; Gradient elution: B in A from 35%; Flow rate: 120 mL/min; Gradient time: 4.2 min) .
36-12-P1 (105 mg, 0.204 mmol, 42.0%yield) was obtained as a yellow solid which was checked by LCMS (Rt = 0.485 min, MS m/z (ESI) : 516.1 [M+H] +) and SFC (Rt = 1.113 min, ee%= 99.7%, Column: Chiralpak OZ-3 50X4.6mm I.D., 3um. Mobile phase: Phase A for CO2, and Phase B for IPA+ACN (0.05%DEA) ; Isocratic elution: 30%B in A; Flow rate: 3mL/min; Detector: PDA; Column Temp: 35C; Back Pressure: 100Bar. ) .
36-12-P2 (100 mg, 0.194 mmol, 40.0%yield) was obtained as a yellow solid which was checked by LCMS (Rt = 0.488 min, MS m/z (ESI) : 516.1 [M+H] +) and SFC (Rt = 1.847 min, ee%= 99.1%, Column: Chiralpak OZ-3 50X4.6mm I.D., 3um. Mobile phase: Phase A for CO2, and Phase B for IPA+ACN (0.05%DEA) ; Isocratic elution: 30%B in A; Flow rate: 3mL/min; Detector: PDA; Column Temp: 35C; Back Pressure: 100Bar. ) .
General procedure for preparation of compound 36-P1-1
To a solution of 36-12-P1 (100 mg, 0.194 mmol) in DCM (2.00 mL) was added BBr3 (0.580 mL, 0.582 mmol) . The mixture was stirred at 0 ℃ for 3 hrs. LCMS (Rt = 0.479 min, MS m/z (ESI) : 502.2 [M+H] +) showed 36-12-P1 was consumed completely. At 0 ℃, methanol (3.00 mL) slowly was added until the BBr3 quenched and then the resulting mixture was adjusted with aq. NaHCO3 12.0 mL to pH = 8, and extracted with DCM (10.0 mL × 3) . The combined organic layers were washed with brine (10.0 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (FA condition, Column: Phenomenex luna C18 150*25mm*10um; mobile phase: water (FA) -ACN; B%: 47%-77%, 10 min; Flowrate: 25 mL/min) . 36-P1-1 (88.3 mg, 0.173 mmol, 77.5%yield) was obtained which was checked by: LCMS (Rt = 0.475 min, MS m/z (ESI) : 502.2 [M+H] +) ;
HPLC (98.3%purity, Rt = 2.437 min, Column: Kinetex C18 LC Column 4.6X50mm, 5um; 50 ℃; A: 0.0375%TFA in water, B: 0.01875%TFA in Acetonitrile; Mobile phase: Ramp from 10%ACN (0.018%TFA) in water (0.037%TFA) to 80%ACN in water in 3.00 min, Flow rate is set at 1.5 mL/min; then hold at 80%ACN for 0.70 minutes, Flow rate is set at 1.5 mL/min; return back to 10%ACN in water and hold for 0.29 min, Flow rate is set at 2.0mL/min. ) ; and
SFC (Rt = 1.659 min, ee%= 97.5%, Column: Chiralpak AD-3 50×4.6mm I.D., 3um, Mobile phase: Phase A for CO2, and Phase B for MeOH (0.05%DEA) ; Gradient elution: B in A from 5%to 40%; Flow rate: 3 mL/min; Detector: PDA; Column Temp: 35C; Back Pressure: 100Bar. ) .
1H NMR: (400 MHz, DMSO-d6) . δ 11.27 (s, 1H) , 10.24 (s, 1H) , 9.31 (s, 1H) , 8.84 (s, 1H) , 7.46-7.43 (m, 2H) , 7.39-7.31 (m, 2H) , 7.23-7.19 (m, 1H) , 6.99-6.97 (m, 1H) , 5.76 (d, J = 16.4 Hz, 1H) , 5.20 (d, J = 10.0 Hz, 1H) , 5.05 (d, J = 16.4 Hz, 1H) , 4.43 (dq, J = 10.0 Hz 5.20 Hz, 1H) , 3.47 (s, 3H) , 1.37 (d, J = 5.2 Hz, 3H) . 19F NMR: (400 MHz, DMSO-d6) . δ -114.06.
