Pyrrolidine modulators of CCR5 chemokine receptor activity

• US 20020094989A1
• Filed: 10/10/2001
• Published: 07/18/2002
• Est. Priority Date: 10/11/2000
• Status: Abandoned Application

• Current Assignee: Amy Gentry, Charles G. Caldwell, Christopher A. Willoughby, Christopher L. Lynch, Dong-Ming Shen, Dooseop Kim, Jeffrey J. Hale, Kevin T. Chapman, Liya Chen, Malcolm Maccoss, Sander G. Mills, Zenon D Konteatis
• Original Assignee: Amy Gentry, Charles G. Caldwell, Christopher A. Willoughby, Christopher L. Lynch, Dong-Ming Shen, Dooseop Kim, Jeffrey J. Hale, Kevin T. Chapman, Liya Chen, Malcolm Maccoss, Sander G. Mills, Zenon D Konteatis
• Inventors: Konteatis, Zenon D., Gentry, Amy, Willoughby, Christopher A., MacCoss, Malcolm, Shen, Dong-Ming, Lynch, Christopher L., Hale, Jeffrey J., Caldwell, Charles G., Mills, Sander G., Kim, Dooseop, Chapman, Kevin T., Chen, Liya
• Application Number:
  US09/974,000
• Publication Number:
  US 20020094989A1
• Time in Patent Office: Days
• US Class Current: 514/253.04
• CPC Class Codes: C07D 209/94 containing carbocyclic rings other than six-membered
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 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 471/14 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Pyrrolidine compounds of Formula I:

(wherein ¹, R², R³, R⁴, R⁵,R^6a, R^6b, R⁷ and R⁸ are defined herein) are described. The compounds are modulators of CCR5 chemokine receptor activity. The compounds are useful, for example, in the prevention or treatment of infection by HIV and the treatment of AIDS, as compounds or pharmaceutically acceptable salts, or as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

Claims

1. A compound of Formula I:

2. The compound according to claim 1 wherein R¹ is:

(1) —

CO₂H,

(2) —

P(O)(OH)₂, or

(3) -tetrazolyl;

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein R¹ is:

(1) —

CO₂H, or

(2) -tetrazolyl;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein R¹ is —

CO₂H;

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein R² is:

6. The compound according to claim 1, wherein R² is:

7. The compound according to claim 1 wherein R³ is phenyl, thienyl, pyrazolyl, thiazolyl, thiadiazolyl, furanyl, oxadiazolyl, pyrazinyl, pyrimidinyl, or pyridyl, any one of which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:

(a) halo,

(b) —

CF₃,

(c) hydroxy,

(d) C_1-3 alkyl, and

(e) —

O-C_1-3 alkyl;

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein R³ is phenyl or thienyl, either of which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:

(a) halo,

(b) —

CF₃,

(c) hydroxy, and

(d) C_1-3 alkyl;

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 wherein R³ is phenyl or thienyl, wherein the phenyl is optionally substituted with 1-5 substituents independently selected from fluoro and chloro;

or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 wherein R³ is unsubstituted phenyl, 3-fluorophenyl, or 3-thienyl;

or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 wherein R⁴ and R⁵ are both hydrogen;

or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, wherein R^6a and R^6b are each independently C_1-6 alkyl or C_3-6 cycloalkyl, either of which is unsubstituted or substituted with 1-7 substituents independently selected from:

(a) halo,

(b) —

CF₃,

(c) hydroxy, and

(d) —

O-C_1-3 alkyl;

or R^6a and R^6b together with the carbon atom to which they are attached form;

(a) a 3- to 6-membered saturated carbocyclic ring,

(b) a 4- to 6-membered saturated heterocyclic ring containing one oxygen atom, or

(c) a 5- or 6-membered saturated carbocyclic ring to which is fused a C3-6 cycloalkyl;

wherein the ring system of (a), (b), or (c) is optionally substituted with from 1 to 3 substituents selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, —

