METHODS FOR TREATING HEMATOLOGICAL MALIGNANCIES AND EWING'S SARCOMA

1 .- 149 . (canceled)

150 . A method of treating acute myeloid leukemia or acute lymphoblastic leukemia in a subject, comprising administering a menin inhibitor and a second therapeutic agent to the subject, wherein the second therapeutic agent is a FLT3 inhibitor.

151 . The method of claim 150 , wherein the menin inhibitor is a compound of Formula (I-B-1):

or a pharmaceutically acceptable salt thereof, wherein:

C is selected from C3-12 carbocycle and 3- to 12-membered heterocycle;

L 2 is selected from bond, —C(O)—, —C(O)O—, —C(O)N(R 51 )—, —C(O)N(R 51 )C(O)—,

—C(O)N(R 51 )C(O)N(R 51 )—, —C(NR 51 )—, —C(NR 51 )N(R 51 )—, —S(O) 2 —, —S(O)O—, —S(O)—, —S(O) 2 O—, —S(O) 2 N(R 51 )—, —S(O)N(R 51 )—, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, wherein each alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene is optionally substituted with one or more R 50 ;

L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R 56 and optionally further substituted with one or more R 50 ;

R 1 and R 3 are each independently selected from hydrogen and R 50 ;

R 2 is R 50 ;

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

m and p are each independently an integer from 0 to 6;

n is an integer from 0 to 5;

R 50 is independently selected at each occurrence 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 , and —P(O)(R 52 ) 2 , or two R 50 groups attached to the same carbon are taken together to form ═O, ═S, or ═N(R 52 );

C 1-10 alkyl, C2-1o alkenyl, and C2-1o alkynyl, each of which is optionally substituted at each occurrence with one or more substituents 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 , ═O, ═S, ═N(R 52 ), C3-12 carbocycle, and 3- to 12-membered heterocycle; and

C3-12 carbocycle and 3- to 12-membered heterocycle,

wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R 50 is optionally substituted with one or more substituents 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 , ═O, ═S, ═N(R 52 ), C 1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 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 , and —C(O)NR 53 R 54 ;

C 1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, —NO 2 , —CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 3 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 , ═O, ═S, ═N(R 52 ), C3-12 carbocycle, and 3- to 12-membered heterocycle; and

C3-12 carbocycle and 3- to 12-membered heterocycle,

wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R 51 is optionally substituted with one or more substituents 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 , ═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, C 1-6 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;

R 56 is independently selected at each occurrence from:

—NO 2 , —OR 59 , —SR 52 , —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 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, or two R 56 groups attached to the same carbon are taken together to form ═O, ═S, or ═N(R 52 ),

wherein each C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl in R 56 is optionally substituted at each occurrence with one or more substituents independently selected from halogen, —NO 2 , —CN, —OR 59 , —SR 52 , —N(R 12 ) 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 , ═O, ═S, ═N(R 52 ), C3-12 carbocycle, and 3- to 12-membered heterocycle;

wherein each C 3-12 carbocycle and 3- to 12-membered heterocycle in R 56 is optionally substituted with one or more substituents 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 , ═O, ═S, ═N(R 52 ), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; and

further wherein R 56 optionally forms a bond to ring C; and

R 59 is independently selected at each occurrence from C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 1-6 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;

wherein when R 56 is —CH 3 , L 3 is not further substituted with —OH, —NH 2 , or —CN.

152 . The method of claim 151 , wherein

R 2 is selected from halogen, —OR 52 , N(R 52 ) 2 , —CN, C1-3 alkyl, —CH 2 OR 52 , —CH 2 N(R 52 ) 2 , C1-3 alkyl-N(R 52 ) 2 , C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl; and

R 3 is selected from hydrogen, halogen, —OH, —N(R 52 ) 2 , —CN, —C(O)OR 52 , C1-3 alkyl, and C1-3 haloalkyl.

153 . The method of claim 151 , wherein R 1 is C1-3 haloalkyl.

154 . The method of claim 151 , wherein m is 0 and n is an integer from 1 to 3.

155 . The method of claim 151 , wherein L 2 is C 1-4 alkylene, optionally substituted with one or more R 50 ; and L 3 is C 1-4 alkylene, optionally substituted with one or more R 50 .

156 . The method of claim 151 , wherein the compound of Formula (I-B-1) or a pharmaceutically acceptable salt thereof is a compound of Formula (I-B-6) or Formula (I-B-8):

or a pharmaceutically acceptable salt thereof.

157 . The method of claim 151 , wherein the compound of Formula (I-B-1) is:

or a pharmaceutically acceptable salt thereof.

158 . The method of claim 150 , wherein the subject has a nucleoporin 98 (NUP98) gene fusion, a mutation in the nucleophosmin (NPM1) gene, a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, a mutation in the FMS-like tyrosine kinase-3 (FLT3) gene, a mutation in the isocitrate dehydrogenase 1 (IDH1) gene, a mutation in the isocitrate dehydrogenase 2 (IDH2) gene, or a mixed lineage leukemia (MLL) gene amplification.

159 . The method of claim 150 , wherein the subject has a mixed lineage leukemia (MLL) gene rearrangement or a partial tandem duplication of MLL.

160 . The method of claim 150 , wherein the subject has a mixed lineage leukemia (MLL) gene rearrangement.

161 . The method of claim 150 , wherein the subject has a partial tandem duplication of the mixed lineage leukemia (MLL) gene.

162 . The method of claim 150 , wherein the subject has a mutation in the nucleophosmin (NPM1) gene.

163 . The method of claim 150 , wherein the subject has a nucleoporin 98 (NUP98) gene fusion.

164 . The method of claim 150 , wherein the subject has a mutation in the isocitrate dehydrogenase 1 (IDH1) gene.

165 . The method of claim 150 , wherein the subject has a mutation in the isocitrate dehydrogenase 2 (IDH2) gene.

166 . The method of claim 150 , wherein the subject has a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene.

167 . The method of claim 150 , wherein the subject has a mutation in the FMS-like tyrosine kinase-3 (FLT3) gene.

168 . The method of claim 150 , wherein the FLT3 inhibitor is quizartinib, crenolanib besylate, gilteritinib, lestaurtinib, midostaurin, pexidartinib, ponatinib, SKLB1028, sorafenib, sunitinib, or XL999.

169 . The method of claim 150 , wherein the FLT3 inhibitor is quizartinib, midostaurin, or gilteritinib.