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1. WO2007087283 - THIOPHENE-CARBOXAMIDES USEFUL AS INHIBITORS OF PROTEIN KINASES

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

We claim :

1. A compound of formula I :



wherein
R1 is H , Ci~6aliphatic , or C3-.6cycloaliph.atic ;
G is -C (R) 2- or -O- ;
L is Co-3aliphatic optionally substituted with 0-3 JL; Ring A is 5-6 membered aromatic monocyclic ring containing
0-3 heteroatoms selected from O, KT, and S; Ring A is optionally substituted with 0-3 JA; Ring A is fused to

Ring A' ;
Ring A' is a 5-8 membered aromatic or nonarorαatic monocyclic ring containing 0-3 heteroatoms selected from 0, N, and

S; Ring A' is optionally substituted with 0-4 JA' ;
Ring B is 5-6 membered aromatic monocyclic ring containing
0-3 heteroatoms selected from O, N, and S; Ring B is optionally substituted with 0-5 JB and optionally fused to Ring B' ;
Ring B' is a 5-8 membered aromatic or nonaromatic monocyclic ring containing 0-3 heteroatoms selected from 0, 3SI, and

S; Ring B' is optionally substituted with 0-4 JB' ;
each vTA, JA' , JB, and JB' is independently Ci_6haloalkyl , halo,

NO2, CN, Q, or -Z-Q;
Z is independently Ci-βaliphatic optionally interrupted with

0-3 occurrences of -NR-, -0-, -S-, -C(O)-, -C(=NR)-,

-C(=N0R)-, -SO-, or -SO2-; each Z is optionally
substituted with 0-2 Jz;

Q is H; Ci-6 aliphatic,- a 3-8-meπibered aromatic or nonaromatic monocyclic ring having 0-3 heteroatoms independently
selected from O, N, and S; or an 8-12 membered aromatic or nonaromatic bicyclic ring system having 0-5
heteroatoms independently selected from 0, N, and S;
each Q is optionally substituted with 0-5 JQ;
each JL and Jz is independently H, halo, Ci-6 aliphatic,
C3-6cycloaliphatic, NO2, CN, -NH2, -NH(Ci_4 aliphatic),
-N(Ci-4 aliphatic)2, -OH, -O(Ci-4 aliphatic), -CO2H,
-CO2(C1-4 aliphatic), -0(haloCi-4 aliphatic), or halo (Ci-4 aliphatic) ;
each JQ is independently M or -Y-M;
each Y is independently an unsubstituted Ci-galiphatic
optionally interrupted with 0-3 occurrences of -NR-,
-0-, -S-, -C(O)-, -SO-, or -SO2-;
each M is independently H, Ci-e aliphatic, C3-6cycloaliphatic, halo{Ci-4 aliphatic), -0(haloCi_4 aliphatic), C3-6 *
heterocyclyl , halo, NO2, CN, OH, OR'; SH, SR', NH2, HHR', N(R' )2, COH, COR', CONH2, CONHR', C0NR'2, NHCOR',
NR' COR7, NHCONH2 , NHCONHR' , NHCON(R' )2, SO2NH2, SO2NHR',
SO2N(R') 2, IsIHSO2R' , or NR' SO2R' ;
R is H or unsubstituted

R' is unsubstituted Ci_6aliphatic; or two R' groups, together with the atom to which they are bound, form an
unsubstituted 3-8 membered nonaromatic monocyclic ring having 0-1 heteroatoms independently selected from 0, N, and S;

provided that Ring A fused to Ring A' does not form

2. The compound of claim 1, wherein G is -C(R)2-.

3. The compound of claim 1, wherein G is 0.

4. The compound of any one of claims 1-3, wherein R1 is H.

5. The compound of any one of claims 1-4, wherein Ring A is a 5-membered ring containing 1-3 heteroatoms selected from O,

N, and S .

6. The compound of claim 5, wherein Ring A is a 5-membered aromatic ring containing 1-2 heteroatoms selected from 0, N, and S .

7. The compound of claim 6, wherein Ring A is a 6-membered aromatic ring containing 1-2 heteroatoms selected from 0, W, and S.

8. The compound of any one of claims 1-7, wherein Ring A' is a 5-6 membered aromatic ring containing 0-3 heteroatoms selected from 0, N, and S.

9. The compound of any one of claims 1-8, wherein Ring A-A' is as represented in formula I-a;
H-bond donor

H-bond acceptor


I-a
wherein ring A contains a heteroatom (an H-bond acceptor) selected from 0, N, and S, which is adjacent to another atom (an H-bond donor) selected from NH and C-JA; which is
adjacent to the point of attachment; JA is selected from H, OH, SH, NH2, and NHR.

