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1. (WO2015177326) 5-CHLORO-2-DIFLUOROMETHOXYPHENYL PYRAZOLOPYRIMIDINE COMPOUNDS WHICH ARE JAK INHIBITORS
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WHAT IS CLAIMED IS:

1. A compound of Formula (00A) :


and stereoisomers and salts thereof, wherein: R00 is H or C¾; R01 is H or NH2; R° is H or NH2; and Ring Q is either (i) or


wherein: t 1 and t2 are each independently 0 or 1 ; X A and X B are independently selected from the group consisting of H, Ci-C6 alkyl, C2-C4 alkenyl, -NRaRb, C2-C5 alkynyl, 3-6-membered cycloalkyl, 6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, and 5-10 membered heteroaryl; wherein when either of ΧΛ and XD are independently Ci-C6 alkyl, C2-C4 alkenyl, C2-Cs alkynyl, 3-6-membered cycloalkyl, 6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, and 5-10 membered heteroaryl, each of X A and X B is independently optionally substituted by Y1, wherein Y1 is selected from:

(a) Ci-C6 alkyl optionally substituted by T1, wherein T1 is selected from the group consisting of OH, halo, CN, imino, 3-6 membered cycloalkyl, 3-11 membered

heterocycloalkyl, 3-11 membered heterocycloalkenyl, 5-10 membered heteroaryl, -O-(Ci-C6 alkyl), C(0)OH, oxetan-3-ylmethyl, -C(0)0-(Ci-C6 alkyl), -S-(Ci-C6 alkyl), -S02-(Ci-C6 alkyl), -NRaRb, -N(+)RaRbRc wherein Rc is methyl, -C(0)NRaRb, -(2-oxoindolin-l-yl), -OC(0)-3-6 membered cycloalkyl, and phenyl, wherein each alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, and phenyl of T1 is optionally substituted by OH, -C(0)0-(Ci-C6 alkyl), Ci-C6 alkyl, halo, CN, oxo, -(Q-C6 alkyl)CONRaRb, -NRaRb, phenyl, or -0-(Ci-C6 alkyl) optionally substituted by OH;

(b) 3-11 membered heterocycloalkyl, -(Ci-C6 alkylene)-3-l l membered heterocycloalkyl, -C(0)-3-l l membered heterocycloalkyl, -(Ci-C6 alkylene)C(0)-3- 11 membered heterocycloalkyl, or -OC(0)-4-6 membered heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted by OH, halo, CN, Ci-C6 alkyl, -(Ci-C6 alkylene)-CF3, oxo, -C(0)-(Ci-C6 alkyl), -C(0)0-(Ci-C6 alkyl), -C(0)0-(Ci-C6 alkylene)-phenyl, -S02-(Ci-C6 alkyl), -C(0)NRaRb, -NRaRb, -(Ci-C6 alkylene)-phenyl, or -C(0)-4-6 membered heterocycloalkyl optionally substituted by -NRaRb;

(c) N(+)(AA)3, wherein each AA is independently Ci-C6 alkyl optionally substituted by phenyl;

(d) 3-6 membered cycloalkyl optionally substituted by OH, halo, NRaRb, or CN;

(e) CN, halo, or oxo;

(f) -C(0)-(Ci-C6 alkyl), -C(0)OH, -C(0)0-(Ci-C6 alkylene) -phenyl, -S02-(C1-C6 alkyl), -C(0)NRaRb, or -C(0)-4-6 membered heterocycloalkyl optionally substituted by -(Ci-Ce alkyl) or -NRaRb, or -C(0)0-(Ci-C6 alkyl) optionally substituted by OH, NRaRb, or 3-11 membered heterocycloalkyl wherein said heterocycloalkyl is optionally substituted by Ci-C6 alkyl;

(g) OH, -O-phenyl, or -0-(Ci-C6 alkyl), wherein the alkyl is optionally substituted by

OH or -NRaRb;

(h) phenyl optionally substituted by OH, halo, Ci-C6 alkyl, CF3, or CN;

(i) 5-6 membered heteroaryl optionally substituted by OH, halo, Ci-C6 alkyl, CF3, CN, or 3-11 membered heterocycloalkyl optinally substituted by Ci-C6 alkyl or 3-11 membered heterocycloalkyl;

