# US 2019/0315751 A1 · Pyrrolo[1,2-a]pyrimidinyl carboxamide compounds and their use in the treatment of medical disorders

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2019/0315751 A1
- Document ID: US20190315751A1
- Status: Published application
- Kind: A1
- Application number: 16/091,337
- Filed: 2017-04-06
- Published: 2019-10-17
- Earliest claimed: 2016-04-06
- Assignees: Lysosomal Therapeutics Inc.
- Applicants: Lysosomal Therapeutics Inc.
- Inventors: Renato T. Skerlj; Elyse Marie Josee Bourque; Peter T. Lansbury; William J. Greenlee; Andrew C. Good
- Web page: https://patentgrep.com/patent/US20190315751A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 493/08: Bridged systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides substituted pyrrolo[1,2-a]pyrimidinyl carboxamide and related organic compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat medical disorders, e.g., Gaucher disease, Parkinson's disease, Lewy body disease, dementia, or multiple system atrophy, in a patient. Exemplary substituted pyrrolo[1,2-a]pyrimidinyl carboxamide compounds described herein include substituted 2-heterocyclyl-4-alkyl-pyrrolo [1,2-a]pyrimidine-8-carboxarnide compounds and variants thereof.

## Claims

### Claim 1

A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R1 and R2 each represent independently for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4hydroxyalkyl, C1-4 cyanoalkyl, C1-4 alkoxyl, —(C1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, halogen, hydroxyl, or —N(R4)2;
R3 represents independently for each occurrence hydrogen, C1-6 alkyl, or C3-6 cycloalkyl;
R4 represents independently for each occurrence hydrogen, C1-4 alkyl, cyclopropyl, or —C(O)R3;
R5 represents independently for each occurrence C1-4 alkyl or C3-6 cycloalkyl;
R6 represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, cyano, halogen, hydroxyl, or —N(R4)2;
X1 is a carbonyl-containing linker selected from —C(O)N(H)-ψ, —C(O)N(H)(C1-6 alkylene optionally substituted with C1-4 alkoxyl or C3-6 cycloalkyl)-ψ, —C(O)N(H)(C1-6 haloalkylene)-ψ, —C(O)N(H)(C3-6 cycloalkylene)-ψ, —C(O)N(H)(3-6 membered heterocycloalkylene)-ψ, —C(O)-(3-6 membered heterocycloalkylene containing at least one ring —N(H)— group)-ψ, —C(O)N(H)C(O)-ψ, and —C(O)N(H)C(O)(C1-6 alkylene)-ψ;
where ψ is a bond to A1;
A1 is one of the following:
a cyclic group selected from a 3-14 membered saturated carbocyclyl, a 5-14 membered partially unsaturated carbocyclyl, a 3-16 membered heterocyclyl, or phenyl; each of which is substituted by 0, 1, or 2 occurrences of Y1 and 0, 1, 2, or 3 occurrences of Y2; or
C1-8 alkyl or C2-6 alkynyl;
A2 is one of the following:
a cyclic group selected from a 5-12 membered heterocyclyl, 5-10 membered cycloalkyl, or phenyl; each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, C3-5 cycloalkyl, cyano, halogen, hydroxyl, —N(R4)2, —C(O)N(R4)2, and heteroaryl;
—N(R4)(3-10 membered heterocycloalkyl or C3-10 cycloalkyl, each optionally substituted by 1, 2, or 3 R6 groups) or —O-(3-10 membered heterocycloalkyl or C3-10 cycloalkyl, each optionally substituted by 1, 2, or 3 R6 groups); or
—(O)N(R4)(aryl or heteroaryl);
Y1 represents, independently for each occurrence, one of the following:
2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl, a 3-10 membered heterocyclyl, or C3-6 halocycloalkyl;
3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, —O—C3-6 cycloalkyl, —O-(3-6 membered heterocyclyl), —O-(6-10 membered aryl), or —O—(C2-6 alkynyl); or
C2-6 alkynyl, —C≡C—(C1-6 alkylene)-OR4, —C≡C—(C1-6 alkylene)-N(R3)2, —(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl;
Y2 represents, independently for each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6hydroxyalkyl, hydroxyl, C1-6 alkoxyl, —O—(C1-8 haloalkyl), cyano, azido, —N(R3)2, —(C1-6 alkylene)-(5-6 membered heterocyclyl), —(C1-6 alkylene)-CO2R3, —CO2R3, —C(O)R5, —S(O)2R5, —C(O)N(R5)2, —C(O)N(R3)2, or C1-6haloalkyl-substituted C3-6 cycloalkyl;
m is 1 or 2; and
n is 1, 2, or 3.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X1 is —C(O)N(H)-ψ.

