IP Library › Granted Patent US 8,466,155

Granted Patent B2

US 8,466,155 · App. 12/893,240 · Granted Jun 18, 2013

Pyrimidines

Inventors: Heinz Stadtmueller (Vienna, AT); Ioannis Sapountzis (Vienna, AT)

Assignee: Boehringer Ingelheim International GmbH

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Patent No.: US 8,466,155
App. No.: 12/893,240
Granted: Jun 18, 2013
Kind: B2

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Abstract

The present invention encompasses compounds of general formulae (1 a ) and (1 b ) wherein the groups R 1 to R 5 , A, Q, m, n, p and q are defined as in claim 1 , which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and their use as medicaments.

Claims (104)

1. A compound of formula (1a) or (1b)

wherein

A denotes a group, optionally substituted by one or more, identical or different R 2 , selected from among C 3-10 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-15 aryl and 5-12-membered heteroaryl;

Q denotes a group, optionally substituted by one or more, identical or different R 4 , selected from among phenyl and 56 membered heteroaryl;

R 1 denotes a group selected from among halogen, —OR c , —OCF 3 , —SR c , —NR c R c , —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 haloalkyloxy;

R 2 , R 4 and R 5 each independently of one another denote hydrogen or a group selected from among R a , R b and R a substituted by one or more, identical or different R c and/or R b ;

R 3 denotes a group selected from among —OS(O)R c , —OS(O) 2 R c , —OS(O) 2 R c , —OS(O)NR c R c , —OS(O) 2 NR c R c , —OC(O)R c , —OC(O)OR c , —OC(O)SR c , —OC(O)NR c R c , —SC(O)R c , —SC(O)OR c , —SC(O)NR c R c , —N(R g )C(O)R c , —N[C(O)R c ] 2 , —N(OR g )C(O)R c , —N[C(O)R c ]NR c R c , —N(R g )S(O)R c , —N(R g )S(O)OR c , —N(R g )S(O) 2 R c , —N[S(O) 2 R c [ 2 , —N(R g )S(O) 2 OR c , —N(R g )S(O) 2 NR c R c , —N(R g )[S(O) 2 ] 2 R c , —N(R g )C(O)OR c , —N(R g )C(O)SR c , —N(R g )C(O)NR c R c , —N(R g )C(O)NR g NR c R c , —[N(R g )C(O)] 2 R c , —N(R g )[C(O)] 2 R c , —N{[C(O)] 2 R c } 2 , —N(R g )[C(O)] 2 OR c , —N(R g )[C(O)] 2 NR c R c , —N{[C(O)] 2 OR c } 2 , —N{[C(O)] 2 NR c R c } 2 and —[N(R g )C(O)] 2 OR c ;

each R a is independently selected from among C 1-6 alkyl, C 3-10 cycloalkyl, C 4-16 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 membered heteroarylalkyl;

each R b is a suitable group and each is independently selected from among ═O, —OR c , C 1-3 haloalkyloxy, —OCF 3 , ═S, —SR c , ═NR c , ═NOR c , ═NNR c R c , ═NN(R g )C(O)NR c R c , —NR c R c , —ONR c R c , —N(OR c )R c , —N(R g )NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R c , —S(O)OR c , —S(O) 2 R c , —S(O) 2 OR c , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R c , —OS(O) 2 R c , —OS(O) 2 OR c , —OS(O)NR c R c , —OS(O) 2 NR c R c , —C(O)R c , —C(O)OR c , —C(O)SR c , —C(O)NR c R c , —C(O)N(R g )NR c R c , —C(O)N(R g )OR c , —C(NR g )NR c R c , —C(NOH)R c , —C(NOH)NR c R c , —OC(O)R c , —OC(O)OR c , —OC(O)SR c , —OC(O)NR c R c , —OC(NR g )NR c R c , —SC(O)R c , —SC(O)OR c , —SC(O)NR c R c , —SC(NR g )NR c R c , —N(R g )C(O)R c , —N[C(O)R c ] 2 , —N(OR g )C(O)R c , —N(R g )C(NR g )R c , —N(R g )N(R g )C(O)R c , —N[C(O)R c ]NR c R c , —N(R g )C(S)R c , —N(R g )S(O)R c , —N(R g )S(O)OR c , —N(R g )S(O) 2 R c , —N[S(O) 2 R c ] 2 , —N(R g )S(O) 2 OR c , —N(R g )S(O) 2 NR c R c , —N(R g )[S(O) 2 ] 2 R c , —N(R g )C(O)OR c , —N(R g )C(O)SR c , —N(R g )C(O)NR c R c , —N(R g )C(O)NR g NR c R c , —N(R g )N(R g )C(O)NR c R c , —N(R g )C(S)NR c R c , —[N(R g )C(O)] 2 R c , —N(R g )[C(O)] 2 R c , —N{[C(O)] 2 R c } 2 , —N(R g )[C(O)] 2 OR c , —N(R g )[C(O)] 2 NR c R c , —N{[C(O)] 2 OR c } 2 , —N{[C(O)] 2 NR c R c } 2 , —[N(R g )C(O)] 2 OR c , —N(R g )C(NR g )OR c , —N(R g )C(NOH)R c , —N(R g )C(NR g )SR c and —N(R g )C(NR g )NR c R c ;

