SUBSTITUTED MENIN-MLL INHIBITOR COMPOUND AND PHARMACEUTICAL COMPOSITION COMPRISING IT

Abstract

This document provides methods for inhibiting the interaction between menin and MLL and MLL fusion oncoproteins. The methods are useful for the treatment of leukemia, solid tumors, diabetes, and other diseases dependent on the activity of MLL1, MLL2, MLL fusion proteins, and / or menin. Compositions for use in the aforementioned methods are also provided. Claim 1: A compound characterized in that it has formula (1), or a pharmaceutically acceptable salt, isotopic form, or prodrug thereof, wherein: H is selected from a C₅₋₁₂ carbocycle and a 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R⁵⁰; A is selected from a linkage, a C₅₋₁₂ carbocycle, and a 3- to 12-membered heterocycle; B is selected from C₅₋₁₂ carbocycle and 3- to 12-membered heterocycle; C is a 3- to 12-membered heterocycle;L¹, L² and L³ are selected independently of each other between a bond, -O-, -S-, -N(R⁵¹)-, -N(R⁵¹)CH₂-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R⁵¹)-, -C(O)N(R⁵¹)C(O)-, C(O)N(R⁵¹)C(O)N(R⁵¹)-, -N(R⁵¹)C(O)-, -N(R⁵¹)C(O)N(R⁵¹)-, -N(R⁵¹)C(O)O-, -OC(O)N(R⁵¹)-, -C(NR⁵¹)-, -N(R⁵¹)C(NR⁵¹)-, -C(NR⁵¹)N(R⁵¹)-, -N(R⁵¹)C(NR⁵¹)N(R⁵¹)-, -S(O)₂-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)₂-, -S(O)₂O-, -N(R⁵¹)S(O)₂-, -S(O)₂N(R⁵¹)-, -N(R⁵¹)S(O)-, -S(O)N(R⁵¹)-, -N(R⁵¹)S(O)₂N(R⁵¹)-, -N(R⁵¹)S(O)N(R⁵¹)-; alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R⁵⁰, wherein two R⁵⁰ groups attached to the same atom or to different atoms of any of L¹, L² or L³ may together optionally form a bridge or a ring;RA, RB and RC are selected independently of each other in each case from R⁵⁰, or two RA groups, two RB groups or two RC groups attached to the same or different atoms can optionally form together a bridge or a ring; m, nyp are independently of each other an integer between 0 and 6; R⁵⁰ is selected independently in each case from: halogen, -NO₂, -CN, -OR⁵², -SR⁵², -N(R⁵²)₂, -NR⁵³R⁵⁴, -S(=O)R⁵², -S(=O)₂R⁵², -S(=O)₂N(R⁵²)₂, -S(=O)₂NR⁵³R⁵⁴, -NR⁵²S(=O)₂R⁵², -NR⁵²S(=O)₂N(R⁵²)₂, -NR⁵²S(=O)₂NR⁵³R⁵⁴, -C(O)R⁵², -C(O)OR⁵², -OC(O)R⁵², -OC(O)OR⁵², -OC(O)N(R⁵²)₂, -OC(O)NR⁵³R⁵⁴, -NR⁵²C(O)R⁵², -NR⁵²C(O)OR⁵², -NR⁵²C(O)N(R⁵²)₂, -NR⁵²C(O)NR⁵³R⁵⁴, -C(O)N(R⁵²)₂, -C(O)NR⁵³R⁵⁴, -P(O)(OR⁵²)₂-, -P(O)(R⁵²)₂, =O, =S =N(R⁵²);C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is optionally independently substituted in each case with one or more substituents selected from halogen, -NO₂, -CN, -OR⁵₲, -SR⁵₲, -N(R⁵₲)₂, -NR⁵⁳R⁵⁴, -S(=O)R⁵₲, -S(=O)₂R⁵₲, -S(=O)₂N(R⁵₲)₂, -S(=O)₂NR⁵⁳R⁵⁴, -NR⁵₲S(=O)₂R⁵₲, -NR⁵²S(=O)₂N(R⁵²)₂, -NR⁵²S(=O)₂NR⁵³R⁵⁴, -C(O)R⁵², -C(O)OR⁵², -OC(O)R⁵², -OC(O)OR⁵², -OC(O)N(R⁵²)₂, -OC(O)NR⁵³R⁵⁴, -NR⁵²C(O)R⁵², -NR⁵²C(O)OR⁵², -NR⁵²C(O)N(R⁵²)₂, -NR⁵²C(O)NR⁵³R⁵⁴, -C(O)N(R⁵²)₂, -C(O)NR⁵³R⁵⁴, -P(O)(OR⁵²)₂, -P(O)(R⁵²)₂, =O, =S, =N(R⁵²), C₅₋₁₂ carbocycle, and 3- to 12-membered heterocycle;and C₅₋₁₂ carbocycle and 3- to 12-membered heterocycle, wherein each C₅₋₁₂ carbocycle and 3- to 12-membered heterocycle at R⁵⁰ is optionally independently substituted with one or more substituents selected from