Rip1 kinase inhibitor and use thereof
AssigneeSironax (Beijing) Co., Ltd.
InventorsYaning Su, Hanying Ruan, Zhiyuan Zhang, Yanping Xu, Yimin Jianng
Life of this patent
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Abstract
Provided are novel compounds of general formula (I) that inhibit RIP1 kinase or a pharmaceutically acceptable salt thereof, a composition comprising such compounds, and use of such compounds in inhibiting programmed necrosis, inhibiting RIP1 kinase, or treating or preventing a disease that is at least partially mediated by RIP1 kinase.
Claims30
A compound of general formula (I), or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof:
- wherein,
- Ring A is C6-C12aryl;
- C3-C8cycloalkyl;
- or 5 to 12 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said aryl, cycloalkyl or heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano, hydroxy, nitro, —NR1R2, —C(═O)R1, —C(═O)OR1, —OC(═O)R1, —C(═O)NR1R2, —SR1, —S(═O)R1, —S(═O)2R1 and —S(═O)2NR1R2;
- Ring Ar2 is C6-C12arylene;
- C3-C8cycloalkylene;
- 3 to 12 membered heterocyclylene containing 1 or 2 heteroatoms independently selected from N, O and S;
- or 5 to 12 membered heteroarylene containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said arylene, cycloalkylene, heterocyclylene or heteroarylene is substituted with 0, 1, 2 or 3 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano, hydroxy, nitro, —NR1R2, —C(═O)R1, —C(═O)OR1, —OC(═O)R1, —C(═O)NR1R2, —SR1, —S(═O)R1, —S(═O)2R1 and —S(═O)2NR1R2, and wherein said heterocyclylene is optionally further substituted with one ═O group;
- Ring Ar3 is C6-C12aryl;
- 3 to 12 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S;
- or 5 to 12 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said aryl, heterocyclyl or heteroaryl is substituted with 0, 1, 2 or 3 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano, hydroxy, nitro, —NR1R2, —C(═O)R1, —C(═O)OR1, —OC(═O)R1, —C(═O)NR1R2, —SR1, —S(═O)R1, —S(═O)2R1 and —S(═O)2NR1R2, and wherein said heterocyclyl is optionally further substituted with one ═O group;
- L is selected from C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene;
- Xis CR1R2, O orS;
- Q is C or N;
- W is CR3, —C(═O)— or N;
- the dashed line between Q and W represents a single bond or a double bond, provided that when Q is C, the dashed line between Q and W represents a double bond and at the same time W is CR3 or N, and when Q is N, the dashed line between Q and W represents a single bond and at the same time W is —C(═O)—;
- each of R1 and R2 is independently H or C1-C6alkyl;
- and
- R3 is H, halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano, hydroxy, nitro or —NR1R2.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein Ring A is C3-C8 cycloalkyl, preferably C4-C7 cycloalkyl, more preferably cyclopentyl or cyclohexyl, still more preferably cyclohexyl, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano and hydroxy, preferably substituted with 0, 1 or 2 substituents independently selected from halogen and cyano, more preferably substituted with 0, 1 or 2 substituents independently selected from F, Cl and cyano.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein Ring A is 5 to 12 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, preferably 5 or 6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, for example pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, more preferably 6 membered heteroaryl containing 1 or 2 N atoms, for example pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, still more preferably pyridinyl, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano and hydroxy, preferably substituted with 0, 1 or 2 substituents independently selected from halogen and cyano, more preferably substituted with 0, 1 or 2 substituents independently selected from F, Cl and cyano.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein Ring Ar2 is C6-C12 arylene, preferably phenylene or naphthylene, more preferably phenylene, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano and hydroxy, preferably substituted with 0 or 1 C1-C6alkyl groups, more preferably substituted with 0 or 1 substituents independently selected from methyl and ethyl.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein Ring Ar2 is C3-C8 cycloalkylene, preferably C4-C7 cycloalkylene, more preferably cyclopentylene or cyclohexylene, still more preferably cyclopentylene, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano and hydroxy, preferably substituted with 0 or 1 C1-C6alkyl groups, more preferably substituted with 0 or 1 substituents independently selected from methyl and ethyl.