IP Library › Patent Application 19029076

Patent Application

App. No. 19/029,076

SUBSTITUTED INHIBITORS OF MENIN-MLL AND METHODS OF USE

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Patent No.: US None
App. No.: 19/029,076

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Abstract

The present disclosure provides methods of inhibiting the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins. The methods are useful for the treatment of leukemia, solid cancers, diabetes and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, and/or menin. Compositions for use in these methods are also provided.

Claims (53)

1 .- 126 . (canceled)

127 . A compound of Formula (I-I):

or a pharmaceutically acceptable salt thereof, wherein:

A is selected from

each of Z 1 , Z 2 , Z 3 , and Z 4 is independently selected from —C(R A1 )(R A2 )—, —C(R A1 )(R A2 )—C(R A1 )(R A2 )—, —C(O)—, and —C(R A1 )(R A2 )—C(O)—, wherein no more than one of Z 1 , Z 2 , Z 3 , and Z 4 is —C(O)— or —C(R A1 )(R A2 )—C(O)—;

Z 5 and Z 6 are each independently selected from —C(H)— and —N—;

B is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle;

C is selected from bond, C 3-12 carbocycle, and 3- to 12-membered heterocycle;

each of L 1 , L 2 , L 3 and L 4 is independently selected from bond, —O—, —S—, —N(R 51 )—, —N(R 51 )CH 2 —, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R 51 )—, —C(O)N(R 51 )C(O)—, —C(O)N(R 51 )C(O)N(R 51 )—, —N(R 51 )C(O)—, —N(R 51 )C(O)N(R 51 )—, —N(R 51 )C(O)O—, —OC(O)N(R 51 )—, —C(NR 51 )—, —N(R 51 )C(NR 51 )—, —C(NR 51 )N(R 51 )—, —N(R 51 )C(NR 51 )N(R 51 )—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R 51 )S(O) 2 —, —S(O) 2 N(R 51 )—, —N(R 51 )S(O)—, —S(O)N(R 51 )—, —N(R 51 )S(O) 2 N(R 51 )—, and —N(R 51 )S(O)N(R 51 )—or from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R 50 , wherein two R 50 groups attached to the same atom or different atoms of any one of L 1 , L 2 , or L 3 can together optionally form a bridge or ring;

R 50 is, at each occurrence, independently selected from:

halogen, —NO 2 , —CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, ═N(R 52 );

C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO 2 , —CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, ═N(R 52 ), C 3-12 carbocycle, and 3- to 12-membered heterocycle; and

C 3-12 carbocycle and 3- to 12-membered heterocycle,

wherein each C 3-12 carbocycle and 3- to 12-membered heterocycle in R 50 is independently optionally substituted with one or more substituents selected from halogen, —NO 2 , —CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, ═N(R 52 ), C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 51 is independently selected at each occurrence from:

hydrogen, —C(O)R 52 , —C(O)OR 52 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 ;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO 2 , —CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, ═N(R 52 ), C 3-12 carbocycle and 3- to 12-membered heterocycle; and

C 3-12 carbocycle and 3- to 12-membered heterocycle,

wherein each C 3-12 carbocycle and 3- to 12-membered heterocycle in R 51 is independently optionally substituted with one or more substituents selected from halogen, —NO 2 , —CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)N 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, ═N(R 52 ), C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 52 is independently selected at each occurrence from hydrogen; and C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO 2 , —NH 2 , —NHCH 3 , —NHCH 2 CH 3 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , C 3-12 carbocycle, or 3- to 6-membered heterocycle;

R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;

R 57 is selected from:

hydrogen, halogen, —NO 2 , —CN, —SR 52 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 58 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)NH(C 1-6 alkyl), —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═S, ═N(R 52 ); and

C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, each of which is independently substituted at each occurrence with one or more substituents selected from —NO 2 , —CN, —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═S, and ═N(R 52 ); and

R 58 is selected from hydrogen; and C 1-20 alkyl, C 3-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO 2 , —NH 2 , —NHCH 3 , —NHCH 2 CH 3 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , C 3-12 carbocycle, or 3- to 6-membered heterocycle;

R A1 is, at each occurrence, independently selected from hydrogen and R 50 ;

R A2 is, at each occurrence, independently selected from hydrogen and R 50 ;

R B is, at each occurrence, independently selected from R 50 , or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring;

R H2 is independently selected at each occurrence from R 50 .

R C is, at each occurrence, independently selected from hydrogen or R 50 , or two R C groups attached to the same atom or different atoms can together optionally form a bridge or ring;

r is an integer from 1 to 6; and

each of p and q is independently an integer from 0 to 12.

128 . The compound of claim 127 , wherein L 4 is selected from —O— and —NH—.

129 . The compound of claim 127 , wherein R H2 is selected from halo, —C(O)R 52 , and —C(O)N(R 52 ) 2 .

130 . The compound of claim 127 , wherein C is C 3-12 carbocycle or 3- to 12-membered heterocycle.

131 . The compound of claim 127 , wherein L 3 is C 1-6 alkylene, optionally substituted with one or more R 50 .

132 . The compound of claim 131 , wherein L 3 is selected from

wherein any one of which is optionally substituted with one or more R 50 .

133 . The compound of claim 127 , wherein B—(R B ) p is

134 . The compound of claim 127 , wherein:

A is

135 . The compound of claim 127 , wherein:

A is

136 . The compound of claim 127 , wherein Z 5 and Z 6 are each N.

137 . The compound of claim 127 , wherein R A1 is, at each occurrence, independently selected from hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, —CN, —NO 2 , and —OH.

138 . The compound of claim 127 , wherein R A2 is, at each occurrence, independently selected from hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, —CN, —NO 2 , and —OH.

139 . The compound of claim 127 , wherein A is selected from:

140 . The compound of claim 127 , wherein L 1 is a bond or —N(R 51 )—.

141 . The compound of claim 127 , wherein L 2 is C 1-4 alkylene, optionally substituted with one or more R 50 .

142 . A compound selected from:

and pharmaceutically acceptable salts thereof.

143 . A pharmaceutical composition comprising a compound of claim 127 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

144 . A method of treating a hematological cancer in a subject exhibiting a mutation in the nucleophosmin (NPM1) gene, DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, FMS-like tyrosine kinase-3 (FLT3) gene, isocitrate dehydrogenase 1 (IDH1) gene, or isocitrate dehydrogenase 2 (IDH2) gene, or combination thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 127 , or a pharmaceutically acceptable salt thereof.