# US 12,180,186 B2 · Quaternary indazole glucocorticoid receptor antagonists

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- Number: US 12,180,186 B2
- Document ID: US12180186B2
- Status: Granted
- Kind: B2
- Application number: 18/448,696
- Filed: 2023-08-11
- Published: 2024-05-09
- Granted: 2024-12-31
- Earliest claimed: 2020-06-22
- Assignees: Corcept Therapeutics, Inc.
- Applicants: Corcept Therapeutics Incorporated
- Inventors: Hazel Hunt; Lorna Duffy; Ian Strutt; Morgan Jouanneau; Thomas Hornsby; Mark Mills; Andrew William Phillips; Jon-Paul Ward
- Web page: https://patentgrep.com/patent/US12180186B2

## CPC

- C07D 401/14: containing three or more hetero rings
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 471/10: Spiro-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 487/08: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present disclosure provides compounds of Formula I or II. Compounds of Formula I or II may be used in pharmaceutical formulations, and may be used for modulating glucocorticoid receptors.

## Claims

### Claim 1

A method of treating a disorder or condition through modulating a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound of Formula IVa,
or a pharmaceutically acceptable salt thereof, thereby treating the disorder or condition,
wherein
R1 is heterocycloalkyl having 5 to 6 ring members and 1 to 2 heteroatoms each N, phenyl or a heteroaryl having 5 to 6 ring members and 1 to 2 heteroatoms each N or S, each substituted with 1 to 3 R1a groups; and
each R1a is independently hydrogen, C1-3 alkyl, C1-3 deuteroalkyl, C1-3 alkoxy, C1-3 hydroxyalkyl halogen, C1-3 haloalkyl, oxo, —CN, C3-6 cycloalkyl, or heterocycloalkyl having 3 to 5 nog members and 1 to 2 heteroatoms each N or O,
A1, A2, A3 and A4 are each independently ═CR2, or ═N;
each R2 is independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, hydroxy or —CN;
each R3a is independently hydrogen —OH or oxo;
R3b is C1-6 alkyl, C2-6 alkynyl, C2-6 alkoxyalkyl, C2-6 alkynyl-C3-6, cycloalkyl, C1-6 alkyl-C6-12 aryl, C2-6 alkenyl-C6-12 aryl, C2-6 alkynyl-C6-12 aryl, C1-6alkyl-O—C6-12 aryl, C1-6 alkoxyalkyl-C6-12 aryl, —C(O)—C6-12 aryl, or C1-6 alkyl-heteroaryl, wherein each heteroaryl has 5 to 10 ring members and 1 to 3 heteroatoms each independently N, O or S, and wherein each aryl and heteroaryl are substituted with 1 to R3b3 groups;
each R3b3 is hydrogen C1-6 alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, C1-6 hydroxyalkyl, halogen, C1-6 haloalkyl, or C1-6 haloalkoxy;
R4 is C1-6 alkyl, C1-6 haloalkyl, —CN, C3-8 cycloalkyl, 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently N, O or S, C6-12 aryl, or 5 to 10 membered heteroaryl having 1 to 5 heteroatoms each independently N, O or S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each dependently substituted with 1 to 5 R4a groups;
each R4a is hydrogen, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, C1-6 hydroxyalkyl, halogen, C1-6 haloalkyl, —CN, —OH, oxo, S(O)2R4b, —S(O)2N(R4b)(R4c), C3-6 cycloalkyl, C6-12 aryl, —O—C6-12 aryl, wherein each aryl is optionally substituted with C1-6 alkoxy;
each R4b and R4c is hydrogen or C1-6 alkyl;
L1 is absent; and
L2 is absent, —CH2, —C(O)—, C(O)CH2CH2—, —C(O)CH2)3O—, or —S(O)2—.

