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US 11,498,928 B2Granted
Macrocyclic spiroethers as Mcl-1 inhibitors
AssigneesAscentage Pharma (Suzhou) Co., Ltd., The Regents of the University of Michigan, Ascentage Pharma Group Corp Limited
InventorsJianyong Chen, Yunlong Zhou, Guozhi Tang, Chengzhe Wu, Leilei Zhao, Lingling Jiao, Binghua Sheng, Shaomeng Wang, Chao-Yie Yang, Hao Chen, Wenliang Hu, Yu Jing
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Abstract
Provided are compounds represented by Formula (I-A) and the pharmaceutically acceptable salts and solvates thereof, wherein R8, R9a, R9b, R9c, R9d, X, Y, Z, Z1, W, and (aa) are as defined as set forth in the specification. Provided are also compounds of Formula (I-A) for use to treat a condition or disorder responsive to Mcl-1 inhibition such as cancer.
Claims47
A compound of Formula I-A:
- wherein:
- X is selected from the group consisting of:
- wherein the bond projecting to the right is attached to the —S(═O)2— group;
- R8 is selected from the group consisting of hydrogen and C1-C3 alkyl;
- or
- X and R8 taken together form a spirocycle of Formula X-3:
- wherein the bond projecting to the right is attached to the —S(═O)2— group;
- Y is selected from the group consisting of —O— and —S—;
- Z is selected from the group consisting of —R, —N(R1a)(R1b), and —OR1;
- Z1 is selected from the group consisting of hydrogen, (hydroxy)C1-C4 alkyl, (C1-C3 alkoxy)C1-C3 alkyl, (heterocyclo)C1-C4 alkyl, (alkylsulfonyl)C1-C4 alkyl, (phenyl)C1-C4 alkyl, (heteroaryl)C1-C4 alkyl, (amino)C1-C4 alkyl, (amido)C1-C4 alkyl, (carboxy)C1-C4 alkyl, (alkoxycarbonyl)C1-C4 alkyl, (aminocarbonyl)C1-C4 alkyl, (aminosulfonyl)C1-C4 alkyl, and —C(═O)R15;
- R is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, and 4- to 10-membered heterocyclo;
- R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, (hydroxy)C1-C4 alkyl, (C1-C3 alkoxy)C1-C3 alkyl, (heterocyclo)C1-C4 alkyl, (alkylsulfonyl)C1-C4 alkyl, (phenyl)C1-C4 alkyl, (heteroaryl) C1-C4 alkyl, (amino)C1-C4 alkyl, (amido)C1-C4 alkyl, (carboxy)C1-C4 alkyl, (alkoxycarbonyl)C1-C4 alkyl, (aminocarbonyl)C1-C4 alkyl, and (aminosulfonyl)C1-C4 alkyl;
- R1a is selected from the group consisting of hydrogen, C1-C6 alkyl, (hydroxy)C1-C4 alkyl, (C1-C3 alkoxy)C1-C3 alkyl, (heterocyclo)C1-C4 alkyl, (alkylsulfonyl)C1-C4 alkyl, (phenyl)C1-C4 alkyl, (heteroaryl)C1-C4 alkyl, (amino)C1-C4 alkyl, (amido)C1-C4 alkyl, (carboxy)C1-C4 alkyl, (alkoxycarbonyl)C1-C4 alkyl, (aminocarbonyl)C1-C4 alkyl, and (aminosulfonyl)C1-C4 alkyl;
- R1b is selected from the group consisting of hydrogen and C1-C3 alkyl;
- R2a is selected from the group consisting of hydrogen and C1-C3 alkyl;
- R3a is selected from the group consisting of hydrogen and C1-C3 alkyl;
- or
- R2a and R3a taken together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or 4- to 10-membered heterocyclo;
- R2b is selected from the group consisting of hydrogen and C1-C3 alkyl;
- R2c is selected from the group consisting of hydrogen and C1-C3 alkyl;
- R2d is selected from the group consisting of hydrogen and C1-C3 alkyl;
- R3b is selected from the group consisting of hydrogen and C1-C3 alkyl;
- R3c is selected from the group consisting of hydrogen, C1-C6 alkyl, (hydroxy)C1-C4 alkyl, (C1-C3 alkoxy)C1-C3 alkyl, (heterocyclo)C1-C4 alkyl, (alkylsulfonyl)C1-C4 alkyl, (phenyl)C1-C4 alkyl, (heteroaryl)C1-C4 alkyl, (amino)C1-C4 alkyl, (amido)C1-C4 alkyl, (carboxy)C1-C4 alkyl, (alkoxycarbonyl)C1-C4 alkyl, (aminocarbonyl)C1-C4 alkyl, and (aminosulfonyl)C1-C4 alkyl;
- R9a, R9c, and R9d are independently selected from the group consisting of hydrogen and halo;
- R9b is halo;
- R15 is 4- to 10-membered heterocyclo;
- W is selected from the group consisting of —CH═ and —N═;
- represents a single or double bond;
- each C3-C7 cycloalkyl is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halo, hydroxy, amino, cyano, C1-C6 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 7-membered heterocyclo, alkylsulfonyl, alkylcarbonyl, and phenyl;
- each 4- to 10-membered heterocyclo is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of halo, hydroxy, amino, cyano, C1-C6 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 7-membered heterocyclo, alkylsulfonyl, alkylcarbonyl, and phenyl;
- and
- each phenyl is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of halo, hydroxy, amino, cyano, C1-C6 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 7-membered heterocyclo, alkylsulfonyl, alkylcarbonyl, and phenyl, or a pharmaceutically acceptable salt thereof.
