IP Library › Granted Patent US 9,434,726

Granted Patent B2

US 9,434,726 · App. 14/124,325 · Granted Sep 6, 2016

Substituted pyrido[3,4-b]pyrazines as Syk inhibitors

Inventors: Wei-Guo Su (Shanghai, CN); Wei Deng (Shanghai, CN); Jianguo Ji (Shanghai, CN)

Assignee: HUTCHISON MEDIPHARMA LIMITED

C07D471/04 C07D519/00

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Quick Facts

Patent No.: US 9,434,726
App. No.: 14/124,325
Granted: Sep 6, 2016
Kind: B2

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Abstract

Provided are pyridopyrazine compounds of formula (I), pharmaceutical compositions thereof and methods of use therefore, wherein R 1 , R 2 , R 3 , R 4 and m are as defined in the specification.

Claims (546)

1. A compound of formula (I):

and/or a pharmaceutically acceptable salt thereof, wherein

R 1 is independently chosen from hydrogen and C 1 -C 6 alkyl;

R 2 is aryl, or heteroaryl, which is optionally substituted by one or more groups (i) selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)OR 7 , —NR 5 C(O)NR 10 R 11 , —NO 2 , or —S(O) n NR 5 R 6 , or (ii) selected from C 1-6 alkyl, cycloalkyl, heterocycyl, heteroaryl, and aryl, wherein each of (ii) is optionally substituted with one or more groups selected from halo, hydroxy, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, —C 1 -C 4 alkyl-OH, —NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —N(C 1 -C 4 alkyl)C(O)(C 1 -C 4 alkyl), —C(O) C 1 -C 4 alkyl, —C(O) C 1 -C 4 haloalkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 4 alkyl), —NHSO 2 (C 1 -C 4 alkyl), and heterocyclyl optionally substituted by —SO 2 (C 1 -C 4 alkyl),

R 3 and R 4 are independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, each of which, except for hydrogen, is optionally substituted with one or more groups selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)OR 7 , —NR 5 C(O)NR 10 R 11 , —NO 2 , —S(O) n NR 5 R 6 , C 1-6 alkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, alkenyl, and alkynyl, wherein the heterocyclyl is optionally substituted by one or more groups selected from —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 alkyl-OH, halo, hydroxy, —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —C(O)C 1 -C 4 alkyl, —C(O)C 1 -C 4 haloalkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , and heteroaryl,

or R 3 and R 4 , together with the N atom to which they are attached, can form a 4-12 membered monocyclic, fused bicyclic or spirocyclic ring optionally containing an additional 1-3 heteroatoms chosen from N and O, which is optionally substituted with one or more groups selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)OR 7 , —NR 5 C(O)NR 10 R 11 , —NO 2 , —S(O) n NR 5 R 6 , C 1-6 alkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, alkenyl, and alkynyl, wherein the C 1-6 alkyl is optionally substituted by one or more groups selected from hydroxy, —NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), and —NHSO 2 (C 1 -C 4 alkyl),

m is 0, 1 or 2,

n is 1 or 2,

R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, each of which, except for hydrogen, is optionally substituted with one or more groups selected from halo, hydroxy, C 1-6 alkyl, cycloalkyl, heterocyclyl, amino, and amide, wherein the amino is optionally substituted by one or two —C 1 -C 4 alkyl,

or R 5 and R 6 , R 5 and R 7 , R 5 and R 8 , R 5 and R 9 , and R 5 and R 10 together with the atom(s) to which they are attached can form a ring, which is optionally substituted with one or more groups selected from halo, hydroxy, C 1 -6 alkyl, cycloalkyl, heterocycyl, amino, and amide.

2. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein

R 1 is independently chosen from hydrogen, and C 1 -C 6 alkyl;

R 2 is C 5 -C 10 aryl or 5-10 membered heteroaryl, which is optionally substituted by one or more groups (i) selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NO 2 , or —S(O) n NR 5 R 6 , or (ii) selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, or C 5 -C 10 aryl, wherein each of (ii) is optionally substituted with one or more groups selected from halo, hydroxy, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, —C 1 -C 4 alkyl-OH, —NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —N(C 1 -C 4 alkyl)C(O)(C 1 -C 4 alkyl), —C(O) C 1 -C 4 alkyl, —C(O)—C 1 -C 4 haloalkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 4 alkyl), —NHSO 2 (C 1 -C 4 alkyl), and heterocyclyl optionally substituted by —SO 2 (C 1 -C 4 alkyl),

R 3 and R 4 are independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and 3-8 membered heterocyclyl, each of which, except for hydrogen, is optionally substituted with one or more groups selected from halo, —NR 5 R 6 , —OR 7 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —S(O) n NR 5 R 6 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, and C 5 -C 10 aryl, wherein the 3-8 membered heterocyclyl is optionally substituted by one or more groups selected from —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 alkyl-OH, halo, -hydroxy, —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —C(O)C 1 -C 4 alkyl, —C(O)C 1 -C 4 haloalkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , and heteroaryl,

or R 3 and R 4 , together with the N atom to which they are attached, can form a 4-12 membered monocyclic, fused bicyclic or spirocyclic ring optionally containing an additional 1-3 heteroatoms chosen from N and O, which is optionally substituted with one or more groups selected from —NR 5 R 6 , —OR 7 , —C(O)OR 7 , —C(O)NR 5 R 6 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)NR 10 R 11 , —S(O) n NR 5 R 6 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, and C 5 -C 10 aryl, wherein the C 1-6 alkyl is optionally substituted by one or more groups selected from hydroxy, —NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), and —NHSO 2 (C 1 -C 4 alkyl),

m is 0 or 1,

n is 2,

or R 5 and R 6 , R 5 and R 7 , R 5 and R 8 , R 5 and R 9 , and R 5 and R 10 together with the atom(s) to which they are attached can form a ring.

3. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein

R 1 is independently chosen from hydrogen and methyl;

R 2 is independently selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, furyl, and indolyl, which is optionally substituted by one or more groups (i) selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —CN, —C(O)NR 5 R 6 , —NR 5 S(O) n R 8 , or —S(O) n NR 5 R 6 ; or (ii) selected from methyl, ethyl, i-propyl, t-butyl, cyclopentyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, pyrazolyl, imidazolinyl, and phenyl, wherein each of (ii) is optionally substituted by one or more groups selected from halo, hydroxy, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, —C 1 -C 4 alkyl-OH, —NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —N(C 1 -C 4 alkyl)C(O)(C 1 -C 4 alkyl), —C(O)—C 1 -C 4 alkyl, —C(O)—C 1 -C 4 haloalkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 4 alkyl), —NHSO 2 (C 1 -C 4 alkyl), and heterocycyl optionally substituted by —SO 2 (C 1 -C 4 alkyl),

R 3 and R 4 are independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclohexyl, phenyl, pyrrolidinyl, and pipericnyl, each of which, except for hydrogen, is optionally substituted with one or more groups (i) selected from halo, —NR 5 R 6 , —OR 7 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —S(O) n NR 5 R 6 ; or (ii) selected from cyclopropyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, pyridyl, pyrazolyl, and imidazolinyl, each of said piperidinyl, morpholinyl, and thiomorpholinyl is optionally substituted by one or more groups selected from —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 alkyl-OH, halo, hydroxy, —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —C(O)C 1 -C 4 alkyl, —C(O)C 1 -C 4 haloalkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , and heteroaryl,

or R 3 and R 4 , together with the N atom to which they are attached, can form a 4-12 membered monocyclic, fused bicyclic or spirocyclic ring optionally containing an additional 1-3 heteroatoms chosen from N and O, which is optionally substituted with one or more groups (i) selected from —NR 5 R 6 , —OR 7 , —C(O)NR 5 R 6 , —NR 5 S(O) n NR 10 R 11 , —NRC(O)NR 10 R 10 , and —S(O) n R 5 R 6 ; or (ii) selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl, wherein each of (ii) is optionally substituted by one or more groups selected from hydroxy, —NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), and —NHSO 2 (C 1 -C 4 alkyl),