10 . The compound according to claim 9 , wherein the lαeteroatom of ring A is N and JA is H .

11 . The compound of any one of claims 1-4 , wherein Ring A-A' is selected from the following:


12 . The compound of claim 11 , wherein Ring A-A' is


13. The compound of claim 11, wherein Ring A-A' is



and JA is H.
14. The compound of claim 11, wherein Ring A-A' is
.

15, The compound of claim 11 , wherein Ring A-A' is



16 The compound, of claim 11, wherein Ring A-A' is


17. The compound of any one of claims 1-4, wherein Ring A-A' is:


18. The compound of any one of claims 1-17, wherein Ring B is a 6 membered aromatic ring containing 0-2 nitrogen atoms.

19. The compound of any one of claims 1-17, wherein Ring B is fused to Ring B' .

20. The compound of claim 19, wherein Ring B' is a 5-6 membered aromatic ring containing 0-3 heteroatoms selected from O, N, and S.

21. The compound of any one of claims 1-20, wherein JΛ is H, Cα-6 aliphatic, C3-6cycloaliphatic, halo(Ci-4 aliphatic), -0{haloCi-4 aliphatic), C3-6 heterocyclyl, halo, NO2, CN, OH, OR, SH, SR, NH2, NHR, N(R)2/ COH, COR, CONH2, CONHR, CONR2, NHCOR, NRCOR, NHCONH2, NHCONHR, NHCON(R)2/ SO2NH2, SO2NHR, SO2N(R)2, NHSO2R, or NRSO2R.

22. The compound of claim 21, wherein JA is H.

23. The compound of any one of claims 1-22, wherein JA' is H, Ci-6 aliphatic, C3_6cycloaliphatic, halo(Ci-4 aliphatic), -0(haloCi_4 aliphatic), C3-e heterocyclyl, halo, NO2/ CN, OH, OR, SH, SR, NH2, NHR, N(R)2, COH, COR, CONH2, CONHR, CONR2, NHCOR, NRCOR, NHCONH2, NHCONHR, NHCON(R)2, SO2NH2, SO2NHR, SO2N(R)2, NHSO2R, or NRSO2R.
24. The compound of claim 23, wherein JA' is -NHCOR.

25. The compound of claim 24, wherein JA' is -NHCOR and the R is Cχ-6 alkyl .

26. The compound of claim 25, wherein the alkyl is methyl.

27. The compound of claim 25, wherein the alkyl is ethyl.

28. The compound of any one of claims 1-27, wherein JB is H1 Ci-6 aliphatic, C3-.6cycloaliphatic, halo(Ci-4 aliphatic), -0 {haloCi_4 aliphatic), C3_6 heterocyclyl, halo, NO2, CN, OH, OR, SH, SR, NH2, NHR, N(R)2, COH, COR, CONH2, CONHR, CONR2, NHCOR, NRCOR, NHCONH2, NHCONHR, NHCON(R)2, SO2NH2, SO2NHR, SO2N(R)2, NHSO2R, or NRSO2R.

29. The compound of any one of claims 1-28, wherein JB' is H, Ci-6 aliphatic, Ca-ecycloaliphatic, halo(Cα_4 aliphatic), -0 (haloCi-4 aliphatic), C3-6 heterocyclyl , halo, NO2, CN, OH, OR, SH, SR, NH2, NHR, N(R)2, COH, COR, CONH2, CONHR, CONR2, NHCOR, NRCOR, NHCONH2, NHCONHR, NHCON(R)2, SO2NH2, SO2NHR, SO2N(R)2, NHSO2R, or NRSO2R.

30. A compound selected from the following compounds:





31. A compound selected from the following compounds:



1-7 1-8 •1-9


-10 1-11 1-12


-16 1-17 1-18



-19 1-20 1-21

1-22 1-23 1-24


1-25 .
32. A composition comprising a compound of any one of claims 1-31, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
33. A method of inhibiting protein kinase activity in a patient comprising administering to said patient
a) a composition of claim 32; or
b) a compound of any one of claims 1-31.

34. A method of inhibiting protein kinase activity in a biological sample comprising contacting said biological sample with:
a) a composition of claim 32; or
b) a compound of any one of claims 1-31.

35. The method of claim 33 or claim 34, wherein said protein kinase is PLK.

36. The method of claim 35, wherein said protein kinase is PLKl.

37. A method of treating a proliferative disorder, a neurodegenerative disorder, an autoimmune disorder, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising the step of administering to a patient:
a) a composition of claim 32; or
b) a compound of any one of claims 1-30.