O-C_1-4 alkyl, —

O-C_1-4 haloalkyl, or hydroxy;

or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1, wherein R^6a and R^6b are each C_1-3 alkyl;

or one of R^6a and R^6b is C_1-3 alkyl, and the other of R^6a and R^6b is C_3-6 cycloalkyl;

or R^6a and R^6b together with the carbon atom to which they are attached form cyclobutylidenyl, cyclopentylidenyl, cyclohexylidenyl, bicyclo[3.1.0]cyclohexylidenyl, tetrahydropyranylidenyl, or tetrahydrofuranylidenyl;

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1, wherein R⁷ is hydrogen;

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1, wherein R⁸ is hydrogen;

or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, wherein R⁸ is methyl;

or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1 wherein R⁹ is hydrogen, fluoro, hydroxy or C_1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1 wherein R⁹ is hydrogen or fluoro;

or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1 wherein R⁹ is hydrogen;

or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1, wherein Y is

(1) a direct single bond;

(2) —

C_1-6 alkyl-, which is optionally substituted with 1-7 substituents independently selected from;

(a) halo,

(b) hydroxy,

(c) —

O-C_1-3 alkyl, and

(d) —

CF₃;

(3) —

(C_0-2 alkyl)—

Z¹—

(C_0-2 alkyl)-, wherein the alkyl is unsubstituted;

 

Z¹ is selected from —

SO₂—

, —

N(R^u)—

, —

SO—

, —

SO₂N(R^u)—

, —

S—

, and —

O—

; and

R^u is C_1-4 alkyl, C_2-5 alkenyl, or C_1-3 alkyl-C_3-6 cycloalkyl;

or

(4) —

(C_0-2 alkyl)—

Z²—

(CO₂ alkyl)—

, wherein the alkyl is optionally substituted with 1-4 substituents independently selected from;

(a) halo,

(b) hydroxy,

(c) —

O-C_1-3 alkyl, and

(d) —

CF₃;

 

and wherein

Z² is selected from —

C(═

O)NR^v—

, —

NR^vC(═

O)—

, —

OC(═

O)NR^v—

, —

NR^vC(═

O)O—

, and —

NR^wC(═

O)NR^v—

;

R^v is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C2-6 alkynyl, benzyl, phenyl, or C_1-6 alkyl-C_3-6 cycloalkyl;

wherein any of which except hydrogen is optionally substituted with from 1 to 3 substituents independently selected from halo, C_1-3 alkyl, —

O-C_1-6 alkyl and —

CF₃; and

R^w is —

H or C_1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 1, wherein Y is

(1) a direct single bond;

(2) —

C_2-4 alkyl-, which is optionally substituted with 1-6 substituents independently selected from;

(a) halo,

(b) —

O-C_1-3 alkyl, and

(c) —

CF₃;

(3) selected from

—

(C_0-2 alkyl)—

SO₂—

(C_0-2 alkyl)—

,

—

(C_0-2 alkyl)—

SO₂N(R^u)—

(C_0-2 alkyl),

—

(C_0-2 alkyl)—

SO—

(CO₂ alkyl)—

,

—

(C_0-2 alkyl)—

S—

(CO₂ alkyl)—

,

—

(C_0-2 alkyl)—

O—

(CO₂ alkyl)—

, and

—

(C_0-2 alkyl)—

N(R^u)—

(CO₂ alkyl)—

; and

where R^u is C_2-4 alkyl, C_2-3 alkenyl or C_1-2 alkyl-C_1-3 cycloalkyl;

(4) —

(C_0-2 alkyl)—

Z²—

(CO₂ alkyl)—

, wherein the alkyl is not substituted;

and where

Z² is selected from —

C(═

O)NR^v—

, —

NR^vC(═

O)—

, —

OC(═

O)NR^v—

, —

NR^vC(═

O)O—

, and —

NR^wC(═

O)NR^v—

;

R^v is hydrogen, C_1-3 alkyl, C_2-3 alkenyl, or C_2-3 alkynyl; and

R^w is —

H or C_1-4 alkyl;

or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 1, wherein Y is

(1) a direct single bond;

(2) C_2-4 alkyl, which is optionally substituted with from 1 to 6 fluoros;

(3) selected from;

