RU2003107014A

RU2003107014A - SUBSTITUTED PYRAZOLES

Info

Publication number: RU2003107014A
Application number: RU2003107014/04A
Authority: RU
Inventors: Хьюи КАЙ; Джеймс П. Эдвардс; Стивен П. Медуна; Барбара А. ПАЙО; Джианмей ВЕЙ
Original assignee: Орто-Макнейл Фармасьютикал, Инк.
Priority date: 2000-08-14
Filing date: 2001-08-10
Publication date: 2004-08-20

Claims

1. The compound of formula (I)

wherein the dashed line adjacent to CR ⁶ is either absent or represents an sp ² bond;

Y represents nitrogen or R ²⁰ C;

Z represents nitrogen or R ²¹ C;

T represents nitrogen or R ² C;

S represents nitrogen or R ³ C,

provided that from 0 to 3 of S, T, Y and Z are nitrogen, and additionally provided that one of S, T, Y and Z can be = N ⁺ -O ^- if the other three are not nitrogen

R ²⁰ selected from hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, cyano, nitro, C _1-5 halogenated, R ^o R ^p N, R ^o R ^p NC = O, C _2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl) -C _1-5 alkylene, phenyl, (phenyl) C _1-5 alkylene, R ¹⁴ OC = O, R ¹⁴ S, R ¹⁴ SO and R ¹⁴ SO ₂ ;

R ^{21 is} selected from hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, cyano, nitro, C _1-5 haloalkyl, R ^c R ^d N, R ^c R ^d NC = O, C _2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl) -C _1-5 alkylene, phenyl, (phenyl) C _1-5 alkylene, R ¹⁵ OC = O, R ¹⁵ S, R ¹⁵ SO and R ¹⁵ SO ₂ ;

R ² selected from hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, cyano, nitro, C _1-5 halogenated, R ^e R ^f N, R ^e R ^f NC = O, C _2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl) -C _1-5 alkylene, phenyl, (phenyl) C _1-5 alkylene, R ¹⁶ OC = O, R ¹⁶ S, R ¹⁶ SO and R ¹⁶ SO ₂ ;

R ^{3 is} selected from hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, cyano, nitro, C _1-5 haloalkyl, R ^g R ^h N, C _2-8 acyl, 4-7 membered heterocyclyl , (4-7 membered heterocyclyl) -C _1-5 alkylene, phenyl, (phenyl) C _1-5 alkylene, R ¹⁷ OC = O, R ^m R ⁿ NC = O, R ^m R ⁿ NSO ₂ , R ¹⁷ S, R ¹⁷ SO and R ¹⁷ SO ₂ ;

R ⁵ and R ^{6 are} independently selected from hydrogen and C _1-5 alkyl;

R ⁷ and R ⁸ independently represent hydrogen, C _1-5 alkyl, C _1-5 alkenyl, C _1-5 alkoxy, C _1-5 alkylthio, halogen or 4-7 membered carbocyclyl or heterocyclyl, alternatively, R ⁷ and R ⁸ may be combined together to form an optionally substituted 5-7 membered carbocyclic or heterocyclic ring, said ring may be unsaturated or aromatic, said ring being optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxy, cyano, nitro, amino, R ^t , R ^t O-, R ^t S-, R ^t O (C _1-5 alkylene) -, R ^t O (C = O) -, R ^t ( C = O) -, R ^t (C = S) -, R ^t (C = O) O-, R ^t O (C = O) (C = O) -, R ^t SO ₂ , NHR ^u (C = NH) -, NHR ^u SO ₂ - and NHR ^u (C = O) -;

R ^t represents C _1-6 alkyl, phenyl, benzyl, phenethyl or C _2-5 heterocyclyl, (C _1-5 heterocyclyl) C _1-6 alkylene, NH ₂ , mono- or di (C _1-6 alkyl) N -, or R ⁴⁹ OR ⁵⁰ -, in which R ⁴⁹ represents H, C _1-5 alkyl, C _2-5 alkenyl, phenyl, benzyl, phenethyl, C _1-5 heterocyclyl or (C _1-5 heterocyclyl) C _{1 -6} alkylene, and R ⁵⁰ represents C _1-5 alkylene, phenylene or bivalent C _1-5 heterocyclyl;

