Azepane inhibitors of menin-MLL interaction

A method of treating a cancer selected from leukemia or a solid tumor cancer comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I)

• or a tautomer or a stereoisomeric form thereof, or a pharmaceutical composition comprising the compound of Formula (I), or a tautomer or a stereoisomeric form thereof;
• wherein
• R1 is selected from the group consisting of CH3, CH2F, CHF2 and CF3;
• R2 is selected from the group consisting of hydrogen and CH3;
• Y1 is selected from the group consisting of hydrogen;
• C1-6 alkyl;
• C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom optionally substituted with a C1-4alkyl or cyclopropyl substituent;
• and C1-4alkyl substituted with a substituent selected from the group consisting of fluoro, -CN, phenyl, -OR1Y, and NR2Y, R2YY;
• wherein
• R1Y is selected from the group consisting of hydrogen;
• C1-4alkyl optionally substituted with a substituent selected from the group consisting of fluoro, -CN and
• -C(═O)NR1YR2Y;
• C2-4alkyl substituted with a substituent selected from the group consisting of -OR3y and -NR1yR2y;
• and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
• R2Y and R2YY are each independently selected from the group consisting of hydrogen;
• C1-4alkyl optionally substituted with a -C(═O)NR1yR2y substituent;
• C2-4alkyl substituted with a substituent selected from the group consisting of -OR3Y and -NR1yR2y;
• and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
• Y2 and Y3 are each independently selected from the group consisting of hydrogen;
• OH;
• NH2;
• -C(═O)NR1yR2y;
• C1-6 alkyl;
• and C1-4alkyl substituted with a substituent selected from the group consisting of fluoro, -CN, -OR3Y, and -NR4YR4YY;
• with the proviso that when Y2 and Y3 are both substituents at the same carbon atom, and one of Y2 or Y3 is OH or NH2, then the other Y2 or Y3 is H, C1-6 alkyl, C1-4 alkyl substituted with a substituent selected from the group consisting of fluoro and -CN, or C2-4alkyl substituted with a substituent selected from the group consisting of -OR3Y and
• NR4YR4YY;
• wherein
• R3Yis selected from the group consisting of hydrogen;
• C1-4alkyl optionally substituted with a substituent selected from the group consisting of fluoro, -CN and -C(═O)NR4yR5y;
• C2-4alkyl substituted with a substituent selected from the group consisting of -OR6y and—NR4yR5y;
• and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
• R4Y and R4YY are each independently selected from the group consisting of hydrogen;
• C1-4alkyl optionally substituted with a substituent selected from the group consisting of fluoro, -CN and -C(═O)NR4yR2y;
• C2-4alkyl substituted with a substituent selected from the group consisting of -OR6y and -NR4yR5y;
• and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
• wherein
• R1y, R2y, R3y, R4y, R5y and R6y are each independently selected from the group consisting of hydrogen;
• C1-4 alkyl;
• and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
• and
• -L-R3 is selected from (a), (b), (c), (d), (e), or (f):
• (a) -L-R3 is -NHR1A, wherein R1A is selected from the group consisting of hydrogen;
• C1-6 alkyl optionally substituted with one, two or three fluoro substituents;
• and C2-6alkyl substituted with a substituent selected from the group consisting of -OR1a and
• NR2aR2aa wherein R1a, R2a and R2aa are each independently selected from the group consisting of hydrogen, C1-4alkyl and cyclopropyl;
• with the proviso that when R1A is hydrogen, then Y1 is not hydrogen;
• or
• (b) L is selected from the group consisting of -O-, -O-CR1BR1BB-, -N(RB)-,
• -N(RB)-CR1BR1BB, and -(NRB)-CHR1B-CHR2B-;
• and R3 is selected from the group consisting of Ar;
• Het1;
• Het2;
• and a 7- to 10-membered saturated spirocarbobicyclic system;
• wherein
• RB is selected from the group consisting of hydrogen;
• C1-4alkyl optionally substituted with a substituent selected from the group consisting of fluoro, phenyl and -CN;
