Aminopyrrolidines as chemokine receptor antagonists

• US 20080176883A1
• Filed: 11/16/2007
• Published: 07/24/2008
• Est. Priority Date: 11/17/2006
• Status: Active Grant

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbvie Incorporated
• Inventors: Dixon, Richard W., Wu, Xiaoyun, Wang, Lu, George, Dawn M., Hobson, Adrian D., Li, Biqin, Wishart, Neil, Friedman, Michael
• Granted Patent: US 8,754,107 B2
• Time in Patent Office: Days
• US Class Current: 514/278
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/438 The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4747 spiro-condensed
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/553 having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 207/14 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/10 : Spiro-condensed systems
• CPC Class Codes: C07D 487/14 : Ortho-condensed systems

Abstract

The present invention is directed to novel aminopyrrolidines of formula I

pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, stereoisomers thereof or pro-drugs thereof, wherein the variables are as defined herein. The compounds of formula (I) are useful as chemokine receptor antagonists and as such would be useful in treating certain conditions and diseases, especially inflammatory conditions and diseases and proliferative disorders and conditions, for example, cancers.

Claims

1. A compound of formula I

2. A compound of claim 1 wherein

X is —

N(R²)—

Y-Z;

or

X is

3. The compound of claim 2 wherein X is

—

N(R²)—

Y-Z,

4. The compound of claim 3 wherein

Y is selected from the group consisting of a bond, optionally substituted (C₁-C₆)alkyl, optionally substituted piperidinyl, optionally substituted —

CH₂-pyrimidinyl, optionally substituted indanyl, optionally substituted tetrahydrofuranyl and optionally substituted tetrahydropyranyl;

Z is selected from the optionally substituted group consisting of (C₁-C₄)alkyl, cyclohexyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl, 1,3-dihydrobenzoimidazol-2-one, benzothiazolyl, benzo[b]thiophenyl, chromanyl, indanyl, indolyl, morpholinyl, naphthyl, phenyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, 4,5,6,7-tetrahydrobenzofuranyl, tetrahydrofuranyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydronaphthyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, tetrahydrothiopyranyl, tetrahydrothiopyranyl 1,1-dioxide, —

CH₂-benzofuranyl, —

CH₂-phenyl, —

CH₂-pyridinyl, —

(C₂)alkyl-diphenyl, —

CH₂-tetrahydropyranyl;

D is C(R⁵)₂;

E is C(R⁵)₂;

M is a bond, O, C(O), optionally substituted pyrrolidinyl, optionally substituted (C₁-C₄)alkyl, —

CH₂—

NH—

C(O) or (C₁)alkyl-C(O)O;

wherein the alkyl portion of the moiety is connected to W;

T is H or NH₂ or is selected from the optionally substituted group consisting of (C₁-C₄)alkyl, benzothiazolyl, benzo[b]thiophenyl, 1H-benzotriazolyl, decahydroisoquinolinyl, imidazolyl, indanyl, indenyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, morpholinyl phenyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, tetrazolyl, [1,2,3]triazolyl and [1,2,4]triazolyl,

A is a bond or (C₁-C₅)alkyl);

G is a bond, N(R²), C(O), phenyl, pyridinyl or 5,6,7,8-tetrahydro[1,6]naphthyridinyl, (C₁-C₂)alkyl, (C₂)alkenyl or N(R²)—

C(O), N(H)—

(C₁)alkyl-C(O), wherein the nitrogen is attached to A;

or

G is N(R²)—

(C₁-C₂)alkyl, N(H)—

(C₂)alkyl (C₁)alkyl-NH—

S(O)₂, (C₁)alkyl-NH—

C(O) wherein the alkyl portion of the moiety is attached to A;

Q is H, methyl, isopropyl or cyclopropyl;

R¹ is selected from the optionally substituted group consisting of adamantanyl, benzo[1,3]dioxolyl, benzimidazolyl, diphenyl(C₁-C₂)alkyl, fluorenyl, furanyl, indanyl, indolyl, isoquinolinyl, isoxazolyl, naphthyl, oxazolyl, phenyl, piperidinyl, pyrazolyl, pyridinyl, dihydropyrazolo[1,5-a]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, quinolinyl, quinazolinyl, 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydro[1,6]naphthyridinyl,

R² is H or (C₁)alkyl;

R³ is H, OH, F, CH₃, OCH₃, CF₃, CN, —

CH₂—

O—

CH₃, —

CH₂—

C(O)—

O—

CH₃—

C(O)—

OCH₃, —

NH-phenyl, —

O-phenyl, indolyl, optionally substituted phenyl, phenoxy or C(O)NH₂;

R⁴ is H, CN or OH;

m is 0 or 1; and

n is 1.