General procedure for preparation of compound 36-P1-2
To a solution of 36-12-P2 (105 mg, 0.227 mmol) in DCM (2.00 mL) was added BBr3 (0.610 mL, 0.611 mmol) . The mixture was stirred at 0 ℃ for 3 hrs. LCMS (Rt = 0.481 min, MS m/z (ESI) : 502.1 [M+H] +) showed 36-12-P2 was consumed completely. At 0 ℃, methanol (3.00 mL) slowly was added until the BBr3 quenched and then the resulting mixture was adjusted with aq. NaHCO3 12.0 mL to pH = 8, and extracted with DCM (10.0 mL × 3) . The combined organic layers were washed with brine (10.0 mL × 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a
residue. The crude product was purified by prep-HPLC (FA condition, Column: Phenomenex luna C18 150*25mm*10um; mobile phase: water (FA) -ACN; B%: 47%-77%, 10 min; Flowrate: 25 mL/min) . 36-P1-2 (57.72 mg, 0.115 mmol, 50.7%yield) was obtained which was checked by: LCMS (Rt = 0.481 min, MS m/z (ESI) : 502.2 [M+H] +) ;
HPLC (99.9%purity, Rt = 2.437 min, Column: Kinetex C18 LC Column 4.6X50mm, 5um; 50 ℃; A: 0.0375%TFA in water, B: 0.01875%TFA in Acetonitrile; Mobile phase: Ramp from 10%ACN (0.018%TFA) in water (0.037%TFA) to 80%ACN in water in 3.00 min, Flow rate is set at 1.5 mL/min; then hold at 80%ACN for 0.70 minutes, Flow rate is set at 1.5 mL/min; return back to 10%ACN in water and hold for 0.29 min, Flow rate is set at 2.0mL/min. ) ; and
SFC (Rt = 2.040 min, ee%= 100%, Column: Chiralcel OD-3 50×4.6mm I.D., 3um, Mobile phase: Phase A for CO2, and Phase B for MeOH (0.05%DEA) ; Gradient elution: B in A from 5%to 40%;
Flow rate: 3 mL/min; Detector: PDA; Column Temp: 35C; Back Pressure: 100Bar. ) .
1H NMR: (400 MHz, DMSO-d6) . δ 11.28 (s, 1H) , 10.25 (s, 1H) , 9.31 (s, 1H) , 8.85 (s, 1H) , 7.46-7.43 (m, 2H) , 7.39-7.31 (m, 2H) , 7.24-7.19 (m, 1H) , 6.99-6.97 (m, 1H) , 5.76 (d, J = 16.4 Hz, 1H) , 5.21 (d, J = 10.0 Hz, 1H) , 5.05 (d, J = 16.4 Hz, 1H) , 4.41 (dq, J = 10.0 Hz 5.20 Hz, 1H) , 3.47 (s, 3H) , 1.37 (d, J = 5.2 Hz, 3H) . 19F NMR: (400 MHz, DMSO-d6) . δ -114.05.
Example A: TREX1 Enzymatic Assay
The Enzymatic assay for TREX1 was performed by a FRET assay using a custom dsDNA substrate processing a fluorophore-quencher on 3’ end and a 5’ fluorophore. Specifically, ssDNA oligos were resuspended at a concentration of 200 uM in Duplex Buffer to anneal to dsDNA. 5 uL 1.5 nM TREX1 protein (His tagged full length in house purified) in assay buffer (50 mM Tris pH 7.4 , 150 mM NaCl, 0.01%Tween-20, 2 mM DTT, 0.1 mg/mL BSA, 5 mM MgCl2, in MilliQ) was added into each plate. Then added 5 uL test compounds into assay plate and mixed with enzyme. Dispensed 2 uL of 0.5M EDTA to the plate as negative control. After incubating at 25 ℃ for 1 hours, 5uL dsDNA in assay buffer were added into the plate at 30 nM concentration. Plates were sealed and incubated at 25 ℃ for 1 hour. The reaction was quenched by dispensing 2 uL of 0.5 M EDTA to remaining wells and incubating for 30 min at 25 ℃. The plates were read with an Envision instrument and the raw data was then analyzed by XLfit 5.3.1.
