OA20154A - Macrocyclic compounds for treating disease. - Google Patents
Macrocyclic compounds for treating disease. Download PDFInfo
- Publication number
- OA20154A OA20154A OA1202000195 OA20154A OA 20154 A OA20154 A OA 20154A OA 1202000195 OA1202000195 OA 1202000195 OA 20154 A OA20154 A OA 20154A
- Authority
- OA
- OAPI
- Prior art keywords
- alkyl
- nhs
- cycloalkyl
- nhc
- membered heterocycloalkyl
- Prior art date
Links
- 201000010099 disease Diseases 0.000 title abstract description 31
- 150000002678 macrocyclic compounds Chemical class 0.000 title description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 644
- 229910020008 S(O) Inorganic materials 0.000 claims description 508
- 150000001875 compounds Chemical class 0.000 claims description 219
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 189
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 155
- 229910004749 OS(O)2 Inorganic materials 0.000 claims description 101
- -1 Ci-C6 alkyl Chemical group 0.000 claims description 98
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 97
- YZCKVEUIGOORGS-OUBTZVSYSA-N deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 92
- 229910052805 deuterium Inorganic materials 0.000 claims description 92
- 229910052736 halogen Inorganic materials 0.000 claims description 89
- 150000002367 halogens Chemical class 0.000 claims description 89
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 71
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 71
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 71
- 229910003827 NRaRb Inorganic materials 0.000 claims description 60
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 51
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 50
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 49
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 48
- 125000002950 monocyclic group Chemical group 0.000 claims description 48
- 229910003813 NRa Inorganic materials 0.000 claims description 42
- 229910052799 carbon Inorganic materials 0.000 claims description 41
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 41
- 125000001072 heteroaryl group Chemical group 0.000 claims description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- 229910004664 ORa Inorganic materials 0.000 claims description 29
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 26
- 229910014585 C2-Ce Inorganic materials 0.000 claims description 22
- 125000003342 alkenyl group Chemical group 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- 229910003667 SRa Inorganic materials 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims description 9
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 229910052702 rhenium Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 229910004755 ORb Inorganic materials 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 3
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- 239000008194 pharmaceutical composition Substances 0.000 abstract description 19
- 201000011510 cancer Diseases 0.000 abstract description 18
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- 239000000203 mixture Substances 0.000 description 102
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 94
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 92
- 239000000243 solution Substances 0.000 description 68
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- 210000004027 cells Anatomy 0.000 description 46
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- 239000000377 silicon dioxide Substances 0.000 description 45
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- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical group CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 43
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 37
- 239000008079 hexane Substances 0.000 description 35
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- 239000007832 Na2SO4 Substances 0.000 description 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 27
- 125000004432 carbon atoms Chemical group C* 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 230000002401 inhibitory effect Effects 0.000 description 20
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- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 18
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- 238000000034 method Methods 0.000 description 14
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- 125000003118 aryl group Chemical group 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 239000000651 prodrug Substances 0.000 description 12
- 229940002612 prodrugs Drugs 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- OOWSDKUFKGVADH-UHFFFAOYSA-N 1-diphenylphosphoryloxy-2,3,4,5,6-pentafluorobenzene Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1OP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 OOWSDKUFKGVADH-UHFFFAOYSA-N 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 10
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
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- 239000007858 starting material Substances 0.000 description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
- 108091000081 Phosphotransferases Proteins 0.000 description 8
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- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
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- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000002503 metabolic Effects 0.000 description 1
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- 125000005341 metaphosphate group Chemical group 0.000 description 1
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- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
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- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000003279 phenylacetic acid Substances 0.000 description 1
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- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl N-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-M propane-1-sulfonate Chemical class CCCS([O-])(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical class CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical class [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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- 125000004076 pyridyl group Chemical group 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229910052904 quartz Inorganic materials 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 230000002285 radioactive Effects 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
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- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical class OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical class [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000004666 short chain fatty acids Chemical class 0.000 description 1
- 235000021391 short chain fatty acids Nutrition 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- RHLFTMGPBSLHRS-UHFFFAOYSA-M sodium;2-phenylbutanoate Chemical class [Na+].CCC(C([O-])=O)C1=CC=CC=C1 RHLFTMGPBSLHRS-UHFFFAOYSA-M 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 101700045897 spk-1 Proteins 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 102000009076 src-Family Kinases Human genes 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical class [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
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- 230000004083 survival Effects 0.000 description 1
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- 230000002194 synthesizing Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 239000001962 taste-modifying agent Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran THF Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 201000005161 thyroid carcinoma Diseases 0.000 description 1
- 201000005204 thyroid medullary carcinoma Diseases 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
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- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 description 1
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- 238000001890 transfection Methods 0.000 description 1
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- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
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- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- 239000000080 wetting agent Substances 0.000 description 1
- GDJZZWYLFXAGFH-UHFFFAOYSA-M xylenesulfonate group Chemical group C1(C(C=CC=C1)C)(C)S(=O)(=O)[O-] GDJZZWYLFXAGFH-UHFFFAOYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-QIUUJYRFSA-N β-D-glucuronic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-QIUUJYRFSA-N 0.000 description 1
Abstract
The present disclosure relates to certain macrocyclic derivatives, pharmaceutical compositions containing them, and methods of using them to treat disease, such as cancer.
Description
MACROCYCLIC COMPOUNDS FOR TREATING DISEASE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application daims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Serial No. 62/607,528 filed on December 19, 2017, U.S. Provisional Application Serial No. 62/727,124 filed on September5, 2018, and U.S. Provisional Application Serial No. 62/779,283 filed on December 13, 2018, the entire disclosures of which are incorporated herein by reference.
TECHNICAL FIELD
The présent disclosure relates to certain macrocyclic dérivatives, pharmaceutical compositions containing them, and methods of using them to treat disease, such as cancer.
BACKGROUND
Protein kinases regulate various functions in the cell including cell growth, prolifération and survival. Dysrégulation of protein kinases is often the cause of many solid malignancies (Manning G. et al. Science. 2002, 298, 1912-1934). The use of protein kinase inhibitors has led to substantial clinical benefit in patients harboring oncogenic aberrations. More than thirty protein kinase inhibitors hâve been approved for clinical treatment of cancer (Berndt N. et al. Curr. Opin. Chem. Biol. 2017, 39:126132). RET is a receptor tyrosine kinase that was initially discovered in 1985 through transfection of NIH3T3 cells with human lymphoma DNA (Takahashi, M. et al. Cell. 1985, 42:581-588.). RET is expressed with its highest levels in early embryogenesis (during which it has diverse rôles in different tissues) and decreases to relatively low levels in normal adulttissues Pachnis, V., étal. Development 1993, 119, 1005-1017). RET plays a critical rôle in the development of enteric nervous System and kidneys during embryogenesis (Schuchardt, A. et al. Nature 1994, 367:380-383). RET activation régulâtes the downstream signalling pathways (RAS/MAPK/ERK, PI3K/AKT, and JAK-STAT etc.), leading to cellular prolifération, migration, and différentiation (Mulligan, LM. Nat Rev Cancer. 2014, 14(3):173-86).
Gain-of-function mutations of RET with constitutive activation hâve been found in heritable and sporadic tumors including activating point mutations within the full-length RET protein or genomic rearrangements that produce chimeric RET oncoproteins in the cytosol. The heritable oncogenic RET mutations are found in multiple endocrine neoplasia type 2 (MEN2) including medullary thyroid cancer (MTC) and familial MTC with more than 80 pathogenic variants spanning RET exons 5-16 reported (Mulligan, LM. Nat Rev Cancer. 2014, 14(3):173-86). Among them, RET M918Tand RET A883F are found in 40-65% of sporadic MTC. The somatic mutation, chimeric RET fusion oncoproteins hâve been identified in sporadic tumors. The RET rearrangements are originally reported in papillary thyroid cancers (PTCs) (Grieco, M. et al. Cell. 1990, 23; 60 (4):557-63.). The resulting fusion transcripts composed ofthe 3’ end of RET kinase domain and the 5’ end of separate partner genes (CCDC6, NCOA4, TRIM24, TRIM33, PRKAR1A, GOLGA5, KTN1, ERC1, MBD1, and TRIM27 etc.). RET fusions are identified in approximately 20%-40% of PTCs, and CCDC6-RET and NCOA4-RET are the most commonly identified RET fusions in PTCs (Drilon A, et al. Nat Rev Clin Oncol. 2017 Nov14. doi: 10.1038/nrclinonc.2017.175). RET gene fusions are also found in approximately 1%-2% of non-small cell lung cancer (NSCLC) (Gainor JF, Shaw AT. Oncologist. 2013, 18(7):865-75), and over 50% of RET fusions in NSCLC is KIF5BRET, representing the most frequent RET fusion form. However, the RET inhibitors hâve relatively low response rates and short treatment duration in the treatment of NSCLC patients with KIF5B-RET fusion gene in multiple clinical trials (Drilon, A. Nat Rev Clin Oncol. 2017 Nov 14. doi:10.1038/nrclinonc. 2017.175). It was reported that the kinesin and kinase domains of KIF5B-RET act together to establish an emergent microtubule and RAB-vesicle-dependent RET-SRC-EGFR-FGFR signaling hub (Das TK and Cagan RL Cell Rep. 2017, 20(10):2368-2383). The inhibition of SRC kinase will hâve the potential to stop the recruitment of multiple RTKs via the N terminus ofthe KIF5B-RET fusion protein and the oncogenic signaling to increase the therapeutic efficiency of RET inhibitors. In addition, Src family tyrosine kinases regulate MTC cellular prolifération in vitro and médiate growth signais by increasing DNA synthesis and decreasing apoptosis (Liu Z, et al. J. Clin. Endocrinol. Metab. 2004, 89, 35033509). Therefore, a dual inhibitor of RET and SRC represents a highly desired therapeutic intervention to maximally target abnormal RET signaling in cancers.
SUMMARY
In one aspect, the disclosure relates to a compound ofthe formula I
wherein
L is independently -C(R1)(R2)- or X;
X is -O-, -S-, -S(O)- or -S(O)2-;
each R1 and R2 is independently H, deuterium, halogen, C-i-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl, -ORa, -OC(O)Ra, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or R1 and R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, C6-Ci0aryl, mono- or bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, CrC6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;
M is CR3 or N;
M1 is CR4;
each R3, R4, and R5 is independently hydrogen, deuterium, halogen, -ORC, OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, NRcC(O)Rd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, 3
NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, P(O)2ORC, -CN, -NO2, C-i-C6 alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, C6-C10aryl, or mono- or bicyclic heteroaryl, or R4 and R5 taken together with the ring to which they are attached form a C5-Cs cycloalkyl, or a 5- to 8-membered heterocycloalkyl, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, mono- or bicyclic heteroaryl, C5-C8 cycloalkyl, or 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or-NO2;
R6 is H, deuterium, CrC6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in Ci-C8 alkyl, C2-C8 alkenyl, C2-Ce alkynyl, C3-C8 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, -ORe, -OC(O)Re, OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, P(O)ORe, -P(O)2ORe, -CN, or-NO2;
R7 and R8 combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Ci0aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 7membered heteroaryl is independently optionally substituted by deuterium, halogen, ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or-NO2;
Y is O, S, NR9, or CR9R10;
R9 and R10 are each independently H, deuterium, halogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C^Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl is optionally substituted by a halogen, -ORe, -OC(O)Re, OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, P(O)ORe, or-P(O)2ORe;
each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-Cealkynyl, C3-Ce cycloalkyl, 3to 7-membered heterocycloalkyl, C6-Ci0aryl, 5- to 7- membered heteroaryl;
each of Z1, Z2, Z3, Z4, Z5, and Z6 is independently N, NH, C or CH;
p is 1,2, 3, or 4; and t is 1,2, 3, 4, or 5; or a pharmaceutically acceptable sait thereof.
In another aspect, the disclosure relates to a compound of the formula I
wherein
L is independently -C(R1)(R2)- or X;
Xis O, S, S(O)orS(O)2;
each R1 and R2 is independently H, deuterium, halogen, CrC6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl, -ORa, -OC(O)Ra, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, 5
PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or R1 and R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in Ci-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, C6-Ci0aryl, mono- or bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, C-rC6 haloalkyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, -ORe, OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or-NO2;
M is CR3 or N;
M1 is CR4;
each R3, R4, and R5 is independently hydrogen, deuterium, halogen, -ORC, OC(O)RC, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, NRcC(O)Rd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORC, -C(O)NRcRd, C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, P(O)2ORc, -CN, -NO2, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl, or R4 and R5 taken together with the ring to which they are attached form a C5-C8 cycloalkyl, or a 5- to 8-membered heterocycloalkyl, wherein each hydrogen atom in Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, mono- or bicyclic heteroaryl, C5-C8 cycloalkyl, or 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or-NO2;
R6 is H, deuterium, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, βίο 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in Ci-C6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 6
7-membered heterocycloalkyl, C6-Cioaryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C3-C6 cycloalkyl, or 5- to 7membered heterocycloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;
R7 and R8 combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Ci0aryl, or 5- to 7membered heteroaryl is independently optionally substituted by deuterium, halogen, ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or-NO2;
Yis O, S, NR9, orCR9R10;
R9 and R10 are each independently H, deuterium, halogen, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Cioaryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C-ioaryl, or mono- or bicyclic heteroaryl is optionally substituted by a halogen, -ORe, -OC(O)Re, OC(O)NR®Rf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, P(O)ORe, or-P(O)2OR®;
each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3to 7-membered heterocycloalkyl, C6-Ci0aryl, 5- to 7- membered heteroaryl;
each of Z1, Z2, Z3, Z4, Z5, and Z6 is independently N, NH, C or CH;
p is 1,2, 3, or 4; and t is 1,2, 3, 4, or 5;
or a pharmaceutically acceptable sait thereof.
In another aspect, the disclosure relates to a compound or a pharmaceutically acceptable sait thereof, having the formula II
Ri wherein
M is CR3 or N;
M1 is CR4;
Xis O, S, S(O), orS(O)2;
each R1 and R2 is independently H, deuterium, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-Ci0aryl, -ORa, -SRa, -NRaRb, -C(O)ORa, -C(O)NRaRb; wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl and C6-Cioaryl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCrC6 alkyl, -NH2, -OC(O)CrC6 alkyl, -OC(O)N(C1-C6 alkyl)2, OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(Ci-C6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), OC(=N)NH2, -OS(O)Ci-C6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(Ci-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(CrC6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)C(O)NH2, -N(Ci-C6 alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(CrC6 alkyl)C(O)OCi-C6 alkyl, -NHC(O)OH, -N(Ci-C6 alkyl)C(O)OH, -NHS(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-C6 alkyl)S(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)S(O)2C1-C6 alkyl, -NHS(O)NH2, -NHS(O)2NH2i -N(Ci-C6 alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)2NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(CrC6 alkyl)2, -NHS(O)2N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)NH(CrC6 alkyl), -N(CrC6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-C6 alkyl, -CO2H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(CrC6 alkyl), -C(O)N(Ci-C6 alkyl)2, -SCrC6 alkyl, -S(O)CrC6 alkyl, -S(O)2CiC6 alkyl, -S(O)NH(Ci-C6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(CrC6 alkyl)2, -S(O)2N(CiC6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(Ci-C6 alkyl)2, -OS(O)2N(CrC6 alkyl)2,
-OS/OJNHiCi-Ce alkyl), -OS(O)2NH(C1-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(CrCe alkyl)2, -P(0)(CrC6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
R3, R4, and R5 are each independently H, fluoro, chloro, bromo, Ci-C6 alkyl, -OH, -CN, -OCi-C6 alkyl, -NHCi-C6 alkyl, -N(CrC6 alkyl)2 or-CF3;
R6 is H, Ci-Ce alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C-i-C6 alkyl or 3-to 7-membered heterocycloalkyl is independently optionally substituted by halogen, -OH, -CN, -OCi-C6 alkyl, -NH2, -NH(C-|-C6 alkyl), N(Ci-C6 alkyl)2, -CO2H, -C(O)OCrC6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), C(O)N(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;
R7 and R8 combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Ci0aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Cioaryl, or 5- to 7membered heteroaryl is independently optionally substituted by deuterium, halogen, OH, -OCi-C6 alkyl, -OC(O)CrC6 alkyl, -OC(O)NH2, -OC(O)NH(Ci-C6 alkyl), -OC(O)N(Ci-C6 alkyl)2, -OC(=N)NH2, -OC(=N)NH(Ci-C6 alkyl), -OC(=N)N(CrC6 alkyl)2, -OS(O)CrC6 alkyl, -OS(O)2Ci-C6 alkyl, -OS(O)NH2, -OS(O)NH(Ci-C6 alkyl), -OS(O)N(Ci-C6 alkyl)2, -OS(O)2NH2, -OS(O)2NH(Ci-C6 alkyl), -OS(O)2N(C1-C6 alkyl)2, SH, -SCrC6 alkyl, -S(O)CrC6 alkyl, -S^CrCg alkyl, -S(O)NH2, -S(O)NH(Ci-C6 alkyl), -S(O)(Ci-C6 alkyl)2, -S(O)2NH2, -S(O)2NH(Ci-C6 alkyl), -S(O)2N(Ci-C6 alkyl)2, -NH2, -NH(C1-C6 alkyl), -N(CrC6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)C(O)Ci-C6 alkyl, NHC(O)OH, -NHC(O)OCi-C6 alkyl, -N(CrC6 alkyl)C(O)OH, -N(Ci-C6 alkyl)C(O)OCrC6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -NHC(O)N(CrC6 alkyl)2, -N(CrC6 alkyl)C(O)NH2, -N(Ci-C6 alkyl)C(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHS(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)S(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-C6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2, -Ν^-Οθ alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)S(O)N(Ci-C6 alkyl)2, -NHS(O)2NH2, -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)2N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)2NH2> -N(Ci-C6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(CrC6 alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-C6 alkyl, -C(O)OCrC6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(Ci-C6 alkyl)2, -P(CrC6 alkyl)2, -P(O)(CrC6 alkyl)2, -Ρ(Ο)2(Ο!-Ο6 alkyl)2, -P(O)NH2, -P(O)NH(Ci-C6 alkyl), -P(O)N(Ci-C6 alkyl)2, -P(O)2NH2, -P(O)2NH(CrC6 alkyl), -P(O)2N(CrC6 alkyl)2, -P(O)OH, -P(O)OCrC6 alkyl, -P(O)2OH, -P(O)2OCi-C6 alkyl, -CN, or-NO2;
Y is O, S, NR9, orCR9R10;
R9 and R10 are each independently H, deuterium, halogen, or Ci-C6alkyl, wherein each hydrogen atom in Ci-C6 alkyl is optionally substituted by a halogen, -OH, OCrC6 alkyl, -00(0)0^ alkyl, -OC(O)N(Ci-C6 alkyl)2, -OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(Ci-C6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), -OC(=N)NH2, -OS(O)CiC6 alkyl, -OS(O)2Ci-C6 alkyl, -OS(O)N(CrC6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)2NH(Ci-C6 alkyl), -OS(O)2NH2, -SH, -SCr C6 alkyl, -S(O)CrC6 alkyl, -S(O)2Ci-C6 alkyl, -S(O)N(CrC6 alkyl)2, -S(O)NH(Ci-C6 alkyl), -S(O)NH2, -S(O)2N(Ci-C6 alkyl)2, -S(O)2NH(Ci-C6 alkyl), -S(O)2NH2, -N(CrC6 alkyl)2, -NH(CrC6 alkyl), -NH2, -N(Ci-C6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)Ci-C6 alkyl, N(CrC6 alkyl)C(O)OCi-C6 alkyl, -N(Ci-C6 alkyl)C(O)OH, -NHC(O)OCi-C6 alkyl, NHC(O)OH, -N(Ci-C6 alkyl)C(O)N(CiC6 alkyl)2, -N(CrC6 alkyl)C(O)NH(CiC6 alkyl), -N(Ci-C6 alkyl)C(O)NH2, -NHC(O)N(CiC6 alkyl)2, -NHC(O)NH(C1C6 alkyl), -NHC(O)NH2, -N(C1-C6 alkyl)S(O)Ci-C6 alkyl, -NHS(O)Ci-C6 alkyl, -N(CrC6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(CrC6 alkyl)S(O)N(CrC6 alkyl)2, -N(Ci-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(Ci-C6 alkyl)S(O)NH2, -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)NH(CrC6 alkyl), -NHS(O)NH2, -N(Ci-C6 alkyl)S(O)2N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)2NH(C1-C6 alkyl), -N(CrC6 alkyl)S(O)2NH2, -NHS(O)2N(CrC6 alkyl)2, -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)2NH2, -C(O)Ci-C6 alkyl, -C(O)OC!-C6 alkyl, -C(O)N(CrC6 alkyl)2, -C(O)NH(Cr C6 alkyl), -C(O)NH2, -P(CrC6 alkyl)2, -P(O)(CrC6 alkyl)2, -P(O)2(CrC6 alkyl)2, -P(O)N(Ci-C6 alkyl)2, -Ρ(Ο)2Ν(Ο!-Ο6 alkyl)2, -P(O)OCrC6 alkyl, or -P(O)2OCi-C6 alkyl;
each of Z1, Z2, Z3, Z4, Z5, and Z6 is independently N, NH, C or CH; and n is 2 or 3.
In another aspect, the disclosure relates to a compound selected from the group consisting of
wherein
M is CR3 or N;
M1 is CR4;
Xis O, S, S(O), orS(O)2;
R1 and R2 are each independently H, deuterium, C-i-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10aryl, -ORa, -SRa, -NRaRb, -C(O)ORa, -C(O)NRaRb;
wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl and C6-Ci0aryl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCrCe alkyl, -OCi-C6 alkyl(C6-C10 aryl), -NH2, -OC(O)Ci-C6 alkyl, -OC(O)N(Ci-C6 alkyl)2, -OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(Ci-C6 alkyl)2, -OC(=N)NH(C1-C6 alkyl), -OC(=N)NH2, -OS(O)CrC6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(Ci15 C6 alkyl), -N(CrC6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)C(O)NH2, -NiC^Ce alkyl)C(O)NH(CrC6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(Ci-C6 alkyl)C(O)OC-rC6 alkyl, -NHC(O)OH, -N(CrC6 alkyl)C(O)OH, -NHS(O)CrC6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-C6 alkyljSiOjCrCe alkyl, -N(CrC6 alkyl)S(O)2CrC6 alkyl, -NHS(O)NH2, -NHS(O)2NH2, -N(Ci-C6 alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)2NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)2N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)N(Ci-C6 alkyl)2, -Νί^C6 alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-C6 alkyl, -CO2H, -C(O)OCrC6 alkyl, -C(O)NH2, -C(O)NH(CrC6 alkyl), -C(O)N(CrC6 alkyl)2, -SC^Ce alkyl, -S(O)CrC6 alkyl, -S(O)2Cr C6 alkyl, -S(O)NH(CrC6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(Ci-C6 alkyl)2, -S(O)2N(CiC6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(Ci-C6 alkyl)2, -OS(O)2N(CrC6 alkyl)2, -OS(O)NH(C1-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(CrC6 alkyl)2, -P(O)(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
R3, R4, and R5 are each independently H, fluoro, chloro, bromo, Ci-Ce alkyl, -OH, -CN, -OCi-C6 alkyl, -NHCi-C6 alkyl, -N(C1-C6 alkyl)2 or-CF3;
R6 is H, Ci-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in Ci-C6 alkyl or 3-to 7-membered heterocycloalkyl is independently optionally substituted by halogen, -OH, -CN, -OCi-C6 alkyl, -NH2, -NH(Ci-C6 alkyl), N(Ci-C6 alkyl)2, -CO2H, -C(O)OCrC6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), C(O)N(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;
R7 and R8 combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Ci0aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Ci0aryl, or 5- to 7membered heteroaryl is independently optionally substituted by deuterium, halogen, OH, -0CrC6 alkyl, -OC(O)Ci-C6 alkyl, -OC(O)NH2, -ΟΟ(Ο)ΝΗ(Ο!-Ο6 alkyl), -OC(O)N(Ci-C6 alkyl)2, -OC(=N)NH2, -OC(=N)NH(Ci-C6 alkyl), -OC(=N)N(C1-C6 alkyl)2, -OS(O)CrC6 alkyl, -OS(O)2Ci-C6 alkyl, -OS(O)NH2, -OS(O)NH(Ci-C6 alkyl), -OS(O)N(Ci-C6 alkyl)2, -OS(O)2NH2, -OS(O)2NH(Ci-C6 alkyl), ^(O^NiCrCs alkyl)2, SH, -SCrC6 alkyl, -S(O)Ci-C6 alkyl, -S(O)2Ci-C6 alkyl, -S(O)NH2, -S(O)NH(Ci-C6 alkyl), -S(O)(CrC6 alkyl)2, -S(O)2NH2, -S(O)2NH(Ci-C6 alkyl), -S(O)2N(Ci-C6 alkyl)2, -NH2i -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -NHC(O)C!-C6 alkyl, -N(Ci-C6 alkyl)C(O)Ci-C6 alkyl, NHC(O)OH, -NHC(O)OCrC6 alkyl, -N(Ci-C6 alkyl)C(O)OH, -N(CrC6 alkyl)C(O)OCi-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)C(O)NH2, -N(CrC6 alkyl)C(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyQCiOjNiCrCe alkyl)2, -NHS(O)Ci-C6 alkyl, -N(CrC6 alkyl)S(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-C6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)NH2, -Ν(ΟΊ-Ο6 alkyDSiOJNHiCrCe alkyl), -N(Ci-C6 alkyl)S(O)N(Ci-C6 alkyl)2, -NHS(O)2NH2, -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)2N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)2NH2, -Ν(ΟΊ-Ο6 alkyOSiO^NHiCrCe alkyl), -N(Ci-C6 alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-C6 alkyl, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(Ci-C6 alkyl)2, -P(CrC6 alkyl)2, -P(O)(Ci-C6 alkyl)2, -P(O)2(Ci-C6 alkyl)2, -P(O)NH2, -Ρ(Ο)ΝΗ(Ο-ι-Ο6 alkyl), -P(O)N(Ci-C6 alkyl)2, -P(O)2NH2, -P(O)2NH(Ci-C6 alkyl), -P(O)2N(Ci-C6 alkyl)2, -P(O)OH, -P(O)OCi-C6 alkyl, -P(O)2OH, -P(O)2OCi-C6 alkyl, -CN, or -NO2;
Y is O, S, NR9, orCR9R10; and
R9 and R10 are each independently H, deuterium, halogen, or Ci-C6 alkyl, wherein each hydrogen atom in Ci-Ce alkyl is optionally substituted by a halogen, -OH, OCi-C6 alkyl, -OC(O)Ci-C6 alkyl, -OC(O)N(Ci-C6 alkyl)2, -OCiOjNHiCrCe alkyl), -OC(O)NH2, -OC(=N)N(Ci-C6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), -OC(=N)NH2, -OS(O)Cr C6 alkyl, -OS(O)2Ci-C6 alkyl, -OS(O)N(Ci-C6 alkyl)2, -OS(O)NH(C1-C6 alkyl), -OS(O)NH2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)2NH(Ci-C6 alkyl), -OS(O)2NH2, -SH, -SCr C6 alkyl, -S(O)Ci-C6 alkyl, -5(0)^-06 alkyl, -S(O)N(Ci-C6 alkyl)2, -S(O)NH(Ci-C6 alkyl), -S(O)NH2, -S(O)2N(Ci-C6 alkyl)2, -SiO^NHCCrCe alkyl), -S(O)2NH2, -N(CrC6 alkyl)2, -NH(Ci-C6 alkyl), -NH2, -Ν(0Ί-06 alkyl)C(O)Ci-C6 alkyl, -NHC(O)Ci-C6 alkyl, N(Ci-C6 alkyl)C(O)OCi-C6 alkyl, -N(CrC6 alkyl)C(O)OH, -NHC(O)OCi-C6 alkyl, NHC(O)OH, -N(Ci-C6 alkyl)C(O)N(CiC6 alkyl)2, -N(Ci-C6 alkyl)C(O)NH(CiC6 alkyl), -N(Ci-C6 alkyl)C(O)NH2, -ΝΗΟ^Ν^Οβ alkyl)2, -NHC(O)NH(CiC6 alkyl), -NHC(O)NH2, -N(Ci-C6 alkyl)S(O)Ci-C6 alkyl, -NHS(O)Ci-C6 alkyl, -Ν(0Ί-06 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-C6 alkyl)S(O)N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)NH2, -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)NH2, -N(Ci-C6 alkyl)S(O)2N(Ci-C6 alkyl)2, -ΝίΟ^Οθ alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)2NH2, -NHS(O)2N(Ci-C6 alkyl)2, -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)2NH2, -C(O)Ci-C6 alkyl, -C(O)OCi-C6 alkyl, -C(O)N(Ci-C6 alkyl)2, -C(O)NH(CiC6 alkyl), -C(O)NH2, -P(Ci-C6 alkyl)2, -P(O)(Ci-C6 alkyl)2, -P(O)2(Ci-O6 alkyl)2, -P(O)N(Ci-C6 alkyl)2, -P(O)2N(Ci-C6 alkyl)2, -PiOjOCrCe alkyl, or -P(O)2OCi-C6 alkyl.
Additional embodiments, features, and advantages ofthe disclosure will be apparent from the following detailed description and through practice ofthe disclosure. The compounds ofthe présent disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any ofthe embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another.
