# US 12,595,264 B2 · Heterocyclic GLP-1 agonists

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- Number: US 12,595,264 B2
- Document ID: US12595264B2
- Status: Granted
- Kind: B2
- Application number: 18/044,743
- Filed: 2021-09-08
- Published: 2023-10-19
- Granted: 2026-04-07
- Earliest claimed: 2020-09-10
- Assignees: Gasherbrum Bio, Inc.
- Applicants: Gasherbrum Bio, Inc.
- Inventors: Qinghua Meng; Weiqiang Xing; Haizhen Zhang; Xichen Lin; Hui Lei; Andrew Jennings
- Web page: https://patentgrep.com/patent/US12595264B2

## CPC

- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07D 487/04: Ortho-condensed systems
- A61K 31/155: Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 38/26: Glucagons
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/12: Antihypertensives
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07F 9/6561: containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07B 2200/07: Optical isomers
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

This disclosure relates to GLP-1 agonists of Formula (I), including pharmaceutically acceptable salts and solvates thereof, and pharmaceutical compositions including the same.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
Ring A is C6-10 aryl, C5-10 cycloalkyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl, each of which is optionally substituted with from 1-5 substituents each independently selected from the group consisting of: halo, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;
R1, R2 and R3 are each independently selected from the group consisting of H and C1-6 alkyl which is optionally substituted with from 1-6 substituents each independently selected from the group consisting of halo, —OH, and C1-6 alkoxy;
L1 is selected from the group consisting of: —C(═O)—, —CH2—, —CH(C1-6 alkyl)-, and —S(═O)2;
Ring B is selected from the group consisting of:
wherein bb represents point of attachment to L1;
R4, R5, R6, and R7 are independently selected from the group consisting of: H, halo, and C1-6 alkyl;
L3 is a bond or C1-3 alkylene;
L4 is a bond or C1-5 alkylene;
R8a and R8b are independently selected from the group consisting of: H and C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of: halo and C3-15 cycloalkyl; or
R8a and R8b taken together with the carbon atom to which each is attached forms a C3-15 cycloalkyl ring which is optionally substituted with from 1-3 independently selected C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with from 1-6 independently selected Rf,
R9 is selected from the group consisting of: C(═O)OH, C(═O)(OC1-6 alkyl), C(═O)NR9aR9b, (IX-1), (IX-2), (IX-3), and (IX-4):
R9a is H or C1-6 alkyl;
R9b is H, C1-6 alkyl, C(═O)(C1-6 alkyl), S(O)0-2(C1-6 alkyl), or cyano;
R9c, R9d, R9e, R9f, and R9g are each independently selected from the group consisting of: H; C1-6 alkyl optionally substituted with from 1-6 independently selected halo and C1-6 alkoxy; and C(═O)(C1-6 alkyl);
Ring C is selected from the group consisting of 3-12 membered heterocyclyl; C3-10 cycloalkyl; and 5-10 membered heteroaryl, each of which is optionally substituted with from 1-3 RCa;
each RCa is independently selected from the group consisting of: halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and NRcRd;
or a pair of RCa on the same or different ring atoms, taken together with the ring atom(s) to which each is attached, forms a carbocyclic ring including from 3-8 ring atoms;
L2 is selected from the group consisting of:
wherein aa represents the point of attachment to Q;
n1 is an integer from 1-3;
L2A is a bond or C1-10 alkylene;
RLa is selected from the group consisting of H, C1-6 alkyl, and C(═O)(C1-6 alkyl);
each of RLb and RLc is independently selected from the group consisting of: H and C1-6 alkyl;
Q is selected from the group consisting of: C1-10 alkyl; C3-15 cycloalkyl; 3-12 membered heterocyclyl; 5-10 membered heteroaryl; and C6-10 aryl, each of which is optionally substituted with from 1-6 independently selected RQ;
each RQ is independently selected from the group consisting of:
(a) halo;
(b) cyano;
(c) OH or oxo;
(d) —NRcRd,
(e) —C(═O)NRcRd or —S(O)2NRcRd,
(f) —S(═O)0-2Re;
(g) C1-6 alkyl optionally substituted with from 1-6 independently selected Rf,
(h) C1-6 alkoxy optionally substituted with from 1-6 independently selected Rf;
(i) 3-12 membered heterocyclyl optionally substituted with from 1-6 independently selected Rg;
(j) C6-10 aryl optionally substituted with from 1-6 independently selected Rg;
(k) 5-10 membered heteroaryl optionally substituted with from 1-6 independently selected Rg;
(l) C3-8 cycloalkyl optionally substituted with from 1-6 independently selected Rg;
(m) —P(═O)RaRb, and
(n) —(CRhRh)q1—S(O)2-Le-Re, wherein q1 is 1, 2, or 3;
Ra and Rb are independently selected from the group consisting of C1-6 alkyl which is optionally substituted with from 1-6 substituents each independently selected from the group consisting of C1-6 alkoxy, C3-6 cycloalkyl, and halo; C3-6 cycloalkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of C1-3 alkyl and halo; and C6-10 aryl optionally substituted with from 1-3 independently selected C1-3 alkyl; or
Ra and Rb taken together with the phosphorous atom to which each is attached forms a ring including from 5-8 ring atoms, wherein from 0-2 ring atoms (in addition to the phosphorous attached to Ra and Rb) are heteroatoms each independently selected from the group consisting of: O, S, and N, wherein the ring is optionally substituted with from 1-3 independently selected C1-6 alkyl;
each Rc and Rd are independently selected from the group consisting of: H, C1-6 alkyl, C3-6 cycloalkyl, C(═O)(C1-6 alkyl), C(═O)(C3-6 cycloalkyl), C(═O)O(C1-6 alkyl), S(O)1-2(C1-6 alkyl), and S(O)1-2(C3-6 cycloalkyl), wherein the C1-6 alkyl, C(═O)(C1-6 alkyl), C(═O)(C3-6 cycloalkyl), C(═O)O(C1-6 alkyl), S(O)1-2(C1-6 alkyl), and S(O)1-2(C3-6 cycloalkyl) are each optionally substituted with from 1-6 substituents independently selected from the group consisting of: —OH, halo, and C1-6 alkoxy;
Re is H, or Re is selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, and 3-8 membered heterocyclyl, each of which is optionally substituted with from 1-3 substituents each independently selected from the group consisting of: halo, cyano, C1-3 alkyl, C1-3 haloalkyl, —OH, NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, C1-3 alkoxy, and C1-3 haloalkoxy;
Le is a bond, NRc, or O;
each Rf is independently selected from the group consisting of halo, —OH, NRcRd, C1-6 alkoxy, C1-6 haloalkoxy, and 3-12 membered heterocyclyl which is optionally substituted with from 1-4 substituents each independently selected from the group consisting of —OH, C1-6 alkyl, and 3-12 membered heterocyclyl;
each Rg is independently selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, NRcRd, cyano, halo, C3-6 cycloalkyl, and 3 to 12 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C1-6 alkyl and C(═O)C1-6 alkyl; and
each occurrence of Rh is independently selected from the group consisting of: H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, and halo; or
a pair of Rh on the same or different carbon atom(s), taken together with the carbon atom(s) connecting them forms C3-6 cycloalkyl or 4-8 membered heterocyclyl, each of which is optionally substituted with from 1-3 substituents each independently selected from the group consisting of: halo, cyano, C1-3 alkyl, C1-3 haloalkyl, —OH, C1-3 alkoxy, and C1-3 haloalkoxy.