29 more elements
A compound of Formula XVIII-A:
- wherein:
- X selected from the group consisting of:
- wherein the carbon atom bearing R3a and R3b of X-1 and the nitrogen atom of X-2 are attached to R11;
- R8 is selected from the group consisting of hydrogen and C1-C3 alkyl;
- or
- X and R8 taken together form a spirocycle of Formula X-3:
- wherein the nitrogen atom of X-3 is attached R11;
- Y is selected from the group consisting of —O— and —S—;
- Z is selected from the group consisting of —R, —N(R1a)(R1b), and —OR1;
- Z1 is selected from the group consisting of hydrogen, (hydroxy)C1-C4 alkyl, (C1-C3 alkoxy)C1-C3 alkyl, (heterocyclo)C1-C4 alkyl, (alkylsulfonyl)C1-C4 alkyl, (phenyl)C1-C4 alkyl, (heteroaryl) C1-C4 alkyl, (amino)C1-C4 alkyl, (amido)C1-C4 alkyl, (carboxy)C1-C4 alkyl, (alkoxycarbonyl)C1-C4 alkyl, (aminocarbonyl)C1-C4 alkyl, (aminosulfonyl)C1-C4 alkyl, and —C(═O)R15;
- R is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, and 4- to 10-membered heterocyclo;
- R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, (hydroxy)C1-C4 alkyl, (C1-C3 alkoxy)C1-C3 alkyl, (heterocyclo)C1-C4 alkyl, (alkylsulfonyl)C1-C4 alkyl, (phenyl)C1-C4 alkyl, (heteroaryl) C1-C4 alkyl, (amino)C1-C4 alkyl, (amido)C1-C4 alkyl, (carboxy)C1-C4 alkyl, (alkoxycarbonyl)C1-C4 alkyl, (aminocarbonyl)C1-C4 alkyl, and (aminosulfonyl)C1-C4 alkyl;
- R3a is selected from the group consisting of hydrogen, C1-C6 alkyl, (hydroxy)C1-C4 alkyl, (C1-C3 alkoxy)C1-C3 alkyl, (heterocyclo)C1-C4 alkyl, (alkylsulfonyl)C1-C4 alkyl, (phenyl)C1-C4 alkyl, (heteroaryl)C1-C4 alkyl, (amino)C1-C4 alkyl, (amido)C1-C4 alkyl, (carboxy)C1-C4 alkyl, (alkoxycarbonyl)C1-C4 alkyl, (aminocarbonyl)C1-C4 alkyl, and (aminosulfonyl)C1-C4 alkyl;
- R1b is selected from the group consisting of hydrogen and C1-C3 alkyl;
- R2a is selected from the group consisting of hydrogen and C1-C3 alkyl;
- R3a is selected from the group consisting of hydrogen and C1-C3 alkyl;
- or
- R2a and R3a taken together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or 4- to 10-membered heterocyclo;
- R2b is selected from the group consisting of hydrogen and C1-C3 alkyl;
- R2c is selected from the group consisting of hydrogen and C1-C3 alkyl;
- R2d is selected from the group consisting of hydrogen and C1-C3 alkyl;
- R3b is selected from the group consisting of hydrogen and C1-C3 alkyl;
- R3c is selected from the group consisting of hydrogen, C1-C6 alkyl, (hydroxy)C1-C4 alkyl, (C1-C3 alkoxy)C1-C3 alkyl, (heterocyclo)C1-C4 alkyl, (alkylsulfonyl)C1-C4 alkyl, (phenyl)C1-C4 alkyl, (heteroaryl)C1-C4 alkyl, (amino)C1-C4 alkyl, (amido)C1-C4 alkyl, (carboxy)C1-C4 alkyl, (alkoxycarbonyl)C1-C4 alkyl, (aminocarbonyl)C1-C4 alkyl, and (aminosulfonyl)C1-C4 alkyl;
- R9a, R9c, and R9d are independently selected from the group consisting of hydrogen and halo;
- R9b is halo;
- R15 is 4- to 10-membered heterocyclo;
- W is selected from the group consisting of —CH═ and —N═;
- represents a single or double bond;
- R10 is selected from the group consisting of hydrogen and C1-C6 alkyl;
- when X is X-1, then R11 is selected from the group consisting of —OR12, —SR14, —S(═O)2R14, and —S(═O)—O−M+;
- R12 is selected from the group consisting of hydrogen and —C(═O)R13;
- R13 is selected from the group consisting of phenyl and naphthyl;
- R14 is selected from the group consisting of amino and 5- or 6-membered heteroaryl;
- and
- M+ selected from the group consisting of Li+, Na+, and K+;
- and
- when X is X-2, then R11 is —S(═O)2NH2;
- and
- each C3-C6 cycloalkyl is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halo, hydroxy, amino, cyano, C1-C6 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 10-membered heterocyclo, alkylsulfonyl, alkylcarbonyl, and phenyl;
- each 4- to 10-membered heterocyclo is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of halo, hydroxy, amino, cyano, C1-C6 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 10-membered heterocyclo, alkylsulfonyl, alkylcarbonyl, and phenyl;
- and
- each phenyl is unsubstituted or substituted with one, two, three, or four substituents independently selected from the group consisting of halo, hydroxy, amino, cyano, C1-C6 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 10-membered heterocyclo, alkylsulfonyl, alkylcarbonyl, and phenyl, or a pharmaceutically acceptable salt thereof.
39 more elements
Dependencies are inferred from the claim text.