# US 9,040,547 B2 · Pyrrolopyrimidine and purine derivatives

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- Number: US 9,040,547 B2
- Document ID: US9040547B2
- Status: Granted
- Kind: B2
- Application number: 13/617,035
- Filed: 2012-09-14
- Published: 2013-03-28
- Granted: 2015-05-26
- Earliest claimed: 2011-09-22
- Assignees: Pfizer Inc.
- Applicants: Hengmiao Cheng; Theodore Otto Johnson, Jr.; John Charles Kath; Kevin Kun-Chin Liu; Elizabeth Ann Lunney; Asako Nagata; Sajiv Krishnan Nair; Simon Paul Planken; Scott Channing Sutton
- Inventors: Hengmiao Cheng; Theodore Otto Johnson, Jr.; John Charles Kath; Kevin Kun-Chin Liu; Elizabeth Ann Lunney; Asako Nagata; Sajiv Krishnan Nair; Simon Paul Planken; Scott Channing Sutton
- Web page: https://patentgrep.com/patent/US9040547B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D 473/18: one oxygen and one nitrogen atom, e.g. guanine
- 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 present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Q, T, V, W, X, Y, Z, ring A, R1, R2, R3, R4, R5, R5a, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17 and m are defined herein. There novel pyrrolopyrimidine and purine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. Additional embodiments relate to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.

## Claims

### Claim 1

A compound of formula (I):
wherein
X is N or CR7;
Y is absent, O, S or NR8;
Q, T, V and W are each independently C or N, provided that at least two of Q, T, V and W are N and at least one of Q, T, V and W is C, and provided that when Q and T are N, at least one of R1 and R2 is absent, and further provided that when T and V are N, at least one of R2 and R3 is absent;
R1 and R4 are each independently absent, hydrogen, cyano, difluoromethyl, trifluoromethyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, —N(R9)(R10), C3-C5 cycloalkyl or 4-6 membered heterocycloalkyl, wherein the C1-C6 alkyl may be optionally substituted by halogen, hydroxy, C1-C6 alkoxy or N(R11)(R12);
R2 and R3 are each independently absent, hydrogen, C1-C6 alkyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, wherein the C1-C6 alkyl and C1-C6 alkoxy in R2 and R3 are each independently optionally substituted by one or more R13 groups, and further wherein the C3-C7 cycloalkyl and the 3-7 membered heterocycloalkyl in R2 and R3 are each independently optionally substituted by one or more R14 groups; or
R1 and R2 or R2 and R3 may combine to form a C5-C7 cycloalkyl ring or a 5-7 membered heterocycloalkyl ring, wherein the C5-C7 cycloalkyl ring and the 5-7 membered heterocycloalkyl ring are each independently optionally substituted by one or more R13 groups;
ring A is absent, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C5-C10 aryl or 5-12 membered heteroaryl;
R5 and R5a are each independently absent, halogen, cyano, hydroxy, difluoromethyl, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C5 cycloalkyl or 4-6 membered heteroaryl, wherein the C1-C3 alkyl is optionally substituted by hydroxy, difluoromethyl, trifluoromethyl, C1-C3 alkoxy or C3-C5 cycloalkyl;
R6 is
Z is absent when the attachment point of R6 on ring A is a nitrogen atom, and Z is —NR17— when ring A is absent or when the attachment point of R6 on ring A is a carbon atom;
R7 is hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or 4-6 membered heteroaryl, wherein the C1-C6 alkyl may be optionally substituted by hydroxy or C1-C3 alkoxy, and further wherein the 4-6 membered heteroaryl may be optionally substituted by C1-C3 alkyl;
R8 is hydrogen or C1-C3 alkyl;
R9 and R10 are each independently hydrogen or C1-C6 alkyl; or R9 and R10 together with the nitrogen to which they are attached, may combine to form a 4-7 membered ring, when R9 and R10 are each C1-C3 alkyl, wherein the 4-7 membered ring is optionally substituted by one or more R14 groups;
R11 and R12 are each independently hydrogen or C1-C3 alkyl;
each R13 is independently halogen, cyano, hydroxy, C1-C6 alkoxy, —N(R9)(R10), —CON(R9)(R10) or 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl in R13 is optionally substituted by one or more R14 groups;
each R14 is independently halogen, C1-C3 alkyl, hydroxy, C1-C6 alkoxy, —NH2, —NHCH3 or N(CH3)2;
R15 and R16 are each independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl of one of R15 and R16 is optionally substituted by —N(R9)(R10);
R17 is hydrogen or C1-C3 alkyl; and
m is 0, 1 or 2, provided that when ring A is absent, m is 2; or
a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound or salt of claim 1, wherein X is CR7.