each R b independently denotes hydrogen or a group optionally substituted by one or more, identical or different R d and/or R e selected from among C 1-6 alkyl, C 3-10 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 membered heteroarylalkyl;

each R d is a suitable group and each is independently selected from among ═O, —OR e , C 1-3 haloalkyloxy, —OCF 3 , ═S, —SR e , ═NR e , ═NOR e , ═NNR e R e , ═NN(R g )C(O)NR e R e , —NR e R e , —ONR e R e , —N(R g )NR e R e , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R e , —S(O)OR e , —S(O) 2 R e , —S(O) 2 OR e , —S(O)NR e R e , —S(O) 2 NR e R e , —OS(O)R e , —OS(O) 2 R e , —OS(O) 2 OR e , —OS(O)NR e R e , —OS(O) 2 NR e R e , —C(O)R e , —C(O)OR e , —C(O)SR e , —C(O)NR e R e , —C(O)N(R g )NR e R e , —C(O)N(R g )OR e , —C(NR g )NR e R e , —C(NOH)R e , —C(NOH)NR e R e , —OC(O)R e , —OC(O)OR e , —OC(O)SR e , —OC(O)NR e R e , —OC(NR g )NR e R e , —SC(O)R e , —SC(O)OR e , —SC(O)NR e R e , —SC(NR g )NR e R e , —N(R g )C(O)R e , —N[C(O)R e ] 2 , —N(OR g )C(O)R e , —N(R g )C(NR g )R e , —N(R g )N(R g )C(O)R e , —N[C(O)R e ]NR e R e , —N(R g )C(S)R e , —N(R g )S(O)R e , —N(R g )S(O)OR e , —N(R g )S(O) 2 R e , —N[S(O) 2 R e ] 2 , —N(R g )S(O) 2 OR e , —N(R g )S(O) 2 NR e R e , —N(R g )[S(O) 2 ] 2 R e , —N(R g )C(O)OR e , —N(R g )C(O)SR e , —N(R g )C(O)NR e R e , —N(R g )C(O)NR g NR e R e , —N(R g )N(R g )C(O)NR e R e , —N(R g )C(S)NR e R e , —[N(R g )C(O)] 2 R e , —N(R g )[C(O)] 2 R e , —N{[C(O)] 2 R e } 2 , —N(R g )[C(O)] 2 OR e , —N(R g )[C(O)] 2 NR e R e , —N{[C(O)] 2 OR e } 2 , —N{[C(O)] 2 NR e R e } 2 , —[N(R g )C(O)] 2 OR e , —N(R g )C(NR g )OR e , —N(R g )C(NOH)R e , —N(R g )C(NR g )SR e and —N(R g )C(NR g )NR e R e ;

each R e independently denotes hydrogen or a group optionally substituted by one or more, identical or different R f and/or R g selected from among C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 membered heteroarylalkyl;

each R f is a suitable group and each is independently selected from among halogen and —CF 3 ;

each R g independently denotes hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkyl, 5-12 membered heteroaryl or 6-18 membered heteroarylalkyl;

m and p independently of one another denote 0, 1, 2 or 3 and n and q denote 0, 1, 2 or 3;

a tautomer thereof, a racemate thereof, an enantiomer thereof, a diastereomer thereof or a mixture of any of the foregoing, or a salt thereof.

2. The compound of formula (1a) according to claim 1

wherein

R 1 , R 2 , R 3 , R 4 , A, Q, n and m are defined as in claim 1 .

3. The compound according to claim 2 , wherein

n is 1.

4. The compound according to claim 1 , wherein

m is equal to 0.

