# US 11,110,082 B2 · Tyrosine kinase inhibitors

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- Number: US 11,110,082 B2
- Document ID: US11110082B2
- Status: Granted
- Kind: B2
- Application number: 16/575,852
- Filed: 2019-09-19
- Published: 2020-03-12
- Granted: 2021-09-07
- Earliest claimed: 2016-07-08
- Assignees: Rigel Pharmaceuticals, Inc.
- Applicants: Rigel Pharmaceuticals, Inc.
- Inventors: Sacha Holland; Rajinder Singh; Somasekhar Bhamidipati; Pingyu Ding; Rao Kolluri; Ihab Darwish; Esteban Masuda; Jiaxin Yu
- Web page: https://patentgrep.com/patent/US11110082B2

## CPC

- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/04: Ortho-condensed 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
- 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

Disclosed are imidazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein X, Y and Z are as described herein. In certain embodiments, a compound disclosed herein inhibits a cellular TAM receptor, and can be used to treat disease mediated by or involving the TAM receptor family.

## Claims

### Claim 1

A compound having the structure formula (I):
or a pharmaceutically acceptable salt, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
X is hydrogen, Cak(C0-C6alkyl), Hca(C0-C6alkyl), Ar(C0-C6alkyl), Het(C0-C6alkyl), halogen or Hca(C1-C6alkyl)—O—, wherein Ar, Het, Cak, Hca and the alkyl group is optionally substituted by one to four —RX1 groups, wherein
each —RX1 is independently halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, —C1-C60alkoxy, oxo, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2, —CH2—OP(O)(OR), Ar(C0-C6alkyl), Het(C0-C6alkyl), Cak(C0-C6alkyl) or Hca(C0-C6alkyl),
or two —RX1 groups taken together, when attached to adjacent atoms, form a Cak, Hca or Het, wherein the Cak Hca and the Het comprise a 3-8 membered ring optionally substituted with one or two —RX2 groups,
or two —RX1 groups taken together, when attached to the same carbon atom, form a Hca, wherein the Hca comprises a 3-8 membered ring optionally substituted with one or two —RX2 groups,
or two —RX1 groups taken together, when attached to non-adjacent atoms, and combined with X, form a bridged Hca optionally substituted with one or two —RX2 groups,
wherein each —RX2 is independently halogen, cyano, nitro, oxo, —OR, —SR, —NR2, —C(O)OR, —C(O)NR2, —C(O)R, —S(O)R, —S(O)2R, —S(O)OR, —S(O)2OR, —S(O)NR2, —S(O)2NR2, —OC(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)R, —N(R)S(O)2R, C1-C6alkyl, or C1-C6haloalkyl;
Y is Cak(C0-C8alkyl) optionally substituted by one or two —RY1 groups;
wherein each —RY1 is independently halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, —C1-C6alkyl, oxo, —OR, —SR, —NR2, N(R)C(NR2)NR2, —C(O)R, —C(O)OR, C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
Z is Cak, optionally substituted by one to three —RZ1 groups;
wherein each —RZ1 is independently halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, —C1-C6alkoxy, oxo, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR); and
each R is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, Hca(C0-C6alkyl), Cak(C0-C8alkyl), C1-C6alkyl-CN, —CH2C(O)NH2, C1-C6alkyl-OH,
wherein
Hca is a 3-15 membered ring or ring system comprising at least one ring, 1-4 O, S, or N atoms, provided no O or S is adjacent to another O or S;
Het is a 5-15 membered aromatic ring or ring system comprising at least one ring and 1-4 O, S, or N atoms, provided no O or S is adjacent to another O or S;
Cak is a 3-8 membered non-aromatic carbocyclic ring or ring system, which may be saturated or partially unsaturated; and
Ar is a 6-16 membered aromatic ring or ring system having at least one carbocyclic aromatic ring optionally fused one or more aromatic or non-aromatic rings.

### Claim 2 (depends on 1)

The compound of claim 1, having the structure of formula (Ie):

### Claim 3 (depends on 2)

The compound of claim 2, wherein RY1 is —OR.

