KAT6a, KAT6b, and KAT7 inhibitors and uses thereof

Abstract

The present invention provides compounds of Formula I:, I which are useful for the inhibition of KAT6A, KAT6B, and / or KAT7. Compounds of Formula I are useful for the treatment of cancer, including bladder cancer, breast cancer, cervical cancer, colorectal cancer including colon and rectal adenocarcinomas, leukemias including acute myeloid leukemia (AML), lung adenocarcinoma, medulloblastoma, osteosarcoma, ovarian cancer, and prostate cancer.

Description

KAT6A, KAT6B, AND KAT7 INHIBITORS AND USES THEREOF FIELD

[0001] The present invention relates to inhibitors of histone lysine acetyltransferases 6A, 6B, and 7 (KAT6A, KAT6B, and / or KAT7) and uses thereof.BACKGROUND

[0002] Lysine acetyltransferases (KATs) regulate chromatin structure and gene expression through acetylation of histone lysine residues, thereby modulating transcriptional programs governing cell proliferation, differentiation, and survival. KAT6A (also known as MOZ or MYST3), KAT6B (also known as MORF, MYST4, OR QKF), and KAT7 (also known as HBO1 or MYST2) are MYST family histone lysine acetyl transferases that are important in cell cycle regulation (Carrozza, etal., TRENDS IN GENETICS, 19, 321-329 (2003)). KAT6A dysregulation has been documented in multiple types of cancer including breast cancer, prostate cancer, ovarian cancer, cervical cancer, lung adenocarcinoma, colon and rectal adenocarcinomas, and medulloblastoma (Shikhar Sharma, etal., CELL CHEMICAL BIOLOGY, 30, 1191-1210 (October 19, 2023)). Pharmacologic inhibition of KAT6A and KAT6B has been shown to suppress tumor cell proliferation and induce cellular senescence in preclinical models, thereby validating these enzymes as therapeutic targets (Baell etal., NATURE, 560, 253-257 (2018)). KAT7 expression is associated with several cancers, such as leukemias, including acute myeloid leukemia (AML), breast cancer, osteosarcoma, colorectal cancer, bladder cancer, and prostate cancer (Hao Wang, et al., THERANOSTICS, 15(4), 1478-1495 (2025)). Combined inhibition of KAT6A and KAT7 has been shown to provide increased efficacy in preclinical cancer models and may diminish the development of treatment resistance (Shellaina Gordon, etal., Catalytic Inhibition ofKAT6 / KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL Leukaemia, (doi: https: / / doi.org / 10.1101 / 2024.12.11.627663 (December 12, 2024)). Accordingly, inhibition of KAT6A, KAT6B, and / or KAT7 represents a promising strategy to modulate pathological epigenetic regulation in cancer and other diseases characterized by aberrant transcriptional control. Certain KAT6A inhibitors have been described in US 11,492,346, US 11,976,075, US 2024 / 0109880, WO 2024 / 199254, and WO 2025 / 036328. Additional KAT6A / B and KAT7 inhibitors are needed to provide new treatments for certain cancers.SUMMARY OF THE INVENTION

[0003] An aspect of the invention is to provide compounds of Formula I:or a pharmaceutically acceptable salt thereof, wherein:Ri is selected from a bond, CH2, and NRiR1' is selected from hydrogen and methyl;Ring A is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, any of which may be further substituted by one, two, or three Ra;Ra is independently selected from halo, hydroxy, C1-C3 haloalkyl, -(CH2)i-3NRbRb’, -C(O)O(C1-C4 alkyl), -C(O)NRbRb’, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C3-C6 cycloalkoxy, -O- C1-C3 haloalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl; wherein C1-C3 haloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C2-C3 alkenyl, C2-C3 alkynyl, may be further substituted by one Ra and wherein 3-10 membered cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl may be further substituted by one, two, or three Ra;Ra is selected from C1-C3 alkoxy, phenyl, 3-6-membered cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, and heteroaryl;Ra is selected from halo, hydroxy, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ci-C3 haloalkyl, and C1-C3 alkoxy;Rb and Rb’ are independently selected from hydrogen and C1-C4 alkyl, or Rb and Rb’ taken together with nitrogen to which they are attached form a C3-C7 heterocycloalkyl;R2 is selected from hydrogen, fluoro, and methyl;R3 is selected from a bond, C1-C4 alkylenyl, NRi', and O;R4 is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -O-cyclopropyl, -O-cyclobutyl, cyclopropyl, or cyclobutyl, where cyclopropyl and cyclobutyl may be substituted up to two times with fluoro;R5 is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -O-cyclopropyl, -O-cyclobutyl, cyclopropyl, or cyclobutyl, where cyclopropyl and cyclobutyl may be substituted up to two times with fluoro;or R4 and R5, together with the atoms to which they are attached, form a ring selected from 5-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 5-8 membered cycloalkenyl, 5-8 membered heterocycloalkenyl, 5-10 membered aryl, and 5-10 membered heteroaryl, any of which may be further substituted by one to two R4, wherein R4 is selected from fluoro, methyl, and cyclopropyl;Ring B is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, and 5-6 membered lactam, any one of which may be further substituted by one or two Rc, wherein Rc is selected from halo, hydroxy, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, and C1-C3 alkoxy.

[0004] An aspect of the invention is to provide compounds of Formula I- A:N - SR2N I B HR3RsLAor a pharmaceutically acceptable salt thereof, wherein:Ri is selected from a bond, CH2, and NRiR1' is selected from hydrogen and methyl;Ring A is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, any of which may be further substituted by one, two, or three Ra;Ra is independently selected from halo, hydroxy, C1-C3 haloalkyl, -(CH2)i-3NRbRb’, -C(O)O(C1-C4 alkyl), -C(O)NRbRb’, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C3-C6 cycloalkoxy, -O- C1-C3 haloalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl; wherein C1-C3 haloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C2-C3 alkenyl, C2-C3 alkynyl, may be further substituted by one Ra and wherein 3-10 memberedcycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl may be further substituted by one, two, or three Ra;Ra is selected from C1-C3 alkoxy, phenyl, 3-6-membered cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, and heteroaryl;Ra is selected from halo, hydroxy, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ci-C3 haloalkyl, and C1-C3 alkoxy;Rb and Rb’ are independently selected from hydrogen and C1-C4 alkyl, or Rb and Rb’ taken together with nitrogen to which they are attached form a C3-C7 heterocycloalkyl;R2 is selected from hydrogen, fluoro, and methyl;R3 is selected from a bond, C1-C4 alkylenyl, NRi', and O;R4 is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -O-cyclopropyl, -O-cyclobutyl, cyclopropyl, or cyclobutyl, where cyclopropyl and cyclobutyl may be substituted up to two times with fluoro;R5 is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -O-cyclopropyl, -O-cyclobutyl, cyclopropyl, or cyclobutyl, where cyclopropyl and cyclobutyl may be substituted up to two times with fluoro;or R4 and R5, together with the atoms to which they are attached, form a ring selected from 5-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 5-8 membered cycloalkenyl, 5-8 membered heterocycloalkenyl, 5-10 membered aryl, and 5-10 membered heteroaryl, any of which may be further substituted by one to two R4, wherein R4 is selected from fluoro, methyl, and cyclopropyl;Ring B is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, and 5-6 membered lactam, any one of which may be further substituted by one or two Rc, wherein Rc is selected from halo, hydroxy, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, and C1-C3 alkoxy, provided that only one of Ra and R5 may be methoxy.

[0005] An aspect of the invention is to provide compounds of Formula I-B:I-Bor a pharmaceutically acceptable salt thereof, wherein:R1 is selected from a bond, -CH2-, -CH(OMe)CH2-, -O-, and -NR1-';R1' is selected from hydrogen and methyl;Ring A is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, any of which may be further substituted by one, two, or three Ra;Ra is independently selected from halo, hydroxy, C1-C3 haloalkyl, -(CH2)i-3NRbRb’, -C(O)O(C1-C4 alkyl), -C(O)NRbRb’, -SO2(heteroaryl), cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C3-C6 cycloalkoxy, -O- C1-C3 haloalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl; wherein C1-C3 haloalkyl, C1-C3 alkyl, Ci-C3 alkoxy, C2-C3 alkenyl, C2-C3 alkynyl, may be further substituted by one Ra and wherein 3-10 membered cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl may be further substituted by one, two, or three Ra;Ra is selected from C1-C3 alkoxy, phenyl, 3-6-membered cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, and heteroaryl;Ra is selected from halo, hydroxy, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ci-C3 haloalkyl, and C1-C3 alkoxy;Rb and Rb’ are independently selected from hydrogen and C1-C4 alkyl, or Rb and Rb’ taken together with nitrogen to which they are attached form a C3-C7 heterocycloalkyl;R2 is selected from hydrogen, fluoro, and methyl;R3 is selected from a bond, C1-C4 alkylenyl, NRi', and O;R4 is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -O-cyclopropyl, -O-cyclobutyl, cyclopropyl, or cyclobutyl, where cyclopropyl and cyclobutyl may be substituted up to two times with fluoro;R5 is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -O-cyclopropyl, -O-cyclobutyl, cyclopropyl, or cyclobutyl, where cyclopropyl and cyclobutyl may be substituted up to two times with fluoro;or R4 and R5, together with the atoms to which they are attached, form a ring selected from 5-8 membered cycloalkenyl, 5-8 membered heterocycloalkenyl, 5-10 membered aryl, and 5-10 membered heteroaryl, any of which may be further substituted by one to two R4, wherein R4 is selected from fluoro, methyl, and cyclopropyl;Ring B is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, and 5-6 membered lactam, any one of which may be further substituted by one or two Rc, wherein Rc is selected from halo, hydroxy, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, and C1-C3 alkoxy, provided that:i) when Rs is methoxy, then A is not methoxyphenyl or dimethoxyphenyl; and ii) when R2, R4, and Rs are all hydrogen, then A is not dimethoxphenyl.

[0006] An aspect of the invention is to provide compounds of Formula I, Formula I- A, or Formula I-B, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from C5-C8 cycloalkyl, phenyl substituted one or two times with Ra, and heteroaryl substituted once with Ra.

[0007] An aspect of the invention is to provide compounds of Formula I, Formula I- A, or Formula I-B, or a pharmaceutically acceptable salt thereof, wherein Ra is independently selected from halo, C1-C4 alkyl, and C1-C3 alkoxy.

[0008] An aspect of the invention is to provide compounds of Formula I, Formula I- A, or Formula I-B, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

[0009] An aspect of the invention is to provide compounds of Formula I, Formula I- A, or Formula I-B, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from hydrogen, halo, and cyclopropyl.

[0010] An aspect of the invention is to provide compounds of Formula I, Formula I- A, or Formula I-B, or a pharmaceutically acceptable salt thereof, wherein Rs is selected from hydrogen, halo, and C1-C3 alkoxy.

[0011] An aspect of the invention is to provide compounds of Formula I, Formula I- A, or Formula I-B, or a pharmaceutically acceptable salt thereof, wherein R4 and Rs, together with the atoms they are attached to, form a 2,3-dihydrofuryl, 3,4-dihydro-2H- pyranyl, 2-oxabicyclo[4.1.0]hept-3-enyl, 2,3-dihydro-l,4-dioxinyl, imidazolyl, or 2,3,4,5-tetrahydrooxepinyl ring.

[0012] An aspect of the invention is to provide compounds of Formula I, Formula I- A, or Formula I-B, or a pharmaceutically acceptable salt thereof, wherein R4 and R5, together with the atoms they are attached to, form a 2,3-dihydrofuryl, 3,4-dihydro-2H- pyranyl, 2-oxabicyclo[4.1,0]hept-3-enyl, or imidazolyl ring, any of which may be substituted one or two times with methyl.

[0013] An aspect of the invention is to provide compounds of Formula I, Formula I- A, or Formula I-B, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-6-membered heteroaryl or 5-6-membered lactam, either of which may be further substituted by one Rb.

[0014] An aspect of the invention is to provide compounds of Formula I, Formula I- A, or Formula I-B, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-6-membered heteroaryl which may be further substituted by one Rb.

[0015] An aspect of the invention is to provide compounds of Formula I, Formula I- A, or Formula I-B, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-membered heteroaryl.

[0016] An aspect of the invention is to provide compounds of Formula I, Formula I- A, or Formula I-B, or a pharmaceutically acceptable salt thereof, wherein Ring B is imidazolyl or thiazolyl.

[0017] An aspect of the invention is to provide compounds of Formula I, Formula I- A, or Formula I-B, or a pharmaceutically acceptable salt thereof, wherein R3is -CH2- or -O-.

[0018] An aspect of the invention is to provide compounds of Formula I, Formula I- A, or Formula I-B, or a pharmaceutically acceptable salt thereof, wherein Rb is C1-C4 alkyl.

[0019] An aspect of the invention is to provide compounds of Formula II:A N - SR2N I B HR;Rsor a pharmaceutically acceptable salt thereof, wherein:Ri is selected from a bond, -CH2-, -CH(0Me)CH2-, and -NRiRi' is selected from hydrogen and methyl;Ring A is selected from C5-C8 cycloalkyl, phenyl substituted one or two times with Ra, and heteroaryl substituted one time with Ra;Ra is independently selected from halo, C1-C4 alkyl, and C1-C3 alkoxy;R2 is hydrogen or fluoro;R3 is -CH2- or -O-;R4 is selected from hydrogen, halo, and cyclopropyl;R5 is selected from hydrogen, halo, and C1-C3 alkoxy; orR4 and R5, together with the atoms they are attached to, form a 2,3-dihydrofuryl optionally substituted with methyl, 3,4-dihydro-2H- pyranyl, 2-oxabicyclo[4.1.0]hept-3-enyl, or imidazolyl optionally substituted with methyl; andRing B is 5-6 membered heteroaryl.

[0020] An aspect of the invention is to provide compounds of Formula II, or a pharmaceutically acceptable salt thereof, wherein Ring A is C5-C8 cycloalkyl and Ring B is selected from pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, indazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, each of which may be substituted one time with Rb.

[0021] An aspect of the invention is to provide compounds of Formula II, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl substituted one or two times with Ra, and Ring B is selected from pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, indazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, each of which may be substituted one time with Rb.

[0022] An aspect of the invention is to provide compounds of Formula II, or a pharmaceutically acceptable salt thereof, wherein Ring A is heteroaryl substituted one time with Ra, and Ring B is selected from pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, indazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, each of which may be substituted one time with Rb.

[0023] An aspect of the invention is to provide compounds of Formula II, or a pharmaceutically acceptable salt thereof, wherein Ring A is C5-C8 cycloalkyl or phenyl substituted one or two times with Ra, and Ring B is selected from pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl,isoxazolyl, indazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, each of which may be substituted one time with Rb.

[0024] An aspect of the invention is to provide compounds of Formula II, or a pharmaceutically acceptable salt thereof, wherein Ring A is C5-C8 cycloalkyl or heteroaryl substituted one time with Ra, and Ring B is selected from pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, indazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, each of which may be substituted one time with Rb.

[0025] An aspect of the invention is to provide compounds of Formula II, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl substituted one or two times with Ra or heteroaryl substituted one time with Ra, and Ring B is selected from pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, indazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, each of which may be substituted one time with Rb.

[0026] An aspect of the invention is to provide compounds of Formula II, or a pharmaceutically acceptable salt thereof, wherein Ring B is pyrazolyl or thiazolyl.

[0027] An aspect of the invention is to provide compounds of Formula III:N - SR2N I B HR3R5or a pharmaceutically acceptable salt thereof, wherein:Ri is selected from a bond, CH2, -CH(0Me)CH2-, and NRi';Ri' is selected from H and methyl;R2 is selected from H and F;Ring A is selected from C5-C8 cycloalkyl, phenyl substituted one or two times with Ra, and heteroaryl substituted one time with Ra;Ra is independently selected from halo, C1-C4 alkyl, and C1-C3 alkoxy;R3 is -CH2- or -O-;R4 is selected from hydrogen, halo, and cyclopropyl;R5 is selected from hydrogen, halo, and C1-C3 alkoxy; orR4 and R5, together with the atoms they are attached form 2, 3 -dihydrofuryl optionally substituted with methyl, 3,4-dihydro-2H- pyranyl, or 2-oxabicyclo[4.1.0]hept-3-enyl; and Ring B is 5-6-membered heteroaryl.

[0028] An aspect of the invention is to provide compounds of Formula III, or a pharmaceutically acceptable salt thereof, wherein Ring B is pyrazolyl or thiazolyl.

[0029] An aspect of the invention is to provide compounds of Formula IV:N - S / ' \ ZR2R4IVor a pharmaceutically acceptable salt thereof, wherein:Ri is selected from a bond, CH2, and NRi;R1' is selected from hydrogen and methyl;Ring A is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, any of which may be further substituted by one, two, or three Ra;Ra is independently selected from halo, hydroxy, C1-C3 haloalkyl, -(CH2)i-3NRbRb’, -C(O)O(C1-C4 alkyl), -C(O)NRbRb’, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C3-C6 cycloalkoxy, -O- C1-C3 haloalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl; wherein C1-C3 haloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C2-C3 alkenyl, C2-C3 alkynyl, may be further substituted by one Ra and wherein 3-10 membered cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl may be further substituted by one, two, or three Ra;Ra is selected from C1-C3 alkoxy, phenyl, 3-6-membered cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, and heteroaryl;Ra is selected from halo, hydroxy, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ci-C3 haloalkyl, and C1-C3 alkoxy;Rb and Rb’ are independently selected from hydrogen and C1-C4 alkyl, or Rb and Rb’ taken together with nitrogen to which they are attached form a C3-C7 heterocycloalkyl;R2 is selected from hydrogen, fluoro, and methyl;R3 is selected from a bond, C1-C4 alkylenyl, NRi', and O;R4 and R5, together with the atoms to which they are attached, form a ring selected from 5-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 5-8 membered cycloalkenyl, 5-8 membered heterocycloalkenyl, 5-10 membered aryl, and 5-10 membered heteroaryl, any of which may be further substituted by one to two R4, wherein R4 is selected from fluoro, methyl, and cyclopropyl;Ring B is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, and 5-6 membered lactam, any one of which may be further substituted by one or two Rc, wherein Rc is selected from halo, hydroxy, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, and C1-C3 alkoxy.