The data from Example A is shown in Table 1.
Table 1
A = IC50 > 0 and < 100 nM;
B = IC50 > 100 nM and < 1000 nM;
C = IC50 > 1000 nM
A = IC50 > 0 and < 100 nM;
B = IC50 > 100 nM and < 1000 nM;
C = IC50 > 1000 nM
Example B: Pharmacokinetics study
Six male SD rats were assigned into 2 groups. Animals in Group 1 were given 1 mg/kg of TA by intravenous injection without fasting, animals in Groups 2 were given 5 mg/kg of TA by oral administration with fasting. Blood samples of Group 1 were collected via submandibular vein at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h, and blood samples of Group 2 were collected via submandibular vein at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h. Blood samples were placed into tubes containing K2-EDTA and centrifuged at 6800 g for 6 minutes at 2~8 ℃ to separate plasma from the samples. Following centrifugation, the resulting plasma was transferred to clean tubes. The samples were stored frozen at -80 ℃ until bioanalysis. Pharmacokinetic parameters were calculated by the concentration data of TA in plasma samples using non-compartment model of Phoenix7.0 software.
Ref compound 1 is
in WO2022232004 Ex2.
Ref compound 2 is
in WO2022232004 Ex122.
The data from Example B is shown in Table 2.
Table 2
Claims (44)
- A compound of Formula (I) , or a pharmaceutically acceptable salt thereof:
wherein:ring A is selected from C6-10aryl and C2-9heteroaryl;ring B is selected from C6-10aryl and C2-9heteroaryl;X is selected from -O-, -N (R8) -, -C (R7) (R7a) -, -O-C (R7) (R7a) -, -C (R7) (R7a) -O-, -S-C (R7) (R7a) -, -C (R7) (R7a) -S-, -S (O) 2-C (R7) (R7a) -, -C (R7) (R7a) -S (O) 2-, -N (R8) -C (R7) (R7a) -, -C (R7) (R7a) -N (R8) -, -N (R8) -C (O) -, -C (O) -N (R8) -, -S (O) 2-N (R8) -, -N (R8) -S (O) 2-, -N=C (R8a) -, -C (R8a) =N-, -C (R7) (R7a) -C (R7) (R7a) -, -O-C (R7) (R7a) -C (R7) (R7a) -, -C (R7) (R7a) -C (R7) (R7a) -O-, -C (R7) (R7a) -O-C (R7) (R7a) -, -N (R8) -C (R7) (R7a) -C (R7) (R7a) -, -C (R7) (R7a) -C (R7) (R7a) -N (R8) -, -C (R7) (R7a) -N (R8) -C (R7) (R7a) -, and -C (R7) (R7a) -C (R7) (R7a) -C (R7) (R7a) -;Y is -C (H) -or -N-;L is -N (R3a) -, -O-, -S-, C1-6alkylene, or C3-6cycloalkylene, wherein C1-6alkylene and C3- 6cycloalkylene are optionally substituted with one, two, or three groups selected from R15a; wherein when L is -N (R3a) -, -O-, or -S-, then Y is -C (H) -;R1 is selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15b;R2 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;R3 and R3a are each independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15c; or R3 and R3a together with the atoms to which they are attached form a 5 or 6-membered heterocycloalkyl ring, wherein the 5 or 6-membered heterocycloalkyl ring is optionally substituted with one, two, or three groups selected from R15c;R4 is selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from R15d;each R5 and each R6 are independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, -SR10, -SF5, -N (R10) (R11) , -C (O) OR10, -OC (O) N (R10) (R11) , -N (R12) C (O) N (R10) (R11) , -N (R12) C (O) OR13, -N (R12) S (O) 2R13, -C (O) R13, -S (O) R13, -OC (O) R13, -C (O) N (R10) (R11) , -C (O) C (O) N (R10) (R11) , -N (R12) C (O) R13, -S (O) 2R13, -S (O) 2N (R10) (R11) -, -N=S (=O) (R13) 2, -S (=O) (=NH) N (R10) (R11) , -S (=O) (=NH) (R13) , -S (=O) (=NR13) R13, -CH2C (O) N (R10) (R11) , -CH2N (R12) C (O) R13, -CH2S (O) 2R13, -CH2S (O) 2N (R10) (R11) , -Si (C1-6alkyl) 3, and -P (O) (R10) 2, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15e;each R7 and each R7a are independently selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from R15f;R8 is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -C (O) OR10, -C (O) R13, -S (O) R13, -C (O) N (R10) (R11) , and -S (O) 2R13, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15g;R8a is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, -SR10, -N (R10) (R11) , -C (O) OR10, -OC (O) N (R10) (R11) , -N (R12) C (O) N (R10) (R11) , -N (R12) C (O) OR13, -N (R12) S (O) 2R13, -C (O) R13, -S (O) R13, -OC (O) R13, -C (O) N (R10) (R11) , -C (O) C (O) N (R10) (R11) , -N (R12) C (O) R13, -S (O) 2R13, and -S (O) 2N (R10) (R11) -, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15h;each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, -CH2-C6-10aryl, C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6-10aryl, C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;each R11 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R10 and R11, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl;each R12 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;each R13 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;each R15a, R15b, R15c, R15d, R15e, R15f, R15g, and R15h are each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1- 9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N (R10) (R11) , -C (O) OR10, -OC (O) N (R10) (R11) , -N (R12) C (O) N (R10) (R11) , -N (R12) C (O) OR13, -N (R12) S (O) 2R13, -C (O) R13, -S (O) R13, -OC (O) R13, -C (O) N (R10) (R11) , -C (O) C (O) N (R10) (R11) , -N (R12) C (O) R13, -S (O) 2R13, -S (O) 2N (R10) (R11) -, -N=S (=O) (R13) 2, -S (=O) (=NH) N (R10) (R11) , -S (=O) (=NH) (R13) , -S (=O) (=NR13) R13, -CH2C (O) N (R10) (R11) , -CH2N (R12) C (O) R13, -CH2S (O) 2R13, -CH2S (O) 2N (R10) (R11) , -Si (C1-6alkyl) 3, and -P (O) (R10) 2, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR10, -SR10, -SF5, -N (R10) (R11) , -C (O) OR10, -OC (O) N (R10) (R11) , -N (R12) C (O) N (R10) (R11) , -N (R12) C (O) OR13, -N (R12) S (O) 2R13, -C (O) R13, -S (O) R13, -OC (O) R13, -C (O) N (R10) (R11) , -C (O) C (O) N (R10) (R11) , -N (R12) C (O) R13, -S (O) 2R13, -S (O) 2N (R10) (R11) -, -N=S (=O) (R13) 2, -S (=O) (=NH) N (R10) (R11) , -S (=O) (=NH) (R13) , -S (=O) (=NR13) R13, -CH2C (O) N (R10) (R11) , -CH2N (R12) C (O) R13, -CH2S (O) 2R13, -CH2S (O) 2N (R10) (R11) and -P (O) (R10) 2;n is 0, 1, 2, 3, or 4; andp is 0, 1, 2, 3, or 4. - The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is -N (R3a) -.
- The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is -CH (R15a) -.
- The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein X is -O-C (R7) (R7a) -.
- The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein X is -N (R8) -C (R7) (R7a) -.
- The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein X is -C (R7) (R7a) -C (R7) (R7a) -.
- The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R7 and R7a are each hydrogen.
- The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein ring A is C2-9heteroaryl.
- The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein ring A is 5-6 membered heteroaryl.
- The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.
- The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein ring B is C2-9heteroaryl.
- The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein ring B is 5-6 membered heteroaryl.
- The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl.
- The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:ring A is phenyl or 5-6 membered heteraryl;ring B is phenyl or 5-6 membered heteraryl; andL is -N (R3a) -, -CH2-, -C (R15a) 2-, or -CHR15a-.
- The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, whereinis
- The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, whereinis wherein n is 1, 2, or 3.
- The compound of of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, whereinis
- The compound of of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, whereinis wherein p is 1, 2, or 3.