### Claim 4 (depends on 3)

The compound of claim 3, wherein X is hydrogen, Cak(C0-C6alkyl) or Hca(C0-C6alkyl), wherein each Cak, Hca and alkyl group is optionally substituted by one to three —RX1 groups.

### Claim 5 (depends on 3)

The compound of claim 3, wherein X is hydrogen or Hca(C0-C6alkyl), wherein each Hca and alkyl group is optionally substituted by one to three —RX1 groups.

### Claim 6 (depends on 5)

The compound of claim 5, having the structure of formula (If):

### Claim 7 (depends on 5)

The compound of claim 5, having the structure of formula (II):
or a pharmaceutically acceptable salt, or N-oxide thereof, or a solvate or hydrate thereof, wherein
ring A is Hca;
a is 0 or 1; and
p is 1, 2, 3 or 4; and
each —RX1 is independently halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, —C1-C6alkoxy, oxo, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2, —CH2—OP(O)(OR), Ar(C0-C6alkyl), Het(C0-C6alkyl), Cak(C0-C6alkyl) or Hca(C0-C6alkyl).

### Claim 8 (depends on 7)

The compound of claim 7, wherein
(a) ring A is
wherein
p is 0, 1, 2, 3 or 4;
X1 is —O—, —S—, —S(O)—, —S(O)2—, —CR2—, —C(R)(RX1)—, —C(RX1)2—, —N(R)— or —N(RX1)—;
X2 is —O—, —S—, —S(O)—, —S(O)2—, —CR2—, —C(R)(RX1)—, —C(RX1)2—, —N(R)— or —N(RX1)—; and
X3 is —O—, —S—, —S(O)—, —S(O)2—, —CR2—, —C(R)(RX1)—, —C(RX1)2—, —N(R)— or —N(RX1)—;
(b) ring A is
wherein
p is 0, 1, 2, 3 or 4;
X2 is —O—, —S—, —S(O)—, —S(O)2—, —CR2—, —C(R)(RX1)—, —C(RX1)2—, —N(R)— or —N(RX1)—;
(c) ring A is
wherein
p is 0, 1 or 2;
o is 0, 1 or 2; and
ring B is Hca or Het, each comprising a 3-8 membered ring optionally substituted with one or two —RX2 groups;
(d) ring A is
wherein
p is 0, 1 or 2;
o is 0, 1 or 2;
n is 0, 1 or 2;
m is 0, 1 or 2; and
X4 is —O—, —S—, —S(O)—, —S(O)2—, —CR2—, —C(R)(RX1)—, —C(RX1)2—, —N(R)— or —N(RX1)—;
(e) ring A is
wherein
X6 is —O—, —S—, —S(O)—, —S(O)2—, —CR2—, —C(R)(RX1)—, —C(RX1)2—, —N(R)— or —N(RX1)—; and
X7 is —CR—, —C(RX1)— or —N—;
p is 0, 1 or 2;
q is 0, 1 or 2;
r is 0, 1 or 2; and
s is 0, 1 or 2.

### Claim 9 (depends on 1)

The compound of claim 1, wherein
(a) ring A is
wherein
p is 0, 1, 2, 3 or 4;
X1 is —O—, —S—, —S(O)—, —S(O)2—, —CR2—, —C(R)(RX1)—, —C(RX1)2—, —N(R)— or —N(RX1)—;
X2 is —S—, —S(O)—, —S(O)2—, —CR2—, —C(R)(RX1)—, —C(RX1)2—, —N(R)— or —N(RX1)—; and
X3 is —O—, —S—, —S(O)—, —S(O)2—, —CR2—, —C(R)(RX1)—, —C(RX1)2—, —N(R)— or —N(RX1)—;
(b) ring A is
wherein
p is 0, 1, 2, 3 or 4;
X2 is —S—, —S(O)—, —S(O)2—, —CR2—, —C(R)(RX1)—, —C(RX1)2—, —N(R)— or —N(RX1)—;
(c) ring A is
wherein
p is 0, 1 or 2;
o is 0, 1 or 2; and
ring B is Hca or Het, each comprising a 3-8 membered ring optionally substituted with one or two —RX2 groups;
(d) ring A is
wherein
p is 0, 1 or 2;
o is 0, 1 or 2;
n is 0, 1 or 2;
m is 0, 1 or 2; and
X4 is —O—, —S—, —S(O)—, —S(O)2—, —CR2—, —C(R)(RX1)—, —C(RX1)2—, —N(R)— or —N(RX1)—;
(e) ring A is
wherein
X6 is —O—, —S—, —S(O)—, —S(O)2—, —CR2—, —C(R)(RX1)—, —C(RX1)2—, —N(R)— or —N(RX1)—; and
X7 is —CR—, —C(RX1)— or —N—;
p is 0, 1 or 2;
q is 0, 1 or 2;
r is 0, 1 or 2; and
s is 0, 1 or 2.