[0030] An aspect of the invention is to provide compounds of Formula V:N - SR2N I BH*3Rsor a pharmaceutically acceptable salt thereof, wherein:R1 is selected from a bond, -CH2-, -CH(OMe)CH2-, -O-, and -NR1-';R1' is selected from hydrogen and methyl;Ring A is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, any of which may be further substituted by one, two, or three Ra;Ra is independently selected from halo, hydroxy, C1-C3 haloalkyl, -(CH2)i-3NRbRb’, -C(O)O(C1-C4 alkyl), -C(O)NRbRb’, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C3-C6 cycloalkoxy, -O- C1-C3 haloalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl; wherein C1-C3 haloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C2-C3 alkenyl, C2-C3 alkynyl, may be further substituted by one Ra and wherein 3-10 memberedcycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl may be further substituted by one, two, or three Ra;Ra is selected from C1-C3 alkoxy, phenyl, 3-6-membered cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, and heteroaryl;Ra is selected from halo, hydroxy, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ci-C3 haloalkyl, and C1-C3 alkoxy;Rb and Rb’ are independently selected from hydrogen and C1-C4 alkyl, or Rb and Rb’ taken together with nitrogen to which they are attached form a C3-C7 heterocycloalkyl;R2 is selected from hydrogen, fluoro, and methyl;R3 is selected from a bond, C1-C4 alkylenyl, NRi', and O;R4 and R5, together with the atoms to which they are attached, form a ring selected from 5-8 membered cycloalkenyl, 5-8 membered heterocycloalkenyl, 5-10 membered aryl, and 5-10 membered heteroaryl, any of which may be further substituted by one to two R4, wherein R4 is selected from fluoro, methyl, and cyclopropyl;Ring B is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, and 5-6 membered lactam, any one of which may be further substituted by one or two Rc, wherein Rc is selected from halo, hydroxy, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, and C1-C3 alkoxy.

[0031] An aspect of the invention is to provide compounds of Formula V which are of Formula V-A:or a pharmaceutically acceptable salt thereof, wherein:R1 is selected from a bond, -CH2-, -CH(OMe)CH2-, -O-, and -NR1-';Ri' is selected from hydrogen and methyl;Ring A is selected from C3-C8 cycloalkyl, aryl, and heteroaryl, any of which may be substituted by one or two Ra;Ra is independently selected from halo, hydroxy, C1-C3 haloalkyl, -(CH2)i-3NRbRb’, -cyano, C1-C4 alkyl, and C1-C3 alkoxy;Rb and Rb’ are independently selected from hydrogen and C1-C4 alkyl;R2 is selected from hydrogen and fluoro;R3 is -CH2- or -O-;R4 and Rs, together with the atoms to which they are attached, form a 5-8 membered heterocycloalkenyl or 5-10 membered heteroaryl, either of which may be further substituted by one to two R4, wherein R4 is selected from methyl; andRing B is selected from 5-6 membered heteroaryl.

[0032] An aspect of the invention is to provide compounds of Formula V-A, or a pharmaceutically acceptable salt thereof, where R4and R5, together with the atoms to which they are attached, form 2,3-dihydrofuryl optionally substituted with methyl, 3,4-dihydro-2H- pyranyl, or 2-oxabicyclo[4.1.0]hept-3-enyl.

[0033] An aspect of the invention is to provide compounds of Formula V-A, or a pharmaceutically acceptable salt thereof, where Ring B is pyrazolyl or thiazolyl.

[0034] An aspect of the invention is to provide compounds of Formula V-A, or a pharmaceutically acceptable salt thereof, where R4and R5, together with the atoms to which they are attached, form 2,3-dihydrofuryl optionally substituted with methyl, 3,4-dihydro-2H- pyranyl, or 2-oxabicyclo[4.1.0]hept-3-enyl, and Ring B is pyrazolyl or thiazolyl.

[0035] An aspect of the invention is to provide compounds of Formula V-A, or a pharmaceutically acceptable salt thereof, where R4and R5, together with the atoms to which they are attached, form 2,3-dihydrofuryl optionally substituted with methyl, 3,4-dihydro-2H- pyranyl, or 2-oxabicyclo[4.1.0]hept-3-enyl, and Ring B is pyrazol-l-yl.

[0036] An aspect of the invention is to provide compounds of Formula I-B that are selective for KAT6A relative to KAT7.

[0037] Another aspect of the invention is to provide compounds or Formula I-B that are selective for KAT6A and KAT6B relative to KAT7.

[0038] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula I, I-A, I-B, II, III, IV, V, or V-A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0039] A further aspect of the present invention provides a compound of Formula I, I-A, I-B, II, III, IV, V, or V-A, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0040] Another aspect of the present invention provides a method for treating a KAT6A, KAT6B, or KAT7 susceptible cancer comprising administering to a patient in need thereof an effective amount of a compound of Formula I, I-A, I-B, II, III, IV, V, or V-A, or a pharmaceutically acceptable salt thereof.

[0041] Another aspect of the present invention provides a method for treating a KAT6A, KAT6B, or KAT7 susceptible cancer selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer including colon and rectal adenocarcinomas, leukemias including acute myeloid leukemia (AML), lung adenocarcinoma, medulloblastoma, osteosarcoma, ovarian cancer, and prostate cancer comprising administering to a patient in need thereof an effective amount of a compound of Formula I, I-A, I-B, II, III, IV, V, or V-A or a pharmaceutically acceptable salt thereof.

[0042] A further aspect of the present invention provides a method of inhibiting KAT6A, KAT6B, and / or KAT7, comprising administering to a subject in need thereof an effective amount of a compound of Formula I, I-A, I-B, II, III, IV, V, or V-A, or a pharmaceutically acceptable salt thereof.

[0043] A further aspect of the present invention provides the use of a compound of Formula I, I-A, I-B, II, III, IV, V, or V-A, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the inhibition of KAT6A, KAT6B, and / or KAT7.

[0044] A further aspect of the present invention provides the use of a compound of Formula I, I-A, I-B, II, III, IV, V, or V-A, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a KAT6A, KAT6B, or KAT7 susceptible cancer.

[0045] A further aspect of the present invention provides the use of a compound of Formula I, I-A, I-B, II, III, IV, V, or V-A, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a KAT6A, KAT6B, or KAT7 susceptible cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer including colon and rectaladenocarcinomas, leukemias including acute myeloid leukemia (AML), lung adenocarcinoma, medulloblastoma, osteosarcoma, ovarian cancer, and prostate cancer.DETAILED DESCRIPTION

[0046] Terms used herein but not separately defined are taken to have their normal and customary meaning as understood by one of ordinary skill in the art.

[0047] The term “halo” is taken to mean fluoro, chloro, bromo, or iodo.

[0048] The term “Ci - C3 alkoxy” is taken to mean a straight or branched alkyl chain of from 1 to 3 carbon atoms attached to an oxygen atom and includes methoxy, ethoxy, propoxy, and isopropoxy, and the like.

[0049] The term “Ci - C4 alkyl” is taken to mean a straight or branched alkyl chain of from 1 to 4 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like. Similarly, the term “Ci - C3 alkyl” is taken to mean a straight or branched alkyl chain of from 1 to 3 carbon atoms and includes methyl, ethyl, propyl, isopropyl and the like.

[0050] The term “C2 - C4 alkenyl” is taken to mean a straight or branched alkenyl chain of from 2 to 4 carbon atoms and includes ethenyl, propen-2-yl, propen-3 -yl, 2-methylpropen-3-yl, and the like.

[0051] The term “C2 - C4 alkynyl” is taken to mean a straight or branched alkynyl chain of from 2 to 4 carbon atoms and includes ethynyl, prop-l-yn-3-yl, prop-2-yn-l-yl, but-l-ynyl, 3-methyl-1-butyn-l-yl, and the like. Similarly, “C2 - C3 alkynyl” is taken to mean an alkynyl chain of from 2 to 3 carbon atoms and includes ethynyl, prop-l-yn-3-yl and prop-l-yn-l-yl.

[0052] The term “Ci - C3 haloalkyl” is taken to mean a straight or branched alkyl chain of from 1 to 3 carbon atoms where at least one hydrogen atom is replaced with a halogen, and includes, for example, mono-, di-, or trifluoromethyl and 2,2,2-trifluoroethyl.

[0053] The term “Ci - C4 alkylenyl” is taken to mean a linear or branched chain of carbon atoms with two points of attachment, and includes -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH(CH3)CH2-, and the like.

[0054] The term “cycloalkyl” is taken to mean a single, bicyclic, or spirofused carbocyclic ring of from 3 to 10 carbon atoms and includes cyclopropyl, cyclopentyl, spiro[2.2]pentyl, cyclohexyl, bicyclo[2.1.1]hexyl, cycloheptyl, bicyclo[2.2.1]heptyl, spiro[2.4]heptyl, bicyclo[2.2.2]octyl, decalinyl and the like. Similarly, “C3 - Cs cycloalkyl” is taken to mean a single, bicyclic, or spirofused carbocyclic ring of from 3 to 8 carbon atoms and includes cyclopropyl, cyclobutyl,cyclopentyl, spiro[2.2]pentyl, cyclohexyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.2]octan-l-yl, and the like.

[0055] The term “cycloalkenyl” is taken to mean a single, bicyclic, or spirofused carbocyclic ring of from 3 to 10 carbon atoms that contains at least one carbon-carbon double bond.

[0056] The term “heterocycloalkyl” is taken to mean a single, bicyclic, or spirofused ring comprising 3 to 10 atoms selected from carbon and at least one other atom selected from nitrogen, oxygen, and sulfur, and includes oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, 6- oxaspiro [4, 5] decyl, 2-oxa-6-azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, 2-oxa-7-azaspiro[3.3]heptyl, and the like.

[0057] The term “heterocycloalkenyl” is taken to mean a single, bicyclic, or spirofused ring comprising 3 to 10 atoms selected from carbon and at least one other atom selected from nitrogen, oxygen, and sulfur that contains at least one double bond and includes azepinyl, 1,4-diazepinyl, pyranyl, 2,3-dihydrofuryl, 3,4-dihydro-2H- pyranyl, 2-oxabicyclo[4.1.0]hept-3-enyl, and the like.

[0058] The term “aryl” is taken to mean phenyl or naphthyl. It will be understood that a phenyl ring may be fused with a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring to form, for example, tetrahydronaphthyl, indenyl, 2,3-dihydroindenyl, chromanyl, isochromanyl, 1 / 7-isochromenyl, 2 / 7-chromenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[b][l,4]dioxinyl, 27 / -benzo[b][l,4]oxazinyl, 2H-benzo[e][l,3]oxazinyl, and the like.

[0059] The term “heteroaryl” is taken to mean an aromatic heterocyclic compound comprising 5 to 13 atoms selected from carbon and at least one atom selected from nitrogen, oxygen, and sulfur, and includes furyl, pyrrolyl, thienyl, benzothienyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, benzofuryl, isobenzofuryl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, imidazolyl, benzimidazolyl, pyrazolyl, triazolyl, oxazolyl, benzo [d]oxazolyl, isoxazolyl, benzoisoxaolyl, thiazolyl, benzothiazolyl, isothiazolyl, oxadiazolyl, purinyl, pteridinyl, carbazolyl, and the like.

[0060] The term “4-6 membered lactam” is a cyclic amide selected from 2-azetidinone, 2-pyrrolidinone, and 2-piperidinone.

[0061] The term “patient” means mammal and “mammal” includes, but is not limited to, a human.

[0062] The term “therapeutically effective amount” means an amount of a compound of the disclosure that is sufficient to treat in one or more doses a condition or detrimental effect thereof herein described or an amount of a compound of the disclosure that is sufficient to inhibit KAT6A, KAT6B, and / or KAT7 to achieve the objectives of the disclosure.

[0063] The compounds of the present disclosure are effective over a dosage range. It will be understood that the amount of the compound administered will be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the selected compound or compounds to be administered, the age, weight, and response of the individual patient, and the severity of the patient’s symptoms. (See, for example, Goodman and Gilman’s, THE PHARMACEUTICAL BASIS OF THERAPEUTICS, 10thEdition, A. Gilman, J. Hardman, and L. Limbird, eds., McGraw-Hill Press, 155-173 (2001)). Dosage administration may be adjusted to provide an optimal therapeutic benefit to an individual patient and to manage or avoid drug-related toxicities. For example, in addition to single daily dosing, multiple smaller daily doses or administration on a staggered daily, weekly, or monthly schedule may be appropriate.

[0064] The terms “treatment”, “treat”, or “treating” are meant to include the full spectrum of pharmaceutical intervention for a patient suffering from a KAT6A, KAT6B, or KAT7 mediated disorder, and includes restraining, slowing, or reversing the progression or severity of an existing symptom, condition, or disorder in a patient in need thereof. Treating may be carried out by an attending physician or caregiver, prescribing a compound of Formula I, I- A, I-B, II, III, IV, V, or V-A, or a pharmaceutically acceptable salt thereof, for administration and thereby causing the application of the compound to a subject, through ingestion, infusion, injection, or any other means, whether by self-administration or by administration by a clinician or other qualified provider.

[0065] The compounds described herein, unless otherwise specified, encompass and include all isomers and stable isotopic variants of the compounds of the present disclosure, such as deuterated compounds. All isotopic variants of the compounds herein, whether radioactive or not, are contemplated within the scope of the present disclosure. Further, certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)- according to the Cahn-Ingold-Prelog R-S system.For example, when variables R4 and R5 of compounds of this disclosure, taken together with the atoms to which they are attached form a 2-oxabicyclo[4.1.0]hept-3-enyl ring, the bicyclic ring system of the compound has two asymmetric carbon atoms. The racemic and chiral forms of the bicyclic ring are illustrated below with their (R)- and (S)- designations:

[0066] The present chemical entities, pharmaceutical compositions, and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, and mixtures of stereoisomers and diastereomers.

[0067] Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions,” John Wiley & Sons, Inc., 1981). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0068] An aspect of this invention is to provide compounds where R4 and R5, taken together with the atoms to which they are attached, form a ring. The skilled person will appreciate that said ring formed in these compounds necessarily is fused to a benzene ring and therefore comprises two sp2hybridized carbon atoms regardless of the resonance form of the fused benzene ring as illustrated below:For purposes of this disclosure, the ring formed in compounds where R4 and R5 taken together with the atoms to which they are attached form a ring will be considered to include at least one carbon-carbon double bond which is located at the ring fusion with the benzene ring of the benzoisothiazole core, and it is intended that all resonance forms are intended for all compounds regardless of the specific form depicted. The skilled person will further appreciate that the structures in this paragraph are for illustration purposes only and are not intended to limit the scope of the invention in any way.

[0069] An embodiment of the invention provides compounds of Formula I, I- A, I-B, II, III, IV, V, or V-A:or a pharmaceutically acceptable salt thereof, which are inhibitors of KAT6A, KAT6B, and / or KAT7. In an embodiment, Ring A of Formula I, I-A, I-B, II, III, IV, V, or V-A is C3-C8 cycloalkyl. In an embodiment, Ring A of Formula I, I-A, I-B, II, III, IV, V, or V-A is C5-C8 cycloalkyl. In an embodiment, Ring A of Formula I, I-A, I-B, II, III, IV, V, or V-A is cyclohexyl or bicyclo[2.2.2]octan-l-yl. In an embodiment, Ring A of Formula I, I-A, I-B, II, III, IV, V, or V-A is phenyl which may be substituted one, two, or three times with Ra, where each Ra is independently selected from the group consisting of halo, C1-C3 alkoxy, cyano, hydroxy, C1-C4 alkyl, C1-C3 haloalkyl, -O- C1-C3 haloalkyl, -C(O)O(Ci-C4 alkyl), and -C(O)NRbRb’. In an embodiment, Ring A of Formula I, I-A, I-B, II, III, IV, V, or V-A is phenyl which may be substituted one, two, or three times with Ra, where each Ra is independently selected from the group consisting of fluoro, chloro, bromo, methoxy, ethoxy, cyclopropoxy, cyano, hydroxy, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, methoxyethyl, trifluoromethoxy, methoxycarbonyl, N-methylcarboxamido. In an embodiment, Ring A of Formula I, I-A, I-B, II, III, IV, V, or V-A is selected from tetrahydronaphthyl, 2,3-dihydroindenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[ / ?][l,4]dioxinyl, chromanyl, isochromanyl, and benzo[<7]dioxolyl, each of which may be substituted one, two, or three times with Ra, where each Ra is independently selected from the group consisting of fluoro, methyl, methoxy, cyano, and ethynyl. In an embodiment, Ring A of Formula I, I-A, I-B, II, III, IV, V, or V-A is selected from tetrahydronaphthyl, 2,3-dihydroindenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[ / ?][l,4]dioxinyl, chromanyl, and benzo [< / ]dioxolyl, each of which may be substituted one, two, or three times with Ra, where each Ra is independently selected from the group consisting of fluoro, methyl, methoxy, cyano, and ethynyl. In an embodiment, Ring A of Formula I, I-A, I-B, II, III, IV, V, or V-A is selected from pyridinyl, indolyl, benzoxazolyl, quinolinyl, benzofuryl, benzoxazolyl, benzothiazolyl, pyrazolyl, and quinoxalinyl, each of which may be substituted one, two, or three times with Ra, where each Ra is independently selected fromthe group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, methoxy, ethynyl, 2-cyclopropylethyn- 1 -yl, phenyl, and propynyl.