5. The compound of formula (1 b) according to claim 1

wherein

R 1 , R 2 , R 3 , R 5 , A, p and q are defined as in claim 1 .

6. The compound according to claim 5 , wherein

q is equal to 1 or 2.

7. The compound according to claim 5 , wherein

p is equal to 0.

8. The compound according to claim 1 , wherein

R 3 is selected from among —N(R g )C(O)R c , —N(OR g )C(O)R c , —N(R g )S(O) 2 R c , —N(R g )C(O)OR c and —N(R g )C(O)NR c R c and

R c and R g are defined as in claim 1 .

9. The compound according to claim 1 , wherein the group

denotes

R 6 and R 7 are defined as R 2 in claim 1 ,

r is equal to 1 or 2 and

A is defined as in claim 1 .

10. The compound according to claim 9 , wherein

A is a group selected from among phenyl and 5-10 membered heteroaryl and

R 6 , R 7 and r are defined as in claim 9 .

11. The compound according to claim 10 , wherein

A is a phenyl;

r has the value 1 or 2; and

each R 7 is independently selected from among halogen, C 1-6 alkyl and C 1-6 alkoxy.

12. The compound according to claim 9 , wherein

R 6 is selected from among hydrogen, R a2 , R b2 and R a2 substituted by one or more, identical or different R b2 and/or R c2 ;

each R a2 is independently selected from among C 1-6 alkyl and 3-7 membered heterocycloalkyl;

each R b2 is a suitable substituent and is independently selected from among O═, —OR c2 , —NR c2 R c2 , —C(O)R c2 , —C(O)OR c2 , —C(O)NR c2 R c2 , —C(O)N(R g2 )OR c2 , —N(R g2 )C(O)R c2 , -vN(R g2 )C(O)OR c2 and —N(R g2 )C(O)NR c2 R c2 ,

each R c2 independently denotes hydrogen or a group optionally substituted by one or more, identical or different R d2 and/or R e2 , selected from among C 1-6 alkyl, C 3-6 cycloalkyl and 3-7 membered heterocycloalkyl;

each R d2 is a suitable substituent and is independently selected from among —OR e2 , —NR e2 R e2 , —C(O)N(R g2 )OR e2 and —C(O)NR e2 R e2 ;

each R e2 independently denotes hydrogen or a group optionally substituted by one or more, identical or different R f2 and/or R g2 , selected from among C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl;

each R f2 independently denotes —OR g2 and

each R g2 is independently selected from among hydrogen, C 1-6 alkyl and C 4-9 cycloalkylalkyl.

13. The compound according to claim 1 selected from the group consisting of:

4-[4-((1R,2R)-1-methanesulphonylamino-indan-2-yloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;

2-fluoro-4-[4-((1R,2R)-1-methanesulphonylamino-indan-2-yloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;

2-fluoro-4-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;

4-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;

2-fluoro-4-[4-((1R,2R)-2-methanesulphonylamino-cyclopentyloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;

4-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-3-methoxy-N-((3S,4S)-3-methoxy-1-methyl-piperidin-4-yl)-benzamide;

2-fluoro-4-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-((3S,4S)-3-methoxy-1-methyl-piperidin-4-yl)-benzamide;

2-chloro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;

2-fluoro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;

4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-3-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide;

3-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-4-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;

2-chloro-4-{5-chloro-4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;

4-{5-chloro-4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-pyrimidin-2-ylamino}-2-fluoro-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;

4-{5-chloro-4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-pyrimidin-2-ylamino}-2-fluoro-5-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide;

N-((1R,2R)-2-{2-[4-(4-tert-butyl-piperazin-1-yl)-2-methoxy-phenylamino]-5-trifluoromethyl-pyrimidin-4-yloxy}-indan-1-yl)-N-methyl-methanesulphonamid;

2-chloro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide;

2-fluoro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide;

2-chloro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;

2-fluoro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;

2-fluoro-4-[4-((1R,2R)-2-methanesulphonylamino-cyclohexyloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide

and a tautomer or salt of any of the foregoing compounds.

14. A method for treating prostate cancer in a warm-blooded animal comprising administering to said animal a therapeutically effective amount of a compound according to claim 1 .

15. The compound of claim 1 which is a pharmaceutically acceptable salt.

16. A pharmaceutical composition of matter comprising a compound according to claim 1 as an active ingredient.

17. The pharmaceutical composition of matter according to claim 16 comprising as an additional active ingredient a cytostatic or cytotoxic substance which is not a compound according to claim 1 .

18. A compound having the following structure