R ^u may be H, in addition to the values indicated for R ^t ;

R ^c represents hydrogen, C _1-5 alkyl, phenyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ¹⁰ OC = O-, R ⁱ R ^j NC = O, R ¹⁰ SO-, R ¹⁰ SO ₂ - and R ⁱ R ^j NSO ₂ ;

R ^e represents hydrogen, C _1-5 alkyl, phenyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁴⁰ OC = O, R ⁴³ R ⁴⁴ NC = O, R ⁴⁰ SO, R ⁴⁰ SO ₂ and R ⁴³ R ⁴⁴ NSO ₂ ;

R ^m represents hydrogen, C _1-5 alkyl, phenyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁴¹ OC = O, R ⁴⁵ R ⁴⁶ NC = O, R ⁴¹ SO, R ⁴¹ SO ₂ and R ⁴⁵ R ⁴⁶ NSO ₂ ;

R ^o represents hydrogen, C _1-5 alkyl, phenyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁴² OC = O, R ⁴⁷ R ⁴⁸ NC = O, R ⁴² SO, R ⁴² SO ₂ and R ⁴⁷ R ⁴⁸ NSO ₂ ;

each of the radicals R ^d , R ^f , R ⁿ and R ^{p is} independently selected from hydrogen, C _1-5 alkyl, phenyl and C _2-5 heterocyclyl, in addition to R ^c and R ^d , R ^e and R ^f , R ^m and R ⁿ , or R ^o and R ^p , independently, may be combined together to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic;

each of the radicals R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ⁴⁰ , R ⁴¹ and R ⁴² , independently, is C _1-5 alkyl, phenyl or C _2-5 heterocyclyl ;

each of the radicals R ⁱ and R ^j , R ^k and R ^l , R ⁴³ and R ⁴⁴ , R ⁴⁵ and R ⁴⁶ , R ⁴⁷ and R ⁴⁸ independently represent hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl or C _2-5 heterocyclyl, in addition to which R ⁱ and R ^j , and R ^k and R ^l , R ⁴³ and R ⁴⁴ , R ⁴⁵ and R ⁴⁶ , and R ⁴⁷ and R ⁴⁸ , independently, can be combined to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic;

R ^g represents hydrogen, C _1-5 alkyl, phenyl or C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁹ OC = O, R ¹⁸ R ¹⁹ NC = O, R ⁹ SO, R ⁹ SO ₂ or R ¹⁸ R ¹⁹ NSO ₂ ;

R ^h represents hydrogen, C _1-5 alkyl, phenyl or C _2-5 heterocyclyl; alternatively, R ^g and R ^h can be combined so as to form an optionally substituted 4-7 membered heterocyclic ring system, said ring the system may be saturated, unsaturated or aromatic;

R ¹⁸ and R ¹⁹ independently represent hydrogen, C _1-5 alkyl, phenyl or C _2-5 heterocyclyl; alternatively, R ¹⁸ and R ¹⁹ may be combined to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic;

n is 0, 1 or 2;

G is C _3-6 alkenediyl or C _3-6 alkanediyl optionally substituted with hydroxy, halogen, C _1-5 alkyl, C _1-5 alkoxy, oxo, hydroxyimino, CO ₂ R ^k , NR ^k R ^l , (L ) -C _1-4 alkylene, R ^k R ^l NCO ₂ , [(L) -C _1-5 alkylene] amino, N ₃ or (L) -C _1-5 alkoxy;

L represents amino, mono- or di-C _1-5 alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl or piperazinyl, in which the existing nitrogen atom of the ring system may optionally be substituted with C _1-5 alkyl, benzyl, C _2-5 acyl C _1-5 alkylsulfonyl or C _1-5 alkoxycarbonyl;

Ar is a monocyclic or bicyclic aryl or heteroaryl ring system, optionally substituted with 1 to 3 substituents independently selected from halogen, C _1-5 alkoxy, C _1-5 alkyl, C _2-5 alkenyl, cyano, azido, nitro, R ²² R ²³ N, R ²² S, R ²² SO, R ²² SO _2, R ²² OC = O, R ²² R ²³ NC = O, C _1-5 haloalkyl, C _1-5 haloalkoxy, C _1-5 haloalkylthio and C _1-5 alkylthio;