[0070] In an embodiment, variable R4 of Formula I, I- A, I-B, II, III, IV, V, or V-A is hydrogen, halo, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or cyclopropyl. In an embodiment, variable R4 of Formula I, LA, I-B, II, III, IV, V, or V-A is fluoro, bromo, methyl, cyclopropyl, methoxy, difluoromethyl, or ethoxy. In an embodiment, variable R4 of Formula I, I- A, I-B, II, III, IV, V, or V-A is hydrogen, halo, or trifluoromethyl.

[0071] In an embodiment, variable R5 of Formula I, I- A, I-B, II, III, IV, V, or V-A is hydrogen, halo, C1-C3 alkyl, C1-C3 alkoxy, cyclopropyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, or cyclopropoxy. In an embodiment, Rs of Formula I, I- A, I-B, II, III, IV, V, or V-A is hydrogen, fluoro, chloro, methyl, ethyl, cyclopropyl, methoxy, ethoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, or cyclopropoxy. In an embodiment, variable Rs of Formula I, I- A, I-B, II, III, IV, V, or V-A is hydrogen, halo, or C1-C3 alkoxy.

[0072] In an embodiment, variables R4 and Rs of Formula I, I- A, I-B, IV, or V taken together with the carbon atoms to which they are attached, form a ring selected from 5-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 5-8 membered cycloalkenyl, 5-8 membered heterocycloalkenyl, 5-10 membered aryl, and 5-10 membered heteroaryl, any of which may be further substituted by one to two R4. In an embodiment, variables R4 and Rs of Formula I, I- A, I-B, IV, or V taken together with the carbon atoms to which they are attached, form a 5-8 membered cycloalkyl ring, any of which may be substituted by one to two R4. In an embodiment, variables R4 and Rs of Formula I,, I- A, I-B, IV, or V taken together with the carbon atoms to which they are attached, form a 5-8 membered heterocycloalkyl ring, any of which may be further substituted by one to two R4. In an embodiment, variables R4 and Rs of Formula I, I- A, I-B, IV, or V taken together with the carbon atoms to which they are attached, form a 5-8 membered cycloalkenyl ring, any of which may be further substituted by one to two R4. In an embodiment, variables R4 and Rs of Formula I, I- A, I-B, IV, or V taken together with the carbon atoms to which they are attached, form a 5-8 membered heterocycloalkenyl ring, any of which may be further substituted by one to two R4. In an embodiment, variables R4 and Rs of Formula I, I- A, I-B, IV, or V taken together with the carbon atoms to which they are attached, form a 5-8 membered aryl ring any of which may be further substituted by one to two R4. In an embodiment, variables R4 and Rs of Formula I, LA, I-B, IV, or V taken together with the carbon atoms to which they are attached,form a 5-8 membered heteroaryl ring, any of which may be further substituted by one to two R4. In an embodiment, variables R4 and R5 of Formula I, I- A, I-B, IV, or V taken together with the carbon atoms to which they are attached, form 2,3-dihydrofuran, 1,3-dioxole, 2H-pyran, 3,4-dihydro-2H-pyran, 2,3-dihydro-l,4-dioxine, 3-oxabicyclo[4.1,0]hept-4-ene, 6-oxaspiro[2.5]oct-4-ene, 5-oxaspiro[2.5]oct-6-ene, 2,5-dihydrooxepine, 2,3,4,5-tetrahydrooxepine, 3-oxabicyclo[5.1.0]oct-4-ene, 6-oxaspiro[2.6]non-7-ene, or 5-oxaspiro[2,6]non-6-ene, each of which may be substituted one to two times with methyl or fluoro. In an embodiment, variables R4 and Rs of Formula I, I- A, I-B, IV, or V, taken together with the carbon atoms to which they are attached, form 2,3-dihydrofuryl optionally substituted with methyl, 3,4-dihydro-2H- pyranyl, or 2-oxabicyclo[4.1.0]hept-3-enyl.

[0073] In one embodiment, Ring B of Formula I, I- A, I-B, II, III, IV, V, or V-A, is a 5-6 membered heteroaryl selected from pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, indazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which may be substituted one time with Rb, wherein Rb is selected from the group consisting of fluoro, methyl, hydroxy, and hydroxymethyl. In one embodiment, Ring B of Formula I, I-A, I-B, IV, or V, is a 5-membered heteroaryl which may be substituted one time with Rb, wherein Rb is selected from the group consisting of fluoro, methyl, hydroxy, and hydroxymethyl. In one embodiment, Ring B of Formula I, I-A, I-B, II, III, IV, V, or V-A is a 5-membered heteroaryl selected from imidazolyl and thiazolyl. In one embodiment, Ring B of Formula I, I-A, I-B, IV, or V, is a 5-6 membered heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, each of which may be substituted one or two times with Rb, wherein Rb is independently in each instance selected from fluoro and methoxy.

[0074] An embodiment of the invention is a compound of Formula V:N - S, R2N I B HR3RSor a pharmaceutically acceptable salt thereof, wherein variables R4 and R5 taken together with the carbon atoms to which they are attached, form a ring selected from 5-8 membered cycloalkenyl,5-8 membered heterocycloalkenyl, 5-10 membered aryl, and 5-10 membered heteroaryl, any of which may be further substituted by one to two R4, which are inhibitors of KAT6A, KAT6B, and / or KAT7. In an embodiment, Ring A of Formula V is C3-C8 cycloalkyl. In an embodiment, Ring A of Formula V is C5-C8 cycloalkyl. In an embodiment, Ring A of Formula V is cyclohexyl or bicyclo[2.2.2]octan-l-yl. In an embodiment, Ring A of Formula V is phenyl which may be substituted one, two, or three times with Ra, where each Ra is independently selected from the group consisting of halo, C1-C3 alkoxy, cyano, hydroxy, C1-C4 alkyl, C1-C3 haloalkyl, -O- C1-C3 haloalkyl, -C(O)O(Ci-C4 alkyl), and -C(O)NRbRb’. In an embodiment, Ring A of Formula V is phenyl which may be substituted one, two, or three times with Ra, where each Ra is independently selected from the group consisting of fluoro, chloro, bromo, methoxy, ethoxy, cyclopropoxy, cyano, hydroxy, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, methoxyethyl, trifluoromethoxy, methoxycarbonyl, N-methylcarboxamido. In an embodiment, Ring A of Formula V is selected from tetrahydronaphthyl, 2,3-dihydroindenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[ / ?][l,4]dioxinyl, chromanyl, isochromanyl, and benzo[<7]dioxolyl, each of which may be substituted one, two, or three times with Ra, where each Ra is independently selected from the group consisting of fluoro, methyl, methoxy, cyano, and ethynyl. In an embodiment, Ring A of Formula V is selected from tetrahydronaphthyl, 2,3-dihydroindenyl, 2, 3 -dihydrobenzofuryl, 2,3-dihydrobenzo[ / ?][l,4]dioxinyl, chromanyl, and benzo[<7]dioxolyl, each of which may be substituted one, two, or three times with Ra, where each Ra is independently selected from the group consisting of fluoro, methyl, methoxy, cyano, and ethynyl. In an embodiment, Ring A of Formula V is selected from pyridinyl, indolyl, benzoxazolyl, quinolinyl, benzofuryl, benzoxazolyl, benzothiazolyl, pyrazolyl, and quinoxalinyl, each of which may be substituted one, two, or three times with Ra, where each Ra is independently selected from the group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, methoxy, ethynyl, 2-cyclopropylethyn-l-yl, phenyl, and propynyl.

[0075] In an embodiment, variables R4 and R5 of Formula V, taken together with the carbon atoms to which they are attached, form a 5-8 membered cycloalkenyl ring, any of which may be further substituted by one to two R4. In an embodiment, variables R4 and Rs of Formula V, taken together with the carbon atoms to which they are attached, form a 5-8 membered heterocycloalkenyl ring, any of which may be further substituted by one to two R4. In an embodiment, variables R4 and Rs of Formula V, taken together with the carbon atoms to whichthey are atached, form a 5-8 membered aryl ring any of which may be further substituted by one to two R4. In an embodiment, variables R4 and Rs of Formula V, taken together with the carbon atoms to which they are attached, form a 5-8 membered heteroaryl ring, any of which may be further substituted by one to two R4. In an embodiment, variables R4 and Rs of Formula V, taken together with the carbon atoms to which they are attached, form imidazolyl optionally substituted with methyl. In embodiment, variables R4 and Rs of Formula V, taken together with the carbon atoms to which they are attached, form 2,3-dihydrofuran, 1,3-dioxole, 2H-pyran, 3,4-dihydro-2H-pyran, 2,3-dihydro-l,4-dioxine, 3-oxabicyclo[4.1.0]hept-4-ene, 6-oxaspiro[2.5]oct-4-ene, 5-oxaspiro[2.5]oct-6-ene, 2,5-dihydrooxepine, 2,3,4,5-tetrahydrooxepine, 3-oxabicyclo[5.1.0]oct-4-ene, 6-oxaspiro[2.6]non-7-ene, 5-oxaspiro[2,6]non-6-ene, each of which may be substituted one to two times with fluoro or methyl. In an embodiment, variables R4 and Rs of Formula V, taken together with the carbon atoms to which they are atached, form 2,3-dihydrofuran, 1,3-dioxole, 3,4-dihydro-2H-pyran, or 2,3-dihydro-l,4-dioxine. In an embodiment, variables R4 and Rs of Formula V, taken together with the carbon atoms to which they are atached, form 2,3-dihydrofuryl optionally substituted with methyl, 3,4-dihydro-2H- pyranyl, or 2-oxabicyclo[4.1.0]hept-3-enyl. In one embodiment, Ring B of Formula V is a 5-6 membered heteroaryl selected from pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, indazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which may be substituted one time with Rb, wherein Rb is selected from the group consisting of fluoro, methyl, hydroxy, and hydroxymethyl. In one embodiment, Ring B of Formula V is imidazolyl or thiazolyl. In one embodiment, Ring B of Formula V is a 3-6 membered heterocycloalkyl selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, each of which may be substituted one or two times with Rb, wherein Rb is independently in each instance selected from fluoro and methoxy.

[0076] A compound of Formula I, I- A, I-B, II, III, IV, V, or V-A is capable of reacting with inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Such pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, for example, P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SCIENCES, (VCHA / Wiley - VCH, 2002); S. M. Berge, et al., Pharmaceutical Salts, 66 JOURNAL OF PHARMACEUTICAL SCIENCES 1 (1977).

[0077] The compounds of Formula I, I- A, I-B, II, III, IV, V, or V-A, or a pharmaceutically acceptable salt thereof, is preferably formulated as a pharmaceutical composition using apharmaceutically acceptable carrier and that may be administered to a subject in need thereof by a variety of routes. Preferably, such pharmaceutical compositions are for oral administration. Such pharmaceutical compositions and methods for preparing them are well known in the art. See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (L. V. Allen ed., Pharmaceutical Press, 22ndEdition, 2012).

[0078] A compound of Formula I, I-A, I-B, II, III, IV, V, or V-A, or a pharmaceutically acceptable salt thereof, may be administered either simultaneously with, or before, or after, one or more other therapeutic agents. The compound of Formula I, I-A, I-B, II, III, IV, V, or V-A, or a pharmaceutically acceptable salt thereof, when administered with one or more therapeutic agents, may be administered separately, by the same or different route or routes of administration, or together in the same pharmaceutical composition as the other therapeutic agent or agents. Where one or more additional therapeutic agents are administered, the administration of each therapeutic agent may be simultaneous, separate, or sequential. In one embodiment of the invention, a compound of Formula I, I-A, I-B, II, III, IV, V, or V-A, or a pharmaceutically acceptable salt thereof, is administered in combination with a CDK4 inhibitor. In one embodiment of the invention, a compound of Formula I, I-A, I-B, II, III, IV, V, or V-A, or a pharmaceutically acceptable salt thereof, is administered in combination with an antiestrogen. In one embodiment, a compound of Formula I, I-A, I-B, II, III, IV, V, or V-A, or a pharmaceutically acceptable salt thereof, is administered in combination with a CDK4 inhibitor and an antiestrogen. In one embodiment, the CDK4 inhibitor is a selective CDK4 inhibitor. In one embodiment, the CDK4 inhibitor is a CDK4 / 6 inhibitor. In one embodiment, the CDK4 inhibitor is a selective CDK4 inhibitor is 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino-2,3-dideoxy-D-threo-pentitol, or a pharmaceutically acceptable salt thereof. In an embodiment of the invention, the CDK4 / 6 inhibitor is abemiciclib, ribociclib, or palbociclib. In an embodiment of the invention, the antiestrogen is an aromatase inhibitor, a selective estrogen receptor degrader (SERD) or a selective estrogen receptor modulator (SERM). In one embodiment of the invention, the antiestrogen is fulvestrant or letrozole.

[0079] Compounds of this disclosure are named according to IUPAC, and may also be named according to CAS, and other naming conventions may be used to unambiguously identify a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0080] The compounds employed as initial starting materials in the synthesis of compounds of this disclosure are well known and, to the extent not commercially available, are readily synthesized using specific references provided, by standard procedures commonly employed by those of ordinary skill in the art or are found in general reference texts. Examples of known procedures and methods include those in general reference texts such as: COMPREHENSIVE ORGANIC TRANSFORMATIONS (VCH Publishers Inc., 1989); COMPENDIUM OF ORGANIC SYNTHETIC METHODS (Wiley Interscience, Volumes 1 - 10, 1974 - 2002); Michael B. Smith and Jerry March, ADVANCED ORGANIC CHEMISTRY, REACTIONS, MECHANISMS, AND STRUCTURE (Wiley Interscience, 5thed. 2001); Francis A. Carey and Richard J. Sundberg, ADVANCED ORGANIC CHEMISTRY, PART B, REACTIONS AND SYNTHESIS (Kluwer Academic / Plenum Publishers, 4thed.2000), and references cited therein.

[0081] The compounds of Formula I, I- A, I-B, II, III, IV, V, or V-A, or pharmaceutically acceptable salts thereof, may be prepared by a variety of procedures known in the art, some of which are illustrated in the Schemes, Preparations, and Examples below. The specific steps and methodology for each of the synthetic routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare compounds of Formula I, I- A, I-B, II, III, IV, V, or V-A, or pharmaceutically acceptable salts thereof. The products of each step in the schemes below may be isolated by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. In the schemes below, all substituents are as previously defined unless otherwise indicated. The reagents and starting materials are readily available to one of ordinary skill in the art.

[0082] Certain abbreviations are defined as follows: “ACN” means acetonitrile; “aq” means aqueous; “CAM” means ceric ammonium molybdate; “DCE” means 1,2-di chloroethane; “DCM’ means dichloromethane; “DIAD” means diisopropyl azodicarboxylate; “DMF” means dimethylformamide; “DMS” means dimethyl sulfide; “DMSO” means dimethyl sulfoxide; “dppf ’ means l,l'-bis(diphenylphosphino)ferrocene; “EtOAc” means ethyl acetate; “EtOH” means ethanol; “h” means hour / s; “FA” means formic acid; “KHMDS” means potassium bis(trimethylsilyl)amide; “MeCN” means acetonitrile; “MeOH” means methanol; “min” means minute / s; “MTBE” means methyl tert-butyl ether; “NaO / Bu” means sodium tert-butoxide; “NBS” means A-bromosuccinimide; “SSPhos” means sodium 2’-(dicyclohexylphosphino)-2,6-dimethoxy-l,l’-bipheny 1-3 -sulfonate hydrate; “TEA” means tri ethylamine; “THF” means tetrahydrofuran; and “TfOH” means trifluoromethanesulfonic acid.Scheme 1

[0083] Scheme 1 depicts the preparation of compounds of the present disclosure beginning with a sulfonyl- or sulfamoylhalide of formula (i) where Y is a halide, such as a sulfonyl or sulfamoyl chloride, and an amine of formula (ii) in the presence of a suitable base, such as sodium tert-butoxide, in a suitable organic solvent such as tetrahydrofuran.Scheme 2

[0084] Scheme 2 depicts the preparation of amine (ii) beginning with an appropriately substituted -fluoronitrile (iii). Sodium sulfide is added to a solution of o-fluoronitrile (iii) in an appropriate solvent, such as dimethylsulfoxide. To this solution are added ammonium hydroxide and aqueous sodium hypochlorite and the mixture is stirred at room temperature for at least 1 hour to provide, after a standard workup the amine (ii).Scheme 3

[0085] Scheme 3 depicts the preparation of o-fluoronitrile (iii). When R3 is a bond or C1-4 alkylene, an appropriately substituted o-fluoro-p-bromonitrile (iv) is reacted with an appropriate potassium trifluoroborate (v) under palladium catalyzed Suzuki-Miyuara cross-coupling conditions. The o-fluoro-p-bromonitrile (iv) may be reacted with an appropriate potassium trifluoroborate (v) in the presence of an appropriate palladium catalyst, such as allylpalladium(II) chloride dimer, a suitable base, such as cesium carbonate, and SSPhos in a suitable solvent, such as methoxy cyclopentane and water, at 100 °C for about 12 hr. Compounds of formula (iii) where R3 is NRi, and O are prepared from an appropriately substituted -fluoro- / ?-bromonitrile (iv) and amine (vi), Z = NRi ) or alcohol ((vi), Z = OH) under standard nucleophilic aromatic substitution reaction conditions well known to the skilled artisan. The requisite o-fluoro-p-bromonitriles (iv) are either commercially available or may be prepared from commercially available starting materials by methods well known to the skilled artisan.Preparation 14-bromo-5-cyclopropyl-2-fluorobenzonitrile

[0086] Two reactions were set up in parallel. CuBr (1.71 g, 11.92 mmol) was added to a solution of 4-amino-5-cyclopropyl-2-fluorobenzonitrile (1.40 g, 7.95 mmol) inMeCN (30 mL). tert-Butyl nitrite (1.23 g, 11.92 mmol, 1.42 mL) was added dropwise at 0 °C and the mixture was stirred at 60 °C for 3 hr. The mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Commercial hexanes / EtOAc = 5 / 1) and the two batches combined to give 2.2g (58%) of the title compound as a white solid.1H NMR (DMSO-de, 400 MHz) 87.94 (d, 1H), 7.61 (d, 1H), 2.05 (m, 1H), 1.00 (m, 2H), 0.78 (m, 2H).

