# US 11,433,053 B2 · LSD1 inhibitor and preparation method and application thereof

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- Number: US 11,433,053 B2
- Document ID: US11433053B2
- Status: Granted
- Kind: B2
- Application number: 16/479,602
- Filed: 2018-01-24
- Published: 2020-11-05
- Granted: 2022-09-06
- Earliest claimed: 2017-01-24
- Assignees: Medshine Discovery Inc.
- Applicants: Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.
- Inventors: Lingyun Wu; Li Zhang; Lele Zhao; Jianjun Sun; Zhaoguo Chen; Jian Li; Shuhui Chen
- Web page: https://patentgrep.com/patent/US11433053B2

## CPC

- A61K 31/4245: Oxadiazoles
- A61K 31/135: having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)}
- A61K 31/165: having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K 31/277: having a ring, e.g. verapamil
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/4035: Isoindoles, e.g. phthalimide
- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K 31/415: 1,2-Diazoles
- A61K 31/417: Imidazole-alkylamines, e.g. histamine, phentolamine
- A61K 31/4188: condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
- A61K 31/4192: 1,2,3-Triazoles
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/423: condensed with carbocyclic rings
- A61K 31/426: 1,3-Thiazoles
- A61K 31/428: condensed with carbocyclic rings
- 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 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/451: having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/472: Non-condensed isoquinolines, e.g. papaverine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 33/243: Platinum; Compounds thereof
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- C07C 211/40: containing only non-condensed rings
- C07C 229/14: to carbon atoms of carbon skeletons containing rings
- C07C 229/38: having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C 233/58: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C 255/46: to carbon atoms of non-condensed rings
- C07C 255/58: containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C 271/24: with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 207/06: with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D 207/09: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 207/335: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D 209/20: substituted additionally by nitrogen atoms, e.g. tryptophane
- C07D 209/44: Iso-indoles; Hydrogenated iso-indoles
- C07D 211/18: with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D 211/34: with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 211/62: attached in position 4
- C07D 213/38: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
- C07D 213/79: Acids; Esters
- C07D 217/02: with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D 217/26: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 223/16: Benzazepines; Hydrogenated benzazepines
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- C07D 241/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 243/14: 1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D 249/06: with aryl radicals directly attached to ring atoms
- C07D 249/08: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D 257/04: Five-membered rings
- C07D 261/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 261/20: condensed with carbocyclic rings or ring systems
- C07D 263/32: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 263/34: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 263/56: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D 265/30: not condensed with other rings
- C07D 271/06: 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D 271/10: 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D 277/28: Radicals substituted by nitrogen atoms
- C07D 277/56: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 295/135: with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07B 2200/07: Optical isomers
- C07C 2601/02: with a three-membered ring
- C07C 2601/04: with a four-membered ring
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

A cyclopropylamine compound as a lysine-specific demethylase 1 (LSD1) inhibitor. Particularly, the present invention relates to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. The present invention also provides an application of the same in preparing a drug for treating an LSD1-related disease.