R ²² represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl, benzyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ¹¹ OC = O, R ²⁴ R ²⁵ NC = O, R ¹¹ S, R ¹¹ SO, R ¹¹ SO ₂ or R ²⁴ R ²⁵ NSO ₂ ;

R ²³ represents hydrogen, C _1-5 alkyl, phenyl, benzyl or C _2-5 heterocyclyl; alternatively, R ²² and R ²³ may be combined to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic;

R ²⁴ and R ²⁵ independently represent hydrogen, C _1-5 alkyl, phenyl, benzyl or C _1-5 heteroaryl; alternatively, R ²⁴ and R ²⁵ can be combined to form an optionally substituted 4-7 membered carbocyclic or heterocyclic rings, said ring may be saturated, unsaturated or aromatic;

R ³² represents hydrogen, C _1-5 alkyl, cyano, C _1-5 hydroxyalkyl, C _2-8 acyl, - (C = O) NR ^v R ^x , CHO or C _1-6 alkoxycarbonyl, where each R ^v and R ^{x is} independently selected from H, C _1-5 alkyl, C _1-5 hydroxyalkyl, C _1-5 heterocyclyl, (C _1-5 heterocyclyl) C _1-5 alkylene, C _1-5 aminoalkylene, C _3-8 acyloxy CHO, C _1-6 alkoxycarbonyl and cyano;

Q represents NR ³³ , S or O;

R ³³ represents hydrogen, C _1-5 alkyl, phenyl, benzyl, phenethyl, C ₂ - ₅ heterocyclyl, (C _2-5 heterocyclyl) C _1-5 alkylene, C _2-8 acyl, aroyl, R ³⁵ OC = O R ³⁶ R ³⁷ NC = O, R ³⁵ SO, R ³⁵ S, R ³⁵ SO ₂ and R ³⁶ R ³⁷ NSO ₂ ;

R ³⁵ is selected from hydrogen, C _1-5 alkyl, phenyl, benzyl, phenethyl, and C ₂ - ₅ heteroaryl;

R ³⁶ and R ^{37 are} each independently selected from hydrogen, C _1-5 alkyl, phenyl or C _2-5 heteroaryl; alternatively, R ³⁶ and R ³⁷ may be combined to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic,

where each of the above hydrocarbyl or heterocarbyl groups, unless otherwise indicated, and in addition to any specific substituent, may optionally and independently be substituted by 1-3 substituents selected from methyl, halogenmethyl, hydroxymethyl, halogen, hydroxy, amino, nitro, cyano , C _1-5 alkyl, C _1-5 alkoxy, -COOH, C _2-6 acyl, [(di (C _1-4 alkyl) amino] C _2-5 alkylene, [(di (C _1-4 alkyl) amino] C _2-5 alkyl-NH-CO- and C _1-5 haloalkoxy,

or its pharmaceutically acceptable salt, amide and ester, or its stereoisomeric form.

2. The compound according to claim 1, where one of S, T, Y and Z represents nitrogen.

3. The compound according to claim 1, where S and T are CR ³ and CR ² , respectively.

4. The compound according to claim 1, where S, T, Y and Z are CR ³ , CR ² , CR ²⁰ and CR ²¹ , respectively.

5. The compound according to claim 1, where (a) Z represents N, Y represents N, S represents CR ³ and T represents CR ² , or (b) S represents N, T represents N, Y represents CR ²⁰ and Z represents CR ²¹ .

6. The compound according to claim 1, where R ² represents hydrogen, halogen, C _1-5 alkoxy, cyano, R ^e R ^f N or 5-6-membered heterocyclyl.

7. The compound according to claim 1, where R ³ represents hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, cyano, R ¹⁷ OC = O or R ^g R ^h N, where R ^g and R ^h represent H or C _1-5 alkyl or are combined together to form a 5-6 membered heterocyclyl.

8. The compound according to claim 1, where each of R ² and R ³ independently selected from hydrogen, halogen and 5-6-membered heterocyclyl.

9. The compound according to claim 1, where R ⁵ and R ^{6 are} independently selected from hydrogen and C _1-3 alkyl, preferably one of R ⁵ and R ⁶ is H, and more preferably R ⁵ and R ⁶ are each H.