[0087] The compound in the following table was prepared essentially as described in Preparation 1.Prep. No. Chemical name Structure1H NMRF4-bromo-5- DMSO-de, 400 MHz 2 cyclopropyl-2,3- 8 7.50 (d, 1H), 2.05 (m, 1H), difluorobenzonitrile 0.95 (m, 2H), 0.80 (m, 2H).Preparation 3Potassium (( l / 7-pyrazol- l-yl)methyl)trifluoroborate

[0088] KHMDS (1 M in THF, 299 mL) was added to a solution of IH-pyrazole (17.63 g, 258.9 mmol) and potassium (bromomethyl)trifluoroborate (40 g, 199.2 mmol) in methoxycyclopentane (800 mL) at 0 °C over 0.5 hr. The mixture was stirred at 80 °C for 8 h, then poured into water (200 mL) and concentrated under reduced pressure to give a residue. The crude product was stirred with acetone (500 mL) at 40 °C for 1.5 h, then filtered. The filtrate was concentrated under reduced pressure to give a residue, which was stirred with MTBE / acetone (200 mL / 80 mL) at 20 °C for 15 min. The precipitate was collected by filtration and dried to give a yellow solid, which was stirred with DCM / MeOH (200 mL / 10 mL) at 20°C for 0.5 hr. The solid was collected after filtration and dried to give 15 g (39% yield) of the title compound as a light yellow solid. 'H NMR (DMSO-de,400 MHz) 3 (ppm): 7.50 (d, 1 H), 7.19 (d, 1 H), 6.02 (m, 1 H), 3.06 (m, 2 H); MS m / z: [M++l] = 189.2.Preparation 44-amino-5 -cy clopropyl-2, 3 -difluorobenzonitrile4-amino-5-bromo-2,3-difluoro-benzonitrile

[0089] A solution of 4-amino-2,3-difluoro-benzonitrile (4.00 g, 26.0 mmol) in MeCN (200 mL) was treated with NBS (4.62 g, 26.0 mmol). The mixture was stirred at 50 °C for 3 hr. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 6.0 g (99%) of the title compound as a light yellow solid. This material was used without further purification.4-amino-5-cyclopropyl-2,3-difluorobenzonitrile

[0090] A mixture of 4-amino-5-bromo-2,3-difluoro-benzonitrile (3.00 g, 12.9 mmol), cyclopropylboronic acid (1.66 g, 19.3 mmol), Pd(dppf)Ch (942.1 mg, 1.29 mmol), Cs2CO3(8.39 g, 25.8 mmol) in 1,4-dioxane (180 mL) and H2O (30 mL) was degassed and purged with N2 for 3 times. The mixture was then heated and stirred at 90 °C for 3 hr under N2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Commercial hexanes / EtOAc = 3 / 1) to give 3.4 g (68%) of the title compound as a light yellow solid.1H NMR (DMSO-de, 400 MHz) 87.05 (d, 1H), 6.55 (s, 2H), 1.60 (m, 1H), 0.81 (m, 2H), 0.51 (m, 2H).Preparation 55 -bromo- 7 -fluor ochromane- 8-carbonitrilea) 2-(allyloxy)-4-bromo-6-fluorobenzonitrile

[0091] A stirred solution of 4-bromo-2,6-difluoro-benzonitrile (30.0 g, 138 mmol) and prop-2-en-l-ol (8.79 g, 151 mmol) in 1,4-dioxane (216 mL) and THF (84 mL) was cooled to 0 °C then treated with NaH (6.60 g, 165 mmol, 60% in mineral oil) in portions. The reaction was gradually warmed to 20 °C and stirred for 12 hr. The reaction was quenched with 1N aq. HCl (600 mL) and extracted into EtOAc (600 mL then 3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield 37.9 g of the title compound as a yellow solid. This material was used in the next step without further purification.b) 3-allyl-4-bromo-6-fluoro-2-hydroxybenzonitrile

[0092] A solution of 2-allyloxy-4-bromo-6-fluoro-benzonitrile (34.8 g, 136 mmol) in toluene (340 mL). was stirred at 290 °C for 20 min in a sealed vessel. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Commercial hexanes / EtOAc = 10 / 1 to 1 / 1) to give 22.2 g (61%) of the title compound as a yellow solid.1HNMR(DMSO-d6,400MHz) d 11.29 (m, 1H), 7.32 (m, 1H), 5.74 (m, 1H), 5.02 (dd, 1H), 4.85 (m, 1H), 3.50 (br s, 2H).c) 4-bromo-6-fluoro-2-hydroxy-3-(3-hydroxypropyl)benzonitrile

[0093] A solution of 3-allyl-4-bromo-6-fluoro-2-hydroxybenzonitrile (500.0 mg, 1.95 mmol, 1 eq) in THF (10 mL) was treated dropwise with BH3·THF (1 M in THF, 2.34 mL, 2.34 mmol) at 0 °C. The mixture was stirred at this temperature for another 2 hr, and then NaOH (3 M aq., 1.37 mL) and 30% aq. H2O2 (0.32 mL, 3.33 mmol) were added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 15 min. The reaction mixture was quenched by adding 2 M aq. HCl (10 mL) at 0 °C then diluted with H2O (5 mL) and extracted with EtOAc (30 mL, then 3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Commercial hexanes / EtOAc= 3 / 1 to 1 / 1) to give 120 mg (22%) of the title compound as a yellow oil.1H NMR (DMSO-de, 400 MHz) 87.34 (d, 1H), 3.44 (t, 2H), 2.79 (m, 2H), 1.64 (m, 2H).d) 5-bromo-7-fluorochromane-8-carbonitrile

[0094] A solution of 4-bromo-6-fluoro-2-hydroxy-3-(3-hydroxypropyl)benzonitrile (1.20 g, 4.38 mmol) in THF (24 mL) was cooled to 0 °C then treated with DIAD (1.02 mL, 5.25 mmol) and PPh3 (1.38 g, 5.25 mmol). The mixture was stirred at 20 °C for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Commercial hexanes / EtOAc = 5 / 1 to 3 / 1) to give 700 mg of the title compound as a yellow oil.1H NMR (DMSO-de, 400 MHz) 87.47 (d, 1H), 4.38 (m, 2H), 2.72 (m, 2H), 2.03 (m, 2H).Preparation 67-bromo-5-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carbonitrilea) 4-bromo-2-fluoro-6-(prop-2-yn-l-yloxy)benzonitrile

[0095] A solution of 4-bromo-2-fluoro-6-hydroxy-benzonitrile (23.0 g, 106 mmol) in acetone (230 mL) was treated with K2CO3 (44.15 g, 319.4 mmol) and 3 -bromoprop- 1-yne (17.21 mL, 159.7 mmol) at 0 °C. The mixture was stirred at 65 °C for 12 hr. The mixture was poured into H2O (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 26 g (96%) of the title compound as a yellow solid. This material was used in the next step without further purification. 'H NMR (DMSO-de, 400 MHz) 8 7.60 (m, 1H), 7.46 (s, 1H), 5.11 (d, 2H), 3.78 (t, 1H).b) 5-bromo-7-fluoro-2H-chromene-8-carbonitrile

[0096] A solution of 4-bromo-2-fluoro-6-(prop-2-yn-l-yloxy)benzonitrile (20.0 g, 39.4 mmol in toluene (600 mL) was pumped (25 mL / min) into a flow reactor (stainless steel, Coils reactor, 6.350(l / 4")mm, 500 mL, 280.0 °C). The residence time of flow reactor was set to 20.0 min with the pressure adjusted to 5 MPa. The mixture was collected and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc =100 / 0 to 95 / 5) to give 16.0 g (70%) of the title compound as a pink solid.1H NMR (DMSO-de, 400 MHz) 87.45 (d, 1H), 6.59 (td, 1H), 6.13 (td, 1H), 5.06 (dd, 2H).c) 7-bromo-5-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carbonitrile

[0097] A solution of 5-bromo-7-fluoro-2H-chromene-8-carbonitrile (5.00 g, 19.68 mmol); triethylammonium bis(catecholato)iodomethylsilicate (14.39 g, 29.52 mmol); and 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (776.3 mg, 984.0 pmol) in DMSO (250 mL) was pumped (0.916 mL / min) into a flow reactor (fluorinated ethylene propylene, Coils reactor, 3.175(l / 8”)mm, 54.95 mL, 40.0 °C) with light source (450 nm, 200 W). The residence time of flow reactor was set to 60.0 min. The mixture was poured into H2O (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Commercial hexanes / EtOAc = 10 / 1) to give 3.00 g (57%) of the title compound as a lightyellow oil. 'H NMR (DMSO-de, 400 MHz) 87.52 (d, 1H), 4.45 (dd, 1H,), 4.16 (dd, 1H), 2.25 (dt, 1H), 1.90 (m, 1H), 1.20 (m, 1H), 0.84 (q, 1H).Preparation 78-bromo-6-fluorochromane-5-carbonitrilea) 5-(allyloxy)-4-bromo-2-fluorobenzonitrile

[0098] A stirred solution of 4-bromo-2-fluoro-5-hydroxybenzonitrile (14.5 g, 67.4 mmol) in DMF (150 mL) was treated with Cs2CO3(32.8 g, 101 mmol). The reaction mixture was cooled to 0 °C, and 3 -bromoprop- 1-ene (16.30 g, 134.9 mmol) was added. The mixture was stirred at 20 °C for 16 h. The mixture was poured into water (140 mL) and extracted with EtOAc (2 x 200 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, hexanes / EtOAc = 9: 1) to give 16.0 g (93%) of the title compound. 'H NMR (DMSO-de, 400 MHz) 88.00 (dt, 1H), 7.70 (m, 1H), 6.10 (m, 1H), 5.49 (t, 1H), 5.35 (m, 1H), 4.73 (m, 2H).b) 2-allyl-4-bromo-6-fluoro-3-hydroxybenzonitrile

[0099] A stirred solution of 5-(allyloxy)-4-bromo-2-fluorobenzonitrile (16.00 g, 62.22 mmol) in 1,2-dichlorobenzene (140 mL) was heated to 180 °C and stirred at this temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, hexanes / EtOAc = 92: 8) to give 11.0g (69%) of the title compound. MS / H Z: [M++l] = 256.0.c) 4-bromo-6-fluoro-3-hydroxy-2-(3-hydroxypropyl)benzonitrile

[0100] A stirred solution of 2-allyl-4-bromo-6-fluoro-3 -hydroxybenzonitrile (5.00 g, 19.0 mmol) in THF (50 mL) at 0 °C was added BH3 DMS (2.20 g, 29.4 mmol) and stirred for 1 h. Then 30% aq. hydrogen peroxide (10.0 mL) and saturated aq. NaHCCh (1.60 g, 19.2 mmol) were added while keeping the reaction temperature below 5 °C. The mixture was allowed to warm up to 20 °C and stirred for 2 h. The mixture was acidified to pH 2 using 2AT aq. HC1 (100 mL) then extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (S1O2, hexanes / EtOAc = 95:5) to give 3.00 g (56%) of the title compound. MS m / z-. [M++l] =274.0.d) 8-bromo-6-fluorochromane-5-carbonitrile

[0101] A stirred solution of 4-bromo-6-fluoro-3-hydroxy-2-(3-hydroxypropyl)benzonitrile (3.00 g, 11.0 mmol) and PPhs (4.30 g, 16.5 mmol) in THF (30 mL) was treated with DI AD (3.30 g, 16.5 mmol). The reaction was stirred at 0 °C for 1 h then warmed to 20 °C. H2O (100 mL) was added, and the mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, hexanes / EtOAc = 95:5) to give 1.50 g (53%) of the title compound. 'H NMR (DMSO-de, 400 MHz) 87.79 (d, 1H), 4.35 (m, 2H), 2.93 (t, 2H), 2.00 (td, 2H).Preparation 84-bromo-6-fluoro-2,3-dihydrobenzofuran-7-carbonitrilea) 4-bromo-6-fluoro-2-hydroxy-3-(2-hydroxyethyl)benzonitrile

[0102] A solution of 3-allyl-4-bromo-6-fluoro-2-hydroxybenzonitrile (2.50 g, 9.80 mmol) in MeOH (25 mL) and DCM (25 mL) was cooled to -78 °C and sparged with O3 gas for 15 min. NaBH4 (2.50 g, 19.6 mmol) was then added in portions at -78 °C. The reaction was stirred at this temperature for 30 min then warmed to 20 °C over a period of 1 hr and stirred at this temperature for another 8 hr. The mixture was then quenched with lA7aq. HC1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with saturated aq. NaHCCh solution (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2.40 g (94%) of the title compound. MS m / z [M'-l] = 257.8b) 4-bromo-6-fluoro-2,3-dihydrobenzofuran-7-carbonitrile

[0103] A stirred solution of 4-bromo-6-fluoro-2-hydroxy-3-(2-hydroxyethyl)benzonitrile (2.40 g, 9.27 mmol) in THF (24 mL) at 0 °C was treated with PPhs (3.64 g, 13.9 mmol) and DIAD (2.80 g, 13.9 mmol). The reaction mixture was stirred at 0 °C for 1 h then quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, hexanes / EtOAc = 95:5) to give 1.20 g (54%) of the title compound. 'H NMR (DMSO-de, 400 MHz) 87.32 (d, 1H), 4.88 (t, 2H), 3.23 (td, 2H).Preparation 96-fluoro-4-(thiazol-2-yloxy)-2,3-dihydrobenzofuran-7-carbonitrilea) 6-fluoro-4-hydroxy-2,3-dihydrobenzofuran-7-carbonitrile

[0104] A stirred solution of 4-bromo-6-fluoro-2,3-dihydrobenzofuran-7-carbonitrile (2.50 g, 10.37 mmol) in 1,4-di oxane (25 mL) and water (25 mL) was treated with KOH (1.70 g, 31.1 mmol). The mixture was sparged with N2 gas for 30 min. LBuXPhos (1.30 g, 3.11 mmol) and Pd2(dba)3 (2.80 g, 3.11 mmol) were then added. The reaction mixture was heated at 100 °C and stirred at this temperature for 3 hr. The reaction mixture was cooled to 20 °C and treated with 1 M aq. HC1 to adjust the pH to ~5. Water (100 mL) was added, and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered,and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, hexanes / EtOAc = 7:3) to give 1.80 g (96%) of the title compound. MS m / z [M’-l] = 178.0b) 6-fluoro-4-(thiazol-2-yloxy)-2,3-dihydrobenzofuran-7-carbonitrile

[0105] A stirred solution of 6-fluoro-4-hydroxy-2,3-dihydrobenzofuran-7-carbonitrile (0.25 g, 1.4 mmol) and 2-bromothiazole (0.45 g, 2.8 mmol) in xylenes (7.5 mb) was treated with Cs2CO3(1.27 g, 3.91 mmol). The mixture was sparged with N2 gas for 10 min, followed by addition of JosiPhos SL-J009-1 Pd G3 catalyst (0.059 g, 0.14 mmol). The mixture was then heated at 150 °C and stirred at this temperature for 3 hr. The reaction mixture was cooled to 20 °C, quenched with water (30 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, hexanes / EtOAc = 85 / 15) to give 0.180 g (49%). MS / H Z: [M++l] = 263.0Preparation 104-bromo-6-fluoro-2-methyl-2,3-dihydrobenzofuran-7-carbonitrile

[0106] Two reactions were set up in parallel. A solution of 3-allyl-4-bromo-6-fluoro-2-hydroxybenzonitrile (3.00 g, 11.7 mmol) in DCE (90 mL) was added TfOH (653 pL, 7.38 mmol). The mixture was stirred at 60 °C for 12 hr. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue from both batches were combined and purified by column chromatography (SiO2, petroleum ether / EtOAc = 10 / 1 to 3 / 1) to give 3.00 g of the title compound as a white solid.NMR (DMSO-de, 400 MHz) 87.30 (d, 1 H), 5.29 (td, 1H), 3.34 (m, 1H), 2.83 (ddd, 1H), 1.48 (d, 3H).Preparation 117-bromo-5-fluoro-2,3-dihydrobenzofuran-4-carbonitrilea) 4-bromo-6-fluoro-3-hydroxy-2-(2-hydroxyethyl)benzonitrile

[0107] A solution of 2-allyl-4-bromo-6-fluoro-3 -hydroxybenzonitrile (6.00 g, 23.5 mmol) in MeOH (60 mL) and DCM (60 mL) was cooled to -78 °C and sparged with O3 gas until a pale blue color persisted. N2 gas was then bubbled through the mixture for 30 min before adding NaBH4 (1.70 g, 47.1 mmol) in portions at -78 °C. The reaction was warmed to 20 °C and stirred at this temperature for 30 min. The mixture was diluted with EtOAc (500 mL), successively washed with IA7 aq. HC1 solution (300 mL), saturated aq. NaHCCh solution (300 mL), and brine (300 mL), then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 5.10 g (83%) of the title compound. MS m / z [M'-l] = 257.9.b) 7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-carbonitrile

[0108] A stirred solution of 4-bromo-6-fluoro-3-hydroxy-2-(2-hydroxyethyl)benzonitrile (5.10 g, 19.8 mmol) in THF (50 mL) at 0 °C was treated with PPhs (7.70 g, 29.7 mmol) and DIAD (5.90 g, 29.7 mmol). The reaction mixture was stirred at 0 °C for 1 hr then at 20 °C for another 1 hr. The reaction was quenched with water (150 mL) and extracted with EtOAc (2 x 200 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, hexanes / EtOAc = 95:5) to give 2.60 g (54%) of the title compound.NMR (DMSO-d6, 400 MHz) 87.69 (d, 1H), 4.76 (t, 2H), 3.52 (d, 2H).Preparation 124-bromo-6-fluoro-1-methyl-1H-benzo[d]imidazole-7-carbonitrile and 7-bromo-5-fluoro-1-methyl-1H-benzo[d]imidazole-4-carbonitrileFa) 4-bromo-6-fluoro-1H-benzo[d]imidazole-7-carbonitrile

[0109] A solution of 2-amino-4-bromo-6-fluoro-3 -nitro-benzonitrile (5.00 g, 19.2 mmol) in HCO2H (50 mL) and n-BuOH (50 mL) was treated with Fe (10.74 g, 192.3 mmol) and NH4CI (10.28 g, 192.3 mmol). The reaction was stirred at 110 °C for 6 hr then filtered at room temperature. The filtrate and filter cake were collected separately. The filter cake was suspended in THF (400 mL) and was stirred at 20 °C for 1 hr, then filtered again. The two filtrates were combined and concentrated under reduced pressure. The residue was triturated with H2O (100 mL) at 20 °C for 10 min then air-dried to give 2.5 g (52%) of the title compound as a grey solid.1H NMR (DMSO-de, 400 MHz) 88.58 (s, 1H), 7.77 (d, 1H).b) 4-bromo-6-fluoro-1-methyl-1H-benzo[d]imidazole-7-carbonitrile and 7-bromo-5-fluoro-1-methyl-1H-benzo[d]imidazole-4-carbonitrile

[0110] A solution of 4-bromo-6-fluoro-lH-benzo[d]imidazole-7-carbonitrile (2.50 g, 10.4 mmol) in DMF (50 mL) treated with K2CO3 (2.88 g, 20.8 mmol) and stirred at 20 °C for 30 min. Mel (778 pL, 12.5 mmol) was added to the mixture and stirred at 20°C for 6 hr. The mixture was poured into H2O (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, petroleum ether / EtOAc = 1 / 0 to 3 / 7) to give 1.50 g of a mixture of the title compounds as a gray solid. 'H NMR (DMSO-de, 400 MHz) 88.57 (s, 1H), 8.50 (s, 1H), 7.81 (d, 1H), 7.78 (d, 1H), 4.11 (s, 3H), 4.05 (s, 3H).Preparation 137-bromo-5-fluoro-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carbonitrileF

[0111] A solution of 7-bromo-5-fluoro-3H-benzimidazole-4-carbonitrile (2.00 g, 8.33 mmol) in DMF (100 mL) was cooled to at 0 °C then treated with NaH (60 wt% in mineral oil, 399.95 mg, 10.00 mmol) and stirred at 0 °C for 30 min. Then 2-(trimethylsilyl)ethoxymethyl chloride (1.62 mL, 9.17 mmol) was added to the mixture at 0 °C. The reaction was stirred at 20 °C for 1.5 hr then quenched with saturated aqueous NH4CI (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography (SiO2, hexanes / ethyl acetate = 3 / 1) to afford 2.00 g of the title compound as a yellow oil.Preparation 144-((1H-pyrazol-1-yl)methyl)-2-fluoro-6-methoxybenzonitrile

[0112] A mixture of potassium ((lH-pyrazol-l-yl)methyl)trifluoroborate (2.45 g, 13.04 mmol), 4-bromo-2-fluoro-6-methoxy-benzonitrile (3 g, 13.04 mmol), Cs2CO3(12.75 g, 39.12 mmol), SSPhos (1.38 g, 2.61 mmol) and allylpalladium(II) chloride dimer (238.58 mg, 1.30mmol) in methoxy cyclopentane (40 mL) and water (10 mL) was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 12 hr under N2 atmosphere, then cooled and poured into water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated NaCl(aq) (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-80% EtOAc / petroleum ether) to give 2 g (64% yield) of the title compound as a yellow solid. 'H NMR (DMSO-de, 400 MHz) d (ppm): 3.91 (s, 3 H), 5.44 (s, 2 H), 6.33 (m, 1 H), 6.69 (d, 1 H), 6.99 (s, 1 H), 7.52 (s, 1 H), 7.89 (d, 1 H); MS m / z: [M+l]+= 232.3.

[0113] The compounds in the following table were prepared essentially as described in Preparation 14.Prep. MS(m / z)Chemical name Structure No. [M+1]+4-((lH-pyrazol-l-yl)methyl)-2,6- 15 220.3 difluorobenzonitrile4-((1H-pyrazol-1-yl)methyl)-2,5-difluorobenzonitrilez zo o4- (( 1 H-pyrazol- 1 -y l)methy 1) - 5 - 17 242.1 cyclopropyl-2-fluorobenzonitrileZ - - -,,4-((1H-pyrazol-1-yl)methyl)-5-cyclopropyl-2,3-difluorobenzonitrileF4-((1H-pyrazol-1-yl)methyl)-2,3-19 220.2 difluorobenzonitrileuCo5-((1H-pyrazol-1-yl)methyl)-7-fluorochromane-8-carbonitrile7-((177-pyrazol-l-yl)methyl)-5-fluoro- l,la,2,7Z>- 270.1 tetrahydrocyclopropa[c]chromene-4- o o*Zzz z O - ' — - - - -1carbonitrilep O u- - - 8-((l / 7-pyrazol- 1 -yl)methyl)-6- o u O - ' - 'z z z z 258.1 fluorochromane-5-carbonitrile-(( 1 H-pyrazol - 1 -yl)methyl)-6-fluoro- 244.2 2,3-dihydrobenzofuran-7-carbonitrile-(( 1 H-pyrazol - 1 -y l)methyl)-6-fluoro-2- methyl-2,3-dihydrobenzofuran-7- 258.1 carbonitrileF NC.7-((17 / -pyrazol-l-yl)methyl)-5-fluoro- 244.1 2,3-dihydrobenzofuran-4-carbonitrile X / JU —O N\ - -OF-(( 1 H-pyrazol - 1 -y l)methyl)-6-fluoro- 1 -NC\methyl-l / 7-benzo[<7]imidazole-7- 256.1 carbonitrile\==N7-(( 1 / 7-pyrazol - 1 -y l)methyl)-5-fluoro- 1 - 27 methyl- l / 7-benzo[< / ] imidazole-4- 256.1 oz - carbonitrile VT4-(( 1 / 7-pyrazol - 1 -y l)methyl)-6-fluoro- 1 - \ / o c-***28 ((2-(trimethylsilyl)ethoxy)methyl)-l / 7- ^ z. Z \ >< 1= 372.2 benzo[<7]imidazole-7-carbonitrileCM zXPreparation 296-((17 / -Pyrazol-l-yl)methyl)-4-methoxybenzo[<7]isothiazol-3-amine

[0114] Na2S (304 mg, 3.89 mmol) was added to a solution of 4-((1H-pyrazol-1-yl)methyl)-2-fluoro-6-methoxybenzonitrile (600 mg, 2.59 mmol) in DMSO (10 mL). The mixture was stirred at 70 °C for 16 h. Ammonia solution (28 wt% in water, 6 mL, 7.27 mmol) and NaClO solution (10%, 6 mL) were added, and the mixture was stirred at 20 °C for 1 hr. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc 30 mL (3 x 10 mL). The combined organic layers were washed with saturated NaCl(aq) (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes / EtOAc = 5 / 1) to give 250 mg (39% yield) of the title compound as a yellow solid. 'H NMR (DMSO-de, 400 MHz) d 3.90 (s, 3 H), 5.42 (s, 2 H), 6.30 (m, 1 H), 6.50 (s, 2 H), 6.74 (s, 1 H), 7.13 (s, 1 H), 7.49 (s, 1 H), 7.87 (d, 1 H); MS m / z: [M+l]+= 261.3.

[0115] The following compounds were prepared by the method of Preparation 29:Prep. MS(m / z)Chemical name StructureNo. [M+l]+6-((17 / -pyrazol-l -yl)methyl)-4- 30 249.2 fluorobenzo[<7] isothiazol-3 -amineN — s6-((177-pyrazol-l -yl)methyl)-5- 249.2 fl uorobenzo[<7] isothiazol-3 -amine O'z - F« —> / = / 5-((177-pyrazol-l-yl)methyl)-3,4-dihydro- ^^ z Z287.2 2H-chromeno[8,7-<7]isothiazol-9-amine CM zIN - SH2N*^ X6-((177-pyrazol-l -yl)methyl)-5- I X bJ Mz zcy c 1X 0 271.1 l opropy 1 benzo[<7] isothiazol-3 -amine° / - ^ / \^ Zz ZZH i 1 / =\ \ \ / \ 0)~~~ ~H2N- \4-((177-pyrazol- 1 -yl)methyl)-2-methyl-2,3- JCUO _ - _ - _ 287.1 dihydrobenzofuro[7,6-<7]isothiazol-8-amine6-((177-pyrazol-l -yl)methyl)-5- cyclopropyl-7-fluorobenzo[c / ]isothiazol-3- 289.1 amine6-((177-pyrazol-l -yl)methyl)-7- 249.0 fl uorobenzo[<7] isothiazol-3 -amineN - s7-((177-pyrazol-l-yl)methyl)-5,5a,6,6a- tetrahydrocyclopropa[3,4]chromeno[8,7- 299.1 ord\ isothiazol-3 -amine 0 -5-((177-pyrazol-l-yl)methyl)-8,9-dihydro- 287.1 777- chromeno [ 5, 6-<7] isothiazol- 1 -amineN - sH2N-^ \4-(( 177-pyrazol- 1 -yl)methyl)-2, 3 - z I 272.6-<7]isothiazol-8-amine z N 8 dihydrobenzofuro[7, z Xx oozyNz / \^z \ Z zH N i - \ sz« y—- H4 (th2N - \- iazol-2-yloxy)-2,3- 292.0 dihydrobenzofuro[7,6-<7]isothiazol-8-amine 1 1 X)z- _ z, - _ON - s5-(( 177-pyrazol- 1 -yl)methyl)-7, 8-H2N”^ X273.2 dihydrobenzofuro[4,5-<7]isothiazol- 1 -amine JCUO\ - 0N -S4-(( 177-pyrazol- 1 -yl)methy 1)- 1 -methyl- 177-H2N"^ X imidazo[4',5':5,6]benzo[l,2-<7]isothiazol-8- 285.1JUUOamine\=N4-((177-pyrazol-l-yl)methyl)-3-methyl-377- imidazo[4',5':5,6]benzo[l,2-<7]isothiazol-8- 285.1 amine4-(( 1 / 7-pyrazol - 1 -yl)methyl)- 1 -((2- (trimethylsilyl)ethoxy)methyl)-l / 7- 44 401.2 imidazo[4',5':5,6]benzo[l,2-< / ]isothiazol-8- aminePreparation 452-[3-(Dimethylamino)-6-dimethyliminio-xanthen-9-yl]-4-[2-[3-methoxy-4-[[4-methoxy-6- (pyrazol-l-ylmethyl)-l,2-benzoxazol-3-yl]sulfamoyl]anilino]ethylcarbamoyl] benzoatea) 4-Methoxy-6-(pyrazol-l-ylmethyl)-l, 2-benzoxazol-3-amine

[0116] K2CO3 (1.34 g, 9.73 mmol) and Mhydroxyacetamide (852.20 mg, 11.35 mmol) were added to a solution of 2-fluoro-6-methoxy-4-(pyrazol-l-ylmethyl)benzonitrile (750.0 mg, 3.24 mmol) in DMF (10 mb) and H2O (3 mb). The mixture was stirred at 70 °C for 12 hr. The mixture was poured into H2O (10 mb). The yellow precipitate was collected in a Buchner funnel under suction filtration, filtered and concentrated under reduced pressure to give 650 mg (74% yield) of the title compound as a yellow solid, used in the next step without further purification. MS m / z [M+l]+, 245.2.b) 2- Meth oxy- [4-methoxy-6-(pyrazol- 1-ylmethyl)- 1,2-benzoxazol-3-yl] -4-nitro-benzene sulfonamide

[0117] NaO / Bu (2 M, 3.38 mb) was added to a solution of 4-methoxy-6-(pyrazol-l-ylmethyl)-1,2-benzoxazol-3 -amine (550 mg, 2.25 mmol) in THF (10 mb) at 0 °C and the mixture was stirred for 0.5 hr. 2-Methoxy-4-nitro-benzenesulfonyl chloride (567mg, 2.25 mmol) was added and the resulting mixture was stirred at 20 °C for 4.5 hr. The mixture was poured into H2O (6 mb) and the pH adjusted to 2 with HC1 (2 M). The mixture was poured into H2O (20 mb) and extracted with ethyl acetate (3 x 30 mb). The combined organic layers were washed with brine (50 mb), dried over Na2SO4, filtered and concentrated under reduced pressure to give 700 mg (68%) of the title compound as a yellow solid. 'H NMR (DMSO-de, 400 MHz) 811.0 (br s, 1H), 8.06 (m, 1H), 7.93(m, 2H), 7.87 (d, 1H), 7.50 (d, 1H), 6.86 (s, 1H), 6.76 (s, 1H), 6.30 (m, 1H), 5.45 (s, 2H), 3.93 (s, 3H), 3.78 (s, 3H); MS m / z [M+l]+, 460.2.c) 4-Amino-2-methoxy-N-[4-methoxy-6-(pyrazol-l-ylmethyl)-l,2-benzoxazol-3-yl]benzene sulfonamide

[0118] SnC12*2H2O (1.47 g, 6.53 mmol) and HC1 (6 M, 435 pL) were added to a solution of 2-methoxy- / V-[4-methoxy-6-(pyrazol-l -ylmethyl)-!,2-benzoxazol-3-yl]-4-nitro-benzenesulfonamide (600 mg, 1.31 mmol) in EtOH (20 mL). The mixture was stirred at 70 °C for 1 hr then poured into H2O (50 mL) and extracted with DCM (5 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 600 mg (70% yield) of the title compound as a yellow solid.NMR (DMSO-de, 400 MHz) 89.03 (br s, 1H), 7.87 (d, 1H), 7.49 (d, 1H), 7.42 (d, 1H), 6.81 (s, 1H), 6.74 (s, 1H), 6.29 (m, 1H,), 6.15 (m, 2H), 5.43 (s, 2H), 3.91 (s, 3H), 3.67 (s, 3H); MS m / z [M+l]+, 430.2.d) tert-Butyl N-[2-[3-methoxy-4-[[4-methoxy-6-(pyrazol-l-ylmethyl)-l,2-benzoxazol-3-yl] sulfamoyl] anilin o] ethyl] carbamate

[0119] A solution of 4-amino-2-methoxy-A-[4-methoxy-6-(pyrazol-l-ylmethyl)-l,2-benzoxazol-3-yl]benzenesulfonamide (200 mg, 466 pmol) and tert-butyl A-(2-oxoethy I (carbamate (74 mg, 466 pmol) in MeOH (10 mL) was stirred at 20 °C for 1 hr. Sodium cyanoborohydride (87.80 mg, 1.40 mmol) was added and the mixture was stirred at 40 °C for 14 hr. The mixture was poured into H2O (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 0 / 1) to give 90 mg (23% yield) of the title compound as a white solid. MS m / z [M+l]+, 573.3.e) 4-(2-Aminoethylamino)-2-methoxy-A-[4-methoxy-6-(pyrazol-l-ylmethyl)-l,2-benzoxazol-3-yl] benzenesulfonamide

[0120] HC1 (4 M in EtOAc, 2 mL) was added to a solution of tert-butyl A-[2-[3-methoxy-4-[[4-methoxy-6-(pyrazol-l -ylmethyl)- l,2-benzoxazol-3-yl]sulfamoyl]anilino]ethyl]carbamate (90 mg, 157 pmol) in DCM (5 mL). The mixture was stirred at 20°C for 2 hr then concentrated under reduced pressure to give 75 mg of the title compound HC1 salt as a light yellow solid, used in the next step without further purification. MS m z [M+l]+, 473.2.f) 2- [3-(Dimethylamino)-6-dimethyliminio-xanthen-9-yl] -4- [2- [3-methoxy-4- [ [4-methoxy-6-(pyrazol-l-ylmethyl)-l,2-benzoxazol-3-yl]sulfamoyl]anilino]ethylcarbamoyl] benzoate

[0121] TEA (15 mg, 20.5 pL, 147 pmol) and 2-[3-(dimethylamino)-6-dimethyliminio -xanthen-9-yl]-4-(2,5-dioxopyrrolidin-l-yl)oxycarbonyl-benzoate (26 mg, 49 pmol) were added to a solution of 4-(2-aminoethylamino)-2-methoxy-N-[4-methoxy-6-(pyrazol-l-ylmethyl)-l,2-benzoxazol-3-yl]benzenesulfonamide (HC1 salt, 25 mg, 49 pmol) in DMF (1 mL). The mixture was stirred at 20°C for 2 hr, then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H2O(0.2% FA)-ACN]; gradient: 20%-50% B over 8.0 min) to give 6.7 mg (15% yield) of the title compound as a purple solid.1H NMR (DMSO-de, 400 MHz) 88.81 (m, 1H), 8.14 (m, 1H), 8.06 (d, 1H), 7.86 (d, 1H), 7.64 (s, 1H), 7.49 (d, 1H), 7.45 (d, 1H), 6.77 (s, 1H), 6.72 (m, 2H), 6.53 (m, 6H), 6.30 (d, 1H), 6.29 (m, 2H), 5.42 (s, 2H), 3.90 (s, 3H), 3.69 (s, 3H), 3.21 (m, 2H), 2.95 (s, 12H); MS m / z [M+l]+, 885.3.EXAMPLESExample 1N-(6-((17 / -pyrazol-l-yl)methyl)-4-methoxybenzo[<7]isothiazol-3-yl)-2,6- dimethoxybenzenesulfonamide

[0122] NaOt-Bu (2 M in THF, 288 pL) was added dropwise to a solution of 6-((17 / -pyrazol-l-yl)methyl)-4-methoxybenzo[<7]isothiazol-3 -amine (30 mg, 115 pmol) in THF (2 mL) at 0 °C and the mixture was stirred for 1 hr. 2,6-Dimethoxybenzenesulfonyl chloride (82 mg, 346 pmol) in THF (1 mL) was added dropwise at 0 °C and the resulting mixture was stirred at 20 °C for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-HPLC (eluting with 25-60% ACN in water, FA modifier) to give 7.5 mg (14% yield) of the title compound as a white solid. 'H NMR (400 MHz, DMSO-t / e) d (ppm): 3.73 (s, 6 H), 4.08 (s, 3 H), 5.46 (s, 2 H), 6.30 (s, 1 H), 6.72 (d, 2 H), 6.95 (s, 1 H), 7.28 (s, 1 H), 7.44 (m, 1 H), 7.50 (s, 1 H), 7.89 (d, 1 H), 9.36 (br s, 1 H); MS m / z [M+l]+, 461.0.

