# US 12,178,807 B2 · Macrocyclic tyrosine kinase inhibitor and uses thereof

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- Number: US 12,178,807 B2
- Document ID: US12178807B2
- Status: Granted
- Kind: B2
- Application number: 17/292,084
- Filed: 2019-11-08
- Published: 2021-12-30
- Granted: 2024-12-31
- Earliest claimed: 2018-11-09
- Assignees: Xuanzhu Biopharmaceutical Co., Ltd.
- Applicants: Xuanzhu Biopharmaceutical Co., Ltd.
- Inventors: Bin Liu
- Web page: https://patentgrep.com/patent/US12178807B2

## CPC

- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 31/122: having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 38/13: Cyclosporins
- A61P 35/00: Antineoplastic agents
- C07D 471/22: in which the condensed systems contains four or more hetero rings
- C07D 498/22: in which the condensed system contains four or more hetero rings
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention belongs to the technical field of medicine, and relates to a macrocyclic tyrosine kinase inhibitor and the uses thereof. Specifically, the invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt, ester or stereoisomer thereof, a preparation method therefor, a pharmaceutical formulation or a pharmaceutical composition containing same, and medical uses thereof.

## Claims

### Claim 1

A compound of general formula (IV) or a pharmaceutically acceptable salt, ester or stereoisomer thereof,
wherein:
M2 is N; M6 is N; M5 is CH;
ring C is pyrrolidinyl or piperidinyl optionally, each one of which is substituted with a substituent selected from: R4, R5, R6, halogen, amino, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, di(C1-4 alkyl)amino, halo C1-4 alkyl, hydroxy C1-4 alkyl, amino C1-4 alkyl and halo C1-4 alkoxy;
—(X2)p— is —C(R5)(R6)—, —C(R5)(R6)—C(R5)(R6)— or —O—C(R5)(R6), and the left chemical bond thereof is connected to ring A and the right chemical bond thereof is connected to X3;
—(X3)q— is —C(R5)(R6)—C(R5)(R6)—, —C(R5)(R6)—N(R4)— or —C(R5)(R6)—O—, and the left chemical bond thereof is connected to X2 and the right chemical bond thereof is connected to carbonyl;
ring A is selected from phenyl and 5-6 membered monoheteroaryl;
R2, when present, is independently selected from hydrogen, halogen and the following groups optionally substituted with 1 to 3 Q1: C1-4 alkyl, —ORa and —NRaRb; Q1, when present, is independently selected from hydroxy, amino, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, di(C1-4 alkyl)amino, halo C1-4 alkyl, hydroxy C1-4 alkyl, amino C1-4 alkyl and halo C1-4 alkoxy;
Ra and Rb, when present, are each independently selected from hydrogen and C1-4 alkyl;
R5 and R6, when present, are each independently selected from hydrogen, halogen, hydroxy, amino, C1-4 alkyl and C1-4 alkoxy;
R4, when present, is independently selected from hydrogen and C1-4 alkyl optionally substituted with 1 to 2 Q2; Q2, when present, is independently selected from hydroxy, amino, halogen and C1-4 alkoxy; and
n is 0, 1 or 2.

### Claim 2 (depends on 1)

The compound or the pharmaceutically acceptable salt, ester or stereoisomer thereof according to claim 1, wherein:
ring C pyrrolidinyl;
ring A is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl and tetrazinyl;
R2, when present, is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl and trifluoromethoxy;
R5 and R6, when present, are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, methoxy, ethoxy, propoxy and isopropoxy; and
R4, when present, is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and sec-butyl.

### Claim 3 (depends on 1)

The compound or the pharmaceutically acceptable salt, ester or stereoisomer thereof according to claim 1,
wherein:
ring A is selected from
and the wavy line marked with “1” represents the connection point of ring A to L1 and the wavy line marked with “2” represents the connection point of ring A to X2;
—(X2)p— is selected from —CH2—, —CH2 and —O—CH2—, and the left chemical bond thereof is connected to ring A and the right chemical bond thereof is connected to X3;
—(X3)q— is selected from —CH(R6)—N(R4)— and —CH(R6)—O—, and the left chemical bond thereof is connected to X2 and the right chemical bond thereof is connected to carbonyl; and
R6, when present, is hydrogen or C1-4 alkyl;
R4, when present, is hydrogen or C1-4 alkyl.