1. A compound of the formula I wherein
L is independently -C(R1)(R2)- or X;
X is -O-, -S-, -S(O)- or -S(O)2-;
each R1 and R2 is independently H, deuterium, halogen, C-i-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl, -ORa, -OC(O)Ra, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or R1 and R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, C6-Ci0aryl, mono- or bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, CrC6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, OS(O)2R®, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;
M is CR3 or N;
M1 is CR4;
each R3, R4, and R5 is independently hydrogen, deuterium, halogen, -ORC, OC(O)RC, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, NRcC(O)Rd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, P(O)2ORc, -CN, -NO2, C-i-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, C6-C-ioaryl, or mono- or bicyclic heteroaryl, or R4 and R5 taken together with the ring to which they are attached form a Cs-Cs cycloalkyl, or a 5- to 8-membered heterocycloalkyl, wherein each hydrogen atom in C-|-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, mono- or bicyclic heteroaryl, C5-C8 cycloalkyl, or 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C-i-C6 alkyl, Ci-C8 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or-NO2;
R6 is H, deuterium, CrC6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, -ORe, -OC(O)R®, OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, P(O)ORe, -P(O)2ORe, -CN, or-NO2;
R7 and R8 combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Ci0aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Ci0aryl, or 5- to 7membered heteroaryl is independently optionally substituted by deuterium, halogen, ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)R®, -OS(O)2Re, -OS(O)NReRf, OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf,
-NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or-NO2;
Y is O, S, NR9, orCR9R10;
R9 and R10 are each independently H, deuterium, halogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl is optionally substituted by a halogen, -ORe, -OC(O)Re, OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, P(O)ORe, or-P(O)2ORe;
each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, Ci-C6 alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C3-Ce cycloalkyl, 3to 7-membered heterocycloalkyl, C6-Ci0aryl, 5- to 7- membered heteroaryl;
each of Z1, Z2, Z3, Z4, Z5, and Z6 is independently N, NH, C or CH;
p is 1, 2, 3, or 4; and t is 1,2, 3, 4, or 5;
or a pharmaceutically acceptable sait thereof.
1a. A compound of the formula I
wherein
L is independently -C(R1)(R2)- or X;
X is O, S, S(O) orS(O)2;
each R1 and R2 is independently H, deuterium, halogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, or mono- or bicyclic heteroaryl, -ORa, -OC(O)Ra, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra,
OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or R1 and R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, C6-C10aryl, mono- or bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C3 alkyl, Ci-C6 haloalkyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, -ORe, OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or-NO2;
M is CR3 or N;
M1 is CR4;
each R3, R4, and R5 is independently hydrogen, deuterium, halogen, -ORC, OC(O)RC, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, NRcC(O)Rd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORc, -C(O)NRcRd, C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, P(O)2ORc, -CN, -NO2, CrC6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, C6-C10aryl, or mono- or bicyclic heteroaryl, or R4 and R5 taken together with the ring to which they are attached form a C5-Cs cycloalkyl, or a 5- to 8-membered heterocycloalkyl, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Ce cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cwaryl, mono- or bicyclic heteroaryl, C5-C8 cycloalkyl, or 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or-NO2;
R6 is H, deuterium, C-i-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3to 7-membered heterocycloalkyl, C6-C10aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C3 cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-C10aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C3-C6 cycloalkyl, or 5- to 7membered heterocycloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;
R7 and R8 combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, Ce-Cw aryl, or 5- to 7membered heteroaryl is independently optionally substituted by deuterium, halogen, ORe, -OC(O)Re, -OC(O)NR®Rf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or-NO2;
YisO, S, NR9, orCR9R10;
R9 and R10 are each independently H, deuterium, halogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C-i-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, or mono- or bicyclic heteroaryl is optionally substituted by a halogen, -ORe, -OC(O)Re, OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, P(O)ORe, or-P(O)2ORe;
each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-Ce cycloalkyl, 3to 7-membered heterocycloalkyl, C6-Ci0aryl, 5- to 7- membered heteroaryl;
each of Z1, Z2, Z3, Z4, Z5, and Z6 is independently N, NH, C or CH;
p is 1,2, 3, or 4; and t is 1,2, 3, 4, or 5;
or a pharmaceutically acceptable sait thereof.
2. The compound of clause 1, or a pharmaceutically acceptable sait thereof, wherein p is 1.
3. The compound of clause 1 or 2, or a pharmaceutically acceptable sait thereof, wherein t is 3.
3a. The compound of clause 1 or 2, or a pharmaceutically acceptable sait thereof, wherein t is 3 or 4.
4. The compound of clause 1, or a pharmaceutically acceptable sait thereof, having the formula II
wherein
M is CR3 or N;
M1 is CR4;
X is O, S, S(O), orS(O)2;
each R1 and R2 is independently H, deuterium, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-Ci0aryl, -ORa, -SRa, -NRaRb, -C(O)ORa, -C(O)NRaRb; wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl and C6-Ci0 aryl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCi-C6 alkyl, -NH2, -OC(O)Ci-C6 alkyl, -OC(O)N(Ci-C6 alkyl)2, OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(CrC6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), OC(=N)NH2, -OS(O)Ci-C6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(Ci-C6 alkyl), -N(CrC6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(CrC6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)C(O)NH2, -N(CrC6 alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(CrC6 alkyl)C(O)OCi-C6 alkyl, -NHC(O)OH, -N(Ci-C6 alkyl)C(O)OH, -NHS(O)Ci-C6 alkyl, 19
-NHS(O)2C1-C6 alkyl, -N(CrC6 alkyl)S(O)Ci-C6 alkyl, -N(CrC6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)2NH2, -N(Ci-C6 alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)2NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(C-i-C6 alkyl)2, -NHS(O)2N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)2NH(Ci-C6 alkyl), -NiC^Ce alkyl)S(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-C6 alkyl, -CO2H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(Ci-C6 alkyl)2, -SCi-C6 alkyl, -8(0)0^06 alkyl, -S(O)2Cr C6 alkyl, -S(O)NH(CrC6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(Ci-C6 alkyl)2, -S(O)2N(Cr C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OSiOjNiCrCe alkyl)2, -OS(O)2N(CrC6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)2NH(C1-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(CrC6 alkyl)2, -P(O)(CrC6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
R3, R4, and R5 are each independently H, fluoro, chloro, bromo, Ci-C6 alkyl, -OH, -CN, -OCrC6 alkyl, -NHCrC6 alkyl, -N(CrC6 alkyl)2 or-CF3;
R6 is H, Ci-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in CrC6 alkyl or 3-to 7-membered heterocycloalkyl is independently optionally substituted by halogen, -OH, -CN, -OCi-Ce alkyl, -NH2, -NH(Ci-Ce alkyl), N(CrC6 alkyl)2, -CO2H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), C(O)N(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;
R7 and R8 combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Ci0aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Ci0aryl, or 5- to 7membered heteroaryl is independently optionally substituted by deuterium, halogen, OH, -0CrC6 alkyl, -OC(O)CrC6 alkyl, -OC(O)NH2, -OC(O)NH(CrC6 alkyl), -OC(O)N(Ci-C6 alkyl)2, -OC(=N)NH2, -OC(=N)NH(Ci-C6 alkyl), -OC(=N)N(Ci-C6 alkyl)2, -OS(O)CrC6 alkyl, -OS(O)2Ci-C6 alkyl, -OS(O)NH2, -OS(O)NH(Ci-C6 alkyl), -OS(O)N(Ci-C6 alkyl)2, -OS(O)2NH2, -OS(O)2NH(Ci-C6 alkyl), -OS(O)2N(C1-C6 alkyl)2, SH, -SCrC6 alkyl, -S(O)Ci-C6 alkyl, -S(O)2Ci-C6 alkyl, -S(O)NH2, -S(O)NH(CrC6 alkyl), -S(O)(CrC6 alkyl)2, -S(O)2NH2, -S(O)2NH(Ci-C6 alkyl), -SiOhNiCrCe alkyl)2, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -NHC(O)CrC6 alkyl, -N(CrC6 alkyl)C(O)Ci-C6 alkyl, NHC(O)OH, -NHC(O)OCi-C6 alkyl, -N(Ci-C6 alkyl)C(O)OH, -N(Ci-C6 alkyOCiOjOCrCe alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)C(O)NH2, -N(Ci-C6 alkyl)C(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)C(O)N(CrC6 alkyl)2, -NHS(O)Ci-C6 alkyl, -N(CrC6 alkyl)S(O)Ci-C6 alkyl, -NHS(O)2CrC6 alkyl, -N(CrC6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)NH(C1-C6 alkyl), -NHSCOjNiCrCe alkyl)2, -N(Ci-C6 alkyl)S(O)NH2, -N(Ci-C6 alkyQSiOjNHiCrCe alkyl), -N(Ci-C6 alkyl)S(O)N(Ci-C6 alkyl)2, -NHS(O)2NH2, -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)2N(C1-C6 alkyl)2, -N(CrC6 alkyl)S(O)2NH2, -N(CrC6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-C6 alkyl, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(Ci-C6 alkyl)2, -P(Ci-C6 alkyl)2, -P(O)(Ci-C6 alkyl)2, -P(O)2(CrC6 alkyl)2, -P(O)NH2, -P(O)NH(Ci-C6 alkyl), -Ρ^Ν^-Οδ alkyl)2, -P(O)2NH2, -P(O)2NH(Ci-C6 alkyl), -P^NiCrCe alkyl)2, -P(O)OH, -P(O)OCrC6 alkyl, -P(O)2OH, -P(O)2OCi-C6 alkyl, -CN, or-NO2;
Yis O, S, NR9, orCR9R10;
R9 and R10 are each independently H, deuterium, halogen, or Ci-C6 alkyl, wherein each hydrogen atom in Ci-C6 alkyl is optionally substituted by a halogen, -OH, OCrCe alkyl, -OCfOjCrCe alkyl, -OC(O)N(Ci-C6 alkyl)2, -OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(CrC6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), -OC(=N)NH2, -OS(O)Cr C6 alkyl, -OS^C^Ce alkyl, -OS(O)N(CrC6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)2NH(Ci-C6 alkyl), -OS(O)2NH2, -SH, -SCr C6 alkyl, -S(O)Ci-C6 alkyl, -S(O)2Ci-C6 alkyl, -S(O)N(Ci-C6 alkyl)2, -S(O)NH(CrC6 alkyl), -S(O)NH2, -S(O)2N(Ci-C6 alkyl)2, -S(O)2NH(CrC6 alkyl), -S(O)2NH2, -N(CrC6 alkyl)2, -NH(Ci-C6 alkyl), -NH2, -N(Ci-C6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)CrC6 alkyl, N(Ci-C6 alkyl)C(O)OCi-C6 alkyl, -N(Ci-C6 alkyl)C(O)OH, -NHC(O)OCi-C6 alkyl, NHC(O)OH, -N(Ci-C6 alkyl)C(O)N(C1C6 alkyl)2, -N(Ci-C6 alkyl)C(O)NH(CiC6 alkyl), -N(CrC6 alkyl)C(O)NH2, -NHC(O)N(CiC6 alkyl)2, -NHCiOjNHi^Ce alkyl), -NHC(O)NH2, -N(CrC6 alkyl)S(O)Ci-C6 alkyl, -NHS(O)Ci-C6 alkyl, -N(CrC6 alkyl)S(O)2CrC6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(CrC6 alkyl)S(O)N(CrC6 alkyl)2, -N(CrC6 alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)NH2, -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)NH2, -NfCrCe alkyl)S(O)2N(Ci-C6 alkyl)2, -N(Ci-C6 alkyOSiO^NHiCrCe alkyl), -N(Ci-C6 alkyl)S(O)2NH2, -NHS(O)2N(C1-C6 alkyl)2, -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)2NH2, -C(O)Ci-C6 alkyl, -C(O)OC^-C6 alkyl, -C(O)N(Ci-C6 alkyl)2, -C(O)NH(CiC6 alkyl), -C(O)NH2, -P(CrC6 alkyl)2, -P(O)(Ci-C6 alkyl)2, -PiOMCrCe alkyl)2, -P(O)N(Ci-C6 alkyl)2, -P(O)2N(Ci-C6 alkyl)2, -P(O)OCrC6 alkyl, or-P(O)2OCi-C6 alkyl;
each of Z1, Z2, Z3, Z4, Z5, and Z6 is independently N, NH, C or CH; and n is 2 or 3.
5. The compound of any of the preceding clause, having the formula III
or a pharmaceutically acceptable sait thereof.
6. The compound of clause 4 or 5, or a pharmaceutically acceptable sait thereof, wherein n is 2.
6a. The compound of clause 4 or 5, or a pharmaceutically acceptable sait thereof, wherein n is 2 or 3.
7. The compound of any one ofthe preceding clauses, having the formula IV
or a pharmaceutically acceptable sait thereof.
7a. The compound of any one of the preceding clauses, having the formula IV or
R
IV or a pharmaceutically acceptable sait thereof.
V
8. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein Y is O.
9. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein M is CR3.
10. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein R3 is H, deuterium, Ci-C6 alkyl or halogen.
11. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein R3 is H or F.
12. The compound of any one of clauses 1 to 8, or a pharmaceutically acceptable sait thereof, wherein M is N.
13. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein M1 is CR4.
14. The compound of any one ofthe preceding clauses, or a pharmaceutically acceptable sait thereof, wherein R4 is H, deuterium, Ci-C6 alkyl or halogen.
15. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein R4 is H or Cl.
16. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein R5 is F.
17. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein R2 is H.
17a. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein at least one of R2 is H.
18. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein R1 is H.
18a. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein at least one of R1 is H.
19. The compound of any one of clauses 1 to 17, or a pharmaceutically acceptable sait thereof, wherein R1 is C^Ce alkyl.
a. The compound of any one of clauses 1 to 17, or a pharmaceutically acceptable sait thereof, wherein at least one of R1 is Ci-Ce alkyl.
20. The compound of any one of clauses 1 to 17, or a pharmaceutically acceptable sait thereof, wherein R1 is H, and R2 is Ci-C6 alkyl.
20a. The compound of any one of clauses 1 to 16, or a pharmaceutically acceptable sait thereof, wherein R1 is H, and R2 is Ci-C6 alkyl; or R1 is Ci-C6 alkyl, and R2 is H; or R1 is H or Ci-Ce alkyl, and R2 is H; or R1 is H, and R2 is C3-C7 cycloalkyl; or 23
R1 is C3-C7 cycloalkyl, and R2 is H; or wherein one of R1 is Ci-C6 alkyl, any other R1, when présent, is H, and any R2, when présent, is H .
21. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein R7 and R8 combine to form a 5- or 6-membered cycloalkyl, wherein each hydrogen atom in the 5- or 6-membered cycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCi-C6 alkyl, OCi-C6 alkyl(C6-C10 aryl), -NH2, -OC(O)Ci-C6 alkyl, -OC(O)N(Ci-C6 alkyl)2, OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(CrC6 alkyl)2, -ΟΟ(=Ν)ΝΗ(Ο!-Ο6 alkyl), OC(=N)NH2, -OS(O)Ci-C6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(Ci-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(C1-C6 alkyl)C(O)NH2, -N(CrC6 alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(CrC6 alkyl)C(O)OCi-C6 alkyl, -NHC(O)OH, -N(CrC6 alkyl)C(O)OH, -NHS(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(CrC6 alkyl)S(O)CrC6 alkyl, -N(CrC6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)2NH2, -N(Ci-C6 alkyl)S(O)NH2, -N(Ci-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)2N(CtC6 alkyl)2, -N(CrC6 alkyl)S(O)NH(CrC6 alkyl), -N(CrC6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-C6 alkyl, -CO2H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(CrC6 alkyl), -C(O)N(C1-C6 alkyl)2, -SCrC6 alkyl, -S(O)CrC6 alkyl, -S(O)2Cr C6 alkyl, -S(O)NH(Ci-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(CrC6 alkyl)2, -S(O)2N(CiC6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(Ci-C6 alkyl)2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)2NH(CrC6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(Ci-C6 alkyl)2, -P(O)(CrC6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.
21a. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein R7 and R8 combine to form a 4-, 5- or 6-membered cycloalkyl, wherein each hydrogen atom in the 5- or 6-membered cycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCi-C6 alkyl, OCrC6 alkyl(C6-Cio aryl), -NH2, -OC(O)CrC6 alkyl, -OC(O)N(CrC6 alkyl)2, OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(CrC6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), OC(=N)NH2, -OS(O)CrC6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(Ci-C6 alkyl), -N(CrC6 alkyl)2, -NHC(O)CrC6 alkyl, -N(Ci-C6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)C(O)NH2, -N(CrC6 alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(CrC6 alkyl)C(O)OCi-C6 alkyl, -NHC(O)OH, -N(Ci-C6 alkyl)C(O)OH, -NHS(O)Ci-C6 alkyl, 24
-NHS(O)2Ci-C6 alkyl, -N(CrC6 alkyQSiOjCrCe alkyl, -N(CrC6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)2NH2, -N(CrC6 alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)2NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(CrC6 alkyl)2, -NHS(O)2N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(CrC6 alkyl)S(O)2N(C-i-C6 alkyl)2, -C(O)Ci-C6 alkyl, -CO2H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -CiOJNiCrCe alkyl)2, -SCrC6 alkyl, -S(O)Ci-C6 alkyl, -S(O)2CiC6 alkyl, -S(O)NH(CrC6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(Ci-C6 alkyl)2, -S(O)2N(Cr C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(Ci-C6 alkyl)2, -OSiOhNiCrCe alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(Ci-C6 alkyl)2, -P(O)(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.
22. The compound of any one of clauses 1 to 20, or a pharmaceutically acceptable sait thereof, wherein R7 and R8 combine to form a 3-, 4-, 5- or 6-membered heterocycloalkyl, wherein each hydrogen atom in the 3-, 4-, 5- or 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCrC6 alkyl, -OCrC6 alkyl(C6-Ci0 aryl), -NH2, -OC(O)Ci-C6 alkyl, -OC(O)N(CrC6 alkyl)2, -OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(CrC6 alkyl)2, -OC(=N)NH(C1-C6 alkyl), -OC(=N)NH2, -OS(O)Ci-C6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(Ci-C6 alkyl), -N(CrC6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(CrC6 alkyl), -NiC^Ce alkyl)C(O)NH2, -N(Ci-C6 alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(C1-C6 alkyl)2, -N(Ci-C6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(CrC6 alkyl)C(O)OCi-C6 alkyl, -NHC(O)OH, -N(Ci-C6 alkyl)C(O)OH, -NHS(O)Ci-C6 alkyl, -NHS(O)2CrC6 alkyl, -N(Ci-C6 alkyljS^CrCe alkyl, -N(Ci-C6 alkyl)S(O)2Ci-C6 alkyl,-NHS(O)NH2, -NHS(O)2NH2, -N(CrC6 alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)2NH2, -NHS(O)NH(Ci-C6 alkyl), -NHSiOhNHCCrCe alkyl), -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)2N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)NH(CrC6 alkyl), -N(CrC6 alkyl)S(O)2NH(CrC6 alkyl), -N(Ci-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -C(O)Ci-C6 alkyl, -CO2H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(Ci-C6 alkyl)2, -SCrC6 alkyl, -S(O)CrC6 alkyl, -S(O)2CiC6 alkyl, -S(O)NH(CrC6 alkyl), -SiOkNHtCrCe alkyl), -S(O)N(CrC6 alkyl)2, -S(O)2N(Cr C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(CrC6 alkyl)2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(CrC6 alkyl)2, -P(O)(CrC6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.
23. The compound of clause 22, or a pharmaceutically acceptable sait thereof, wherein R7 and R8 combine to form a tetrahydrofuran ring.
24. The compound of clause 21, or a pharmaceutically acceptable sait thereof, wherein R7 and R8 combine to form a cyclopentane ring.
24a. The compound of clause 21 or 21a, or a pharmaceutically acceptable sait thereof, wherein R7 and R8 combine to form a cyclobutane ring, cyclopentane ring, or 5 cyclohexane ring.
25. The compound of clause 1, or a pharmaceutically acceptable sait thereof, selected form the group consisting of
wherein
M is CR3 or N;
M1 is CR4;
Xis O, S, S(O), orS(O)2;
R1 and R2 are each independently H, deuterium, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-Ci0aryl, -ORa, -SRa, -NRaRb, -C(O)ORa, -C(O)NRaRb; wherein each hydrogen atom in Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-Ci0aryl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCi-C6 alkyl, -OCrC6 alkyl(C6-Ci0 aryl), -NH2, -OC(O)Ci-C6 alkyl, -OC(O)N(Ci-C6 alkyl)2, -OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(CrC6 alkyl)2, -OC(=N)NH(C1-C6 alkyl), -OC(=N)NH2, -OS(O)CrC6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(Cr C6 alkyl), -N(Ci-C6 alkyl)2, -NHC(O)CrC6 alkyl, -N(CrC6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)C(O)NH2, -N(Ci-C6 alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(CrC6 alkyl)C(O)OCi-C6 alkyl, -NHC(O)OH, -N(Ci-C6 alkyl)C(O)OH, -NHS(O)Ci-C6 alkyl, -NHSiO^CrCe alkyl, -Ν^-Οβ alkyl)S(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)S(O)2CrC6 alkyl, -NHS(O)NH2, -NHS(O)2NH2i -N(CrC6 alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)2NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)2NH(CrC6 alkyl), -NHS(O)N(CrCe alkyl)2, -NHS(O)2N(CrC6 alkyl)2, -N(CrC6 alkyl)S(O)NH(CrC6 alkyl), -N(Ci-C6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(CrC6 alkyl)S(O)N(C1-C6 alkyl)2, -N(Cr C6 alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)C^-C6 alkyl, -CO2H, -C(O)OCi-C6 alkyl, -C(O)NH2, 29
-C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SCrC6 alkyl, -S(O)CrC6 alkyl, -5(0)2^C6 alkyl, -S(O)NH(CrC6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(CrC6 alkyl)2, -S(O)2N(Cr C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(Ci-C6 alkyl)2, -OS(O)2N(C!-C6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OSiOhNHiCrCe alkyl), -OS(O)NH2, -OS(O)2NH2, -PiCrCe alkyl)2, -P(O)(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
R3, R4, and R5 are each independently H, fluoro, chloro, bromo, Ci-Ce alkyl, -OH, -CN, -OC-i-C6 alkyl, -NHCi-C6 alkyl, -N(C1-C6 alkyl)2 or-CF3;
R6 is H, Ci-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in CrC6 alkyl or 3-to 7-membered heterocycloalkyl is independently optionally substituted by halogen, -OH, -CN, -OCi-C6 alkyl, -NH2, -NH(Ci-C6 alkyl), N(Ci-C6 alkyl)2, -CO2H, -C(O)OCrC6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), C(O)N(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;
R7 and R8 combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 7membered heteroaryl is independently optionally substituted by deuterium, halogen, OH, -OCrC6 alkyl, -OC(O)CrC6 alkyl, -OC(O)NH2, -OC(O)NH(C1-C6 alkyl), -OC(O)N(Ci-C6 alkyl)2, -OC(=N)NH2, -OC(=N)NH(C1-C6 alkyl), -OC(=N)N(CrC6 alkyl)2, -OS(O)CrC6 alkyl, -OS(O)2CrC6 alkyl, -OS(O)NH2, -OS(O)NH(Ci-C6 alkyl), -OS(O)N(CrC6 alkyl)2, -OS(O)2NH2, -OS(O)2NH(Ci-C6 alkyl), -OS(O)2N(CrC6 alkyl)2, SH, -SCrC6 alkyl, -S(O)CrC6 alkyl, -SCO^-Ce alkyl, -S(O)NH2, -S(O)NH(C1-C6 alkyl), -S(O)(CrC6 alkyl)2, -S(O)2NH2, -S(O)2NH(Ci-C6 alkyl), -S(O)2N(CrC6 alkyl)2, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(CrC6 alkyl)C(O)Ci-C6 alkyl, NHC(O)OH, -NHC(O)OCi-C6 alkyl, -N(Ci-C6 alkyl)C(O)OH, -N(Ci-C6 alkyl)C(O)OCi-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(C1-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)C(O)NH2, -N(Ci-C6 alkyl)C(O)NH(C1-C6 alkyl), -N(CrC6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHS(O)Ci-C6 alkyl, -N(CrC6 alkyl)S(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(CrC6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)N(CrC6 alkyl)2, -N(C-|-C6 alkyl)S(O)NH2, -N(Ci-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(CrC6 alkyl)S(O)N(Ci-C6 alkyl)2, -NHS(O)2NH2, -NHS(O)2NH(C1-C6 alkyl), -NHS(O)2N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)2NH2, -N(Ci-C6 alkyl)S(O)2NH(CrC6 alkyl), -N(Ci-C6 alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-C6 alkyl, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(Ci-C6 alkyl)2, -P(CrC6 alkyl)2, -P(O)(CrC6 alkyl)2, -P(O)2(CrC6 alkyl)2, -P(O)NH2, -P(O)NH(Ci-C6 alkyl), -P(O)N(CrC6 alkyl)2, -P(O)2NH2,
-P(O)2NH(Ci-C6 alkyl), -P(O)2N(CrC6 alkyl)2, -P(O)OH, -P(O)OCrC6 alkyl, -P(O)2OH, -P(O)2OCi-C6 alkyl, -CN, or -NO2;
Yis O, S, NR9, orCR9R10; and
R9 and R10 are each independently H, deuterium, halogen, or C-|-C6 alkyl, wherein each hydrogen atom in Ci-Ce alkyl is optionally substituted by a halogen, -OH, OCi-C6 alkyl, -00(0)0^ alkyl, -OC(O)N(Ci-C6 alkyl)2, -OC(O)NH(CrC6 alkyl), -OC(O)NH2, -OC(=N)N(Ci-C6 alkyl)2, -OC(=N)NH(C1-C6 alkyl), -OC(=N)NH2, -OS(O)Cr C6 alkyl, -OS(O)2CrC6 alkyl, -OS^N^-Cs alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)2NH(Ci-O6 alkyl), -OS(O)2NH2, -SH, -SCr 06 alkyl, -S(O)Ci-C6 alkyl, -S(O)2Ci-C6 alkyl, -S(O)N(Ci-C6 alkyl)2, -S(O)NH(Ci-C6 alkyl), -S(O)NH2, -S(O)2N(Ci-C6 alkyl)2, -S(O)2NH(C1-C6 alkyl), -S(O)2NH2, -N(CrC6 alkyl)2, -NH(CrC6 alkyl), -NH2, -N(0i-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)Ci-C6 alkyl, N(CrC6 alkyl)C(O)OCi-C6 alkyl, -N(CrC6 alkyl)C(O)OH, -NHC(O)OCi-C6 alkyl, NHC(O)OH, -N(Ci-C6 alkyl)C(O)N(CiC6 alkyl)2, -N(CrC6 alkyl)C(O)NH(CiC6 alkyl), -N(Ci-C6 alkyl)C(O)NH2, -NHC(O)N(CiC6 alkyl)2, -NHC(O)NH(C1C6 alkyl), -NHC(O)NH2, -N(0i-C6 alkyl)S(O)Ci-C6 alkyl, -NHS(0)0i-06 alkyl, -N(Ci-C6 alkyl)S(O)2Ci-O6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(CrC6 alkyl)S(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)NH2, -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)NH2, -N(Ci-C6 alkyl)S(O)2N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)2NH2, -NHS(O)2N(Oi-O6 alkyl)2, -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)2NH2, -C(O)Ci-C6 alkyl, -C(O)OCi-C6 alkyl, -C(O)N(Ci-C6 alkyl)2, -C(O)NH(CiC6 alkyl), -C(O)NH2, -PCCrCe alkyl)2, -P(0)(CrC6 alkyl)2, -P(O)2(Ci-C6 alkyl)2, -P(O)N(Ci-C6 alkyl)2, -P(O)2N(CrC6 alkyl)2, -P(0)0CrC6 alkyl, or -P(O)2OOi-C6 alkyl.
26. The compound of clause 25, or a pharmaceutically acceptable sait thereof, wherein M is CR3.
27. The compound of clause 25 or 26, or a pharmaceutically acceptable sait thereof, wherein R3 is H, deuterium, Ci-Ce alkyl or halogen.
28. The compound of any one of clauses 25 to 27, or a pharmaceutically acceptable sait thereof, wherein R3 is H or F.
29. The compound of clause 25, or a pharmaceutically acceptable sait thereof, wherein M is N.
30. The compound of any one of clauses 25 to 29, or a pharmaceutically acceptable sait thereof, wherein M1 is CR4.
31. The compound of any one of clauses 25 to 30, or a pharmaceutically acceptable sait thereof, wherein R4 is H, deuterium, Ci-C6 alkyl or halogen.
32. The compound of any one of clauses 25 to 31, or a pharmaceutically acceptable sait thereof, wherein R4 is H or Cl.
33. The compound of any one of clauses 25 to 32, or a pharmaceutically acceptable sait thereof, wherein R5 is F.
34. The compound of any one of clauses 25 to 33, or a pharmaceutically acceptable sait thereof, wherein R2 is H.
35. The compound of any one of clauses 25 to 34, or a pharmaceutically acceptable sait thereof, wherein R1 is CrC6 alkyl.
36. The compound of any one of clauses 25 to 33, or a pharmaceutically acceptable sait thereof, wherein R2 is Ci-Ce alkyl.
36a. The compound of any one of clauses 25 to 33, or a pharmaceutically acceptable sait thereof, wherein R2 is Ci-Ce alkyl; or C3-C7 cycloalkyl.
37. The compound of any one of clauses 25 to 36, or a pharmaceutically acceptable sait thereof, wherein R7 and R8 combine to form a 5- or 6-membered cycloalkyl, wherein each hydrogen atom in the 5- or 6-membered cycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCi-Ce alkyl, OCi-C6 alkyl(C6-Ci0 aryl), -NH2, -OC(O)Ci-C6 alkyl, -OC(O)N(Ci-C6 alkyl)2, OC(O)NH(Ci-C6 alkyl), -OC(O)NH2j -OC(=N)N(CrC6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), OC(=N)NH2, -OS(O)Ci-C6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(C1-C6 alkyl), -N(CrC6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(CrC6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)C(O)NH2, -N^-Cs alkyl)C(O)NH(Ci-C6 alkyl), -NHCtOMCrCe alkyl)2, -N(CrC6 alkyl)C(O)N(CrC6 alkyl)2, -NHC(O)OCi-C6 alkyl, -NiCrCs alkyl)C(O)OCi-C6 alkyl, -NHC(O)OH, -N(Ci-C6 alkyl)C(O)OH, -NHS(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-C6 alkyl)S(O)Ci-C6 alkyl, -N(CrC6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)2NH2j -N(Ci-C6 alkyl)S(O)NH2, -N(Ci-C6 alkyl)S(O)2NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)2N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)NH(Ci-C6 alkyl), -N^-Cs alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)2N(Ci-Ce alkyl)2, -C(O)Ci-C6 alkyl, -CO2H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(Ci-C6 alkyl)2, -SCi-C6 alkyl, -S(O)CrC6 alkyl, -S(O)2CiC6 alkyl, -S(O)NH(CrC6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(Ci-C6 alkyl)2, -5(0)^(^C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(Ci-C6 alkyl)2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(CrC6 alkyl)2, -P(O)(Ci-Ce alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.
