Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme

1. 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 fused aryl:

wherein

represents the aryl group, and

represents the carbocycle or heterocycle;

or

(2)

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)— \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)—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 ) 2 , (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* 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. The chemical entity of claim 1 , wherein W is —NH—.

3. The chemical entity of claim 1 , wherein each of R Y1 , R Y2 and R Y3 is independently selected from —H, (a) halo and (b1) C 1-3 alkyl.

4. The chemical entity of claim 3 , wherein each of R Y1 , R Y2 , and R Y3 is —H.

5. The chemical entity of claim 1 , wherein Z is optionally substituted fused aryl:

wherein

represents the aryl group, and

represents the carbocycle or heterocycle;

R S4.2 is 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 ;

R S5.2 is 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 ;

R S8.2 is 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, (g) C 1-3 haloalkoxy, (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 ;

R S9.2 is 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, (g) C 1-3 haloalkoxy, (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 , (aa) C 3-6 carbocyclyl, (cc) 5- to 6-membered heterocyclyl, (ee) C 6 aryl and (gg) 5- to 6-membered heteroaryl;

wherein each of (aa) and (cc) is optionally substituted with 1-2 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) and (gg) 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 .

6. The chemical entity of claim 5 wherein:

the aryl group is a C 6 aryl group;

the carbocycle is a C 5-6 carbocycle; and

the heterocycle is a 5- to 6-membered heterocycle having one ring heteroatom selected from —O—, —N(R* 1 )— and —S—.

7. The chemical entity of claim 5 , wherein Z is optionally substituted indanyl, 2 ,3-dihydrobenzofuranyl or 1,3-dihydroisobenzofuranyl.

8. The chemical entity of claim 5 , wherein:

R S4.2 is selected from —H, (a) —F, Cl, (b1) C 1-2 aliphatic, (b2) R ^2-1 , (c) —OR* 2 , (d) —N(R* 2 ) 2 and (e) —SR †2 ;

R S5.2 is selected from —H, (a) halo, (b1) C 1-2 aliphatic, (b2) R ^2-1 , (c) —OR* 2 , (d) —N(R* 2 ) 2 , (e) —SR †2 and (f) —CF 3 ;

R S8.2 is —H; and

R S9.2 is selected from —H, (a) —F, Cl, (b1) C 1-2 aliphatic, (b2) R ^2-1 , (c) —OR* 2 , (d) —N(R *2 ) 2 , (e) —SR †2 , (f) —CF 3 and (g) —OCF 3 .

9. The chemical entity of claim 5 , wherein the compound is

I-023 (rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3- dihydroxycyclopentyl)methyl rel-sulfamate;

I-026 (rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3- dihydroxycyclopentyl)methyl rel-sulfamate;

I-041 (rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate; or

I-053 (rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-1,3-dihydroisobenzofuran-5-yl)pyrazolo[1,5-a]-pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate.

10. The chemical entity of claim 1 , wherein Z is

wherein

X 4 is —O—, —N(R* 2 )—, —S— or —C(O)—;

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

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

each instance of R S7.4 is 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 .

11. The chemical entity of claim 10 , wherein

each instance of R S7.4 is independently selected from (a) —F, —Cl, —Br, (b1) C 1-2 aliphatic, (b2) R #2-1 , (c) —OR* 2 and (d) —N(R* 2 ) 2 ,

wherein each instance of R #2-1 is independently C 1-2 alkyl unsubstituted or substituted with 1 substituent selected from (a) —F, —Cl, (c) —OR* 2 and (d) —N(R* 2 ) 2 .

12. The chemical entity of claim 10 , wherein n1+n2=0 or 1.

13. The chemical entity of claim 10 , wherein the compound is

I-010 (rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-019 (rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-037 (rac)-[(1R,2R,3S,4R)-4-{[2-(9H-carbazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methyl rel-sulfamate;

I-056 (rac)-((1R,2R,35,4R)-4-((2-(Dibenzo[b,d]thiophen-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-062 (rac)-[(1R,2R,3S,4R)-4-{[2-(9H-carbazol-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methyl rel-sulfamate;

I-085 (rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(9-oxo-9H-fluoren-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate;

I-093 (rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate; or

I-103 (rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate.

14. A chemical entity comprising the compound ((3aR,4R,6R,6aS)-2,2-dimethyl-6-((2-(3-((trifluoromethyl)thio)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol or a salt thereof.

15. A pharmaceutical composition comprising, the chemical entity of claim 1 , and a pharmaceutically acceptable carrier.