10. The compound according to claim 1, where one of R ⁷ and R ⁸ represents H, and the other represents a 5-7-membered carbocyclyl or heterocyclyl.

11. The compound according to claim 1, where R ⁷ and R ^{8 are} combined together to form an optionally substituted 5-7 membered carbocyclic or heterocyclic ring, preferably R ⁷ and R ^{8 are} combined to form a six membered heterocyclyl.

12. The compound of claim 11, wherein R ⁷ and R ^{8 are} combined to form a 5-7 membered heterocyclyl, optionally N-substituted with R ^t (C = O) -, R ^t SO ₂ -, or NHR ^u (C = O) -, where R ^t represents C _1-6 alkyl, phenyl or C _2-5 heterocyclyl and R ^u represents H, C _1-6 alkyl, phenyl or C _2-5 heterocyclyl.

13. The compound according to claim 1, where each of R ^c , R ^e , R ^m and R ^o independently selected from hydrogen, C _1-5 alkyl, C _2-8 acyl, (C _1-5 alkyl) OC = O and corresponding groups RRNC = O, RSO, RSO ₂ and RRNSO ₂ .

14. The compound according to claim 1, where each of R ^c , R ^d , R ^g , R ^h , R ^o , R ^f and R ^p independently selected from hydrogen and C _1-5 alkyl; or, independently, R ^e and R ^f , R ^g and R ^h or R ^o and R ^{p are} combined to form an optionally substituted 4-7 membered carbocyclic or heterocyclic ring, preferably wherein R ^e and R ^f together form morpholinyl, piperidinyl or pyrrolidinyl.

15. The compound according to claim 1, where each of R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ⁴⁸ , R ⁱ , R ^j , R ^k and R ^l independently represents hydrogen or C _1-5 alkyl .

16. The compound according to claim 1, where each of R ⁹ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently represents C _1-5 alkyl.

17. The compound according to claim 1, where R ^g represents C _1-5 alkyl, C _2-8 acyl, R ⁹ OC = O, R ¹⁸ R ¹⁹ NC = O, R ⁹ SO, R ⁹ SO ₂ or R ¹⁸ R ¹⁹ NSO ₂ and R ^h represents H or C _1-5 alkyl, alternatively R ^g and R ^h can be combined to form an optionally substituted 5-6 membered heterocyclyl, preferably R ^g and R ^h each a C _1-3 alkyl.

18 The compound according to claim 1, where R ¹⁸ and R ¹⁹ independently represent hydrogen or C _1-5 alkyl.

19. The compound according to claim 1, where n = 1.

20. The compound according to claim 1, where G is C _3-4 alkanediyl optionally substituted with hydroxy, halogen, [(L) -C _1-5 alkylene] amino or (L) -C _1-5 alkyloxy groups, preferably G represents C ₃ alkanediyl optionally substituted with a hydroxy group.

21. The compound according to claim 1, where R ²⁰ and R ^{21 are} independently selected from hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, cyano, nitro, 4-7 membered heterocyclyl, and R ^o R ^p N or R ^c R ^d N, respectively, preferably R ²⁰ and R ^{21 are} independently selected from hydrogen, halogen, a 5-6 membered heterocyclyl, and R ^o R ^p N or R ^c R ^d N, respectively.

22. The compound according to claim 1, where Ar is a monocyclic ring system, optionally substituted with 1 or 2 substituents selected from halogen, C _1-5 alkyl, cyano, nitro, R ²² R ²³ N, C _1-3 halogenated, and C _1-3 haloalkoxy.

23. The compound according to item 22, where Ar is a six-membered aromatic ring system, monosubstituted in the 4-position with halogen, methyl, CF ₃ or OCF ₃ , or disubstituted in 3-4 positions with substituents independently selected from halogen, CF ₃ , methyl and OCF ₃ .

24. The compound according to item 22, where each of R ²² , R ²³ and R ²⁴ independently represents hydrogen or C _1-5 alkyl.

25. The compound according to claim 1, where R ²⁵ and R ^{26 are} independently hydrogen or C _1-5 alkyl, or alternatively R ²⁵ and R ^{26 are} combined to form an optionally substituted 4-7 membered heterocyclic ring, which may be saturated, unsaturated or aromatic.