[0123] Beginning with the appropriate amine and sulfonyl or sulfamoyl chloride, the following compounds were prepared essentially as described in Example 1:MSExample Chemical name Structure (m / z)[M+l]+N-(6-(( 1 H-pyrazol- 1 -yl)- methyl)-4-methoxybenzo-Meo\ V2 [d\ isothiazol-3 -yl)-2- 431.0 methoxybenzenesulfon- O " n oMeO^ Namide7V-(6-(( l / f-pyrazol- 1 -yl)-Cl\ Vmethyl)-4-methoxybenzo- X / \ J \3 435.0[d\ isothiazol-3 -yl)-2- OHn o chlorobenzenesulfonamide MeO^ —N7V-(6-((17 / -pyrazol- 1 - yl)methyl)-4-Meo\ V ^-sk zs\ J \4 methoxybenzo [d\ isothiazol 432.0 -3 -yl)-2-methoxypyridine- v “ X i nMeO^N3 -sulfonamide7V-(6-(( l / f-pyrazol- 1 -yl)- methyl)-4-methoxybenzo- N-S\ J \5 [<7]isothiazol-3-yl)-2,4- 461.0 dimethoxybenzenesulfon- MeOXMeO^amide7V-(6-(( l / f-pyrazol- 1 -yl)- methyl)-4-methoxybenzo- °V° / / ^syF\ Z \ - - J \ A \.6 [d] isothiazol-3 -yl)-2-meth- \\ \H449.0 oxy- 5 -fluorobenzeneV^^OMe JBN / ^MeO^ Nsulfonamide7V-(6-(( 1 / 7-pyrazol- 1 -yl)- V / / "s(methyl)-4-methoxybenzo- / \ - - J X \407.1 [<7] isothiazol-3 - U XXX> yl)cyclohexanesulfonamide MeO^ N 7V-(6-(( 177-pyrazol- 1 -yl)- methyl)-4-methoxybenzo- X \ X v< _ / N - J X / \X 421.1 [<7] isothiazol-3 -yl)cyclo- hexylmethanesulfonamide MeO^ XX ONTV-(cyclohexylsulfamoyl)- 6-((177-pyrazol-l -yl)meth- XX VN — \ A. 422.1 yl)-4-methoxybenzo- XX / O[d] isothiazole-3 -amine MeO^ N7V-(7V-cyclohexyl-7V- methylsulfamoyl)-6-((177- XX °v°pyrazol- 1 -y l \ A / \ N-' J-'X \)meth-yl)-4- 436.1 methoxybenzo- ' X i oMeO^ ' N[d\ isothiazole-3 -amine7V-(6-(( 177-pyrazol- 1 -yl)- methyl)-4-fluorobenzo-Meo\ v°[d\ isothiazol-3 -yl)-2- Xz \ X \ 419.0 methoxybenzenesulfon- O " X X oamide7V-(6-(( 177-pyrazol- 1 -yl)- methyl)-4-fluorobenzo-Meo\ V ^-s[d\ isothiazol-3 -yl)-2, 6- / L / \ - - X / / \X 449.0 dimethoxybenzenesulfon- XX^OMeI J. N / amide7V-(6-(( 1 / 7-pyrazol- 1 -yl)- methyl)-5-fluorobenzo-M6°\ k \ / s^\° J \[d\ isothiazol-3 -yl)-2- 419.0OHn IL o -z methoxybenzenesulfon- N amide F7V-(6-(( 177-pyrazol- 1 -yl)-Meo\methyl)-5-fluorobenzo- k / s\ / / \[d\ isothiazol-3 -yl)-2, 6- 449.0kz '°Me1 JL dimethoxybenzenesulfon- Namide / o - 7V-(5-((177-pyrazol-l -yl)- CTMeO\ N-smethyl)-3,4-dihydro-2H- / \ J / \\< £ x>\ ochromeno[8,7-<7]isothiazol- ° / - 7^ 457.1O " / \^ / “ZX i o9-yl)-2-methoxybenzene- i \ ' N\ / CA - sulfonamide7V-(5-((177-pyrazol- 1 - z - - yl)methyl)-3,4-dihydro- 277-chromeno[8,7-d]iso- o 487.1 thiazol-9-yl)-2,6-dimeth- oxybenzenesulfonamide7V-(6-(( 177-pyrazol- 1 -yl)- °%Z N-Smethyl)-4-methoxy- \ \benzo[d] isothiazol-3 -y 1)- 443.0 2,3-dihydrobenzofuran-7- CA” n o\ / MeO^ N sulfonamide7V-(6-(( 177-pyrazol- 1 -yl)-O\Z N-Smethyl)-4-methoxy- / ^y \ \benzo[d] isothiazol-3 -yl)- 458.0(A" J I O benzo[d]thiazole-4- \ _ IJ MeO N sulfonamide7V-(6-(( 1 / 7-pyrazol- 1 -yl)- methyl)-4-methoxy-E‘°\s\ / / \benzo [d] isothiazol-3 -yl)-2- 463.0o " n oethoxy-5-fluorobenzene- \ MeO^ —NFsulfonamideN-(6-(( 1 / 7-pyrazol- 1 -yl)- Fmethyl)-4-methoxy- benzo [d] isothiazol-3 -yl)-2- o vN — J \~ A\. 470.1 fluoroquinoline- 8 - L> " JU O sulfonamide MeO^NN-(6-(( 1 / 7-pyrazol- 1 -yl)- methyl)-4-methoxy- V \ j \benzo [d] isothiazol-3 -y 1) - 5 - N — \ A. 487.0 fluoro-2-trifluoromethyl- V ACF1 1 OMeO^ ' N benzenesulfonamideN-(6-(( 1 / 7-pyrazol- 1 -yl)- methyl)-4-methoxy- °W° N-S / \ / \benzo [d] isothiazol-3 -y 1) - 5 - MeO~^ / 499.0 methoxy-2-trifluorometh- V XcF 1 1 OMeO^ — N ylbenzenesulfonamideN-(6-(( 1 / 7-pyrazol- 1 -yl)- methyl)-4-methoxy- N-S\ / \benzo [d] isothiazol-3 -yl)-2- 465.0 chloro-4-methoxy- LA» n oMeO MeO^ — —NbenzenesulfonamideN-(6-(( 1 / 7-pyrazol- 1 -yl)- methyl)-4-methoxy- °v°\ / / \benzo [d] isothiazol-3 -yl)-4- / N - \n \H449.1 fluoro-2-methoxy- JL JLF MeO^ Nbenzenesulfonamide7V-(6-(( 1 / 7-pyrazol- 1 -yl)- methyl)-5-cyclopropyl- benzo [d] isothiazol-3 -yl)-2- z — - 441.0 methoxybenzene- sulfonamide7V-(6-(( 177-pyrazol- 1 -yl)-Meo\ V ) 1= / k / \ / / \methyl)-5-cyclopropyl- N- — \\ ®benzo[d] isothiazol-3 -y 1)- qKzi §V / ^°MeII JL N 471.1 2,6-dimethoxybenzene- sulfonamideO7V-(6-(( 177-pyrazol- 1 -yl)- methyl)-4-methoxy- Vs\ / / \benzo [d] isothiazol-3 -yl)-2-F~\ Z - - \ 444.0 cyano- 5 -fluoroMeO^ N benzenesulfonamide7V-(6-(( 177-pyrazol- 1 -yl)- methyl)-4-methoxy- °V° N-S\ / \Me-. _ / benzo [d] isothiazol-3 -yl)-2- \ H r-==\ 450.0 chloro-5-methylpyridine-3- I k II I ON "MeO N sulfonamide7V-(6-(( 177-pyrazol- 1 -yl)- methyl)-4-methoxy-,N— sbenzo [d] isothiazol-3 -yl)- 495.1A3,5- dimethyl- 1 -phenyl- 1 H-Hif ] O\. - / N Me 4L AMeCT — ' N pyrazole-4-sulfonamide7V-(6-(( 177-pyrazol- 1 -yl)- methyl)-4-methoxy- °V°\ / \benzo [d] isothiazol-3 -y 1) - 5 - F\ Z - - \ A- \\ \H433.0 fluoro-2-methyl- Vz^MeJ L / MeO^ Nbenzenesulfonamide7V-(6-(( 1 / 7-pyrazol- 1 -yl)- methyl)-4-methoxy- °v°benzo[d] isothiazol-3 -yl)- MeO~^ / N — / K 461.1 2,5-dimethoxy- MeO^ N benzenesulfonamideN-(6-(( 1 / 7-pyrazol- 1 -yl)- methyl)-4-methoxy- Vx^ / \ / \benzo [d] isothiazol-3 -y 1) - 5 -C|-\ Z - - \ xS.\\ \Hx==\ 465.0 chloro-2-methoxy- 11 xlMeO^ N benzenesulfonamideN-(6-(( 1 / 7-pyrazol- 1 -yl)- Vmethyl)-4-methoxy- \benzo[d] isothiazol-3 -yl)- OHX I Q 459.0 2,3 -dihydrobenzo[b] [1,4]- 0 \ MeO^Ndioxine-6-sulfonamideN-(6-(( 1 / 7-pyrazol- 1 -yl)- methyl)-4-methoxy- °V° N-S\ / \benzo [d] isothiazol-3 -yl)-2- / N - \ xk.U \ H ^Ss r====\ 453.0 chloro-4-fluoro- kA X 1 OF MeO^ N benzenesulfonamideN-(6-(( 1 / 7-pyrazol- 1 -yl)- methyl)-4-methoxy- N-Sx^ / \ J \benzo [d] isothiazol-3 -yl)-2- / N-^ \ xs.U \H485.0 trifluoromethoxy- V^X^OCF31 1MeO^ N benzenesulfonamide7V-(5-((177-pyrazol-l -yl)- °%Z N-Smethyl)-3,4-dihydro-277- x^ Z \ / / \MeO-^ / N — xK\\ \chromeno[8,7-<7]isothiazol-HII 487.1 9-yl)-2, 5 -dimethoxy - benzenesulfonamide7V-(5-((177-pyrazol-l -yl)- V r-5?methyl)-3,4-dihydro-277- \ / / \N-" \ A.chromeno[8,7-<7]isothiazol- II I y 491.0 9-yl)-5-chloro-2-methoxy- '"'N benzenesulfonamide7V-(5-((177-pyrazol-l -yl)- methyl)-3,4-dihydro-277- \ V\ / \ J \chromeno[8,7-<7]isothiazol- / \\ \Hr===\J| 499.1 9-yl)-5-isopropyl-2- I methoxy- benzenesulfonamide7V-(4-(( 1 / 7-pyrazol- 1 -yl)- °\Z N-Smethyl)-2-methyl-2,3- \ \< \Hdihydrobenzofur[7,6-<7]iso- V^x^'°Me1 JL N z 457.1 thiazol-8-yl)-2-methoxy- benzenesulfonamide7V-(4-(( 1 / 7-pyrazol- 1 -yl)- methyl)-2-methyl-2,3-Meok\ \ / \^° / / \dihydrobenzofur[7,6-<7]iso- V^X ^~OMe1 JL N Z 487.1 thiazol-8-yl)-2,6-di- methoxy- benzenesulfonamide7V-(6-((177-pyrazol- 1 - yl)methyl)-4-methoxy- °V \° J \benzo [<7] isothiazol-3 -y 1) - 3 - / Al \Hr==\ 460.1H2N\\ \ || ] \ \ (aminomethyl)-4-methoxy- MeO MeCT — ' ' N benzenesulfonamide7V-(6-((17 / -pyrazol- 1 - Vyl)methyl)-5-, _ z \ N- — J! \ Z \^cyclopropylbenzo[<7] isothiaH\ JHY ] 401.1 zol-3-yl)-l / f-pyrazole-4- - N sulfonamide7V-(6-((17 / -pyrazol- 1 - \ Vyl)methyl)-5- V z \ J! \cyclopropylbenzo[<7] isothiaH\ j " 11 1 415.1 y^ Nzol-3-yl)-5-methyl-l / f- pyrazole-4-sulfonamide7V-(6-((17 / -pyrazol- 1 - yl)methyl)-5- \ y _ V z\ / / \cyclopropylbenzo[<7] isothia°OHi ) o 416.0 zol-3-yl)-5- N methylisoxazole-4- sulfonamide7V-(6-((17 / -pyrazol- 1 - °V°yl)methyl)-5-cyclo- z^ z \Z^Z N- J^ \! Z \s^ propylbenzo[<7]isothiazol- £> " n 426.1 3-yl)-6-methylpyridine-3- sulfonamide7V-(6-((17 / -pyrazol- 1 - °V-° N-Syl)methyl)-5-cyclo- Z z^^Zz \ N- J^!\ z \^ propylbenzo[<7]isothiazol- V ZNT 1 426.1 / N3 -y 1)- 5 -methy Ipyr idine-2- sulfonamide7V-(6-((177-pyrazol- 1 - \ Vyl)methyl)-5- cyclopropylbenzo[<7] isothia \ I ] 429.1 zol-3-yl)- 1,5-dimethyl- 177- ' N pyrazole-4-sulfonamide7V-(6-((177-pyrazol- 1 - \ \ _ V / s\ J \yl)methyl)-5- \ NH— / Xcyclopropylbenzo[<7] isothia IL y^ JL J. N / 429.1 zol-3-yl)-3,5-dimethyl-177- pyrazole-4-sulfonamide7V-(6-((177-pyrazol- 1 - V \ j r-5? \yl)methyl)-5- cyclopropylbenzo[<7] isothiahnAHii i 451.1 zol-3-yl)-177-pyrrolo[2,3- b]pyridine-3-sulfonamide7V-(6-((177-pyrazol- 1 - yl)methyl)-5- °v°cyclopropylbenzo[<7] isothia480.1 zol-3-yl)- 1,3-dimethyl- 177- - NZJ T 1 o pyrazolo[3,4-7]pyridine-5- sulfonamide7V-(6-((177-pyrazol- 1 - yl)methyl)-5- °V° / ?"s4O / ===-_ / \ _ _ \ cyclopropylbenzo[<7] isothia531.1 zol-3 -yl)- 1 -(( 177-pyrazol-4- rynyl)sulfonyl)-177-pyrazole- N AH / \4-sulfonamide7V-(6-((177-pyrazol- 1 - yl)methyl)-5- \ V / / "sv cyclopropylbenzo[<7] isothia o \ _ <1 \°u / f H'Wzol-3 -yl)- 5 -methyl- 1 -((3- J 559.1 t JI / N. / methyl- l / f-pyrazol-4- h rk y / _ f 1 " yl)sulfonyl)-l / 7-pyrazole- N AH / \4-sulfonamide7V-(6-((177-pyrazol- 1 - yl)methyl)-5- cyclopropylbenzo[<7] isothia 389.1° ~ / xzol-3- w;yl)cyclobutanesulfonamideIZ°\ / ^'z7V-(6-((177-pyrazol- 1 - 1yl)methyl)-5- j~\fluorobenzo[<7] isothiazol-3 - 403.1H Oyl)-l- z- - - phenylmethanesulfonamide FX7V-(6-((177-pyrazol- 1 -Meo\ VX / \yl)methyl)-5-cyclopropyl- J \7-fluorobenzo[<7]isothiazol- 459.1O " Y l ON3 -yl)-2-methoxy- benzenesulfonamide7V-(6-((177-pyrazol- 1 -Meo\ VX / \yl)methyl)-5-cyclopropyl- / N - J \ \ ^F7-fluorobenzo[<7]isothiazol- Vx^"0MeII J. N z 489.1'"'N3-yl)-2,6-dimethoxy- benzenesulfonamide7V-(6-((177-pyrazol- 1 - yl)methyl)-7- Vfluorobenzo[<7] isothiazol-3 - / / ^ 407.2 yl)- 1,2-dimethyl- 177- JHimidazole-4-sulfonamide7V-(6-((177-pyrazol- 1 - yl)methyl)-7- °V°fluorobenzo[<7] isothiazol-3 - 429.2 yl)benzofuran-2- FY XX O sulfonamide7V-(6-((177-pyrazol- 1 - yl)methyl)-7-. _ / \ / \fluorobenzo[<7] isothiazol-3 - 445.2< 1,H( T yl)benzo[7]thiophene-3- Q sulfonamide7V-(6-((177-pyrazol- 1 - yl)methyl)-7- K V\ y \fluorobenzo[<7] isothiazol-3 - S N - \ 367.2 yl)- 1 -cyclopropylU COmethanesulfonamide7V-(6-((177-pyrazol- 1 - yl)methyl)-7- / \ / \ J \fluorobenzo[<7] isothiazol-3 - ‘--' X N-^ \ As. / F 381.1 yl)- 1 -( 1 -methy Icycloprop- lX / O yl)methanesulfonamide7V-(6-((177-pyrazol- 1 - °v°yl)methyl)-7- _ _ / s\ / / \N-^ \ As / F 395.2 fluorobenzo[<7] isothiazol-3 - X uCQyl)cyclohexanesulfonamide7V-(5-((177-pyrazol- 1 - Vyl)methyl)-3,4-dihydro- / _ _] / \ N - / X / \2 / 7-chromeno[8,7- 419.1 v XX / O<7]isothiazol-9-yl)cyclo- pentanesulfonamide7V-(5-((177-pyrazol- 1 - yl)methyl)-3,4-dihydro- V\ \ \2 / 7-chromeno[8,7- 473.1 d\ isothiazol-9-yl)- 1 - XX / O (bicy clo[2.2.2] octan- 1 - yl)methanesulfonamide7V-(5-((177-pyrazol- 1 - yl)methyl)-3,4-dihydro-Me0\ X -Z N— s2 / 7-chromeno[8,7- Z~~— / / - H - \ / K r-==\ <7]isothiazol-9-yl)-2- 491.2 cyclohexyl-2- o xxx> methoxy ethane- 1 - sulfonamide7V-(5-((177-pyrazol- 1 - yl)methyl)-3,4-dihydro- n — ’s2 / 7-chromeno[8,7- 493.1 d} isothiazol-9-yl)- 1 -(3 - Ct isopropoxytetrahydrofuran-N3 -yl)methanesulfonamide7V-(5-((177-pyrazol- 1 -Meo\yl)methyl)-8,9-dihydro- 777-chromeno[5,6-<7]iso- 457.2O " i i othiazol- 1 -yl)-2-methoxy- f N benzenesulfonamide7V-(7-((177-pyrazol- 1 - yl)methyl)-5,5a,6,6a-MeOy °V°tetrahydrocyclopropa[3,4]- 469.1 chromeno[8,7-<7]isothiazol- G jCi — N3 -yl)-2-methoxy- benzenesulfonamide / i--“ '^z \^x Z' yy y7V-(7-((177-pyrazol- 1 - CT yy J yy J i i i\ \ ® °O- 'yl)methyl)-5,5a,6,6a- tetrahydrocyclopropa[3,4]c. JA 499.1 hromeno [ 8, 7-<7] isothiazol- \_S 'o -J- - \ / \ / \ / o o o 4? — — — Ns s E - - - - - - 3-yl)-2,6-dimethoxy- benzenesulfonamide7V-(4-((177-pyrazol- 1 - yl)methyl)-2,3-dihydro- benzofuro[7,6-<7]isothiazol- 443.2 8-yl)-2-methoxy- X N benzenesulfonamide2-methoxy-7V-(4-(thiazol-2- yloxy)-2,3- “e°\ k \ / \S° / / \N - - dihydrobenzofuro[7,6- 462.0O Y 1 J > <7]isothiazol-8- o / yl)benzenesulfonamide7V-(4-((177-pyrazol- 1 - yl)methyl)-2,3-dihydro- benzofuro[7,6-<7]isothiazol- 473.4 8-yl)-2,6-dimethoxy- < N benzenesulfonamide7V-(4-((177-pyrazol- 1 -M6°\yl)methyl)-2,3-dihydro- k / s\ J \benzofuro[7,6-<7]isothiazol- 473.2 O " 1 1 o8-yl)-2, 5 -dimethoxy - \ oNOMe \ / benzenesulfonamide7V-(4-((177-pyrazol- 1 -MeO\ °V° N-syl)methyl)-2,3-dihydro- benzofuro[7,6-<7]isothiazol- 477.0 Q " 1 1 O8-yl)-5-chloro-2-methoxy- \ oz NCl \ / benzenesulfonamide7V-(4-((177-pyrazol- 1 -MeO\yl)methyl)-2,3-dihydro- k / \ / / \benzofuro[7,6-<7]isothiazol- 485.2 O " i i o8-yl)-5-isopropyl-2-meth- OZyTNoxybenzenesulfonamide7V-(5-((177-pyrazol- 1 -Me°\ °V° N-syl)methyl)-7,8-dihydro- benzofuro[4,5-<7]isothiazol- 443.2 O " i i o1 -yl)-2-methoxy- / N benzenesulfonamide \ - O7V-(4-((177-pyrazol- 1 -MeO\ \s° z^-syl)methyl)-177-imidazo- X / \ / \[4',5':5,6]benzo[l,2-<7]iso- 471.1 Xx ^~°Me1 JL N zthiazol-8-yl)-2,6-dimeth- oxybenzenesulfonamide \=N7V-(4-((177-pyrazol- 1 - yl)methy 1)- 1 -methyl- 177-Meo\ r-sk zs\ / / \ imidazo[4',5':5,6]benzo[l,2 / - - \.xk.485.1 -<7]isothiazol-8-yl)-2,6- Xx ^OMe1 J. N Z dimethoxybenzene- \=NsulfonamideTV- (4- ((1 / 7-pyrazol- 1 - yl)methyl)-3-methyl-377- imidazo[4',5':5,6]benzo[l,279-<7]isothiazol-8-yl)-2,6- dimethoxybenzene- sulfonamideExample 80A-(7-((l / 7-pyrazol-l -yl)methyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]chromeno[8,7-< / ]isothiazol- 3 -yl)-2-methoxybenzenesulfonamide - Diastereomer 1andExample 81A-(7-((177-pyrazol-l-yl)methyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]chromeno[8,7-<7]isothiazol- 3-yl)-2-methoxybenzenesulfonamide - Diastereomer 2

