# US 11,993,602 B2 · PRMT5 inhibitors

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- Number: US 11,993,602 B2
- Document ID: US11993602B2
- Status: Granted
- Kind: B2
- Application number: 17/266,474
- Filed: 2019-08-05
- Published: 2021-09-09
- Granted: 2024-05-28
- Earliest claimed: 2018-08-07
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme LLC; David Witter; Shuhei Kawamura; Michelle Machacek; Ryan Quiroz; Michael H. Reutershan; Sebastian Schneider; Phieng Siliphaivanh; Yingchun Ye; Charles S. Yeung
- Inventors: David Witter; Shuhei Kawamura; Michelle Machacek; Ryan Quiroz; Michael H. Reutershan; Sebastian Schneider; Phieng Siliphaivanh; Yingchun Ye; Charles S. Yeung
- Web page: https://patentgrep.com/patent/US11993602B2

## CPC

- C07D 487/04: Ortho-condensed systems
- C07H 19/14: Pyrrolo-pyrimidine radicals
- A61P 35/00: Antineoplastic agents
- 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)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a compound of Formula (I) Formula (I) or the pharmaceutically acceptable salts thereof, which are PRMT5 inhibitors.

## Claims

### Claim 1

A compound having formula I
or a pharmaceutically acceptable salt thereof, wherein
A is O or CH2;
R1 is halogen, NH2, OC1-6alkyl, NHCH3, CHF2, C1-6alkyl, cyclopropyl, CH2OH, or C(CH3)2OH;
R2 is H, C1-6alkyl, CF3 or CHF2;
R3 is H, halogen, CH3, CF3, or CHF2, and R4 is H or NHR5, or R3 and R4 together with the atom to which they are attached form a 5-membered saturated ring containing zero or one N atom, wherein the ring is unsubstituted or substituted with CH3;
R5 is H, CH3, C2H5, CH2CH2CH3, CH(CH3)2, CH2CHF2, CH2CF3, or CH2—C3-8cycloalkyl;
R6 is H, C1-4alkyl, or halogen;
R7 is H, NH2, or C1-6alkyl;
Z1 is CH or N;
Z2 is CH or N;
Z3 is CH or N;
Z4 is CH or N; and
Z5 is CR 3 or N.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is NH2, Cl, NHCH3, OCH3, or CH3.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is H or CH3.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is NH2.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is NHCH2CHF2.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is H.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is CH2CHF2.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R6 is H, F or CH3.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is CH3 or NH2.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula
or a pharmaceutically acceptable salt thereof, wherein
A is O or CH2;
R1 is halogen, NH2, or OC1-6alkyl;
R2 is H or C1-6alkyl;
R3 is H, CH3, or halogen;
R4 is H or NHR5; and
R5 is H or CH2—C3-8cycloalkyl.

### Claim 11 (depends on 10)

The compound of claim 10, or a pharmaceutically acceptable salt thereof, having the formula

### Claim 12 (depends on 10)

The compound of claim 10, or a pharmaceutically acceptable salt thereof, having the formula

### Claim 13 (depends on 10)

A compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein
A is 0 or CH2;
R1 is C1, NH2, or OCH3;
R2 is H or CH3;
R3 is H, Br, F, CH3, or Cl; and
R4 is NH2 or NH—CH2-cyclopropyl.

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is
(2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
7-[5-O-(2-amino-3-chloroquinolin-7-yl)-4-thio-beta-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine,
7-[5-O-(2-amino-3-fluoroquinolin-7-yl)-4-thio-beta-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine,
7-(5-O-{2-[(cyclopropylmethyl)amino]quinolin-7-yl}-4-thio-beta-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,
(2R,3S,4R,5R)-2-(((2-amino-3-chloroquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyltetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyltetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(((2-((cyclopropylmethyl)amino)quinolin-7-yl)oxy)methyl)-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(((2-((cyclopropylmethyl)amino)quinolin-7-yl)oxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-5-(4-methoxy-7H-pyrrolo[2,3-d] pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(((2-aminoquinolin-7-yl)oxy)methyl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2S,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(2-(2-aminoquinolin-7-yl)ethyl)tetrahydrothiophene-3,4-diol,
(2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(2-(2-aminoquinolin-7-yl)ethyl)tetrahydrothiophene-3,4-diol,
(2S,3S,4R,5R)-2-[2-(2-aminoquinolin-7-yl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-[2-(2-aminoquinolin-7-yl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2S,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-{2-[2-amino-3-(trifluoromethyl)quinolin-7-yl]ethyl}-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2S,3S,4R,5R)-2-{2-[2-amino-3-(trifluoromethyl)quinolin-7-yl]ethyl}-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-[2-(2-amino-3-fluoroquinolin-7-yl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2S,3S,4R,5R)-2-[2-(2-amino-3-fluoroquinolin-7-yl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-[2-(2-amino-3-chloroquinolin-7-yl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2S,3S,4R,5R)-2-[2-(2-amino-3-chloroquinolin-7-yl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(2-{2-[(2,2-difluoroethyl)amino] quinolin-7-yl}ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2S,3S,4R,5R)-2-(2-{2-[(2,2-difluoroethyl)amino] quinolin-7-yl}ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(2-(2-amino-3-methyl quinolin-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2S,3S,4R,5R)-2-(2-(2-amino-3-methyl quinolin-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyltetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyltetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-2-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-2-methyl-5-(4-(methyl amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3R,4S,5R)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-(methyl amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(2-amino-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2S,3S,4R,5R)-2-(2-((R)-2-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2S,3S,4R,5R)-2-(2-((S)-2-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2S,3S,4R,5R)-2-(2-(2-amino-3-(difluoromethyl)quinolin-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,
(2S,3S,4R,5R)-2-(2-(2-amino-3-chloroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol, or
(2R,3S,4R,5R)-2-(2-(2-amino-3-chloroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol.

### Claim 15 (depends on 1)

A composition for treating cancer ameliorated by inhibition of PRMT5 comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 15)

A method for treating cancer ameliorated by inhibition of PRMT5 comprising administering to a patient in need thereof a composition of claim 15.

### Claim 17 (depends on 1)

A method for treating cancer ameliorated by inhibition of PRMT5 comprising administering to a patient in need thereof a compound of claim 1, or a pharmaceutically acceptable salt thereof.