- The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula (Ia-3) to Formula (Ia-5) :
wherein:Z1 is CH, CR5, N, NH, NR5, O or S;Z2 is CH, CR5, N, NH, NR5, O or S ;Z3 is CH, CR5, N, NH, NR5, O or S;Z4 is CH, CR5, N, NH, NR5, O or S;Z11 is CH, CR6, N, NH, NR6, O or S;Z22 is CH, CR6, N, NH, NR6, O or S;Z33 is CH, CR6, N, NH, NR6, O or S;Z44 is CH, CR6, N, NH, NR6, O or S;k is 0 or 1; andq is 0 or 1. - The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula (Ib) :
- The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula (Ic-1) :
- The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from R15c.
- The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R3 is C1-6alkyl optionally substituted with one, two, or three groups selected from R15c.
- The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein R3 is unsubstituted C1-6alkyl.
- The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R3 is -CH3.
- The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein R3a is C1-6alkyl optionally substituted with one, two, or three groups selected from R15c.
- The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R3a is unsubstituted C1-6alkyl.
- The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R3a is -CH3.
- The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R15a is C1-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and -OR10.
- The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein R15a is unsubstituted C1-6alkyl.
- The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R15a is -CH3.
- The compound of any one of claims 1-31 or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -OR10, wherein C1-6alkyl is optionally substituted with one, two, or three groups selected from R15e.
- The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein n is 1.
- The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein n is 0.
- The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -OR10, wherein C1-6alkyl is optionally substituted with one, two, or three groups selected from R15e.
- The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein p is 1.
- The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein p is 0.
- A compound, or a pharmaceutically acceptable salt thereof, selected from:
- A compound, or a pharmaceutically acceptable salt thereof, selected from:
- A compound, or a pharmaceutically acceptable salt thereof, selected from:
- A pharmaceutical composition comprising a compound of any one of claims 1-40, or a phfarmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- A method of treating cancer in a mammal in need thereof, comprising administering to the mammal a compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof.
- The method of claim 42, wherein the cancer is a solid tumor.
- The method of claim 43, wherein the cancer is head and neck cancer, intra-hepatic cholangiocarcinoma, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.
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CNPCT/CN2022/137271 | 2022-12-07 | ||
CNPCT/CN2023/075901 | 2023-02-14 | ||
CN2023075901 | 2023-02-14 | ||
CN2023096905 | 2023-05-29 | ||
CNPCT/CN2023/096905 | 2023-05-29 |
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Citations (5)
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WO2014108406A1 (en) * | 2013-01-08 | 2014-07-17 | Savira Pharmaceuticals Gmbh | Pyrimidone derivatives and their use in the treatment, amelioration or prevention of a viral disease |
WO2020118133A1 (en) * | 2018-12-06 | 2020-06-11 | Constellation Pharmaceuticals, Inc. | Modulators of trex1 |
WO2021016317A1 (en) * | 2019-07-23 | 2021-01-28 | Constellation Pharmaceuticals, Inc. | Modulators of trex1 |
WO2021222761A1 (en) * | 2020-05-01 | 2021-11-04 | Constellation Pharmaceuticals, Inc. | Modulators of trex1 |
WO2022232004A1 (en) * | 2021-04-26 | 2022-11-03 | Constellation Pharmaceuticals, Inc. | Modulators of trex1 |
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- 2023-09-21 WO PCT/CN2023/120257 patent/WO2024061300A1/en unknown
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2014108406A1 (en) * | 2013-01-08 | 2014-07-17 | Savira Pharmaceuticals Gmbh | Pyrimidone derivatives and their use in the treatment, amelioration or prevention of a viral disease |
WO2020118133A1 (en) * | 2018-12-06 | 2020-06-11 | Constellation Pharmaceuticals, Inc. | Modulators of trex1 |
WO2021016317A1 (en) * | 2019-07-23 | 2021-01-28 | Constellation Pharmaceuticals, Inc. | Modulators of trex1 |
WO2021222761A1 (en) * | 2020-05-01 | 2021-11-04 | Constellation Pharmaceuticals, Inc. | Modulators of trex1 |
WO2022232004A1 (en) * | 2021-04-26 | 2022-11-03 | Constellation Pharmaceuticals, Inc. | Modulators of trex1 |
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