[0124] Racemic A-(7-((17 / -pyrazol-l-yl)methyl)-5, 5a, 6,6a- tetrahydrocyclopropa[3,4]chromeno[8,7-<7]isothiazol-3-yl)-2-methoxybenzenesulfonamide (100.0 mg, 200.6 pmol) was separated by SFC (column: DAICEL CHIRALPAK® OD (250 x 30 mm, 10 pm); mobile phase A: CO2; mobile phase B: EtOH with 0.1% NH4OH; gradient elution with 25% to 45% mobile phase B over 23 min). The first eluting isomer was collected to yield 23.0 mg (22%) of Diastereomer 1 as a white solid. MS m / z [M⁺+1] = 469.1. The second eluting isomer was collected to yield 23.6 mg (23%) of Diastereomer 2 as a white solid. MS m / z: [M++l] = 469.1.A^-(7-((17 / -pyrazol-l-yl)methyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]chromeno[8,7-<7]isothiazol- 3 -yl)-2,6-dimethoxybenzenesulfonami de - Diastereomer 1andExample 83 / V-(7-((l / 7-pyrazol-l -yl)methyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]chromeno[8,7-< / ]isothiazol- 3-yl)-2,6-dimethoxybenzenesulfonamide - Diastereomer 2

[0125] Racemic ^-(7-((17 / -pyrazol-l-yl)methyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]chromeno[8,7-<7]isothiazol-3-yl)-2,6-dimethoxybenzenesulfonamide (100.0 mg, 200.6 pmol) was separated by SFC (column: DAICEL CHIRALPAK® AD (250 x 30 mm, 10 pm); mobile phase A: CO2; mobile phase B: 50% MeOH / 50% MeCN with 0.1% NH4OH; isocratic elution with 38% mobile phase B). The first eluting isomer was collected to yield 23.0 mg (22%) of Diastereomer 1 as a white solid. MS m / z [M++l] = 499.1. The second eluting isomer was collected to yield 28.8 mg (28%) of Diastereomer 2 as a white solid. MS m z [M++l] = 499.1.Example 842-hydroxyphenyl (6-((lH-pyrazol-l-yl)methyl)-5-cyclopropylbenzo[d]isothiazol-3-yl)sulfamate

[0126] A solution of 6-((17 / -pyrazol-l-yl)methyl)-5-cyclopropylbenzo[<7]isothiazol-3-amine (200.0 mg, 739. 8 pmol) in THF (6 mL) was treated with Z-BuONa (2 M in THF, 739.8 pL) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. A solution of benzo[<7][l,3,2]dioxathiole 2,2-dioxide (191.0 mg, 1.11 mmol) in THF (1 mL) was added, and the mixture was stirred at 20 °C for 1 hr.The mixture was quenched with saturated aq. NH4Cl (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified first by preparative TLC (SiO2, EtOAc) then purified by preparative HPLC (column: Phenomenex Luna C18 (100 x 40 mm, 5 μm; mobile phase A: H2O with 0.04% HC1; mobile phase B: MeCN; gradient elution with 30%-70% B over 8.0 min) to give 27 mg (36%) as a white solid. MS m / z [M++l] = 443.1. 'H NMR (DMSO-d6, 400 MHz) 87.98 (s, 1H), 7.86 (d, 1H), 7.48 (m, 2H), 7.06 (m, 2H), 6.90 (m, 1H), 6.72 (m, 1H), 6.34 (t, 1H), 5.70 (s, 2H), 2.08 (m, 1H), 0.95 (m, 2H), 0.66 (m, 2H).Example 852-methoxyphenyl (6-((17 / -pyrazol-l-yl)methyl)-5-cyclopropylbenzo[<7]isothiazol-3-yl)sulfamate

[0127] A solution of 2-hydroxyphenyl (6-((lH-pyrazol-l-yl)methyl)-5-cyclopropylbenzo[d]isothiazol-3-yl)sulfamate (30.0 mg, 67.8 pmol) in DMF (1 mL) was treated with Ag2CO3(56.1 mg, 203 pmol) and Mel (42.2 pL, 678 pmol) at 25 °C. The mixture was stirred at 50 °C for 3 hr then quenched with H2O (0.1 mL) at 25 °C. The resulting mixture was purified by preparative-HPLC (column: Advanchrom Cl 8 (100 x 25 mm, 5 pm); mobile phase A: H2O with 10 mM NH4HCO3; mobile phase B: MeCN; gradient elution with 40%-70% B over 8.0 min) to give 2.0 mg (6%) of the title compound as an off-white solid. MS m / z [ N-l] = 457.1.Materials and Methods

[0128] Plasmid of human His-KAT6A (residues 497-780) was obtained from Addgene (#25181). Plasmids of human NusA-KAT6A (residues 507-778) and human His-KAT7 (residues 325-611) were prepared in a pET28-based vector using standard cloning techniques with final expressed sequences described in SDPBank.

[0129] Human His-KAT6A (residues 497-780) was overexpressed in E. coli Rosetta2(DE3)pLysS, and purified using affinity chromatography, size-exclusion chromatography, and ion exchange chromatography. Briefly, cells were grown at 37°C in TB medium supplemented with 50 pM ZnCl2 and 50 μg / mL kanamycin to an OD of 0.8, cooled to17°C, induced with 400 pM isopropyl- 1 -thio-D-galactopyranoside (IPTG), and incubated overnight for 20 hours at 17°C. Cells were harvested by centrifugation and stored at -80°C. Cell pellets were lysed in buffer A (50 mM HEPES, pH 7.5, 500 mM NaCl, 0.5 mM Tris(2-carboxyethyl)phosphine (TCEP), 10% glycerol, and 10 mM imidazole) using a Microfluidizer (Microfluidics), and the lysate was centrifuged at 30,000g for 40 min. The cleared lysate was incubated with Ni-NTA beads (Qiagen) for 45 min, washed with buffer A, transferred to an FPLC-compatible column, and further washed with buffer A supplemented with 1.5 M NaCl for 20 column volumes. Protein was eluted with buffer B (25 mM HEPES, pH 7.5, 100 mM NaCl, 0.5 mM TCEP, and 400 mM imidazole). The eluate was concentrated and further purified using a Superdex 200 16 / 600 column (Cytiva) in buffer C (20 mM HEPES, pH 7.5, 100 mM NaCl, 5% glycerol, and 0.5 mM TCEP). Thrombin was added to fractions containing KAT6A protein and incubated overnight at 4°C. The sample was diluted fivefold in buffer D (20 mM MES, pH 6.0, 0.5 mM TCEP) and subjected to a Capto HisRes S 5 / 50 column. Cleaved KAT6A was eluted using a linear gradient with buffer E (20 mM MES, pH 6.0, 1 M NaCl, 0.5 mM TCEP). Fractions containing KAT6A were pooled, buffer-exchanged into buffer F (20 mM MES, pH 6.0, 100 mM NaCl, 5% glycerol, 0.5 mM TCEP), concentrated to ~2-5 mg / mL, and stored at -80°C.

[0130] Human NusA-KAT6A (residues 507-778) was expressed and purified following the same protocol as His-KAT6A, except 100 pg / mL ampicillin was used for expression, and the NusA tag was removed using TEV protease.

[0131] Human KAT6B catalytic domain construct consisting of residues 718-1008 with an N-terminal FLAG tag was purchased from Active Motif (Carlsbad, CA) (Cat. No. 81924).

[0132] Human His-KAT7 (residues 325-611) was expressed E. coli BL21 (DE3), and purified using affinity chromatography and size-exclusion chromatography. Briefly, cells were grown at 37°C in TB medium supplemented with 50 pM ZnCh and 50 pg / mL kanamycin to an OD of 0.8, cooled to 17°C, induced with 400 pM IPTG, incubated overnight for 20 hours at 17°C, collected by centrifugation, and stored at -80°C. Cell pellets were lysed in buffer L (50 mM Tris, pH 8.0, 500 mM NaCl, 0.5 mM TCEP, 10% glycerol, and 10 mM imidazole) using a Microfluidizer (Microfluidics), and the resulting lysate was centrifuged at 30,000g for 40 min. The cleared lysate was incubated with Ni-NTA beads for 45 min, washed with buffer A, transferred to an FPLC-compatible column, and further washed with buffer L supplemented with 1.5 M NaCl for 20 column volumes. Protein was eluted with buffer M (25 mM Tris, pH 8.0, 200 mM NaCl, 0.5 mMTCEP, and 400 mM imidazole). The eluted material was concentrated and further purified using a Superdex 200 16 / 600 column in buffer N (20 mM Tris, pH 8.0, 500 mM NaCl, 5% glycerol, and 0.5 mM TCEP). Fractions containing KAT7 were concentrated to ~l-2 mg / mL and stored at -80 °C.KAT6A Catalytic Activity Assay

[0133] KAT6A catalytic activity assays for detection of the coenzyme A product of the acetyltransferase reaction were performed at room temperature in a buffer consisting of 50 mM Tris-HCl (pH 8.0), 0.5 mM EDTA and 0.01% Triton X-100. Test compounds were dissolved in DMSO at 100 times (100X) the final maximal tested concentration. A solution of each test compound at 3 times (3X) the maximal tested concentration was prepared by diluting the 100X DMSO stock solution in buffer. Nine two-fold serial dilutions of the 3X compound solution, and buffer alone, were prepared using assay buffer containing 3% DMSO, such that the DMSO concentration at all compound concentrations was 3%. In addition, to represent 100% inhibition, samples were prepared consisting of 3 micromolar PF-9363 (MedChemExpress). For a 9-microliter assay volume, 3 microliters of the compound serial dilutions and PF-9363 were transferred into a black polystyrene, low-volume, 384- well assay plate (Proxiplate, Revvity) in quadruplicate. To one pair of compound dilutions was added 3 microliters of 3X substrates consisting of 3.3 micromolar histone H4 peptide containing amino acid residues 1-20 (H4(l-20), AnaSpec) and 4.2 micromolar acetyl-CoA (Sigma-Aldrich) in assay buffer. The reactions were initiated by addition of 3 microliters of 12 nM KAT6A catalytic domain construct consisting of residues 501-778 with an N-terminal NusA domain (NusA-KAT6A(507-778)). To the second pair of serial dilutions was added 6 microliters of 300 nM / V-acetyl-L-cysteine (Sigma- Aldrich) in assay buffer, used for testing and correcting for interference with thiol-containing product detection according to the method of Shapiro et al. (Correction for interference by test samples in high-throughput assays. J. BlOMOL. SCREEN., 14, 1008-10016 (2009)) After 1 hour, reactions were terminated by addition of 3 microliters of 4 micromolar ThioGlo-1 (Cayman Chemicals) in assay buffer to all wells. ThioGlo-1 rapidly reacts with coenzyme A to produce a fluorescent product. Simultaneously, it inactivates KAT6A by reacting with cysteine residues in the protein. Fluorescence intensity was measured 5 minutes later with a CLARIOstar Plus plate reader (BMG Labtech) using excitation at 384 nm and emission at 513 nm. In some cases, the assay was scaled up in volume by 3.33 -fold.

[0134] To calculate ICso’s, duplicate interference-corrected fluorescence intensities were averaged and used to calculate % inhibition at each inhibitor concentration:% inhibition = 100 x (1 - (F - MIN) / (MAX - MIN)) where F is the corrected fluorescence intensity for the inhibitor concentration, MAX is the fluorescence intensity of the uninhibited reaction, and MIN is the fluorescence intensity of the completely inhibited reaction. % inhibition versus inhibitor concentration data were used to calculate the concentration producing 50% inhibition (IC50) by nonlinear regression using the Hill equation:% inhibition = 100 x [I]n / (IC50n+ [I]n)where [I] is the inhibitor concentration and n is the Hill slope. Calculations were made using GraphPad Prism software.KAT6B Catalytic Activity Assay

[0135] KAT6B catalytic activity assays for detection of the coenzyme A product of the acetyltransferase reaction were performed at room temperature in a buffer consisting of 50 mM Tris-HCl (pH 8.0), 0.5 mM EDTA and 0.01% Triton X-100. Test compounds were dissolved in DMSO at 100 times (100X) the final maximal tested concentration. A solution of each test compound at 3 times (3X) the maximal tested concentration was prepared by diluting the 100X DMSO stock solution in buffer. Nine two-fold serial dilutions of the 3X compound solution, and buffer alone, were prepared using assay buffer containing 3% DMSO, such that the DMSO concentration at all compound concentrations was 3%. In addition, to represent 100% inhibition, samples were prepared consisting of 3 micromolar PF-9363 (MedChemExpress). For a 9-microliter assay volume, 3 microliters of the compound serial dilutions and PF-9363 were transferred into a black polystyrene, low-volume, 384- well assay plate (Proxiplate, Revvity) in quadruplicate. To one pair of compound dilutions was added 3 microliters of 3X substrates consisting of 12 micromolar histone H4 peptide containing amino acid residues 1-20 (H4(l-20), AnaSpec) and 0.36 micromolar acetyl-CoA (Sigma- Aldrich) in assay buffer. The reactions were initiated by addition of 3 microliters of 6 nM KAT6B catalytic domain construct consisting of residues 718-1008 with an TV-terminal FLAG tag (Active Motif, Cat. No. 81924). To the second pair of serial dilutions was added 6 microliters of 60 nM / V-acetyl-L-cysteine (Sigma- Aldrich) in assay buffer, used for testing and correcting for interference with thiol-containing product detection according to the method of Shapiro et al. (Correction for interference by test samples inhigh-throughput assays. J. BlOMOL. SCREEN., 14, 1008-10016 (2009)) After 1 hour, reactions were terminated by addition of 3 microliters of 4 micromolar ThioGlo-1 (Cayman Chemicals) in assay buffer to all wells. ThioGlo-1 rapidly reacts with coenzyme A to produce a fluorescent product. Fluorescence intensity was measured 5 minutes later with a CLARIOstar Plus plate reader (BMG Labtech) using excitation at 384 nm and emission at 513 nm. In some cases, the assay was scaled up in volume by 3.33 -fold.