37a. The compound of any one of clauses 25 to 36, or a pharmaceutically acceptable sait thereof, wherein R7 and R8 combine to form a 4-, 5- or 6-membered cycloalkyl, wherein each hydrogen atom in the 5- or 6-membered cycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCi-C6 alkyl, OCi-C6 alkyl(C6-C10 aryl), -NH2, -OC(O)CrC6 alkyl, -OC(O)N(Ci-C6 alkyl)2, OC(O)NH(C1-C6 alkyl), -OC(O)NH2, -OC(=N)N(Ci-C6 alkyl)2, -OC(=N)NH(C1-C6 alkyl), OC(=N)NH2, -OS(O)CrC6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(CrC6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)C(O)NH2, -N(CrC6 alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -NiCrCe alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(CrC6 alkyl)C(O)OCi-C6 alkyl, -NHC(O)OH, -N(C-i-C6 alkyl)C(O)OH, -NHS(O)CrC6 alkyl, -NHS(O)2C1-C6 alkyl, -N(CrC6 alkyl)S(O)Ci-C6 alkyl, -N(CrC6 alkyl )S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)2NH2, -NiCrCe alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)2NH2, -NHS(O)NH(C1-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)2N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)S(O)2NH(C1-C6 alkyl), -N(Ci-C6 alkyl)S(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)2N(C1-C6 alkyl)2, -C(O)Ci-C6 alkyl, -CO2H, -C(O)OCrC6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(Ci-C6 alkyl)2, -SCi-C6 alkyl, -S(O)Ci-C6 alkyl, -8(0^C6 alkyl, -S(O)NH(Ci-C6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(Ci-C6 alkyl)2, -S(O)2N(CiC6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(Ci-C6 alkyl)2, -OS(O)2N(CrC6 alkyl)2, -OS(O)NH(C1-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(CrC6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.
38. The compound of any one of clauses 25 to 36, or a pharmaceutically acceptable sait thereof, wherein R7 and R8 combine to form a 3-, 4-, 5- or 6-membered heterocycloalkyl, wherein each hydrogen atom in the 3-, 4-, 5- or 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCrC6 alkyl, -OCrC6 alkyl(C6-Ci0aryl), -NH2, -00(0)^-06 alkyl, -OC(O)N(CrC6 alkyl)2, -OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(Ci-C6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), -OC(=N)NH2, -OS(O)Ci-C6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(CrC6 alkyl), -N(CrC6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(CrC6 alkyl)C(O)C-i-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(C1-C6 alkyl), -N(Ci-C6 alkyl)C(O)NH2, -N(CrC6 alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(C-i-C6 alkyl)C(O)OCi-C6 alkyl, -NHC(O)OH, -N(Ci-C6 alkyl)C(O)OH, -NHS(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(CrC6 alkyl)S(O)Ci-C6 alkyl, -N(CrC6 alkyl)S(O)2Ci-C6 alkyl,-NHS(O)NH2, -NHS(O)2NH2, -N(Ci-C6 alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)2NH2,
-NHS(O)NH(Ci-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)2N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(Ci-C6 alkyl)S(O)N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-C6 alkyl, -CO2H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(CrC6 alkyl), -C(O)N(Ci-C6 alkyl)2, -SCrC6 alkyl, -S(O)CrC6 alkyl, -S(O)2CiC6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C-i-C6 alkyl), -S(O)N(Ci-C6 alkyl)2, -S(O)2N(CiC6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(C1-C6 alkyl)2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)2NH(C1-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(Ci-C6 alkyl)2, -P(O)(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.
39. The compound of clause 38, or a pharmaceutically acceptable sait thereof, wherein R7 and R8 combine to form a tetrahydrofuran ring.
40. The compound of clause 37, or a pharmaceutically acceptable sait thereof, wherein R7 and R8 combine to form a cyclopentane ring.
40a. The compound of clause 37 or 37a, or a pharmaceutically acceptable sait thereof, wherein R7 and R8 combine to form a cyclobutane ring, cyclopentane ring, or cyclohexane ring.
41. The compound of any of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein X is O.
42. The compound of clause 1, selected from the group consisting of
or a pharmaceutically acceptable sait thereof.
43. A pharmaceutical composition comprising a compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, and optionally at least one diluent, carrier or excipient.
44. A method of treating cancer comprising administering to a subject in need of 10 such treatment an effective amount of at least one compound of any one of clauses 1 to 42, or a pharmaceutically acceptable sait thereof.
45. Use of a compound of any one of clauses 1 to 42, or a pharmaceutically acceptable sait thereof, in the préparation of a médicament for the treatment of cancer.
46. Use of a compound of any one of clauses 1 to 42, or a pharmaceutically acceptable sait thereof, for treating cancer.
47. A method of inhibiting RET or SRC, comprising contacting a cell comprising one or more of such kinases with an effective amount of at least one compound of any one of clauses 1 to 42, or a pharmaceutically acceptable sait thereof, and/or with at least one pharmaceutical composition ofthe disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.
48. A compound of any one of clauses 1 to 42, for use in treating cancer in a patient.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows the pharmacodynamie inhibiting activity of Compound 5 on RET in RET-driven cells, specifically that Compound 5 caused the suppression of RET autophosphorylation at IC50s of around 0.3 nM in TT.
Fig. 2 shows the pharmacodynamie inhibiting activity of Compound 5 on RET in RET-driven cells, specifically that Compound 5 caused the suppression of RET autophosphorylation at IC50s of around 1-3 nM in Ba/F3 KIF5B-RET WT.
Fig. 3 shows the pharmacodynamie inhibiting activity of Compound 5 on RET in RET-driven cells, specifically that Compound 5 caused the suppression of RET autophosphorylation at IC50s of around 3-10 nM in Ba/F3 KIF5B-RET G810R.
Fig. 4A is a chart that shows that Compound 5 dosed at 2 mg/kg BID and 5 mg/kg BID for 27 days decreased tumor size in test mice compared to untreated control. Untreated control (·), 2 mg/kg (--), 5 mg/kg (-*-)
Fig. 4B is a chart that shows % weight change for test mice dosed at 2 mg/kg BID and 5 mg/kg BID for 27 days compared to untreated control. Untreated control (-·), 2 mg/kg (-·-), 5 mg/kg (-*-).
Fig. 5A is a chart that shows the effect of Compound 5 dosed at 1 mg/kg BID and 5 mg/kg BID for 10 days on tumor size in test mice compared to untreated control. Untreated control (-·-), 1 mg/kg (-a-), 5 mg/kg (-▼-).
Fig. 5B is a chart that shows % weight change for test mice dosed at 1 mg/kg BID and 5 mg/kg BID for 10 days compared to untreated control. Untreated control (“♦“ ), 1 mg/kg (^-), 5 mg/kg (-*-).
Fig. 6A is a chart that shows the effect of Compound 5 dosed at 1 mg/kg BID, 5 mg/kg BID, and 10 mg/kg BID for 14 days on tumor size in test mice compared to untreated control. Untreated control (♦“), 1 mg/kg (-*-), 5 mg/kg (-a-), 10 mg/kg (-Ψ)
Fig. 6B is a chart that shows % weight change for test mice dosed at 1 mg/kg BID, 5 mg/kg BID, and 10 mg/kg BID for 14 days compared to untreated control. Untreated control (-·“), 1 mg/kg (-*-), 5 mg/kg 10 mg/kg (-▼-).
Fig. 7A is a chart that shows the effect of Compound 5 dosed at 1 mg/kg BID and 5 mg/kg BID for 21 days on tumor size in test mice compared to untreated control. Untreated control (“·“), 1 mg/kg (--), 5 mg/kg (-*-).
Fig. 7B is a chart that shows % weight change for test mice dosed at 1 mg/kg BID and 5 mg/kg BID for 21 days compared to untreated control. Untreated control (-·), 1 mg/kg (--), 5 mg/kg (-*-).
DETAILED DESCRIPTION
Before the présent disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the présent disclosure will be limited only by the appended daims.
Unless defined otherwise, ail technical and scientific terms used herein hâve the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. Ail patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a définition set forth in this section is contrary to or otherwise inconsistent with a définition set forth in a patent, application, or other publication that is herein incorporated by reference, the définition set forth in this section prevails over the définition incorporated herein by reference.
As used herein and in the appended daims, the singularforms “a,” “an,” and “the” include plural referents unless the context clearly dictâtes otherwise. It is further noted that the daims may be drafted to exclude any optional element. As such, this statement is intended to serve as antécédent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim éléments, or use of a “négative” limitation.
As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.
To provide a more concise description, some ofthe quantitative expressions given herein are not qualified with the term “about”. It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including équivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.
Except as otherwise noted, the methods and techniques ofthe présent embodiments are generally performed according to conventional methods well known in the art and as described in various general and more spécifie references that are cited and discussed throughout the présent spécification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-lnterscience, 2001.
Chemical nomenclature for compounds described herein has generally been derived using the commercially-available ACD/Name 2014 (ACD/Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).
It is appreciated that certain features ofthe disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features ofthe disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. Ail combinations ofthe embodiments pertaining to the Chemical groups represented by the variables are specifically embraced by the présent disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, ail subcombinations ofthe Chemical groups listed in the embodiments describing such variables are also specifically embraced by the présent disclosure and are disclosed herein just as if each and every such sub-combination of Chemical groups was individually and explicitly disclosed herein.
DEFINITIONS
As used herein, the term “alkyl” includes a chain of carbon atoms, which is optionally branched and contains from 1 to 20 carbon atoms. It is to be further understood that in certain embodiments, alkyl may be advantageously of limited length, including C1-C12, C1-C10, C1-C9, Ci-Cs, C1-C7, Ci-Ce, and C1-C4, lllustratively, such 38 particularly limited length alkyl groups, including CrC8, C1-C7, Ci-C6, and Ci-C4, and the like may be referred to as “lower alkyl.” Illustrative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like. Alkyl may be substituted or unsubstituted. Typical substituent groups include cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, oxo, (=O), thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, Nthiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, and amino, or as described in the various embodiments provided herein. It will be understood that “alkyl” may be combined with other groups, such as those provided above, to form a functionalized alkyl. By way of example, the combination of an “alkyl” group, as described herein, with a “carboxy” group may be referred to as a “carboxyalkyl” group. Other non-limiting examples include hydroxyalkyl, aminoalkyl, and the like.
As used herein, the term “alkenyl” includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon double bond (i.e. C=C). It will be understood that in certain embodiments, alkenyl may be advantageously of limited length, including C2-C12, C2-C9, C2-C8, C2-C7, C2-C6, and C2-C4. Illustratively, such particularly limited length alkenyl groups, including C2-C8, C2-C7, C2-C6, and C2-C4 may be referred to as lower alkenyl. Alkenyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or3-butenyl, and the like.
As used herein, the term “alkynyl” includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon triple bond (i.e. C^C). It will be understood that in certain embodiments, alkynyl may each be advantageously of limited length, including C2-C12, C2-C9, C2-C8, C2-C7, C2-C6, and C2-C4. Illustratively, such particularly limited length alkynyl groups, including C2-C8, C2-C7, C2-C6, and C2-C4 may be referred to as lower alkynyl. Alkenyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative alkenyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
As used herein, the term “aryl” refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron System. It will be understood that in certain embodiments, aryl may be advantageously 39 of limited size such as C6-Cioaryl. Illustrative aryl groups include, but are not limited to, phenyl, naphthylenyl and anthracenyl. The aryl group may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
As used herein, the term “cycloalkyl” refers to a 3 to 15 member all-carbon monocyclic ring, including an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a “fused” ring System means that each ring in the System shares an adjacent pair of carbon atoms with each other ring in the System) group, or a carbocyclic ring that is fused to another group such as a heterocyclic, such as ring 5- or 6-membered cycloalkyl fused to a 5- to 7- membered heterocyclic ring, where one or more ofthe rings may contain one or more double bonds but the cycloalkyl does not contain a completely conjugated pi-electron System. It will be understood that in certain embodiments, cycloalkyl may be advantageously of limited size such as C3-C13, C3-C9, C3-C6 and C4-C6. Cycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl, norbornenyl, 9H-fluoren-9-yl, and the like. Illustrative examples of cycloalkyl groups shown in graphical représentations include the following entities, in the form of properly bonded moieties:
As used herein, the term “heterocycloalkyl” refers to a monocyclic or fused ring group having in the ring(s) from 3 to 12 ring atoms, in which at least one ring atom is a heteroatom, such as nitrogen, oxygen or sulfur, the remaining ring atoms being carbon atoms. Heterocycloalkyl may optionally contain 1,2, 3 or 4 heteroatoms. A heterocycloalkyl group may be fused to another group such as another heterocycloalkyl, or a heteroaryl group. Heterocycloalkyl may also hâve one or more double bonds, including double bonds to nitrogen (e.g. C=N or N=N) but does not contain a completely conjugated pi-electron system. It will be understood that in certain embodiments, heterocycloalkyl may be advantageously of limited size such as 3- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 3-, 4-, 5- or 6-membered heterocycloalkyl, and the like. Heterocycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative heterocycloalkyl groups include, but are not limited to, oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, oxepanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2, 3, 4-tetrahydropyridinyl, and the like. Illustrative examples of heterocycloalkyl groups shown in graphical représentations include the following entities, in the form of properly bonded moieties:
As used herein, the term “heteroaryl” refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon atoms, and also having a completely conjugated pi-electron system. It will be understood that in certain embodiments, heteroaryl may be advantageously of limited size such as 3- to 7membered heteroaryl, 5- to 7-membered heteroaryl, and the like. Heteroaryl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl, pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and carbazoloyl, and the like. Illustrative examples of heteroaryl groups shown in graphical représentations, include the following entities, in the form of properly bonded moieties:
H H
M R /N m /0 (~j -.S q
0,0, O, U.O, Q, O,Q.nO, U.
As used herein, “hydroxy” or ““hydroxyl” refers to an -OH group.
As used herein, “alkoxy” refers to both an -O-(alkyl) or an -O-(unsubstituted cycloalkyl) group. Représentative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
As used herein, “aryloxy” refers to an -O-aryl or an -O-heteroaryl group. Représentative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and the like.
As used herein, “mercapto” refers to an -SH group.
As used herein, “alkylthio” refers to an -S-(alkyl) or an -S-(unsubstituted cycloalkyl) group. Représentative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
As used herein, “arylthio” refers to an -S-aryl or an -S-heteroaryl group. Représentative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like.
As used herein, “halo” or “halogen” refers to fluorine, chlorine, bromine or iodine.
As used herein, “cyano” refers to a -CN group.
The term “oxo” représente a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone.
As used herein, “bond” refers to a covalent bond.
The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In some embodiments, “substituted” means that the specified group or moiety bears one, two, or three substituents. In other embodiments, “substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” means the specified group or moiety bears one substituent.
As used herein, “optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “wherein each hydrogen atom in Ci-C6 alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by Οι-Ce alkyl” means that an alkyl may be but need not be présent on any of the Ci-C6 alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-Ci0 aryl, or mono- or bicyclic heteroaryl by replacement of a hydrogen atom for each alkyl group, and the description includes situations where the Ci-Cs alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl is substituted with an alkyl group and situations where the CrCg alkyl, C2-C6 alkenyl, C2C6 alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl is not substituted with the alkyl group.
As used herein, “independently” means that the subsequently described event or circumstance is to be read on its own relative to other similar events or circumstances. For example, in a circumstance where several équivalent hydrogen groups are optionally substituted by another group described in the circumstance, the use of “independently optionally” means that each instance of a hydrogen atom on the group 43 may be substituted by another group, where the groups replacing each ofthe hydrogen atoms may be the same or different. Or for example, where multiple groups exist ail of which can be selected from a set of possibilities, the use of “independently” means that each ofthe groups can be selected from the set of possibilities separate from any other group, and the groups selected in the circumstance may be the same or different.
As used herein, the phrase “taken together with the carbon to which they are attached” or “taken together with the carbon atom to which they are attached” means that two substituents (e.g. R1 and R2) attached to the same carbon atom form the groups that are defined by the claim, such as C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl. In particular, the phrase “taken together with the carbon to which they are attached” means that when, for example, R1 and R2, and the carbon atom to which they are attached form a C3-C6 cycloalkyl, then the formed ring will be attached at the same carbon atom. For example, the phrase “R1 and R2 taken together with the carbon to which they are attached form a C3-C6 cycloalkyl” used in connection with the embodiments described herein includes fragments represented as follows:
where the above spirocyclic rings can be optionally substituted as defined in a given embodiment.
As used herein, the phrase “taken together with the carbons to which they are attached” or “taken together with the carbon atoms to which they are attached” means that two substituents (e.g. R1 and R2) attached to different carbon atoms form the groups that are defined by the claim, such as C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl. In particular, the phrase “taken together with the carbons to which they are attached form a” means that when, for example, R1 and R2, and the carbon atoms, which are not the same carbon atom, to which they are attached form a C3-C6 cycloalkyl, then the formed ring will be attached at different carbon atoms. For example, the phrase “R1 and R2 taken together with the carbons to which they are attached form a C3-C6 cycloalkyl” used in connection with the embodiments described herein includes fragments represented as follows:
where the above fused rings can be optionally substituted as defined in a given embodiment. Likewise, the phrase “R7 and R8 combine to form a C3-C7 cycloalkyl, a 5to 8-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 7-membered heteroaryl” also means that R7 and R8 are taken together with the carbon atoms to which they are attached to form a a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 7-membered heteroaryl. In particular, “R7 and R8 combine to form a C3-C7 cycloalkyl” used in connection with the embodiments described herein includes fragments represented by the following:
where the above fused rings can be optionally substituted as defined in a given embodiment. One of skiil in the art will appreciate that ail stereochemical arragnements are included within the structures provided above, such as with respect to the fivecarbon ring formed by R7 and R8 as provided in the following fragments:
As used herein, the term “pharmaceutically acceptable sait” refers to those salts which counter ions which may be used in pharmaceuticals. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergie response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable sait. Such salts include:
(1) acid addition salts, which can be obtained by reaction ofthe free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or (2) salts formed when an acidic proton présent in the parent compound either is replaced by a métal ion, e.g., an alkali métal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, and the like.
Pharmaceutically acceptable salts are well known to those skilled in the art, and any such pharmaceutically acceptable sait may be contemplated in connection with the embodiments described herein. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acétates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, yhydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.
For a compound of Formula I, II, III, IV or V that contains a basic nitrogen, a pharmaceutically acceptable sait may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, ptoluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible 46 mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as équivalents or acceptable substitutes in light ofthe ordinary level of skill in this technology.
The disclosure also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula I, II, III, IV or V, and treatment methods employing such pharmaceutically acceptable prodrugs. The term “prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a Chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula I, II, III, IV or V). A pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the sélection and préparation of suitable prodrug dérivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
The présent disclosure also relates to pharmaceutically active métabolites of compounds of Formula I, II, III, IV or V, and uses of such métabolites in the methods of the disclosure. A “pharmaceutically active métabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula I, II, III, IV or V, or sait thereof. Prodrugs and active métabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academie Publishers, 1991).
Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or géométrie isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvaté, or polymorph of such a compound, or a mixture thereof. For example, it will be appreciated that compounds depicted by a structural formula containing the symbol “'Sxsxvx, ” jnclude both stereoisomers for the carbon atom to which the symbol “^χτυχ, js attached, specifically both the bonds and............. are encompassed by the meaning of “'ΛΛΛ'” For examp|ei jn some exemplary embodiments, certain compounds provided herein can be described by the formula
which formula will be understood to encompass compounds having both stereochemical configurations at the relevant carbon atom, specifically in this example
and other stereochemical combinations.
Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds hâve structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18O, 170,31P, 32P, 35S, 18F, 36CI, and 125l, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with 14C), reaction kinetic studies (with, for example 2H or 3H), détection or imaging techniques [such as positron émission tomography (PET) or single-photon émission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and préparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -A-B-, where A # B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.
REPRESENTATIVE EMBODIMENTS
In some embodiments, compounds described herein comprise a moiety ofthe formula
wherein Z1-Z6 and Y are defined as described herein, and the substituents on the nonaromatic ring marked by a bond and ~ correspond to R7 and R8 as described herein. In other embodiments, compounds described herein comprise a moiety of the formula
wherein Z1-Z6, R9, and R10 are otherwise defined as described herein, and the substituents on the non-aromatic ring marked by a bond and ~ correspond to R7 and R8 as described herein. In still other embodiments, compounds described herein comprise a moiety of the formula
wherein Z1-Z6 and Y are otherwise defined as described herein, and the substituents on the non-aromatic ring marked by a bond and ~ correspond to R7 and R8 as described herein. In some embodiments, each of Z1, Z2, Z3, Z4, Z5, and Z6 is independently N, NH, C or CH. In some embodiments, Z1, Z3 and Z6 are N, Z2 and Z5 are CH, and Z4 is C. In some embodiments, Z1, Z3 and Z6 are N, Z2 and Z5 are CH, Z4 is C, and Y is O. In some embodiments, Z1, Z2 and Z6 are N, Z5 is CH, and Z3 and Z4 are C. In some embodiments, Z1, Z2 and Z6 are N, Z5 is CH, Z3 and Z4 are C, and Y is O. In some embodiments, Z2, Z4 and Z5 are N, Z1 and Z6 are CH, and Z3 is C. In some embodiments, Z2, Z4 and Z5 are N, Z1 and Z6 are CH, Z3 is C and Y is O. In some embodiments, Z1, Z4 and Z6 are N, Z2 and Z5 are CH, and Z3 is C. In some embodiments, Z1, Z4 and Z6 are N, Z2 and Z5 are CH, Z3 is C, and Y is O. In some embodiments, Z2 and Z4 are N, Z1, Z5 and Z6 are CH, and Z3 is C. In some embodiments, Z2 and Z4 are N, Z1, Z5 and Z6 are CH, Z3 is C, and Y is O.
In still other embodiments, compounds described herein comprise a moiety ofthe formula
wherein Y is otherwise defined as described herein, and the substituents on the nonaromatic ring marked by a bond and ~ correspond to R7 and R8 as described herein. In stiil other embodiments, compounds described herein comprise a moiety ofthe formula
wherein Y is otherwise defined as described herein. In stiil other embodiments, compounds described herein comprise a moiety of the formula
In stiil other embodiments, compounds described herein comprise a moiety of the formula
compounds described herein comprise a moiety of the formula
compounds described herein comprise a moiety ofthe formula
In some embodiments, L is -C^XR2)-- In some embodiments, L is X. In some embodiments, when t is 1, L is -C(R1)(R2)-.
In some embodiments, X is -O-. In some embodiments, X is -S-. In some embodiments, X is -S(O)-. In some embodiments, X is -S(O)2. In some embodiments, when t is 1, L is not X. In some embodiments, when t is 2, 2, or 4, the L attached directly to the amide nitrogen in the macrocycle is not X.
In some embodiments, each R1 and R2 is independently H, deuterium, halogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Cioaryl, or mono- or bicyclic heteroaryl, -ORa, -OC(O)Ra, OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or R1 and R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 6membered heterocycloalkyl, wherein each hydrogen atom in Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Cioaryl, monoor bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-C6 haloalkyl, -ORe, -OC(O)Re, OC(O)NReRf, -OC(=N)NR®Rf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, P(O)ORe, -P(O)2ORe, -CN, or-NO2.
In some embodiments, R1 and R2 are each independently H, deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-Ci0aryl, -ORa, -SRa, -NRaRb, C(O)ORa, -C(O)NRaRb; wherein each hydrogen atom in Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C10aryl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OC-|-C6 alkyl, -OCi-Ce alkyl(C6-Ci0aryl), -NH2, -OC(O)CrC6 alkyl, -OC(O)N(Ci-C6 alkyl)2, -OC(O)NH(CrC6 alkyl), -OC(O)NH2, -OC(=N)N(C1-C6 alkyl)2, -OC(=N)NH(C1-C6 alkyl), -OC(=N)NH2, -OS(O)CrC6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(CrC6 alkyl), -N(Ci-C6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)C(O)NH2, -N(CrC6 alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)C(O)N(CiC6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(CrC6 alkyl)C(O)OCi-C6 alkyl, -NHC(O)OH, -N(CrC6 alkyl)C(O)OH, -NHS(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-C6 alkyl)S(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)S(O)2CrC6 alkyl,-NHS(O)NH2, -NHS(O)2NH2i N(CrC6 alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)2NH2, -NHS(O)NH(C1-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)2N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(CrC6 alkyl)S(O)N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -C(O)Ci-C6 alkyl, -CO2H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(CrC6 alkyl)2, -SCrC6 alkyl, -S(O)Ci-C6 alkyl, -S(O)2CrC6 alkyl, -S(O)NH(C!-C6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(Ci-C6 alkyl)2, -S(O)2N(Ci-C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(CrC6 alkyl)2, -OS(O)2N(CrC6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(Ci-C6 alkyl)2, -P(O)(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.
In some embodiments, R1 is H. In some embodiments, R2 is H. In some embodiments, R1 is CrCe alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 is C3-C6 cycloalkyl. In some embodiments, R1 is cyclopropyl. In some embodiments, R2 is Ci-C6 alkyl. In some embodiments, R2 is methyl. In some embodiments, R2 is C3-C6 cycloalkyl. In some embodiments, R2 is cyclopropyl. In some embodiments, R1 is H and R2 is Ci-Ce alkyl. In some embodiments, R1 and R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R1 and R2 taken together with the carbon or carbons to which they are attached form a cyclopropane ring.
In some embodiments, M is CR3. In some embodiments, M is N. In some embodiments, M1 is CR4.
In some embodiments, each R3, R4, and R5 is independently hydrogen, deuterium, halogen, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)RC, OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORC, C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, P(O)ORC, -P(O)2ORc, -CN, -NO2, CrC6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl, or R4 and R5 taken together with the ring to which they are attached form a C5-C8 cycloalkyl, or a 5- to 8-membered heterocycloalkyl, wherein each hydrogen atom in Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C8-Cioaryl, mono- or bicyclic heteroaryl, C5-C8 cycloalkyl, or 5- to 8membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, P(O)2ORe, -CN, or -NO2. In some embodiments, each R3, R4, and R5 are each independently H, fluoro, chloro, bromo, Ci-C8 alkyl, -OH, -CN, -OCi-Ce alkyl, -NHC-i-Ce alkyl, -N(Ci-C6 alkyl)2 or -CF3. In some embodiments, R3 is H, deuterium, CrC6 alkyl or halogen. In some embodiments, R3 is H or F. In some embodiments, R4 is H, deuterium, Ci-Ce alkyl or halogen. In some embodiments, R4 is H or Cl. In some embodiments, R5 is F.
In some embodiments, R6 is H, deuterium, Ci-C6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C-i-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, -ORe, OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, 55
OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or-NO2. In some embodiments, R6 is H, C-i-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in Ci-C6 alkyl or 3-to 7-membered heterocycloalkyl is independently optionally substituted by halogen, -OH, -CN, -OCi-C6 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(C1-C6 alkyl)2, -CO2H, -C(O)OCrC6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl.
In some embodiments, R7 and R8 combine to form a C3-C7 cycloalkyl, a 5- to 8membered heterocycloalkyl, C6-Ci0aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5-to 8-membered heterocycloalkyl, C6-Ci0aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by deuterium, halogen, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or-NO2.
In some embodiments, R7 and R8 combine to form a C3-C7 cycloalkyl, a 5- to 8membered heterocycloalkyl, C6-Ci0aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Ci0aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by deuterium, halogen, -OH, -OCrC6 alkyl, -OC(O)CrC6 alkyl, -OC(O)NH2, -OC(O)NH(CrC6 alkyl), -OC(O)N(Ci-C6 alkyl)2, -OC(=N)NH2, -OC(=N)NH(Ci-C6 alkyl), -OC(=N)N(CrC6 alkyl)2, -OS(O)CrC6 alkyl, -OS(O)2Ci-C6 alkyl, -OS(O)NH2, -OS(O)NH(Ci-C6 alkyl), -OS(O)N(Ci-C6 alkyl)2, -OS(O)2NH2, -OS(O)2NH(CrC6 alkyl), -OS(O)2N(Ci-C6 alkyl)2, SH, -SCi-C6 alkyl, -S(O)Ci-C6 alkyl, -S(O)2CrC6 alkyl, -S(O)NH2, -S(O)NH(Ci-C6 alkyl), -S(O)(Ci-C6 alkyl)2, -S(O)2NH2, -S(O)2NH(Ci-C6 alkyl), -S(O)2N(Ci-C6 alkyl)2, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)C(O)Ci-C6 alkyl, NHC(O)OH, -NHC(O)OCi-C6 alkyl, -N(Ci-C6 alkyl)C(O)OH, -N(Ci-C6 alkyOCiOJOCrCe alkyl, -NHC(O)NH2, -NHC(O)NH(CrC6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)C(O)NH2, -N(Ci-C6 alkyl)C(O)NH(CrC6 alkyl), -N(CrC6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHS(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)S(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(CrC6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)NH(Ci-C6 alkyl), -N^-Cs alkyl)S(O)N(Ci-C6 alkyl)2, -NHS(O)2NH2, -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)2N(Ci-C6 alkyl)2, -Ν(Οι-06 alkyl)S(O)2NH2, -N(C-,-C6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)CrC6 alkyl, -C(O)OC^-C6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(Ci-C6 alkyl)2, -P(CrC6 alkyl)2, -P(O)(Ci-C6 alkyl)2, -P(O)2(Ci-C6 alkyl)2, -P(O)NH2, -P(O)NH(Ci-C6 alkyl), -P(O)N(Ci-C6 alkyl)2, -P(O)2NH2, -P(O)2NH(Ci-C6 alkyl), -P(O)2N(CrC6 alkyl)2, -P(O)OH, -P(O)OCrC6 alkyl, -P(O)2OH, -P(O)2OCi-C6 alkyl, -CN, or -NO2.