m is 0 or 1,

n is 2,

R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pyrrolidinyl, tetrahydrofuryl, and piperidinyl, each of which, except for hydrogen, is optionally substituted with one or more groups selected from halo, methoxy, ethoxy, n-propoxy, i-propoxy, pyrrolidinyl, tetrahydrofuryl, piperidinyl, morpholinyl, amino, and amide, wherein amino is optionally substituted by one or two —C 1 -C 4 alkyl,

or R 5 an R 6 , R 5 and R 7 , R 5 and R 8 , R 5 and R 9 , and R 5 an R 10 together with the atom(s) to which they are attached can form a ring.

4. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein

R 1 is independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl;

R 2 is independently selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolinyl, oxazolyl, and quinolinyl, which is optionally substituted by one or more groups selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)OR 7 , —NR 5 C(O)NR 10 R 11 , —NO 2 , and —S(O) n R 5 R 6 ;

R 3 and R 4 are independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzoimidazolinyl, indolyl, quinolinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, and oxazepanyl, each of which, except for hydrogen, is optionally substituted with one or more groups selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)OR 7 , —NR 5 C(O)NR 10 R 11 , —NO 2 , and —S(O) n R 5 R 6 ;

or R 3 and R 4 , together with the N atom to which they are attached, form a 4-12 membered monocyclic, fused bicyclic or spirocyclic ring optionally containing an additional 1-3 heteroatoms chosen from N and O, which is optionally substituted with one or more groups selected from (i) halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)OR 7 , —NR 5 C(O)NR 10 R 11 , —NO 2 , and —S(O) n R 5 R 6 ; or (ii) selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzoimidazolinyl, indolyl, quinolinyl, phenyl, naphthyl, and C 2 -C 6 alkynyl;

m is 0, 1 or 2;

n is 1 or 2;

R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzoimidazolinyl, indolyl, quinolinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, and oxazepanyl;

or R 5 and R 6 , R 5 and R 7 , R 5 and R 8 , R 5 and R 9 , and R 5 and R 10 together with the atom(s) to which they are attached form a ring, which is optionally substituted with one or more groups selected from (i) halo and hydroxy; or (ii) selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, amino, and amide.

5. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 1 is independently chosen from hydrogen, methyl, ethyl, n-propyl, or i-propyl.

6. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.

7. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 2 is C 5 -C 10 aryl, or 5-10 membered heteroaryl, which is optionally substituted by one or more groups (i) selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)OR 7 , —NR 5 C(O)NR 10 R 11 , —NO 2 , or —S(O) n NR 5 R 6 , or (ii) selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, and C 5 -C 10 aryl, wherein each of (ii) is optionally substituted with one or more groups selected from halo, hydroxy, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, —C 1 -C 4 alkyl-OH, —NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —N(C 1 -C 4 alkyl)C(O)(C 1 -C 4 alkyl), —C(O) C 1 -C 4 alkyl, —C(O)C 1 -C 4 haloalkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , SO 2 NH(C 1 -C 4 alkyl), —NHSO 2 (C 1 -C 4 alkyl), and heterocyclyl optionally substituted by —SO 2 (C 1 -C 4 alkyl),

R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, each of which, except for hydrogen, is optionally substituted with one or more groups selected from halo, hydroxy, C 1-6 alkyl, cycloalkyl, amino, and amide, wherein the amino is optionally substituted by one or two —C 1 -C 4 alkyl,

8. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 2 is independently selected from phenyl-naphtyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzoimidazolinyl, indolyl, or quinolinyl, which is optionally substituted by one or more groups (i) selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)OR 7 , —NR 5 C(O)NR 10 R 11 , —NO 2 , or —S(O) n NR 5 R 6 ; or (ii) selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzoimidazolinyl, indolyl, quinolinyl, phenyl, or naphthyl, wherein each of (ii) is optionally substituted with one or more groups selected from halo, hydroxy, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, —C 1 -C 4 alkyl-OH, —NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —N(C 1 -C 4 alkyl)C(O)(C 1 -C 4 alkyl), —C(O)—C 1 -C 4 alkyl, —C(O)—C 1 -C 4 haloalkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 4 alkyl), —NHSO 2 (C 1 -C 4 alkyl), and heterocyclyl optionally substituted by —SO 2 (C 1 -C 4 alkyl),

