# US 2017/0253618 A1 · Novel imidazopyridazine compounds and their use

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- Number: US 2017/0253618 A1
- Document ID: US20170253618A1
- Status: Published application
- Kind: A1
- Application number: 15/513,811
- Filed: 2015-09-23
- Published: 2017-09-07
- Earliest claimed: 2014-09-24
- Assignees: Hutchison Medipharma Limited
- Applicants: Hutchison Medipharma Limited
- Inventors: Wei-Guo Su; Guangxiu Dai; Welhan Zhang; Wei Deng
- Web page: https://patentgrep.com/patent/US20170253618A1

## CPC

- 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
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This disclosure provides novel imidazopyridazine compounds of formula (I) and pharmaceutical acceptable salt thereof, pharmaceutical compositions containing them, a process for preparing them, and their practical effect in inhibiting PI3K and potential use in treating a disease responsive to inhibition of PI3K, for example, an inflammatory disease, autoimmune disease or cancer.

## Claims

### Claim 1

A compound of formula (I):
and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein
Ar is aryl or heteroaryl, each of which is optionally substituted with one or more groups chosen from deuterium, halo, —CN, —OH, —SH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, —O(C1-6 alkyl), —(C1-6 alkyl)OH, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), and —S(O)2(C1-6 alkyl);
W is chosen from heteroaryl and —N(R3)heteroaryl, wherein said heteroaryl is optionally substituted with one or more groups chosen from halo, —CN, —OH, —SH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, —O(C1-6 alkyl), —(C1-6 alkyl)OH, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), —COOH, —C(O)NH2, —C(O)NH(C1-6 alkyl), —C(O)N(C1-6 alkyl)(C1-6 alkyl), —SO2(C1-6 alkyl), phenyl, and 5- or 6-membered heteroaryl; in which each of said phenyl or 5- or 6-membered heteroaryl as the substituent of W is optionally substituted with one or more groups chosen from halo, —CN, —OH, —SH, C1-6 alkyl, C1-6 haloalkyl, —O(C1-6 alkyl), —(C1-6 alkyl)OH, —NH2, —NH(C1-6 alkyl), and —N(C1-6 alkyl)(C1-6 alkyl);
R1 is independently chosen from H, halo, —CN, C1-6 alkyl, C1-6 haloalkyl, —(C1-6 alkyl)OH, —(C1-6 alkyl)O(C1-6 alkyl), and C2-6 alkynyl;
R2 is chosen from H, C1-6 alkyl, and C3-8 cycloalkyl, each of which except for H, is optionally substituted with one or more groups chosen from halo, —CN, C1-6 alkyl, C1-6 haloalkyl, and —OH;
R3 is H or C1-6 alkyl;
m is 1 or 2.

### Claim 2

(canceled)

### Claim 3 (depends on 1)

The compound of formula (I) according to claim 1, and/or a pharmaceutically acceptable salt thereof; and/or solvates, racemic mixture, enantiomers, diasteromers, tautomers thereof, wherein W is chosen from nitrogen-containing heteroaryl and —N(R3) nitrogen-containing heteroaryl, wherein said nitrogen-containing heteroaryl is optionally substituted with one or more groups chosen from fluoro, chloro, bromo, —CN, —OH, —SH, C1-6 alkyl, C1-6 haloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), —COOH, —C(O)NH2, phenyl, and 5- or 6-membered heteroaryl; in which each of said phenyl and 5- or 6-membered heteroaryl as the substituent of W is optionally substituted with one or more groups chosen from halo, —OH, C1-6 alkyl, and —O(C1-6 alkyl).

### Claim 4

(canceled)

### Claim 5 (depends on 1)

The compound of formula (I) according to claim 1, and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, tautomers thereof, wherein W is chosen from
each of which is optionally substituted with one or more groups chosen from fluoro, chloro, bromo, —CN, —OH, —SH, C1-6 alkyl, C1-6 haloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), —COOH, —C(O)NH2, —C(O)NH(C1-6 alkyl), phenyl, and 5- or 6-membered heteroaryl; in which each of said phenyl and 5- or 6-membered heteroaryl as the substituent of W is optionally substituted with one or more groups chosen from halo, —CN, —OH, —SH, C1-6 alkyl, C1-6 haloalkyl, —O(C1-C6 alkyl), —(C1-6 alkyl)OH, —NH2, —NH(C1-6 alkyl), or —N(C1-6 alkyl)(C1-6 alkyl).

### Claim 6

(canceled)

### Claim 7 (depends on 5)

The compound of formula (I) according to claim 5, and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, tautomers thereof, wherein W is
which is optionally substituted with one or more groups chosen from fluoro, chloro, bromo, —CN, —OH, —SH, C1-6 alkyl, C1-6 haloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), —COOH, —C(O)NH2, phenyl, and 5- or 6-membered heteroaryl; in which each of said phenyl and 5- or 6-membered heteroaryl as the substituent of W is optionally substituted with one or more groups chosen from halo, —OH, C1-6 alkyl, and —O(C1-6 alkyl).