halogen, -NO₂, -CN, -OR⁵₲, -SR⁵₲, -N(R⁵₲)₂, -NR⁵⁳R⁵⁴, -S(=O)R⁵₲, -S(=O)₂R⁵₲, -S(=O)₂N(R⁵₲)₂, -S(=O)₂NR⁵⁳R⁵⁴, -NR⁵₲S(=O)₂R⁵₲, -NR⁵²S(=O)₂N(R⁵²)₂, -NR⁵²S(=O)₂NR⁵³R⁵⁴, -C(O)R⁵², -C(O)OR⁵², -OC(O)R⁵², -OC(O)OR⁵², -OC(O)N(R⁵²)₂, -OC(O)NR⁵³R⁵⁴, -NR⁵²C(O)R⁵², -NR⁵²C(O)OR⁵², -NR⁵²C(O)N(R⁵²)₂, -NR⁵²C(O)NR⁵³R⁵⁴, -C(O)N(R⁵²)₂, -C(O)NR⁵³R⁵⁴, -P(O)(OR⁵²)₂, -P(O)(R⁵²)₂, =O, =S, =N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R⁵¹ is selected independently in each case from: hydrogen, -C(O)R⁵², -C(O)OR⁵², -C(O)N(R⁵²)₂, -C(O)NR⁵³R⁵⁴;C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is optionally independently substituted in each case with one or more substituents selected from halogen, -NO₂, -CN, -OR⁵², -SR⁵², -N(R⁵²)₂, -NR⁵³R⁵⁴, -S(=O)R⁵², -S(=O)₂R⁵², -S(=O)₂N(R⁵²)₂, -S(=O)₂NR⁵³R⁵⁴, -NR⁵²S(=O)₂R⁵², -NR⁵²S(=O)₂N(R⁵²)₂, -NR⁵²S(=O)₂NR⁵³R⁵⁴, -C(O)R⁵², -C(O)OR⁵², -OC(O)R⁵², -OC(O)OR⁵², -OC(O)N(R⁵²)₂, -OC(O)NR⁵³R⁵⁴, -NR⁵²C(O)R⁵², -NR⁵²C(O)OR⁵², -NR⁵²C(O)N(R⁵²)₂, -NR⁵²C(O)NR⁵³R⁵⁴, -C(O)N(R⁵²)₂, -C(O)NR⁵³R⁵⁴, -P(O)(OR⁵²)₂, -P(O)(R⁵²)₂, =O, =S, =N(R⁵²), C₅₋₁₂ carbocycle and 3- to 12-membered heterocycle;and C₅₋₁₂ carbocycle and 3- to 12-membered heterocycle, wherein each C₅₋₁₂ carbocycle and 3- to 12-membered heterocycle at R⁵¹ is optionally independently substituted with one or more substituents selected from halogen, -NO₂, -CN. -OR⁵², -SR⁵², -N(R⁵²)₂, -NR⁵³R⁵⁴, -S(=O)R⁵², -S(=O)₂R⁵², -S(=O)₂N(R⁵²)₂, -S(=O)₂NR⁵³R⁵⁴, -NR⁵²S(=O)₂R⁵², -NR⁵²S(=O)₂N(R⁵²)₂, -NR⁵²S(=O)₂NR⁵³R⁵⁴, -C(O)R⁵², -C(O)OR⁵², -OC(O)R⁵², -OC(O)OR⁵², -OC(O)N(R⁵²)₂, -OC(O)NR⁵³R⁵⁴, -NR⁵²C(O)R⁵², -NR⁵²C(O)OR⁵², -NR⁵²C(O)N(R⁵²)₂, -NR⁵²C(O)NR⁵³R⁵⁴, -C(O)N(R⁵²)₂, -C(O)NR⁵³R⁵⁴, -P(O)(OR⁵²)₂, -P(O)(R⁵²)₂, =O, =S, =N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R⁵² is selected independently in each case from hydrogen;and C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₅₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with halogen, -CN, -NO₂, -NH₂, -NHCH₃, -NHCH₂CH₃, =O, -OH, -OCH₃, -OCH₂CH₃, C₅₋₁₂ carbocycle, or 3- to 6-membered heterocycle; R⁵⁳ and R⁵⁴ are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R⁵⁰; R⁵⁷ is selected from: halogen, -NO₂, -CN, -SR⁵², -NR⁵³R⁵⁴, -S(=O)R⁵², -S(=O)OR⁵⁸, -S(=O)₂N(R⁵²)₂, -S(=O)₂NR⁵³R⁵⁴, -NR⁵²S(=O)₂R⁵², -NR⁵²S(=O)₂N(R⁵²)₂, -NR⁵²S(=O)₂NR⁵³R⁵⁴, -C(O)OR⁵², -OC(O)R⁵², -OC(O)OR⁵², -OC(O)N(R⁵²)₂, -OC(O)NR⁵³R⁵⁴, -NR⁵²C(O)OR⁵², -NR⁵²C(O)N(R⁵²)₂, -NR⁵²C(O)NR⁵³R⁵⁴, -C(O)NH(C₁₋₆ alkyl), -C(O)NR⁵³R⁵⁴, -P(O)(OR⁵²)₂, -P(O)(R⁵²)₂, =S, =N(R⁵²);and C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is independently substituted in each case with one or more substituents selected from -NO₂, -CN, -SR⁵₲, -N(R⁵₲)₂, -NR⁵⁳R⁵⁴, -S(=O)R⁵₲, -S(=O)₂R⁵₲, -S(=O)₂N(R⁵₲)₂, -S(=O)₂NR⁵⁳R⁵⁴, -NR⁵⁲S(=O)₂R⁵₲, -NR⁵⁲S(=O)₂N(R⁵₲)₂, -NR⁵²S(=O)₂NR⁵³R⁵⁴, -C(O)R⁵², -C(O)OR⁵², -OC(O)R⁵², -OC(O)OR⁵², -OC(O)N(R⁵²)₂, -OC(O)NR⁵³R⁵⁴, -NR⁵²C(O)R⁵², -NR⁵²C(O)OR⁵², -NR⁵²C(O)N(R⁵²)₂, -NR⁵²C(O)NR⁵³R⁵⁴, -P(O)(OR⁵²)₂, -P(O)(R⁵²)₂, =S, and =N(R⁵²); and R⁵⁸ is selected from hydrogen;and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₅₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with halogen, -CN, -NO₂, -NH₂, -NHCH₃, -NHCH₂CH₃, =O, -OH, -OCH₃, -OCH₂CH₃, C₅₋₁₂ carbocycle, or 3- to 6-membered heterocycle, wherein for a compound or salt of formula (1), when C is azetidinylene, piperidinylene, or piperazinylene and R⁵⁷ is -S(=O)₂R⁵⁸, -S(=O)₂N(R⁵²)₂, or -NR⁵²S(=O)₂R⁵²: p is an integer between 1 and 6; and / or L³ is replaced by one or more R⁵⁰, where L³ is not -CH₂CH(OH)-.;

