# US 2019/0375764 A1 · Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof

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- Number: US 2019/0375764 A1
- Document ID: US20190375764A1
- Status: Published application
- Kind: A1
- Application number: 16/433,361
- Filed: 2019-06-06
- Published: 2019-12-12
- Earliest claimed: 2018-06-07
- Applicants: Sunovion Pharmaceuticals Inc.
- Inventors: Nandkumar Nivritti BHOGLE; Yuji FUJIWARA; Kenjiro HIRA; Tomoya KARASAWA; Kostas SARANTEAS; John R. SNOONIAN; Harold Scott WILKINSON; Haitao ZHANG
- Web page: https://patentgrep.com/patent/US20190375764A1

## CPC

- C07D 498/04: Ortho-condensed systems
- A61P 25/24: Antidepressants
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present disclosure relates to salts of (R)-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine, crystalline forms thereof, and methods of preparation thereof, which are useful in the treatment of CNS disorders.

## Claims

### Claim 1

A compound
(R)-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine tosylate (Compound 1 Tosylate);
(R)-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine benzenesulfonate (Compound 1 Besylate);
(R)-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine fumarate (Compound 1 Fumarate);
(R)-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine phosphate (Compound 1 Phosphate); or
(R)-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine hydrochloride (Compound 1 Hydrochloride);
or a hydrate or solvate thereof,
wherein Compound 1 Hydrochloride is crystalline and is Form HB or Form HC.

### Claim 2 (depends on 1)

The compound of claim 1, wherein Compound 1 Tosylate, Compound 1 Besylate, Compound 1 Fumarate, or Compound 1 Phosphate is a solid form.

### Claim at position 3

3-5. (canceled)

### Claim 6 (depends on 1)

The compound of claim 1 having Form TA.

### Claim at position 5

7-15. (canceled)

### Claim 16 (depends on 1)

The compound of claim 1, wherein the compound is (R)-1-(3,4-dihydro-1H-[1,4] oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine benzenesulfonate (Compound 1 Besylate).

### Claim at position 7

17-18. (canceled)

### Claim 19 (depends on 1)

The compound of claim 1 having Form BA.

### Claim at position 9

20-27. (canceled)

### Claim 28 (depends on 1)

The compound of claim 1, wherein the compound is (R)-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine hydrochloride (Compound 1 Hydrochloride).

### Claim 29

(canceled)

### Claim 30 (depends on 28)

The compound of claim 28 having Form HB.

### Claim 31 (depends on 28)

The compound of claim 28 having Form HC.

### Claim at position 14

32-42. (canceled)

### Claim 43 (depends on 28, 29)

The compound of claim 28 or 29 having Form HD.

### Claim at position 16

44-45. (canceled)

### Claim 46 (depends on 1)

The compound of claim 1, wherein the compound is (R)-1-(3,4-dihydro-1H-[1,4] oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine fumarate (Compound 1 Fumarate).

### Claim at position 18

47-49. (canceled)

### Claim 50 (depends on 46)

The compound of claim 46 having Form FA.

### Claim at position 20

51-60. (canceled)

### Claim 61 (depends on 46)

The compound of claim 46 having Form FB.

### Claim at position 22

62-71. (canceled)

### Claim 72 (depends on 1)

The compound of claim 1, wherein the compound is (R)-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine phosphate (Compound 1 Phosphate).

### Claim 73

(canceled)

### Claim 74 (depends on 72)

The compound of claim 72 having Form PA.

### Claim at position 26

75-83. (canceled)

### Claim 84 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, and one or more pharmaceutically acceptable excipients.

### Claim 85 (depends on 1)

A method for treating a neurological or psychiatric disorder in a patient, comprising administering to said patient an effective amount of a compound of any one claim 1.

### Claim 86 (depends on 85)

The method according to claim 85, wherein the neurological or psychiatric disorder is depression, bipolar disorder, pain, schizophrenia, obsessive compulsive disorder, addiction, social disorder, attention deficit hyperactivity disorder, an anxiety disorder, autism, cognitive impairments, or suicidality.

### Claim at position 30

87-89. (canceled)

### Claim 90 (depends on 85)

The method according to claim 85, wherein the neurological or psychiatric disorder is depression.

### Claim 91 (depends on 90)

The method according to claim 90, wherein the depression is treatment-resistant depression (TRD), major depressive disorder (MDD), unipolar depression, bipolar depression or depression associated with another disease or disorder.