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein Ring Ar2 is 3 to 12 membered heterocyclylene containing 1 or 2 heteroatoms independently selected from N, O and S, preferably 5 or 6 membered heterocyclylene containing 1 or 2 heteroatoms independently selected from N, O and S, for example pyrrolidinylene, tetrahydrofuranylene, tetrahydrothiophenylene, pyrazolidinylene, imidazolidinylene, oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, pyrrolinylene, dihydrofuranylene, dihydrothiophenylene, pyrazolinylene, imidazolinylene, oxazolinylene, isoxazolinylene, thiazolinylene, isothiazolinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, dihydropyridinylene, dihydropyrazinylene, dihydropyrimidinylene, dihydropyridazinylene, more preferably 6 membered heterocyclylene containing 1 N atom, for example piperidinylene, dihydropyridinylene, still more preferably dihydropyridinylene, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano and hydroxy and further substituted with one ═O group, preferably substituted with 0 or 1 C1-C6alkyl groups and further substituted with one ═O group, more preferably substituted with 0 or 1 substituents independently selected from methyl and ethyl and further substituted with one ═O group.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein Ring Ar2 is 5 to 12 membered heteroarylene containing 1 or 2 heteroatoms independently selected from N, O and S, preferably 5 or 6 membered heteroarylene containing 1 or 2 heteroatoms independently selected from N, O and S, for example pyrrolylene, furanylene, thiophenylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, oxadiazolylene, thiadiazolylene, tetrazolylene, triazolylene, pyridinylene, pyridazinylene, pyrimidinylene, pyrazinylene or triazinylene, more preferably 6 membered heteroarylene containing 1 or 2 N atoms, for example pyridinylene, pyridazinylene, pyrimidinylene or pyrazinylene, still more preferably pyridinylene or pyrimidinylene, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano and hydroxy, preferably substituted with 0 or 1 C1-C6alkyl groups, more preferably substituted with 0 or 1 substituents independently selected from methyl and ethyl.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein Ring Ar3 is C6-C12aryl, preferably phenyl or naphthyl, more preferably phenyl, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano, hydroxy, —NR1R2 and —C(═O)NR1R2, preferably substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, —NH2 and —C(═O)NH2, more preferably substituted with 0, 1 or 2 substituents independently selected from chloro, methyl, methoxy, hydroxy, —NH2 and —C(═O)NH2.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein Ring Ar3 is 3 to 12 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, preferably 5 or 6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, for example pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, pyrrolinyl, dihydrofuranyl, dihydrothiophenyl, pyrazolinyl, imidazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydropyridinyl, dihydropyrazinyl, dihydropyrimidinyl, dihydropyridazinyl, more preferably 6 membered heterocyclyl containing 1 or 2 N atoms, for example dihydropyridinyl, dihydropyrazinyl, dihydropyrimidinyl, dihydropyridazinyl, still more preferably dihydropyrimidinyl, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano, hydroxy, —NR1R2 and —C(═O)NR1R2 and further substituted with one ═O group, preferably substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, —NH2 and —C(═O)NH2 and further substituted with one ═O group, more preferably substituted with 0, 1 or 2 substituents independently selected from chloro, methyl, methoxy, hydroxy, —NH2 and —C(═O)NH2 and further substituted with one ═O group.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein Ring Ar3 is 5 to 12 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, for example pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, cinnolinyl, furopyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, purinyl, quinolinyl, thienopyridinyl, preferably pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazopyridinyl or imidazopyridazinyl, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano, hydroxy, —NR1R2 and —C(═O)NR1R2, preferably substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, —NH2 and —C(═O)NH2, more preferably substituted with 0, 1 or 2 substituents independently selected from chloro, methyl, methoxy, hydroxy, —NH2 and —C(═O)NH2.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein L is C1-C6alkylene or C2-C6alkynylene, preferably methylene, ethylene, n-propylene or ethynylene, more preferably ethylene or ethynylene.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein X is CR1R2 or O, preferably CH2 or O.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein Q is C and the dashed line between Q and W represents a double bond and at the same time W is CR3 or N.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein Q is N and the dashed line between Q and W represents a single bond and at the same time W is —C(═O)—.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein W is CR3, preferably CH, CF, CCl, CBr, C(CH3) or C(C2H5).