### Claim 3 (depends on 1)

The compound of claim 1, wherein X1 is —C(O)N(H)(C1-6 alkylene)-ψ.

### Claim 4 (depends on 1)

The compound of claim 1, wherein X1 is —C(O)N(H)(C(CH3)2)-ψ or —C(O)N(H)(C(H)(CH3))-ψ.

### Claim 5 (depends on 1)

The compound of claim 1, wherein X1 is —C(O)N(H)(C1-6 haloalkylene)-ψ.

### Claim 6 (depends on 1)

The compound of claim 1, wherein X1 is —C(O)N(H)C(H)(CF3)-ψ.

### Claim 7 (depends on 1)

The compound of claim 1, wherein A2 is a 5-12 membered heterocyclyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, C3-5 cycloalkyl, cyano, halogen, hydroxyl, and —N(R4)2.

### Claim 8 (depends on 1)

The compound of claim 1, wherein A2 is a 5-6 membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, C3-5 cycloalkyl, cyano, halogen, hydroxyl, and —N(R4)2.

### Claim 9 (depends on 1)

The compound of claim 1, wherein A2 is a 5-6 membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, and thiazolyl, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4haloalkyl, C1-4 alkoxyl, C3-5 cycloalkyl, cyano, halogen, hydroxyl, and —N(R4)2.

### Claim 10 (depends on 1)

The compound of claim 1, wherein A2 is pyridinyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4haloalkyl, C1-4 alkoxyl, C3-5 cycloalkyl, cyano, halogen, hydroxyl, and —N(R4)2.

### Claim 11 (depends on 1)

The compound of claim 1, wherein A2 is 3-pyridinyl optionally substituted by 1 or 2 substituents independently selected from the group consisting of C1-4 alkyl, C1-4haloalkyl, C1-4 alkoxyl, C3-5 cycloalkyl, cyano, and halogen.

### Claim 12 (depends on 1)

The compound of claim 1, wherein A2 is a 5-6 membered heterocycloalkyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4haloalkyl, C1-4 alkoxyl, C3-5 cycloalkyl, cyano, halogen, hydroxyl, and —N(R4)2.

### Claim 13 (depends on 1)

The compound of claim 1, wherein A2 is a 5-6 membered heterocycloalkyl selected from the group consisting of morpholinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, C3-5 cycloalkyl, cyano, halogen, hydroxyl, and —N(R4)2.

### Claim 14 (depends on 1)

The compound of claim 1, wherein A2 is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4haloalkyl, C1-4 alkoxyl, C3-5 cycloalkyl, cyano, halogen, hydroxyl, and —N(R4)2.

### Claim 15 (depends on 1)

The compound of claim 1, wherein A2 is —N(R4)(3-10 membered heterocycloalkyl or C3-10 cycloalkyl, each optionally substituted by 1, 2, or 3 R6 groups) or —O-(3-10 membered heterocycloalkyl or C3-10 cycloalkyl, each optionally substituted by 1, 2, or 3 R6 groups).

### Claim 16 (depends on 1)

The compound of claim 1, wherein A2 is located at the 2-position of the pyrrolo[1,2-a]pyrimidinyl.

### Claim 17 (depends on 1)

The compound of claim 1, wherein A2 is located at the 4-position of the pyrrolo[1,2-a]pyrimidinyl.

### Claim 18 (depends on 1)

The compound of claim 1, wherein n is 1.

### Claim 19 (depends on 16)

The compound of claim 16, wherein n is 1, and the R1 group is located at the 4-position of the pyrrolo[1,2-a]pyrimidinyl.

### Claim 20 (depends on 17)

The compound of claim 17, wherein n is 1, and the R1 group is located at the 2-position of the pyrrolo[1,2-a]pyrimidinyl.