### Claim 2

A method of treating a disorder or condition through antagonizing a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment, an effective amount of a compound of Formula IVa,
or a pharmaceutically acceptable salt thereof,
wherein
R1 is heterocycloalkyl having 5 to 6 ring members and 1 to 2 heteroatoms each N, phenyl or a heteroaryl having 5 to 6 ring members and 1 to 2 heteroatoms each N or S, each substituted with 1 and 3 R1a groups; and
each R1a is independently hydrogen, C1-3 alkyl, C1-3 deuteroalkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, halogen, C1-3 haloalkyl, oxo, —CN, C3-6 cycloalkyl, or heterocycloalkyl having 3 to 5 ring members and 1 to 2 heteroatoms each N or O;
A1, A2, A3 and A4 are independently ═CR2— or ═N—,
each R2 is independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, hydroxy or —CN;
each R3a is independently hydrogen, —OH, or oxo;
R3b is C1-6 alkyl, C2-6 alkynyl, C2-6 alkoxyalkyl, C2-6 alkynyl-C3-6 cycloalkyl, C1-6 alkyl-C6-12 aryl, C2-6 alkenyl-C6-12 aryl, C2-6 alkynyl-C6-12 aryl, C1-6 alkyl-O—C6-12 aryl, C1-6 alkoxyalkyl-C6-12 aryl, —C(O)—C6-12 aryl, or C1-6 alky-heteroaryl, wherein each heteroaryl has 5 to 10 ring members and 1 to 3 heteroatoms each independently N, O or S, and wherein each aryl and heteroaryl are substituted with 1 to 3 R3b3 groups;
each R3b3 is hydrogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, C1-6 hydroxyalkyl, halogen, C1-6 haloalkyl, or C1-6 haloalkoxy;
R4 is C1-6 alkyl, C1-6 haloalkyl, —CN, C3-2 cycloalkyl, 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently N, O or S, C6-12 aryl, or 5 to 10 membered heteroaryl having 1 to 5 heteroatoms each independently N, O or S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently substituted with 1 to 5 R4a groups,
each R4a is hydrogen, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, C1-6 hydroxyalkyl, halogen, C1-6 haloalkyl, —CN, —OH, oxo, —S(O)2R4b, —S(O)2N(R4b)(R4c), C3-6 cycloalkyl, C6-12 aryl, —O—C6-12 aryl, wherein each aryl is optionally substituted with C1-6 alkoxy;
each R4b and R4c is hydrogen or C1-6 alkyl;
L1 is absent; and
L2 is absent —CH2—, —C(O)C—, —C(O)CH2—, —C(O)CH2CH2—, —C(O)CH2O—, C(O)(CH2)3O—, or —S(O)2—.

### Claim 3 (depends on 2)

The method of claim 2, wherein the disorder or condition is selected from the group consisting of amyotrophic lateral sclerosis (ALS), obesity, diabetes, cardiovascular disease, hypertension, Syndrome X, depression, anxiety, glaucoma, neurodegeneration, Alzheimer's disease, Parkinson's disease, Cushing's Syndrome, Cushing Disease, cancer, liver disease, osteoporosis, muscle frailty, a disorder caused by adrenal disease-related cortisol excess, addiction, psychosis, anorexia, cachexia, post-traumatic stress syndrome, post-surgical bone fracture, a GR-related metabolic disorder, major psychotic depression, mild cognitive impairment, dementia, hyperglycemia, a stress disorder, antipsychotic induced weight gain, delirium, cognitive impairment in depressed patients, postpartum psychosis, postpartum depression, and a neurological disorder in a premature infant.

### Claim 4 (depends on 2)

The method of claim 2, wherein
R1 is

### Claim 5 (depends on 4)

The method of claim 4, wherein the compound has the structure:

### Claim 6 (depends on 5)

The method of claim 5, wherein the compound has the structure:

### Claim 7 (depends on 6)

The method of claim 6, wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 7)

The method of claim 7, wherein
R3b is ethyl, —CH2C≡CH, —CH2OMe,

### Claim 9 (depends on 8)

The method of claim 8, wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 9)

The method of claim 9, wherein L2 is —C(O)— or —S(O)2—.

### Claim 11 (depends on 10)

The method of claim 10, wherein the compound has the structure:

### Claim 12 (depends on 11)

The method of claim 11, wherein
R4 is methyl, —CF2CH3, —CN,

### Claim 13 (depends on 2)

The method of claim 2, wherein
R1 is
A1 is ═CH— or ═N—;
A2 and A4 are each ═CH—;
A3 is ═CH—, ═C(Me)-, ═C(Et)-, ═C(iPr)-, ═C(OMe)-, ═C(F), ═C(Cl)—, or ═C(CN)—;
each R3a is hydrogen, —OH, or oxo;
R3b is ethyl, —CH2C≡CH, —CH2OMe,
L1 and L2 together are absent, —CH2—, —C(O)—, —C(O)CH2—, —C(O)CH2CH2—, —C(O)CH2O—, —C(O)(CH2)3O—, or —S(O)2—; and
R4 is methyl, —CF2CH3, —CN,

### Claim 14 (depends on 2)

The method of claim 2, wherein
R1 is
A1 is ═CH—;
A2 and A4 are each ═CH—;
A3 is ═CH—, ═C(Me)-, —C(Et)-, ═C(OMe)-, ═C(Cl)—, or ═C(CN)—;
each R3a is hydrogen, —OH, or oxo;
R3b is —CH2OMe,
L1 and L2 together are —CH2-, —C(O)—, —C(O)CH2—, —C(O)CH2CH2—, —C(O)CH2O—, or —S(O)2—; and
R4 is methyl, —CF2CH3,

### Claim 15 (depends on 2)

The method of claim 2, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 2)

The method of claim 2, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 2)

The method of claim 2, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 2)

The method of claim 2, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 2)

The method of claim 2, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 2)

The method of claim 2, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 2)

The method of claim 2, wherein the compound is:
or a pharmaceutically acceptable salt thereof.