In some embodiments, R7 and R8 combine to form a 5- or 6-membered cycloalkyl, wherein each hydrogen atom in the 4-, 5- or 6-membered cycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OC-i-C6 alkyl, OCi-C6 alkyl(C6-Ci0aryl), -NH2, -OC(O)Ci-C6 alkyl, -OC(O)N(CrC6 alkyl)2, OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(CrC6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), OC(=N)NH2, -05(0)0^ alkyl, -OS(O)2Ci-C6 alkyl, -NH(Ci-C6 alkyl), -N(CrC6 alkyl)2, -NHC(O)CrC6 alkyl, -N(CrC6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)C(O)NH2, -N(CrC6 alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)C(O)N(C1-C6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(CrC6 alkyl)C(O)OC1-C6 alkyl, -NHC(O)OH, -N(Ci-C6 alkyl)C(O)OH, -NHS(O)Ci-C6 alkyl, -NHS(O)2C1-C6 alkyl, -N(CrC6 alkyl)S(O)CrC6 alkyl, -N(Ci-C6 alkyl)S(O)2CrC6 alkyl, -NHS(O)NH2, -NHS(O)2NH2, -N(Ci-C6 alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)2NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(CrC6 alkyl)2, -NHS(O)2N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-C6 alkyl, -CO2H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(CrC6 alkyl), -C(O)N(Ci-C6 alkyl)2, -SCrC6 alkyl, -S(O)CrC6 alkyl, -S(O)2CiC6 alkyl, -S(O)NH(C-i-C6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(CrC6 alkyl)2, -5(0)^(^C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(CrC6 alkyl)2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -PiCrCe alkyl)2, -P(O)(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.
In some embodiments, R7 and R8 combine to form a 3-, 4-, 5- or 6-membered heterocycloalkyl, wherein each hydrogen atom in the 3-, 4-, 5- or 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCrCe alkyl, -OCrC6 alkyl(C6-Ci0 aryl), -NH2, -OC(O)Ci-C6 alkyl, -OC(O)N(CrC6 alkyl)2, -OC(O)NH(CrC6 alkyl), -OC(O)NH2, -0C(=N)N(CrC6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), -OC(=N)NH2, -OS(O)Ci-C6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(CrC6 alkyl), -N(CrC6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)C(O)CrC6 alkyl, -NHC(O)NH2,
-NHC(O)NH(Ci-C6 alkyl), -NiCrCe alkyl)C(O)NH2, -N(Ci-C6 alkyl)C(O)NH(Ci-C6 alkyl), -ΝΗΟ(Ο)Ν(Ο-|-Ο6 alkyl)2, -N(Ci-C6 alkyOCiOjNiCrCe alkyl)2, -NHC(O)OCi-C6 alkyl, -N(C-i-C6 alkyl)C(O)OCi-C6 alkyl, -NHC(O)OH, -N(Ci-C6 alkyl)C(O)OH, -NHS(O)CrC6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-C6 alkyl)S(O)Ci-C6 alkyl, -N(CrC6 alkyl)S(O)2Ci-C6 alkyl,-NHS(O)NH2, -NHS(O)2NH2, -N(CrC6 alkyl)S(O)NH2, -N(Ci-C6 alkyl)S(O)2NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHSiOjNiCvCe alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-C6 alkyOSiOjNiCrCe alkyl)2, -N(Ci-C6 alkyl)S(O)2N(CrC6 alkyl)2, -C(O)Ci-C6 alkyl, -CO2H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(Ci-C6 alkyl)2, -SCi-C6 alkyl, -S(O)Ci-C6 alkyl, -S(O)2CiC6 alkyl, -S(O)NH(Ci-C6 alkyl), -S(O)2NH(Ci-C6 alkyl), -SiOjNiCrCe alkyl)2, -S(O)2N(Cr C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(Ci-C6 alkyl)2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -Ρ^Λ alkyl)2, -P(O)(Ci-Ce alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl. In some embodiments, R7 and R8 combine to form a tetrahydrofuran ring. In some embodiments, R7 and R8 combine to form a cyclopentane ring.
In some embodiments, Y is -O-, -S-, -NR9, or-CR9R10-. In some embodiments, Y is -O-.
In some embodiments, R9 and R10 are each independently H, deuterium, halogen, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cwaryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C-i-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Cioaryl, or mono- or bicyclic heteroaryl is optionally substituted by a halogen, -ORe, -OC(O)R®, -OC(O)NReRf, -OC(=N)NR®Rf, -OS(O)Re, -OS(O)2Re, -OS(O)NR®Rf, -OS(O)2NR®Rf, -SR®, -S(O)R®, -S(O)2Re, -S(O)NR®Rf, -S(O)2NR®Rf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NR®C(O)NReRf, -NR®S(O)Rf, -NR®S(O)2Rf, -NReS(O)NReRf, -NR®S(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)R®Rf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or-P(O)2ORe.
In some embodiments, R9 and R10 are each independently H, deuterium, halogen, or Ci-C6 alkyl, wherein each hydrogen atom in Ci-Ce alkyl is optionally substituted by a halogen, -OH, -OCi-C6 alkyl, -OC(O)Ci-C6 alkyl, -ΟΟ(Ο)Ν(Ο!-Ο6 alkyl)2, -OCiOjNHiCrCe alkyl), -OC(O)NH2, -OC(=N)N(Ci-C6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), -OC(=N)NH2, -08(0)0^06 alkyl, -OS(O)2Ci-C6 alkyl, -OS(O)N(Ci-C6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)2NH(C1-C6 alkyl), -OS(O)2NH2, -SH, -SCrCe alkyl, -S(O)Ci-C6 alkyl, -8(0)^-06 alkyl, -S(O)N(Ci-C6 alkyl)2, -8(0)1^((^-06 alkyl), -S(O)NH2, -S(O)2N(Ci-C6 alkyl)2, -S^NH^-Ce alkyl), -S(O)2NH2, -N(Ci-C6 alkyl)2, -NH(Ci-C6 alkyl), -NH2, -N(C1-C6 alkyl)C(O)CrC6 alkyl, -NHC(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)C(O)OCi-C6 alkyl, -N(Ci-C6 alkyl)C(O)OH, NHC(O)OCi-C6 alkyl, -NHC(O)OH, -N(CrC6 alkylKXOjN^Ce alkyl)2, -N(Ci-C6 alkyl)C(O)NH(C-|C6 alkyl), -N(Ci-C6 alkyl)C(O)NH2, -NHC(O)N(CiC6 alkyl)2, -NHC(O)NH(C1C6 alkyl), -NHC(O)NH2, -N(Ci-C6 alkyl)S(O)Ci-C6 alkyl, -NHS(O)Ci-C6 alkyl, -N(Ci-C6 alkyDSiO^CrCe alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-C6 alkyDSiOjNiCrCe alkyl)2, -N(Ci-C6 alkyl)S(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)S(O)NH2, -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)NH(C1-C6 alkyl), -NHS(O)NH2, -N(Ci-C6 alkyl)S(O)2N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)2NH2, -NHS(O)2N(C1-C6 alkyl)2, -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)2NH2, -C(O)Ci-C6 alkyl, -C(O)OCi-C6 alkyl, -C(O)N(Ci-C6 alkyl)2, -C(O)NH(Ci-C6 alkyl), -C(O)NH2, -P(Ci-C6 alkyl)2, -P(O)(Ci-C6 alkyl)2, -P(O)2(Ci-C6 alkyl)2, -P(O)N(Ci-C6 alkyl)2, -P(O)2N(C1-C6 alkyl)2, -PiOjOCrCe alkyl, or -P(O)2OCi-C6 alkyl.
In some embodiments, each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 7- membered heteroaryl.
In some embodiments, p is 1,2, 3, or 4. In some embodiments, p is 1.
In some embodiments, t is 1,2, 3, 4, or 5. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 3 or 4.
In some embodiments, n, if présent, is 1,2, or 3. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 2 or 3.
The following represent illustrative embodiments of compounds ofthe formula I, II, III, and IV:
Compoun d | Structure | Name |
1 | o | (3a/?, 11 S,20aS)-7-fluoro-11 -methyl2,3,3a, 12,13,20a-hexahydro-1 H,5H17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3, 4-/]pyrazolo[4,3- /][1,4,8,10]benzoxatriazacyclotridecin14(11/7)-one |
2 | F~0-o^ O0XJQ | (7S)-3-amino-11 -fluoro-7-methyl-4-oxo14-(propan-2-yl)-4,5,6,7,13,14hexahydro-1,15-ethenopyrazolo[4,3/][1,4,8,10]benzoxatriazacyclotridecine12-carbonitrile |
3 | %4 «7 o | (3aR,11S,20aS)-7,9-difluoro-11-methyl2,3,3a,12,13,20a-hexahydro-1/-/,5/-/- 17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3, 4-/]pyrazolo[4,3- /][1,4,8,10]benzoxatriazacyclotridecin- 14(11H)-o ne |
4 | x y o | (3a/?, 11 S,20aR)-7-fluoro-11 -methyl- 1,3,3a,12,13,20a-hexahydro-5/-/-17,19- (metheno)furo[3',4':5,6][1,4]oxazino[3,4- /]pyrazolo[4,3- ή[1,4,8,10]benzoxatriazacyclotridecin- 14(11/-/)-one |
5 | f-VN\ 5 ΐΛο^Α NH V 4° CVU7 | (3aR,11S,20aS)-7-fluoro-11-methyl2,3,3a,12,13,20a-hexahydro-1 /-/,5/-/17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3, 4-/]pyrazolo[4,3-f]pyrido[3,2- /][1,4,8,10]oxatriazacyclotridecin- 14(11/7)-one |
6 | x4 H 1 O | (3aR, 12/?,20aS)-7-fluoro-12-methyl- 2,3,3a,12,13,20a-hexahydro-1/-/,5/-/- 17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3, 4-/] py razo lo [4,3 -f] py ri d o [3,2- /][1,4,8,10]oxatriazacyclotridecin- 14(11/-/)-one |
7 | o X y W | (3aR,12/?,20aS)-7,9-difluoro-12-methyl2,3,3a,12,13,20a-hexahydro-1/-/,5/-/17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3, 4-/]pyrazolo[4,3- ή[1,4,8,10]benzoxatriazacyclotridecin14(11H)-one |
8 | F^V U ^~X~° N H λ 4° | (2aR, 10S,19aS)-6-fluoro-10-methyl- 1,2,2a, 11,12,19a-hexahyd ro-4H-16,18(metheno)cyclobuta[5,6][1,4]oxazino[3,4- /]pyrazolo[4,3-f]pyrido[3,2- /][1,4,8,10]oxatriazacyclotridecin- 13(10H)-one |
9 | f-<nv X N H ''-ÇXXj | (2aS, 10S, 19a/?)-6-fluoro-10-methyl1,2,2a,11,12,19a-hexahydro-4/7-16,18- (metheno)cyclobuta[5,6][1,4]oxazino[3,4- /] pyrazo lo [4,3-f] pyrid o [3,2- /][1,4,8,10]oxatriazacyclotridecin13(10/7)-one |
10 | o T u i z ° | (2aR,11R,19aS)-6-fluoro-11-methyl- 1,2,2a,11,12,19a-hexahydro-4/7-16,18(metheno)cyclobuta[5,6][1,4]oxazino[3,4- /]pyrazolo[4,3-f]pyrido[3,2- /][1,4,8,1O]oxatriazacyclotridecin- 13(10/-/)-one |
11 | m o z 1 η λ o | (2aS,11R,19aR)-6-fluoro-11-methyl- 1,2,2a, 11,12,19a-hexahydro-4/7-16,18(metheno)cyclobuta[5,6][1,4]oxazino[3,4- /]pyrazolo[4,3-f]pyrido[3,2- /][1,4,8,1O]oxatriazacyclotridecin- 13(10/-/)-one |
12 | f-ΖΛ K NH λ -Λο LX0Xn.J | (4aR,12S,21 aS)-8-fluoro-12-methyl- 1,2,3,4,4a,13,14,21 a-octahydro-6H- 18,20- (metheno)pyrazolo[4',3':6,7]pyrido[3',2':1 2,13][1,4,8,10]oxatriazacyclotridecino[9, 10-c][1,4]benzoxazin-15(12A7)-one |
13 | fV^ / Y NH A 4=0 11 J^/N'N 0 N | (4aR,13R,21 aS)-8-fluoro-13-methyl- 1,2,3,4,4a,13,14,21a-octahydro-6H- 18,20- (methenojpyrazolo^'.S'ÆJjpyridotS'^':! 2,13][1,4,8,10]oxatriazacyclotridecino[9, 10-c][1,4]benzoxazin-15(12/7)-one |
14 | LL· | (3a/?,12/?,20aS)-12-cyclopropyl-7-fluoro- 2,3,3a,12,13,20a-hexahydro-1/-/,5/-/- 17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3, 4-/] pyrazo lo [4,3-f] pyrid o [3,2- /][1,4,8,10]oxatriazacyclotridecin- 14(11/-/)-one |
15 | F-Tz ° H N Λ yo CQwU | (3aR, 11 S,21 aS)-7-fluoro-11 -methyl2,3,3a,11,12,13,14,21a-octahydro- 1 H, 5/7,15H-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin-15one |
16 | %4 ai o | (3aR, 13R,21 aS)-7-fluoro-13-methyl- 2,3,3a,11,12,13,14,21a-octahydro- 1/-/,5/-/,15/-/-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin-15- |
one | ||
17 | ο _fz + % l_L | (3aR,12S,21 aS)-7-fluoro-12-methyl2,3,3a,11,12,13,14,21a-octahydro1/7,5/7,15/7-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e] py razo lo [3, À-h] py rid o [2,3- b][1,5,7,11]oxatriazacyclotetradecin-15one |
18 | 0 NH | (3a'/?,20a'S)-7'-fluoro- 1 Ή,2Ή,3Ή,3άΉ,5Ή, 1177,13'/7, 14’H,20a' /-/-spiro[cyclopropane-1,12'- [10,20]dioxa[4,9,13,16,17,18]hexaaza[17 ,19](metheno)cyclopenta[5,6][1,4]oxazin o[3,4-/]pyrazolo[4,3-f]pyrido[3,2- /][1,4,8,10]oxatriazacyclotridecin]-14'- one |
19 | Ρ-ΓΤ/Ά H N \ >0 N | (3aR,21aS)-7-fluoro- 2,3,3a,11,12,13,14,21a-octahydro- 1H,5H,15H-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-/7]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin-15one |
20 | o H\j \ yo CL0A^n7 | (3a'R,21 a'S)-7'-fluoro- 1 Ή,2Ή,3Ή,3&Ή,5Ή,11 Ή,13Ή,14Ή,15' /7,21 a'/-/-spiro[cyclopropane-1,12'- [10,21]dioxa[4,9,14,17,18,19]hexaaza[18 ,20](metheno)cyclopenta[5,6][1,4]oxazin o[4,3-e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin]-15'one |
21 | W üf o | (3a/?,20aS)-7-fluoro-12,12-dimethyl2,3,3a,12,13,20a-hexahydro-1/7,5/7- 17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3, 4-/]pyrazolo[4,3-f]pyrido[3,2- /][1,4,8,10]oxatriazacyclotridecin- 14(11/7)-one |
22 | /7^ O &F o | (3a'/?,20a'S)-7'-fluoro- 1 Ή,2Ή,3Ή,3άΉ,5Ή, 1 TH, 13Ή, 14'H,20a' /7-spiro[cyclobutane-1,12'- [10,20]dioxa[4,9,13,16,17,18]hexaaza[17 ,19](metheno)cyclopenta[5,6][1,4]oxazin o[3,4-/]pyrazolo[4,3-/]pyriclo[3,2- /][1,4,8,10]oxatriazacyclotridecin]-14'one |
23 | I ΗΝ \ )=° ^^Ν Ν^7 | (3a'/?,21 a'S)-7'-fluoro- 1 'H,2'H,3'H,3a’H,5’H, 1 VH, 1377, 1477, 15' /7,21 a'/7-spiro[cyclobutane-1,12'- [10,21 ]dioxa[4,9,14,17,18,19]hexaaza[18 ,20](metheno)cyclopenta[5,6][1,4]oxazin o[4,3-e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin]-15'one |
24 | ΤΡ Ο τ ο | (3aS, 11 a/?, 14aS,21 a/?)-18-fluoro- 2,3,3a,11,11a,12,13,14,14a,21a- decahydro-1 /7,10/7,20/7-7,5- (metheno)cyclopenta[b]cyclopenta[5,6][1 ,4]oxazino[3,4-/]pyrazolo[4,3-/]pyrido[3,2/][1,4,8,10]oxatriazacyclotndecin-10-one |
25 | JP ° ύ-Τ Ο ΤΙ | (3a'/?,20a'S)-3,3,7'-trifluoro- 1 'H,2'H,3'H,3a'H,5'H, 1 VH, 13Ή, 14'H,20a' H-spiro[cyclobutane-1,12'- [10,20]dioxa[4,9,13,16,17,18]hexaaza[17 ,19](metheno)cyclopenta[5,6][1,4]oxazin o[3,4-/]pyrazolo[4,3-/]pyrido[3,2- /][1,4,8,10]oxatriazacyclotridecin]-14'- one |
26 | Ο Ο ύ·Τ Ο | (3a'/?,20a'S)-7'-fluoro- 1 'H,2'H,3'H,3a’H,5'HX 177,13ΉΧ 4'H,20a' /7-spiro[cyclopentane-1,12'- [10,20]dioxa[4,9,13,16,17,18]hexaaza[17 ,19](metheno)cyclopenta[5,6][1,4]oxazin o[3,4-/]pyrazolo[4,3-/]pyrido[3,2- /][1,4,8,10]oxatriazacyclotridecin]-14'- one |
27 | ττ A VLZ^O 1 ] ΗΝ \ Α° | (3a/?,21aS)-7-fluoro-12,12-dimethyl- 2,3,3a,11,12,13,14,21a-octahydro1/7,5H,15H-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin-15one |
28 | f^n /-^ L-γΌ ] ] ΗΝ \ Α° ^^Ν^Ν^Α vÇCna | (3a/?, 13S,21 aS)-7-fluoro-13-methyl- 2,3,3a,11,12,13,14,21a-octahydro- 1/7,5/7,15/7-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11 ]oxatriazacyclotetradecin-15one |
29 | AM Μ J ÂyA ο | (3a/?,21aS)-7-fluoro-12-methyl- 2,3,3a,11,12,13,14,21a-octahydro- 1/-/,5/-/,15/-/-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin-15one |
30 | AM Η t ο | (3a/?, 11S,20a/?)-7-fluoro-11-methyl- 1,3,3a,12,13,20a-hexahydro-5/7-17,19(metheno)furo[3',4':5,6][1,4]oxazino[3,4- /]pyrazolo[4,3-f]pyrido[3,2- /][1,4,8,10]oxatriazacyclotridecin- 14(11/-/)-0 ne |
31 | χοχ A /—\ _Γ ν ο ζ Μ Μ CÏ/^ ο | (3aS, 11 S,20aS)-7-fluoro-11 -methyl1,3,3a, 12,13,20a-hexahydro-5H-17,19- (metheno)furo[3',4':5,6][1,4]oxazino[3,4- /]pyrazolo[4,3-f]pyrido[3,2- /][1,4,8,10]oxatriazacyclotridecin- 14(11/-/)-one |
32 | _ ΟΗ ___Λ 1 ] ΗΝ \ >° | (3aR, 12S,21 aS)-7-fluoro-12-hydroxy- 2,3,3a,11,12,13,14,21a-octahydro- 1H,5H,15H-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-/7]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin-15one |
33 | ο οΜ^ΆΑ; 1 ^° W μΑ LL | (3af?,21 aS)-7-fluoro-12,12-dihydroxy- 2,3,3a,11,12,13,14,21a-octahydro- 1 H,5H, 15/7-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-/?]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin-15one |
34 | ΑΜ ο | (3aR,21aS)-7-fluoro-13,13-dimethyl- 2,3,3a,11,12,13,14,21a-octahydro- 1/-/,5/-/,15/-/-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin-15one |
35 | Ο | (3aR,11 R,21 aS)-7-fluoro-11 -methyl- 2,3,3a,11,12,13,14,21a-octahydro- 1/-/,5/-/,15/7-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin-15- one |
36 | ο ο τ ? U- | | (3aR, 11 S,20aS)-2-acetyl-7-fluoro-11 methyl-2,3,3a,12,13,20a-hexahydro1 H,5H-A 7,19-(metheno)pyrazolo[4,3f]pyrido[3,2- l]pyrrolo[3',4':5,6][1,4]oxazino[3,4/][1,4,8,10]oxatriazacyclotridecin14(11/-/)-one |
37 | Ο yy ? Μ ζΑ ,Ζ ο (1 1— λ—/ ιί CT' | (3aS, 11 S,20aR)-2-acetyl-7-fluoro-11 methyl-2,3,3a,12,13,20a-hexahydro1 /-/,5H-17,19-(metheno)pyrazolo[4,3f]pyrido[3,2- l]pyrrolo[3',4':5,6][1,4]oxazino[3,4/][1,4,8,10]oxatriazacyclotridecin- 14(11H)-one |
38 | F ,—( ïyo। 1 HN \ )=0 | (3aR,12S,21aS)-7,12-difluoro- 2,3,3a,11,12,13,14,21a-octahydro- 1H,5H,15H-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin-15- one |
39 | F Ido 1 ] HN \ )=0 N | 3aR,12R,21aS)-7,12-difluoro- 2,3,3a,11,12,13,14,21a-octahydro- 1H,5H,15H-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin-15- one |
40 | txT q HN αχχΓ | (3aR,21aS)-7,12,12-trifluoro- 2,3,3a,11,12,13,14,21a-octahydro- 1 H,5/-/,15H-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin-15one |
41 | F^/^N xÀo^X | HN \ d° wî | (3aR,11R,14S,22aS)-7-fluoro- 2,3,3a,12,13,14,15,22a-octahydro- 1 /-/,5/-/-11,14-methano-19,21 (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-/?]pyrido[2,3- b][1,5,7,11 ]oxatriazacyclopentadecin- 16(11/-/)-one |
42 | Λ 7 Μ | (3aR 11 S, 14/?,22aS)-7-fluoro- 2,3,3a,12,13,14,15,22a-octahydro- 1/7,5/7-11,14-methano-19,21- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e] py razo lo [3, À-h] py rid o [2,3- b][1,5,7,11]oxatriazacyclopentadecin- 16(11/7)-one |
43 | _ OH FS^N _? 7 HN αχ+Γ | (3aR, 12R,21 aS)-7-fluoro-12-hyd roxy- 2,3,3a,11,12,13,14,21a-octahydro- 1H,5H,15H-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-/7]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin-15one |
44 | .....Xn H Ll_ \/ | (3aS,11R,20aR)-7-fluoro-11-methyl- 2,3,3a,12,13,20a-hexahydro-1/-/,5/-/- 17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3, 4-/]pyrazolo[4,3-/]pyriclo[3,2- /][1,4,8,10]oxatriazacyclotridecin- 14(11H)-one |
45 | 7 HN \ >=o /•^Ν^Ν\χ\ | (3a'/?,21 a'S)-7'-fluoro- 1 'H,2’H,3'H,3a'H,5'H, 1 TH, 12Ή, 14' H, 15' H,21 a'H-spiro[cyclobutane-1,13'- [10,21]dioxa[4,9,14,17,18,19]hexaaza[18 ,20](metheno)cyclopenta[5,6][1,4]oxazin o[4,3-e]pyrazolo[3,4-/7]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin]-15'one |
46 | F^N /^X 7 HN «xd | (3a/?,11s,13S,21aS)-7-fluoro- 2,3,3a,12,13,14,15,21a-octahydro- 1 /-/,5/-/,11H-11,13-methano-18,20(metheno)cyclopenta[5,6][1,4]oxazino[4, 3-e]pyrazolo[3,4-/?]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecine |
47 | B-Xj /TX O Ο Ή | (3aR, 12S,20aS)-12-(difluoromethyl)-7fluoro-2,3,3a,12,13,20a-hexahydro- 1 Η,5Η-17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3, 4-/] pyrazo lo [4,3-/] pyrid o [3,2- /][1,4,8,10]oxatriazacyclotridecin- 14(11H)-one |
48 | # + o AA o | (3aR,12S,20aS)-7-fluoro-12- (trifluoromethyl)-2,3,3a, 12,13,20a- hexahydro-1 H,5H-17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3, 4-/]pyrazolo[4,3-/]pyndo[3,2- /][1,4,8,10]oxatriazacyclotridecin- 14(11H)-o ne |
49 | OH YX A (° H'N 0 αχΥ | (3a/?, 11 S,20aS)-7-fluoro-11 (hydroxymethyl)-2,3,3a,12,13,20ahexahydro-1 /-/,5/-/-17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3, 4-/]pyrazolo[4,3-/]pyrido[3,2- /][1,4,8,10]oxatriazacyclotridecin- 14(11/7)-one |
Those ski lied in the art will recognize that the species listed or illustrated herein are not exhaustive, and that additional species within the scope of these defined terms may also be selected.
PHARMACEUTICAL COMPOSITIONS
For treatment purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceuticallyacceptable excipients. A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration ofthe compounds described herein and are compatible with the active ingrédient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents. In preferred embodiments, pharmaceutical compositions according to the invention are stérile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.
Stérile compositions are also contemplated by the invention, including compositions that are in accord with national and local régulations governing such compositions.
The pharmaceutical compositions and compounds described herein may be formulated as solutions, émulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for préparation of various dosage forms. Pharmaceutical compositions of the invention may be administered by a suitable route of delivery, such as oral, parentéral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.
For oral administration, the compounds the invention may be provided in a solid form, such as a tablet or capsule, or as a solution, émulsion, or suspension. To préparé the oral compositions, the compounds ofthe invention may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnésium stéarate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include éthanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if présent, may be magnésium stéarate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
Capsules for oral administration include hard and soft gelatin capsules. To préparé hard gelatin capsules, active ingredient(s) may be mixed with a solid, semisolid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingrédient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
Liquids for oral administration may be in the form of suspensions, solutions, émulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stéarate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), 68 propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl phydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
For parentéral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents ofthe invention may be provided in stérile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonie sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to préparé an injectable formulation. Illustrative infusion doses range from about 1 to 1000 pg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
For nasal, inhaled, or oral administration, the inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier. The inventive compositions may be formulated for rectal administration as a suppository.
Fortopical applications, the compounds of the présent invention are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. Fortopical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents ofthe invention may utilize a patch formulation to effect transdermal delivery.
As used herein, the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or récurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing régression ofthe disorderordisease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
The term “subject” refers to a mammalian patient in need of such treatment, such as a human.
Exemplary diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation. Cancer includes, for example, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, rénal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma. Pain includes, for example, pain from any source or etiology, including cancer pain, pain from chemotherapeutic treatment, nerve pain, pain from injury, or other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, Type I diabètes, and lupus. Exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophie latéral sclerosis, and Huntington’s disease. Exemplary inflammatory diseases include atherosclerosis, allergy, and inflammation from infection or injury.
In one aspect, the compounds and pharmaceutical compositions ofthe invention specifîcally target receptor tyrosine kinases, in particular RET. In another aspect, the compounds and pharmaceutical compositions ofthe invention specifîcally target nonreceptor tyrosine kinases, in particular SRC. In yet another aspect, the compounds and pharmaceutical compositions of the invention specifîcally target receptor tyrosine kinases and non-receptor tyrosine kinases, such as RET and SRC, respectively. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of one or more of these kinases. In preferred embodiments, methods of treatment target cancer. In other embodiments, methods are for treating lung cancer or non-small cell lung cancer.
In the inhibitory methods ofthe invention, an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with abnormal signaling due to upregulation of RET and/or SRC.
In treatment methods according to the invention, an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of 70 administration or drug delivery, the pharmacokinetics ofthe agent, the severity and course ofthe infection, the subject’s health status, condition, and weight, and the judgment of the treating physician. An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
Once improvement ofthe patient’s disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function ofthe symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms hâve been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any récurrence of symptoms. Patients may also require chronic treatment on a long-term basis.
DRUG COMBINATIONS
The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingrédients in the treatment of the diseases and disorders described herein. Further additional active ingrédients include other therapeutics or agents that mitigate adverse effects of thérapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The additional active ingrédients may be administered in a separate pharmaceutical composition from a compound of the présent invention or may be included with a compound of the présent invention in a single pharmaceutical composition. The additional active ingrédients may be administered simultaneously with, prior to, or after administration of a compound of the présent invention.
Combination agents include additional active ingrédients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease. For example, compositions and formulations of the invention, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions. For cancer indications, additional such agents include, but are not limited to, kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), ALK inhibitors (e.g., crizotinib) standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone thérapies, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatories such as NSAIDs. The pharmaceutical compositions ofthe invention may additionally comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.
CHEMICAL SYNTHESIS
Exemplary Chemical entities useful in methods of the description will now be described by reference to illustrative synthetic schemes for their general préparation below and the spécifie examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or désirable to employ, in the place ofthe ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups.
Abbreviations: The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art:
g | grams |
eq | équivalents |
mmol | millimoles |
mL | milliliters |
EtOAc | ethyl acetate |
MHz | mégahertz |
ppm | parts per million |
δ | Chemical shift |
s | singlet |
d | doublet |
t | triplet |
q | quartet |
quin | quintet |
br | broad |
m | multiplet |
Hz | hertz |
THF | tetrahydrofuran |
°C | degrees Celsius |
PE | Petroleum ether |
EA | ethyl acetate |
Rf | retardation factor |
N | normal |
J | coupling constant |
DMSO-c/6 | deuterated dimethyl sulfoxide |
n-BuOH | n-butanol |
DIEA | n,n-diisopropylethylamine |
TMSCI | trimethylsilyl chloride |
min | minutes |
hr | hours |
Me | methyl |
Et | ethyl |
i-Pr | iso propyl |
TLC | thin layer chromatography |
M | molar |
Compd# | compound number |
MS | mass spectrum |
m/z | mass-to-charge ratio |
Ms | methanesulfonyl |
FDPP | pentafluorophenyl diphenylphosphinate |
Boc | tert-butyloxycarbonyl |
TFA | trifluoroacetic acid |
Tos | toluenesulfonyl |
DMAP | 4-(dimethylamino)pyridine |
μΜ | micromolar |
ATP | adenosine triphosphate |
IC50 | half maximal inhibitory concentration |
U/mL | units of activity per milliliter |
KHMDS | potassium bis(trimethylsilyl)amide |
DIAD | diisopropyl azodicarboxylate |
MeTHF | 2-methyltetrahydrofuran |
MOM | methoxymethyl |
DCM | dichloromethane |
DMF | A/,A/-dimethylformamide |
DPPA | diphenyl phosphoryl azide |
DBU | 1,8-diazabicyclo[5.4.0]undec-7-ene |
DIPEA | A/,A/-diisopropylethylamine |
TBAF | Tetrabutylammonium Fluoride |
TEA | Triethylamine |
TBS | Tert-butyldimethylsilyl |
General Method A.