### Claim 21 (depends on 1)

The compound of claim 1, wherein the compound is represented by Formula I-A:
or a pharmaceutically acceptable salt thereof, wherein:
R1 represents independently for each occurrence C1-4 alkyl, C1-4haloalkyl, C1-4 alkoxyl, —(C1-4 alkylene)-(C1-4 alkoxyl), cyclopropyl, chloro, or fluoro;
R2 is hydrogen;
R3 and R4 each represent independently for each occurrence hydrogen or C1-4 alkyl;
X1 is a carbonyl-containing linker selected from —C(O)N(H)-ψ, —C(O)N(H)(C1-6 alkylene optionally substituted C3-6 cycloalkyl)-ψ, or —C(O)N(H)(C1-6 haloalkylene)-ψ; where ψ is a bond to A1;
A1 is a cyclic group selected from:
C3-10 cycloalkyl substituted by 0 or 1 occurrence of Y1 and 0, 1, or 2 occurrences of Y2; and
phenyl substituted by 0 or 1 occurrence of Y1 and 0, 1, or 2 occurrences of Y2;
A2 is a 5-12 membered heterocyclyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, C3-5 cycloalkyl, cyano, halogen, and hydroxyl;
Y1 represents, independently for each occurrence, one of the following:
2-8 membered heteroalkyl or —O—(C2-6alkynyl); or
C2-6 alkynyl or —C≡C—(C1-6 alkylene)-OR4; and
Y2 represents, independently for each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6hydroxyalkyl, hydroxyl, C1-6 alkoxyl, cyano, or —N(R3)2.

### Claim 22 (depends on 21)

The compound of claim 21, wherein R1 represents independently for each occurrence methyl, halomethyl, —(CH2)1-2—O—(C1-3 alkyl), cyclopropyl, chloro, or fluoro.

### Claim 23 (depends on 21)

The compound of claim 21, wherein A1 is C3-7 cycloalkyl substituted once by Y1 and 0-1 occurrences of Y2.

### Claim 24 (depends on 21)

The compound of claim 21, wherein A1 is cyclohexyl substituted once by Y1.

### Claim 25 (depends on 21)

The compound of claim 21, wherein A1 is C3-7 cycloalkyl.

### Claim 26 (depends on 21)

The compound of claim 21, wherein A1 is cyclopropyl.

### Claim 27 (depends on 21)

The compound of claim 21, wherein any occurrence of Y2 is independently C1-3 alkyl, halogen, or C1-3haloalkyl.

### Claim 28 (depends on 21)

The compound of claim 21, wherein Y1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl.

### Claim 29 (depends on 21)

The compound of claim 21, wherein Y1 is —O—(C1-7 alkyl).

### Claim 30 (depends on 21)

The compound of claim 21, wherein Y1 is —O-butyl, —O-pentyl, or —O-hexyl.

### Claim 31 (depends on 21)

The compound of claim 21, wherein A2 is a 5-6 membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4haloalkyl, C1-4 alkoxyl, C3-5 cycloalkyl, cyano, halogen, hydroxyl, and —N(R4)2.

### Claim 32 (depends on 21)

The compound of claim 21, wherein A2 is a 5-6 membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, furanyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, and thiazolyl, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4haloalkyl, C1-4 alkoxyl, C3-5 cycloalkyl, cyano, halogen, hydroxyl, and —N(R4)2.

### Claim 33 (depends on 21)

The compound of claim 21, wherein A2 is pyridinyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4haloalkyl, C1-4 alkoxyl, C3-5 cycloalkyl, cyano, halogen, hydroxyl, and —N(R4)2.

### Claim 34 (depends on 21)

The compound of claim 21, wherein A2 is 3-pyridinyl optionally substituted by 1 or 2 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4haloalkyl, C1-4 alkoxyl, C3-5 cycloalkyl, cyano, and halogen.

### Claim at position 35

35-111. (canceled)

### Claim 112 (depends on 1)

The compound of claim 1, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 113 (depends on 1)

A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 114

(canceled)

### Claim 115 (depends on 1)

A method of treating a disorder selected from the group consisting of Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open angle glaucoma, multiple sclerosis, endometriosis, and multiple myeloma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 to treat the disorder.

### Claim at position 40

116-121. (canceled)