### Claim 4 (depends on 1)

The compound or the pharmaceutically acceptable salt, ester or stereoisomer thereof according to claim 1, wherein the compound is selected from the following compounds:
No.
Compound
Compound 1
Compound 2
Compound 2-1
Compound 3
Compound 3-1
Compound 4
Compound 5
Compound 6
Compound 7
Compound 8
Compound 9
Compound 10
Compound 11
Compound 11-1
wherein * represents that a carbon atom is a chiral carbon atom having a single configuration (R configuration or S configuration).

### Claim 5 (depends on 4)

The compound or the pharmaceutically acceptable salt, ester or stereoisomer thereof according to claim 4, wherein the compound is selected from:
No.
Compound
Compound 2′
Compound 3′
Compound 11′

### Claim 6 (depends on 1)

A pharmaceutical formulation comprising the compound or the pharmaceutically acceptable salt, ester or stereoisomer thereof according to claim 1, and one or more pharmaceutically acceptable carriers and/or excipients.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, ester or stereoisomer thereof according to claim 1, and one or more second therapeutically active agents selected from:
a drug for the treatment of pain, which is selected from Nav1.7 channel modulators, opioid analgesics, non-steroidal anti-inflammatory drugs, sedatives, selective/non-selective cyclooxygenase inhibitors, antiepileptics, antidepressants, local anesthetics, 5-HT receptor blockers, 5-HT receptor agonists, ergot alkaloids, β-receptor blockers, M receptor blockers, nitrates and vitamin K;
a drug for the treatment of cancer, which is selected from mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormones, angiogenesis inhibitors, cell growth inhibitors, targeted antibodies, HMG-CoA reductase inhibitors and prenyl-protein transferase inhibitors;
a drug for the treatment of neurodegenerative diseases, which is selected from dopamine-mimetics, dopamine receptor agonists, agents affecting dopamine metabolism, NMDA receptor antagonists, adenosine A2A receptor inhibitors, agents affecting DA release and reuptake, central anticholinergics, cholinesterase inhibitors, 5-HT agonists, a2 adrenergic receptor antagonists, antidepressants, cholinergic receptor agonists, β/γ secretase inhibitors, H3 receptor antagonists and antioxidant agents;
a drug for the treatment of autoimmune diseases, which is selected from antirheumatic drugs, non-steroidal anti-inflammatory drugs, glucocorticoid drugs, TNF antagonists, cyclophosphamide, mycophenolate mofetil and cyclosporine, which is used for alleviating the disease; and
a drug for the treatment of inflammation, which is selected from steroidal anti-inflammatory drugs and non-steroidal anti-inflammatory drugs.

### Claim 8 (depends on 5)

A method for preparing the compound of general formula (IV) or the pharmaceutically acceptable salt, ester or stereoisomer thereof,
wherein
M1 is CH: M4 is CH: M3 is C: M7 is C;
X1, together with L1, forms pyrrolidinyl or piperidinyl; optionally, each one of which is substituted with a substituent selected from: R4, R5, R6, halogen, amino, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, di(C1-4 alkyl)amino, halo C1-4 alkyl, hydroxy C1-4 alkyl, amino C1-4 alkyl and halo C1-4 alkoxy;
ring B is absent;
the other substituents and variables are defined as claim 5, and the method comprises the steps as follows:
intermediate 1 and intermediate 2 are subjected to substitution reaction, deprotection reaction, acylation reaction (using an acylation reagent) in the presence of an organic solvent and a catalyst at a proper temperature to obtain the compound of the general formula (I).

### Claim 9 (depends on 1)

The compound or the pharmaceutically acceptable salt, ester or stereoisomer thereof according to claim 1, wherein ring A is phenyl or 5-6 membered nitrogen-containing heteroaryl.

### Claim 10 (depends on 1)

The compound or the pharmaceutically acceptable salt, ester or stereoisomer thereof according to claim 1,
wherein:
R6, when present, is hydrogen or methyl;
R4, when present, is hydrogen or methyl.