26. The compound according A.25, where R ²⁵ and R ²⁶ independently represent hydrogen or C _1-5 alkyl.

27. The compound according to claim 1, where Q represents NR ³³ or S.

28. The compound of claim 27, wherein Q is NR ³³ , R ³³ is H or C _2-5 heterocyclyl, and R ³² is H, C _1-5 alkyl, C _1-5 hydroxyalkyl, - (C = O) NR ^v R ^x , CHO or C _1-6 alkoxycarbonyl, where each of R ^v and R ^{x is} independently selected from H, C _1-5 hydroxyalkyl, (C _1-5 heterocyclyl) -C _1-5 alkylene and C _{1 -5} aminoalkylene.

29. The compound of claim 27, wherein Q is S and R ³³ is NR ³⁶ R ³⁷ (C = O) -, wherein each of R ³⁶ and R ^{37 is} independently selected from hydrogen and C _1-5 alkyl.

30. The compound according to claim 1, where R ^{35 is} selected from hydrogen and C _1-5 alkyl, R ³⁶ and R ³⁷ each independently selected from hydrogen, C _1-5 alkyl, or, alternatively, R ³⁶ and R ³⁷ can be combined together to form an optionally substituted 4-7 membered heterocyclic ring.

31. The compound according to claim 1, where Y represents nitrogen or R ²⁰ C, Z represents nitrogen or R ²¹ C, T represents nitrogen or R ² C, S represents nitrogen or R ³ C, provided that from 0 to 2 of S, T, Y and Z are nitrogen, R ² is hydrogen, halogen, hydroxy, C _1-5 alkoxy, C _1-5 alkyl, 5-6 membered heterocyclyl or R ^e R ^f N, R ³ represents hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, 5-6 membered heterocyclyl or R ^g R ^h N, R ⁵ and R ⁶ each represent H, R ⁷ and R ^{8 is} independently combined to form an optionally substituted 5-7 membered enasyschennogo heterocyclic ring, each of R ^a, R ^e, R ^m, and R ^o is independently selected from hydrogen, C _1-5 alkyl, C _2-8 acyl, (C _1-5 alkyl) OC = O, and the respective RRNC = O groups , RSO, RSO ₂ , and RRNSO ₂ , each of R ^b , R ^f , R ⁿ and R ^{p is} independently selected from hydrogen and C _1-5 alkyl, each of R ⁹ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ⁴⁰ , R ⁴¹ and R ⁴² independently represents C _1-5 alkyl, each of R ^c , R ^d , R ⁱ , R ^j , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ^k and R ^l independently represent hydrogen or C _1-5 alkyl, R ^g represents hydrogen or C _1-5 alkyl, C _2-8 acyl, R ⁹ OC = O, R ¹⁸ R ¹⁹ NC = O, R ⁹ SO, R ⁹ SO ₂ or R ¹⁸ R ¹⁹ NSO ₂ , R ^h represents hydrogen or C _1-5 alkyl, alternatively, R ^g and R ^h may be combined together to form an optionally substituted 4-7 membered carbocyclic or heterocyclic ring, which may be saturated, unsaturated or aromatic, R ¹⁸ and R ¹⁹ independently represent hydrogen or C _1-5 alkyl, n = 0 or 1, G is C _3-4 alkenediyl or C _3-4 alkanediyl optionally substituted with hydroxy, halogen, C _1-5 alkyloxy, oxo, hydroxyimino, CO ₂ R ^k , R ^k R ^l NCO _2, N _3, or (L) -C _1-5 alkoxy, L is amino, mono- or di-C _1-5 alkylamino, pyrrole dinil, morpholinyl, piperidinyl, homopiperidinyl or piperazinyl, available ring system nitrogen atoms optionally substituted by C _1-5 alkyl, benzyl, C _2-5 acyl or C _1-5 alkyloxycarbonyl, R ²⁰ and R ²¹ are independently selected from hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, cyano, nitro and R ^o R ^p N, alternatively, R ³ and R ²⁰ or R ³ and R ²¹ may be combined to form an optionally substituted 5-6 membered carbocyclic or heterocyclic ring, which may be saturated, unsaturated or aromatic, Ar is a monocycle cyclically or bicyclic aryl or heteroaryl ring optionally substituted with hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, cyano, nitro, R ²² R ²³ N, R ²⁴ SO _2, R ²⁴ OC = O, R ²⁵ R ²⁶ NC = O, CF ₃ , OCF ₃ , SCF ₃ or C _1-5 alkylthio, R ²² represents hydrogen, C _1-5 alkyl, phenyl, benzyl, phenethyl, C _2-5 heteroaryl, C _2-8 acyl, aroyl, R ²⁴ OC = O, R ²⁵ R ²⁶ NC = O, R ²⁴ SO, R ²⁴ SO ₂ or R ²⁵ R ²⁶ NSO ₂ , R ²³ represents hydrogen or C _1-5 alkyl, alternatively, R ²² and R ²³ may be combined to form an optionally substituted 4-7 membered carbocyclic or heterocyclic ring, which which may be saturated, unsaturated or aromatic, R ²⁴ represents hydrogen or C _1-5 alkyl, R ²⁵ and R ²⁶ independently represent hydrogen or C _1-5 alkyl, or alternatively R ²⁵ and R ²⁶ may be combined with the formation of an optionally substituted 4-7 membered carbocyclic or heterocyclic ring, which may be saturated, unsaturated or aromatic, R ³² represents hydrogen, C _1-5 alkyl, C _1-5 hydroxyalkyl, CHO, C _2-6 acyl, C _{1 -6} alkoxycarbonyl or - (C = O) NR ^v R ^x , where each R ^v R ^{x is} independently selected from H, C _1-5 alkyl la, C _1-5 hydroxyalkyl, C _3-8 acyloxy, (amino) C _1-6 alkylene, (C _1-5 heterocyclyl) C _1-5 alkylene or C _1-6 alkoxycarbonyl, Q represents NR ³³ or S, R ³³ represents hydrogen, C _1-5 alkyl, phenyl, benzyl, (C _2-5 heterocyclyl) C _1-5 alkylene, C _2-8 acyl, aroyl, R ³⁵ OC = O, R ³⁶ R ³⁷ NC = O R ³⁵ SO ₂ and R ³⁶ R ³⁷ NSO ₂ , R ^{35 is} selected from hydrogen and C _1-5 alkyl, R ³⁶ and R ^{37 are} each independently selected from hydrogen and C _1-5 alkyl.