(j) isoindolin-2-yl optionally substituted by halo;

(k) -NRaRb, and

(1) -0-CH2C(0)-3-l l membered heterocycloalkyl;

wherein Ra and Rb are independently selected from:

(a) H,

(b) Ci-C6 alkyl optionally substituted by OH, halo, CN, -C(0)OH, - C(0)0-(Ci-C6alkyl), -C(0)0-(3-l l membered heterocycloalkyl), - C(0)0-(Ci-C6 alkyl)-S-(Ci-C6 alkyl), -S-(Ci-C6 alkyl), naphthylenyl, - NRazRbz, -C(0)NRazRbz, oxo, -0-(Ci-C6 alkyl), 5-6 membered heteroaryl optionally substituted by Ci-C6 alkyl or halo, or benzo[l,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl optionally substituted by oxo;

(c) -(Ci-C6 alkylene)-3-6 membered cycloalkyl wherein the alkylene is optionally substituted by OH, halo, or CN;

(d) -(Ci-C6 alkylene) -phenyl wherein alkylene is optionally substituted by halo and the phenyl is optionally substituted by OH, halo, CF3, Ci-C6 alkyl, -0-(Ci-C6 alkyl), -S-(Ci-C6 alkyl, or -O-phenyl;

(e) -(Ci-C6 alkylene)-4-6 membered heterocycloalkyl wherein the heterocycloalkyl is optionally substituted by halo, oxo, or Ci-C6 alkyl;

(f) -(Ci-C6 alkylene) -O-phenyl wherein the phenyl is optionally substituted by halo, Ci-C6 alkyl, or -O-phenyl;

(g) -(Ci-C6 alkyl)3-6 membered cycloalkyl optionally substituted by OH, halo, CN, or Ci-C6 alkyl optionally substituted by OH or CN;

(h) C2-C5 alkenyl;

(i) 4-6 membered heterocycloalkyl optionally substituted by halo,

(j) -(Ci-C6 alkylene)-3-6 membered cycloalkyl substituted by hydroxymethyl,

(k) phenyl,

(1) -C(0)(Ci-C6 alkyl),

(m)-C(0)0(Ci-C6 alkyl),

(n) -C(0)0(3-6 membered cycloalkyl), and

(o) -C(0)-phenyl,

and Rbz are each independently selected from

(a) H,

(b) Ci-C6 alkyl optionally substituted by OH, halo, CN, -C(0)OH, - C(0)0-(Ci-C6alkyl), -C(0)0-(3-l l membered heterocycloalkyl), - C(0)0-(Ci-C6 alkyl)-S-(Ci-C6 alkyl), -S-(Ci-C6 alkyl), naphthylenyl, - oxo, -0-(Ci-C6 alkyl), 5-6 membered heteroaryl optionally substituted by Ci-C6 alkyl or halo, or benzo[l,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl optionally substituted by oxo;

(c) -(Ci-C6 alkylene)-3-6 membered cycloalkyl wherein the alkylene is optionally substituted by OH, halo, or CN;

(d) -(Ci-C6 alkylene) -phenyl wherein alkylene is optionally substituted by halo and the phenyl is optionally substituted by OH, halo, CF3, Ci-C6 alkyl, -0-(Ci-C6 alkyl), -S-(Ci-C6 alkyl, or -O-phenyl;

(e) -(Ci-C6 alkylene)-4-6 membered heterocycloalkyl wherein the heterocycloalkyl is optionally substituted by halo, oxo, or Ci-C6 alkyl; (f) -(Ci-C6 alkylene)-0-phenyl wherein the phenyl is optionally substituted by halo, Ci-C6 alkyl, or -O-phenyl;

(g) -(Ci-C6 alkyl)3-6 membered cycloalkyl optionally substituted by OH, halo, CN, or Ci-C6 alkyl optionally substituted by OH or CN;

(h) C2-C5 alkenyl;

(i) 4-6 membered heterocycloalkyl optionally substituted by halo,

(j) -(Ci-C6 alkylene)-3-6 membered cycloalkyl substituted by hydroxymethyl,

(k) phenyl,

(1) -C(0)(Ci-C6 alkyl),

(m)-C(0)0(Ci-C6 alkyl),

(n) -C(0)0(3-6 membered cycloalkyl), and

(o) -C(0)-phenyl,

with the following provisos: when R , R , and R are each H and Ring Q is


where t1 is 0, then XA is not methyl, 2-methylpropan-2-ol, or tetrahydropyranyl.