38. The method according to claim 33 or claim 37,
comprising administering to said patient an additional therapeutic agent selected from a chemotherapeutic or antiproliferative agent, an anti-inflammatory agent, an
immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein:
said additional therapeutic agent is appropriate for the disease being treated; and
said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

39. A method of treating melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from colon, breast, gastric, ovarian, cervical, lung, central nervous system (CWS) , renal, prostate, bladder, or pancreatic, in a patient wherein said method comprises administering to said patient
a) a composition of claim— 32; or
b) a compound of any one of claims 1-30.

40. A method of treating cancer in a patient wherein said method comprises administering to said patient
a) a composition of claim 32; or
b) a compound of any one of claims 1-30.

41. The method of claim 40, wherein said method comprises the step of disrupting mitosis of the cancer cells by inhibiting PLK with:
a) a composition of claim 32; or
b) a compound of any one of claims 1-30.

42. A process for preparing a compound of formula I :



I
wherein G is O, R1 is H, and Ring A, Ring B, <JA, JB and L are as defined according to any one of claims 1-30, comprising reacting a compound of formula 5

5
wherein Ring A, Ring B, JA, JB and L are as defined according to any one of claims 1-30,
under suitable amide forming conditions to form the compound of formula I .

43. The process of claim 42, further comprising the step of coupling a compound of formula 4;



4
wherein X is halo and Ring B, JB, and L are as defined
according to any one of claims 1-30;
with a compound of formula i,


wherein CP is a cross-coupling group and ring A and JA are as defined according to any one of claims 1-30;
under suitable cross-coupling conditions, to form the
compound of formula 5.

44. The process of claim 42, further comprising the step of coupling a compound of formula 4;

(JB)θ-5


4
wherein X is halo and Ring B, JB, and L are as defined
according to any one of claims 1-30;

with a coupling group precursor under suitable coupling group formation conditions to form a compound of formula 5a:



5a
wherein CP is a cross-coupling group, and Ring B, JB, and L
are as defined according to any one of claims 1-30.

45. The process of claim 44 further comprising the step of coupling the compound of formula 5a with a compound of formula ii ,



wherein X is halo and Ring A and JA are as defined according to any one of claims 1-30; under suitable cross- coupling conditions to form a compound of formula 5
wherein L, Ring A, Ring B, JA, and JB are as defined
according to any one of claims 1-30.

46. The process of claim 43 or claim 44, further
comprising the step of coupling a compound of formula 3:
3
wherein X is halo;
LG L- (JB)o-5
with
wherein LG is a suitable leaving group and L, Ring B, and JB are as defined according to any one of claims 1-30;
under suitable 0-C bond coupling conditions to form the
compound of formula 4.

47. A process for preparing a compound of formula 5:


wherein Ring A, Ring B, JA, JB and L are as defined according to any one of claims 1-30,
wherein G is O, R1 is H, and Ring A, Ring B, JA, JB and L are as defined according to any one of claims 1-30,
comprising reacting a compound of formula 7 :


LG L-with (JB)θ-5
wherein LG is a suitable leaving group and L, Ring B, and JB are as defined according to any one of claims 1-30;

under suitable O-C bond coupling conditions to form the
compound of formula 5.

48. The process of claim 47, further comprising the steps of:
a) coupling a compound of formula 2:



2
with a compound of formula i,

(JA)o-3—f A rCP

wherein CP is a cross-coupling group and ring A and JA are as defined according to any one of claims 1-30, under suitable cross-coupling conditions, to form a
compound of formula 6 :



6;
b) deprotecting the compound of formula 6 under
suitable deprotection conditions to form the compound of formula 7.

49. The process of claim 47, further comprising the steps Of:
a) coupling a compound of formula 2:


with a coupling group precursor under suitable
coupling group formation conditions to form a
compound of formula 5b:



5b
wherein CP is a cross-coupling group;

(JA)o-3'
b) coupling the compound of formula 5b with
wherein X is a halo and ring A and JA are as defined herein,
to form a compound of formula 6 :



6;
c) deprotecting the compound of formula 6 under suitable deprotection conditions to form a compound of formula 7.

50. The process of claim 47, further comprising the step

of adding
,
wherein ring A is an aromatic ring containing a nitrogen atom capable of nucleophilic attack and JA is as defined according to any one of claims 1-30/ to a compound of formula 8 :



8 via suitable conjugate addition conditions to form the compound of formula 9 :



51. A process for preparing a compound of formula I:


wherein G is 0, R1 is H, and Ring A, Ring B, JA, JB and L are as defined according to any one of claims 1-30, comprising reacting a compound of formula 12a/b:



12a/b
wherein Ring A, Ring B, JA, JB, L, and R3 are as defined according to any one of claims 1-30,
under suitable boronation conditions to form the compound of formula 5a or a compound of formula 5a/b:



5 a/b,
wherein Ring- A, Ring B, JA, JB, L, R3, and R4 are as defined according to any one of claims 1-30.