32. The compound according to claim 1, where one of R ⁵ and R ⁶ is H, R ⁷ and R ^{8 are} combined to form an optionally substituted 6-membered carbocyclic or heterocyclic ring, and Ar is a monocyclic ring optionally substituted with 1 or 2 substituents selected from halogen, C _1-5 alkyl, cyano, nitro, R ²² R ²³ N, CF ₃ and OCF ₃ .

33. The compound according to p, where both R ⁵ and R ⁶ each represents H, and Ar is a six-membered ring substituted by halogen, CF ₃ , methyl, halogenmethyl or OCF ₃ in the 3-4-position, or disubstituted in 3-4 positions.

34. The compound of claim 33, wherein R ⁷ and R ⁸ combined together form pyridinyl, pyrimidinyl or piperazinyl, optionally N-substituted with - (C = O) R ^t , SO ₂ -R ^t or - (C = O ) NHR ^u .

35. The compound of claim 32, wherein R ²² and R ²³ , taken together, are independently morpholinyl, piperidyl or pyrrolidinyl, optionally substituted.

36. The compound according to claim 1, where there is no dashed line located next to CR ⁶ .

37. The compound according to claim 1, selected from the following compounds:

1- [4- (5-chloro-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-1-yl] propan-2-ol;

1- [4- (7-chloro-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-1-yl] propan-2-ol;

1- [4- (5-chloro-2-methyl-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6, 7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol;

1- {4- [6-chloro-1- (2-morpholin-4-yl-ethyl) -1H-indol-3-yl] piperidin-1-yl} -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl ) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [3, 2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [2, 3-b] pyridin-3-yl) piperidin-1-yl] propan-2-ol;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-morpholin-4- yl-1H-pyrrolo [2,3-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol;

1- [4- (6-dimethylamino-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4, 5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (6-morpholin-4- yl-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (6-morpholin-4- yl-5-hydroxy-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol;

(2-Hydroxyethyl) amide 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1 -yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid;

(2-aminoethyl) amide 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1 -yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid; and

(2-Morpholin-4-yl-ethyl) amide 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c ] pyridin-1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid.