### Claim 2 (depends on 1)

The compound of claim 1, wherein Q is
wherein n1 is 0 or 1.

### Claim 3 (depends on 1)

The compound of claim 1, wherein Q is phenyl optionally substituted with from 1-6 independently selected RQ.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the RQ para to L2 is —P(═O)RaRb.

### Claim 5 (depends on 4)

The compound of claim 4, wherein Ra and Rb are independently selected C1-6 alkyl optionally substituted with from 1-6 substituents each independently selected from the group consisting of C1-6 alkoxy, C3-6 cycloalkyl, and halo.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R1, R2, and R3 are H.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R1 and R2 are H; and R3 is C1-6 alkyl.

### Claim 8 (depends on 7)

The compound of claim 7, wherein R3 is methyl.

### Claim 9 (depends on 1)

The compound of claim 1, wherein L2 is

### Claim 10 (depends on 1)

The compound of claim 1, wherein Ring A is
wherein RAA, RAB, and RAC are independently halo or C1-6 alkyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein L1 is C(═O).

### Claim 12 (depends on 1)

The compound of claim 1, wherein Ring B is

### Claim 13 (depends on 12)

The compound of claim 12, wherein R4, R5, and R6 are each H.

### Claim 14 (depends on 12)

The compound of claim 12, wherein R7 is H.

### Claim 15 (depends on 1)

The compound of claim 1, wherein both of L3 and L4 are bonds.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R8a and R8b taken together with the carbon atom to which each is attached forms a C3-5 cycloalkyl ring which is optionally substituted with from 1-2 independently selected C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with from 1-3 independently selected Rf.

### Claim 17 (depends on 1)

The compound of claim 1, wherein R8a and R8b taken together with the carbon atom to which each is attached forms:

### Claim 18 (depends on 1)

The compound of claim 1, wherein R9 is

### Claim 19 (depends on 1)

The compound of claim 1, wherein Ring C is tetrahydropyranyl which is optionally substituted with from 1-3 independently RCa.

### Claim 20

A compound selected from the group consisting of the compounds in Table C1 or Table C2,
TABLE C1
Compound No.
Structure
101
102
103
104
105
106
107
108
109/110
111/112
113
114
115
116
117
118
TABLE C2
Compound No.
Structure
105a
106a
107a
108a
109a
110a
single diastereomer 2
111a
single diastereomer 2
112a
single diastereomer 1
113a
single diastereomer 2
114a
single diastereomer 2
115a
single diastereomer 2
116a
single diastereomer 2
117a
single diastereomer 2
118a
single diastereomer 2
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 21 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

### Claim 22 (depends on 1, 21)

A method for treating a GLP-1 associated disease, disorder, or condition, the method comprising administering to a patient in need thereof an effective amount of a compound as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 21, wherein the disease, disorder, or condition is selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, early onset type 2 diabetes mellitus, idiopathic type 1 diabetes mellitus (Type 1b), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain from use of other agents, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral adipose deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attacks, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, post-prandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder/major depressive disorder, skin and connective tissue disorders, foot ulcerations, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's, Alzheimer's disease, impaired cognition, schizophrenia, Polycystic Ovary Syndrome (PCOS), or any combination thereof.

### Claim 23 (depends on 22)

The method of claim 22, wherein the disease, disorder, or condition is type 2 diabetes mellitus.

### Claim 24 (depends on 22)

The method of claim 22, wherein the disease, disorder, or condition is obesity.