(a) —

SO₂CH₂CH₂—

,

(b) —

SO₂—

N(CH₂CH₃)—

,

(c) —

CH₂SO₂—

N(CH₂CH₃)—

,

(d) —

SO—

CH₂CH₂—

,

(e) —

SCH₂CH₂—

,

(f) —

CH₂—

O—

CH₂—

,

(g) —

N(CH₂CH₃)—

,

(h) —

N(CH₂CH₂CH₃)—

,

(i) —

N(allyl)—

, and

(j) —

N(CH₂-cyclopropyl)—

;

or

(4) selected from;

(a) —

CH₂OC(═

O)—

N(C_1-4 alkyl)—

,

(b) —

CH₂—

OC((═

O)N(allyl)—

,

(c) —

CH₂NHC(═

O)N(C_1-4 alkyl)—

,

(d) —

CH₂NHC(═

O)N(allyl), and

(e) —

CH₂CH₂NHC(═

O)N(CH₂CH₃)—

.

or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 1, wherein Y is a direct single bond;

or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 1 wherein R¹⁰ is phenyl, benzoimidazolyl, imidazolyl, pyridoimidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, thiazolyl, imidazothiophenyl, indazolyl, tetrahydropyridoimidazolyl, tetrahydroindazolyl, dihydrothiopyranopyrazolyl, dihydrodioxothiopyranopyrazolyl, dihydropyranopyrazolyl, tetrahydropyridopyrazolyl, benzopyrazolyl, pyridopyrazolyl, or triazolyl;

any one of which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from;

(a) halo,

(b) cyano,

(c) hydroxy,

(d) C_1-6 alkyl, which is unsubstituted or substituted with 1-5 of R^e where R^e is independently selected from halo, cyano, hydroxy, —

O-C_1-6 alkyl, —

C_3-5 cycloalkyl, —

CO₂H, —

CO₂(C16 alkyl), —

CF₃, —

SO₂R^a, —

NR^aR^b,

where R^a and R^b are independently selected from hydrogen, C_1-6 alkyl, C_5-6 cycloalkyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from halo, C_1-3 alkyl, —

O-C_1-3 alkyl, C_1-3 fluoroalkyl, and —

O-C_1-3 fluoroalkyl,

 

phenyl, naphthyl, biphenyl, and heterocycle,

wherein the phenyl, naphthyl, biphenyl or heterocycle is unsubstituted or substituted with 1-7 of R^f where R^f is independently selected from halo, cyano, hydroxy, C_1-4 alkyl, —

O-C_1-4 alkyl, —

O-C_3-5 cycloalkyl, —

CO₂H, —

C_0-2(C_1-6 alkyl), —

CF₃, —

OCF₃, —

SO₂R^a, —

N(R^a)SO₂R^b and —

NR^aR^b,

(e) —

O-C_1-6 alkyl, which is unsubstituted or substituted with 1-5 of R^e,

(f) —

NO₂,

(g) phenyl,

(h) —

CO₂R^a,

(i) tetrazolyl,

(j) —

NR^aR^b,

(k) —

NR^a—

COR^b,

(l) —

NR^a—

CO₂R^b,

(m) —

CO—

NR^aR^b,

(n) —

OCO—

NR^aR^b,

(o) —

NR^aCO—

NR^aR^b,

(p) —

S(O)_m—

R^a, wherein m is an integer selected from 0, 1 and 2,

(q) —

S(O)₂NR^aR^b,

(r) —

NR^aS(O)₂—

R^b,

(s) —

NR^aS(O)₂—

NR^aR^b;

(t) —

C_3-6 cycloalkyl, and

(u) —

O-C_3-6 cycloalkyl;

and with the proviso that

(A) when R¹⁰ is a heterocycle selected from pyrazolyl and imidazolyl, then the heterocycle is unsubstituted or substituted with 1 or 2 substituents independently selected from any of substituents (a) to (u) as defined above; and