38. The compound according to claim 1, selected from the following compounds:

1- [1- {2-hydroxy-3- [4- (1H-indol-3-yl) piperidin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone;

1- [4- (5-fluoro-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-1-yl] propan-2-ol;

1- [3- (4-bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-chloro-1H- indol-3-yl) piperidin-1-yl] propan-2-ol;

1- [3- (4-bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-chloro-2- methyl-1H-indol-3-yl) piperidin-1-yl] propan-2-ol;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-methyl-1H- indol-3-yl) piperidin-1-yl] propan-2-ol;

3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperidine -4-yl) -1H-indol-5-carbonitrile;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-methoxy-1H- indol-3-yl) piperidin-1-yl] propan-2-ol;

3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] ethyl ester] propyl} piperidin-4-yl) -1H-indole-5-carboxylic acid;

1- [4- (6-chloro-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-1-yl] propan-2-ol;

1- [1- (3- {4- [6-chloro-1- (2-morpholin-4-yl-ethyl) -1H-indol-3-yl] piperidin-1-yl} -2-hydroxypropyl) - 3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [3, 2-b] pyridin-3-yl) piperidin-1-yl] propan-2-ol;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [2, 3-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-hydroxy-1H- pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol;

1- [4- (5-dimethylamino-1H-pyrrolo [3,2-b] pyridin-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4, 5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol;

1- [4- (5-dimethylamino-1H-pyrrolo [2,3-c] pyridin-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4, 5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol;

3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperidine -4-yl) -1H-pyrrolo [2,3-b] pyridin-6-carbonitrile;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- {4- [1- (2-morpholine -4-yl-ethyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] piperidin-1-yl} propan-2-ol;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (7-morpholin-4- yl-1H-pyrrolo [2,3-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol;

1- [4- (6-fluoro-2-hydroxymethyl-benzo [b] thiophen-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4.5, 6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol;

6-fluoro-3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl ] propyl} piperidin-4-yl) benzo [b] thiophene-2-carbaldehyde;

6-fluoro-3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridine ester 1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid;

amide 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid;

and 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl ethylamide } piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid.

39. The compound according to claim 1, selected from the following compounds:

1- {4- [6-chloro-1- (2-morpholin-4-yl-ethyl) -1H-indol-3-yl] piperidin-1-yl} -3- [5-methanesulfonyl-3- (4 trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol;

(2-Morpholin-4-yl-ethyl) amide 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c ] pyridin-1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-hydroxy-1H- pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol; and

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (6-morpholin-4- yl-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol.

40. The compound according to claim 1, selected from the following compounds:

1- (3- (4-chloro-3-methylphenyl) -1- {2-hydroxy-3- [4- (1H-indol-3-yl) piperidin-1-yl] propyl} -1,4, 6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl) ethanone;

1- [1- {3- [4- (5-chloro-1H-indol-3-yl) piperidin-1-yl] -2-hydroxypropyl} -3- (4-trifluoromethylphenyl) -1,4,6, 7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone;

1- {3- [4- (5-chloro-1H-indol-3-yl) piperidin-1-yl] propyl} -5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7- tetrahydro-1H-pyrazolo [4,3-c] pyridine;

1- [4- (6-chloro-1-methyl-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6, 7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol;

1- [4- (6-chloro-1-methanesulfonyl-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6, 7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol;

1- [3- (4-bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (7-chloro-1H- indol-3-yl) piperidin-1-yl] propan-2-ol;

3- (1- {3- [3- (4-bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl} piperidin- 4-yl) -1H-indol-5-carbonitrile;

1- [3- (4-bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- {4- [6-chloro-1- (2-morpholin-4-yl-ethyl) -1H-indol-3-yl] piperidin-1-yl} propan-2-ol;

1- [3- (4-bromophenyl) -1- (3- {4- [6-chloro-1- (2-morpholin-4-yl-ethyl) -1H-indol-3-yl] piperidin-1- yl} -2-hydroxypropyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone;