### Claim 3 (depends on 1)

The compound or salt of claim 1, wherein Y is O.

### Claim 4 (depends on 1)

The compound or salt of claim 1, wherein Y is NR8.

### Claim 5 (depends on 2)

The compound or salt of claim 2, wherein R7 is hydrogen, halogen, cyano or 4-6 membered heteroaryl.

### Claim 6 (depends on 2)

The compound or salt of claim 2, wherein R7 is hydrogen.

### Claim 7 (depends on 5)

The compound or salt of claim 5, wherein the halogen is fluorine or chlorine.

### Claim 8 (depends on 2)

The compound or salt of claim 2, wherein R7 is cyano.

### Claim 9 (depends on 2)

The compound or salt of claim 2, wherein R7 is 4-6 membered heteroaryl optionally substituted by C1-C3 alkyl.

### Claim 10 (depends on 1)

The compound or salt of claim 1, wherein m is 0.

### Claim 11 (depends on 1)

The compound or salt of claim 1, wherein m is 1.

### Claim 12 (depends on 1)

The compound or salt of claim 1, wherein Q and T are N.

### Claim 13 (depends on 1)

The compound or salt of claim 1, wherein T and V are N.

### Claim 14 (depends on 1)

The compound or salt of claim 1, wherein R6 is

### Claim 15 (depends on 1)

The compound or salt of claim 1, wherein ring A is phenyl.

### Claim 16 (depends on 1)

The compound or salt of claim 1, having formula (Ia):
wherein
G is CH or N; and
p is 1 or 2.

### Claim 17 (depends on 16)

The compound or salt of claim 16, wherein G is CH.

### Claim 18 (depends on 16)

The compound or salt of claim 16, wherein G is N.

### Claim 19 (depends on 16)

The compound or salt of claim 16, wherein p is 1.

### Claim 20 (depends on 16)

The compound or salt of claim 16, wherein p is 2.

### Claim 21

A compound, which is selected from the group consisting of:
1-{(3R,4R)-3-[({5-chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one;
N-[3-({5-(1-methyl-1H-pyrazol-4-yl)-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)phenyl]prop-2-enamide;
N-[trans-3-({2-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)cyclobutyl]-N-methylprop-2-enamide;
1-[(3S,4R)-3-({5-chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4-(1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl]prop-2-en-1-one;
1-[(3R,4S)-3-({5-chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4-(trifluoromethyl)pyrrolidin-1-yl]prop-2-en-1-one;
N-methyl-N-[trans-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)cyclobutyl]prop-2-enamide;
1-{(3R,4R)-3-[({5-chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-fluoropyrrolidin-1-yl}prop-2-en-1-one; and
1-{(3R,4R)-3-methoxy-4-[({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]pyrrolidin-1-yl}prop-2-en-1-one,
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

### Claim 23 (depends on 21)

A pharmaceutical composition comprising a compound of claim 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