(B) when R¹⁰ is a heterocycle selected from;

then the heterocycle is unsubstituted in the pyrazolyl or imidazolyl ring, and is either unsubstituted in the other ring or is substituted with 1 or 2 substituents independently selected from any of substituents (a) to (u) as defined above;

or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 1, wherein R¹⁰ is phenyl, benzimidazolyl, imidazolyl, pyridoimidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, thiazolyl, imidazothiophenyl, indazolyl, tetrahydropyridoimidazolyl, tetrahydroindazolyl, dihydrothiopyranopyrazolyl, dihydrodioxothiopyranopyrazolyl, dihydropyranopyrazolyl, tetrahydropyridopyrazolyl, or triazolyl;

any one of which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from;

(a) halo,

(b) cyano,

(c) —

NO₂,

(d) —

CF₃,

(e) —

CHF₂,

(f) —

CH₂F,

(g) —

CH₂OH,

(h) —

CH₂OCH₃,

(i) —

(CH₂)_1-2SO₂-(C_1-2 alkyl)

(j) phenyl,

(k) C_1-6 alkyl, which is unsubstituted or substituted with phenyl, which is unsubstituted or substituted with 1-4 of R^f where R^f is independently selected from halo, cyano, hydroxy, —

O-C_1-6 alkyl, —

O-C_3-5 cycloalkyl, —

CO₂H, —

CO₂(C_1-6 alkyl), —

CF₃, —

OCF₃, —

SO₂-(C_1-3 alkyl), and —

N(R^a)SO₂—

(C_1-3 alkyl),

(l) —

O-C_1-6 alkyl,

(m) —

C_3-5 cycloalkyl,

(n) —

CH₂—

(C_3-5 cycloalkyl), and

(o) —

O-C3-5 cycloalkyl;

and with the proviso that

(A) when R¹⁰ is a heterocycle selected from pyrazolyl and imidazolyl, then the heterocycle is unsubstituted or substituted with 1 or 2 substituents independently selected from any of substituents (a) to (o) as defined above; and

(B) when R¹⁰ is a heterocycle selected from;

then the heterocycle is unsubstituted in the pyrazolyl or imidazolyl ring, and is either unsubstituted in the other ring or is substituted with 1 or 2 substituents independently selected from any of substituents (a) to (o) as defined above;

or a pharmaceutically acceptable salt thereof.

26. The compound according to claim 1, wherein R¹⁰ is:

(i) pyrazolyl or imidazolyl, either of which is unsubstituted or substituted with 1 or 2 substituents independently selected from;

(a) fluoro,

(b) chloro,

(c) C_1-6 alkyl,

(d) —

CH₂-phenyl, wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from chloro, fluoro, —

CN, —

C_1-3 alkyl, —

O-C_1-3 alkyl, —

O-cyclopropyl, —

O-cyclobutyl, —

CF₃, —

OCF₃, —

SO₂—

(C_1-3 alkyl), and —

N(H)SO₂—

(C_1-3 alkyl),

(e) —

CH₂CH₂-phenyl, and

(f) phenyl;

or

each of which is unsubstituted in the pyrazolyl or imidazolyl ring, and is either unsubstituted in the other ring or is substituted with 1 or 2 substituents independently selected from;

(a) halo,

(b) C_1-4 alkyl,

(c) C_1-4 haloalkyl,

(d) —

OH,

(e) —

O-C_1-4 alkyl,

(f) —

O-C_1-4 haloalkyl, and

(g) —

CN;

or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 1 which is of the stereochemical configuration:

28. The compound of claim 1, which is a compound of formula (II):

29. The compound of claim 1, which is a compound of formula (II):

30. The compound according to claim 29, wherein R¹⁰ is:

31. The compound according to claim 30, wherein R¹² and R¹⁴ are both ethyl;

or a pharmaceutically acceptable salt thereof.

32. The compound according to claim 1, which is 1-{[(3S,4S)-3-[(4-{3-ethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}piperidin-1-yl)methyl]-4-(3-fluorophenyl)pyrrolidin-1-yl]methyl}cyclohexanecarboxylic acid;

or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition which comprises an inert carrier and an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

34. A method for modulating CCR5 chemokine receptor activity in a subject which comprises administering to the subject an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

35. A method for preventing infection by HIV, treating infection by HIV, delaying of the onset of AIDS, or treating AIDS in a patient, which comprises administering to the patient of an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.