2. The compound of claim 1, further defined as a compound of Formula (II):


wherein:

w is 0 or 1 ;

R is H or NH2;

R is selected from the group consisting of

a. H,

b. Ci-C6 alkyl optionally substituted by OH, halo, CN, -0-(Ci-C6 alkyl), naphthylenyl, 5-6 membered heteroaryl, or -C(0)NRvRw, wherein Rv and Rw are independently H or Ci-C6 alkyl optionally substituted by halo, c. -(Ci-C6 alkylene)-3-6 membered cycloalkyl wherein the cycloalkyl is optionally substituted by CN,

d. -(Ci-C6 alkylene)-phenyl wherein the alkyl is optionally substituted by halo and wherein the phenyl is optionally substituted by OH, halo, CF3, Ci-C6 alkyl, -0-(Ci-C6 alkyl) or -O-phenyl,

e. -(Ci-C6 alkylene)-4-6 membered heterocycloalkyl wherein the heterocycloalkyl is optionally substituted by halo or Ci-C6 alkyl, f. -(Ci-C6 alkyl ene)-0-phenyl wherein the phenyl is optionally substituted by halo or Ci-C6 alkyl, or

g. 3-6 membered cycloalkyl;

R2b is selected from the group consisting of H, Ci-C6 alkyl optionally substituted halo, or C2-C5 alkenyl;

or R and R together form a 3-11 membered heterocycloalkyl optionally substituted by OH;

R3b is absent or methyl, wherein when R3b is methyl, the nitrogen to which it is attached is N+ and w is 1 ;

R4b is a bond or Ci-C6 alkylene;

R5b is selected from the group consisting of H, OH, and phenyl; and

Ring F is a 3-7 membered heterocycloalkyl wherein plb is 0, 1 or 2 and p2b is 0, 1 or 2;

wherein w is equal to 1 only when R3b is methyl.

3. The compound of claim 1, further defined as a compound of Formula (la) or Formula (lb):

(la)


(lb)

wherein:

Rua is H or NH2;

Rla is bound to a nitrogen atom of Ring A in (la) or is bound to a carbon atom of Ring B in (lb), and is selected from the group consisting of:

a. H,

b. Ci-C6 alkyl optionally substituted by OH, halo, -0-(Ci-C6 alkyl), -S02- (Ci-C6 alkyl), -(2-oxoindolin-l-yl), -OC(0)-3-6 membered cycloalkyl, - OC(0)-4-6 membered heterocycloalkyl, or phenyl;

c. -(Ci-C6 alkylene)-0-(Ci-C6 alkylene) -phenyl wherein the phenyl is optionally substituted by halo;

d. -(Ci-C6 alkylene)-3-6 membered cycloalkyl wherein the cycloalkyl is optionally substituted by halo, OH, or CN;

e. -(Ci-C6 alkylene)-4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by oxo, Ci-C6 alkyl, -C(0)-(Ci- C6 alkyl), -C(0)0-(Ci-C6 alkyl), -S02-(C1-C6 alkyl), -C(0)-4-6 membered heterocycloalkyl, or -C(0)N(Ci-C6 alkyl)(Ci-C6 alkyl);

f. -C(0)0-(Ci-C6 alkylene)-OH; and

g. -C(0)0-(Ci-C6 alkylene)-phenyl;

h. -NR R , wherein Ra and R are independently selected from the group consisting of H and Ci-C6 alkyl optionally substituted by OH, halo, CN, phenyl, and 3-7 membered heterocycloalkyl;

R2a is selected from the group consisting of H, Ci-C6 alkyl optionally substituted by OH, and phenyl;

R3a is selected from the group consisting of H, Ci-C6 alkyl optionally substituted by OH, and phenyl;

Ring A is a 3-7 membered heterocycloalkyl; and

Ring B is a 3-7 membered heterocycloalkyl or a 3-7 membered heterocyclyalkenyl, wherein pla is 0, 1 or 2 and p2a is 0, 1 or 2,

provided that Ring A and Ring B together form a 6-11 membered bicyclic heterocycloalkyl.

