Aminopyrrolidines as chemokine receptor antagonists

• US 8,754,107 B2
• Filed: 11/16/2007
• Issued: 06/17/2014
• Est. Priority Date: 11/17/2006
• Status: Expired due to Fees

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbvie Incorporated
• Inventors: George, Dawn M., Dixon, Richard W., Friedman, Michael, Hobson, Adrian D., Li, Biqin, Wang, Lu, Wu, Xiaoyun, Wishart, Neil
• Primary Examiner(s): Kosack, Joseph
• Assistant Examiner(s): COUGHLIN, MATTHEW P
• Application Number:
  US11/985,724
• Publication Number:
  US 20080176883A1
• Time in Patent Office: 2,405 Days
• Field of Search: 544/284, 544/293, 544/230, 544/130, 546/208, 546/17, 546/210, 546/200, 546/87, 514/211.15, 514/278, 514/326, 514/266.22, 514/266.2, 514/318, 514/292, 514/235.5, 514/217.08, 540/544, 540/602
• US Class Current: 514/326
• 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. The compound or stereoisomer of claim 1, or a salt of the compound or stereoisomer, wherein

X is

3. The compound or stereoisomer of claim 2, or a salt of the compound or stereoisomer, wherein X is

4. The compound or stereoisomer of claim 3, or a salt of the compound or stereoisomer, wherein

M is a bond, 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 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;

Q is H, methyl, isopropyl or cyclopropyl;

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

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 or stereoisomer of claim 4, or a salt of the compound or stereoisomer, wherein

M is a bond, 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 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;

Q is H or isopropyl;

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

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 or stereoisomer of claim 5, or a salt of the compound or stereoisomer, wherein

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 indanyl, indenyl and phenyl;

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

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 or stereoisomer of claim 6, or a salt of the compound or stereoisomer, wherein

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 indanyl, indenyl and phenyl;

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

W is CH.

8. The compound or stereoisomer of claim 7, or a salt of the compound or stereoisomer, wherein

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 indanyl, indenyl and phenyl;

G is NH, NH—

CH₂, or NH—

C(O), 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, 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 or stereoisomer of claim 8, or a salt of the compound or stereoisomer, wherein

M is bond or (C₁)alkyl;

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

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

R² is H.

10. The compound or stereoisomer of claim 9, or a salt of the compound or stereoisomer, wherein

W is CH;

M is a bond;

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

R³ is H, OH or CH₃;

m is 1; and

n is 1.

11. The compound or stereoisomer of claim 10, or a salt of the compound or stereoisomer, wherein

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.

12. The compound or stereoisomer of claim 10, or a salt of the compound or stereoisomer, wherein X is

13. The compound or stereoisomer of claim 12, or a salt of the compound or stereoisomer, 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.

14. A method of treating a CCR2 dependent disease or condition, wherein the CCR2 dependent disease or condition is an autoimmune disease selected from 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 and systemic lupus erythematosus, comprising administering a therapeutically effective amount of a compound of formula I

15. The method of claim 14 wherein the autoimmune disease is multiple sclerosis.

16. A pharmaceutical composition comprising a compound of formula I

17. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of