# US 11,111,240 B2 · Sultam compound and application method thereof

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- Number: US 11,111,240 B2
- Document ID: US11111240B2
- Status: Granted
- Kind: B2
- Application number: 16/086,721
- Filed: 2017-03-22
- Published: 2021-02-18
- Granted: 2021-09-07
- Earliest claimed: 2016-03-22
- Assignees: Chai Tai Tianqing Pharmaceutical Group Co., Ltd.; Lianyungang Runzhong Pharmaceutical Co., Ltd.; Centaurus Biopharma Co., Ltd.
- Applicants: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.; Lianyungang Runzhong Pharmaceutical Co., Ltd.; Centaurus Biopharma Co., Ltd.
- Inventors: Li Zhu; Xiaowei Duan; Liguang Dai; Zhao Yang; Yanqing Yang; Hui Zhang; Yuandong Hu; Yong Peng; Yongxin Han; Rui Zhao; Xin Tian; Shanchun Wang
- Web page: https://patentgrep.com/patent/US11111240B2

## CPC

- A61K 31/425: Thiazoles
- C07D 275/03: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 417/14: containing three or more hetero rings
- A61K 31/433: Thidiazoles
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D 285/10: 1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided are a sultam compound having isocitrate dehydrogenase 1 (IDH1) inhibitory activity as represented by formula I or pharmaceutically-acceptable salts, solvates or hydrates thereof, a preparation method thereof, and a pharmaceutical composition containing the compound. The compound or the pharmaceutically-acceptable salts, solvates or hydrates thereof, and the pharmaceutical composition containing the compound can be used to treat IDH1 mutation-induced cancers.

## Claims

### Claim 1

A compound represented by formula I or a pharmaceutically acceptable salt thereof,
wherein,
X is CH2 or NR5;
R1 is C3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R6;
R2 is phenyl or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R7;
R3 is phenyl, 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, phenyl CH2—, or 5- to 6-membered heteroaryl CH2— containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R8;
R4 is halogen, amino, hydroxyl, C1-3 haloalkyl or C1-6 alkyl;
R5 is hydrogen or C1-6 alkyl;
R6 is halogen, amino, hydroxyl, cyano, C1-3 haloalkyl, C1-6 alkyl or C3-6 cycloalkyl;
R7 is halogen, amino, hydroxyl, cyano, C1-3 haloalkyl,
C1-6 alkyl or C3-6 cycloalkyl; or R7 forms a O→N coordination linkage with N atom in R2;
R8 is halogen, amino, hydroxyl, cyano, C1-3 haloalkyl, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl or C2-6 alkynyl;
R9 is H, C1-6 alkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, phenyl, or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R10;
R10 is halogen, amino, hydroxyl, cyano, C1-3 haloalkyl, C1-6 alkyl or C3-6 cycloalkyl;
m is 0 or 1.

### Claim 2 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein,
X is CH2 or NR5;
R1 is C3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R6;
R2 is phenyl or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R7;
R3 is phenyl, 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, phenyl CH2—, or 5- to 6-membered heteroaryl CH2— containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R8;
R4 is halogen, amino, hydroxyl, C1-3 haloalkyl or C1-6 alkyl;
R5 is hydrogen or C1-6 alkyl;
R6 is halogen, amino, hydroxyl, cyano, C1-3 haloalkyl, C1-6 alkyl or C3-6 cycloalkyl;
R7 is halogen, amino, hydroxyl, cyano, C1-3 haloalkyl, aminosulfonyl, N-substituted aminosulfonyl, C1-6 alkyl or C3-6 cycloalkyl;
R8 is halogen, amino, hydroxyl, cyano, C1-3 haloalkyl, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl or C2-6 alkynyl;
m is 0 or 1.