R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, each of which, except for hydrogen, is optionally substituted with one or more groups selected from halo, hydroxy, C 1-6 alkyl, cycloalkyl, amino, and amide, wherein the amino is optionally substituted by one or two —C 1 -C 4 alkyl,

9. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 2 is independently selected from

each of which is optionally substituted by one or more groups (i) selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)OR 7 , —NR 5 C(O)NR 10 R 11 , —NO 2 , or —S(O) n NR 5 R 6 , or (ii) selected from C 1-6 alkyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein each of (ii) is optionally substituted with one or more groups selected from halo, hydroxy, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, —C 1 -C 4 alkyl-OH, —NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —N(C 1 -C 4 alkyl)C(O)(C 1 -C 4 alkyl), —C(O)—C 1 -C 4 alkyl, —C(O)—C 1 -C 4 haloalkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 4 alkyl), —NHSO 2 (C 1 -C 4 alkyl), and heterocyclyl optionally substituted by —SO 2 (C 1 -C 4 alkyl),

R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, each of which, except for hydrogen, is optionally substituted with one or more groups selected from halo, hydroxy, C 1-6 alkyl, cycloalkyl, amino, and amide, wherein the amino is optionally substituted by one or two —C 1 -C 4 alkyl,

10. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 2 is

which is optionally substituted by one or more groups (i) selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —CN, —C(O)NR 5 R 6 , —NR 5 S(O) n R 8 , or —S(O) n NR 5 R 6 , or (ii) selected from C 1-6 alkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, wherein each of (ii) is optionally substituted with one or more groups selected from halo, hydroxy, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, —NH 2 , —C(O)—C 1 -C 4 alkyl, —C(O)—C 1 -C 4 haloalkyl, —SO 2 (C 1 -C 4 alkyl), and —SO 2 (C 1 -C 4 haloalkyl),

R 5 , R 6 , R 7 , and R 8 are independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, each of which, except for hydrogen, is optionally substituted with one or more groups selected from halo, hydroxy, C 1-6 alkyl, cycloalkyl, amino, and amide, or R 5 and R 6 , R 5 and R 7 , and R 5 and R 8 together with the atom(s) to which they are attached can form a ring.

11. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 2 is

which is optionally substituted by one or more groups (i) selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NO 2 , or —S(O) n NR 5 R 6 , or (ii) selected from C 1-6 alkyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein each of (ii) is optionally substituted with one or more groups selected from halo, hydroxy, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, —C 1 -C 4 alkyl-OH, —NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —N(C 1 -C 4 alkyl)C(O)(C 1 -C 4 alkyl), —C(O)C 1 -C 4 alkyl, —C(O)C 1 -C 4 haloalkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 4 alkyl), —NHSO 2 (C 1 -C 4 alkyl), and heterocyclyl optionally substituted by —SO 2 (C 1 -C 4 alkyl),

R 5 , R 6 , R 7 , R 8 , and R 9 , are independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, each of which, except for hydrogen, is optionally substituted with one or more groups selected from halo, hydroxy, C 1-6 alkyl, cycloalkyl, amino, and amide, wherein the amino is optionally substituted by one or two —C 1 -C 4 alkyl, or R 5 and R 6 , R 5 and R 7 , R 5 and R 8 , and R 5 and R 9 together with the atom(s) to which they are attached can form a ring, which is optionally substituted with one or more groups selected from halo, hydroxy, C 1-6 alkyl, cycloalkyl, amino, and amide.

12. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 2 is independently selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzoimidazolinyl, indolyl, and quinolinyl, which is optionally substituted by one or more groups selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)OR 7 , —NR 5 C(O)NR 10 R 11 , —NO 2 , and —S(O) n R 5 R 6 .

13. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 2 is independently selected from

which is optionally substituted by one or more groups selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O)R 8 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)OR 7 , —NR 5 C(O)NR 10 R 11 , —NO 2 , and —S(O) n R 5 R 6 .

14. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 2 is

which is optionally substituted by one or more groups selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NR 5 S(O) n NR 10 R 11 , —NRC(O)OR 7 , —NR 5 C(O)NR 10 R 11 , —NO 2 , and —S(O) n R 5 R 6 .

15. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 2 is

which is optionally substituted by one or more groups selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)OR 7 , —NR 5 C(O)NR 10 R 11 , —NO 2 , and —S(O) n R 5 R 6 .

16. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 5 -C 10 aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl, each of which, except for hydrogen, is optionally substituted with one or more groups selected from halo, —NR 5 R 6 , —OR 7 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , or —S(O) n NR 5 R 6 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, and C 5 -C 10 aryl, wherein the 3-8 membered heterocyclyl is optionally substituted by one or more groups selected from —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 alkyl-OH, halo, hydroxy, oxo, —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —C(O)C 1 -C 4 alkyl, —C(O)C 1 -C 4 haloalkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , and heteroaryl,

or R 3 and R 4 , together with the N atom to which they are attached, can form a 4-12 membered monocyclic, fused bicyclic or spirocyclic ring optionally containing an additional 1-3 heteroatoms chosen from N and O, which is optionally substituted with one or more groups selected from —NR 5 R 6 , —OR 7 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)NR 10 R 11 , —S(O) n NR 5 R 6 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, and C 5 -C 10 aryl, wherein the C 1 -C 6 alkyl is optionally substituted by one or more groups selected from hydroxy, —NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), and —NHSO 2 (C 1 -C 4 alkyl),

R 5 , R 6 , R 7 , R 10 , and R 11 are independently selected from hydrogen, alkyl, and heterocyclyl, each of which, except for hydrogen, is optionally substituted with one or more groups selected from halo, hydroxy, C 1-6 alkyl, cycloalkyl, amino, and amide,

or R 5 and R 6 , R 5 and R 7 , and R 5 and R 10 together with the atom(s) to which they are attached can form a ring.

17. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzoimidazolinyl, indolyl, quinolinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, and oxazepanyl, each of which, except for hydrogen, is optionally substituted with one or more groups (i) selected from halo, —NR 5 R 6 , —OR 7 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , and —S(O) n NR 5 R 6 ; or (ii) selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzoimidazolinyl, indolyl, quinolinyl, phenyl, and naphthyl,

or R 3 and R 4 , together with the N atom to which they are attached, can form a 4-12 membered monocyclic, fused bicyclic or spirocyclic ring optionally containing an additional 1-3 heteroatoms chosen from N and O, which is optionally substituted with one or more groups (i) selected from halo, —NR 5 R 6 , —OR 7 , —C(O)OR 7 , —C(O)NR 5 R 6 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)NR 10 R 11 , or —S(O) n NR 5 R 6 ; or (ii) selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzoimidazolinyl, indolyl, quinolinyl, phenyl, and naphthyl,

or R 5 and R 6 , R 5 and R 7 , and R 5 and R 10 together with the atom(s) to which they are attached can form a ring.

18. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, each of which, except for hydrogen, is optionally substituted with one or more groups selected from halo, —NR 5 R 6 , —OR 7 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —S(O) n NR 5 R 6 , C 1-6 alkyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein the 3-8 membered heterocyclyl is optionally substituted by one or more groups selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —C 1 -C 4 alkyl-OH, halo, hydroxy, oxo, —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), CONH(C 1 -C 4 alkyl), —CONH 2 , —C(O)C 1 -C 4 alkyl, —C(O)C 1 -C 4 haloalkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , and heteroaryl,

R 5 , R 6 , and R 7 are independently selected from hydrogen, alkyl, and heterocyclyl, each of which except for hydrogen, is optionally substituted with one or more group selected from halo, hydroxy, C 1-6 alkyl, cycloalkyl, amino, and amide,

or R 5 and R 6 , R 5 and R 7 , and R 5 and R 10 together with the atom(s) to which they are attached can form a ring.

19. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 , together with the N atom to which they are attached form a 4-7 membered monocyclic ring optionally containing an additional 1-3 heteroatoms chosen from N and O, which is optionally substituted with one or more groups selected from —NR 5 R 6 , —OR 7 , —C(O)OR 7 , —C(O)NR 5 R 6 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)NR 10 R 11 , —S(O) n NR 5 R 6 , C 1-6 alkyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl, wherein the C 1-6 alkyl is optionally substituted by one or more groups selected from hydroxy, —NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), and —NHSO 2 (C 1 -C 4 alkyl),

or R 5 and R 6 , R 5 and R 7 , R 5 and R 8 , R 5 and R 9 , and R 5 and R 10 together with the atom(s) to which they are attached can form a ring.

20. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzoimidazolinyl, indolyl, quinolinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, and oxazepanyl, each of which, except for hydrogen, is optionally substituted with one or more groups selected from halo, —NR 5 R 6 , —OR 7 , —S(O) n R 8 , —C(O)R 9 , —C(O)OR 7 , —CN, —C(O)NR 5 R 6 , —NR 5 C(O)R 9 , —NR 5 S(O) n R 8 , —NR 5 S(O) n NR 10 R 11 , —NR 5 C(O)OR 7 , —NR 5 C(O)NR 10 R 11 , —NO 2 , and —S(O) n R 5 R 6 .

21. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen and R 3 is C 1-6 alkyl, which is optionally substituted with one or more groups selected from alkyl, cycloalkyl, heterocyclyl and heteroaryl, wherein heterocyclyl is optionally substituted by one or more groups chosen from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —C 1 -C 4 alkyl-OH, halo, hydroxy, oxo, —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —C(O)C 1 -C 4 alkyl, —C(O)C 1 -C 4 haloalkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , and heteroaryl.

22. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 , together with the N atom to which they are attached can form a 7-12 membered fused bicyclic ring optionally containing an additional 1-3 heteroatoms chosen from N and O.

23. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 , together with the N atom to which they are attached can form a 7-12 membered spirocyclic ring optionally containing an additional 1-3 heteroatoms chosen from N and O.

24. The compound of claim 1 , and/or a pharmaceutically acceptable salt thereof, wherein m is 1.

25. A pharmaceutical composition comprising at least one compound of claim 1 , and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

26. A method for inhibiting a spleen tyrosine kinase in a system or a subject, comprising administering to a system or a subject in need thereof a therapeutically effective amount of a compound of claim 1 .

27. The method of claim 26 , wherein the subject suffers from a disease chosen from the group consisting of allergic asthma, allergic rhinitis, rheumatoid arthritis, multiple sclerosis, lupus, systemic lupus erythematosus, lymphoma, B cell lymphoma, T cell lymphoma, leukemia, leucopenia, neutropenia, thrombocytopenia, granuloctopenia, pancytoia and idiopathic thrombocytopenic purpura.

28. A compound chosen from the group consisting of: 1 to 233, 236-238, 241, 246-250, 253, 256-275, 279-280, 283-288, 290, 293, 303-306, 308-310, 312-367, 372-373, 380-381, 384-391, 394-482, and 484-516

Compound

Structure

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232, 233

236

237

238

241

246

247

248

249

250

253

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

279

280

283

284

285

286

287

288

290

293

303

304

305

306

308

309

310

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

372, 373

380, 381

384, 385

386, 387

388, 389

390, 391

394, 395

396, 397

398, 399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476, 477

478

479

480

481

482

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507, 508

509

510

511

512

513

514

515

and 516

and/or a pharmaceutically acceptable salt thereof.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 6, 2013

From: SU, WEI-GUO; DENG, WEI; JI, JIANGUO

To: HUTCHISON MEDIPHARMA LIMITED

Reel/Frame 031731/0228 →

Priority Claims (1)

WO PCT/CN2011/075431 · Jun 8, 2011 · international

Continuity (1)

Related Publication 20140121200A1 · May 1, 2014