### Claim 8 (depends on 7)

The compound of formula (I) according to claim 7, and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, tautomers thereof, wherein W is
which is optionally substituted with one or more groups chosen from chloro, —CN, —NH2, NH(C1-6 alkyl), —COOH, —C(O)NH2, phenyl, pyridyl, oxadiazolyl, pyrazolyl and tetrazolyl; in which each of said phenyl, pyridyl, oxadiazolyl, pyrazolyl, and tetrazolyl is optionally substituted with one or more groups chosen from halo, —OH, C1-6 alkyl, or —O(C1-6 alkyl).

### Claim 9 (depends on 1)

The compound of formula (I) according to claim 1, and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, tautomers thereof, wherein Ar is chosen from phenyl, naphthyl, pyridyl, pyrazolyl, quinolyl, thienyl, benzothiazolyl, indolyl, and 2,3-dihydro-1,4-benzodioxinyl, each of which is optionally substituted with one or more groups chosen from D, halo, —CN, C1-6 alkyl, —(C1-6 alkyl)OH, C1-6 haloalkyl, and —S(O)2(C1-6 alkyl).

### Claim 10 (depends on 9)

The compound of formula (I) according to claim 9, and/or a pharmaceutically acceptable salt thereof; and/or solvates, racemic mixture, enantiomers, diasteromers, tautomers thereof, wherein Ar is phenyl or pyridyl, each of which is optionally substituted with one or more groups chosen from halo, —CN, and C1-6 haloalkyl.

### Claim 11

(canceled)

### Claim 12 (depends on 1)

The compound of formula (I) according to claim 1, and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, tautomers thereof, wherein R1 is independently chosen from H, halo, —CN, and C1-6 alkyl.

### Claim 13 (depends on 1)

The compound of formula (I) according to claim 1, and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, tautomers thereof, wherein R2 is C1-6 alkyl.

### Claim 14

(canceled)

### Claim 15

(canceled)

### Claim 16 (depends on 1)

The compound of formula (I) according to claim 1, and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, tautomers thereof, wherein formula (I) is formula (I-1),

### Claim 17

(canceled)

### Claim 18

(canceled)

### Claim 19 (depends on 16)

The compound of formula (I) according to claim 16, and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, tautomers thereof, wherein W is chosen from
each of which is optionally substituted with one or more groups chosen from fluoro, chloro, bromo, —CN, —OH, —SH, C1-6 alkyl, C1-6 haloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), phenyl, and 5- or 6-membered heteroaryl.

### Claim 20

(canceled)

### Claim 21

(canceled)

### Claim 22 (depends on 16)

The compound of formula (I) according to claim 16, and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, tautomers thereof, wherein W is
which is optionally substituted with one or more groups chosen from —CN, —NH2, and tetrazolyl.

### Claim 23 (depends on 16)

The compound of formula (I) according to claim 16, and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, tautomers thereof, wherein Ar is chosen from phenyl, naphthyl, pyridyl, pyrazolyl, quinolyl, thienyl, and benzothiazolyl, each of which is optionally substituted with one or more groups chosen from halo, —CN, C1-6 alkyl, —(C1-6 alkyl)OH, and C1-6 haloalkyl.

### Claim 24 (depends on 1)

The compound of formula (I) according to claim 1, and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, which is chosen from:

### Claim 25 (depends on 1)

A pharmaceutical composition, comprising a compound of formula (I) according to claim 1, and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 26 (depends on 1)

A method of in vivo or in vitro inhibiting the activity of PI3K, comprising contacting the PI3K with an amount of a compound of formula (I) according to claim 1 and/or at least one pharmaceutically acceptable salt thereof effective to inhibit the activity of PI3K.

### Claim 27 (depends on 1)

A method of treating a disease responsive to inhibition of PI3K in a subject, comprising administering to the subject in need thereof an amount of a compound of formula (I) according to claim 1 and/or a pharmaceutically acceptable salt thereof effective to inhibit said PI3K in said subject.

### Claim 28 (depends on 27)

The method of claim 27, wherein said disease responsive to inhibition of PI3K is an inflammatory disease, autoimmune disease or cancer.

### Claim 29 (depends on 27)

The method of claim 27, wherein said disease responsive to inhibition of PI3K is an inflammatory disease or autoimmune disease chosen from rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, lupus, systemic lupus erythematosus, psoriasis, and multiple sclerosis, or solid tumor or hematological malignancy chosen from leukemia, multiple myeloma (MM), and lymphoma, wherein said leukemia is chosen from acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML); and said lymphoma is chosen from Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL).

### Claim 30

(canceled)

### Claim 31

(canceled)

### Claim 32

A compound of formula (II)
and/or a salt thereof; and/or a racemic mixture or enantiomer thereof;
wherein
Ar is aryl or heteroaryl, each of which is optionally substituted with one or more groups chosen from deuterium, halo, —CN, —OH, —SH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, —O(C1-6 alkyl), —(C1-6 alkyl)OH, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), and —S(O)2(C1-6 alkyl); and
R2 is chosen from H, C1-6 alkyl, and C3-8 cycloalkyl, each of which except for H, is optionally substituted with one or more groups chosen from halo, —CN, C1-6 alkyl, C1-6 haloalkyl, and —OH.

### Claim 33

(canceled)