# US 10,864,202 B2 · Inhibitors of lysine specific demethylase-1

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- Number: US 10,864,202 B2
- Document ID: US10864202B2
- Status: Granted
- Kind: B2
- Application number: 16/705,135
- Filed: 2019-12-05
- Published: 2020-04-09
- Granted: 2020-12-15
- Earliest claimed: 2014-09-05
- Assignees: Celgene Quanticel Research, Inc.
- Applicants: Celgene Quanticel Research, Inc.
- Inventors: Young K. Chen; Toufike Kanouni; Jeffrey Alan Stafford; James Marvin Veal
- Web page: https://patentgrep.com/patent/US10864202B2

## CPC

- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/497: containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/5386: spiro-condensed or forming part of bridged ring systems
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61P 35/00: Antineoplastic agents
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: 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 487/10: Spiro-condensed systems
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D 498/08: Bridged systems
- 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 relates generally to compositions and methods for treating cancer and neoplastic disease. Provided herein are substituted heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of lysine specific demethylase-1. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.

## Claims

### Claim 1

A compound having the structure of Formula (IV), or a pharmaceutically acceptable salt thereof,
wherein,
X and Y are each independently chosen from C—H, C—F, C—CH3, or N;
Z is chosen -G, —CH2-G, —CH2—CH2-G, —N(R′)-G, —N(R′)—CH2-G, —O-G, —O—CH2-G, or —C(O)N(R2)(R3);
X1, X2, and X3 are any one of the following;
(i) X1 is N; X2 is N; and X3 is C—R4;
(ii) X1 is N; X2 is C—R4; and X3 is C—R4;
(iii) X1 is C—R4; X2 is N; and X3 is N;
(iv) X1 is C—R4; X2 is C—R4; and X3 is N;
(v) X1 is C—R4; X2 is N; and X3 is C—R4;
(vi) X1 is N; X2 is N; and X3 is N;
G is carbocyclyl, aryl, heterocyclyl or heteroaryl;
R1 is hydrogen or alkyl;
R2 and R3 are independently selected from hydrogen, alkyl, heterocyclyl, heterocyclylalkyl, or optionally, R2 and R3 join to form an N-linked heterocyclyl ring system;
R4 is hydrogen, halogen, C1-C3 alkyl or C1-C3 alkoxy; and
R is aryl, heteroaryl, alkynyl, or cycloalkylalkynylene.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is aryl or heteroaryl.

### Claim 3 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Formula (IV) is Formula (IVa):

### Claim 4 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Formula (IV) is Formula (IVb):

### Claim 5 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Formula (IV) is Formula (IVd):

### Claim 6 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Formula (IV) is Formula (IVe):

### Claim 7 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Formula (IV) is Formula (IVf):

### Claim 8 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Formula (IV) is Formula (IVg):

### Claim 9 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X is C—H.

### Claim 10 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X is C—F.

### Claim 11 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X is C—CH3.

### Claim 12 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X is N.

### Claim 13 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y is C—H.

### Claim 14 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y is C—F.

### Claim 15 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein Y is C—CH3.

### Claim 16 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y is N.

### Claim 17 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X is C—H and Y is C—H.

### Claim 18 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is selected from the group consisting of:
(a) —O—CH2-G;
(b) —O-G;
(c) —N(R′)—CH2-G;
(d) —N(R′)-G;
(e) —CH2—CH2-G;
(f) —CH2-G;
(g) -G; and
(h) —C(O)N(R2)(R3).

### Claim 19 (depends on 18)

The compound of claim 18, or pharmaceutically acceptable salt thereof, wherein:
(a) R2 and R3 are independently selected from hydrogen or alkyl; or
(b) R2 and R3 are independently selected from heterocyclyl or heterocyclylalkyl; or
(c) R2 and R3 join to form an N-linked heterocyclyl ring system.

### Claim 20 (depends on 18)

The compound of claim 18, or pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or alkyl.

### Claim 21 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R4 is hydrogen or C1-C3 alkoxy.

### Claim 22 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein G is a heterocyclyl or a nitrogen-containing heterocyclyl.

### Claim 23 (depends on 22)

The compound of claim 22, or pharmaceutically acceptable salt thereof, wherein the nitrogen-containing heterocyclyl is a 5- or 6-membered heterocyclyl.

### Claim 24 (depends on 22)

The compound of claim 22, or pharmaceutically acceptable salt thereof, wherein the heterocyclyl is chosen from:

### Claim 25 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of:
(a) heteroaryl;
(b) a monocyclic nitrogen-containing heteroaryl;
(c) a bicyclic nitrogen-containing heteroaryl; and
(d) aryl.