5. The compound of claim 4 wherein

Y is selected from the group consisting of a bond, optionally substituted (C₁-C₆)alkyl, optionally substituted piperidinyl and optionally substituted —

CH₂-pyrimidinyl and optionally substituted indanyl;

Z is selected from the optionally substituted group consisting of (C₁-C₄)alkyl, cyclohexyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl, benzo[b]thiophenyl, chromanyl, indanyl, indolyl, morpholinyl, naphthyl, phenyl, piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, 4,5,6,7-tetrahydrobenzofuranyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydronaphthyl, tetrahydropyranyl, —

CH₂-benzofuranyl, —

CH₂-phenyl, —

CH₂-pyridinyl, —

(C₂)alkyl-diphenyl, —

CH₂-tetrahydropyranyl;

D is C(R⁵)₂;

E is C(R⁵)₂;

M is a bond, O, C(O), optionally substituted (C₁-C₄)alkyl, —

CH₂—

NH—

C(O) or (C₁)alkyl-C(O)O;

wherein the alkyl portion of the moiety is connected to W;

T is H or is selected from the optionally substituted group consisting of (C₁-C₄)alkyl, benzo[b]thiophenyl, decahydroisoquinolinyl, imidazolyl, indanyl, indenyl, indolyl, 1,2,3,4-tetrahydroisoquinolinyl, morpholinyl phenyl, pyridinyl and pyrrolidinyl;

A is a bond or (C₁-C₅)alkyl);

G is a bond, N(R²), C(O), phenyl, pyridinyl or 5,6,7,8-tetrahydro[1,6]naphthyridinyl, (C₁-C₂)alkyl, (C₂)alkenyl or N(R²)—

C(O), N(H)—

(C₁)alkyl-C(O), wherein the nitrogen is attached to A;

or

G is N(R²)—

(C₁-C₂)alkyl, N(H)—

(C₂)alkyl (C₁)alkyl-NH—

S(O)₂, (C₁)alkyl-NH—

C(O) wherein the alkyl portion of the moiety is attached to A;

Q is H or isopropyl;

R¹ is selected from the optionally substituted group consisting of adamantanyl, benzo[1,3]dioxolyl, diphenyl(C₁-C₂)alkyl, fluorenyl, indanyl, indolyl, isoxazolyl, naphthyl, phenyl, piperidinyl, pyridinyl, quinazolinyl, 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydro[1,6]naphthyridinyl,

R² is H or (C₁)alkyl;

R³ is H, OH, F, CH₃, OCH₃, CF₃, CN, —

CH₂—

O—

CH₃, —

CH₂—

C(O)—

O—

CH₃, —

C(O)—

OCH₃, —

NH-phenyl, indolyl, optionally substituted phenyl, phenoxy or C(O)NH₂;

R⁴ is H, CN or OH;

m is 0 or 1; and

n is 1.

6. The compound of claim 5 wherein

Y is a bond, or is selected from the optionally substituted group consisting of (C₁-C₄)alkyl and indanyl;

Z is selected from the optionally substituted group consisting of (C₁-C₄)alkyl, benzo[b]thiophenyl, indolyl, naphthyl, phenyl and tetrahydropyranyl;

M is a bond, C(O), 0, optionally substituted (C₁-C₄)alkyl, —

CH₂—

NH—

C(O) or (C₁)alkyl-C(O)O;

T is H or is selected from the optionally substituted group consisting of (C₁-C₄)alkyl, benzo[b]thiophenyl, decahydroisoquinolinyl, imidazolyl, indanyl, indenyl, indolyl, phenyl, pyridinyl and pyrrolidinyl;

G is a bond, CH₂, N(R²), N(R²)—

CH₂ or N(R²)—

C(O) wherein the N is attached to A;

R¹ is selected from the optionally substituted group consisting of benzo[1,3]dioxolyl, diphenyl(C₁-C₂)alkyl, indanyl, naphthyl, phenyl, piperidinyl, pyridinyl, quinazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and 5,6,7,8-tetrahydro[1,6]naphthyridinyl; and

R³ is H, OH, F, CH₃, OCH₃, CF₃, —

CH₂—

O—

CH₃, —

CH₂—

C(O)—

O—

CH₃, —

C(O)—

OCH₃, —

NH-phenyl, phenyl, phenoxy or C(O)NH₂.