## Claims

### Claim 1

A compound of formula (I), a pharmaceutically acceptable salt thereof or a tautomer thereof,
wherein,
f is 1 or 2;
r is 0, 1 or 2;
e is 0, 1, or 2;
p is 0 or 1;
m is 0, 1 or 2; n is 1 or 2; or the structural unit
each of R1 and R2 is independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH2 and —COOH, or is a C1-3 alkyl optionally substituted by 1, 2 or 3 of R; or, R1 and R2 are connected together to form a 3-6-membered ring;
R3 is -L-R5, or selected from the group consisting of a 5-12 membered heteroaryl, a C3-7 cycloalkyl and a 4-8 membered heterocycloalkyl, each of which is optionally substituted by 1, 2 or 3 of R;
R4 is H, or selected from the group consisting of a C1-6 alkyl and a C1-6 heteroalkyl, each of which is optionally substituted by 1, 2 or 3 of R;
R5 is selected from the group consisting of cyclohexyl-CH2—, phenyl, a 5-10 membered heteroaryl, a C3-10 cycloalkyl, a 4-10 membered heterocycloalkyl, a 5-6 membered heterocycloalkyl-C(═O)— and a 5-6 membered heterocycloalkyl-C1-3 alkyl-, each of which is optionally substituted by 1, 2 or 3 of R;
R6 is H, or selected from the group consisting of a C1-6 alkyl and a C1-6 heteroalkyl, each of which is optionally substituted by 1, 2 or 3 of R;
L is —C(═O)—, or selected from the group consisting of —C1-6 alkyl- and -5-9 membered heteroaryl-, -4-8 membered heterocycloalkyl-, -phenyl- and —C3-6 cycloalkyl-, each of which is optionally substituted by 1, 2 or 3 of R;
R is selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CN, —COOH and NH2—C(═O)—, or selected from the group consisting of C1-6 alkyl, C1-6 heteroalkyl, phenyl-C1-6 alkyl-, phenyl, 5-6 membered heteroaryl, phenyl-C(═O)—, C3-6 cycloalkyl-C(═O)—, C3-6 cycloalkyl-C(═O)—NH, C3-6 cycloalkyl-NH—C(═O)— and C3-6 cycloalkyl-C1-3 alkyl-, each of which is optionally substituted by 1, 2 or 3 of R′;
R′ is selected from the group consisting of F, Cl, Br, I, OH, NH2, COOH, C1-3 alkyl, C1-3 alkyl substituted by 1-3 halogen(s), C1-3 alkyl-NH—, N,N-di(C1-3 alkyl)-amino, C1-3 alkyl-O—C(═O)—, C3-6 cycloalkyl and C1-3 alkoxyl;
each of the “hetero” in the 5-12 membered heteroaryl, 4-8 membered heterocycloalkyl, C1-6 heteroalkyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, 4-10 membered heterocycloalkyl is independently selected from the group consisting of —NH—, —S—, N, —O—, ═O, —C(═O)—, —NH—C(═O)—, —O—C(═O)—, —S(═O)2—, —S(═O)—, —C(═O)—NH—;
in any above cases, the number of the heteroatom or the heteroatomic group in the 5-12 membered heteroaryl, 4-8 membered heterocycloalkyl, C1-6 heteroalkyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, 4-10 membered heterocycloalkyl is independently 1, 2, 3 or 4.

### Claim 2 (depends on 1)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1, wherein R′ is selected from the group consisting of F, Cl, Br, I, OH, NH2, Me, Et, CF3, CHF2, CH2F, NHCH3, N(CH3)2, COOH, —C(═O)—O—CH3, —O—CH3 and

### Claim 3 (depends on 1)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1, wherein R is selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CN, COOH, NH2—C(═O)—, or selected from the group consisting of methyl, ethyl, propyl, isobutyl, tert-butyl, C1-6 alkoxyl, phenyl-C1-3 alkyl-, phenyl, pyridyl, 1,2,4-triazolyl, phenyl-C(═O)—, C1-3 alkyl-C(═O)—, C1-3 alkyl-NH—, cyclopropyl-C(═O)—, C1-3 alkyl-O—C(═O)—C1-3 alkyl-, C1-3 alkyl-O—C(═O)—, C1-3 alkyl-S(═O)2—, cyclopropyl-C(═O)—NH—, cyclopropyl-NH—C(═O)—, C1-3 alkyl-NH—C(═O)—, cyclobutane-CH2— and C1-3 alkyl-C(═O)—NH—, each of which is optionally substituted by 1, 2 or 3 of R′.

### Claim 4 (depends on 1)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1, wherein each of R1 and R2 is independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH2, —COOH, Me and Et.

### Claim 5 (depends on 1)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1, wherein L is —C(═O)—, or selected from the group consisting of -1,2,4-oxadiazolyl-, -methylene-, -ethyl-, -1,3,4-oxadiazolyl-, -isoxazolyl-, -oxazolyl-, -piperidyl-, -1,2,3-triazolyl-, -cyclopropanyl- and -phenyl-, each of which is optionally substituted by 1, 2 or 3 of R.

### Claim 6 (depends on 1)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1, wherein R5 is selected from the group consisting of phenyl, pyridyl, piperidinyl, pyrrolidinyl, azetidinyl, cyclohexyl, cyclobutyl, benzo[d][1,3] m-dioxacyclopentenyl, piperidyl-2-keto, 7-azaspiro[3.5]nonyl, cyclohexyl-CH2—, 3a,7a-dihydro-1H-indolyl, pyrazolyl, 3a,7a-dihydrobenzo[d]thiazolyl, pyrimidinyl, cyclopentyl, spiro[3.3]heptanyl, bicyclo[2.2.2]octyl, octahydrocyclopenta[c]pyrrolyl, 2-azaspiro[3.5]nonyl, piperidinyl-C(═O)—, 4,5,6,7-tetrahydro-1H-benzo [d]imidazolyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridyl, piperidinyl-CH2—, bicyclo[1.1.1]pentyl and piperazinyl, each of which is optionally substituted by 1, 2 or 3 of R.