• and C2-4alkyl substituted with a substituent selected from the group consisting of -OR1b and -NR2bR2bb;
• wherein
• R1b, R2b, and R2bb are each independently selected from the group consisting of hydrogen, C1-4 alkyl and cyclopropyl;
• R1B is selected from the group consisting of hydrogen;
• -C(═O)NR3BR3BB;
• C1-4alkyl optionally substituted with a substituent selected from the group consisting of fluoro, phenyl, Het1, and -CN;
• C2-4alkyl substituted with a substituent selected from the group consisting of -OR4B and -NR5BR5BB;
• and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
• and R1BB is selected from the group consisting of hydrogen and methyl;
• or R1B and R1BB together with the carbon to which they are attached form a C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
• R2B is selected from the group consisting of hydrogen;
• -OR6B;
• -NR7BR7BB;
• -C(═O)NR8BR8BB;
• C1-4alkyl optionally substituted with a substituent selected from the group consisting of fluoro, -CN, -OR4B, and -NR5BR5BB;
• and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
• wherein
• R3B, R3BB, R4B, R5BB, R5BB, R6B, R7B, R7BB, R8B and R8BB are each independently selected from the group consisting of hydrogen;
• C1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, -CN and
• C(═O)NR9BR9BB;
• and C2-4alkyl substituted with a substituent selected from the group consisting of -OR10B and -NR11BR11BB;
• wherein
• R9B, R9BB, R10B, R11Band R11BBare each independently selected from the group consisting of hydrogen;
• C1-4 alkyl;
• and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
• or
• (c) -L-R3 is selected from the group consisting of -N(RC)-CHR1C-CO2R2C;
• -N(RC)-CHR3C-CONR4CR4CC;
• -N(RC)-COR5C;
• -N(RC)-SO2NR6CR6CC;
• wherein
• RC is selected from the group consisting of hydrogen;
• C1-4alkyl optionally substituted with a substituent selected from the group consisting of fluoro, phenyl and -CN;
• and C2-4alkyl substituted with a substituent selected from the group consisting of -OR1c and -NR2cR2cc;
• R1C and R3C are each selected from the group consisting of hydrogen;
• -C(═O)NR3cR3cc;
• C1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, phenyl, Het1, and -CN;
• C2-4alkyl substituted with a substituent selected from the group consisting of -OR4c and -NR5cR5cc and
• C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
• R4C and R6C are each selected from the group consisting of hydrogen, and C1-4alkyl optionally substituted with a substituent selected from the group consisting of NR6cR6cc, Ar, and Het1;
• R2C is selected from the group consisting of hydrogen;
• C1-4alkyl optionally substituted with Ar or Het1;
• Ar;
• Het1;
• Het2;
• and a 7- to 10-membered saturated spirocarbobicyclic system;
• R5C is selected from the group consisting of hydrogen;
• C1-4alkyl optionally substituted with -NR2cR2cc Ar or Het1;
• Ar;
• Het1;
• Het2;
• and a 7- to 10-membered saturated spirocarbobicyclic system;
• wherein
• R1c, R2c, R2cc, R3c, R3cc, R4c, R5c, and R5cc are each independently selected from the group consisting of hydrogen and C1-4 alkyl;
• and
• R6c and R6cc are each independently selected from the group consisting of hydrogen, and C1-4 alkyl optionally substituted with a substituent selected from the group consisting of -NHC1-4 alkyl and cyclopropyl;
• and
• R4CC and R6CCare each independently selected from the group consisting of hydrogen;
• C1-4 alkyl optionally substituted with Ar or Het1;
• Ar;
• Het1;
• Het2;
• and a 7- to 10-membered saturated spirocarbobicyclic system;
• or R4C and R4CC, or R6C and R6CC together with the nitrogen atom to which they are attached, form a N-linked Het2;
• or
• (d) L is selected from -N(RD)-CR1DR1DD- and-N(RD)-CR1DR1DD-CR2DR2DD-;
• wherein
• RD is selected from the group consisting of hydrogen;
• C1-4alkyl optionally substituted with a substituent selected from the group consisting of fluoro and -CN;
• and C2-4alkyl substituted with a substituent selected from -OR1d and
• NR2dR2dd;
• wherein
• R1d, R2d and R2dd are each independently selected from the group consisting of hydrogen and C1-4 alkyl;
