Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme

Patent metadata

Field	Value
Publication number	US-9290500-B2
Application number	US-201313767314-A
Country	US
Kind code	B2
Filing date	Feb 14, 2013
Priority date	Feb 17, 2012
Publication date	Mar 22, 2016
Grant date	Mar 22, 2016

Abstract

Disclosed are chemical entities that inhibit ubiquitin-activating enzyme (UAE), each of which is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein Y is

and W, Z, X Y , R Y1 , R Y2 and R Y3 are defined herein; pharmaceutical compositions comprising the chemical entities; and methods of using the chemical entities. These chemical entities are useful for treating disorders, particularly cell proliferation disorders, including cancers.

First claim

What is claimed is:

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 aryl:

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 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 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, (ft) -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

wherein
independently

represents C 1-6 alkyl; and
each of m1, m2 and m3 is independently 0 or 1;
each instance of R^ 4-2 is

wherein
independently

represents C 1-4 alkyl; and
each of m1 and m2 is independently 0 or 1;
each instance of R #4-2 is

wherein
independently

represents C 1-4 alkyl; and
each of m1 and m2 is independently 0 or 1; and

each instance of R #2-1 is

wherein
independently

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 phenyl:

each of R S7.1a and R S7.1b 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 ;
R S8.1 is selected from —H, (a) halo, (A) 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 ;
R S9.1 is selected from —H, (a) halo, (b1) C 1-6 aliphatic, (b2) (c) —OR* 6 , (d) —N(R* 6 ) 2 , (e) —SR †6 , 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 A is 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, (131) 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 .

6. The chemical entity of claim 5 , wherein at least 2 of R S7.1a , R S7.1b , R S8.1 and R S9.1 are —H.

7. The chemical entity of claim 5 , wherein:
R S9.1 is 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 , (

Assignees

• Millennium Pharm Inc

Inventors

• Afroze Roushan
• Bharathan Indu T
• Ciavarri Jeffrey P
• Fleming Paul E
• Gaulin Jeffrey L
• Girard Mario
• Langston Steven P
• Soucy Francois
• Wong Tzu-Tshin
• Ye Yingchun

Classifications

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title