7. The compound of claim 6 wherein

Z is selected from the optionally substituted group consisting of (C₁-C₂)alkyl, indolyl, benzo[1,3]dioxolyl, phenyl and tetrahydropyranyl;

M is a bond, C(O), optionally substituted (C₁-C₄)alkyl, —

CH₂—

NH—

C(O) or (C₁)alkyl-C(O)O;

T is H or is selected from the optionally substituted group consisting of (C₁-C₂)alkyl, —

O—

(C₁-C₄)alkyl, decahydroisoquinolinyl, imidazolyl, indanyl, indenyl, phenyl, pyridinyl and pyrrolidinyl;

G is a bond, CH₂, N(H), C(O), N(H)CH₂ or N(R²)—

C(O) wherein the N is attached to A;

R¹ is selected from the optionally substituted group consisting of benzo[1,3]dioxolyl, indanyl, diphenylalkyl, naphthyl, phenyl, piperidinyl, quinazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydro[1,6]naphthyridinyl; and

W is CH or N.

8. The compound of claim 7 wherein

D is C(R⁵);

E is C(R⁵);

M is a bond, C(O), (C₁-C₂)alkyl or (C₁)alkyl-C(O)O;

T is H or is selected from the optionally substituted group consisting of (C₁-C₂)alkyl, decahydroisoquinolinyl, imidazolyl, indanyl, indenyl, indolyl, phenyl and pyridinyl;

G is a bond, N(H), C(O), NH—

CH₂ or N(H)—

CO wherein the N is attached to A;

Q is H;

R¹ is selected from the optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyl, diphenylalkyl, naphthyl, phenyl, piperidinyl and quinazolinyl;

R³ is H, OH, CH₃, —

CH₂—

O—

CH₃, —

CH₂—

C(O)—

O—

CH₃, —

C(O)—

OCH₃ or —

NH-phenyl; and

m is 1.

9. The compound of claim 8 wherein

Y is (C₁-C₄)alkyl;

Z is selected from the optionally substituted group consisting of benzo[1,3]dioxolyl and phenyl;

M is bond or (C₁)alkyl;

T is H or is selected from the optionally substituted group consisting of (C₁-C₂)alkyl, imidazolyl, indanyl, indenyl, indolyl, phenyl and pyridinyl;

R¹ is selected from the optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyl, diphenylalkyl, naphthyl, phenyl, piperidinyl and quinazolinyl; and

R² is H.

10. The compound of claim 9 wherein

W is CH or N;

M is a bond;

T is H or is selected from the optionally substituted group consisting of imidazolyl, indanyl, indenyl, phenyl and pyridinyl;

R³ is H, OH or CH₃;

m is 1; and

n is 1.

11. The compound of claim 10 wherein

T is H or is selected from the optionally substituted group consisting of indanyl, indenyl and phenyl;

A is a bond or CH₂;

G is NH, NH—

CH₂, or NH—

C(O) wherein the N is attached to A;

R¹ is selected from the optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyl, phenyl, piperidinyl and quinazolinyl; and

R⁵ is H or CH₃.

12. The compound of claim 11 wherein

Y is CH₂;

Z is phenyl optionally substituted with one or more CH₃;

E is CH₂;

W is CH;

T is H or is selected from the optionally substituted group consisting of indanyl, indenyl and phenyl and is optionally substituted with one or more substituents selected from the group consisting of Cl, F, OH CN, CH₃ and OCH₃;

A is CH₂;

D is CH₂; and

R¹ is selected from the optionally substituted group consisting of phenyl and quinazolinyl;

wherein

R¹ is optionally substituted with one or more substitutents selected from the group consisting of Cl, F, CH₃ and CF₃.

13. The compound of claim 11 wherein X is

14. The compound of claim 13 wherein

G is NH or —

NH—

C(O) wherein the N is attached to A;

R¹ is phenyl or quinazolinyl and R¹ is optionally substituted with one or more Cl;

R³ is H, OH or CH₃; and

p is 1.

15. The compound of claim 13 wherein the compound is

16. A method of treating a CCR² dependent disease or condition comprising administering a therapeutically effective amount of a compound of formula I

17. The method of claim 16 wherein the disease is an autoimmune disease.

18. The method of claim 17 wherein the autoimmune disease is rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease (COPD), sepsis, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn'"'"'s disease, lupus, multiple sclerosis, juvenile chronic arthritis, Lyme arthritis, reactive arthritis, septic arthritis, spondyloarthropathy or systemic lupus erythematosus.

19. The method of claim 18 wherein the autoimmune disease is multiple sclerosis.

20. A pharmaceutical composition comprising a compound of formula I