Claims

CLAIM.

1. A compound of Formula (II-A): FOLLOWS FORMULA 1, (II-A), or a pharmaceutically acceptable salt thereof, characterized in that: C is selected from piperidinyl and piperazinyl; L2 is -CH2-; L3 is -CH2CH(R56)-, and R56 is methyl; R1 is C1-3 haloalkyl; R2 is selected from halogen, -OR52, -N(R52)2, -CN, C1-3 alkyl, C1-3 alkyl-OR52, C1-3 alkyl-N(R52)2, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl; R 3 is selected from hydrogen, halogen, -OH, -N(R 52 )2, -CN, -C(O)OR 52 , C1-3 alkyl and C1-3 haloalkyl; RA and RB are each independently selected in each case from halogen, -CN, -OR 52 , -N(R 52 )2, -NR 53 R 54 , -C(O)R 52 , -C(O)OR 52 , -OC(O)R 52 , -NR 52 C(O)R 52 , -C(O)N(R 52 )2, -C(O)NR 53 R 54 , =O, C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl;RC is selected from -C(O)R 52 , -S(=O)R 52 , -S(=O)2R 52 , -S(=O)2N(R 52 )2, -S(=O)2NR 53 R 54 , -NR 52 S(=O)2R 52 , =O, C1-3 alkyl and C1-3 haloalkyl, or two RC groups attached to different atoms can together form a C1-3 bridge; myp are each independently an integer from 0 to 6; n is an integer from 1 to 4; R 51 is selected from hydrogen and C1-6 alkyl; R 52 is selected independently in each case from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle; and R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle. 17 Claims follow;