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein W is N.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein each of R1 and R2 is independently H.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein each of R1 and R2 is independently C1-C6alkyl, preferably methyl or ethyl.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein R3 is H, halogen or C1-C6alkyl, preferably H, F, Cl, Br, methyl or ethyl, more preferably H, Cl or methyl.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein
- Ring A is phenyl or naphthyl;
- C4-C7 cycloalkyl;
- or 5 or 6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano and hydroxy;
- Ring Ar2 is phenylene or naphthylene;
- C4-C7cycloalkylene;
- 5 or 6 membered heterocyclylene containing 1 or 2 heteroatoms independently selected from N, O and S;
- or 5 or 6 membered heteroarylene containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano and hydroxy and the heterocyclylene is further substituted with one ═O group;
- Ring Ar3 is phenyl or naphthyl;
- 5 or 6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S;
- or 5 to 12 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, cyano, hydroxy, —NR1R2 and —C(═O)NR1R2 and the heterocyclyl is further substituted with one ═O group;
- L is selected from C1-C6alkylene or C2-C6alkynylene;
- X is CR1R2 or O;
- Q is C or N;
- W is CR3, —C(═O)— or N;
- the dashed line between Q and W represents a single bond or a double bond, provided that when Q is C, the dashed line between Q and W represents a double bond and at the same time W is CR3 or N, and when Q is N, the dashed line between Q and W represents a single bond and at the same time W is —C(═O)—;
- each of R1 and R2 is independently H, methyl or ethyl;
- and
- R3 is H, halogen or C1-C6alkyl.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein
- Ring A is phenyl;
- cyclopentyl or cyclohexyl;
- or 6 membered heteroaryl containing 1 or 2 N atoms, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from halogen and cyano;
- Ring Ar2 is phenylene;
- cyclopentylene or cyclohexylene;
- 6 membered heterocyclylene containing 1 N atom;
- or 6 membered heteroarylene containing 1 or 2 N atoms, wherein the above groups are substituted with 0 or 1 C1-C6alkyl groups and the heterocyclylene is further substituted with one ═O group;
- Ring Ar3 is phenyl;
- 6 membered heterocyclyl containing 1 or 2 N atoms;
- or pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazopyridinyl or imidazopyridazinyl, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, —NH2 and —C(═O)NH2 and the heterocyclyl is further substituted with one ═O group;
- L is selected from methylene, ethylene, n-propylene or ethynylene;
- X is CH2 or O;
- Q is C or N;
- W is CR3, —C(═O)— or N;
- the dashed line between Q and W represents a single bond or a double bond, provided that when Q is C, the dashed line between Q and W represents a double bond and at the same time W is CR3 or N, and when Q is N, the dashed line between Q and W represents a single bond and at the same time W is —C(═O)—;
- and
- R3 is H, F, Cl, Br, methyl or ethyl.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein
- Ring A is phenyl;
- cyclohexyl;
- or pyridinyl, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from F, Cl and cyano;
- Ring Ar2 is phenylene;
- cyclopentylene;
- dihydropyridinylene;
- or pyridinylene or pyrimidinylene, wherein the above groups are substituted with 0 or 1 substituents independently selected from methyl and ethyl and the dihydropyridinylene is further substituted with one ═O group;
- Ring Ar3 is phenyl;
- dihydropyrimidinyl;
- or pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazopyridinyl or imidazopyridazinyl, wherein the above groups are substituted with 0, 1 or 2 substituents independently selected from chloro, methyl, methoxy, hydroxy, —NH2 and —C(═O)NH2 and the dihydropyrimidinyl is further substituted with one ═O group;
- L is selected from ethylene or ethynylene;
- X is CH2 or O;
- Q is C or N;
- W is CR3, —C(═O)— or N;
- the dashed line between Q and W represents a single bond or a double bond, provided that when Q is C, the dashed line between Q and W represents a double bond and at the same time W is CR3 or N, and when Q is N, the dashed line between Q and W represents a single bond and at the same time W is —C(═O)—;
- and
- R3 is H, Cl or methyl.
A compound or a pharmaceutically acceptable salt, hydrate, solvate and stereoisomer thereof, wherein the compound is any one selected from Compounds 1-66 depicted in the following table:
- Compound 1
- Compound 2
- Compound 3
- Compound 4
- Compound 5
- Compound 6
- Compound 7
- Compound 8
- Compound 9
- Compound 10
- Compound 11
- Compound 12
- Compound 13
- Compound 14
- Compound 15
- Compound 16
- Compound 17
- Compound 18
- Compound 19
- Compound 20
- Compound 21
- Compound 22
- Compound 23
- Compound 24
- Compound 25
- Compound 26
- Compound 27
- Compound 28
- Compound 29
- Compound 30
- Compound 31
- Compound 32
- Compound 33
- Compound 34
- Compound 35
- Compound 36
- Compound 37
- Compound 38
- Compound 39
- Compound 40
- Compound 41
- Compound 42
- Compound 43
- Compound 44
- Compound 45
- Compound 46
- Compound 47
- Compound 48
- Compound 49
- Compound 50
- Compound 51
- Compound 52
- Compound 53
- Compound 54
- Compound 55
- Compound 56
- Compound 57
- Compound 58
- Compound 59
- Compound 60
- Compound 61
- Compound 62
- Compound 63
- Compound 64
- Compound 65
- Compound 66
Dependencies are inferred from the claim text.