### Claim 3 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by formula II,
wherein,
X is CH2 or NR5;
R1 is C3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R6;
R2 is phenyl or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R7;
R3 is phenyl, 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, phenyl CH2—, or 5- to 6-membered heteroaryl CH2— containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R8;
R5 is hydrogen or C1-6 alkyl;
R6 is halogen, amino, hydroxyl, cyano, C1-3 haloalkyl, C1-6 alkyl or C3-6 cycloalkyl;
R7 is halogen, amino, hydroxyl, cyano, C1-3 haloalkyl,
C1-6 alkyl or C3-6 cycloalkyl; or R7 forms a O→N coordination linkage with N atom in R2,
R7 is halogen, amino, hydroxyl, cyano, C1-3 haloalkyl, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl or C2-6 alkynyl;
R9 is H, C1-6 alkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, phenyl, or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R10;
R10 is halogen, amino, hydroxyl, cyano, C1-3 haloalkyl, C1-6 alkyl or C3-6 cycloalkyl.

### Claim 4 (depends on 3)

The compound or the pharmaceutically acceptable salt thereof according to claim 3, wherein,
X is CH2 or NR5;
R1 is C3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R6;
R2 is phenyl or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R7;
R3 is phenyl, 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, phenyl CH2—, or 5- to 6-membered heteroaryl CH2— containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R8;
R5 is hydrogen or C1-6 alkyl;
R6 is halogen, amino, hydroxyl, cyano, C1-3 haloalkyl, C1-6 alkyl or C3-6 cycloalkyl;
R7 is halogen, amino, hydroxyl, cyano, C1-3 haloalkyl, aminosulfonyl, N-substituted aminosulfonyl, C1-6 alkyl or C3-6 cycloalkyl;
R8 is halogen, amino, hydroxyl, cyano, C1-3 haloalkyl, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl or C2-6 alkynyl.

### Claim 5 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof according to claim 1, X is CH2, NH or N(CH3).

### Claim 6 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof according to claim 1, R5 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.

### Claim 7 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof according to claim 1, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl or piperidyl, which may be optionally substituted with one or more groups R6.

### Claim 8 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof according to claim 1, R6 is F, Cl or Br.

### Claim 9 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof according to claim 1, R2 is phenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl or triazinyl, which may be optionally substituted with one or more groups R7.

### Claim 10 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R2 is phenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl or triazinyl, which may be optionally substituted with one or more groups R7; R7 is F, Cl, Br, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, aminosulfonyl or N-substituted aminosulfonyl.

### Claim 11 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof according to claim 1, R7 is F, Cl, Br, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, or
or R7 forms a O→N coordination linkage with N atom in R2.

### Claim 12 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof according to claim 1, R9 is H, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl or triazinyl, which may be optionally substituted with one or more groups R10.

### Claim 13 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof according to claim 1, R3 is phenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazinyl, benzyl, furanylmethylene, thienylmethylene, pyrrolylmethylene, pyrazolylmethylene, imidazolylmethylene, pyridylmethylene, pyrimidinylmethylene, pyridazinylmethylene, pyrazinylmethylene, thiazolylmethylene, isothiazolylmethylene, oxazolylmethylene, isoxazolylmethylene, tetrazolylmethylene or triazinylmethylene, which may be optionally substituted with one or more groups R8.

### Claim 14 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof according to claim 1, R8 is F, Cl, Br, cyano, ethynyl, 1-propynyl or 1-butynyl.

### Claim 15 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is as follows:

### Claim 16 (depends on 1)

A method for treating IDH1 mutation-induced cancers comprising administering a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 1 to a patient in need thereof, wherein the IDH1 mutation has R132X mutation; and the IDH1 mutation-induced cancers are selected from the group consisting of glioblastoma, myelodysplastic syndrome, myeloproliferative neoplasm, acute myelogenous leukemia, sarcoma (preferably chondrosarcoma, fibrosarcoma), melanoma, non-small cell lung cancer, bile duct cancer or angioimmunoblastic non-Hodgkin's lymphoma.

### Claim 17 (depends on 1)

A pharmaceutical composition, which comprises a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 1 and one or more pharmaceutically acceptable carriers or excipients.

### Claim 18 (depends on 7)

The compound or the pharmaceutically acceptable salt thereof according to claim 7, R1 is

### Claim 19 (depends on 9)

The compound or the pharmaceutically acceptable salt thereof according to claim 9, R2 is

### Claim 20 (depends on 13)

The compound or the pharmaceutically acceptable salt thereof according to claim 13, R3 is