• R1D, R1DD, R2D and R2DD are each independently selected from the group consisting of hydrogen and C1-4 alkyl;
• and
• R3 is selected from the group consisting of
• wherein
• R3D, R4D, and R5D are each independently selected from the group consisting of C1-6 alkyl optionally substituted with a -OH, -OC1-6 alkyl, or a -NH2 substituent;
• or
• (e) -L-R3 is
• wherein
• RE is selected from the group consisting of hydrogen and C1-4 alkyl;
• R1E is selected from the group consisting of hydrogen, fluoro and C1-4alkyl;
• and
• R2E is selected from the group consisting of fluoro, -OC1-4 alkyl, and C1-4alkyl optionally substituted with 1, 2 or 3 fluoro substituents;
• or R1E and R2E are bound to the same carbon atom and together form a C3-5cycloalkyl or a C-linked 4- to 6-membered heterocyclyl containing an oxygen atom;
• and
• R3E is selected from the group consisting of hydrogen;
• C1-4alkyl optionally substituted with a fluoro or a -CN substituent;
• and C2-4alkyl substituted with a substituent selected from the group consisting of -OR4E and -NR5ER5EE;
• wherein
• R4E, R5E and R5EE are each independently selected from the group consisting of hydrogen;
• C1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, -CN, and -C(═O)NR6ER6EE;
• C2-4alkyl substituted with a substituent selected from the group consisting of -OR7E and
• NR8ER8EE;
• and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
• wherein
• R6E, R6EE, R7E, R8E and R8EE are each independently selected from the group consisting of hydrogen and C1-4 alkyl;
• or
• (f) -L-R3 is a radical selected from the group consisting of
• wherein R1F is selected from the group consisting of hydrogen, C1-4alkyl and
• C2-4alkyl-NRfRff;
• and R2F and R3F are each independently selected from hydrogen and C1-4alkyl;
• wherein Rf and Rff are each independently selected from the group consisting of hydrogen and C1-4 alkyl;
• and wherein
• Ar is phenyl optionally substituted with one, two, or three substituents each independently selected from the group consisting of halo, -CN, -OR4, -NR5R5,
• C(═O)NR5R5′, and C1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, -CN, -OR6, -NR7R7′ and -C(═O)NR8R8′;
• Het1is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl, and isoxazolyl;
• each of which may be optionally substituted with one, two, or three substituents each independently selected from the group consisting of halo, -CN, -OR4, -NR5R5′, and C1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, -CN, -OR6,
• NR7R7′, and -C(═O)NR8R8′;
• and
• Het2is a non-aromatic heterocyclyl optionally substituted with one, two, or three substituents each independently selected from the group consisting of halo, -CN, -OR4, -NR5R5′, and C1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, -CN, -OR6-NR7R7′ and -C(═O)NR8R8′;
• wherein
• R4, R5, R5′, R6, R7, R7′, R8 and R8′ are each independently selected from the group consisting of hydrogen;
• C1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro and -C(═O)NR9R9′;
• and C2-4alkyl substituted with a substituent selected from the group consisting of -OR10 and -NR11R11′;
• wherein
• R9, R9′, R10, R11 and R11′ are each independently selected from the group consisting of hydrogen;
• C1-4alkyl;
• and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
• or a pharmaceutically acceptable salt or a solvate thereof;
• wherein the solid tumor cancer is selected from prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma or glioblastoma;
• and
• wherein the leukemia is selected from acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, Acute myelogeneous leukemias (AML), Chronic myelogenous leukemias (CML), Acute lymphoblastic leukemias (ALL), Chronic lymphocytic leukemias (CLL), T cell prolymphocytic leukemias (T-PLL), Large granular lymphocytic leukemia, Hairy cell leukemia (HCL), MLL-rearranged leukemias, MLL-PTD leukemias, MLL amplified leukemias, MLL-positive leukemias, and leukemias exhibiting HOX/MEISI gene expression signatures.