Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme

1. A method of treating a disease responsive to UAE inhibition in a subject in need of such treatment comprising, administering to the subject a chemical entity comprising a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

W is —N(R* 3 )—;

Y is

each of R Y1 , R Y2 and R Y3 is independently selected from —H, (a) halo, (b1) C 1-3 aliphatic, (b2) R #2-1 , (c) —OR* 3 , (d) —N(R* 3 ) 2 , (e) —SR †3 , (f) C 1-2 haloalkyl and (g) C 1-2 haloalkoxy;

Z is

(1) optionally substituted aryl:

wherein

represents the aryl group;

(2) optionally substituted fused aryl:

wherein

represents the aryl group,

and

represents the carbocycle or heterocycle;

(3) optionally substituted heteroaryl:

wherein

represents the heteroaryl group;

or

(4)

wherein

X 4 is —O—, —N(R* 3 )—, —S— or —C(O)—; and

each of n1 and n2 is independently 0, 1 or 2,

provided that n1+n2=0, 1 or 2;

each instance of R S1 is independently selected from —H, (a) halo, (c) —OR* 2 , (d) —N(R* 2 ) 2 and (e) —SR †2 ;

each instance of R S2 is independently selected from —H, (a) halo, (c) —OR* 4 , (d) —N(R* 4 ) 2 , (e) —SR †4 , (h) —NO 2 , (i) —CN, (j) —C(O)R †4 , (k) —C(O)—OR* 4 , (l) —C(O)—N(R* 4 ) 2 , (m) —O—C(O)—R †4 , (n) —N(R* 4 )—C(O)—R †4 , (o) —O—C(O)—OR* 4 , (p) —O—C(O)—N(R* 4 ) 2 , (q) —N(R* 4 )—C(O)—OR* 4 and (r) —N(R* 4 )—C(O)—N(R* 4 ) 2 ;

each instance of R S4 is independently selected from —H, (a) halo, (b1) C 1-4 aliphatic, (b2) R #4-2 , (c) —OR* 4 , (d) —N(R* 4 ) 2 and (e) —SR †4 ;

each instance of R S5 is independently selected from —H, (a) halo, (b1) C 1-4 aliphatic, (b2) R ^4-2 , (c) —OR* 4 , (d) —N(R* 4 ) 2 , (e) —SR †4 , (f) C 1-3 haloalkyl, (h) —NO 2 , (i) —CN, (j) —C(O)—R †4 , (k) —C(O)—OR* 4 , (l) —C(O)—N(R* 4 ) 2 , (m) —O—C(O)—R †4 , (n) —N(R* 4 )—C(O)—R †4 , (o) —O—C(O)—OR* 4 , (p) —O—C(O)—N(R* 4 ) 2 , (q) —N(R* 4 )—C(O)—OR* 4 and (r) —N(R* 4 )—C(O)—N(R* 4 ) 2 ;

each instance of R S7 is independently selected from —H, (a) halo, (b1) C 1-4 aliphatic, (b2) R #4-2 , (c) —OR* 4 , (d) —N(R* 4 ) 2 and (e) —SR †4 ;

each instance of R S8 is independently selected from —H, (a)halo, (b1) C 1-4 aliphatic, (b2) R ^4-2 , (c) —OR* 4 , (d) —N(R* 4 ) 2 , (e) —SR †4 , (f) C 1-3 haloalkyl, (g1) C 1-3 haloalkoxy, (g2) C 1-3 haloalkylthio, (h) —NO 2 , (i) —CN, (j) —C(O)—OR †4 , (k) —C(O)—OR* 4 , (l) —C(O)—N(R* 4 ) 2 , (m) —O—C(O)—R †4 , (n) —N(R* 4 )—C(O)—R †4 , (o) —O—C(O)—OR* 4 , (p) —O—C(O)—N(R* 4 ) 2 , (q) —N(R* 4 )—C(O)—OR* 4 and (r) —N(R* 4 )—C(O)—N(R* 4 ) 2 ;

each instance of R S9 is independently selected from —H, (a) halo, (b1) C 1-6 aliphatic, (b2) R ^6-3 , (c) —OR* 6 , (d) —N(R* 6 ) 2 , (e) —SR †6 , (f) C 1-3 haloalkyl, (i) C 1-3 haloalkoxy, (g2) C 1-3 haloalkylthio, (h) —NO 2 , (i) —CN, (i) —C(O)—R †6 , (k) —C(O)—OR* 6 , (I) —C(O)—N(R* 6 ) 2 , (m) —O—C(O)—R †6 , (n) —N(R* 6 )—C(O)—R †6 , (o) —O—C(O)—OR* 6 , (p) —O—C(O)—N(R* 6 ) 2 , (q) —N(R* 6 )—C(O)—OR* 6 , (r) —N(R* 6 )—C(O)—N(R* 6 ) 2 , (s) —Si(R †2 ) 3 , (aa) C 3-8 carbocyclyl, (bb) -A-(C 3-8 carbocyclyl), (cc) 5- to 10-membered heterocyclyl, (dd) -A-(5- to 10-membered heterocyclyl), (ee) C 6-10 aryl, (ff) -A-(C 6-10 aryl), (gg) 5- to 10-membered heteroaryl and (hh) -A-(5- to 10-membered heteroaryl);