### Claim 7 (depends on 5)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 5, wherein -L-R5 is selected from the group consisting of
each of which is optionally substituted by 1, 2 or 3 of R.

### Claim 8 (depends on 1)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1, wherein R3 is -L-R5, or selected from the group consisting of pyrrolidinyl, 1H-imidazolyl, 1H-1,2,4-triazolyl, pyridyl, thiazolyl, thienyl, pyrrolyl, 2H-tetrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, imidazo[1,5-a]pyridyl, oxazolyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, 1,2,3,4-4H-2,7-naphthyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, 2,3,4,5-tetrahydro-1H-benzo[d]azepinyl, azetidinyl, isoindolyl, piperidinyl, 2,3,4,5-tetrahydro-1H-benzo [b]azepinyl, 2,3-dihydro-1H-pyrrolo [3,4-c]pyridyl, benzoisoxazolyl, 5,6,7,8-tetrahydropyridopyrimidinyl, 3a,7a-dihydrobenzo[d]thiazolyl, 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, piperazinyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl, 1,4-diazepine, cyclohexyl and 1,2,4-oxadiazolyl, each of which is optionally substituted by 1, 2 or 3 of R.

### Claim 9 (depends on 1)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1, wherein R4 is selected from the group consisting of H, Me, Et and

### Claim 10 (depends on 1)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1, wherein R6 is selected from the group consisting of H, Me, Et and

### Claim 11 (depends on 1)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1, wherein the structural unit
is selected from the group consisting of

### Claim 12 (depends on 1)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1, which is selected from the group consisting of
wherein,
e, f, m and n are as defined in claim 1;
R is as defined in claim 1;
R5 is as defined in claim 1;
each of q1 and q2 is independently 1 or 2.

### Claim 13

A compound, pharmaceutically acceptable salt or tautomer thereof selected from the group consisting of

### Claim 14 (depends on 1)

A pharmaceutical composition, comprising a therapeutically effective amount of the compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 as an active ingredient, and a pharmaceutically acceptable carrier.

### Claim 15 (depends on 1)

A method for treating LSD1-related disease in a subject in need thereof, comprising administering the compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 to the subject.

### Claim 16 (depends on 14)

A method for treating LSD1-related disease in a subject in need thereof, comprising administering the pharmaceutical composition as defined in claim 14 to the subject.

### Claim 17 (depends on 13)

A method for treating LSD1-related disease in a subject in need thereof, comprising administering the compound, the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 13 to the subject.

### Claim 18 (depends on 13)

A pharmaceutical composition, comprising a therapeutically effective amount of the compound, the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 13 as an active ingredient, and a pharmaceutically acceptable carrier.

### Claim 19 (depends on 18)

A method for treating LSD1-related disease in a subject in need thereof, comprising administering the pharmaceutical composition as defined in claim 18 to the subject.

### Claim 20 (depends on 15)

The method as defined in claim 15, wherein the LSD1-related disease is small cell lung cancer.

### Claim 21 (depends on 16)

The method as defined in claim 16, wherein the LSD1-related disease is small cell lung cancer.

### Claim 22 (depends on 17)

The method as defined in claim 17, wherein the LSD1-related disease is small cell lung cancer.

### Claim 23 (depends on 19)

The method as defined in claim 19, wherein the LSD1-related disease is small cell lung cancer.

### Claim 24 (depends on 1)

A pharmaceutical composition, comprising the compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 1 and Cisplatin.

### Claim 25 (depends on 13)

A pharmaceutical composition, comprising the compound, the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 13 and Cisplatin.

### Claim 26 (depends on 3)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 3, wherein R is selected from the group consisting of
or R is selected from the group consisting of H, F, Cl, Br, I, OH, NH2, Me, Et, —CF3, CN, COOH,

### Claim 27 (depends on 5)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 5, wherein L is —C(═O)—, or selected from the group consisting of
each of which is optionally substituted by 1, 2 or 3 of R.

### Claim 28 (depends on 6)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 6, wherein R5 is selected from the group consisting of
or, R5 is selected from the group consisting of

### Claim 29 (depends on 7)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 7, wherein -L-R5 is selected from the group consisting of

### Claim 30 (depends on 8)

The compound of formula (I), the pharmaceutically acceptable salt or the tautomer thereof as defined in claim 8, wherein R3 is selected from the group consisting of
or, R3 is selected from the group consisting of