1- [1- {2-hydroxy-3- [4- (1H-pyrrolo [2,3-b] pyridin-3-yl) piperidin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1 4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone;

1- [3- (4-bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [2, 3-b] pyridin-3-yl) piperidin-1-yl] propan-2-ol;

1- (3- (4-bromophenyl) -1- {2-hydroxy-3- [4- (1H-pyrrolo [2,3-b] pyridin-3-yl) piperidin-1-yl] propyl} -1 4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl) ethanone;

1- [1- (2-hydroxy-3- {4- [1- (2-morpholin-4-yl-ethyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] piperidin-1- yl} propyl) -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone;

5-methanesulfonyl-1- {3- [4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -3,6-dihydro-2H-pyridin-1-yl] propyl} -3- ( 4-trifluoromethylphenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine; and

5-methanesulfonyl-1- {3- [4- (1H-pyrrolo [2,3-b] pyridin-3-yl) piperidin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -4.5, 6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine.

41. The compound according to claim 1, selected from the following compounds:

1- [3- (4-bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- {4- [1- (2-morpholine -4-yl-ethyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] piperidin-1-yl} propan-2-ol;

1- [3- (4-bromophenyl) -1- (2-hydroxy-3- {4- [1- (2-morpholin-4-yl-ethyl) -1H-pyrrolo [2,3-b] pyridine- 3-yl] piperidin-1-yl} propyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone;

6-chloro-3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridine ester 1-yl] propyl} piperidin-4-yl) pyrrolo [2,3-b] pyridin-1-carboxylic acid;

1- [4- (6-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4, 5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (7-hydroxy-1H- pyrrolo [2,3-b] pyridin-3-yl) piperidin-1-yl] propan-2-ol;

1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (6-morpholin-4- yl-1H-pyrrolo [2,3-b] pyridin-3-yl) piperidin-1-yl] propan-2-ol;

1- [1- {2-hydroxy-3- [4- (1H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1 4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone;

1- [3- (4-bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [3, 2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol;

1- (3- (4-bromophenyl) -1- {2-hydroxy-3- [4- (1H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propyl} -1 4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl) ethanone;

3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] methyl ester] propyl} piperidin-4-yl) -5-hydroxypyrrolo [3,2-c] pyridin-1-carboxylic acid;

3- (1- {3- [5-acetyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl ester } piperidin-4-yl) -6-fluorobenzofuran-2-carboxylic acid;

3- (1- {3- [5-acetyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl ester } piperidin-4-yl) -6-fluorobenzo [b] thiophene-2-carboxylic acid;

1- [4- (6-fluorobenzo [b] thiophen-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-1-yl] propan-2-ol;

1- [1- {3- [4- (6-fluorobenzofuran-3-yl) piperidin-1-yl] -2-hydroxypropyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-5-yl] ethanone;

6-fluoro-3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl ] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid;

6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl dimethyl} dimethyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid;

3- (1- {3- [5-acetyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl} piperidin- 4-yl) -6-fluorobenzo [b] thiophene-2-carbonitrile; and

6-fluoro-3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl ] propyl} piperidin-4-yl) benzo [b] thiophene-2-carbonitrile.

42. A pharmaceutical composition comprising a compound according to claims 1, 31, 37, 38 or 39 and a pharmaceutically acceptable carrier.

43. A method of treating a subject in a condition mediated by cathepsin S, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound according to claims 1, 31, 37, 38 or 39.

44. A method of inhibiting cathepsin S activity in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound according to claims 1, 21, 37 or 39.

45. A method of treating an autoimmune disease or inhibiting the development of an autoimmune disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the compound of claims 1, 21, 37 or 39.

46. The method according to item 45, where the autoimmune disease is selected from the group including lupus, rheumatoid arthritis and asthma.

47. The method according to item 45, where the autoimmune disease is asthma.

48. A method of treating or inhibiting the development of tissue transplant rejection in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the compound of claims 1, 21, 37 or 38.

49. The method of claim 48, wherein said administration is carried out after the subject has undergone a tissue transplant procedure.

50. The method according to p, where the specified introduction to the specified subject is carried out before or during the procedure of tissue transplantation.