### Claim at position 33

92-94. (canceled)

### Claim 95

A process for preparing:
a) crystalline (R)-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine benzenesulfonate (Compound 1 Besylate) comprising precipitating Compound 1 Besylate from a solution comprising Compound 1, benzensulfonic acid, and S2, wherein S2 is a solvent; or
b) crystalline (R)-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine fumarate (Compound 1 Fumarate) comprising precipitating Compound 1 Fumarate from a solution comprising Compound 1, fumaric acid, and S3, wherein S3 is a solvent; or
c) crystalline (R)-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine hydrochloride (Compound 1 Hydrochloride) comprising precipitating Compound 1 Hydrochloride from a solution comprising Compound 1, hydrochloric acid, and S4, wherein S4 is a solvent; or
d) crystalline (R)-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine phosphate (Compound 1 Phosphate) comprising precipitating Compound 1 Phosphate from a solution comprising Compound 1, phosphoric acid, and S5, wherein S5 is a solvent; or
e) crystalline (R)-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine tosylate (Compound 1 Tosylate) comprising precipitating Compound 1 Tosylate from a solution comprising Compound 1, toluenesulfonic acid, and S1, wherein S1 is a solvent; or
f) (R)-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine tosylate (Compound 1 Tosylate) comprising reacting tert-butyl (R)-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)(methyl)carbamate (Compound 7a) with p-toluenesulfonic acid; or
g) tert-butyl (R)-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)(methyl)carbamate (Compound 7a) comprising reacting (R) -2-(3-(2-((tert-butoxycarbonyl)(methyl)amino)-1-hydroxyethyl)-2H-indazol-2-yl)ethyl 4-methylbenzenesulfonate (Compound 6a) with 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine; or
h) (R)-2-(3-(2-((tert-butoxycarbonyl)(methyl)amino)-1-hydroxyethyl)-2H-indazol-2-yl)ethyl 4-methylbenzenesulfonate (Compound 6a) comprising reacting tert-butyl (R)-(2-hydroxy-2-(2-(2-hydroxyethyl)-2H-indazol-3-yl)ethyl)(methyl)carbamate (Compound 5a) with p-toluenesulfonyl chloride; or
i) tert-butyl (R)-(2-hydroxy-2-(2-(2-hydroxyethyl)-2H-indazol-3-yl)ethyl)(methyl)carbamate (Compound 5a) comprising reacting tert-butyl (2-(2-(2-hydroxyethyl)-2H-indazol-3-yl)-2-oxoethyl)(methyl)carbamate (Compound 4a) with a reducing agent; or
j) tert-butyl (2-(2-(2-hydroxyethyl)-2H-indazol-3-yl)-2-oxoethyl)(methyl)carbamate (Compound 4a) comprising reacting 3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-one (Compound 3a) with lithiated tert-butoxycarbonyldimethylamine (Compound 2a); or
k) lithiated tert-butoxycarbonyldimethylamine (Compound 2a) comprising reacting tert-butoxycarbonyldimethylamine (Compound 1a) with a lithiating agent;
l) 3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-one (Compound 3a) comprising reacting 2-bromoethyl 1H-indazole-3-carboxylate (Compound 9a) with B2a, wherein B2a is an alkali metal base; or
m) 2-bromoethyl 1H-indazole-3-carboxylate (Compound 9a) comprising reacting 1H-indazole-3-carboxylic acid (Compound 8a) with 2-bromoethanol, a chlorinating agent, and an amine compound.

### Claim at position 35

96-184. (canceled)

### Claim 185

A process of preparing Compound 1 Tosylate comprising:
A) reacting Compound 1a with a lithiating agent to produce Compound 2a;
reacting Compound 2a with Compound 3a to produce Compound 4a;
reacting Compound 4a with a reducing agent to produce Compound 5a;
reacting Compound 5a with p-toluenesulfonyl chloride to produce Compound 6a;
reacting Compound 6a with a base to produce Compound 7a; and
reacting Compound 7a with p-toluenesulfonic acid to produce Compound 1 Tosylate: or
B) reacting Compound 1a with a lithiating agent to produce Compound 2a;
reacting Compound 8a with 2-bromoethane to produce Compound 9a;
reacting Compound 9a with an alkali metal base to produce Compound 3a;
reacting Compound 2a with Compound 3a to produce Compound 4a;
reacting Compound 4a with a reducing agent to produce Compound 5a;
reacting Compound 5a with p-toluenesulfonyl chloride to produce Compound 6a;
reacting Compound 6a with a base to produce Compound 7a, and
reacting Compound 7a with p-toluenesulfonic acid to produce Compound 1 Tosylate.

### Claim 186

(canceled)

### Claim 187

A compound which is selected from:
a) tert-butyl (R)-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)(methyl)carbamate (Compound 7a) or a salt thereof;
b) tert-butyl (2-(2-(2-hydroxyethyl)-2H-indazol-3-yl)-2-oxoethyl)(methyl)carbamate (Compound 4a) or a salt thereof;
c) 3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-one (Compound 3a) or a salt thereof;
d) 1H-indazole-3-carboxylic acid (Compound 8a) or a salt thereof; and
e) 2-bromoethyl 1H-indazole-3-carboxylate (Compound 9a) or a salt thereof.

### Claim at position 39

188-196. (canceled)