4. The compound of claim 1, further defined as a compound of Formula (III):

wherein:

Ruc is H or NH2;

R3 is (i) or (ii):

(i)

R2c

wherein:

Rlc is selected from the group consisting of H, Ci-C6 alkyl, -(Ci-C6 alkyl)- phenyl, -C(0)-(Ci-C6 alkyl), -C(0)-phenyl, and 4-6 membered heterocycloalkyl;

R2c is H or Ci-C6 alkyl; and

R3c is a bond or Ci-C6 alkylene optionally substituted by oxo; or

Rlc and R2c together form a 3-11 membered heterocycloalkyl optionally substituted by Ci-C6 alkyl, oxo, or -(Ci-C6 alkylene)-phenyl; or

Rlc and R3c together form a 3-7 membered heterocycloalkyl; (ii) H; Ci-C6 alkyl optionally substituted by OH, -S02-(Ci-C6 alkyl), phenyl, or -0-(Ci-C6 alkylene)-phenyl; -(Ci-C6 alkylene)-C(0)0(Ci-C6 alkyl); or 4-6 membered heterocycloalkyl optionally substituted by -C(0)(Ci-C6 alkyl); and

Ring G is a 3-7 membered heterocycloalkyl wherein plc is 0, 1 or 2 and p2c is 0, 1 or 2.

5. The compound of claim 1, further defined as a compound of Formula (IV):

(IV)

wherein:

Rua is H or NH2;

R is 3-11 membered heterocycloalkyl or -C(0)-3-l l membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted Ci-C6 alkyl, CF3, or fluoro, or Rld is -(Ci-C6 alkylene)-NRvRw, wherein Rv and Rw are independently H or Ci-C6 alkyl optionally substituted by halo.

6. The compound of claim 1, further defined as a compound of Formula (V):


wherein:

R0e is H or NH2;

Rle is selected from the group consisting of

a. H,

b. Ci-C6 alkyl optionally substituted by halo, CN, or phenyl,

c. -(Ci-C6 alkylene)-3-6 membered cycloalkyl wherein the cycloalkyl is optionally substituted by CN,

d. -(Ci-C6 alkylene)-4-6 membered heterocycloalkyl wherein the heterocycloalkyl is optionally substituted by Ci-C6 alkyl;

Rze is H or Ci-C6 alkyl;

or R e and R e together form a 3-11 membered heterocycloalkyl optionally substituted by halo or -NRVRW, wherein Rv and Rw are independently H or Ci-C6 alkyl optionally substituted by halo;

R e is a bond or Ci-C6 alkylene optionally substituted by oxo; and

Ring H is a 3-7 membered heterocycloalkyl wherein ple is 0, 1 or 2 and p2e is 0, 1 or 2.

7. The compound of claim 1, further defined as a compound of Formula (VI):


wherein:

Rut is H or NH2;

If

R is selected from the group consisting of Ci-C6 alkyl optionally substituted by halo, 3-6 membered cycloalkyl, or phenyl; and

If 2f

Ring J is a 6-7 membered heterocycloalkyl wherein p is 1 or 2 and p is 1 or 2. 8. The compound of claim 1, further defined as a compound of Formula (VII):

wherein:

R0 is H or NH2;

Rl is selected from the group consisting of Ci-C6 alkyl;

R2 is selected from the group consisting of Ci-C6 alkyl.

9. The compound of claim 1, further defined as a compound of Formula (VIII):


Run is H or NH2;

Rlh is selected from the group consisting of H and Ci-C6 alkyl optionally substituted by CN, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkylene-C(0)0-(Ci-C6 alkylene)-phenyl;

Ring C is 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; and

Ring D is a 3-7 membered heterocycloalkyl substituted at the sole nitrogen by Rlh; and

provided Rings C and D together form a 3-11 membered spiro heterocycloalkyl. 10. The compound of claim 1, further defined as a compound of Formula (IX):


wherein:

R0j is H or NH2;

R3^ is selected from the group consisting of H and Ci-C6 alkyl optionally substituted by OH, 3-6 membered cycloalkyl, -0-(Ci-C6 alkyl), -0-(Ci-C6 alkyl)-OH, -S02-(Ci-C6 alkyl) and phenyl, wherein the phenyl is optionally substituted by CN;

R4^ is selected from the group consisting of H and Ci-C6 alkyl optionally substituted by OH;

or R3^ and R4^ together form a 4-6-membered heterocycloalkyl;

R5^ is selected from the group consisting of H and Ci-C6 alkyl; and

Ring K is a 6-7 membered heterocycloalkyl wherein p1^ is 1 or 2 and p2^ is 1 or 2.

11. The compound of claim 1, further defined as a compound of Formula (X):


wherein:

R is H or NH2;

R is selected from the group consisting of

a. H,

b. Ci-C6 alkyl optionally substituted by halo, CN, or phenyl, c. -(Ci-C6 alkylene)-3-6 membered cycloalkyl wherein the cycloalkyl is optionally substituted by CN,

d. -(Ci-C6 alkylene)-4-6 membered heterocycloalkyl wherein the heterocycloalkyl is optionally substituted by Ci-C6 alkyl;

R2k is selected from the group consisting of H and Ci-C6 alkyl;

or Rlk and R2k together form a 3-11 membered heterocycloalkyl optionally substituted by halo; Ci-C6 alkyl optionally substituted by OH; or -NRVRW, wherein Rv and Rw are independently H or Ci-C6 alkyl optionally substituted by halo; and

R3k is a bond, methylene, or -C(=0)-.

12. The compound of claim 1, wherein X A and X B are independently selected from the group consisting of 3-6-membered cycloalkyl, 6-10 membered aryl, 5-6 membered heterocycloalkenyl, and 5-10 membered heteroaryl, wherein each of X and X are independently optionally substituted by Y1.

13. The compound of claim 1, wherein either X A or X B is a 3-11 membered heterocycloalkyl optionally substituted by Y1.

14. The compound of claim 1, wherein Ring Q is (i).

15. The compound of claim 1 or 14, wherein t1 is 0.

16. The compound of claim 1 or 14, wherein t1 is 1.

17. The compound of claim 1, wherein Ring Q is (ii).

18. The compound of claim 1 or 17, wherein t is 0.

19. The compound of claim 1 or 17, wherein t is 1.

20. The compound of any of claims 1-19, wherein R°, R00 and R01 are each H.

21. The compound of any of claims 1-19, wherein R° is NH2.

22. The compound of claim 1, wherein Ring Q is (i), t1 is 0 or 1, and R°, R00 and R01 are each H.

23. The compound of claim 1, wherein Ring Q is (i), t1 is 1, and XA is NRaRb, wherein Ra and Rb are each independently H, Ci-C6 alkyl optionally substituted with 5-6 membered heteroaryl, or 3-6 membered cycloalkyl optionally substituted by OH, halo, CN, or Ci-C<5 alkyl optionally substituted by OH.

24. The compound of claim 1, wherein Ring Q is (i), t1 is 0, and XA is Ci-C6 alkyl or 3-6 membered cycloalkyl, wherein XA is optionally substituted by -NRaRb, wherein Ra and Rb are independently H or Ci-C6 alkyl.

25. The compound of claim 1, selected from Table 1.

26. A pharmaceutical composition comprising a compound of any of claims 1 -25 and a pharmaceutically acceptable carrier, diluent or excipient.

27. Use of a compound of any of claims 1-25 in therapy.

28. Use of a compound of any of claims 1-25 in the treatment of an inflammatory disease.

29. Use of a compound of any of claims 1-25 for the preparation of a medicament for the treatment of an inflammatory disease.

30. A compound of any of claims 1-25 for use in the treatment of an inflammatory disease.

31. The use or compound of any of claims 28-30, wherein the inflammatory disease is asthma.

32. A method of preventing, treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any of claims 1-25.

33. The method of claim 32, wherein the disease or condition is asthma.

34. The method of claim 32, wherein the Janus kinase is JAKl .

35. The invention as in hereinbefore described.