### Claim 10 (depends on 7)

The compound of claim 7, wherein a is 0.

### Claim 11 (depends on 7)

The compound of claim 7, wherein a is 1.

### Claim 12 (depends on 1)

The compound of claim 1, having the structure of formula (III):
or a pharmaceutically acceptable salt, or N-oxide thereof, or solvate or hydrate thereof,
wherein
a is 0 or 1;
ring A is
(a)
wherein
p is 0, 1, 2 or 3;
X2 is —O—, —S—, —CR2—, —C(R)(RX1)—, —C(RX1)2—, —N(R)— or —N(RX1)—;
(b)
wherein
p is 0, 1 or 2;
ring B is 5-membered Hca or Het; or
(c)
each —RX1 is independently hydrogen, C1-C6alkyl, —C(O)OR, Cak(C0-C6alkyl) or Hca(C1-C6alkyl);
—RY1 is hydrogen or C1-C6alkyl;
Z is Cak; and
each R is independently hydrogen or C1-C6alkyl.

### Claim 13 (depends on 12)

The compound of claim 12, wherein a is 0.

### Claim 14 (depends on 12)

The compound of claim 12, wherein a is 1.

### Claim 15 (depends on 12)

The compound of claim 12, wherein ring A is
wherein
p is 0, 1, 2 or 3; and
X2 is —O—, —S—, —CR2—, —C(R)(RX1)—, —C(RX1)2—, —N(R)— or —N(RX1)—.

### Claim 16 (depends on 12)

The compound of claim 12, wherein ring A is
wherein
p is 0, 1 or 2; and
ring B is 5-membered Hca or Het.

### Claim 17 (depends on 12)

The compound of claim 12, wherein wherein ring A is

### Claim 18 (depends on 1)

The compound of claim 1, having the structure of formula (IV):
or a pharmaceutically acceptable salt, or N-oxide thereof, or solvate or hydrate thereof,
wherein
a is 0 or 1;
each —RX1 is independently hydrogen or C1-C6alkyl;
—RY1 is hydrogen or C1-C6alkyl; and
Z is Cak.

### Claim 19 (depends on 18)

The compound of claim 18, wherein a is 0.

### Claim 20 (depends on 18)

The compound of claim 18, wherein a is 1.

### Claim 21 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable diluent, carrier, or excipient and a compound according to claim 1.

### Claim 22 (depends on 1)

A method of inhibiting a cellular TAM receptor, the method comprising contacting a cell comprising a TAM receptor with a compound according to claim 1.

### Claim 23 (depends on 22)

The method of claim 22, wherein the TAM receptor is a Tyro receptor, an Axl receptor, or a Mer receptor.

### Claim 24 (depends on 1)

A method for treating a disease or condition mediated by or involving the TAM receptor family in a subject in need thereof, comprising administering an effective TAM receptor inhibiting amount of a compound of claim 1, wherein the disease or condition is a hematological neoplasm.

### Claim 25 (depends on 24)

The method of claim 24, wherein the TAM receptor is a Tyro receptor, an Axl receptor, or a Mer receptor.

### Claim 26 (depends on 24)

The method of claim 24, wherein the hematological neoplasm is acute myeloid leukemia AML.

### Claim 27 (depends on 1, 24)

The method of claim 24, further comprising administering a therapeutically effective amount of one or more chemotherapeutic agents in combination with the TAM receptor inhibiting amount of a compound of claim 1.

### Claim 28 (depends on 22)

The method of claim 22, wherein contacting comprises administering the compound to a human subject.