[0136] To calculate ICso’s, duplicate interference-corrected fluorescence intensities were averaged and used to calculate % inhibition at each inhibitor concentration:% inhibition = 100 x (1 - (F - MIN) / (MAX - MIN)) where F is the corrected fluorescence intensity for the inhibitor concentration, MAX is the fluorescence intensity of the uninhibited reaction, and MIN is the fluorescence intensity of the completely inhibited reaction. % inhibition versus inhibitor concentration data were used to calculate the concentration producing 50% inhibition (IC50) by nonlinear regression using the Hill equation:% inhibition = 100 x [I]n / (IC50n+ [I]n)where [I] is the inhibitor concentration and n is the Hill slope. Calculations were made using GraphPad Prism software.KAT7 fluorescence anisotropy-based ligand competition assay

[0137] Assays were performed at room temperature in a buffer consisting of 50 mM HEPES (pH 8.0), 150 mM NaCl, 0.5 mM EDTA, and 0.01% Triton X-100. Compound serial dilutions were prepared as described above, except that the 100% inhibition control consisted of 12 micromolar WM-3835 (MedChem Express). Three microliters / well were plated in 6 replicates in a black polystyrene, low- volume, 384- well assay plate (Proxiplate, Revvity). To all these wells were added 3 microliters of 4 nM of the fluorescence anisotropy probe CTD-187. CTD-187 is a further embodiment of the present invention. The dissociation constant (Kd) of this probe with KAT7 under assay conditions was measured to be 14 nM. To 3 of the serial dilution replicates were added 3 microliters of 24 nM KAT7 (Active Motif). To the remaining 3 replicates were added 3 microliters of assay buffer. These wells were used to measure interference by test compounds with detection of probe fluorescence, according to the method of Shapiro et al (2009). Twenty-four empty wells received 9 microliters of buffer to allow measurement of the florescence background. After a 5-minute incubation, fluorescence anisotropy was measured with a PHERAstar FSX platereader using a fluorescence polarization optics module for 540 nm excitation and 590 nm emission. Average parallel and perpendicular fluorescence intensities were calculated for triplicate wells. Interference correction was applied separately to parallel and perpendicular intensity measurements after subtraction of the background from all wells containing the probe, followed by calculation of anisotropy. Percent inhibition and IC50 calculations were performed as described above.

[0138] Compounds of the invention were tested essentially as described above and representative data are presented in TABLE 1.TABLE 1EXAMPLE KAT6A IC50 (μM) KAT7 IC50 (μM)1 0.006 0.3462 0.029 0.9453 0.096 4.414 0.257 4.715 0.031 0.9566 0.027 0.7937 0.109 2.388 0.048 5.129 0.246 76.710 0.281 ND*11 0.245 2.7512 0.060 3.5413 0.142 1.4714 0.009 0.38915 0.004 0.08416 0.002 0.02417 0.043 1.0318 0.059 0.99619 0.035 2.420 0.023 0.85621 0.484 69.422 0.165 25.223 0.064 3.4624 0.068 1.9725 0.025 0.80426 0.005 0.22227 0.325 >1028 0.213 >1029 0.533 >1030 0.24 >1031 0.007 0.33932 0.007 0.75233 0.46 >1034 0.18 4.4235 0.53 >1036 0.003 0.04837 0.004 0.17938 0.004 0.18239 0.143 5.0240 0.036 2.89*ND = not determined

[0139] Compounds of the invention were tested essentially as described above and representative data are presented in TABLE 2.TABLE 2EXAMPLE KAT6A IC50 (μM) KAT6B IC50 (μM) KAT7 IC50 (μM)4 0.257 1.20 4.71 7 0.109 0.882 2.38 8 0.048 0.381 5.12 9 0.246 1.04 76.7 10 0.281 1.63 5.300.004 0.004 0.084 0.002 0.001 0.024 0.325 7.58 > 10.0 0.213 1.20 > 10.0 0.533 4.20 > 10.0 0.460 3.31 > 10.0 0.003 0.003 0.048 0.004 0.007 0.179 0.003 0.004 0.182 0.143 0.315 5.02 0.036 0.071 2.89 0.108 0.119 2.77 0.764 1.99 8.32 0.393 1.65 3.55 0.566 > 10.0 > 10.0 0.269 1.97 1.86 0.493 5.91 > 10.0 0.604 3.46 8.37 0.059 0.503 5.30 0.097 0.705 1.08 0.096 0.261 2.19 0.016 0.093 0.566 0.185 > 1.00 4.79 0.382 1.40 > 10.0 0.024 0.056 2.42 0.009 0.013 0.555 0.038 0.223 0.176 0.051 0.407 0.213 0.005 0.014 0.11573 0.008 0.024 0.130 74 0.009 0.040 0.167 75 0.002 0.002 0.091 76 0.416 1.41 3.37 77 0.123 0.575 4.55 78 0.868 6.65 > 10.0 79 0.477 3.74 > 10.0 80 0.012 0.078 1.98 81 0.190 0.755 > 10.0 82 0.004 0.013 0.703 83 0.127 0.280 3.95 84 0.586 ND* 7.59*ND = not determined

[0140] These data demonstrate that representative compounds of the invention are inhibitors of KAT6A, KAT6B, and / or KAT7.Assessment of KAT6A inhibitor Cellular Activity in ZR-75-1 Breast Cancer Cells Cell Culture

[0141] ZR-75-1 cells were obtained from the American Type Culture Collection (ATCC, catalog # CRL-1500) and maintained in RPMI-1640 medium (Gibco, catalog # 61870036) supplemented with 10% fetal bovine serum (Corning, catalog # 35-011-CV) and 1% penicillin and streptomycin (Gibco, catalog # 15070063) in a humidified incubator at 37° C and 5% CO2. Cells were passaged at 85% confluence by trypsinization.Assessment of cell proliferation of ZR-75-1 Breast Cancer Cells

[0142] 1,500 cells were seeded into each of the central 60 wells of a 96-well, tissue culture-treated plate (Grenier, catalog # 655088) in 100 pL growth media. Outer wells were filled with 100 pL media without cells. Plates were incubated at room temperature for 10 minutes before placing in the tissue culture incubator overnight. The following day, compounds were dispensed in triplicate wells using the HP D300 Digital Dispenser in a 1:4 dose titration from 1000 nM to 0.02 nM. DMSO was normalized to 0.5% across all wells, including six untreated wells to serve as am untreated control. Cells were incubated with compounds for a total of 10 days, with mediaand compounds being replaced 5 days after initial compound addition. On the tenth day of compound incubation, plates were allowed to cool to room temperature for 20 minutes and 50 pL Cell Titer-Gio 2.0 (Promega, catalog # G9242) was added to each cell-containing well and six media-only blank wells. Plates were agitated at 450 rpm for two minutes at room temperature to ensure complete cellular lysis. Luminescence was detected using the Pherastar FSX microplate reader. For IC50 determination, blank signal was subtracted from luminescence signal from cell-containing wells, and luminescence intensity was normalized to the average intensity of untreated control wells. Curve fits and IC50 values were calculated by non-linear regression in GraphPad PRISM software. Data was collected for two independent biological replicates as shown in TABLE 3.TABLE 3Compound ZR-75-1 ProliferationExample No. IC50 (nM ± StDev)7 447.7 ± 87.68 429.7 ± 206.416 8.1 ± 3.638 2.6 ± 0.440 826.1 ± 24.156 >100064 28.4 ± 171 >100074 198.5 ± 7.882 >1000

[0143] These data demonstrate that the compounds of the invention inhibit proliferation of ZR-75-1 breast cancer cells.Assessment of Histone Three, Lysine 23 Acetylation (H3K23Ac) in ZR-75-1 Breast Cancer Cells

[0144] 500,000 ZR-75-1 cells were seeded into each well of a tissue culture-treated 6-well dish (Corning, catalog # CLS3516). The following day, media was refreshed, and cells were treated with 10, 1, 0.1, 0.01, and 0.001 pM of the indicated compounds or 0.1% DMSO as a negative control. Cells were incubated overnight with compounds. Histones were isolated using the EpiQuick HistoneExtraction Kit (EpiGen Tek catalog # OP-0006-100). Plates were placed on ice,media was removed, and wells were rinsed twice with ice-cold PBS. Cells were scraped into 50 pL lysis buffer supplemented with lx HALT protease cocktail (Thermo Scientific, catalog # 87785) and 2 mM sodium butyrate (Sigma Aldrich, catalog # TR-1008-G). Lysates were incubated on ice 45 minutes with intermittent vortexing to aid lysis. Lysates were cleared by centrifugation at 16,000 x g for 5 minutes at 4° C and moved to a fresh 1.5 mL tube. 15 pL balance buffer supplemented with 1:500 DTT was added to each sample. Protein concentration was determined by the Pierce BCA Assay Kit (Thermo Scientific, catalog # 23227). 5 pg protein from each sample was loaded into a Criterion 26-well 4-20% Tris-Glycine gel (Bio-Rad, catalog # 5671095) and run at 180 V with lx Tris-Glycine-SDS running buffer (Bio-Rad, catalog # 1610732) for 1 hour to separate proteins. Proteins were transferred to nitrocellulose membranes using the Transblot Turbo system (Bio-Rad, catalog # 1704150 and # 1704271). Membranes were blocked for 30 minutes at room temperature with agitation in Intercept TBS Blocking Buffer (Licor Bio, catalog # 927-60001) supplemented with 0.1% Tween-20 (Bio-Rad, catalog # 1706531). Membranes were then incubated with primary antibodies recognizing total Histone Three (Cell Signaling Technologies, catalog # 14269S, 1:2000 dilution) and Histone Three, Lysine 23 Acetylation (Millipore, catalog # 07-355, 1:1000 dilution) in 5% bovine serum albumin (Cell Signaling Technologies, catalog # 9998) in lx TBS (Bio-Rad, catalog # 1706435) supplemented with 0.1% Tween-20 (TBS-T) overnight with agitation. Membranes were washed three times in TBS-T and then incubated with secondary antibodies (Licor Bio, catalog # 925-32211 and # 925-68070, both at 1: 10,000 dilution) for one hour at room temperature with agitation. Membranes were washed three times with TBS-T. Antibody signal was detected by the Licor Odyssey CLx imager (Licor Bio, model # 9140). Antibody signal intensity was quantified using Empiria Software from LicorBio. Data was collected for at least two biological replicates for each compound as shown in TABLE 4.TABLE 4Compound H3K23AcExample No. IC50 (nM)7 >10,0008 374116 51.838 1.740 302756 729464 335371 >10,00074 699682 987

[0145] These data demonstrate that the compounds of the invention inhibit KAT6A function within the cellular environment.

Claims

CLAIMSWe claim:

1. A compound of Formula I-B:I-Bor a pharmaceutically acceptable salt thereof, wherein:R1 is selected from a bond, -CH2-, -CH(OMe)CH2-, -O-, and -NR1-';Ri' is selected from hydrogen and methyl;Ring A is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, any of which may be further substituted by one, two, or three Ra;Ra is independently selected from halo, hydroxy, C1-C3 haloalkyl, -(CH2)i-3NRbRb’, -C(O)O(C1-C4 alkyl), -C(O)NRbRb’, -SO2(heteroaryl), cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C3-C6 cycloalkoxy, -O- C1-C3 haloalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl; wherein C1-C3 haloalkyl, C1-C3 alkyl, Ci-C3 alkoxy, C2-C3 alkenyl, C2-C3 alkynyl, may be further substituted by one Ra and wherein 3-10 membered cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl may be further substituted by one, two, or three Ra;Ra is selected from C1-C3 alkoxy, phenyl, 3-6-membered cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, and heteroaryl;Ra is selected from halo, hydroxy, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ci-C3 haloalkyl, and C1-C3 alkoxy;Rb and Rb’ are independently selected from hydrogen and C1-C4 alkyl, or Rb and Rb’ taken together with nitrogen to which they are attached form a C3-C7 heterocycloalkyl;R2 is selected from hydrogen, fluoro, and methyl;R3 is selected from a bond, C1-C4 alkylenyl, NRi', and O;R4 is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -O-cyclopropyl, -O-cyclobutyl, cyclopropyl, or cyclobutyl, where cyclopropyl and cyclobutyl may be substituted up to two times with fluoro;R5 is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -O-cyclopropyl, -O-cyclobutyl, cyclopropyl, or cyclobutyl, where cyclopropyl and cyclobutyl may be substituted up to two times with fluoro;or R4 and R5, together with the atoms to which they are attached, form a ring selected from 5-8 membered cycloalkenyl, 5-8 membered heterocycloalkenyl, 5-10 membered aryl, and 5-10 membered heteroaryl, any of which may be further substituted by one to two R4, wherein R4 is selected from fluoro, methyl, and cyclopropyl;Ring B is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, and 5-6 membered lactam, any one of which may be further substituted by one or two Rc, wherein Rc is selected from halo, hydroxy, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, and C1-C3 alkoxy, provided that:i) when Rs is methoxy, then A is not methoxyphenyl or dimethoxyphenyl; and ii) when R2, R4, and Rs are all hydrogen, then A is not dimethoxphenyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from hydrogen, halo, and cyclopropyl.

3. The compound of either claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Rs is selected from hydrogen, halo, and C1-C3 alkoxy.

4. A compound of Formula V:or a pharmaceutically acceptable salt thereof, wherein:R1 is selected from a bond, -CH2-, -CH(OMe)CH2-, -O-, and -NR1-';Ri' is selected from hydrogen and methyl;Ring A is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, any of which may be further substituted by one, two, or three Ra;Ra is independently selected from halo, hydroxy, C1-C3 haloalkyl, -(CH2)i-3NRbRb’, -C(O)O(C1-C4 alkyl), -C(O)NRbRb’, -SO2(heteroaryl), cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C3-C6 cycloalkoxy, -O- C1-C3 haloalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl; wherein C1-C3 haloalkyl, C1-C3 alkyl, Ci-C3 alkoxy, C2-C3 alkenyl, C2-C3 alkynyl, may be further substituted by one Ra and wherein 3-10 membered cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl may be further substituted by one, two, or three Ra;Ra is selected from C1-C3 alkoxy, phenyl, 3-6-membered cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, and heteroaryl;Ra is selected from halo, hydroxy, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ci-C3 haloalkyl, and C1-C3 alkoxy;Rb and Rb’ are independently selected from hydrogen and C1-C4 alkyl, or Rb and Rb’ taken together with nitrogen to which they are attached form a C3-C7 heterocycloalkyl;R2 is selected from hydrogen, fluoro, and methyl;R3 is selected from a bond, C1-C4 alkylenyl, NRi', and O;R4 and R5, together with the atoms to which they are attached, form a ring selected from 5-8 membered cycloalkenyl, 5-8 membered heterocycloalkenyl, 5-10 membered aryl, and 5-10 membered heteroaryl, any of which may be further substituted by one to two R4, wherein R4 is selected from fluoro, methyl, and cyclopropyl;Ring B is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, and 5-6 membered lactam, any one of which may be further substituted by one or two Rc, wherein Rc is selected from halo, hydroxy, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, and C1-C3 alkoxy.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R4 and R5, together with the atoms to which they are attached, form a 2,3-dihydrofuryl, 3,4-dihydro-2H-pyranyl, 2-oxabicyclo[4.1.0]hept-3-enyl, 2,3-dihydro-l,4-dioxinyl, 2,3,4,5-tetrahydrooxepinyl, or imidazolyl ring, any of which may be further substituted by one to two R4.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from C5-C8 cycloalkyl, phenyl substituted one or two times with Ra, and heteroaryl substituted one or two times with Ra.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Ra is independently selected from halo, C1-C4 alkyl, and C1-C3 alkoxy.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-6-membered heteroaryl which may be further substituted by one Rb.

10. A compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Rb is C1-C4 alkyl.

11. A pharmaceutical composition comprising a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. A compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in therapy.

13. A method for treating a KAT6A, KAT6B, and / or KAT7 susceptible cancer comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

14. The method of claim 13, wherein the KAT6A, KAT6B, and / or KAT7 susceptible cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer including colonand rectal adenocarcinomas, leukemias including acute myeloid leukemia (AML), lung adenocarcinoma, medulloblastoma, osteosarcoma, ovarian cancer, and prostate cancer.

15. The method of either one of claims 13 or 14, further comprising the administration of at least one additional therapeutic agent.

16. The method of claim 15, wherein an additional therapeutic agent is a CDK4 inhibitor.

17. The use of a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a KAT6A, KAT6B, and / or KAT7 susceptible cancer.

18. The use of claim 17, wherein the KAT6A, KAT6B, and / or KAT7 susceptible cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer including colon and rectal adenocarcinomas, leukemias including acute myeloid leukemia (AML), lung adenocarcinoma, medulloblastoma, osteosarcoma, ovarian cancer, and prostate cancer.

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