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

optionally substituted heteroaryl:

 wherein

represents the heteroaryl group;

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 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 , (l) —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 , (r) —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 †2 ;

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 heteroaryl:

 wherein

represents the heteroaryl group;

each of R S7.3a and R S7.3b is 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 ;

R S8.3 is selected from (a) halo, (b1) C 1-4 aliphatic, (b2) R^ 4-2 , (c) —OR* 4 , (d) —N(R* 4 ) 2 , (o) —SR″, (f) haloalkyl, (g) 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 S9.3 is selected from (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 , —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 1-2 aliphatic, (b2) R #2-1 , (e) —OR* 2 (d) —N(R* 2 ) 2 and (e) —SR †2 ;

provided that at least 1 of R S7.3a , R S7.3b , R S8.3 , and R S9.3 is —H.

6. The chemical entity of claim 5 , wherein Z is optionally substituted 5- to 10-membered heteroaryl having 1 or 2 ring heteroatoms, each independently selected from O, S and NR* 3 .

7. The chemical entity of claim 5 , wherein Z is optionally substituted thienyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, benzo[b]thiophenyl, benzofuranyl, 1H-indolyl, quinolinyl or isoquinolinyl.

8. The chemical entity of any claim 5 , wherein at least 2 of R S7.3a , R S7.3b , R S8.3 and R S9.3 are —H.

9. The chemical entity of claim 5 , wherein:

R S7.3a is —H; and

R S7.3a is selected from —H, (a) halo, (b1) C 1-4 aliphatic and (f) C 1-3 haloalkyl.

10. The chemical entity of claim 9 , wherein:

R S7.3a is —H;

R S7.3b is —H;

R S8.3 is selected from —H, (a) halo, (b1) C 1-4 aliphatic and (f) C 1-3 haloalkyl; and

R S9.3 is selected from —H, (a) halo, (b1) C 1-4 aliphatic, (f) C 1-3 haloalkyl and (ee) phenyl.

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

I-011

(rac)-((1R,2R,3S,4R)-4-(5-chloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-

ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-012

(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(pyridin-2-yl)pyrazolo[1,5-

a]pyrimidin-7-yl]amino}cyclopentyl]methyl rel-sulfamate,

I-017

(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(quinolin-8-yl)pyrazolo[1,5-

a]pyrimidin-7-yl)amino)cyclopentyl)methyl rel-sulfamate;

I-018

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(isoquinolin-4-yl)pyrazolo[1,5-

a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate;

I-022

(rac)-((1R,2R,3S,4R)-4-(2-(benzo[b]thiophen-3-yl)pyrazolo[1,5-a]pyrimidin-

7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-024

(rac)-((1R,2R,3S,4R)-4-(2-(1H-indol-2-yl)pyrazolo[1,5-a]pyrimidin-7-

ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-025

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(quinolin-3-yl)pyrazolo[1,5-

a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate;

I-027

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(isoquinolin-5-yl)pyrazolo[1,5-

a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate;

I-031

(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(4-phenyl-1,3-thiazol-2-

yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopent]methyl rel-sulfamate;

I-032

(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1H-indol-3-yl)pyrazolo[1,5-

a]pyrimidin-7-yl]amino}cyclopentyl]methyl rel-sulfamate;

I-033

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(5-(trifluoromethyl)quinolin-8-

yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate;

I-034

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(quinolin-6-yl)pyrazolo[1,5-

a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate;

I-038

(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(5-methyl-2-phenyl-1,3-thiazol-4-

yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methyl rel-sulfamate;

I-039

(rac)-((1R,2R,3S,4R)-4-(2-(7-chloroquinolin-4-yl)pyrazolo[1,5-a]pyrimidin-

7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-042

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(quinolin-2-yl)pyrazolo[1,5-

a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate;

I-043

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(quinolin-7-yl)pyrazolo[1,5-

a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate;

I-045

(rac)-((1R,2R,3S,4R)-4-((2-(Benzo[b]thiophen-7-yl)pyrazolo[1,5-

a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-049

(rac)-((1R,2R,3S,4R)-4-(2-(benzofuran-3-yl)pyrazolo[1,5-a]pyrimidin-7-

ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-052

(rac)-((1R,2R,3S,4R)-4-(2-(6-tert-butylpyridin-2-yl)pyrazolo[1,5-a]pyrimidin-

7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-054

(rac)-[(1R,2R,3S,4R)-4-{[2-(5-chloro-1H-indol-3-yl)pyrazolo[1,5-

a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methyl rel-sulfamate;

I-055

(rac)-[(1R,2R,3S,4R)-4-{[2-(6-chloro-1H-indol-3-yl)pyrazolo[1,5-

a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentanethyl rel-sulfamate;

I-059

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-(trifluoromethyl)pyridin-4-

yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate;

I-060

(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(5-(trifluoromethyl)thiophen-2-

yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methyl rel-sulfamate;

I-061

(rac)-((1R,2R,3S,4R)-4-((2-(Benzo[b]thiophen-4-yl)pyrazolo[1,5-

a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-064

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(6-(trifluoromethyl)pyridin-2-

yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate;

I-067

(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(2-phenyl-1,3-oxazol-5-

yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methyl rel-sulfamate;

I-071

(rac)-((1R,2R,3S,4R)-4-(2-(5-chlorobenzo[b]thiophen-3-yl)pyrazolo[1,5-

a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-074

(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1H-indol-5-y)pyrazolo[1,5-

a]pyrimidin-7-yl]amino}cyclopentyl]methyl rel-sulfamate;

I-075

(rac)-((1R,2R,3S,4R)-4-(2-(1H-indol-4-yl)pyrazolo[1,5-a]pyrimidin-7-

ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-081

(rac)-((1R,2R,3S,4R)-4-(2-(5-fluorobenzo[b]thiophen-3-yl)pyrazolo[1,5-

a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-086

(rac)-((1R,2R,3S,4R)-4-(2-(benzofuran-2-yl)pyrazolo[1,5-a]pyrimidin-7-

ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-088

(rac)-((1R,2R,3S,4R)-4-(2-(6-chlorobenzo[b]thiophen-2-yl)pyrazolo[1,5-

a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-091

(rac)-((1R,2R,3S,4R)-4-(2-(6-chlorobenzo[b]thiophen-3-yl)pyrazolo[1,5-

a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-092

(rac)-((1R,2R,3S,4R)-4-(2-(5-chlorobenzofuran-3-y)pyrazolo[1,5-

a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate;

I-094

(rac)-((1R,2R,3S,4R)-4-(2-(5-ethylbenzo[b]thiophen-3-yl)pyrazolo[1,5-

a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate; or

I-095

(rac)-((1R,2R,3S,4R)-4-(2-(5-ethylbenzo[b]thiophen-2-yl)pyrazolo[1,5-

a]pyrimidin-7-ylamino)-2,3-dihydroxycyolopentyl)methyl rel-sulfamate.

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