Préparation of teri-butyl {(2S)-2-[4-fluoro-2-({[(1R,2S)-2hydroxycyclopentyl]amino}methyl)phenoxy]propyl}carbamate (A-1 )
Step 1. To an azeotrope dried mixture of A-1-1 (0.9615 g, 5.65 mmol) and A-11A (1.19 g, 6.78 mmol) in DCM (3.62 mL) was added PPh3 (2.22 g, 8.48 mmol) The mixture was stirred until everything dissolved. DIAD (1.83 g, 9.04 mmol, 1.78 mL) was added very slowly with mixing at 0 °C. The reaction was warmed to 25 °C and stirred for 16 hr. DCM (5 mL) and 2M NaOH solution (20 mL) were added and stirred vigorously for 4 hours. The mixture was extracted with DCM (3x15 mL), dried with Na2SO4 and concentrated under reduced pressure. Flash chromatography (ISCO system, silica 12 g, 0-30% ethyl acetate in hexane) provided A-1-2 (1.35 g, 73%).
Step 2. To a solution of A-1-2 (1.35 g, 4.13 mmol) in THF (8.27 mL) at 0 °C was added lithium borohydride (720.51 mg, 33.08 mmol) in small batches and the mixture was stirred for 1 hr and was removed from the cold bath. The mixture stirred at ambient température for 20 hr, then diluted with water (5mL) and extracted with ethyl acetate (3 x 5mL). The combined organic phase was washed with brine and dried over sodium sulfate. Flash column chromatography (ISCO, silica, 24g, ethyl acetate in hexanes) afforded A-1-3 (1.08 g, 3.60 mmol, 87.09% yield).
Step 3. DMSO (422.82 mg, 5.41 mmol, 384.38 uL) in DCM (6 mL) was added dropwise at -78 °C to oxalyl chloride (686.85 mg, 5.41 mmol, 464.09 uL) in DCM (6 mL). The mixture was stirred for 20 minutes and A-1 -3 (1.08 g, 3.61 mmol) in DCM (6 mL) was added dropwise at -78 °C and stirred for 20 minutes followed by addition of TEA (1.83 g, 18.04 mmol, 2.51 mL). The mixture was stirred as température 74 increased to ambient température over 18 h. The reaction was quenched with water (10 mL) and the layers were separated. The aqueous layer was extracted twice more with DCM (2x10 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash chromatography (ISCO, 24 g Silica Gold, 0-30% ethyl acetate in hexanes) afforded A-1-4 (460.2 mg, 1.55 mmol, 42.90% yield).
Step 4. A solution of (1S,2F?)-2-aminocyclopentanol HCl sait (69 mg, 504 pmol), Hunig’s Base (196 mg, 0.26 mL, 1.5 mmol) and A-1 -4 (150.00 mg, 504 pmol) in dry MeOH (2.50 mL) was heated to 65 °C for 1 hr. The reaction was cooled to room température and NaBH4 (38 mg, 1.0 mmol) was added. The mixture was stirred for 2 hr then quenched with water (3 mL) and stirred for 5 min. The mixture was extracted with DCM (3x5 mL), dried with Na2SO4and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 25-50% ethyl acetate in hexane) provided A-1 (125.3 mg, 327 pmol, 64.9% yield).
Compound A-2 was prepared according to General Method A using (1R,2R)-2aminocyclopentanol in step 4.
General Method B.
Préparation of terf-butyl {(2S)-2-[2,4-difluoro-6-({[(1R,2S)-2hydroxycyclopentyl]amino}methyl)phenoxy]propyl}carbamate (A-3)
Step 1. Added K2CO3 (330.00 mg, 2.39 mmol) to A-3-1 (151 mg, 955.08 pmol) and A-3-1 A (283.27 mg, 1.19 mmol) in DMF (4.78 mL) and heated to 50 °C with stirring for 1 hr. The mixture was cooled and diluted with DCM (3 mL), filtered through a syringe filter and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 0-30% ethyl acetate in hexane) provide A-3-2 (301 mg, 954 pmol, 99% yield).
Step 4. A solution of (1 S,2/?)-2-aminocyclopentanol HCl sait (104 mg, 0.76 pmol) and A-3-2 (200 mg, 634 pmol) in dry MeOH (3.17 mL) was heated to 65 °C for 1 75 hour. The reaction was cooled to room température and NaBH4 (72 mg, 1.9 mmol) was added. The mixture was stirred for 2 hours then quenched with water (5 mL) and stirred for 5 min. The mixture was extracted with DCM (3x15 mL), dried with Na2SO4and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 0-20% methanol in dichloromethane) provided A-3 (108 mg, 270 pmol, 42% yield).
Compound A-4 was prepared according to General Method A using (3RAR)-4aminotetrahydrofuran-3-ol in step 4.
Compound A-5 was prepared according to General Method A using 5-Fluoro-210 methoxynicotinaldehyde in step 4.
Compound A-6 was prepared according to General Method A using rac c/s-tertbutyl-3-amino-4-hydroxypyrrolidine-1 -carboxylate and 5-Fluoro-2methoxynicotinaldehyde.
Compd # | Structure | MS [M+H] m/z |
A-1 | y T NHBoc ρ'^'^η ΗΝχOH o | 383.2 |
A-2 | y T NHBoc Ρ^^^η ΗΝχOH X/ | 383.2 |
A-3 | F ! jf T NHBoc ρ'^^η HN OH U | 401.2 |
General Method C.
Préparation of ethyl 6-bromo-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (B-
Br2, AcOH
Step 1. To a solution of B-1-1 (10.00 g, 47.80 mmol, 1.00 eq.) in acetic acid (100.00 mL) was added bromine (7.64 g, 47.80 mmol, 2.46 mL, 1.00 eq.). The mixture was stirred at 180 °C for 6 hr. TLC (petroleum ether/ethyl acetate=1/1) showed the starting material was consumed completely and one new spot was found. The mixture was quenched by water (30 mL). The mixture was filtered and the cake was concentrated to give B-1-2 (10.00 g, 34.71 mmol, 72.62% yield) as a white solid: 1H NMR (400MHz, DMSO-d6) δ: 12.34 (br. s., 1H), 9.25 (s, 1H), 8.15 (s, 1H), 4.28 (q, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).
Step 2. To a solution of B-1-2 (6.00 g, 20.97 mmol, 1.00 eq.) in phosphorus oxychloride (60 mL). The mixture was stirred at 120 °C for 16 hr. TLC (petroleum ether/ethyl acetate=3/1) indicated the starting material was consumed completely and one new spot was found. 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=10/1 to 1/1) to give B-1 (2.50 g, 8.21 mmol, 39.15% yield) as a white solid; 1H NMR (400 MHz, CDCI3) δ: 8.94 (s, 1 H), 8.54 (s, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).
General Method D.
Préparation of (3a/?,11S,20aS)-7-fluoro-11-methyl-2,3,3a,12,13,20a-hexahydro1 /-/,5/-/-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4-/]pyrazolo[4,3d[1,4,8,10]benzoxatriazacyclotridecin-14(11 H)-one (1 )
1. LiOH H2O/THF/MeOH
2. HCI/Et2O DCM
3. FDPP/DIEA DMF/DCM
Step 1. To a solution of B-1 (325 mg, 1.07 mmol) and A-1 (408 mg, 1.07 mmol) in n-BuOH (5.3 mL) was added Hunig's base (689 mg, 5.3 mmol, 929 pL). The mixture was heated to 90 °C for 15 hr. The reaction was cooled and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 10-50% ethyl acetate in hexane) provided 1-1 (197.7 mg, 303 pmol, 28% yield).
Step 2. To a solution of 1-1 (36.6 mg, 48.5 pmol) in DMF (3 mL) was added KOtPent (1.7 M, 86 pL) in toluene. The reaction stirred at room température for 1.5 hours.
The reaction was cooled to -20 °C and quenched with saturated NH4CI sol. (5 mL) then extracted with DCM (3x10 mL). Combined extracts were dried with Na2SO4and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 10-35% ethyl acetate in hexane) provided 1-2 (12.8 mg, 22 pmol, 46% yield).
Step 3. To a solution of 1-2 (12.8 mg, 22 pmol) in MeOH (3 mL) and THF (1 mL) at ambient température was added aqueous LiOH solution (2.0 M, 1.0 mL). The mixture was heated at 60 °C for 17 hr, cooled to -20 °C then quenched with aqueous HCl solution (2.0 M) to acidic. The mixture was extracted with DCM (3x5 mL), dried with Na2SO4, concentrated under reduced pressure, and dried under high vacuum. The crude material was dissolved in DCM (4 mL) followed by addition of HCl in 1,4-dioxane (4 M, 3 mL). The mixture was stirred at ambient température for 1.5 hr, concentrated under reduced pressure, and dried under high vacuum. The crude material was dissolved in in DMF (2.0 mL) and DCM (4.0 mL) and Hünig’s base (185 mg, 1.4 mmol, 250 pL) then FDPP (34.5 mg, 89 pmol) was added in one portion. The reaction was stirred for 1.5 hours then quenched with 2 M Na2CO3 solution (5 mL). The mixture was stirred for 5 min then extracted with DCM (4x10 mL). Combined extracts were dried with Na2SO4 and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 0-5% methanol in dichloromethane) provided 1 (8.13 mg, 19 pmol, 85% yield).
Compounds 2 through 4 were prepared according to General Method D using A2 through A-4 in step 1 respectively.
General Method E.
Préparation of (3aR,11S,20aS)-7-fluoro-11-methyl-2,3,3a,12,13,20a-hexahydro1/-/,5/-/-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4-/]pyrazolo[4,3-f]pyrido[3,2/][1,4,8,10]oxatriazacyclotridecin-14(11/-/)-one (5)
5-4 5
Step 1. To a solution of B-1 (454 mg, 1.49 mmol) and A-5 (358 mg, 1.49 mmol) in t-BuOH (5.0 mL) was added Hunig's base (963 mg, 7.45 mmol, 1.30 mL). The mixture was heated to 105 °C for 17 hr. The reaction was cooled and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 10-40% ethyl acetate in hexane) provided 5-1 (292 mg, 38% yield).
Step 2. To a solution of 5-1 (18.8 mg, 37 pmol) in DMF (3 mL) was added KOtPent (1.7 M, 65 pL) in toluene. The reaction stirred at room température for 20 hours. The reaction was cooled to -20 °C and quenched with saturated NH4CI sol. (5 mL) then extracted with DCM (3x10 mL). Combined extracts were dried with Na2SO4and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 0-5% methanol in dichloromethane) provided 5-2 (6.2 mg, 39% yield).
Step 3. To a solution of 5-2 (6.2 mg, 14.5 pmol) in EtOH (4 mL) was added aqueous HCl solution (4.0 M, 3.0 mL) in 1,4-dioxane. The mixture was heated at 70 °C for 6 hours. The mixture was cooled, concentrated under reduced pressure, and dried under high vacuum to provide crude 5-3. Compound was used as is.
Step 4. Added K2CO3 (14.0 mg, 101 pmol) to 5-3 (6.2 mg, 14.5 pmol) and A-3-1A (17 mg, 73 pmol) in DMF (250 pL) and stirred for 2 hours. The mixture was cooled and 80 quenched with water (5 mL) then extracted with DCM (3x10 mL). Combined extracts were dried with Na2SO4and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 20-100% ethyl acetate in hexane) provide 5-4 (6.1 mg, 73% yield).
Step 5. To a solution of 5-4 (6.1 mg, 10.7 pmol) in MeOH (3 mL) and THF (1 mL) at ambient température was added aqueous LiOH solution (2.0 M, 1.0 mL). The mixture was heated at 60 °C for 16 hr, cooled to -20 °C then quenched with aqueous HCl solution (2.0 M) to acidic. The mixture was extracted with DCM (3x5 mL), dried with Na2SO4, concentrated under reduced pressure, and dried under high vacuum. The crude material was dissolved in DCM (4 mL) followed by addition of HCl in 1,4-dioxane (4 M, 3 mL). The mixture was stirred at ambient température for 2 hours, concentrated under reduced pressure, and dried under high vacuum. The crude material was dissolved in in DMF (2.0 mL) and DCM (4.0 mL) and Hünig’s base (185 mg, 1.4 mmol, 250 pL) then FDPP (34.5 mg, 89 pmol) was added in one portion. The reaction was stirred for 1 hour then quenched with 2 M Na2CO3 solution (5 mL). The mixture was stirred for 5 min then extracted with DCM (4x10 mL). Combined extracts were dried with Na2SO4 and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 0-5% methanol in dichloromethane) provided 5 (3.21 mg, 71% yield).
Compound 6 was prepared according to General Method E using (F?)-3-Boc-4methyl-2,2-dioxo-[1,2,3]oxathiazolidine in step 4.
General Method F.
Préparation of ethyl (5aF?,8aS)-5,5a,6,7,8,8a-hexahydrocyclopenta[b]pyrazolo [1 ',5':1,2]pyrimido[4,5-e][1,4]oxazine-3-carboxylate (C-1 )
Step 1. To a solution of C-1-1 (5.0 g, 28.1 mmol, 1 eq.) and C-1-2 (6.1 g, 39.3 mmol, 1.4 eq.) in EtOH (56 mL) at 90 °C was added NaOEt (2.68 M, 26.2 mL, 2.5 eq.) and was stirred for 6 hours. The reaction mixture cooled and diluted with Toluene (60 5 mL) and concentrated to dryness under reduced pressure. The material was resuspended in Toluene (60 mL) and again concentrated to dryness and placed on a high vac overnight to provide crude C-1-3. Crude material was used as is in next step.
Step 2. The crude C-1-3 from step 1 was suspended in POCI3 (99 g, 60 mL, 646 mmol, 23.00 eq.) and heated to 100 °C for 24 hours. The reaction was cooled to room 10 température and concentrated to dryness under reduced pressure. The crude material was suspended in DCM (100 mL) and water (100 mL) was added. The mixture was stirred for 30 min then extracted with DCM (3 x 100 mL). The combined organic extracts were washed by brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification through a Silica plug (60 g Si), eluted 15 with DCM (~1.5 L) gave C-1-4 (5.68 g, 72% yield, purity = 86% by LC/MS) as a yellow solid.
Step 3. To a solution of C-1-4 (5.68 g, 20.4 mmol) and NH4CI (5.46 g, 102 mmol) in THF (68 mL), EtOH (204 mL) and water (136 mL) at 0 °C was added Zn powder (5.34 g, 81.7 mmol). The mixture was stirred at 0 °C for 3 hours. The reaction mixture was 20 filtered through a celite pad and the celite pad was rinsed with DCM (100 mL). The filtrate was concentrated to dryness under reduced pressure then resuspended in DCM (500 mL) dried with Na2SO4and concentrated under reduced pressure. Purification using a silica plug (50 g Si) and elution with DCM provided C-1-5 (3.17 g, 63.8% yield) as a white solid.
Step 4. To a solution of C-1-5 (1.74 g, 7.1 mmol) and the HCl sait of (1 S,2R)-2aminocyclopentanol (1.08 g, 7.8 mmol) in EtOH (14 mL) was added DIEA (4.6 g, 6.2 mL 35.6 mmol). The mixture was heated to 80 °C for 1 hour. The reaction cooled and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (40 5 g), 20-80% ethyl acetate in hexane) provided C-1-6 (2.13 g, 97% yield) as a white solid.
Step 5. To a solution of C-1-6 (1.0 g, 3.24 mmol) in DMSO (162 mL) was added Cs2CO3 (9.51 g, 29 mmol). The mixture was heated to 100 °C and stirred for 91 hours. The reaction mixture was cooled and quenched with 30% brine solution (700 mL) then extracted with ethyl acetate (4 x 200 mL). Combined extracts were washed with 15% 10 brine solution (2 x 250 mL). Brine solutions were back extracted with ethyl acetate (1 x 250 mL). Organic extracts were combined and dried with brine (250 mL), Na2SO4 and concentrated under reduced pressure to provide C-1 (803 mg, 86% yield, 97% purity by LC/MS) as a light-yellow solid.
Compounds C-2, C-3, and C-4 were prepared according to General Method F 15 using rac c/s-2-aminocyclobutanol, (1 S,2/?)-2-aminocyclohexanol, and rac c/s-4aminooxolan-3-ol, respectively in step 4.
Compd # | Structure | MS [M+H] m/z |
C-1 | H COOEt Wvw | 289.0 |
C-2 | H COOEt | 275.0 |
C-3 | H COOEt αχό | 303.0 |
General Method G.
Préparation of terf-butyl {(2/?)-1-[2-(chloromethyl)-4,6-difluorophenoxy]propan-2yl}carbamate (D-1)
Step 1. To a solution of D-1-1 (200 mg, 1.27 mmol) and D-1-1A (315 mg, 1.33 mmol) in DMF (6.3 mL) was added K2CO3 (437 mg, 3.2 mmol) The reaction was stirred for 2 hours then quenched with citric acid solution (1 M in H2O, 6 mL) was added and the mixture was vigorously stirred for 30 minutes. The mixture was extracted with DCM (3x10 mL) and combined organic extracts were collected and dried over Na2SO4, filtered and concentrated under reduced pressure and high vacuum to afforded desired product D-1-2 (theoretical yield 399 mg). Compound was used as is.
Step 2. To a solution of D-1-2 (399 mg (theoretical), 1.27 mmol) in dry THF (15 mL) was added LiBH4 (193 mg, 8.86 mmol). The mixture was stirred for 20 hours then quenched with water (25 mL) and stirred for 5 min. The mixture was extracted with DCM (3x15 mL), dried with Na2SO4and concentrated under reduced pressure. Flash 84 chromatography (ISCO system, silica (24 g), 0-50% ethyl acetate in hexane) provided D-1-3 (33.2 mg, 8% yield).
Step 3. To a solution of D-1-3 (33.2 mg, 105 pmol) and DIPEA (67.6 mg, 91 pL, 523 pmol) in DCM (525 pL) at 0 °C was added MsCI (15 mg, 10 pL 131 pmol) dropwise. The mixture stirred at 0 °C for 1 hour. The reaction was quenched with water (3 mL) and 2M HCl (100 pL) then extracted with DCM (3x5 mL). The organic phases were combined, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 0-50% ethyl acetate in hexane) provided a mixture of D-1 and D-1A (40.2 mg, 91% yield).
General Method H.
Préparation of (S)-(2-((1 -((tert-butoxycarbonyl)amino)propan-2-yl)oxy)-5fluoropyridin-3-yl)methyl methanesulfonate (D-2)
D-2-3
MsCI
DIPEA DCM
A-3-1A
CS2CO3
NMP
D-2-2
D-2
D-2A
Step 1. D-2-1 (7 g, 45.12 mmol) and pyridine hydrochloride (20.86 g, 180.5 mmol) were mixed in a round bottom flask and heated up to 145°C and the molten mixture was stirred at 145°C for 30 min then cooled down. The mixture was diluted with H2O (200 mL) and ethyl acetate (200 mL), partitioned and the aqueous layer was extracted with EA (5 x 100 mL), organic phases were combined and dried over Na2SO4, the solution was then concentrated under reduced pressure to afford desired product D2-1 (5.19 g, 36.78 mmol, 81.51% yield) as yellow solid.
Step 2. To an ice-bathed mixture of compound D-2-1 (2.37 mg, 16.79 mmol) and Cs2CO3 (21.88 g, 67.15 mmol in NMP (33.57 mL) was added compound A-3-1A (4 g,
16.79 mmol), the reaction was stirred at 0°C for 2 hours. The reaction was diluted with dichloromethane (200 mL) and H2O (100 mL). Citric acid solution (1 M in H2O, 100 mL) was added and the mixture was vigorously stirred for 10 minutes, layers were separated, organic layer was collected and dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (ISCO system, silica (80 g), 0-30% ethyl acetate in hexanes) afforded desired product D-2-2 (4.2 g, 14.06 mmol, 83.79% yield) as white solid.
Step 3. To an ice-bathed solution of compound D-2-2 (4.2 g, 14.06 mmol) in MeOH (46.88 mL) was added NaBH4 (798.17mg, 21.10 mmol). The reaction was stirred under 0 °C for 1 hour. The reaction was quenched with H2O (100 mL) and was extracted with dichloromethane (3 χ 100 mL). The organic phases were combined and dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (ISCO system, silica (80 g), 0-50% ethyl acetate in hexanes) afforded desired product D-2-3 (3.46 g, 11.53 mmol, 81.96% yield) as colorless oil.
Step 4. To a solution of D-2-3 (2.41 g, 8.02 mmol) and the DIPEA (4.15 g, 5.6 mL, 32.1 mmol) in DCM (14 mL) at 0 °C was added MsCI (1.10 g, 0.74 mL 9.62 mmol) dropwise. The mixture stirred at 0 °C for 2 hours. The was quenched with 1 % HCl solution (100 mL) and extracted with DCM (3 χ 100 mL). The organic phases were combined, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (80 g), 0-40% ethyl acetate in hexane) provided D-2 (2.0 g, 66% yield) as a white solid and D-2A (627 mg, 24% yield) as an oil.
Compound D-3 was prepared according to General Method H using (F?)-3-boc-4methyl-2,2-dioxo-[1,2,3]oxathiazolidine in step 2.
Compd # | Structure | MS [M+Na] m/z |
D-1 | N HBoc F | 418.1 |
D-2 | N HBoc N'^^Y^OMs H J F | 401.1 |
General Method I.
Préparation of (3a/?,12/?,20aS)-7,9-difluoro-12-methyl-2,3,3a,12,13,20ahexahydro-1 /-/,5/-/-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4-/]pyrazolo[4,3f|[1,4,8,10]benzoxatriazacyclotridecin-14(11/7)-one (7)
D-2
3. FDPP/DIEA DMF/DCM
1. LiOH H2O/THF/MeOH 2. HCI/Et2O DCM
Step 1. To a solution of C-1 (30 mg, 104 pmol) and D-1 (41 mg, 104 pmol) in DMF (1 mL) was added CS2CO3 (102 mg, 312 pmol). The reaction was stirred at room température for 4 hours. The reaction was cooled, diluted with DCM (3 mL), filtered through a syringe filter and concentrated under reduced pressure. Flash chromatography (ISCO System, silica (12 g), 0-50% ethyl acetate in hexane) provided 7-1 (61 mg, 100% yield).
Step 2. Compound 7-1 was converted to 7 following the procedure used in General Method E.
Compounds 8 and 9 were prepared according to General Method I using starting materials C-2 and D-2 in step 1 and seperating the stereoisomers after the last step.
Compounds 10 and 11 were prepared according to General Method I using starting materials C-2 and D-3 in step 1 and seperating the stereoisomers after the last step.
Compound 12 was prepared according to General Method I using starting materials C-3 and D-2 in step 1.
Compound 13 was prepared according to General Method I using starting materials C-3 and D-3 in step 1.
General Method J.
Préparation of (3aR,12/?,20aS)-12-cyclopropyl-7-fluoro-2,3,3a,12,13,20ahexahydro-1/-/,5/-/-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4-/]pyrazolo[4,3f]pyrido[3,2-/][1,4,8,10]oxatriazacyclotridecin-14(11/-/)-one (14)
14-1
NH2 NHBoc hci r Χγ° BoC2°
MeOH OMe NaHCO3 v Q^e
14-2 THF 14-3
NHBoc
14-4
SOCI2
Imidazole -----»
DCM
NalO4
RuCI3*3H2O ----►
DCM:MeCN:H2O
LiBH4
THF
3. FDPP/DIEA DMF/DCM
1. LiOH H2O/THF/MeOH
2. HCI/Et2O DCM
Step 1. To a solution of 14-1 (1.0 g, 8.69 mmol) in dry MeOH (87 mL) was added HCl (4.0 M, 4.3 mL, 2.0 eq.) in dioxane. The mixture was heated to 70 °C and stirred for 40 hours. The reaction mixture cooled and concentrated to dryness under reduced pressure to provide crude 14-2. The material was used as is in next step.
Step 2. To a solution of crude 14-2 from step 1 in THF (60 mL) was added Boc2O (2.08 g, 9.54 mmol) and NaHCO3 solution (1 M, 34.69 mL). The reaction was stirred for 4 hours then diluted with water (50 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed by brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (40 g), 0-50% ethyl acetate in hexane) provided 14-3 (1.66 g, 83% yield).
Step 3. To a solution of 14-3 (1.66 g, 7.24 mmol) in THF (36 mL) at 0 °C was added LiBH4 (789 mg, 36 mmol). The mixture was slowly warmed to room température and stirred for 20 hours. The reaction mixture was quenched by addition of water (20 mL) and aqueous saturated NH4CI (25 mL) then extracted with ethyl acetate (3 x 50 mL). Combined extracts were dried with brine (50 mL), Na2SO4 and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (40 g), 10-40% ethyl acetate in hexane) provide 14-4 (1.23 g, 84% yield).
Step 4. To a solution of Imidazole (1.0 g, 14.9 mmol) in DCM (16 mL) at -5 °C was added SOCI2 (532 mg, 4.47 mmol, 324 pL) in DCM (5 mL) dropwise. The mixture was stirred at -5 °C for 1 hour. The mixture was cooled to -10 °C and 14-4 (0.5 g, 2.48 mmol) in DCM (4 mL) was added dropwise. The mixture was slowly warmed to 10 °C and stirred at this température for 2 hr. The reaction was quenched with water (10 mL) and stirred at 10 °C for 10 min. The organic layer was removed and washed with 10% citric acid solution (10 mL) then dried with brine (5 mL) and Na2SO4 and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (24 g), 0-20% ethyl acetate in hexane) provide 14-5 (294 mg, 48% yield).
Step 5. To a solution of 14-5 (294 mg, 1.19 mmol) in DCM (5.66 mL) and NalO4 (610.25 mg, 2.85 mmol) in H2O (5.66 mL) at 0 °C was added RuCl3*3H2O (6.2 mg, 24 pmol). The reaction was warmed to room température and stirred for 1 hour. The reaction was quenched with water (15 mL) then extracted with DCM (3x15 mL). Combined extracts were dried with brine (5 mL), Na2SO4and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 0-30% ethyl acetate in hexane) provide 14-6 (308 mg, 98% yield).
Step 6. To a solution of 5-3 (40 mg, 97 pmol) and 14-6 (32 mg, 121 pmol) in DMF (484 pL) was added CS2CO3 (95 mg, 290 pmol). The reaction mixture was stirred for 1 hour then diluted with DCM (5 mL) and filtered through syringe filter then stirred with 20% citric acid solution (10 mL) for 30 min. The mixture was extracted with DCM (3x15 mL) and combined extracts dried with Na2SO4 and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 10-50% ethyl acetate in hexane) provide 14-7 (45.6 mg, 79% yield).
Step 7. Compound 14-7 was converted to 14 following the procedure used in General Method E.
General Method K.
Préparation of (3a/?,11 S,21 aS)-7-fluoro-11 -methyl-2,3,3a,11,12,13,14,21aoctahydro-1 Η,δΗ,Ί 5/7-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4h]pyrido[2,3-ô][1,5,7,11]oxatriazacyclotetradecin-15-one (15)
15-1-1A
PPh3
DIAD
NHBoc
DCM
3. FDPP/DIEA DMF/DCM
1. LiOH H2O/THF/MeOH 2. HCI/Et2O DCM
Step 1. To a solution of 5-3 (50 mg, 121 pmol), 15-1-1A (27.5 mg, 145 pmol) and PPh3 (41 mg, 157 pmol) in DCM (194 pL) at 0 °C was added DIAD (41 mg, 157 pmol). The mixture was warmed to room température and stirred for 16 hours. The reaction cooled and diluted with DCM. The solution was filtered and the filtrate was concentrated under reduced pressure. Flash column chromatography (ISCO, silica, a12g, ethyl acetate in hexanes) to afford 15-1 (58.8 mg, 83% yield)
Step 2. Compound 15-1 was converted to 15 following the procedure used in General Method E.
Compounds 16 and 17 were prepared according to General Method K.
Compound 18 was prepared according to General Method J.
General Method L.
Préparation of (3a/?,21 aS)-7-fluoro-2,3,3a,11,12,13,14,21a-octahydro1/7,5/7,15/7-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-/?]pyrido[2,3£>][1,5,7,11]oxatriazacyclotetradecin-15-one (19)
3. FDPP/DIEA DMF/DCM
1. LiOH H2O/THF/MeOH
2. HCI/Et2O DCM
Step 1. To a solution of 5-3 (40 mg, 97 pmol) and 19-1-1A (23 mg, 116 pmol) in DMF (300 uL) was added K2CO3 (27 mg, 194 pmol). The mixture was mixture was stirred at room température for 16 hr. The reaction cooled and diluted with DCM (5 mL). The solution was filtered and the filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography (ISCO, silica, 12g, ethyl acetate in hexanes) to afford 15 (18.9 mg, 34% yield).
Step 2. Compound 19-1 was converted to 19 following the procedure used in General Method E.
Compound 20 was prepared according to General MethodK.
Compound 21 and 22 were prepared according to General MethodJ.
Compound 23 and 24 were prepared according to General MethodK.
Compound 25 and 26 were prepared according to General MethodJ.
Compound 27, 28, and 29 were prepared according to General Method K.
Compound 30 and 31 were prepared according to General Method I using starting materials D-2A and C-4 in step 1 and separating the stereoisomers after the last step by flash column chromatography (ISCO, reverse phase C-18, 50g, acetonitrile in water with 0.035% TFA).
General Method M.
Préparation of (3a/?,12S,21aS)-7-fluoro-12-hydroxy-2,3,3a,11,12,13,14,21aoctahydro-1 /7,5/7,15/7-18,20-(metheno)cyclopenta[5,6][1 .,4]oxazino[4,3-e]pyrazolo[3,4h]pyrido[2,3-b][1,5,7,11]oxatriazacyclotetradecin-15-one (32) h2n
32-1
OH
OH
TEA, Boc2O --------* BocHN
MeOH
32-2
OH
OH
TBS-CI Imidazole
BocHN
OTBS
OH
32-3 cr 0'
DIEA
THF
DCM
BocHN
OTBS ^BAF Monohydrate
OMOM
32-4
BocHN
32-5
OH
OMOM
1. Imidazole, SOCI2;DCM
THF
2. RuCI3- 3H2O, NalO4 H2O/DCM/ACN
MOMO'
Boc
N '9
S=O .0
N„OH
N 5-3
K2CO3
DMF
32-6
COOEt
OMOM
3. FDPP/DIEA DMF/DCM
32-7
1. LiOH H2O/THF/MeOH
2. HCI/Et2O DCM
Step 1. To a solution of 32-1 (3.1 g, 34.03 mmol) and Boc anhydride (7.43 g, 34.03 mmol) in MeOH (68.05 mL) was added TEA (6.89 g, 68.05 mmol, 9.48 mL). The mixture was stirred at room température for 16 hr. The reaction was concentrated under reduced pressure and purified by flash column chromatography (ISCO, silica, 40g, methanol in dichloromethane) to afford 32-2 (6.36 g, 33.26 mmol, 97.75% yield).
Step 2. 32-2 (6.36 g, 33.26 mmol) and imidazole (4.53 g, 66.52 mmol) were dissolved in THF (110.86 mL) and TBS chloride (6.02 g, 39.91 mmol) was added. The mixture was stirred for 2 hr then diluted with water (200 mL) and extracted with DCM (3 x 200 mL). The combined organic phase was washed with brine (200mL) and dried over Na2SO4. The solution was filtered and the filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography (ISCO System, silica, 80g, 040% ethyl acetate in hexanes) to afford 32-3 (8.75 g, 28.64 mmol, 86.12% yield).
Step 3. To a solution of 32-3 (8.75 g, 28.64 mmol) and DIEA (11.11 g, 85.93 mmol, 14.97 mL) in DCM (95.48 mL) at 0°C was added MOM chloride (3.46 g, 42.96 mmol, 3.26 mL) slowly. The mixture was stirred for 16 hr. warming to ambient température. The reaction was quenched with water (100 mL) and extracted with DCM (3 x 100 mL). The combined extracts were dried over Na2SO4. The crude was purified by flash column chromatography (ISCO, silica, 80g, 0-30% ethyl acetate in hexanes) to afford 32-4 (7.44 g, 21.29 mmol, 74.31% yield).
Step 4. To a solution of 32-4 (7.44 g, 21.29 mmol) in THF (106.43 mL) was added TBAF Monohydrate (11.90 g, 42.57 mmol). The mixture was stirred for 1 hr. then quenched with saturated aqueous NH4CI solution (10 mL) and diluted with DCM (100mL). The mixture was dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure and the crude was purified by flash column chromatography (ISCO, silica, 80 g, ethyl acetate in hexanes) to afford 32-5 (4.67 g, 19.85 mmol, 93.25% yield).
Compound 32 was prepared following General Method J from 32-5 in step 4 and 5-3 in step 6.
General Procedure N.
Préparation of (3aR,21aS)-7-fluoro-12,12-dihydroxy-2,3,3a,11,12,13,14,21aoctahydro-1 /-/,5/-/,15/-/-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4/7]pyrido[2,3-b][1,5,7,11]oxatriazacyclotetradecin-15-one (33)
To a solution of 32 (13.8 mg, 31.33 umol) in DCM (626.66 uL) was added DessMartin Periodinane (26.58 mg, 62.67 umol). The mixture was stirred at room température for 2 hr and quenched with saturated NaHCO3 solution (5 mL). The mixture was extracted with DCM (3x5mL) and the organic layers dried over Na2SO4. The salts were filtered and the filtrate concentrated under reduced pressure. The crude was purified by flash column chromatography (ISCO, silica, 12g, methanol in dichloromethane) and resuit mixture of products was stirred in acetonitrile (1mL) with drops of 2M HCl (2 drops), diluted with 2M sodium carbonate and extracted with dichloromethane (3x5mL) to provide compound 33 (9.1 mg, 19.94 pmol, 64% yield).
Compound 34 and 35 were prepared according to General Method K. General Method O.
Préparation of (3a/?,13/?,21aS)-7-fluoro-13-methyl-2,3,3a,11,12,13,14,21aoctahydro-1 Η,5Η,Ί 5/-/-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4h]pyrido[2,3-b][1,5,7,11]oxatriazacyclotetradecin-15-one (36) and (3aS,11S,20a/?)-2acetyl-7-fluoro-11-methyl-2,3,3a,12,13,20a-hexahydro-1/-/,5/-/-17,19(metheno)pyrazolo[4,3-f]pyrido[3,2-l]pyrrolo[3',4':5,6][1,4]oxazino[3,4/][1,4,8,10]oxatriazacyclotridecin-14(11/-/)-one (37)
Step 1. To a solution of A-6 (255.4 mg, 748.15 umol, racemic mix) dissolved in anhydrous isopropanol (3.74 mL) at room température. DIEA (290.08 mg, 2.24 mmol, 390.94 uL) was added followed by C-1-5 (200.49 mg, 822.96 umol). The mixture stirred 5 at 80 °C for 18 hr and then concentrated under reduced pressure. The crude was purified by flash column chromatography (ISCO, silica, 12g, ethyl acetate in hexanes) to afford 36-1 (142.1 mg, 259.05 umol, 34.63% yield).
Step 2. To a solution of 36-1 (142.1 mg, 259.05 umol) in DMSO (1.30 mL) at room température, Cs2CO3 (168.81 mg, 518.10 umol) was added and the mixture was 10 stirred at room température for 72 hr. Diluted with water (15mL) and extracted with DCM (5mL x 5). The organic layer was back washed with water (1 OmL) and brine (1 OmL), then dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography (ISCO, silica, 12g, ethyl acetate in hexanes) to afford 36-2 (78.1 mg, 15 147.77 umol, 57.04% yield).
To a solution of 36-2 (20.5 mg, 38.79 umol) in anhydrous DCM (2 mL) was added HCl in dioxane (4 M, 1 mL). The mixture was stirred at ambient température for 1 hr, concentrated under reduced pressure, and dried under high vacuum to afford 36-3. Used directly in subséquent step without further purification.
To crude 36-3 (14.5 mg, 33.85 umol) in DCM (338.46 uL) was added acetic acid (3.05 mg, 50.77 umol, 2.90 uL) and Hunig's base (21.87 mg, 169.23 umol, 29.48 uL) followed by FDPP (16.91 mg, 44.00 umol) in one portion. Let stir for 72 hr then quenched with 2 M Na2COs solution (5 mL). Mixture was stirred for 5 min then extracted with DCM (3x10 mL). Combined organic extracts were dried with Na2SÛ4 and concentrated under reduced pressure. Flash chromatography (ISCO System, silica 12 g, methanol in dichloromethane) provide 36-4 (9.9 mg, 21.04 umol, 62.18% yield)
To a solution of 36-4 (9.9 mg, 21.04 umol) dissolved in anhydrous éthanol (1 mL) was added HCl in dioxane (4 M, 1 mL). The mixture was stirred at 70 °C for 2 hr, then concentrated under reduced pressure and dried under high vacuum to afford 36-5. Used directly in subséquent step without further purification.
36-5 was converted to compounds 36 and 37 as a racemic mixture (cis) following the procedure used in General Method E. The mixture was separated by flash column chromatography (ISCO, silica, 12g, methanol in DCM) to provide 36 (1.23 mg, 2.63 umol, 26.89% yield) and 37 (1.38 mg, 2.95 umol, 30.17% yield).
Compound 38, 39, 40, and 41 were prepared according to General Method K.
Compound 42 was prepared according to General Method K using rac trans-tertbutyl-3-hydroxycyclopentyl)carbamate and separating from 41 after final step by flash column chromatography (ISCO, silica, 12g, ethyl acetate in hexanes)
Compound 43 was prepared according to General Method M. Final product was purified by flash column chromatography (ISCO, silica, 12g, ethyl acetate in hexanes)
General Method P.
Préparation of ethyl (5aS,8a/?)-5,5a,6,7,8,8ahexahydrocyclopenta[b]pyrazolo[T,5':1,2]pyrimido[4,5-e][1,4]oxazine-3-carboxylate (C5)
COOEt
MeO
C-5-3
Step 1: (1R, 2S)-2-aminocyclopentanol, HCl (3.6 g, 26.16 mmol) was dissolved in anhydrous MeOH (96.89 mL) and treated with strongly basic ion exchange resin (Amberlite IRN-78). 4-methoxybenzaldehyde (3.56 g, 26.16 mmol) was added and the solution was stirred and heated to 65 °C for 3 hr. The mixture was cooled to room température and NaBH4 (989.68 mg, 26.16 mmol) was added. The reaction was stirred for 30 minutes, then quenched with water (50 mL) and stirred for another 30 minutes. MeOH was removed under reduced pressure and the aqueous phase was extracted with DCM (3 x 50mL). The organic phase was combined and dried over Na2SO4. The crude was purified by flash chromatography (ISCO system, 80g, 0-10% MeOH/DCM) to give C-5-1 (4.92 g, 22.23 mmol, 84.98% yield)
Step 2: C-5-1 (2.6 g, 11.75 mmol), C-1-5 (2.5 g, 10.26 mmol) and DIEA (4.56 g, 35.25 mmol, 6.14 mL) were dissolved in i-PA (58.75 mL). The mixture was stirred at 80 °C for 16 hr after which volatiles were removed under reduced pressure. The resulting crude was purified by flash column chromatography (ISCO, silica, 80g, 0-60% EtOAc in hexanes) to afford C-5-2 (2.1 g, 4.90 mmol, 41.72% yield).
Step 3: C-5-2 (2.1 g, 4.90 mmol) and Cs2CO3 (6.39 g, 19.61 mmol) were dissolved in DMSO (49.01 mL) and stirred at room température for 3 hr. Diluted with water (500mL) and extracted with EtOAc (3x100mL). The combined organic layer was washed with 20% brine solution (3x100mL) and dried over Na2SO4. The crude was purified by flash chromatography (ISCO, 80, 0-60% EtOAc in hexanes) to afford C-5-3 (1.69 g, 4.14 mmol, 84.42% yield).
C-5-3 (1.69 g, 4.14 mmol) was dissolved in TFA (41.38 mL) and stirred at 75°C for 16 hr, the reaction was cooled to room température and TFA was removed under reduced pressure. The residue was treated with Sat. NaHCO3 and EtOAc (100mL each) and separated. The aqueous layer was extracted again with EtOAc (2x 50mL) and the combined organic layer was dried over Na2SO4. The crude was purified by flash column chromatography (ISCO, silica, 80g, 0-80% EtOAc in Hexanes) to afford C-5 (1.12 g, 3.87 mmol, 93.47% yield)
Compounds C-6 and C-7 were prepared according to General Method P using (IR, 2/?)-2-aminocyclopentanol, HCl and (1S, 2S)-2-aminocyclopentanol, HCl respectively in step 1, and in high dilution (30 mM in DMSO) in step 3.
Compd # | Structure | MS [M+H] m/z |
C-5 | H COOEt | 289.1 |
C-6 | H COOEt | 289.1 |
C-7 | H COOEt ^O^^N | 289.1 |
Compound 44 was prepared according to General Method I using starting materials C-5 and D-2.
Compounds 45, 46, 47, and 48 was prepared according to General Method K.
General Method Q
Préparation of (3aR,11S,20aS)-7-fluoro-11-(hydroxymethyl)-2,3,3a,12,13,20ahexahydro-1 H,5H-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4-/]pyrazolo[4,3/]pyrido[3,2-/][1,4,8,10]oxatriazacyclotridecin-14(11/7)-one (49)
Step 1.49-1 (1.00 g, 13.50 mmol) was dissolved in THF (2.70 mL), water (2.70 mL) and methanol (21.60 mL). Ammonium chloride (1.66 g, 31.05 mmol) was added followed by sodium azide (4.39 g, 67.50 mmol). The mixture was stirred at 75 °C for 3 hr and then cooled to ambient température. Volume was carefully reduced under reduced pressure to a third and then diluted with DCM (50mL) and water (50mL). The layers were partitioned and the aqueous layer was extracted 2x with DCM (2x20mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (ISCO, 24g, silica, ethyl acetate in hexanes) gave 49-2 (450.00 mg, 3.84 mmol, 28.46% yield)
Step 2. 49-2 (450.00 mg, 3.84 mmol) was dissolved in THF (19.20 mL) and PPh3 (2.32 g, 8.83 mmol) was added. Stirred for 4hr and water (1.59 g, 88.32 mmol, 1.59 mL) was added and continued to stirfor 16hr when boc anhydride (1.09 g, 4.99 mmol) was added followed by sodium bicarbonate (32.26 mg, 384.00 umol). The mixture was stirred at RT for 4 hr and ethyl acetate and water were added (30 mL each). The layers were partitioned and the aqueous layer was extracted 2x with ethyl acetate (2x 20mL). The combined organic layer was washed with brine and then dried over sodium sulfate. Purified by flash column chromatography (ISCO, 24g, silica, EtOAc in Hexanes) to provide 49-3 (525.30 mg, 2.75 mmol, 71.54% yield).
Step 3. 49-3 (525.86 mg, 2.75 mmol) was dissolved in DCM (4.58 mL) and MOM-CI (332.10 mg, 4.13 mmol, 313.30 uL) was added followed by DIEA (710.82 mg, 5.50 mmol, 960.57 uL) at 0 °C. Stirred for 18 hr slowly warming to RT. Water (5mL) was 98 added and the layers were partitioned. The aqueous layer was extracted 2x with DCM (5mL). The combined organic layer was washed with brine and dried over sodium sulfate. Salts were filtered and volatiles were carefully removed via rotary évaporation at températures < 30 °C to afford 49-4 (132.2 mg, 0.561 mmol, 20% yield). Used directly without further purification.
Compound 49 was prepared according to General Method K using 49-4 and 5-3.
Cp d | Structure | MS [M+H] m/z | 1H NMR (DMSO-d6) δ ppm |
1 | o A M LL | 424.2 | (500 MHz) 9.46 (dd, J=5.73, 4.01 Hz, 1 H) 8.55 (s, 1 H) 7.98 (s, 1 H) 7.36 (dd, J=9.45, 3.15 Hz, 1 H) 7.07 - 7.13 (m, 1 H) 6.96 7.07 (m, 1 H) 5.30 - 5.40 (m, 1 H) 4.63 - 4.74 (m, 1 H) 4.58 (ddd, J=10.45, 7.30, 2.86 Hz, 1 H) 4.53 (t, J=4.01 Hz, 1 H) 4.21 (d, J=14.89 Hz, 1 H) 3.82 (ddd, J=13.46, 6.01, 4.58 Hz, 1 H) 3.18 - 3.24 (m, 1 H) 2.32 - 2.39 (m, 1 H) 2.10 - 2.20 (m, 1 H) 1.89 - 1.97 (m, 2 H) 1.69 - 1.79 (m, 1 H) 1.50 - 1.60 (m, 1 H) 1.44 (d, J=6.30 Hz, 3 H) |
2 | T T o | 424.3 | (300 MHz) 9.52 (br d, J=5.78 Hz, 1 H) 8.63 (s, 1 H) 8.02 (s, 1 H) 7.21 (dd, J=8.99, 2.29 Hz, 1 H) 6.97 - 7.13 (m, 2 H) 5.46 (d, J=15.04 Hz, 1 H) 4.45 - 4.59 (m, 1 H) 4.07 - 4.27 (m, 3 H) 3.86 3.99 (m, 1 H) 3.06 - 3.19 (m, 1 H) 1.63 - 2.22 (m, 5 H) 1.44 (d, J=6.05 Hz, 3 H) |
3 | F fAA'A A7 NH \ To ^A^N^N^J^ Aa n T 0 N | 442.2 | (500 MHz) 9.43 (t, J=5.2 Hz, 1H), 8.58 (s, 1H), 7.99 (s, 1H), 7.25 - 7.11 (m, 2H), 5.30 (d, J=14.8 Hz, 1H), 5.04 - 5.00 (m, 1H), 4.64 (t, J=3.8 Hz, 1H), 4.48 (ddd, J=2.9, 7.3, 10.6 Hz, 1H), 4.26 (d, J=15.1 Hz, 1H), 3.53 3.47 (m, 2H), 2.34 - 2.29 (m, 1H), 2.18 - 2.10 (m, 1H), 1.98 1.91 (m, 2H), 1.73 (br dd, J=8.8, 17.8 Hz, 1H), 1.60 - 1.54 (m, 1H), 1.46 (d, J=6.0 Hz, 3H) |
4 | FO-o^ '—-f NH \ Mo Q 1 T m w AA» | 426.2 | (500 MHz) 9.40 (br t, J=4.58 Hz, 1 H) 8.66 (s, 1 H) 8.02 (s, 1 H) 7.43 (dd, J=9.45, 2.58 Hz, 1 H) 7.06 - 7.15 (m, 1 H) 6.98 - 7.06 (m, 1 H) 5.36 (d, J=14.89 Hz, 1 H) 4.96 - 5.07 (m, 1 H) 4.85 (br s, 1 H) 4.62 - 4.75 (m, 1 H) 4.33 (t, J=7.45 Hz, 1 H) 4.16 - 4.29 (m, 2 H) 4.03 (d, J=10.88 Hz, 1 H) 3.77 - 3.86 (m, 1 H) 3.57 (t, J=8.88 Hz, 1 H) 3.19 - 3.24 (m, 1 H) 1.44 (d, J=5.73 Hz, 3 H) |
5 | 2-4 x y o | 425.3 | (300 MHz) 9.36 - 9.45 (m, 1 H) 8.55 (s, 1 H) 8.07 (d, J=2.93 Hz, 1 H) 7.93 - 8.02 (m, 2 H) 5.10 5.27 (m, 2 H) 4.60 (ddd, J=10.45, 7.34, 3.30 Hz, 1 H) 4.48 - 4.54 (m, 1 H) 4.33 (d, J=14.95 Hz, 1 H) 3.93 (ddd, J=12.95, 8.05, 4.49 Hz, 1 H) 3.09 - 3.21 (m, 1 H) 2.29- 2.40 (m, 1 H) 2.06 - 2.17 (m, 1 H) 1.86 - 2.00 (m, 2 H) 1.66 - 1.80 (m, 1 H) 1.49 - 1.63 (m, 1 H) 1.45 (d, J=6.14 Hz, 3 H) |
6 | o | 425.1 | (500 MHz) 9.53 (d, J=8.02 Hz, 1 H) 8.55 (s, 1 H) 8.09 (d, J=2.86 Hz, 1 H) 8.03 (dd, J=8.59, 2.86 Hz, 1 H) 7.99 (s, 1 H) 5.32 (d, J=14.89 Hz, 1 H) 4.70 (dd, J=10.88, 4.01 Hz, 1 H) 4.61 (ddd, J=10.45, 7.30, 3.44 Hz, 1 H) 4.48 (t, J=4.01 Hz, 1 H) 4.35 (d, J=14.89 Hz, 1H) 4.26 (br dd, J=11.17, 6.59 Hz, 1 H) 4.14 (dd, J=10.60, 1.43 Hz, 1 H) 2.33 2.43 (m, 1 H) 2.07 - 2.19 (m, 1 H) 1.88 - 1.98 (m, 2 H) 1.69 1.82 (m, 1 H) 1.50 - 1.62 (m, 1 H) 1.36 (d, J=6.87 Hz, 3 H) |
7 | o A X M w LL | 442.1 | (500 MHz) 9.89 (br d, J=8.59 Hz, 1 H) 8.58 (s, 1 H) 8.01 (s, 1 H) 7.19 - 7.30 (m, 2 H) 5.46 (br d, J=14.89 Hz, 1 H) 4.74 (br dd, J=9.45, 6.01 Hz, 1 H) 4.53 - 4.64 (m, 2 H) 4.25 (br d, J=15.47 Hz, 1 H) 4.20 (br t, J=7.16 Hz, 1 H) 3.93 - 4.05 (m, 1 H) 2.31 - 2.40 (m, 1 H) 2.09 - 2.20 (m, 1 H) 1.87 - 1.97 (m, 2 H) 1.68 - 1.79 (m, 1 H) 1.48 - 1.59 (m, 1 H) 1.33 (d, J=6.87 Hz, 3 H) |
100
8 | Y. Y nh \ \=O _/Ν-γΝγ4 | 411.1 | 9.37 (br d, J=6.30 Hz, 1 H) 8.62 (s, 1 H) 8.06 (d, J=2.86 Hz, 1 H) 8.01 (s, 1 H) 7.90 (dd, J=8.88, 2.58 Hz, 1H) 5.26 (d, J=15.47 Hz, 1 H) 5.11 - 5.20 (m, 1 H) 5.05 (q, J=6.87 Hz, 1 H) 4.91 (br d, J=2.86 Hz, 1 H) 4.14 (d, J=14.89 Hz, 1 H) 3.93 - 4.02 (m, 1 H) 3.07 - 3.19 (m, 1 H) 2.28 2.35 (m, 1 H) 2.11 - 2.22 (m, 1 H) 2.02 - 2.09 (m, 1 H) 1.94 2.02 (m, 1 H) 1.46 (d, J=6.30 Hz, 3 H) |
9 | o -C M Y+ LL· | 411.0 | 9.38 (br d, J=5.73 Hz, 1 H) 8.68 (s, 1 H) 8.08 (d, J=2.86 Hz, 1 H) 8.03 (s, 1 H) 7.42 (dd, J=8.59, 2.86 Hz, 1 H) 5.34 (br d, J=14.89 Hz, 1 H) 5.10 - 5.21 (m, 1 H) 4.74 (br d, J=2.29 Hz, 1 H) 4.37 4.48 (m, 1 H) 4.24 (d, J=14.89 Hz, 1 H) 3.96 (ddd, J=13.03, 8.16, 4.58 Hz, 1 H) 3.11 - 3.20 (m, 1 H) 2.60 - 2.72 (m, 1 H) 2.41 - 2.48 (m, 1 H) 2.19 - 2.31 (m, 1 H) 2.00 - 2.08 (m, 1 H) 1.46 (d, J=6.30 Hz, 3 H) |
10 | π <4 O Z 1 fi 1 /Jy o | 411.0 | (500 MHz) 9.43 (d, J=8.02 Hz, 1 H) 8.62 (s, 1 H) 8.07 (d, J=2.86 Hz, 1 H) 8.01 (s, 1 H) 7.93 (dd, J=8.59, 2.86 Hz, 1 H) 5.34 (dd, J=14.89, 1.15 Hz, 1 H) 5.03 (q, J=6.68 Hz, 1 H) 4.90 (dt, J=5.73, 2.86 Hz, 1 H) 4.75 (dd, J=10.60, 4.30 Hz, 1 H) 4.25 - 4.34 (m, 1 H) 4.16 (d, J=10.88 Hz, 1 H) 4.13 (dd, J=9.17, 1.72 Hz, 1 H) 2.27 - 2.35 (m, 1 H) 2.13 - 2.22 (m, 1 H) 2.05 - 2.13 (m, 1 H) 1.98 - 2.05 (m, 1 H) 1.38 (d, J=6.87 Hz, 3 H) |
11 | “F| Y O z 1 fi \ Y5 o | 411.0 | (500 MHz) 9.47 (d, J=8.02 Hz, 1 H) 8.68 (s, 1 H) 8.10 (d, J=3.44 Hz, 1 H) 8.03 (s, 1 H) 7.49 (dd, J=8.59, 2.86 Hz, 1 H) 5.45 (d, J=16.04 Hz, 1 H) 4.73 (br d, J=4.01 Hz, 1 H) 4.70 (dd, J=10.88, 4.01 Hz, 1 H) 4.42 4.48 (m, 1 H) 4.24 - 4.31 (m, 2 H) 4.15 (dd, J=10.60, 2.00 Hz, 1 H) 2.65 - 2.73 (m, 1 H) 2.42 (dt, J=18.62, 9.59 Hz, 1 H) 2.19 2.28 (m, 1 H) 1.98 - 2.04 (m, 1 |
101
H) 1.37 (d, J=6.30 Hz, 3 H) | |||
12 | K 0 αχχΓ | 439.1 | (500 MHz) 9.41 (br d, J=7.45 Hz, 1 H) 8.55 (s, 1 H) 8.06 (br s, 1 H) 7.97 (d, J=1.72 Hz, 1 H) 7.95 (br d, J=9.17 Hz, 1 H) 5.07 - 5.20 (m, 2 H) 4.50 (br s, 1 H) 4.33 (br d, J=14.89 Hz, 1 H) 4.26 (br s, 1 H) 3.87 - 3.99 (m, 1 H) 3.09 3.19 (m, 1 H) 2.06 - 2.17 (m, 2 H) 1.87 (br t, J=12.32 Hz, 1 H) 1.78 (brd, J=1.15 Hz, 1 H) 1.47 1.60 (m, 2 H) 1.45 (br d, J=5.73 Hz, 3 H) 1.41 (brd, J=8.59 Hz, 2 H) |
13 | Λ-4 4 1 ο | 439.1 | (500 MHz) 9.51 (d, J=8.59 Hz, 1 H) 8.54 (s, 1 H) 8.08 (d, J=3.44 Hz, 1 H) 8.00 (dd, J=9.16, 2.86 Hz, 1 H) 7.97 (s, 1 H) 5.21 (dd, J=14.89, 1.15 Hz, 1 H) 4.70 (dd, J=10.60, 4.30 Hz, 1 H) 4.47 (br s, 1 H) 4.35 (d, J=14.89 Hz, 1 H) 4.21 - 4.31 (m, 2 H) 4.14 (dd, J=10.31, 1.72 Hz, 1 H) 2.07 2.19 (m, 2 H) 1.83 - 1.92 (m, 1 H) 1.78 (br s, 1 H) 1.38 - 1.59 (m, 4 H) 1.36 (d, J=6.30 Hz, 3 H) |
14 | d &Λ ο | 451.1 | (500 MHz) 9.73 (d, J=9.16 Hz, 1 H) 8.55 (s, 1 H) 8.10 (d, J=2.86 Hz, 1 H) 8.05 (dd, J=8.59, 2.86 Hz, 1 H) 7.99 (s, 1 H) 5.30 - 5.38 (m, 1 H) 4.64 - 4.69 (m, 1 H) 4.58 - 4.64 (m, 1 H) 4.47 (t, J=3.72 Hz, 1 H) 4.37 (d, J=8.02 Hz, 1 H) 4.34 (d, J=4.01 Hz, 1 H) 3.75 (td, J=8.59, 4.01 Hz, 1 H) 2.33 - 2.44 (m, 1 H) 2.07 - 2.19 (m, 1 H) 1.86 - 1.99 (m, 2 H) 1.67 - 1.81 (m, 1 H) 1.51 - 1.63 (m, 1 H) 1.20 - 1.33 (m, 1 H) 0.42 - 0.55 (m, 3 H) 0.27 - 0.37 (m, 1 H) |
15 | d η y yp o | 439.1 | (500 MHz) 8.52 (s, 1 H) 8.11 (t, J=4.30 Hz, 1 H) 8.04 (d, J=2.86 Hz, 1 H) 7.99 (s, 1 H) 7.86 (dd, J=8.59, 2.86 Hz, 1 H) 5.55 (br t, J=6.59 Hz, 1 H) 5.28 (dd, J=14.89, 1.15 Hz, 1 H) 4.54 4.58 (m, 1 H) 4.50 - 4.54 (m, 1 H) 4.29 (d, J=14.89 Hz, 1 H) 3.61 - 3.68 (m, 1 H) 3.34 - 3.37 |
102
(m, 1 H) 2.32 - 2.38 (m, 1 H) 2.09 - 2.16 (m, 2 H) 1.88 - 1.97 (m, 3 H) 1.69 - 1.76 (m, 1 H) 1.51 - 1.59 (m, 1 H) 1.30 (d, J=6.30 Hz, 3 H) | |||
16 | SP o | 439.1 | (500 MHz) 8.55 (s, 1 H) 8.48 (s, 1 H) 8.14 (d, J=6.87 Hz, 1 H) 8.05 - 8.09 (m, 2 H) 7.92 (dd, J=8.59, 2.86 Hz, 1 H) 7.44 (dd, J=8.59, 2.86 Hz, 1 H) 5.54 (t, J=12.03 Hz, 1 H) 5.30 - 5.42 (m, 2 H) 4.76 - 4.83 (m, 1 H) 4.47 4.56 (m, 2 H) 4.17 - 4.38 (m, 5 H) 4.05 (ddd, J=10.60, 6.87, 3.72 Hz, 1 H) 3.91 - 3.97 (m, 1 H) 2.50 - 2.56 (m, 1 H) 2.06 - 2.38 (m, 5 H) 1.82 - 2.00 (m, 6 H) 1.62 - 1.75 (m, 2 H) 1.18 (d, J=6.30 Hz, 3 H) |
17 | Vf 0 HN \ y^o sZXqP^/N^n | 439.1 | (500 MHz) 8.60 (s, 1 H) 8.53 (s, 1 H) 8.17 - 8.22 (m, 1 H) 8.06 (d, J=2.86 Hz, 1 H) 8.02 (s, 1 H) 7.99 (s, 1 H) 7.87 (dd, J=8.88, 2.58 Hz, 1 H) 7.56 (dd, J=8.59, 3.44 Hz, 1 H) 5.27 (dd, J=14.89, 1.15 Hz, 1 H) 4.92 - 4.96 (m, 1 H) 4.51 - 4.57 (m, 2 H) 4.31 (d, J=15.47 Hz, 1 H) 3.95 (dd, J=11.17, 8.88 Hz, 1 H) 3.88 (br dd, J=13.17, 8.02 Hz, 1 H) 3.06 (ddd, J=13.75, 8.59, 2.86 Hz, 1 H) 2.30 - 2.38 (m, 2 H) 2.09 2.16 (m, 1 H) 1.90 - 1.98 (m, 2 H) 1.69 - 1.77 (m, 1 H) 1.52 1.60 (m, 1 H) 1.03 (d, J=6.87 Hz, 3 H) |
18 | χχχ. cCûX | 437.1 | (500 MHz) 9.02 - 9.15 (m, 1 H) 8.47 - 8.63 (m, 1 H) 8.07 (d, J=2.86 Hz, 1 H) 8.02 (dd, J=8.88, 2.58 Hz, 1 H) 7.90 - 7.96 (m, 1 H) 5.34 - 5.56 (m, 1 H) 4.79 - 4.91 (m, 1 H) 4.60 (ddd, J=10.74, 7.30, 3.15 Hz, 1 H) 4.46 (t, J=3.72 Hz, 1 H) 4.26 4.36 (m, 1 H) 3.71 - 3.85 (m, 1 H) 2.32 - 2.41 (m, 1 H) 2.06 2.20 (m, 1 H) 1.87 - 2.03 (m, 3 H) 1.67 - 1.82 (m, 1 H) 1.51 1.63 (m, 1 H) 0.99 - 1.11 (m, 1 H) 0.90 - 0.98 (m, 1 H) 0.73 0.87 (m, 1 H) |
103
19 | x j o | 425.1 | (500 MHz) 8.60 (s, 1 H) 8.53 (s, 1 H) 8.09 - 8.14 (m, 1 H) 8.06 (d, J=2.86 Hz, 1 H) 8.00 (s, 1 H) 7.89 (dd, J=9.17, 2.86 Hz, 1 H) 7.50 (dd, J=8.59, 2.29 Hz, 1 H) 5.32 (dd, J=14.89, 1.15 Hz, 1 H) 4.95 - 5.05 (m, 1 H) 4.51 - 4.59 (m, 2 H) 4.27 - 4.33 (m, 1 H) 4.17 - 4.24 (m, 1 H) 3.67 - 3.74 (m, 1 H) 3.35 - 3.41 (m, 1 H) 2.30 - 2.40 (m, 1 H) 2.10 - 2.18 (m, 2 H) 1.86 - 2.04 (m, 5 H) 1.65 - 1.79 (m, 1 H) 1.48 - 1.61 (m, 1 H) |
20 | x % z-/ X^l O | 451.1 | (500 MHz) 8.87 (t, J=5.16 Hz, 1 H) 8.63 (s, 1 H) 8.05 (d, J=2.86 Hz, 1 H) 8.01 (s, 1 H) 7.61 (dd, J=8.88, 2.58 Hz, 1 H) 5.30 - 5.38 (m, 1 H) 4.93 (dd, J=15.18, 1.43 Hz, 1 H) 4.53 (d, J=15.47 Hz, 1 H) 4.20 - 4.33 (m, 2 H) 3.81 (dt, J=13.17, 4.87 Hz, 1 H) 3.22 3.31 (m, 1 H) 1.61 (s, 3 H) 1.45 (d, J=6.30 Hz, 3 H) 1.36 (s, 3 H) |
21 | s>¥ Ll_ | 439.1 | (500 MHz) 9.09 (s, 1 H) 8.51 8.63 (m, 1 H) 8.06 - 8.14 (m, 2 H) 7.94 - 7.99 (m, 1 H) 5.31 5.59 (m, 1 H) 4.56 - 4.71 (m, 2 H) 4.47 (t, J=3.81 Hz, 1 H) 4.32 (br d, J=14.67 Hz, 1 H) 3.90 3.98 (m, 1 H) 2.36 - 2.44 (m, 1 H) 2.08 - 2.18 (m, 1 H) 1.89 1.98 (m, 2 H) 1.70 - 1.82 (m, 1 H) 1.62 (s, 3 H) 1.53 - 1.59 (m, 1 H) 1.49 (s, 3 H) |
22 | Xv+ HN aXcT | 451.2 | (500 MHz) 8.94 - 9.12 (m, 1 H) 8.49 - 8.65 (m, 1 H) 8.11 (d, J=2.86 Hz, 1 H) 8.06 (dd, J=8.59, 2.29 Hz, 1 H) 7.94 -8.02 (m, 1 H) 5.21 - 5.48 (m, 1 H) 4.74 - 4.95 (m, 1 H) 4.54 - 4.64 (m, 1 H) 4.46 (t, J=3.44 Hz, 1 H) 4.32 - 4.40 (m, 1 H) 4.23 - 4.32 (m, 1 H) 3.38 -3.60 (m, 1 H) 2.65 - 2.84 (m, 1 H) 2.34 - 2.44 (m, 1 H) 2.16 - 2.26 (m, 1 H) 2.02 2.16 (m, 2 H) 1.77 - 1.99 (m, 4 H) 1.66 - 1.77 (m, 1 H) 1.48 1.62(m, 1 H) |
104
23 | Ο χγ j° Η ΥΥ LL | 465.2 | (500 MHz) 8.47 - 8.64 (m, 1 Η) 8.04 - 8.13 (m, 2 Η) 7.99 - 8.04 (m, 1 Η) 7.51 - 7.97 (m, 1 Η) 5.26 - 5.46 (m, 1 Η) 5.06 -5.25 (m, 1 Η) 4.53 - 4.60 (m, 1 Η) 4.51 (t, J=3.72 Hz, 1 H) 4.23 4.34 (m, 1 H) 4.04 - 4.14 (m, 1 H) 3.68 - 3.79 (m, 1 H) 2.31 2.41 (m, 1 H) 2.10 - 2.22 (m, 2 H) 1.87 - 2.04 (m, 7 H) 1.77 1.85 (m, 1 H) 1.66 - 1.75 (m, 1 H) 1.49 - 1.61 (m, 1 H) |
24 | Ύ k γο ΧΧί | 451.2 | (500 MHz) 9.31 (d, J=6.87 Hz, 1 H) 8.54 (s, 1 H) 8.04 (d, J=2.86 Hz, 1 H) 7.97 (s, 1 H) 7.95 (dd, J=8.88, 2.58 Hz, 1 H) 5.73 (td, J=6.30, 3.44 Hz, 1 H) 5.22 (d, J=14.89 Hz, 1 H) 4.57 (ddd, J=10.45, 7.30, 3.44 Hz, 1 H) 4.51 (t, J=4.01 Hz, 1 H) 4.34 (d, J=14.89 Hz, 1 H) 4.25 (quin, J=7.02 Hz, 1 H) 2.31 - 2.40 (m, 1 H) 2.03 - 2.21 (m, 3 H) 1.89 1.98 (m, 2 H) 1.78 - 1.89 (m, 2 H) 1.67 - 1.78 (m, 2 H) 1.51 1.65 (m, 2H) |
25 | F αγ ΗΝ k γο ΧιΥ | 487.1 | (500 MHz) 8.94 - 9.15 (m, 1 H) 8.52 - 8.67 (m, 1 H) 8.12 (d, J=2.29 Hz, 1 H) 8.02 - 8.09 (m, 1 H) 7.93 - 8.02 (m, 1 H) 5.20 5.43 (m, 1 H) 4.99 - 5.12 (m, 1 H) 4.59 (ddd, J=10.45, 7.59, 3.15 Hz, 1 H) 4.47 (t, J=3.72 Hz, 1 H) 4.25 - 4.36 (m, 2 H) 3.89 - 4.19 (m, 1 H) 3.57 - 3.85 (m, 1 H) 2.99 - 3.21 (m, 1 H) 2.74 - 2.87 (m, 1 H) 2.34 - 2.44 (m, 1 H) 2.06 - 2.21 (m, 1 H) 1.88 - 1.99 (m, 2 H) 1.69 - 1.82 (m, 1 H) 1.48 - 1.61 (m, 1 H) |
26 | ΥΧ> ΗΝ \ Χ=ο ΧΥ | 465.2 | (500 MHz) 9.19 (s, 1 H) 8.47 8.64 (m, 1 H) 8.04 - 8.18 (m, 2 H) 7.92 - 8.01 (m, 1 H) 5.26 5.59 (m, 1 H) 4.52 - 4.71 (m, 2 H) 4.46 (t, J=4.01 Hz, 1 H) 4.23 4.36 (m, 1 H) 3.95 - 4.07 (m, 1 H) 2.87 (ddd, J=13.32, 9.02, 4.01 Hz, 1 H) 2.31 - 2.45 (m, 1 H) 2.06 - 2.17 (m, 1 H) 1.85 - 2.06 (m, 5 H) 1.63 - 1.85 (m, 3 H) 1.50 - 1.63 (m, 2 H) 1.39 - 1.50 |
105
(m, 1 Η) | |||
27 | Ή-Χ ] ΗΝ 0X0° | 419.2 | (500 MHz) 8.49 - 8.62 (m, 1 Η) 8.12 - 8.26 (m, 1 Η) 7.92 - 8.09 (m, 3 Η) 5.31 - 5.51 (m, 1 Η) 5.00 - 5.18 (m, 1 Η) 4.57 (ddd, J=10.60, 7.45, 3.15 Hz, 1 H) 4.50 - 4.53 (m, 1 H) 4.29 - 4.34 (m, 1 H) 3.65 - 3.72 (m, 1 H) 3.42 - 3.49 (m, 1 H) 3.13 (dd, J=13.75, 2.29 Hz, 1H) 2.32 2.40 (m, 1 H) 2.08 - 2.19 (m, 1 H) 1.88 - 1.99 (m, 2 H) 1.68 1.78 (m, 1 H) 1.51 - 1.63 (m, 1 H) 1.21 (s, 3 H) 1.02 (s, 3 H) |
28 | -----------. \\ λ / ] | ΗΝ αχτΓ | 439.1 | (500 MHz) 8.49 - 8.61 (m, 1 H) 7.98 - 8.19 (m, 3 H) 7.45 - 7.97 (m, 1 H) 4.75 - 5.66 (m, 2 H) 4.49 - 4.61 (m, 1 H) 4.18 - 4.43 (m, 3 H) 3.92 - 4.14 (m, 1 H) 2.53 - 2.66 (m, 1 H) 2.09 - 2.40 (m, 2 H) 1.46 - 2.01 (m, 5 H) 1.23 (dd, J=18.33, 6.87 Hz, 3 H) |
29 | 1 >0 αχί | 414.3 | (500 MHz) 8.50 - 8.64 (m, 1 H) 8.18 - 8.28 (m, 1 H) 7.99 - 8.09 (m, 2 H) 7.83 - 7.98 (m, 1 H) 5.23 - 5.42 (m, 1 H) 4.78 -4.99 (m, 1 H) 4.49 - 4.61 (m, 2 H) 4.26 - 4.34 (m, 1 H) 3.92 - 4.00 (m, 1 H) 3.57 - 3.91 (m, 1 H) 2.97 - 3.12 (m, 1 H) 2.29 - 2.39 (m, 2 H) 2.07 - 2.18 (m, 1 H) 1.87 - 2.00 (m, 2 H) 1.66 - 1.79 (m, 1 H) 1.49 - 1.61 (m, 1 H) 1.03 (dd, J=6.87, 2.86 Hz, 3 H) |
30 | -qx | ΗΝ <χο | 427.1 | (500 MHz) 9.33 - 9.37 (m, 1 H) 8.67 (s, 1 H) 8.08 (d, J=2.86 Hz, 1 H) 8.02 - 8.06 (m, 2 H) 5.23 (d, J=15.47 Hz, 1 H) 5.14 - 5.20 (m, 1 H) 5.01 - 5.07 (m, 1 H) 4.82 (t, J=3.44 Hz, 1 H) 4.30 - 4.40 (m, 2 H) 4.19 (dd, J=10.31, 3.44 Hz, 1 H) 4.03 (d, J=10.88 Hz, 1 H) 3.90 - 3.97 (m, 1 H) 3.53 - 3.59 (m, 1 H) 3.15 (ddd, J=13.60, 8.74, 2.86 Hz, 1 H) 1.45 (d, J=5.73 Hz, 3 H) |
106
31 | Ο _zA? ? A λ—/ A | 427.1 | (500 MHz) 9.24 (dd, J=6.59, 3.15 Hz, 1 H) 8.75 (s, 1 H) 8.04 - 8.09 (m, 2 H) 7.39 (dd, J=8.59, 2.86 Hz, 1 H) 5.37 (d, J=14.89 Hz, 1 H) 5.21 - 5.28 (m, 1 H) 4.65 (t, J=3.72 Hz, 1 H) 4.61 (t, J=7.16 Hz, 1 H) 4.46 - 4.51 (m, 1 H) 4.35 (d, J=14.89 Hz, 1 H) 4.29 (dd, J=10.88, 4.58 Hz, 1 H) 4.03 (d, J=10.31 Hz, 1 H) 3.88 - 3.95 (m, 1 H) 3.80 - 3.85 (m, 1 H) 3.17 - 3.24 (m, 1 H) 1.46 (d, J=6.30 Hz, 3 H) |
32 | o yA | 441.0 | (500MHz) 8.53 (s, 1 H) 8.13 (dd, J=8.59, 1.72 Hz, 1 H) 8.05 (d, J=2.86 Hz, 1 H) 7.99 (s, 1 H) 7.85 (dd, J=8.59, 2.86 Hz, 1 H) 5.37 (d, J=4.58 Hz, 1 H) 5.28 (dd, J=15.18, 1.43 Hz, 1 H) 5.01 (br d, J=9.74 Hz, 1 H) 4.49 - 4.58 (m, 2 H) 4.30 (d, J=15.47 Hz, 1 H) 4.00 - 4.10 (m, 2 H) 3.91 3.98 (m, 1 H) 3.12 (ddd, J=13.17, 8.59, 2.29 Hz, 1 H) 2.29 - 2.38 (m, 1 H) 2.07 - 2.19 (m, 1 H) 1.86 - 1.98 (m, 2 H) 1.66-1.76 (m, 1 H) 1.48 - 1.59 (m, 1 H) |
33 | o AA 1 A τϋ LL | 457.0 | |
34 | /—k / AAo A— ] HN αχχΓ | 453.2 | (500 MHz) 8.45 - 8.58 (m, 1 H) 8.08 (d, J=2.86 Hz, 1 H) 7.96 - 8.02 (m, 2 H) 7.81 - 7.89 (m, 1 H) 5.39 - 5.57 (m, 1 H) 4.89 - 5.15 (m, 1 H) 4.54 - 4.60 (m, 1 H) 4.44 (t, J=3.72 Hz, 1 H) 4.24 (d, J=15.47 Hz, 1 H) 4.06 (br dd, J=11.17, 5.44 Hz, 1 H) 1.66 2.44 (m, 8 H), 1.54 - 1.58 (m, 3 H) 1.50 - 1.53 (m, 3 H) |
107
35 | ] HN αχχΓ | 439.2 | (500 MHz) 8.59 (s, 1 H) 8.52 (s, 1 H) 8.09 (br t, J=4.58 Hz, 1 H) 8.03 (d, J=2.86 Hz, 1 H) 8.00 (s, 1 H) 7.44 (dd, J=8.59, 2.86 Hz, 1 H) 5.62 (br t, J=6.30 Hz, 1 H) 5.40 (dd, J=15.18, 1.43 Hz, 1 H) 4.23 - 4.31 (m, 2 H) 4.06 (ddd, J=10.60, 6.87, 3.72 Hz, 1 H) 3.56 - 3.65 (m, 1 H) 2.52 - 2.57 (m, 1 H) 2.14 - 2.27 (m, 2 H) 1.86 - 2.01 (m, 5 H) 1.66 - 1.74 (m, 1 H) 1.29 - 1.33 (m, 4 H) |
36 | FO-1 \ V yaxd | 468.2 | (500 MHz) 9.38 (br d, J=4.01 Hz, 1 H) 8.68 (d, J=9.74 Hz, 1 H) 8.09 (t, J=2.58 Hz, 1 H) 7.97 8.05 (m, 2 H) 4.98 - 5.27 (m, 3 H) 4.78 - 4.88 (m, 1 H) 4.22 4.44 (m, 2 H) 3.80 - 3.99 (m, 2 H) 3.67 - 3.69 (m, 1 H) 3.03 3.19 (m, 2 H) 2.00 (d, J=7.45 Hz, 3 H) 1.46 (d, J=6.30 Hz, 3 H) |
37 | ’-ffF \ g 0 /„ ,N N^/ Λχ.ΙθΧ,Ιτ | 468.2 | (500 MHz) 9.17 - 9.24 (m, 1 H) 8.75 (d, J=13.75 Hz, 1 H) 8.10 (t, J=3.15 Hz, 1 H) 8.05 - 8.08 (m, 1 H) 7.39 - 7.57 (m, 1H) 5.35 5.44 (m, 1 H) 5.21 - 5.30 (m, 1 H) 4.28 - 4.73 (m, 4 H) 3.62 4.02 (m, 4 H) 3.19 - 3.24 (m, 1 H) 2.01 - 2.10 (m, 3 H) 1.46 (d, J=6.30 Hz, 3 H) |
38 | M °Ί o | 443.2 | (500 MHz) 8.54 (s, 1 H) 8.19 (t, J=4.87 Hz, 1 H) 8.09 (d, J=2.86 Hz, 1 H) 8.01 (s, 1 H) 7.94 (dd, J=8.88, 2.58 Hz, 1 H) 5.30 - 5.41 (m, 1 H) 5.27 (dd, J=14.89, 1.15 Hz, 1 H) 5.07 - 5.21 (m, 1 H) 4.50 - 4.58 (m, 2 H) 4.30 - 4.39 (m, 2 H) 3.93 - 4.02 (m, 1 H) 3.56 - 3.69 (m, 1 H) 2.30 - 2.39 (m, 1 H) 2.09 - 2.18 (m, 1 H) 1.89 - 1.99 (m, 2 H) 1.65 - 1.79 (m, 1 H) 1.50- 1.65 (m, 1 H) |
39 | M o | 443.2 | (500 MHz) 8.53 - 8.62 (m, 1 H) 8.10 - 8.27 (m, 1 H) 8.08 (t, J=2.58 Hz, 1 H) 8.02 (d, J=2.29 Hz, 1 H) 7.49 - 7.97 (m, 1H) 5.44 - 5.53 (m, 1 H) 5.33 - 5.43 (m, 1 H) 5.00 - 5.21 (m, 1 H) 4.52 4.60 (m, 1 H) 4.22 - 4.41 (m, 3 H) 3.95 - 4.14 (m, 1 H) 3.52 3.67 (m, 1 H) 2.32 - 2.40 (m, 1 H) 2.09 - 2.27 (m, 1 H) 1.87 - |
108
2.00 (m, 2 H) 1.66 - 1.78 (m, 1 H) 1.46 - 1.58 (m, 1 H) | |||
40 | A <Xcj° | 461.1 | (500 MHz) 8.53 - 8.62 (m, 1 H) 8.10 - 8.27 (m, 1 H) 8.08 (t, J=2.58 Hz, 1 H) 8.02 (d, J=2.29 Hz, 1 H) 7.49 - 7.97 (m, 1H) 5.44 - 5.53 (m, 1 H) 5.33 - 5.43 (m, 1 H) 5.00 - 5.21 (m, 1 H) 4.52 4.60 (m, 1 H) 4.22 - 4.41 (m, 3 H) 3.95 - 4.14 (m, 1 H) 3.52 3.67 (m, 1 H) 2.32 - 2.40 (m, 1 H) 2.09 - 2.27 (m, 1 H) 1.87 2.00 (m, 2 H) 1.66 - 1.78 (m, 1 H) 1.46 - 1.58 (m, 1 H) |
41 | AM H < yÿyu o | 10-840 | (300 MHz) 8.34 - 8.67 (m, 2 H) 7.94 - 8.19 (m, 2 H) 7.48 (dd, J=8.67, 2.61 Hz, 1 H) 5.38 - 5.62 (m, 1 H) 5.18 - 5.38 (m, 1 H) 4.50 - 4.85 (m, 1 H) 4.17 - 4.49 (m, 2 H) 3.97 - 4.14 (m, 1 H) 1.60-2.43 (m, 12 H) |
42 | Ά ] HN \ AQ M | 451.2 | (300 MHz) 8.53 (s, 1 H) 8.41 (d, J=10.55 Hz, 1 H) 8.07 (d, J=2.93 Hz, 1 H) 7.98 (s, 1 H) 7.86 (dd, J=8.89, 2.66 Hz, 1 H) 5.37 (br s, 1 H) 5.23 - 5.32 (m, 1 H) 4.69 4.84 (m, 1 H) 4.49 - 4.61 (m, 2 H) 4.31 (br d, J=15.31 Hz, 1 H) 2.23 - 2.39 (m, 2 H) 2.01 - 2.19 (m, 4 H) 1.67 - 1.96 (m, 5 H) 1.50 - 1.64 (m, 1 H) |
43 | OH fM^n MoH HN mî | 441.2 | (300 MHz) 8.50 - 8.67 (m, 1 H) 7.36 - 8.20 (m, 4 H) 5.21 - 5.52 (m, 2 H) 4.85 - 5.11 (m, 1 H) 3.70 - 4.67 (m, 6 H) 2.97 - 3.19 (m, 1 H) 2.03 - 2.42 (m, 2 H) 1.87 - 2.02 (m, 2 H) 1.66 - 1.83 (m, 1 H) 1.56 (br d, J=10.73 Hz, 1 H) |
44 | A H // V M° u_ X/ | 425.1 | (300 MHz) 9.40 (dd, J=7.61,2.11 Hz, 1 H) 8.55 (s, 1 H) 8.07 (d, J=2.93 Hz, 1 H) 7.94 - 8.02 (m, 2 H) 5.11 - 5.27 (m, 2 H) 4.60 (ddd, J=10.41, 7.34, 3.16 Hz, 1 H) 4.51 (t, J=3.76 Hz, 1 H) 4.33 (d, J=14.95 Hz, 1 H) 3.86 - 4.01 (m, 1 H) 3.15 (ddd, J=13.25, 8.76, 2.57 Hz, 1 H) 2.28 - 2.42 (m, 1 H) 2.03 - 2.22 (m, 1 H) 1.85 - 2.00 (m, 2 H) 1.66 - 1.82 (m, 1 H) 1.49 - 1.64 (m, 1 H) |
109
1.45 (d, J=6.24 Hz, 3 H) | |||
45 | 7 XX LL | 465.2 | (300 MHz) 8.43 - 8.62 (m, 1 H) 7.86 - 8.13 (m, 4 H) 5.35 - 5.56 (m, 1 H) 4.65 - 4.93 (m, 1 H) 4.49 - 4.62 (m, 1 H) 4.40 - 4.48 (m, 1 H) 4.25 (br d, J=14.40 Hz, 1 H) 4.06 - 4.17 (m, 1 H) 3.15 3.27 (m, 2 H) 2.09 - 2.35 (m, 4 H) 1.84 - 2.00 (m, 4 H) 1.67 1.77 (m, 3 H) 1.46 - 1.58 (m, 1 H) |
46 | LçLo ^-7 7 HN XxX | 437.1 | (300 MHz) 8.97 - 9.10 (m, 1 H) 8.53 - 8.68 (m, 1 H) 7.96 - 8.11 (m, 3 H) 5.44 - 5.59 (m, 1 H) 5.12 (q, J=4.49 Hz, 1 H) 4.50 - 4.71 (m, 3 H) 4.24 - 4.42 (m, 1 H) 2.79 - 3.10 (m, 2 H) 2.30 - 2.42 (m, 1 H) 2.03 - 2.22 (m, 2 H) 1.87 - 2.01 (m, 2 H) 1.49- 1.82 (m, 3 H) |
47 | LL O 0 | 461.1 | (300 MHz) 9.83 (d, J=9.08 Hz, 1 H) 8.59 (s, 1 H) 8.11 (d, J=2.84 Hz, 1 H) 8.00 - 8.08 (m, 2 H) 6.10 - 6.56 (m, 1 H) 5.32 (dd, J=14.76, 1.38 Hz, 1 H) 4.87 (br dd, J=11.60, 4.81 Hz, 1 H) 4.52 4.67 (m, 2 H) 4.30 - 4.48 (m, 3 H) 2.35 - 2.45 (m, 1 H) 2.08 2.20 (m, 1 H) 1.89 - 1.99 (m, 2 H) 1.69 - 1.81 (m, 1 H) 1.49- 1.63 (m, 1 H) |
48 | JL À\ O | 479.1 | (300 MHz) 10.07 (d, J=8.71 Hz, 1 H) 8.60 (s, 1 H) 8.13 (d, J=2.93 Hz, 1 H) 8.04 - 8.11 (m, 2 H) 5.18 - 5.28 (m, 1 H) 4.95 - 5.08 (m, 2 H) 4.63 (ddd, J=10.34, 7.36, 3.12 Hz, 1 H) 4.36 - 4.51 (m, 3 H) 2.39 (br d, J=10.64 Hz, 1 H) 2.11 - 2.20 (m, 1 H) 1.91 2.00 (m, 2 H) 1.75 (br d, J=8.07 Hz, 1 H) 1.55- 1.64 (m, 1 H) |
49 | F z0H χχ x r° HN 0 αχό” | 441.1 | (300 MHz) 9.12 (t, J=5.00 Hz, 1 H) 8.62 (s, 1 H) 8.06 (d, J=2.93 Hz, 1 H) 8.00 (s, 1 H) 7.55 (dd, J=8.67, 2.80 Hz, 1 H) 5.35 (dd, J=14.81, 1.51 Hz, 1 H) 5.18 (t, J=5.73 Hz, 1 H) 5.08 (t, J=5.87 Hz, 1 H) 4.26-4.38 (m, 2 H) 4.10-4.17 (m, 1 H) 3.76 - 3.91 (m, 2 H) 3.63-3.72 (m, 1 H) |
110
3.41 (ddd, J=13.25, 6.14, 4.17 Hz, 1 H) 2.56-2.65 (m, 1 H) 2.14-2.28 (m, 1 H) 1.91 -2.01 (m, 2 H) 1.63- 1.86 (m, 2 H) |
Biologie assays
In-Vitro Assays
Materials and Methods
Biochemical Kinase Assay Method
The biochemical kinase assay was performed at Reaction Biology Corporation (www.reactionbiology.com, Malvern, PA) following the procedures described in the reference (Anastassiadis T, et al Nat BiotechnoL 2011,29, 1039). Spécifie kinase / substrate pairs along with required cofactors were prepared in reaction buffer; 20 mM Hepes pH 7.5, 10 mM MgCI2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO. Compounds were delivered into the reaction, followed ~ 20 minutes later by addition of a mixture of ATP (Sigma, St. Louis MO) and 33P ATP (Perkin Elmer, Waltham MA) to a final concentration of 10 μΜ. Reactions were carried out at room température for 120 min, followed by spotting of the reactions onto P81 ion exchange filter paper (Whatman Inc., Piscataway, NJ). Unbound phosphate was removed by extensive washing of filters in 0.75% phosphoric acid. After subtraction of background derived from control reactions containing inactive enzyme, kinase activity data was expressed as the percent remaining kinase activity in test samples compared to vehicle (dimethyl sulfoxide) reactions. IC50 values and curve fits were obtained using Prism (GraphPad Software).
Cell lines and cell culture;
Human medulla thyroid carcinoma cell line TT (containing RET M918T mutation) and acute myelogenous cell line KG-1 were purchased from ATCC. Human colon cancer cell line KM12 (containing TPM3-TRKA) was obtained from NCI.
Cloning and Ba/F3 stable cell line création
The EML4-ALK gene (variant 1) was synthesized at GenScript and cloned into pCDH-CMV-MCS-EF1-Puro plasmid (System Biosciences, Inc). Ba/F3-EML4-ALK wild type were generated by transducing Ba/F3 cells with lentivirus containing EML4-ALK wide type. Stable cell lines were selected by puromycin treatment, followed by IL-3 withdrawal. Briefly, 5X106Ba/F3 cells were transduced with lentivirus supernatant in the presence of 8pg/mL protamine sulfate. The transduced cells were subsequently selected with 1 pg/mL puromycin in the presence of IL3-containing medium RPMI1640,
111 plus 10% FBS. After 10-12 days of sélection, the surviving cells were further selected for IL3 independent growth.
The KIF5B-RET gene was synthesized at GenScript and cloned into pCDHCMV-MCS-EF1-Puro plasmid (System Biosciences, Inc). KIF5B-RET point mutation V804M was generated at GenScript by PCR and confirmed by sequencing. Ba/F3KIF5B-RET wild type and mutant were generated by transducing Ba/F3 cells with lentivirus containing KIF5B-RET wide type or mutant. Stable cell lines were selected by puromycin treatment, followed by IL-3 withdrawal. Briefly, 5X106Ba/F3 cells were transduced with lentivirus supematant in the presence of 8pg/mL protamine sulfate. The transduced cells were subsequently selected with 1 pg/mL puromycin in the presence of IL3-containing medium RPMI1640, plus 10% FBS. After 10-12 days of sélection, the surviving cells were further selected for IL3 independent growth.
Cell prolifération assays:
Two thousand cells per well were seeded in 384 well white plate for 24 hrs, and then treated with compounds for 72 hours (37 °C, 5% CO2). Cell prolifération was measured using CelITiter-GIo luciferase-based ATP détection assay (Promega) following the manufactures’s protocol. IC50 déterminations were performed using GraphPad Prism software (GraphPad, Inc., San Diego, CA).
Immunoblotting for cellular kinase phosphorylation assays
Half a million cells per well were seeded in 24 well plate for 24 hrs, and then treated with compounds for 4 hours. Cells were collected after treatment and lysed in RIPA buffer (50 mM Tris, pH 7.4, 150 mM NaCI, 1% NP-40, 0.5% Deoxycholate, 0.1% SDS) supplemented with 10 mM EDTA, 1X Hait protease and phosphatase inhibitors (Thermo Scientific). Protein lysâtes (approximately 20 pg) was resolved on 4-12% Boit Bis-Tris precasted gels with MES running buffer (Life Technologies), transferred to nitrocellulose membranes using Trans-Blot Turbo Transfer System (Bio-Rad) and detected with antibodies targeting phosphorylated RET (Y905) (Cell Signaling Technology), total RET (Cell Signaling Technology), actin (Cell Signaling Technology). Antibodies were typically incubated overnight at 4 oC with gentle shake, followed by washes and incubation with the appropriate HRP-conjugated secondary antibodies. Membranes were incubated with chemiluminescent substrate for 5 min at room température (SuperSignal West Femto, Thermo Scientific). The chemiluminescent images were acquired with a C-DiGit Imaging System (LI-COR Biosciences). The relative density ofthe chemiluminescent bands were quantified via Image Studio Digits from LICOR. The half inhibitory concentration (IC5o) value is calculated using non-linear 112 régression analysis through GraphPad Prism software (GraphPad, Inc., San Diego, CA).
Data and Results:
Enzymatic kinase activities of Compound 1 and 5.
Enzyme | IC50 (nM) at 10 pM ATP | IC50 (nM) at 10 pM ATP |
Compound 1 | Compound 5 | |
RET | 0.0994 | 1.01 |
RET (A883F) | 0.520 | 3.08 |
RET (E762Q) | 2.07 | 0.58 |
RET(G691S) | 3.01 | 0.941 |
RET (L790F) | 0.120 | 1.31 |
RET (M918T) | 0.114 | 1.42 |
RET (R749T) | 0.271 | 0.32 |
RET (R813Q) | 0.341 | 2.46 |
RET (S891A) | 0.664 | 0.303 |
RET (S904A) | 0.159 | 1.22 |
RET (S904F) | 0.0621 | 0.364 |
RET (V778I) | <0.0508 | 0.233 |
RET (V804L) | 10.0 | 2350 |
RET (V804M) | 7.86 | 18.8 |
RET (Y791F) | <0.0508 | 7.95 |
RET (Y806H) | 0.385 | 0.261 |
RET-CCDC6 (PTC1) | 0.0893 | 1.97 |
RET-NCOA4 (PTC3) | 0.0635 | 0.691 |
RET-PRKAR1A (PTC2) | 0.129 | 0.29 |
Src | 0.875 | 1.46 |
FYN | 1.81 | 1.94 |
YES | 1.72 | 2.64 |
HCK | 1.95 | 2.71 |
LYN | 1.97 | 2.03 |
113
Anti-cell prolifération activity
Cpd | BaF3 EML4ALK | KG-1 IC50 (nM) | TT cell (RET C634W ) IC50 (nM) | BaF3 KIF5BRET IC50 (nM) | BaF3 KIF5BRET_V8 04M IC50 (nM) | BaF3 KIF5BRET_G8 10RIC50 (nM) | KM12 cell (TPM3TRKA) IC50 (nM) |
1 | 211.4 | 131.2 | <0.5 | 0.25 | 1002 | 30 | 3.0 |
2 | >10000 | 5000 | 1784 | 1452 | >10000 | 254.9 | |
3 | 1500 | 505 | 7.9 | <0.2 | 1704 | 4.2 | |
4 | 3287 | 5000 | 461.9 | 184.4 | 5000 | 22 | |
5 | 515.6 | 26.8 | 0.9 | 2.4 | 598 | 22 | 6.9 |
6 | 145.5 | 1 | 0.2 | 573.1 | 3 | 0.2 | |
7 | 674.8 | 343.8 | 0.2 | 1845 | 99.2 | 37 | |
8 | 4000 | 188.9 | 341.8 | 1928 | 0.3 | ||
9 | 8000 | 1000 | 2364 | >10000 | 3.3 | ||
10 | 4000 | 78.3 | 274.4 | 1213 | 0.2 | ||
11 | 10000 | 307.3 | 838.9 | 3000 | 0.4 | ||
12 | 2709 | 159.9 | 100.5 | 4619 | 1014 | 13.8 | |
13 | 5000 | 452 | 341.5 | >10000 | 1121 | 28.4 |
114
14 | 907.8 | 273 | 120.3 | 10000 | 530 | 26.6 | |
15 | 364.4 | 5.2 | 1.1 | 1245 | 8.7 | 5.1 | |
16 | 340.5 | 47.4 | 16.6 | 5000 | 41.2 | 45.5 | |
17 | 615.6 | 5 | 1.8 | 2731 | 10.7 | 4 | |
18 | 77.2 | 16.9 | 7.1 | 1533 | 24.4 | 11.3 | |
19 | 895.1 | 73.1 | 5.2 | 3073 | 78 | 7.8 | |
20 | 1400 | 2.4 | 1.1 | 1855 | 7.8 | 0.5 | |
21 | 461.7 | 86.9 | <0.2 | 3459 | 82 | 13.8 | |
22 | 157.5 | 155.8 | - | <0.2 | 1763 | 127.6 | 49.3 |
23 | 1682 | 228.2 | - | 98.9 | 3000 | 422.2 | 52.9 |
24 | 468.9 | 8.7 | - | 1.8 | 1222 | 73.6 | 2.8 |
25 | 3000 | 677.3 | - | 193.3 | 3000 | 559.1 | 277.3 |
26 | 1412 | 737.1 | 160 | 5000 | 323.2 | 210.1 | |
27 | 1000 | 0.3 | - | <0.2 | 2000 | 63 | 0.3 |
28 | 803.5 | 22.8 | - | 1.5 | 2000 | 72 | 11.8 |
29 | 901 | 7.9 | - | 0.3 | 1377 | 133.7 | 1.7 |
115
30 | 2000 | 853.2 | - | 161.9 | 337.2 | 1857 | 13.5 |
31 | 10000 | 10000 | - | 4000 | >10000 | >10000 | 365 |
32 | 1056 | 223 | - | 89 | 5718 | 500.8 | 20.2 |
33 | 2000 | 356.2 | - | 197.9 | 4000 | 1196 | 124.5 |
34 | 1000 | 407.5 | - | 62.2 | 10000 | 651.1 | 50 |
35 | 1105 | 55.7 | - | 8.8 | - | - | <0.2 |
36 | >10000 | 10000 | - | 8000 | - | 1000 | |
37 | >10000 | 3000 | - | 8000 | - | - | 1201 |
38 | 82.1 | <0.2 | - | <0.2 | 349.3 | 0.3 | <0.2 |
39 | 151.5 | 59.2 | - | 10.2 | 3000 | 57.3 | 7.4 |
40 | 1951 | 19.1 | - | <0.2 | 5000 | 1.8 | <0.2 |
41 | 1448 | 389.2 | - | 5.1 | - | 155.6 | 431.2 |
42 | 338.5 | 41 | - | 0.5 | - | 17.4 | 9.8 |
43 | 2991 | 359.4 | - | 68.9 | - | 395.9 | 108.6 |
44 | >10000 | >10000 | - | >10000 | >10000 | >10000 | 668.5 |
45 | 3109 | 1134 | - | 525.7 | 5000 | 1712 | 202.4 |
116
46 | 55.5 | 5.9 | - | <0.2 | 71.5 | 2.9 | 2.8 |
47 | 139.2 | 3.5 | - | <0.2 | 469.3 | 3.6 | <0.2 |
48 | 455.9 | 117 | - | 0.2 | 1067 | 90.9 | 5.9 |
49 | >10000 | 5238 | - | 396.6 | 5000 | 1643 | 1457 |
Compound 5 inhibited the phosphorylation of RET
The pharmacodynamie inhibiting activity of Compound 5 on RET in RET-driven cells was evaluated, and the results were shown in FIGs. 1, 2 and 3. Compound 5 caused the suppression of RET autophosphorylation at IC50s of around 0.3, 1-3 and 310 nM in TT, Ba/F3 KIF5B-RET WT and Ba/F3 KIF5B-RET G810R respectively (FIGS. 1,2 &3).
In Vivo Methods
Cell lines
BaF3 KIF5B-RET WT and BaF3 KIF5B-RET G810R cells were cultured using standard techniques in RPMI-1640 medium (Corning, Inc) with 10% fêtai bovine sérum (Thermo Fisher Scientific, Inc) at 37°C in a humidified atmosphère with 5% CO2. TT cells were cultured using standard techniques in F-12K medium (Corning, Inc) with 10% fêtai bovine sérum (Thermo Fisher Scientific, Inc) at 37°C in a humidified atmosphère with 5% CO2.For implantation, cells were harvested and pelleted by centrifugation at 250g for 2 minutes. Cells were washed once and resuspended in serum-free medium supplemented with 50% matrigel (v/v).
Subcutaneous Xenograft Models in Immune Compromised Mice
For cell derived xenograft models, female SCID/Beige mice (5-8 weeks of âge) were obtained from Charles River Laboratory and were housed in Innovive IVC disposable cages on HEPA filtered ventilated racks with ad libitum access to rodent chow and water. Five million cells in 100 pL serum-free medium supplemented with 50% matrigel (Corning, Inc) were implanted subcutaneously in the right flank région of the mouse. Tumor size and body weight were measured on designated days. Tumor 117 size was measured with an electronic caliper and tumor volume was calculated as the product of length * width2 * 0.5. Mice were randomized by tumor size into treatment groups when tumor volume reached about 200 mm3 and Compound 5 was administered orally (BID) at determined doses.
For PDX models, primary human tumor xenograft model LU2503 tumors were grown in stock mice. Tumor fragments (2-3 mm in diameter) were harvested from stock mice an dinoculated into the right front back of each female BALB/c nude mice for tumor development. Tumor size and body weight were measured on designated days. Tumor size was measured with an electronic caliper and tumor volume was calculated as the product of length * width2 * 0.5. Mice were randomized by tumor size into treatment groups when tumor volume reached about 200 mm3 and Compound 5 was administered orally (BID) at determined doses.
Antitumor Efficacy of Compound 5 in Xenograft Tumor Models
The antitumor efficacy of Compound 5 was evaluated in several tumor xenograft models representing cancer populations in which dysrégulation of RET is implicated.
TT Thyroid Medullary Carcinoma Model
The C634W mutation of RET in TT cells underlies the molecular mechanism for tumor growth. SCID/Beige mice bearing TT tumors (at the average tumor size of around 200 mm3) were dosed with Compound 5 orally BID for 27 days (FIG. 4A). The control group of mice were given vehicle only. Tumor volume (TMV) was measured by caliper on the indicated days and is shown at mean ± sem in FIG. 4A. The mean TMVs are significantly lower in the treated groups compared to that of the control group (p<0.0001) as determined by two-way repeated ANOVA followed by post hoc analysis. Tumor growth inhibition (TGI) was calculated as 100%*{1-[(TMVTreated Last Day ofTreatmentTMVTreated First Day of Treatment)/(TMVcontrol on Last Day of TreatmenfTMVcontrol on First Day of Treatment)]} when TMVTreatej Last Day of Treatment — TMVfreated First Day of Treatment· In the Case Of TMVTreated Last Day of Treatment < TMVTreated First Day of Treatment-, tumor regreSSIOn (REG) WaS Calculated as 1 00% (1 - TMVfreated Last Day of Treatment/TMVTreated First Day of Treatment)· In thlS Study, Compound 5 demonstrated the ability to induce tumor régression of 27% and 35% at the dose of 2 mg/kg BID and 5 mg/kg BID, respectively. Tumor size was reduced in 10 out 10 mice treated with Compound 5 at both dose levels. Body weight of the mice were measured on the designated days ofthe mice as shown in FIG. 4B. No body weight loss or overt abnormality was observed at either dose levels.
118
Inhibition of the growth of BaF3 KIF5B-RET WT tumors and BaF3 KIF5B-RET G81 OR tumors following oral administration of Compound 5
In the BaF3 KIF5B-RET WT and BaF3 KIF5B-RET G810R xenograft tumor models, the growth of tumor is presumably dépendent on the extopic RET activity. SCID/Beige mice bearing BaF3 KIF5B-RET WT tumors (with average tumor size of -210 mm3) were dosed with Compound 5 orally BID for 10 days (FIG. 5A). The control group of mice were given vehicle only. Tumor volume (TIW) was measured by caliper on the indicated days and is shown at mean ± sem in FIG. 5A. The mean TIWs are lower in the groups treated with compound 5 at 1 mg/kg BID (p>0.05) and 5 mg/kg BID (p<0.0001) compared to that of the control group as determined by two-way repeated ANOVA followed by post hoc analysis. Compound 5 demonstrated the ability to inhibit tumor growth at 21% at the dose of 1 mg/kg BID. Compound 5 treatment at 5 mg/kg BID resulted in a tumor régression of 63%, with tumor size réduction in 9 out 10 mice. Body weight of the mice were measured on the designated days of the mice as shown in FIG. 5B. No body weight loss or overt abnormality was observed in compound 5 treatment groups. SCID/Beige mice bearing BaF3 KIF5B-RET G810R tumors (with average tumor size of -170 mm3) were dosed with Compound 5 orally BID for 14 days (FIG. 6A). The control group of mice were given vehicle only. Tumor volume (TIW) was measured by caliper on the indicated days and is shown at mean ± sem in FIG. 6A. The mean TMVs are lower in the groups treated with compound 5 at 1 mg/kg BID (p>0.05), 5 mg/kg BID (p<0.0001) and 10 mg/kg BID (p<0.0001) compared to that ofthe control group as determined by two-way ANOVA followed by post hoc analysis. Compound 5 treatment at 1 mg/mg BID inhibited tumor growth with a TGI of 22%. Compound 5 treatment at 5 mg/kg BID resulted in a tumor régression of 39%, with tumor size réduction in 9 out 10 mice. Compound 5 treatment at 10 mg/kg BID resulted in complété tumor régression in 9 out 9 mice. Body weight of the mice were measured on the designated days of the mice as shown in FIG. 6B. No body weight loss or overt abnormality was observed in compound 5 treatment groups during the treatment period.
CR1520 Patient Derived Xenograft (PDX) Colorectal Cancer Model
The CR1520 is a PDX model derived from a colorectal cancer patient harboring the NCOA4-RET fusion gene. Treating mice bearing CR1520 tumors with Compound 5 at 1 mg/kg BID for 21 days resulted inhibited tumor growth with a TGI of 63%, with 119 tumors grew from 187 mm3 to 872 mm3. For comparison, the tumors grew from 187 mm3 to 2044 mm3 in the vehicle treated group (FIG. 7A). Treating mice bearing CR1520 tumors with Compound 5 at 5 mg/kg BID for 21 days resulted a tumor régression from 187 mm3 to 138 mm3, corresponding to a 26% tumor régression (FIG.
7A). No body weight loss was observed after 21 days of BID treatment with Compound at 1 mg/kg BID or 5 mg/kg BID (FIG. 7B).
CTG-0838 Patient Derived Xenograft (PDX) NSCLC Model
The CTG-0838 is a PDX model derived from a non-small cell lung cancer patient harboring the KIF5B-RET fusion gene. Treating mice bearing CTG-0838 tumors with Compound 5 at 1 mg/kg BID and 2 mg/kg BID for 10 days resulted inhibited tumor growth with a TGI of 71% and 76%, respectively (FIG. 8A). Treating mice bearing CTG0838 tumors with Compound 5 at 5 mg/kg BID for 10 days resulted a tumor régression from 197 mm3 to 174 mm3, corresponding to a 12% tumor régression (FIG. 8A). No body weight loss was observed after 10 days of BID treatment with Compound 5 at the 1,2 or 5 mg/kg BID (FIG.8B).
Claims (16)
- WHAT IS CLAIMED IS:1. A compound of the formula I wherein each L is independently -C(R1)(R2)- or X; with the proviso that, when t is 1, then L is -C(R1)(R2)-;XisO, S, S(O) orS(O)2;each R1 and R2 is independently H, deuterium, halogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, mono- or bi-cyclic heteroaryl, -ORa, -OC(O)Ra, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or R1 and R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, C6-Ci0aryl, mono- or bi-cyclic heteroaryl, or 4- to 6membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;M is CR3 or N;121M1 is CR4;each R3, R4, and R5 is independently hydrogen, deuterium, halogen, -ORC, OC(O)RC, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, NRcC(O)Rd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORC, -C(O)NRcRd, C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, P(O)2ORC, -CN, -NO2, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, C6-Ci0aryl, or mono- or bi-cyclic heteroaryl, or R4 and R5 taken together with the ring to which they are attached form a C5-C8 cycloalkyl, or a 5- to 8-membered heterocycloalkyl, wherein each hydrogen atom in C-i-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, mono- or bi-cyclic heteroaryl, C5-C8 cycloalkyl, or 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2R®, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or-NO2;R6 is H, deuterium, Ci-C6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 3to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bi-cyclic heteroaryl, wherein each hydrogen atom in Ci-C8 alkyl, C2-C8 alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, or mono- or bi-cyclic heteroaryl is independently optionally substituted by deuterium, halogen, C3-C8 cycloalkyl, or 5- to 7membered heterocycloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;R7 and R8 combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 7membered heteroaryl is independently optionally substituted by deuterium, halogen, ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, 122OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf,-NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf,-NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf,-P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or-NO2;Y is O, S, NR9, orCR9R10;R9 and R10 are each independently H, deuterium, halogen, Ci-C6 alkyl, C2-C3 alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bi-cyclic heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, or mono- or bi-cyclic heteroaryl is optionally substituted by a halogen, -ORe, -OC(O)Re, OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, P(O)ORe, or-P(O)2ORe;each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, C6-Ci0aryl, 5- to 7- membered heteroaryl;each of Z1, Z2, Z3, Z4, Z5, and Z6 is independently N, NH, C or CH;p is 1,2, 3, or 4; and t is 1,2, 3, 4, or 5; or a pharmaceutically acceptable sait thereof.
- 2. The compound of claim 1, or a pharmaceutically acceptable sait thereof, wherein p is 1.
- 3. The compound of claim 2, or a pharmaceutically acceptable sait thereof, wherein t is 3 or 4.
- 4. The compound of claim 1, or a pharmaceutically acceptable sait thereof, having the formula II123whereinM is CR3 or N;M1 is CR4;Xis O, S, S(O), orS(O)2;each R1 and R2 is independently H, deuterium, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-Ci0aryl, -ORa, -SRa, -NRaRb, -C(O)ORa, or-C(O)NRaRb; or R1 and R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl; wherein each hydrogen atom in Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-Ci0aryl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCi-C6 alkyl, -NH2, -OC(O)Ci-C6 alkyl, -OC(O)N(C1-C6 alkyl)2, -OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(C1-C6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), -OC(=N)NH2, -OS(O)Ci-C6 alkyl, -OS(O)2CrC6 alkyl, -NH(CrC6 alkyl), -N(Ci-C6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(C1-C6 alkyl)C(O)NH2, -N(Ci-C6 alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)C(O)N(CiC6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(CrC6 alkyOCiOJOCrCe alkyl, -NHC(O)OH, -N(Ci-C6 alkyl)C(O)OH, -NHS(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(C1-C6 alkyl)S(O)Ci-C6 alkyl, -N(CrC6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)2NH2, N(CtC6 alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)2NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)2N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(Ci-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(CrC6 alkyl)S(O)N(C-i-C6 alkyl)2, -N(CrC6 alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)CrC6 alkyl, -CO2H, -C(O)OCrC6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(CrC6 alkyl)2, -SCi-C6 alkyl, -S(O)Ci-C6 alkyl, -S(O)2Ci-C6 alkyl, -S(O)NH(CrC6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(Ci-C6 alkyl)2, -S(O)2N(Ci-C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(CrC6 alkyl)2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl),124-OS(O)NH2, -OS(O)2NH2, -P(C,-C6 alkyl)2, -P(O)(CrC6 alkyl)2, C3-C6 cycloalkyl, or 3- to7-membered heterocycloalkyl;R3, R4, and R5 are each independently H, fluoro, chloro, bromo, Ci-C6 alkyl, -OH,-CN, -OCrC6 alkyl, -NHCi-C6 alkyl, -N(CrC6 alkyl)2 or-CF3;R6 is H, Ci-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in Ci-C6 alkyl or 3-to 7-membered heterocycloalkyl is independently optionally substituted by halogen, -OH, -CN, -OCi-C6 alkyl, -NH2, -NH(Ci-Cg alkyl), N(CrC6 alkyl)2, -CO2H, -C(O)OCrC6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), C(O)N(C1-C6 alkyl)2, C3-C6 cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;R7 and R8 combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Ci0aryl, or 5- to 7membered heteroaryl is independently optionally substituted by deuterium, halogen, OH, -OCrC6 alkyl, -OC(O)Ci-C6 alkyl, -OC(O)NH2, -OC(O)NH(C1-C6 alkyl), -OC(O)N(Ci-C6 alkyl)2, -OC(=N)NH2, -OC(=N)NH(C1-C6 alkyl), -OC(=N)N(CrC6 alkyl)2, -OS(O)CrC6 alkyl, -OS(O)2Ci-C6 alkyl, -OS(O)NH2, -OS(O)NH(C1-C6 alkyl), -OS(O)N(C1-C6 alkyl)2, -OS(O)2NH2, -OS(O)2NH(Ci-C6 alkyl), -OS(O)2N(CrC6 alkyl)2, SH, -SCi-C6 alkyl, -S(O)CrC6 alkyl, -S(O)2CrC6 alkyl, -S(O)NH2, -S(O)NH(Ci-C6 alkyl), -S(O)(Ci-C6 alkyl)2, -S(O)2NH2, -S(O)2NH(Ci-C6 alkyl), -S(O)2N(Ci-C6 alkyl)2, -NH2, -NH(Ci-C6 alkyl), -N(CrC6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)C(O)CrC6 alkyl, NHC(O)OH, -NHC(O)OCi-C6 alkyl, -N(Ci-C6 alkyl)C(O)OH, -N(Ci-C6 alkyl)C(O)OCrC6 alkyl, -NHC(O)NH2, -NHC(O)NH(CrC6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NH(C1-C6 alkyl), -N(Ci-C6 alkyOCiOJNCCrCe alkyl)2, -NHS(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)S(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(CrC6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)N(Ci-C6 alkyl)2, -NHS(O)2NH2, -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)2N(Ci-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2NH2, -N(CrC6 alkyl)S(O)2NH(C1-C6 alkyl), -N^-Ce alkyl)S(O)2N(C1-C6 alkyl)2, -C(O)CrC6 alkyl, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(Ci-C6 alkyl)2, -P(CrC6 alkyl)2, -P(O)(Ci-C6 alkyl)2, -P(O)2(CrC6 alkyl)2, -P(O)NH2, -P(O)NH(C1-C6 alkyl), -P(O)N(C1-C6 alkyl)2, -P(O)2NH2, -P(O)2NH(Ci-C6 alkyl), -P(O)2N(Ci-C6 alkyl)2, -P(O)OH, -P(O)OCi-C6 alkyl, -P(O)2OH, -P(O)2OCi-C6 alkyl, -CN, or -NO2;Y is O, S, NR9, orCR9R10;125R9 and R10 are each independently H, deuterium, halogen, or Ci-Ce alkyl, wherein each hydrogen atom in Ci-C6 alkyl is optionally substituted by a halogen, -OH, OCi-C6 alkyl, -00(0)0^06 alkyl, -OC(O)N(Ci-C6 alkyl)2, -OCiOjNHiCrCe alkyl), -OC(O)NH2, -OC(=N)N(Ci-C6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), -OC(=N)NH2, -03(0)^C6 alkyl, -OS(O)2Ci-C6 alkyl, -OSiOjNiCrCe alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)2NH(Ci-C6 alkyl), -OS(O)2NH2, -SH, -SCr C6 alkyl, -3(0)0^06 alkyl, -3(0^0^06 alkyl, -S(O)N(Ci-C6 alkyl)2, -S(O)NH(CrC6 alkyl), -S(O)NH2, -S(O)2N(CrC6 alkyl)2, -S(O)2NH(CrC6 alkyl), -S(O)2NH2, -N(CrC6 alkyl)2, -NH(Ci-C6 alkyl), -NH2, -N(Ci-C6 alkyljCiOjCrCs alkyl, -NHC(O)C1-C6 alkyl, N(Ci-C6 alkyl)C(O)OCi-C6 alkyl, -N(CrC6 alkyl)C(O)OH, -NHC(O)OCi-C6 alkyl, NHC(O)OH, -N(Ci-C6 alkyl)C(O)N(CiC6 alkyl)2, -N(Ci-C6 alkyl)C(O)NH(CiC6 alkyl), -N(Ci-C6 alkyl)C(O)NH2, -NHC(O)N(CiC6 alkyl)2, -NHC(O)NH(CiC6 alkyl), -NHC(O)NH2, -N(Ci-C6 alkyl)S(O)Ci-C6 alkyl, -NHS(O)Ci-C6 alkyl, -N(CrC6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-C6 alkyl)S(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)S(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)S(O)NH2, -NHS(O)N(Ci-C6 alkyl)2, -NHSiOjNHiCrCe alkyl), -NHS(O)NH2, -N(Ci-C6 alkyQSiOhNiCrCe alkyl)2, -N^-Ce alkyOSCO^NHiCrCe alkyl), -N(CrC6 alkyl)S(O)2NH2, -NHS(O)2N(Ci-C6 alkyl)2, -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)2NH2, -C(O)Ci-C6 alkyl, -C(O)OCi-C6 alkyl, -C(O)N(Ci-C6 alkyl)2, -C(O)NH(Cr C6 alkyl), -C(O)NH2, -P(CrC6 alkyl)2, -P(O)(CrC6 alkyl)2, -P(O)2(CrC6 alkyl)2, -P(O)N(Ci-C6 alkyl)2, -P(O)2N(Ci-C6 alkyl)2, -Ρ(Ο)ΟΟ!-Ο6 alkyl, or -P(O)2OCrC6 alkyl;each of Z1, Z2, Z3, Z4, Z5, and Z6 is independently N, NH, C or CH; and n is 1,2 or 3.
- 5. The compound of claim 1, having the formula III wherein n is 2 or 3;126 or a pharmaceutically acceptable sait thereof.
- 6. The compound of claim 1, having the formula IV or VIV V or a pharmaceutically acceptable sait thereof.
- 7. The compound of any one of the preceding daims, or a pharmaceutically acceptable sait thereof, wherein Y is O.
- 8. The compound of any one of the preceding daims, or a pharmaceutically acceptable sait thereof, wherein R3 is H, deuterium, Ci-Ce alkyl or halogen.
- 9. The compound of any one of the preceding daims, or a pharmaceutically acceptable sait thereof, wherein R4 is H, deuterium, or Cl.
- 10. The compound of any one of the preceding daims, or a pharmaceutically acceptable sait thereof, wherein R5 is F.
- 11. The compound of any one of the preceding daims, or a pharmaceutically acceptable sait thereof, wherein R2 is H.
- 12. The compound of any one of the preceding daims, or a pharmaceutically acceptable sait thereof, wherein R1 is H or C-i-C6 alkyl.
- 13. The compound of any one of daims 1 to 10, or a pharmaceutically acceptable sait thereof, wherein R1 is H, and R2 is CrC6 alkyl; or R1 is Ci-C6 alkyl, and R2 is H; or R1 is127H or Ci-Cg alkyl, and R2 is H; or R1 is H, and R2 is C3-C7 cycloalkyl; or R1 is C3-C7 cycloalkyl, and R2 is H.
- 14. The compound of any one ofthe preceding claims, or a pharmaceutically acceptable sait thereof, wherein R7 and R8 combine to form a 4-, 5- or 6-membered cycloalkyl, wherein each hydrogen atom in the 4-, 5- or 6-membered cycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCrCe alkyl, OCi-C6 alkyl(C6-Ci0aryl), -NH2, -OC(O)Ci-C6 alkyl, -OC(O)N(Ci-C6 alkyl)2, ΟΟ^ΝΗ^-Οβ alkyl), -OC(O)NH2, -OC(=N)N(C1-C6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), OC(=N)NH2, -OS(O)Ci-C6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(CrC6 alkyl), -N(CrC6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)C(O)CrC6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)C(O)NH2, -N(Ci-C6 alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCrC6 alkyl, -N(CrC6 alkyl)C(O)OCi-C6 alkyl, -NHC(O)OH, -N(Ci-C6 alkyl)C(O)OH, -NHS(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(CrC6 alkyl)S(O)Ci-C6 alkyl, -N(CrC6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)2NH2, -N(Ci-C6 alkyl)S(O)NH2, -N(CrC6 alkyl)S(O)2NH2, -NHS(O)NH(C1-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(CrC6 alkyl)S(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)S(O)N(Ci-C6 alkyl)2, -NiC^Ce alkyl)S(O)2N(C1-C6 alkyl)2, -C(O)Ci-C6 alkyl, -CO2H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(CrC6 alkyl)2, -SCrC6 alkyl, -S(O)CrC6 alkyl, -S(O)2CiC6 alkyl, -SiOJNHiCrCe alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(CrC6 alkyl)2, -S(O)2N(CiC6 alkyl)2, -S(O)NH2, -S(O)2NH2, -0S(0)N(CrC6 alkyl)2, -OS(O)2N(CrC6 alkyl)2, -OSiOjNHiCrCe alkyl), -OS(O)2NH(CrC6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(CrC6 alkyl)2, -P(O)(C-i-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl; or R7 and R8 combine to form a 5- or 6-membered heterocycloalkyl, wherein each hydrogen atom in the 5- or 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCi-C6 alkyl, -OCi-C6 alkyl(C6-Ci0aryl), -NH2, -00(0)0^ alkyl, -OC(O)N(Ci-C6 alkyl)2, -OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(C1-C6 alkyl)2, -OC(=N)NH(Ci-C6 alkyl), -OC(=N)NH2, -OS(O)CrC6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -NHC^CrCe alkyl, -N(CrC6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(CrC6 alkyl)C(O)NH2, -N(Ci-C6 alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(CrC6 alkyl)C(O)N(CiC6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(CrC6 alkyl^OjOCrCe alkyl, -NHC(O)OH, -N(Ci-C6 alkyl)C(O)OH, -NHS(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(CrC6128 alkyl)S(O)Ci-C6 alkyl, -N(CrC6 alkyOSiOhCi-Ce alkyl,-NHS(O)NH2, -NHS(O)2NH2, N(Ci-C6 alkyl)S(0)NH2, -N(Ci-C6 alkyl)S(O)2NH2, -NHS(O)NH(Ci-C6 alkyl),-NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)2N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)S(0)NH(Ci-C6 alkyl), -N(CrC6 alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-C65 alkyl)S(O)N(Ci-C6 alkyl)2, -N(Ci-C6 alkyl)S(O)2N(Ci-C6 alkyl)2, -0(0)0^ alkyl, -C02H, -C(0)0Ci-C6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(Ci-C6 alkyl)2, -SC^Ce alkyl, -8(0)0^ alkyl, -S(O)2Ci-C6 alkyl, -S(O)NH(Ci-C6 alkyl), -S(O)2NH(Ci-C6 alkyl), -SiOjNiCrCe alkyl)2, -S(O)2N(C1-C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(CrC6 alkyl)2, -OS(O)2N(Ci-C6 alkyl)2, -Ο8(Ο)ΝΗ(Ο!-Ο6 alkyl), -OSiO^NHiCrCe alkyl),10 -OS(O)NH2, -OS(O)2NH2i -ΡίΟρΟβ alkyl)2, -P(O)(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.
- 15. The compound of claim 14, or a pharmaceutically acceptable sait thereof, whereinR7 and R8 combine to form a tetrahydrofuran ring, cyclobutane ring, cyclopentane ring, 15 or cyclohexane ring.
- 16. The compound of claim 1, selected form the group consisting of
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