### Claim 24

A compound of formula (III):
wherein
X is N or CR7;
Y is absent, O, S or NR8;
R1 and R4 are each independently hydrogen, cyano, difluoromethyl, trifluoromethyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, —N(R9)(R10), C3-C5 cycloalkyl, or 4-6 membered heterocycloalkyl, wherein the C1-C6 alkyl may be optionally substituted by halogen, hydroxy, C1-C6 alkoxy, or N(R11)(R12);
R2 is C1-C6 alkyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, wherein the C1-C6 alkyl and C1-C6 alkoxy in R2 is optionally substituted by one or more R13 groups, and further wherein the C3-C7 cycloalkyl and the 3-7 membered heterocycloalkyl in R2 is optionally substituted by one or more R14 groups; or
R1 and R2 may combine to form a C5-C7 cycloalkyl ring or a 5-7 membered heterocycloalkyl ring, wherein the C5-C7 cycloalkyl ring and the 5-7 membered heterocycloalkyl ring are optionally substituted by one or more R13 groups;
ring A is absent, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C5-C10 aryl or 5-12 membered heteroaryl;
R5 and R5a are each independently absent, halogen, cyano, hydroxy, difluoromethyl, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C5 cycloalkyl or C3-C5 heteroaryl, wherein the C1-C3 alkyl is optionally substituted by hydroxy, difluoromethyl, trifluoromethyl, C1-C3 alkoxy or C3-C5 cycloalkyl;
R6 is
Z is absent when the attachment point of R6 on ring A is a nitrogen atom, and Z is —NR17— when ring A is absent or when the attachment point of R6 on ring A is a carbon atom;
R7 is hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or 4-6 membered heteroaryl, wherein the C1-C6 alkyl may be optionally substituted by hydroxy or C1-C3 alkoxy, and further wherein the 4-6 membered heteroaryl may be optionally substituted by C1-C3 alkyl;
R8 is hydrogen or C1-C3 alkyl;
R9 and R10 are each independently hydrogen or C1-C6 alkyl; or R9 and R10 together with the nitrogen to which they are attached, may combine to form a 4-7 membered ring, when R9 and R10 are each C1-C3 alkyl, wherein the 4-7 membered ring is optionally substituted by one or more R14 groups;
R11 and R12 are each independently hydrogen or C1-C3 alkyl;
each R13 is independently halogen, cyano, hydroxy, C1-C6 alkoxy, —N(R9)(R10), —CON(R9)(R10), 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl in R13 is optionally substituted by one or more R14 groups;
each R14 is independently halogen, C1-C3 alkyl, hydroxy, C1-C6 alkoxy, —NH2, —NHCH3, or N(CH3)2;
R15 and R16 are each independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl of one of R15 and R16 is optionally substituted by —N(R9)(R10);
R17 is hydrogen or C1-C6 alkyl; and
m is 0, 1 or 2, provided that when ring A is absent, m is 2; or
a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 24)

The compound or salt of claim 24, wherein X is CR7.

### Claim 26 (depends on 24)

The compound or salt of claim 24, wherein Y is O.

### Claim 27 (depends on 25)

The compound or salt of claim 25, wherein R7 is hydrogen, halogen, cyano or 4-6 membered heteroaryl.

### Claim 28 (depends on 25)

The compound or salt of claim 25, wherein R7 is halogen.

### Claim 29 (depends on 28)

The compound or salt of claim 28, wherein the halogen is chlorine.

### Claim 30 (depends on 24)

The compound or salt of claim 24, wherein m is 0.

### Claim 31 (depends on 24)

The compound or salt of claim 24, wherein m is 1.

### Claim 32 (depends on 24)

The compound or salt of claim 24, wherein R1 is hydrogen.

### Claim 33 (depends on 24)

The compound or salt of claim 24, wherein R2 is C1-C4 alkyl or C3-C4 cycloalkyl.

### Claim 34 (depends on 24)

The compound or salt of claim 24, wherein R2 is methyl.

### Claim 35 (depends on 24)

The compound or salt of claim 24, wherein R4 is hydrogen.

### Claim 36 (depends on 24)

The compound or salt of claim 24, having formula (IIIb):

### Claim 37 (depends on 36)

The compound or salt of claim 36, wherein R5 and R5a are each independently absent, hydroxy, difluoromethyl, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy, cyclopropyl, —(CH2)—OCH3 or —(CH2)-trifluoromethyl.

### Claim 38 (depends on 36)

The compound or salt of claim 36, wherein R5 and R5a are absent.

### Claim 39 (depends on 36)

The compound or salt of claim 36, wherein R5a is absent.

### Claim 40

A compound, which is
or a pharmaceutically acceptable salt thereof.

### Claim 41

A pharmaceutical composition comprising a compound, which is
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.