wherein each instance of A is independently selected from C 1-3 alkylene, C 0-3,0-3 heteroalkylene, —O—, —S—, —N(R* 1 )— and —C(O)—;

and wherein each of (aa)-(dd) is optionally substituted with 1-3 groups independently selected from (a) halo, (b1) C 1-2 aliphatic, (b2) R #2-1 , (c) —OR* 2 , (d) —N(R* 2 ) 2 and (e) —SR †2 ;

and wherein each of (ee)-(hh) is optionally substituted with 1-3 groups independently selected from (a) halo, (b1) C 1-4 aliphatic, (b2) R #4-2 , (c) —OR* 4 , (d) —N(R* 4 ) 2 and (e) —SR †4 ;

each instance of R *6 is independently —H or C 1-6 alkyl;

each instance of R *4 is independently —H or C 1-4 alkyl;

each instance of R *3 is independently —H or C 1-3 alkyl;

each instance of R *2 is independently —H or C 1-2 alkyl;

each instance of R *1 is independently —H or methyl;

each instance of R †6 is independently C 1-6 alkyl;

each instance of R †4 is independently C 1-4 alkyl;

each instance of R †3 is independently C 1-3 alkyl;

each instance of R †2 is independently C 1-2 alkyl;

each instance of R ^6-3 is independently

wherein

represents C 1-6 alkyl; and

each of m1, m2 and m3 is independently 0 or 1;

each instance of R ^4-2 is independently

wherein

represents C 1-4 alkyl; and

each of m1 and m2 is independently 0 or 1;

each instance of R #4-2 is independently

wherein

represents C 1-4 alkyl; and

each of m1 and m2 is independently 0 or 1; and

each instance of R #2-1 is independently

wherein

represents C 1-2 alkyl; and

m1 is 0 or 1.

2. A method of treating cancer in a subject in need of such treatment comprising, administering to the subject a therapeutically effective amount of a chemical entity comprising a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

W is —N(R* 3 )—;

Y is

each of R Y1 , R Y2 and R Y3 is independently selected from —H, (a) halo, (b1) C 1-3 aliphatic, (b2) R #2-1 , (c) —OR* 3 , (d) —N(R* 3 ) 2 , (e) —SR †3 , (f) C 1-2 haloalkyl and (g) C 1-2 haloalkoxy;

Z is

(1) optionally substituted aryl:

wherein

represents the aryl group;

(2) optionally substituted fused aryl:

wherein

represents the aryl group,

and

represents the carbocycle or heterocycle;

(3) optionally substituted heteroaryl:

wherein

represents the heteroaryl group;

or

(4)

wherein

X 4 is —O—, —N(R* 3 )—, —S— or —C(O)—; and

each of n1 and n2 is independently 0, 1 or 2,

provided that n1+n2=0, 1 or 2;

each instance of R S1 is independently selected from —H, (a) halo, (c) —OR* 2 , (d) —N(R* 2 ) 2 and (e) —SR †2 ;

each instance of R S2 is independently selected from —H, (a) halo, (c) —OR* 4 , (d) —N(R* 4 ) 2 , (e) —SR †4 , (h) —NO 2 , (i) —CN, (i) —C(O)—R †4 , (k) —C(O)—OR* 4 , (I) —C(O)—N(R* 4 ) 2 , (m) —O—C(O)—R †4 , (n) —N(R* 4 )—C(O)—R †4 , (o) —O—C(O)—OR* 4 , (p) —O—C(O)—N(R* 4 ) 2 , (q) —N(R* 4 )—C(O)—OR* 4 and (r) —N(R* 4 )—C(O)—N(R* 4 ) 2 ;

each instance of R S4 is independently selected from —H, (a) halo, (b1) C 1-4 aliphatic, (b2) R #4-2 (c) —OR* 4 , (d) —N(R* 4 ) 2 and (e) —SR †4 ;

each instance of R S5 is independently selected from —H, (a) halo, (b1) C 1-4 aliphatic, (b2) R ^4-2 , (c) —OR* 4 , (d) —N(R* 4 ) 2 , (e) —SR †4 , (f) C 1-3 haloalkyl, (h) —NO 2 , (i) —CN, (j) —C(O)—R †4 , (k) —C(O)—OR* 4 , (l) —C(O)—N(R* 4 ) 2 , (m) —O—C(O)—R †4 , (n) —N(R* 4 )—C(O)—R †4 , (o) —O—C(O)—OR* 4 , (p) —O—C(O)—N(R* 4 ) 2 , (q) —N(R* 4 )—C(O)—OR* 4 and (r) —N(R* 4 )—C(O)—N(R* 4 ) 2 ;