### Claim 26 (depends on 25)

The compound of claim 25, or pharmaceutically acceptable salt thereof, wherein R is chosen from:

### Claim 27 (depends on 25)

The compound of claim 25, or pharmaceutically acceptable salt thereof, wherein the aryl is an optionally substituted phenyl group.

### Claim 28 (depends on 27)

The compound of claim 27, or pharmaceutically acceptable salt thereof, wherein the optionally substituted phenyl group is chosen from 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, 4-(methylsulfonyl)phenyl, or 4-trifluoromethylphenyl.

### Claim 29 (depends on 27)

The compound of claim 27, or pharmaceutically acceptable salt thereof, wherein the optionally substituted phenyl group is chosen from 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, or 3-chloro-4-methoxyphenyl.

### Claim 30 (depends on 1)

A pharmaceutical composition comprising a compound of Formula (IV) as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 31 (depends on 1)

A method of regulating gene transcription in a cell comprising inhibiting lysine-specific demethylase 1 activity by exposing the lysine-specific demethylase 1 enzyme to a compound of Formula (IV) as described in claim 1.

### Claim 32 (depends on 1)

A method of treating acute myeloid leukemia, breast or prostate cancer in a patient in need thereof comprising administering a pharmaceutical composition comprising a compound of Formula (IV) as described in claim 1.

### Claim 33 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the compound is selected from:
4-[5-(4-methylphenyl)-2-{[(3S)-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile;
4-[5-(4-fluorophenyl)-2-{[(3S)-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile;
4-[5-(4-chlorophenyl)-2-{[(3S)-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile;
4-[5-(4-methylphenyl)-2-[(3R)-pyrrolidin-3-ylmethoxy]pyrimidin-4-yl]benzonitrile;
4-{2-[(3aR,6aS)-octahydropyrrolo[3,4-c]pyrrol-2-yl]-5-(4-methylphenyl)pyrimidin-4-yl}benzonitrile;
4-[5-(4-methylphenyl)-2-{octahydro-1H-pyrrolo[3,4-c]pyridin-5-yl}pyrimidin-4-yl]benzonitrile;
4-{2-[(3aR,8aS)-decahydropyrrolo[3,4-d]azepin-6-yl]-5-(4-methylphenyl)pyrimidin-4-yl}benzonitrile;
4-{2-[(3aR,8aS)-decahydropyrrolo[3,4-d]azepin-6-yl]-5-(4-fluorophenyl)pyrimidin-4-yl}benzonitrile;
4-(2-{[(3S)-pyrrolidin-3-ylmethyl]amino}-5-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl)benzonitrile;
4-[5-(2-cyclopropylethynyl)-2-{[(3S)-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile;
4-(2-[(3aR,5S,6aS)-octahydrocyclopenta[c]pyrrol-5-yl] amino -5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile;
(+)-4-(2-{[(3-fluoropyrrolidin-3-yl)methyl] amino}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile;
(+)-4-[5-(4-methylphenyl)-2-[(piperidin-3-yl)amino]pyrimidin-4-yl]benzonitrile;
4-[5-(4-methylphenyl)-2-[(piperidin-4-yl)amino]pyrimidin-4-yl]benzonitrile;
(+)-4-[5-(4-methylphenyl)-2-[(piperidin-3-ylmethyl)amino]pyrimidin-4-yl]benzonitrile;
4-[5-(4-methylphenyl)-2-[(piperidin-4-ylmethyl)amino]pyrimidin-4-yl]benzonitrile;
(+)-4-[5-(4-methylphenyl)-2-[(morpholin-2-ylmethyl)amino]pyrimidin-4-yl]benzonitrile;
(+)-4-[5-(4-fluorophenyl)-2-[(morpholin-2-ylmethyl)amino]pyrimidin-4-yl]benzonitrile;
4-(2-{2,7-diazaspiro[4.4]nonan-2-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile;
4-(2-{2,8-diazaspiro[4.5] decan-2-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile;
4-[5-(4-methylphenyl)-2-{octahydro-1H-pyrrolo[3,4-c]pyridin-2-yl}pyrimidin-4-yl]benzonitrile;
4-[5-(4-methylphenyl)-2-{octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}pyrimidin-4-yl]benzonitrile;
4-(2-{2,8-diazaspiro[4.5] decan-8-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile;
4-(2-{1,8-diazaspiro[4.5] decan-8-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile;
4-[5-(4-methylphenyl)-2-{9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}pyrimidin-4-yl]benzonitrile; and
4-[5-(4-fluorophenyl)-2-{9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}pyrimidin-4-yl]benzonitrile.