each instance of R S7 is independently selected from —H, (a) halo, (b1) C 1-4 aliphatic, (b2) R #4-2 , (c) —OR* 4 , (d) —N(R* 4 ) 2 and (e) —SR †4 ;

each instance of R S8 is independently selected from —H, (a) halo, (b1) C 4 aliphatic, (b2) R ^4-2 (c) —OR* 4 , (d) —N(R* 4 ) 2 , (e) —SR †4 , (f) C 1-3 haloalkyl, (g1) C 1-3 haloalkoxy, (g2) C 1-3 haloalkylthio, (h) —NO 2 , (i) —CN, (i) —C(O)—R †4 , (k) —C(O)—OR* 4 , (l) —C(O)—N(R* 4 ) 2 , (m) —O—C(O)—R †4 , (n) —N(R* 4 )—C(O)—R †4 , (o) —O—C(O)—OR* 4 , (p) —O—C(O)—N(R* 4 ) 2 , (q) —N(R* 4 )—C(O)—OR* 4 and (r) —N(R* 4 )—C(O)—N(R* 4 ) 2 ;

each instance of R S9 is independently selected from —H, (a) halo, (b1) C 1-6 aliphatic, (b2) R ^6-3 , (c) —OR* 6 , (d) —N(R* 6 ), (e) —SR †6 , (f) C 1-3 haloalkyl, (g1) C 1-3 haloalkoxy, (g2) C 1-3 haloalkylthio, (h) —NO 2 , (i) —CN, (j) —C(O)—R †6 , (k) —C(O)—OR* 6 , (l) —C(O)—N(R*) 2 , (m) —O—C(O)—R †6 , (n) —N(R* 6 )—C(O)—R †6 , (o) —O—C(O)—OR* 6 , (p) —O—C(O)—N(R* 6 ) 2 , (q) —N(R* 6 )—C(O)—OR* 6 , (r) —N(R* 6 )—C(O)—N(R* 6 ) 2 , (s) —Si(R †2 ) 3 , (aa) C 3-8 carbocyclyl, (bb) -A-(C 3-8 carbocyclyl), (cc) 5- to 10-membered heterocyclyl, (dd) -A-(5- to 10-membered heterocyclyl), (ee) C 6-10 aryl, (ff) -A-(C 6-10 aryl), (gg) 5- to 10-membered heteroaryl and (hh) -A-(5- to 10-membered heteroaryl);

wherein each instance of A is independently selected from C 1-3 alkylene, C 0-3,0-3 heteroalkylene, —O—, —S—, —N(R* 1 )— and —C(O)—;

and wherein each of (aa)-(dd) is optionally substituted with 1-3 groups independently selected from (a) halo, (b1) C 1-2 aliphatic, (b2) R #2-1 , (c) —OR* 2 , (d) —N(R* 2 ) 2 and (e) —SR †2 ;

and wherein each of (ee)-(hh) is optionally substituted with 1-3 groups independently selected from (a) halo, (b1) C 1-4 aliphatic, (b2) R #4-2 , (c) —OR* 4 , (d) —N(R* 4 ) 2 and (e) —SR †4 ;

each instance of R *6 is independently —H or C 1-6 alkyl;

each instance of R *4 is independently —H or C 1-4 alkyl;

each instance of R 3 is independently —H or C 1-3 alkyl;

each instance of R *2 is independently —H or C 1-2 alkyl;

each instance of R *1 is independently —H or methyl;

each instance of R †6 is independently C 1-6 alkyl:

each instance of R †4 is independently C 1-4 alkyl;

each instance of R †3 is independently C 1-3 alkyl;

each instance of R †2 is independently C 2 alkyl;

each instance of R ^6-3 is independently

wherein

represents C 1-6 alkyl; and

each of m1, m2 and m3 is independently 0 or 1;

each instance of R ^4-2 is independently

wherein

represents C 1-4 alkyl; and

each of m1 and m2 is independently 0 or 1;

each instance of R #4-2 is independently

wherein

represents C 1-4 alkyl; and

each of m1 and m2 is independently 0 or 1; and

each instance of R #2-1 is independently

wherein

represents C 1-2 alkyl; and

m1 is 0 or 1.

3. The method of claim 2 wherein the cancer is lung cancer, ovarian cancer, colon cancer, breast cancer or lymphoma.

4. The method of claim 1 , wherein the compound of Formula I is crystalline Form 1 anhydrous (s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate.

5. The method of claim 1 , wherein the compound of Formula I is crystalline Form 2 monohydrated (s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate.

6. The method of claim 2 , wherein the compound of Formula I is crystalline Form 1 anhydrous (s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate.

7. The method of claim 2 , wherein the compound of Formula I is crystalline Form 2 monohydrated (s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate.