CHANG JONAH J (US)
CURRIE KEVIN S (US)
HOLMBO STEPHEN D (US)
JACOBSEN JESSE M (US)
KUKLA DAVID L (US)
LEE SEUNG H (US)
MOAZAMI YASAMIN (US)
PATEL LEENA B (US)
PAUL THOMAS J (US)
PERREAULT STEPHANE (US)
SALVO PATRICK J (US)
TREIBERG JENNIFER A (US)
WEAVER HEATH A (US)
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What is claimed is: 1. A compound of Formula (I): or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, J is X1 is N, C=O, C-R10, or C-(R10)2; X2 is N, N-R11, C-R12, or C-(R12)2; X3 is N or C-R13; X4 is N or C-R13; X5 is N or C-R13; or A is selected from: C, O, N, 3-10 membered cycloalkyl optionally substituted with one or more R15; or 4-11 membered heterocyclyl, optionally substituted with one or more R15; When A is O, n is 0; when A is N, n is 1; and when A is C, n is 1 or 2; When A is N, n is 0 or 1, and L1 is C or N-R17 and L2, L3 and L4 are each C; L1, L2, are each independently C, C6-10 aryl, 5-12 membered heteroaryl or NH; L3 and L4 are each C; or L1 and L2, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or a 4-12 membered heterocycle, each optionally substituted with one or more with R15; wherein a 4-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged, each optionally substituted with one or more R15 and wherein the C6-10 aryl, or 5-12 membered heteroaryl is monocyclic or bicyclic; or L1 and L3, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or a 4-12 membered heterocycle, each optionally substituted with one or more with R15; wherein a 4-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged, each optionally substituted with one or more R15 and wherein the C6-10 aryl, or 5-12 membered heteroaryl is monocyclic or bicyclic; or L2 and L3, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or a 4-12 membered heterocycle, each optionally substituted with one or more with R15; wherein a 4-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged, each optionally substituted with one or more R15 and wherein the C6-10 aryl, or 5-12 membered heteroaryl is monocyclic or bicyclic; or L3 and L4, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or a 4-12 membered heterocycle, each optionally substituted with one or more with R15; wherein a 4-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged, each optionally substituted with one or more R15 and wherein the C6-10 aryl, or 5-12 membered heteroaryl is monocyclic or bicyclic; or L2 and L4, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or a 4-12 membered heterocycle, each optionally substituted with one or more with R15; wherein a 4-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged, each optionally substituted with one or more R15 and wherein the C6-10 aryl, or 5-12 membered heteroaryl is monocyclic or bicyclic, each optionally substituted with one or more R15; R1 is selected from H, halo, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3, CN, O-R14, C(O)-R14, -SF5; C(O)-N(R17)( R18), N(R17)( R18), N(R17)C(O)-R15, N(R17)C(O)O-R15, N(R7)S(O)2(R15), N(R17)C(O)- N(R17)( R18), S(O)2R15, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-5 alkyl optionally substituted with one or more R15; or C3-10 cycloalkyl optionally substituted with one or more R15; or 5-10 memberedheteroaryl optionally substituted with one or more R15; or C6-10 aryl optionally substituted with one or more R15; or 4-7 memberedheterocyclyl optionally substituted with one or more R15; R2 is selected from H, C1-9 alkyl, C2-9 alkenyl, or C2-9 alkynyl, wherein any alkyl, alkenyl, and alkynyl are optionally substituted with one or more R10; R3 and R4 are each independently selected from H, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, wherein any alkyl, alkenyl, and alkynyl are optionally substituted with one or more R15, C3-12 cycloalkyl optionally substituted with one or more R15, C6-10 aryl optionally substituted with one or more R15, 4- 11 memberedheterocyclyl optionally substituted with one or more R15, or 5-10 membered heteroaryl optionally substituted with one or more R15; or R2 and R3, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, optionally substituted with one or more with R15; wherein a 4-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged optionally substituted with one or more R15; or R3 and R4, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, each optionally substituted with one or more with R15; wherein a 3- 12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged each optionally substituted with one or more R15; or R2 and R4, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, each optionally substituted with one or more with R15; wherein a 3- 12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged each optionally substituted with one or more R15; R5a, R5b R6a, R6b , R7a R7b are each independently selected from H, halo, NO2, CN, O- R14, C(O)- R16, C(O)-N(R17)(R18), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), S(O)2R16, -SF5, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl optionally substituted with one or more R15; C2-9 alkynyl optionally substituted with one or more R15; C2-9 alkenyl optionally substituted with one or more R15; 5-12 memberedheteroaryl optionally substituted with one or more R15; C6-10aryl optionally substituted with one or more R15; 4-12 memberedheterocyclyl optionally substituted with one or more R15; or C3-12 cycloalkyl optionally substituted with one or more R15; or R5a and R5b, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, each optionally substituted with one or more with R15; or R6a and R6b together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, each optionally substituted with one or more with R15; or R7a and R7b, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, each optionally substituted with one or more with R15 wherein a 3-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged each optionally substituted with one or more R15; or Z is selected from: H, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-8 haloalkyl, -O(C1-9 alkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), - O(5-12 membered heteroaryl), -O( 4-12 membered heterocyclyl), -OC(O) (C1-9 alkyl), -OC(O)(C2-6 alkenyl), -OC(O)(C2-6 alkenyl), -OC(O)(C2-6 alkynyl), -OC(O)(C3-15 cycloalkyl), -OC(O)(C1-8 haloalkyl), -OC(O)( C6-10 aryl), -OC(O)(5-12 membered heteroaryl), -OC(O)(4-12 membered heterocyclyl), -NH2, -NH(C1-9 alkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), - NH(C1-8 haloalkyl), -NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocyclyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15 cycloalkyl)2, -N(C1-8 haloalkyl)2, -N(C6-10 aryl)2, -N(5-12 membered heteroaryl)2, -N(h4-12 membered heterocyclyl)2, -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)( C6- 10 aryl), -N(C1-9 alkyl) (5-12 membered heteroaryl), -N(C1-9 alkyl)(4-12 membered heterocyclyl), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), - C(O)(C1-8 haloalkyl), -C(O)( C6-10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C1-9 alkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C6-10 aryl), -C(O)O(5-12 membered heteroaryl), - C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C1-9 alkyl), -C(O)NH(C2-6 alkenyl), - C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C6-10 aryl), - C(O)NH(5-12 membered heteroaryl), -C(O)NH(4-12 membered heterocyclyl), -C(O)N(C1-9 alkyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C6-10 aryl)2, -C(O)N(5-12 membered heteroaryl)2, -C(O)N(4-12 membered heterocyclyl)2, -NHC(O)(C1-9 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)( C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), - NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), - NHC(O)O(C6-10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(5-12 membered heteroaryl), - NHC(O)NH(4-12 membered heterocyclyl), -SH, -S(C1-9 alkyl), -S(C2-6 alkenyl), -S(C2-6 alkynyl), - S(C3-15 cycloalkyl), -S(C1-8 haloalkyl), -S(C6-10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), -S(O)(C1-8 haloalkyl), -S(O)( C6-10 aryl), -S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C1-9 alkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4- 12 membered heterocyclyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R15 is optionally substituted with one or more halo, C1- 9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH(C1-9 alkyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), - NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocyclyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)( C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C1- 9 alkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-12 membered heteroaryl), - NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), - S(O)2(C1-9 alkyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C1-9 alkyl), -S(O)2N(C1-9 alkyl)2, -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heteroaryl), -O(4- 12 membered heterocyclyl), or -O(C1-9 alkyl). 5-12 membered heteroaryl substituted with one or more R13; C6-10 aryl optionally substituted with one or more R15; C3-12 cycloalkyl optionally substituted with one or more R15; 4-12 membered heterocyclyl substituted with one or more R15; wherein any 5-12 membered heteroaryl, C6-10 aryl, C3-12 cycloalkyl, or 4-12 membered heterocyclyl, is monocyclic, bicyclic, substituted with one or more R15 and 3-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged each substituted with one or more R15, R10 is selected from: H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14, C(O)-R16, C(O)-N(R17)( R118), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), S(O)2R16, -SF5, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl or 4-12 memberedheterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more with R16, R11 is selected from: H, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C3-12 cycloalkyl, C6-10 aryl, 6-12 memberedheteroaryl or 4-12 memberedheterocyclyl wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more with R16 R12 is selected from: H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14,, C(O)-R16, C(O)-N(R17)( R118), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), S(O)2R16, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C3-12 cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or 4-12 memberedheterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more with R16 R13 is independently selected from: H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14, C(O)-R16, C(O)-N(R17)( R18), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), -SF5, S(O)2R16, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C3-12 cycloalkyl, C6-10 aryl, 5- 12 membered heteroaryl or 4-12 memberedheterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more with R16; R15 is independently selected from: H, C=O, hydroxy, halo, -NO2, -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-10 aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -O(C1-9 alkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heteroaryl), -O( 4-12 membered heterocyclyl), -OC(O) (C1-9 alkyl), -OC(O)(C2-6 alkenyl), -OC(O)(C2-6 alkenyl), -OC(O)(C2-6 alkynyl), -OC(O)(C3-15 cycloalkyl), -OC(O)(C1-8 haloalkyl), -OC(O)( C6-10 aryl), -OC(O)(5-12 membered heteroaryl), - OC(O)(4-12 membered heterocyclyl), -NH2, -NH(C1-9 alkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), -NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocyclyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15 cycloalkyl)2, -N(C1-8 haloalkyl)2, -N(C6-10 aryl)2, -N(5-12 membered heteroaryl)2, -N(h4-12 membered heterocyclyl)2, -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)( C6-10 aryl), -N(C1-9 alkyl) (5-12 membered heteroaryl), -N(C1-9 alkyl)(4-12 membered heterocyclyl), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), -C(O)(C1-8 haloalkyl), -C(O)( C6-10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C1-9 alkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C6-10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C1-9 alkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C6-10 aryl), -C(O)NH(5-12 membered heteroaryl), -C(O)NH(4-12 membered heterocyclyl), -C(O)N(C1-9 alkyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C6-10 aryl)2, -C(O)N(5-12 membered heteroaryl)2, - C(O)N(4-12 membered heterocyclyl)2, -NHC(O)(C1-9 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)( C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C1-9 alkyl), - NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(5-12 membered heteroaryl), - NHC(O)NH(4-12 membered heterocyclyl), -SH, -S(C1-9 alkyl), -S(C2-6 alkenyl), -S(C2-6 alkynyl), - S(C3-15 cycloalkyl), -S(C1-8 haloalkyl), -S(C6-10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), -S(O)(C1-8 haloalkyl), -S(O)( C6-10 aryl), -S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C1-9 alkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4- 12 membered heterocyclyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R15 is optionally substituted with one or more halo, C1- 9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH(C1-9 alkyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), - NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocyclyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)( C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C1- 9 alkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-12 membered heteroaryl), - NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), - S(O)2(C1-9 alkyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C1-9 alkyl), -S(O)2N(C1-9 alkyl)2, -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heteroaryl), -O(4- 12 membered heterocyclyl), or -O(C1-9 alkyl). R16 is independently selected from: H, C=O, halo, -NO2, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-10 aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, - OH, -O(C1-9 alkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6- 10 aryl), -O(5-12 membered heteroaryl), -O(4-12 membered heterocyclyl), -NH2, -NH(C1-9 alkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), -NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocyclyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15 cycloalkyl)2, -N(C1-8 haloalkyl)2, -N(C6-10 aryl)2, -N(5-12 membered heteroaryl)2, -N(4-12 membered heterocyclyl)2, -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C2- 6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)( C6-10 aryl), -N(C1-9 alkyl)(5-12 membered heteroaryl), -N(C1-9 alkyl)(4- 12 membered heterocyclyl), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), - C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), -C(O)(C1-8 haloalkyl), -C(O)( C6-10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C1-9 alkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C6-10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, - C(O)NH(C1-9 alkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C6-10 aryl), -C(O)NH(5-12 membered heteroaryl), - C(O)NH(4-12 membered heterocyclyl), -C(O)N(C1-9 alkyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C6-10 aryl)2, -C(O)N(5-12 membered heteroaryl)2, -C(O)N(4-12 membered heterocyclyl)2, -NHC(O)(C1-9 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)( C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C6-10 aryl), - NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(5-12 membered heteroaryl), -NHC(O)NH(4-12 membered heterocyclyl), -SH, -S(C1-9 alkyl), -S(C2-6 alkenyl), -S(C2-6 alkynyl), -S(C3-15 cycloalkyl), -S(C1-8 haloalkyl), -S(C6-10 aryl), -S(5-12 membered heteroaryl), -S(4- 12 membered heterocyclyl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), -S(O)(NH)(C3-9 cycloalkyl), -S(O)(N C1-9 alkyl)(C1-9 alkyl), -S(O)(NH)( C6-10 aryl), -S(O)(NH)(5-12 membered heteroaryl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), -S(O)(C1-8 haloalkyl), -S(O)( C6-10 aryl), - S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C1-9 alkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), - S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH(C1-9 alkyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), -NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocyclyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)( C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), S(O)2(C1-9 alkyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5- 12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C1-9 alkyl), -S(O)2N(C1-9 alkyl)2, -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heteroaryl), -O(4- 12 membered heterocyclyl), or -O(C1-9 alkyl); and R17 and R18 are independently selected from: H, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or 4-12 membered heterocyclyl wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more with R16. 2. The compound of claim 1, wherein: L1 and L2, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, optionally substituted with one or more with R15; wherein a 4-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged optionally substituted with one or more R15. 3. The compound of claim 1 wherein: L2 and L3, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, optionally substituted with one or more with R15; wherein a 4-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged optionally substituted with one or more R15. 4. The compound of claim 1, wherein: L3 and L4, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, optionally substituted with one or more with R15; wherein a 4-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged optionally substituted with one or more R1. 5. The compound of claim 1, wherein: L2 and L4, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, optionally substituted with one or more with R15; wherein a 4-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged optionally substituted with one or more R15. 6. The compound of claim 1, wherein the compound is represented by Formula Ia: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J is X1 is N, C=O, C-R10, or C-(R10)2; X2 is N, N-R11, C-R12, or C-(R12)2; X3 is N or C-R13; X4 is N or C-R13; X5 is N or C-R13; or A is selected from: C, O, N, 3-10 membered cycloalkyl optionally substituted with one or more R15; or 4-11 membered heterocyclyl, optionally substituted with one or more R15; When A is O, n is 0; when A is N, n is 1; and when A is C, n is 1 or 2; R1 is selected from H, halo, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3, CN, O-R14, C(O)-R14, -SF5; C(O)-N(R17)( R18), N(R17)( R18), N(R17)C(O)-R15, N(R17)C(O)O-R15, N(R7)S(O)2(R15), N(R17)C(O)- N(R17)( R18), S(O)2R15, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18 C1-5 alkyl optionally substituted with one or more R15; or C3-10 cycloalkyl optionally substituted with one or more R15; 5-10 memberedheteroaryl optionally substituted with one or more R15; C6-10 aryl optionally substituted with one or more R15; or 4-7 memberedheterocyclyl optionally substituted with one or more R15 R2 is selected from H, C1-9 alkyl, C2-9 alkenyl, or C2-9 alkynyl, wherein any alkyl, alkenyl, and alkynyl are optionally substituted with one or more R10; R3 and R4 are each independently selected from H, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, wherein any alkyl, alkenyl, and alkynyl are optionally substituted with one or more R15, C3-12 cycloalkyl optionally substituted with one or more R15, C6-10 aryl optionally substituted with one or more R15, 4- 11 memberedheterocyclyl optionally substituted with one or more R15, or 5-10 membered heteroaryl optionally substituted with one or more R15; or R2 and R3, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, optionally substituted with one or more with R15; wherein a 4-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged optionally substituted with one or more R15; or R3 and R4, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, each optionally substituted with one or more with R15; wherein a 3- 12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged each optionally substituted with one or more R15; or R5a, R5b R6a, R6b , R7a R7b are each independently selected from H, halo, NO2, CN, O- R14, C(O)- R16, C(O)-N(R17)(R18), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), S(O)2R16, -SF5, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18 C1-9 alkyl optionally substituted with one or more R15; C2-9 alkynyl optionally substituted with one or more R15; C2-9 alkenyl optionally substituted with one or more R15; 5-12 memberedheteroaryl optionally substituted with one or more R15; C6-10 aryl optionally substituted with one or more R15; 4-12 memberedheterocyclyl optionally substituted with one or more R15; or C3-12 cycloalkyl optionally substituted with one or more R15; or R5a and R5b, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, each optionally substituted with one or more with R15; or R6a and R6b together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, each optionally substituted with one or more with R15; or R7a and R7b, together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, or a 4-12 membered heterocycle, each optionally substituted with one or more with R15 wherein a 3-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged each optionally substituted with one or more R15; or Z is selected from: -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-8 haloalkyl, -O(C1-9 alkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heteroaryl), -O( 4-12 membered heterocyclyl), -OC(O) (C1-9 alkyl), -OC(O)(C2-6 alkenyl), - OC(O)(C2-6 alkenyl), -OC(O)(C2-6 alkynyl), -OC(O)(C3-15 cycloalkyl), -OC(O)(C1-8 haloalkyl), - OC(O)( C6-10 aryl), -OC(O)(5-12 membered heteroaryl), -OC(O)(4-12 membered heterocyclyl), - NH2, -NH(C1-9 alkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), -NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocyclyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15 cycloalkyl)2, -N(C1-8 haloalkyl)2, -N(C6-10 aryl)2, -N(5-12 membered heteroaryl)2, -N(h4-12 membered heterocyclyl)2, -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)( C6- 10 aryl), -N(C1-9 alkyl) (5-12 membered heteroaryl), -N(C1-9 alkyl)(4-12 membered heterocyclyl), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), - C(O)(C1-8 haloalkyl), -C(O)( C6-10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C1-9 alkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C6-10 aryl), -C(O)O(5-12 membered heteroaryl), - C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C1-9 alkyl), -C(O)NH(C2-6 alkenyl), - C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C6-10 aryl), - C(O)NH(5-12 membered heteroaryl), -C(O)NH(4-12 membered heterocyclyl), -C(O)N(C1-9 alkyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C6-10 aryl)2, -C(O)N(5-12 membered heteroaryl)2, -C(O)N(4-12 membered heterocyclyl)2, -NHC(O)(C1-9 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)( C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), - NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), - NHC(O)O(C6-10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(5-12 membered heteroaryl), - NHC(O)NH(4-12 membered heterocyclyl), -SH, -S(C1-9 alkyl), -S(C2-6 alkenyl), -S(C2-6 alkynyl), - S(C3-15 cycloalkyl), -S(C1-8 haloalkyl), -S(C6-10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), -S(O)(C1-8 haloalkyl), -S(O)( C6-10 aryl), -S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C1-9 alkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4- 12 membered heterocyclyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R15 is optionally substituted with one or more halo, C1- 9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH(C1-9 alkyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), - NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocyclyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)( C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C1- 9 alkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-12 membered heteroaryl), - NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), - S(O)2(C1-9 alkyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C1-9 alkyl), -S(O)2N(C1-9 alkyl)2, -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heteroaryl), -O(4- 12 membered heterocyclyl), or -O(C1-9 alkyl). 5-12 membered heteroaryl substituted with one or more R13; C6-10 aryl optionally substituted with one or more R15; C3-12 cycloalkyl optionally substituted with one or more R15; 4-12 membered heterocyclyl substituted with one or more R15; wherein any 5-12 membered heteroaryl, C6-10 aryl, C3-12 cycloalkyl, or 4-12 membered heterocyclyl, is monocyclic, bicyclic, substituted with one or more R15 and 3-12 membered cycloalkyl or 4-12 membered heterocyclyl is monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged each substituted with one or more R15 R10 is selected from: H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14, C(O)-R16, C(O)-N(R17)( R118), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), S(O)2R16, -SF5, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl or 4-12 memberedheterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more with R16 R11 is selected from: H, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C3-12 cycloalkyl, C6-10 aryl, 6-12 memberedheteroaryl or 4-12 memberedheterocyclyl wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more with R16 R12 is selected from: H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14,, C(O)-R16, C(O)-N(R17)( R118), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), S(O)2R16, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C3-12 cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or 4-12 memberedheterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more with R16 R13 is independently selected from: H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14, C(O)-R16, C(O)-N(R17)( R18), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), -SF5, S(O)2R16, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C3-12 cycloalkyl, C6-10 aryl, 5- 12 membered heteroaryl or 4-12 memberedheterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more with R16; R15 is independently selected from: H, C=O, hydroxy, halo, -NO2, -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-10 aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -O(C1-9 alkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heteroaryl), -O( 4-12 membered heterocyclyl), -OC(O) (C1-9 alkyl), -OC(O)(C2-6 alkenyl), -OC(O)(C2-6 alkenyl), -OC(O)(C2-6 alkynyl), -OC(O)(C3-15 cycloalkyl), -OC(O)(C1-8 haloalkyl), -OC(O)( C6-10 aryl), -OC(O)(5-12 membered heteroaryl), - OC(O)(4-12 membered heterocyclyl), -NH2, -NH(C1-9 alkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), -NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocyclyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15 cycloalkyl)2, -N(C1-8 haloalkyl)2, -N(C6-10 aryl)2, -N(5-12 membered heteroaryl)2, -N(h4-12 membered heterocyclyl)2, -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)( C6-10 aryl), -N(C1-9 alkyl) (5-12 membered heteroaryl), -N(C1-9 alkyl)(4-12 membered heterocyclyl), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), -C(O)(C1-8 haloalkyl), -C(O)( C6-10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C1-9 alkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C6-10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C1-9 alkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C6-10 aryl), -C(O)NH(5-12 membered heteroaryl), -C(O)NH(4-12 membered heterocyclyl), -C(O)N(C1-9 alkyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C6-10 aryl)2, -C(O)N(5-12 membered heteroaryl)2, - C(O)N(4-12 membered heterocyclyl)2, -NHC(O)(C1-9 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)( C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C1-9 alkyl), - NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(5-12 membered heteroaryl), - NHC(O)NH(4-12 membered heterocyclyl), -SH, -S(C1-9 alkyl), -S(C2-6 alkenyl), -S(C2-6 alkynyl), - S(C3-15 cycloalkyl), -S(C1-8 haloalkyl), -S(C6-10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), -S(O)(C1-8 haloalkyl), -S(O)( C6-10 aryl), -S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C1-9 alkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4- 12 membered heterocyclyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R15 is optionally substituted with one or more halo, C1- 9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH(C1-9 alkyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), - NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocyclyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)( C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C1- 9 alkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-12 membered heteroaryl), - NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), - S(O)2(C1-9 alkyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C1-9 alkyl), -S(O)2N(C1-9 alkyl)2, -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heteroaryl), -O(4- 12 membered heterocyclyl), or -O(C1-9 alkyl). R16 is independently selected from: H, C=O, halo, -NO2, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-10 aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, - OH, -O(C1-9 alkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6- 10 aryl), -O(5-12 membered heteroaryl), -O(4-12 membered heterocyclyl), -NH2, -NH(C1-9 alkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), -NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocyclyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15 cycloalkyl)2, -N(C1-8 haloalkyl)2, -N(C6-10 aryl)2, -N(5-12 membered heteroaryl)2, -N(4-12 membered heterocyclyl)2, -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C2- 6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)( C6-10 aryl), -N(C1-9 alkyl)(5-12 membered heteroaryl), -N(C1-9 alkyl)(4- 12 membered heterocyclyl), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), - C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), -C(O)(C1-8 haloalkyl), -C(O)( C6-10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C1-9 alkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C6-10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, - C(O)NH(C1-9 alkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C6-10 aryl), -C(O)NH(5-12 membered heteroaryl), - C(O)NH(4-12 membered heterocyclyl), -C(O)N(C1-9 alkyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C6-10 aryl)2, -C(O)N(5-12 membered heteroaryl)2, -C(O)N(4-12 membered heterocyclyl)2, -NHC(O)(C1-9 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)( C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C6-10 aryl), - NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(5-12 membered heteroaryl), -NHC(O)NH(4-12 membered heterocyclyl), -SH, -S(C1-9 alkyl), -S(C2-6 alkenyl), -S(C2-6 alkynyl), -S(C3-15 cycloalkyl), -S(C1-8 haloalkyl), -S(C6-10 aryl), -S(5-12 membered heteroaryl), -S(4- 12 membered heterocyclyl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), -S(O)(NH)(C3-9 cycloalkyl), -S(O)(N C1-9 alkyl)(C1-9 alkyl), -S(O)(NH)( C6-10 aryl), -S(O)(NH)(5-12 membered heteroaryl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), -S(O)(C1-8 haloalkyl), -S(O)( C6-10 aryl), - S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C1-9 alkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), - S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH(C1-9 alkyl), -NH(C3-15 cycloalkyl), -NH(C1-8 haloalkyl), -NH(C6-10 aryl), -NH(5-12 membered heteroaryl), -NH(4-12 membered heterocyclyl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C3-15 cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)( C6-10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), S(O)2(C1-9 alkyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C6-10 aryl), -S(O)2(5- 12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C1-9 alkyl), -S(O)2N(C1-9 alkyl)2, -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(C6-10 aryl), -O(5-12 membered heteroaryl), -O(4- 12 membered heterocyclyl), or -O(C1-9 alkyl); and R17 and R18 are independently selected from: H, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C6-10 aryl, 5-12 membered heteroaryl or 4-12 membered heterocyclyl wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more with R16. 7. The compound of claim 1 or 6, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J is: 8. The compound of claim 7 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is a 5-10 membered heteroaryl optionally independently substituted with one or more R13. 9. The compound of claim 8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: wherein w is zero to three, inclusive; and t is zero to four, inclusive, and wherein R13 is bound to any substitutable position on Z. 10. The compound of claim 1 or 6, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J is: 11. The compound of claim 10, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is a 5-10 membered heteroaryl optionally independently substituted with one or more R13. 12. The compound of claim 10, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: wherein w is zero to three, inclusive; and t is zero to four, inclusive, and wherein R13 is bound to any substitutable position on Z. 13. The compound of claim 7, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein w is one to two, inclusive; and t is one to three, inclusive. 14. The compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is independently selected from the group consisting of: H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14, C(O)-R16, C(O)-N(R17)( R18), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), -SF5, S(O)2R16, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, and C2-9 alkynyl. Wherein any alkyl, alkenyl, or alkynyl is optionally substituted with one or more with R13. 15. The compound of claim 14, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is independently selected from the group consisting of: H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCHF2, OCF3, N(R17)( R18), CN, O- R14, and C(O)-R16. 16. The compound of claim 15, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R2 is H. 17. The compound of claim 16, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R3 is H, and R4 is C1-9 alkyl, C3-15 cycloalkyl, 4- 12 membered heterocyclyl, C6-10 aryl, or 5-12 membered heteroaryl. Wherein any alkyl, alkenyl, or alkynyl is optionally substituted with one or more with R13. 18. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R4 is methyl or ethyl. 19. The compound of claim 18, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J is independently selected from the group consisting of: 20. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is NH. 21. The compound of claims 20, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R5a, R5b, R6a, R6b R7a and R7b are each H. 22. The compound of claim 19 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is CH2. 23. The compound of claim 22, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R5a, R5b, R6a, R6b R7a and R7b are each H. 24. The compound of claim 19, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is NH and R4 is methyl or ethyl. 25. The compound of claim 24, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J is: 26. The compound of claim 25, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R5a, R5b, R6a, R6b R7a and R7b are each H. 27. The compound of claim 26, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R1 is selected from the group consisting of halo, CH3, CH2F, CHF2, CF3, and C(O)-R14. 28. The compound of claim 27, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R1 is CF3. 29. The compound of claim 28, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: 30. The compound of claim 1 or 6, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof. 31. The compound of claim 30, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: wherein w is zero to three, inclusive; and t is zero to four, inclusive, wherein R13 is bound to any substitutable position on Z. 32. The compound of claim 31, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein w is one to two, inclusive; and t is one to three, inclusive, and wherein R13 is bound to any substitutable position on Z. 33. The compound of claim 32, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is selected from the group consisting of: halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14, C(O)-R16, C(O)-N(R17)( R118), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), -SF5, S(O)2R16, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, and C3-15 cycloalkyl. Wherein any alkyl, alkenyl, or alkynyl is optionally substituted with one or more with R10. 34. The compound of claim 33, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is selected from the group consisting of: halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, N(R17)( R18), CN, O- R14 and C(O)-R16. 35. The compound of claim 34, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R2 is H. 36. The compound of claim 35, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R3 is H, and R4 is C1-9 alkyl or C3-15 cycloalkyl. Wherein any alkyl or cycloalkyl is optionally substituted with one or more with R13. 37. The compound of claim 36, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R4 is methyl or ethyl. 38. The compound of claim 37, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J is independently selected from the group consisting of: 39. The compound of claim 38, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R5a, R5b, R6a, R6b R7a and R7b are each H. 40. The compound of claim 39 wherein R1 is halo, CH3, CH2F, CHF2, CF3, and C(O)-R14. 41. The compound of claim 40, wherein R1 is CF3. 42. The compound of claim 41, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: 43. The compound of claim 1 or 6, wherein J is: , or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. 44. The compound of claim 43, wherein Z is selected from: wherein w is zero to three, inclusive; and t is zero to four, inclusive, and wherein R13 is bound to any substitutable position on Z. 45. The compound of claim 44, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein w is one to two, inclusive; and t is one to three, inclusive, wherein R13 is bound to any substitutable position on Z. 46. The compound of claim 44, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is selected from the group consisting of: halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14, C(O)-R16, C(O)-N(R17)( R118), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), -SF5, S(O)2R16, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl and C3-15 cycloalkyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more with R10. 47. The compound of claim 46, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is independently selected from the group consisting of: halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, N(R17)( R18), CN, O- R14, and C(O)-R16. 48. The compound of claim 47, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R2 is H. 49. The compound of claim 48, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R3 is H, and R4 is C1-9 alkyl, or C3-15 cycloalkyl. Wherein any alkyl, or cycloalkyl is optionally substituted with one or more with R13. 50. The compound of claim 49, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R4 is methyl. 51. The compound of claim 50, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is NH. 52. The compound of claim 48, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R5a, R5b, R6a, R6b R7a and R7b are each H. 53. The compound of claim 48, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R1 is selected from the group consisting of: halo, CH3, CH2F, CHF2, CF3, and C(O)-R14. 54. The compound of claim 53, wherein R1 is CF3. 55. The compound of claim 54, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: 56. The compound of claim 1 wherein J is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof. 57. The compound of claim 56, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from Z is selected from: wherein w is zero to three, inclusive; and t is zero to four, inclusive, and wherein R13 is bound to any substitutable position on Z. 58. The compound of claim 57, wherein w is one to two, inclusive; and t is one to three, inclusive, wherein R13 is bound to any substitutable position on Z. 59. The compound of claim 58, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is independently selected from the group consisting of: H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14, C(O)-R16, C(O)-N(R17)( R118), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), -SF5, S(O)2R16, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, and C2-9 alkynyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more with R10. 60. The compound of claim 59, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is selected from the group consisting of: halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, N(R17)( R18), CN, O- R14 and C(O)-R16. 61. The compound of claim 60, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R2 is H. 62. The compound of claim 60, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R3 is H, and R4 is C1-9 alkyl or C3-15 cycloalkyl. Wherein any alkyl, or cycloalkyl is optionally substituted with one or more with R13. 63. The compound of claim 62, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R4 is methyl or ethyl. 64. The compound of claim 63, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is NH. 65. The compound of claim 64, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R5a, R5b, R6a, R6b R7a and R7b are each H. 66. The compound of claim 65, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R1 is selected from the group consisting of: halo, CH3, CH2F, CHF2, CF3, and C(O)-R14. 67. The compound of claim 66, wherein R1 is CF3 68. The compound of claim 66, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is: 69. The compound of claim 1 or 6, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J is: 70. The compound of claim 69, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is a 5-10 membered heteroaryl optionally substituted with one or more R13. 71. The compound of claim 70, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: wherein w is zero to three, inclusive; and t is zero to four, inclusive, and wherein R13 is bound to any substitutable position on Z. 72. The compound of claim 71, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein w is one to two, inclusive; and t is one to three, inclusive, wherein R13 is bound to any substitutable position on Z. 73. The compound of claim 72, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is selected from the group consisting of: halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14, C(O)-R16, C(O)-N(R17)( R118), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), -SF5, S(O)2R16, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, and C2-9 alkynyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more with R10. 74. The compound of claim 73, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is selected from the group consisting of: halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, N(R17)( R18), CN, O- R14, and C(O)-R16. 75. The compound of claim 74, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R2 is H. 76. The compound of claim 74, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R3 is H, and R4 is C1-9 alkyl or C3-15 cycloalkyl. Wherein any alkyl, or cycloalkyl is optionally substituted with one or more with R13. 77. The compound of claim 76, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R4 is methyl or ethyl. 78. The compound of claim 76, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is NH. 79. The compound of claim 76, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is CH2. 80. The compound of claim 79, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R5a, R5b, R6a, R6b R7a and R7b are each H. 81. The compound of claim 80, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R1 is selected from the group consisting of: halo, CH3 CH2F, CHF2, CF3, and C(O)-R14. 82. The compound of claim 81, wherein R1 is CF3. 83. The compound of claim 82, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: 84. The compound of claim 1 or 6, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J is: 85. The compound of claim 84, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is a 5-10 membered heteroaryl optionally substituted with one or more R13. 86. The compound of claim 85, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: wherein w is zero to three, inclusive; and t is zero to four, inclusive, and wherein R13 is bound to any substitutable position on Z. 87. The compound of claim 86, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein w is one to two, inclusive; and t is one to three, inclusive, wherein R13 is bound to any substitutable position on Z. 88. The compound of claim 87, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is selected from the group consisting of: halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14, C(O)-R16, C(O)-N(R17)( R118), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), -SF5, S(O)2R16, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, and C2-9 alkynyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more with R10. 89. The compound of claim 88, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is selected from the group consisting of: halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, N(R17)( R18), CN, O- R14 and C(O)-R16. 90. The compound of claim 89, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R2 is H. 91. The compound of claim 90, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R3 is H, and R4 is C1-9 alkyl or C3-15 cycloalkyl, wherein any alkyl, or cycloalkyl is optionally substituted with one or more with R13. 92. The compound of claim 91, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R4 is methyl or ethyl. 93. The compound of claim 92, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is NH. 94. The compound of claim 92, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is CH2. 95. The compound of claim 94, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R5a, R5b, R6a, R6b R7a and R7b are each H. 96. The compound of claim 95, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R1 is selected from the group consisting of: halo, CH3 CH2F, CHF2, CF3, and C(O)-R14. 97. The compound of claim 96, wherein R1 is CF3. 98. The compound of claim 97, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: 99. The compound of claim 1or 6, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J is: 100. The compound of claim 99, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is a 5-10 membered heteroaryl optionally substituted with one or more R13. 101. The compound of claim 100, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: wherein w is zero to three, inclusive; and t is zero to four, inclusive, and wherein R13 is bound to any substitutable position on Z. 102. The compound of claim 101, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein w is one to two, inclusive; and t is one to three, inclusive, wherein R13 is bound to any substitutable position on Z. 103. The compound of claim 102 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is selected from the group consisting of: halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14, C(O)-R16, C(O)-N(R17)( R18), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), -SF5, S(O)2R16, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, and C2-9 alkynyl, wherein any alkyl, alkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more with R10. 104. The compound of claim 103, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is selected from the group consisting of: halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, N(R17)( R18), CN, O- R14 and C(O)-R16. 105. The compound of claim 104, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R2 is H. 106. The compound of claim 105, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R3 is H, and R4 is C1-9 alkyl or C3-15 cycloalkyl, wherein any alkyl, or cycloalkyl is optionally substituted with one or more with R13. 107. The compound of claim 106, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R4 is methyl or ethyl. 108. The compound of claim 107, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is NH. 109. The compound of claim 99, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R5a, R5b, R6a, R6b R7a and R7b are each H. 110. The compound of claim 109, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R1 is selected from the group consisting of: halo, CH3 CH2F, CHF2, CF3, and C(O)-R14. 111. The compound of claim 110, wherein R1 is CF3. 112. The compound of claim 111, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: 113. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein L1 and L3, together with the atoms to which they are attached, form a 6 membered cycloalkyl, or 6 membered heterocyclyl each optionally substituted with one or more with R15. 114. The compound of claim 113, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein L1 and L3, together with the atoms to which they are attached, form a structure represented by: wherein X6, X7, X8, X9 and X10 ar 15 17 e independently CH2, CHR , C=O, NR , S, SO, SO2, or O, and wherein p is an integer from 0-10, inclusive. 115. The compound of claim 114, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein L1 and L3, together with the atoms to which they are attached, form a structure represented by: wherein p is an integer from 0-10, inclusive. 116. The compound of claim 114, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein L1 and L3, together with the atoms to which they are attached, form a structure represented by: 117. The compound of any of claims 113-116, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J is selected from the group consisting of: 118. The compound of claim 117, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is NH. 119. The compound of claim 118, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R1 is selected from the group consisting of halo, CH3, CH2F, CHF2, CF3, and C(O)-R14. 120. The compound of claim 119, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R1 is CF3. 121. The compound of claim 120, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein L4 is C. 122. The compound of claim 121, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R7a and R7b are each H. 123. The compound of claim 121, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R7a and R7b are each CH3. 124. The compound of claim 121, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R7a is CH3 and R7b is H. 125. The compound of claim 122, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: wherein w is zero to three, inclusive; and t is zero to four, inclusive, and wherein R13 is bound to any substitutable position on Z. 126. The compound of claim 125, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein w is one to two, inclusive; and t is one to three, inclusive. 127. The compound of claim 126, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: 128. The compound of claim 127, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is independently selected from the group consisting of: H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14, C(O)-R16, C(O)-N(R17)( R18), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), -SF5, S(O)2R16, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, and C2-9 alkynyl. Wherein any alkyl, alkenyl, or alkynyl is optionally substituted with one or more with R13. 129. The compound of claim 128, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is independently selected from the group consisting of: H, halo, NH2, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCHF2, OCF3, CN, O- R14, and C(O)-R16. 130. The compound of claim 129, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: 131. The compound of claim 117, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is O. 132 The compound of claim 131, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R1 is selected from the group consisting of halo, CH3, CH2F, CHF2, CF3, and C(O)-R14. 133. The compound of claim 132, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R1 is CF3. 134. The compound of claim 133, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein L4 is C. 135. The compound of claim 134, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R7a and R7b are each H. 136. The compound of claim 134, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R7a and R7b are each CH3. 137. The compound of claim 134, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R7a is CH3 and R7b is H. 138. The compound of claim 134, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is selected from: wherein w is zero to three, inclusive; and t is zero to four, inclusive, and wherein R13 is bound to any substitutable position on Z. 139. The compound of claim 138, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein w is one to two, inclusive; and t is one to three, inclusive. 140. The compound of claim 139, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is independently selected from the group consisting of: H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, O- R14, C(O)-R16, C(O)-N(R17)( R18), N(R17)( R18), N(R17)C(O)-R16, N(R17)C(O)O- R14, N(R17)S(O)2(R16), -N(R17)C(O)-N(R18)( R18), -SF5, S(O)2R16, S(O)2N(R17)( R18), S(O)(NH)R17, S(O)(NR17)NR18, C1-9 alkyl, C2-9 alkenyl, and C2-9 alkynyl. Wherein any alkyl, alkenyl, or alkynyl is optionally substituted with one or more with R13. 141. The compound of claim 140, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein R13 is independently selected from the group consisting of: H, halo, NH2, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCHF2, OCF3, CN, O- R14, and C(O)-R16. 142. The compound of claim 141, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein Z is: 143. A Compound, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, selected from the group consisting of: 144. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 145. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 146. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 147. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 148. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 149. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 150. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 151. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 152. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 153. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 154. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 155. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 156. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 157. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 158. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 159. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 160. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 161. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 162. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 163. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 164. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 165. The compound of claim 143, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, which is: 166. A pharmaceutical composition comprising a compound of any of claims 1-164, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, and a pharmaceutically acceptable excipient. 167. A method of treating cancer, comprising administering to patient in need thereof a compound of any of claims 1-164, or a pharmaceutical composition of claim 165. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof. 168. A pharmaceutical composition comprising a compound of any of claims 1-157, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, and a pharmaceutically acceptable excipient. 169. A method of treating cancer, comprising administering to patient in need thereof a compound of any of claims 1-157, or a pharmaceutical composition of claim 158. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof. |
Examples [0242] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. i. General scheme A ii. General scheme B iii. General scheme C Examples [0243] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.
iv. General scheme A v. General scheme B vi. General scheme C ii. Synthetic ExamplesExample 1 Preparation of 2-(4-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)py ridin-2-yl)isoquinolin-1(2H)-one [0244] Step 1. To a stirred solution of tert-butyl N-[(1S,3R)-3-hydroxycyclopentyl]carbamate (200 mg, 0.984 mmol) and triethylamine (199 mg, 1.97 mmol) in dichloromethane (4.50 mL) at 0 °C was added p-Toluenesulfonyl chloride (188 mg, 0.984 mmol) dropwise and the mixture was warmed to room temperature and stirred for 2h. Upon completion, the mixture was diluted with water and extracted with dicholoromethane. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0-100% to afford 4-(tert-butoxycarbonylamino)pentyl 4-methylbenzenesulfonate. ES/MS: m/z 380.4 [M+Na] + . [0245] Step 2. To a mixture of 6-bromo-2H-isoquinolin-1-one (55.0 mg, 0.245 mmol) and 4- (tert-butoxycarbonylamino)pentyl 4-methylbenzenesulfonate (102 mg, 0.285 mmol) in DMF (0.70 mL) was added Cs 2 CO 3 (160 mg, 0.491 mmol) and the reaction was stirred at room temperature for 18 h. Upon completion, the mixture was diluted with EtOAc, washed with water, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EA in hexanes 0-100% to afford tert-butyl N-[4-(6-bromo-1-oxo- 2-isoquinolyl)-1-methyl-butyl]carbamate. ES/MS: m/z 411.2 [M+H] + . [0246] Step 3. A solution of tert-butyl N-[4-(6-bromo-1-oxo-2-isoquinolyl)-1-methyl- butyl]carbamate (106 mg, 0.259 mmol), [5-(trifluoromethyl)-2-pyridyl]boronic acid (148 mg, 0.777 mmol), Pd(dppf)Cl 2 (21.4 mg, 0.026 mmol), and KOAc (76.2 mg, 0.777 mmol) in dioxane (2.0 mL) and water (0.30 mL) was purged with nitrogen gas for 5 minutes and heated at 90 °C for 18 hrs. Upon cooling, the mixture was filtered through a pad of Celite ® , concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0- 100% to afford tert-butyl N-[1-methyl-4-[1-oxo-6-[5-(trifluoromethyl)-2-pyridyl]-2- isoquinolyl]butyl]carbamate. ES/MS: m/z 476.6 [M+H] + . [0247] Step 4. To a solution of tert-butyl N-[1-methyl-4-[1-oxo-6-[5-(trifluoromethyl)-2- pyridyl]-2-isoquinolyl]butyl]carbamate (54.2 mg, 0.114 mmol) in dichloromethane (1.10 mL) was added trifluoroacetic acid (0.19 mL, 5.70 mmol) at room temperature and the mixture was stirred for 1hr. Upon completion, the solvent was removed under reduced pressure to afford 2-(4-aminopentyl)-6-[5- (trifluoromethyl)-2-pyridyl]isoquinolin-1-one hydrochloride. ES/MS: m/z 376.3 [M+H] + . [0248] Step 5. A mixture of 2-(4-aminopentyl)-6-[5-(trifluoromethyl)-2-pyridyl]isoquinol in- 1-one hydrochloride (47 mg, 0.11 mmol), 5-chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one (45 mg, 0.14 mmol), and N,N-diisopropylethylamine (0.10 mL, 0.57 mmol) in DMF (2.0 mL) was heated at 80 °C for 15 minutes. Upon completion, the reaction was diluted with EtOAc, washed with water, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0-100% to provide 2-[4-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)-2- pyridyl]isoquinolin-1-one. ES/MS: m/z 668.1 [M+H] + . [0249] Step 6. To a solution of 2-[4-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)-2-pyridyl]isoquinolin-1- one (59.6 mg, 0.084 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.078 mL, 1.02 mmol) at room temperature and the mixture was stirred for 45 minutes. The excess trifluoroacetic acid and solvent was removed under reduced pressure and the residue was dissolved in MeOH (1.0 mL). To this was added ethylenediamine (0.057 mL, 0.84 mmol) and the resulting mixture was stirred at room temperature for 1 hr. Upon completion, the mixture was concentrated in vacuo and purified via reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 2-[4-[[6-oxo-5-(trifluoromethyl)- 1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)-2-pyr idyl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.12 (s, 1H), 8.48 (s, 1H), 8.40 – 8.33 (m, 3H), 8.26 (d, J = 8.1 Hz, 1H), 7.92 (s, 1H), 7.54 (d, J = 7.2 Hz, 1H), 6.79 – 6.75 (m, 1H), 6.39 – 6.31 (m, 1H), 4.03 – 3.96 (m, 3H), 1.77 – 1.63 (m, 3H), 1.52 (s, 1H), 1.17 (d, J = 6.2 Hz, 3H). ES/MS m/z = 538.1 [M+H] + . Example 2 and Example 3 Preparation of 2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4- yl]amino]pentyl]-6-[5-(trifluoromethyl)-2-pyridyl]isoquinoli n-1-one and 2-[(4S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trif luoromethyl)-2-pyridyl]isoquinolin-1- one [0250] Step 1. Examples 2 and Example 3 were separated via chiral SFC (AD-H, 5 ^m, 21x250 mm column; 35% EtOH as co-solvent; 100 bar; 40 °C). The first eluting peak was assigned as the (R)-configuration (Example 2) , and the second eluting peak was assigned as the (S)-configuration (Example 3). The final compounds were free of TFA. [0251] Example 2: 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.12 (s, 1H), 8.48 (s, 1H), 8.40 – 8.33 (m, 3H), 8.26 (d, J = 8.1 Hz, 1H), 7.92 (s, 1H), 7.54 (d, J = 7.2 Hz, 1H), 6.79 – 6.75 (m, 1H), 6.39 – 6.31 (m, 1H), 4.03 – 3.96 (m, 3H), 1.77 – 1.63 (m, 3H), 1.52 (s, 1H), 1.17 (d, J = 6.2 Hz, 3H). ES/MS m/z : 538.1 [M+H] + . [0252] Example 3: 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.12 (s, 1H), 8.48 (s, 1H), 8.40 – 8.33 (m, 3H), 8.26 (d, J = 8.1 Hz, 1H), 7.92 (s, 1H), 7.54 (d, J = 7.2 Hz, 1H), 6.79 – 6.75 (m, 1H), 6.39 – 6.31 (m, 1H), 4.03 – 3.96 (m, 3H), 1.77 – 1.63 (m, 3H), 1.52 (s, 1H), 1.17 (d, J = 6.2 Hz, 3H). ES/MS m/z: 538.1 [M+H] + . Example 4: 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amin o]pentyl]-6 [5- (trifluoromethyl)pyrimidin-2-yl]phthalazin-1-one [0253] The title compound was synthesized as described in Example 1, using 6-bromo-2H- phthalazin-1-one in place of 6-bromoisoquinolin-1(2H)-one.1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.48 (s, 2H), 9.02 (d, J = 1.2 Hz, 1H), 8.85 (dd, J = 8.4, 1.6 Hz, 1H), 8.68 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 6.35 (dd, J = 8.5, 3.1 Hz, 1H), 4.17 (t, J = 6.8 Hz, 2H), 3.98 (d, J = 12.0 Hz, 1H), 1.86 – 1.76 (m, 2H), 1.75 – 1.64 (m, 1H), 1.55 (d, J = 19.6 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 540.1 [M+H] + . Example 5 Preparation of 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amin o]pentyl]-6- [5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one [0254] Step 1. In a vial were placed (4S)-4-(tert-butoxycarbonylamino)pentanoic acid (1000 mg, 4.6 mmol), and triethylamine (0.642 mL, 4.6 mmol) in THF (44.4 mL). The mixture was cool to 0 °C and placed under nitrogen atmosphere. To this solution was added ethyl chloroformate (0.44 mL, 4.6 mmol) and the reaction was stirred for 30 minutes at 0 °C. The mixture was then filtered to remove the precipitated triethylamine hydrochloride. The filtrate containing the mixed anhydride was slowly added to a stirred suspension of sodium borohydride (522 mg, 13.8 mmol) in 20% aqueous THF (10.0 mL) maintained at 10 °C. After the mixture was stirred for 30 minutes, it was acidified with 1N HCl to pH ~ 4. The mixture was then extracted with EtOAc, washed with 2M NaOH solution, washed with brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert- butyl N-[(1S)-4-hydroxy-1-methyl-butyl]carbamate. ES/MS: m/z 204.498 [M+H]. [0255] Step 2. In a vial were placed tert-butyl N-[(1S)-4-hydroxy-1-methyl-butyl]carbamate (450 mg, 2.21 mmol), and triethylamine (0.62 mL, 4.43 mmol) in DCM (10.1 mL). The mixture was cooled to 0 °C and p-toluenesulfonyl chloride (422 mg, 2.21 mmol) was added. After mixture was warmed to room temperature and stirred for 2 h, it was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give [(4S)-4-(tert-butoxycarbonylamino)pentyl] 4- methylbenzenesulfonate. ES/MS m/z: 358.551 [M+H]. [0256] Step 3. In a vial were placed 6-bromo-2H-isoquinolin-1-one (175 mg, 0.94 mmol), [(4S)-4-(tert-butoxycarbonylamino)pentyl] 4-methylbenzenesulfonate (335 mg, 0.94 mmol), and cesium carbonate in DMF (3.7 mL). After the mixture was stirred at room temperature for 16 h, it was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[(1S)-4-(6-bromo-1-oxo-2-isoquinolyl)-1-methyl-butyl]carba mate. ES/MS m/z: 411.125 [M+H]. [0257] Step 4. In a vial were placed tert-butyl N-[(1S)-4-(6-bromo-1-oxo-2-isoquinolyl)-1- methyl-butyl]carbamate (314 mg, 0.77 mmol), 1,1'-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (63 mg, 0.077 mmol), potassium acetate (226 mg, 2.30 mmol), and bis(pinacolato)diboron (292 mg, 1.15 mmol) in dioxane (3.19 mL). The mixture was heated to 100 °C for 1 hr. Upon completion, the reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), filtered through Celite, and concentrated to give tert-butyl N-[(1S)-1-methyl-4-[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-isoquinolyl]butyl]carbamate. ES/MS: m/z 457.26 [M+H]. [0258] Step 5. In a vial were placed tert-butyl N-[(1S)-1-methyl-4-[1-oxo-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2-isoquinolyl]butyl]car bamate (175 mg, 0.38 mmol), 2-iodo-5- (trifluoromethyl)pyrimidine (158 mg, 0.575 mmol), [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (12.5 mg, 0.019 mmol), and 2M aqueous sodium carbonate (0.58 mL, 1.15 mmol) in dioxane (3.5 mL). The mixture was heated to 80 °C for 2 h, and was then quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water, washed with brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to afford tert-butyl N-[(1S)-1-methyl-4-[1-oxo-6-[5-(trifluoromethyl)pyrimidin-2- yl]-2- isoquinolyl]butyl]carbamate. ES/MS: m/z 477.247 [M+H]. [0259] Step 6. In a vial were placed tert-butyl N-[(1S)-1-methyl-4-[1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]butyl]carbama te (120 mg, 0.25 mmol), and trifluoroacetic acid (0.19 mL, 2.5 mmol) in DCM (2.2 mL) and the mixture was stirred for 1 h, and concentrated under vacuum to give 2-[(4S)-4-aminopentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl] isoquinolin-1-one. ES/MS: m/z 377.702 [M+H]. [0260] Step 7. In a vial were placed 5-chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one (123 mg, 0.38 mmol), 2-[(4S)-4-aminopentyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one (94 mg, 0.25 mmol), and N,N-Diisopropylethylamine (0.22 mL, 1.25 mmol) in DMF (0.71 mL). The mixture was heated to 80 °C and stirred for 1 hr. Upon completion, the reaction was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. ES/MS m/z: 669.33 [M+H]. [0261] Step 8. In a vial were placed 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (163 mg, 0.24 mmol), and trifluoroacetic acid (0.16 mL, 2.4 mmol) in DCM (10.7 mL). The mixture was stirred for 1 hr, and then was concentrated under vacuum. The resulting crude product was dissolved in methanol (4.0 mL) and ethylenediamine (0.16 mL, 2.44 mmol) was added and the mixture was stirred for 15 minutes and then concentrated under vacuum. The resulting crude product was purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 2-[(4S)-4-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.43 (s, 2H), 8.75 (s, 1H), 8.50 (dd, J = 8.5, 1.6 Hz, 1H), 8.40 (d, J = 8.5 Hz, 1H), 7.93 (s, 1H), 7.56 (d, J = 7.3 Hz, 1H), 6.86 (d, J = 7.3 Hz, 1H), 6.36 (dq, J = 6.8, 3.3 Hz, 1H), 4.03 – 3.96 (m, 3H), 1.86 – 1.62 (m, 3H), 1.52 (dq, J = 13.2, 6.3 Hz, 1H), 1.18 (d, J = 6.3 Hz, 3H). ES/MS m/z : 539.062. Example 6: 6-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazi n-1-yl)propyl)phenyl)-4- (trifluoromethyl)pyridazin-3(2H)-one [0262] The title compound was synthesized as described in Example 5, using 6-bromo-5- fluoroisoquinolin-1(2H)-one instead of 6-bromoisoquinolin-1(2H)-one to give 5-fluoro-2-[(4S)-4-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.48 (s, 2H), 8.26 – 8.10 (m, 2H), 7.92 (s, 1H), 7.66 (d, J = 7.5 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.35 (dd, J = 8.6, 3.9 Hz, 1H), 4.02 (q, J = 8.4, 7.4 Hz, 3H), 1.71 (ddt, J = 21.7, 13.9, 6.6 Hz, 3H), 1.51 (dq, J = 12.9, 6.1 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 557.002. Example 7: 8-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one [0263] The title compound was synthesized as described in Example 5, using 6-bromo-8- fluoroisoquinolin-1(2H)-one instead of 6-bromoisoquinolin-1(2H)-one to give 8-fluoro-2-[(4S)-4-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.45 (s, 2H), 8.55 (s, 1H), 8.07 (d, J = 12.8 Hz, 1H), 7.92 (s, 1H), 7.60 (d, J = 7.3 Hz, 1H), 6.87 (dd, J = 7.4, 1.9 Hz, 1H), 6.35 (dd, J = 8.8, 3.9 Hz, 1H), 3.96 (t, J = 6.6 Hz, 3H), 1.70 (tq, J = 15.1, 7.8, 7.0 Hz, 3H), 1.51 (dq, J = 13.1, 6.7 Hz, 1H), 1.17 (d, J = 6.2 Hz, 3H). ES/MS m/z: 557.041. Example 8: 7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one [0264] The title compound was synthesized as described in Example 5, using 6-bromo-7- fluoroisoquinolin-1(2H)-one instead of 6-bromoisoquinolin-1(2H)-one to give 7-fluoro-2-[(4S)-4-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.48 (s, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.03 (d, J = 11.3 Hz, 1H), 7.92 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 6.85 (d, J = 7.3 Hz, 1H), 6.36 (dq, J = 7.1, 3.5 Hz, 1H), 4.01 (t, J = 6.8 Hz, 3H), 1.71 (ddt, J = 21.7, 13.8, 6.5 Hz, 3H), 1.52 (tt, J = 13.2, 6.5 Hz, 1H), 1.18 (d, J = 6.2 Hz, 3H). ES/MS: m/z 557.0. Example 9: 7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]-6-[5- (trifluoromethyl)-2-pyridyl]isoquinolin-1-one [0265] The title compound was synthesized as described in Example 5, using 2-bromo-5- (trifluoromethyl)pyridine instead of 2-iodo-5-(trifluoromethyl)pyrimidine to give 7-fluoro-2-[(4S)-4-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)-2- pyridyl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.17 (d, J = 2.3 Hz, 1H), 8.41 (dd, J = 8.5, 2.3 Hz, 1H), 8.30 (d, J = 7.3 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 8.03 (d, J = 11.6 Hz, 1H), 7.92 (s, 1H), 7.52 (d, J = 7.3 Hz, 1H), 6.81 (d, J = 7.3 Hz, 1H), 6.35 (dq, J = 7.0, 3.3 Hz, 1H), 4.00 (t, J = 6.8 Hz, 3H), 1.71 (dtq, J = 22.4, 15.2, 6.9 Hz, 3H), 1.51 (tt, J = 13.3, 6.7 Hz, 1H), 1.17 (d, J = 6.2 Hz, 3H). ES/MS: m/z 556.0. Example 10: 5-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]-6-[5- (trifluoromethyl)-2-pyridyl]isoquinolin-1-one [0266] The title compound was synthesized as described in Example 5, using 6-bromo-5- fluoroisoquinolin-1(2H)-one instead of 6-bromo-7-fluoroisoquinolin-1(2H)-one to give 5-fluoro-2-[(4S)- 4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl ]-6-[5-(trifluoromethyl)-2- pyridyl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 9.17 (d, J = 2.3 Hz, 1H), 8.40 (dd, J = 8.5, 2.3 Hz, 1H), 8.17 (dd, J = 8.5, 3.8 Hz, 2H), 8.03 (t, J = 7.8 Hz, 1H), 7.93 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 6.36 (dq, J = 7.0, 3.4 Hz, 1H), 4.02 (q, J = 6.7 Hz, 3H), 1.72 (dddd, J = 22.5, 15.2, 10.8, 6.4 Hz, 3H), 1.53 (tt, J = 13.0, 6.5 Hz, 1H), 1.18 (d, J = 6.2 Hz, 3H). ES/MS: m/z 556.0. Example 11: 8-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]-6-[5- (trifluoromethyl)-2-pyridyl]isoquinolin-1-one [0267] The title compound was synthesized as described in Example 5, using 6-bromo-8- fluoroisoquinolin-1(2H)-one instead of 6-bromo-7-fluoroisoquinolin-1(2H)-one to give 8-fluoro-2-[(4S)- 4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl ]-6-[5-(trifluoromethyl)-2- pyridyl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.19 – 9.05 (m, 1H), 8.46 – 8.34 (m, 2H), 8.32 (d, J = 1.6 Hz, 1H), 7.97 (dd, J = 13.2, 1.7 Hz, 1H), 7.92 (s, 1H), 7.58 (d, J = 7.4 Hz, 1H), 6.77 (dd, J = 7.4, 2.0 Hz, 1H), 6.36 (dt, J = 8.4, 3.6 Hz, 1H), 3.95 (t, J = 6.6 Hz, 2H), 1.81 – 1.59 (m, 3H), 1.51 (dq, J = 12.6, 6.5 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 556.235. Example 12: 7-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amin o]pentyl]-3-[5- (trifluoromethyl)pyrimidin-2-yl]-1,7-naphthyridin-8-one [0268] The title compound was synthesized as described in Example 5, using 3-bromo-7H- 1,7-naphthyridin-8-one instead of 6-bromo-2H-isoquinolin-1-one and 2-bromo-5- (trifluoromethyl)pyrimidine instead of 2-iodo-5-(trifluoromethyl)pyrimidine.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.69 (d, J = 2.0 Hz, 1H), 9.49 (s, 2H), 9.09 (d, J = 2.0 Hz, 1H), 7.92 (s, 1H), 7.67 (d, J = 7.3 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 6.41 – 6.31 (m, 1H), 4.07 – 3.96 (m, 3H), 1.82 – 1.63 (m, 3H), 1.60 – 1.46 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 540.0 [M+H] + . Example 13: 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amin o]pentyl]-6-[5 (trifluoromethyl)-2-pyridyl]-2,7-naphthyridin-1-one [0269] The title compound was synthesized as described in Example 1 using 6-bromo-2H-2,7- naphthyridin-1-one instead of 6-bromo-2H-isoquinolin-1-one and [(4S)-4-(tert- butoxycarbonylamino)pentyl] 4-methylbenzenesulfonate.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.47 (s, 1H), 9.13 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 8.3 Hz, 1H), 8.65 (s, 1H), 8.42 (dd, J = 8.2, 2.3 Hz, 1H), 7.92 (s, 1H), 7.81 (d, J = 7.3 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 6.41 – 6.30 (m, 1H), 4.07 – 3.93 (m, 3H), 1.81 – 1.60 (m, 3H), 1.60 – 1.46 (m, 1H), 1.17 (d, J = 6.2 Hz, 3H). ES/MS m/z: 539.0 [M+H] + .
Example 14: 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amin o]pentyl]-6-[5- (trifluoromethyl)-2-pyridyl]-2,7-naphthyridin-1-one [0270] The title compound was synthesized as described in Example 1 using 2-bromo-6H-1,6- naphthyridin-5-one instead of 6-bromo-2H-isoquinolin-1-one and [(4S)-4-(tert- butoxycarbonylamino)pentyl] 4-methylbenzenesulfonate.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.16 (s, 1H), 8.78 – 8.68 (m, 2H), 8.53 (d, J = 8.4 Hz, 1H), 8.48 – 8.40 (m, 1H), 7.92 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 6.40 – 6.31 (m, 1H), 4.07 – 3.93 (m, 3H), 1.81 – 1.62 (m, 3H), 1.60 – 1.46 (m, 1H), 1.17 (d, J = 6.2 Hz, 3H). ES/MS m/z: 539.1 [M+H] + . Example 15 Preparation of (S)-2-(4-((5-acetyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)pe ntyl)-7- fluoro-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H )-one [0271] Step 1. In a vial were placed 2-[(4S)-4-aminopentyl]-6-[5-(trifluoromethyl)pyrimidin- 2-yl]isoquinolin-1-one (200 mg, 0.53 mmol), 4-bromo-5-chloro-2-((2- (trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (175 mg, 0.53 mmol), and DIPEA (0.47 mL, 2.7 mmol) in DMF (2.5 mL). After the mixture was stirred at 110 °C for 16 hr, it was loaded onto the Silica pre-packed cartridge and purified by flash chromatography (100% DCM to 100% EtOAc then 100% DCM to 100% MeOH) to give 2-[(4S)-4-[[5-bromo-1-[(4-methoxyphenyl)methyl]-6-oxo-pyrida zin-4- yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoqui nolin-1-one. ES/MS m/z : 669.2 [M+H] + . [0272] Step 2. In a microwave reaction vial were placed (S)-2-(4-((5-bromo-6-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)ami no)pentyl)-7-fluoro-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one (100 mg, 0.15 mmol), tributyl(1-ethoxyvinyl)tin (108 mg, 0.30 mmol), and tetrakis(triphenylphosphine)palladium (17 mg, 0.015 mmol), and dioxane (1.5 mL). The mixture was sonicated for 20 seconds, purged with nitrogen gas for 5 minutes, and heated at 130 °C in a microwave reactor for 1 hr. The reaction was then filtered through a pad of Celite ® , concentrated in vacuo, and used in the next step without further purification. [0273] Step 3. The title compound was synthesized following the procedure described in the step 8 of Example 5, using 2-[(4S)-4-[(5-acetyl-6-oxo-1H-pyridazin-4-yl)amino]pentyl]-6 -[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one instead of (S)-2-(4-((6-oxo-5-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)ami no)pentyl)-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one. 1H NMR (400 MHz, Methanol-d4) δ 9.15 (d, J = 0.9 Hz, 2H), 8.72 (d, J = 1.6 Hz, 1H), 8.53 (dd, J = 8.5, 1.7 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.81 (s, 1H), 7.35 (d, J = 7.4 Hz, 1H), 6.74 (d, J = 7.3 Hz, 1H), 3.99 (dt, J = 19.4, 6.7 Hz, 3H), 2.48 (s, 3H), 1.94 – 1.72 (m, 2H), 1.61 (q, J = 7.2 Hz, 2H), 1.20 (d, J = 6.4 Hz, 3H). ES/MS m/z: 513.2 [M+H] + . Example 16 Preparation of (S)-2-(4-((5-acetyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)pe ntyl)-7- fluoro-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H )-one [0274] Step 1. In a vial were placed (S)-2-(4-aminopentyl)-7-fluoro-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one (117 mg, 0.30 mmol), 4-bromo-5-chloro-2-((2- (trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (202 mg, 0.59 mmol), and DIPEA (0.52 mL, 3.0 mmol) in ACN (2.0 mL). After the mixture was stirred at 110 °C for 16 hr, it was loaded onto a Silica pre-packed cartridge and purified by flash chromatography (100% DCM to 100% EtOAc then 100% DCM to 100% MeOH) to give (S)-2-(4-((5-bromo-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl )-1,6- dihydropyridazin-4-yl)amino)pentyl)-7-fluoro-6-(5-(trifluoro methyl)pyrimidin-2-yl)isoquinolin- 1(2H)-one. ES/MS m/z: 697.3 [M+H] + . [0275] Step 2. In a microwave reaction vial were placed (S)-2-(4-((5-bromo-6-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)ami no)pentyl)-7-fluoro-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one (6.0 mg, 0.0086 mmol), tributyl(1-ethoxyvinyl)tin (35 mg, 0.095 mmol), and tetrakis(triphenylphosphine)palladium (4.0 mg, 0.0036 mmol), and dioxane (1.0 mL). The mixture was sonicated for 20 seconds, purged with N 2 gas for 5 minutes, and placed in the microwave reactor, and stirred at 130 °C for 1.5 hr. The mixture was filtered through a pad of Celite ® , concentrated in vacuo to afford (S)-2-(4-((5-(1-ethoxyvinyl)-6-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)ami no)pentyl)-7-fluoro-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one. [0276] Step 3. The title compound was synthesized following the procedure described in the step 8 of Example 5, using (S)-2-(4-((5-(1-ethoxyvinyl)-6-oxo-1-((2-(trimethylsilyl)eth oxy)methyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)-7-fluoro-6-(5-(trifluoro methyl)pyrimidin-2-yl)isoquinolin-1(2H)- one instead of (S)-2-(4-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)e thoxy)methyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)py rimidin-2-yl)isoquinolin-1(2H)-one. 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.61 (d, J = 8.7 Hz, 1H), 9.48 (s, 2H), 8.44 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.96 (s, 1H), 7.66 – 7.50 (m, 2H), 6.84 (m, 1H), 4.04 (m, 3H), 3.46 (m, 2H), 1.76 (m, 2H), 1.63 – 1.48 (m, 2H), 1.20 (m, 3H), 0.89 (m, 1H). ES/MS m/z : 531.2 [M+H] + . Example 17: Preparation of (S)-6-(5-(difluoromethoxy)pyridin-2-yl)-8-fluoro-2-(4-((6-ox o-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)iso quinolin-1(2H)-one [0277] Step 1. In a vial were placed 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one (1.00 g, 4.13 mmol), [(4S)-4-(tert-butoxycarbonylamino)pentyl] 4-methylbenzenesulfonate (1.77 g, 4.96 mmol), and cesium carbonate (2.69 g, 8.26 mmol) in DMF (14.0 mL). After mixture was stirred at room temperature for 16 hr, it was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[(1S)-4-(6-bromo-8-fluoro-1-oxo-2-isoquinolyl)-1- methyl-butyl]carbamate. ES/MS m/z: 429.1 [M+2+H] ++ . [0278] Step 2. In a vial were placed tert-butyl N-[(1S)-4-(6-bromo-8-fluoro-1-oxo-2- isoquinolyl)-1-methyl-butyl]carbamate (591 mg, 1.38 mmol), and trifluoroacetic acid (1.06 mL, 13.8 mmol) in DCM (14.0 mL). After the mixture was stirred for 1 hr, it was concentrated under vacuum. To the same vial was then added 5-chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl )pyridazin-3- one (682 mg, 2.07 mmol) and N,N-Diisopropylethylamine (1.20 mL, 6.92 mmol) in DMF (7.00 mL). The mixture was heated to 80 °C and stirred for 1 hr, and then quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (MgSO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give 6-bromo-8-fluoro-2-[(4S)-4- [[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl) pyridazin-4- yl]amino]pentyl]isoquinolin-1-one. ES/MS m/z: 621.105 [M+H] + . [0279] Step 3. In a vial were placed 6-bromo-8-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)- 1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl] isoquinolin-1-one (165 mg, 0.267 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (44 mg, 0.054 mmol), potassium acetate (79 mg, 0.80 mmol), and bis(pinacolato)diboron (101 mg, 0.40 mmol) in dioxane (3.00 mL). The mixture was heated to 80 °C and stirred for 1 hr, followed by the addition of 2 M aqueous sodium carbonate (0.25 mL, 0.495 mmol) and 2-bromo-5-(difluoromethoxy)pyridine (55.4 mg, 0.248 mmol). The reaction was then stirred for an additional hour at 80 °C. Upon completion, the mixture was filtered through Celite ® and concentrated under vacuum. To the crude product was then added trifluoroacetic acid (1.65 mL) and the mixture was stirred for 1 hr at room temperature and concentrated under vacuum. The resulting product was dissolved in methanol (4.0 mL) and ethylenediamine (0.16 mL, 2.44 mmol) was added and stirred for 15 minutes, and then was concentrated under vacuum. The crude product was purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 6-[5-(difluoromethoxy)-2-pyridyl]-8-fluoro-2-[(4S)-4-[[6-oxo -5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one. 1 H NMR (400 MHz, DMSO- d6) δ 12.44 (s, 1H), 8.64 (d, J = 2.8 Hz, 1H), 8.27 – 8.21 (m, 1H), 8.21 – 8.17 (m, 1H), 7.94 – 7.88 (m, 1H), 7.88 – 7.81 (m, 1H), 7.57 – 7.51 (m, 1H), 7.62 – 7.23 (m, 1H), 6.77 – 6.67 (m, 1H), 6.38 – 6.30 (m, 1H), 4.02 – 3.90 (m, 3H), 1.78 – 1.44 (m, 4H), 1.18 (d, J = 6.3 Hz, 3H). ES/MS m/z: 554.2105 [M+H] + . Example 18: (S)-6-(8-fluoro-1-oxo-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-d ihydropyridazin-4- yl)amino)pentyl)-1,2-dihydroisoquinolin-6-yl)nicotinonitrile [0280] The title compound was synthesized as described in Example 17, using 2-bromo-5- cyanopyridine instead of 2-bromo-5-(difluoromethoxy)pyridine.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.21 – 9.11 (m, 1H), 8.55 – 8.47 (m, 1H), 8.43 – 8.35 (m, 1H), 8.34 – 8.30 (m, 1H), 8.01 – 7.93 (m, 1H), 7.93 – 7.90 (m, 1H), 7.58 (d, J = 7.3 Hz, 1H), 6.88 – 6.60 (m, 1H), 6.45 – 6.18 (m, 1H), 4.18 – 3.88 (m, 5H), 1.89 – 1.39 (m, 4H), 1.20 – 1.12 (m, 3H). ES/MS m/z: 513.3 [M+H] + . Example 19: (S)-8-fluoro-6-(5-fluoropyridin-2-yl)-2-(4-((6-oxo-5-(triflu oromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0281] The title compound was synthesized as described in Example 17, using 2-bromo-5- fluoropyridine instead of 2-bromo-5-(difluoromethoxy)pyridine.1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.73 (d, J = 2.9 Hz, 1H), 8.28 – 8.21 (m, 1H), 8.18 (d, J = 1.7 Hz, 1H), 7.97 – 7.83 (m, 3H), 7.54 (d, J = 7.4 Hz, 1H), 6.78 – 6.65 (m, 1H), 6.44 – 6.27 (m, 1H), 4.05 – 3.86 (m, 4H), 1.82 – 1.43 (m, 5H), 1.32 – 1.06 (m, 3H). ES/MS m/z: 506.2 [M+H] + . Intermediate 1 Preparation of 6-bromo-7,8-difluoroisoquinolin-1(2H)-one [0282] Step 1. To a vial was added 4-bromo-2,3-difluoro-benzoic acid (1.03 g, 4.36 mmol), amino 2,2-dimethylpropanoate;trifluoromethanesulfonic acid (1.17 g, 4.36 mmol), HATU (1.74 g, 4.58 mmol), and N,N-Diisopropylethylamine (2.28 mL, 13.1 mmol) in DMF (11.0 mL). The reaction was stirred at 25 °C for 1 hour and then quenched with water and extracted with EtOAc (x3). The organic layers were dried (MgSO 4 ) and purified by flash chromatography (100% hexanes to 100% EtOAc to give 4-bromo-2,3-difluoro-N-(pivaloyloxy)benzamide. ES/MS m/z: 337.907 [M+H] ++ . [0283] Step 2. To a vial was added [(4-bromo-2,3-difluoro-benzoyl)amino] 2,2- dimethylpropanoate (459 mg, 1.37 mmol), vinyl acetate (0.252 mL, 2.73 mmol), cesium acetate (131 mg, 0.683 mmol), and (pentamethylcyclopentadienyl)rhodium(III) dichloride dimer (65 mg, 0.137 mmol) in methanol (7.00 mL). The reaction is stirred at 45 °C for 8 hours, and then concentrated under vacuum to give 6-bromo-7,8-difluoroisoquinolin-1(2H)-one which was used directly in the alkylation step. ES/MS m/z : 261.890 [M+H] ++ . Example 20: (S)-8-fluoro-6-(5-fluoropyridin-2-yl)-2-(4-((6-oxo-5-(triflu oromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0284] The title compound was synthesized as described in Example 17, using 2-iodo-5- (trifluoromethyl)pyrimidine instead of 2-bromo-5-(difluoromethoxy)pyridine and 2-bromo-7,8- difluoroisoquinolin-1(2H)-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.56 – 9.44 (m, 2H), 8.31 – 8.17 (m, 1H), 7.92 (s, 1H), 7.56 (d, J = 7.4 Hz, 1H), 6.87 – 6.75 (m, 1H), 6.40 – 6.29 (m, 1H), 4.07 – 3.89 (m, 3H), 1.77 – 1.45 (m, 5H), 1.18 (d, J = 6.3 Hz, 3H). ES/MS m/z: 575.3 [M+H] + . Example 21: 7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]-6-[5- (trifluoromethyl)pyrazin-2-yl]isoquinolin-1-one [0285] The title compound was synthesized as described in Example 5 with the following changes: Step 3.6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 4. The reaction was allowed to proceed for 18 hours rather than 1 hour. The reaction was filtered through Celite © and the filtrate was used directly in the next step. Step 5.2-Bromo-5-(trifluoromethyl)pyrazine was used instead of 2-iodo-5-(trifluoromethyl)pyrimidine and the aqueous workup was omitted.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.40 (d, J = 1.4 Hz, 1H), 9.34 (t, J = 1.9 Hz, 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.08 (d, J = 11.5 Hz, 1H), 7.91 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 6.39 – 6.31 (m, 1H), 4.05 – 3.94 (m, 3H), 1.81 – 1.59 (m, 3H), 1.56 – 1.46 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 557.3 [M+H] + . Example 22: Preparation of (S)-7-fluoro-6-(5-methoxypyrimidin-2-yl)-2-(4-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)iso quinolin-1(2H)-one [0286] The title compound was synthesized as described in Example 5, with the following changes: Step 3.6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 4. The reaction was stirred for 3 hrs rather than 1 hr The reaction was filtered through Celite ® and the filtrate was used directly in the next step. Step 5.2-Bromo-5-methoxy-pyrimidine was used instead of 2-iodo-5-(trifluoromethyl)pyrimidine and the aqueous workup was omitted.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 7.91 (t, J = 5.7 Hz, 2H), 7.83 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.15 (t, J = 1.9 Hz, 1H), 7.12 (dt, J = 8.3, 1.9 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 7.4 Hz, 1H), 6.39 – 6.30 (m, 1H), 4.35 – 4.26 (m, 4H), 4.04 – 3.94 (m, 3H), 1.80 – 1.58 (m, 3H), 1.55 – 1.42 (m, 1H), 1.16 (d, J = 6.3 Hz, 3H). ES/MS m/z: 545.3 [M+H] + . Example 23: (S)-5-(7-fluoro-1-oxo-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-d ihydropyridazin-4- yl)amino)pentyl)-1,2-dihydroisoquinolin-6-yl)pyrazine-2-carb onitrile [0287] The title compound was synthesized as described in Example 5, with the following changes: Step 3.6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 4. The reaction was allowed to proceed for 3 hours rather than 1 hour. The reaction was filtered through Celite ® and the filtrate was used directly in the next step. Step 5.5-Bromopyrazine-2-carbonitrile was used instead of 2-iodo-5-(trifluoromethyl)pyrimidine and the aqueous workup was omitted.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.42 (d, J = 1.5 Hz, 1H), 9.32 (t, J = 1.9 Hz, 1H), 8.36 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 11.6 Hz, 1H), 7.90 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 6.38 – 6.30 (m, 1H), 4.04 – 3.91 (m, 3H), 1.80 – 1.59 (m, 3H), 1.56 – 1.45 (m, 1H), 1.16 (d, J = 6.3 Hz, 3H). ES/MS m/z: 514.3 [M+H] + . Example 24: (S)-2-(7-fluoro-1-oxo-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-d ihydropyridazin-4- yl)amino)pentyl)-1,2-dihydroisoquinolin-6-yl)pyrimidine-5-ca rbonitrile [0288] The title compound was synthesized as described in Example 5, with the following changes: Step 3.6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 4. The reaction was allowed to proceed for 3 hours rather than 1 hour. The reaction was filtered through Celite ® and the filtrate was used directly in the next step. Step 5.2-Bromopyrimidine-5-carbonitrile was used instead of 2-iodo-5-(trifluoromethyl)pyrimidine and the aqueous workup was omitted.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.50 (s, 2H), 8.46 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 11.5 Hz, 1H), 7.92 (s, 1H), 7.53 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 7.3 Hz, 1H), 6.40 – 6.31 (m, 1H), 4.04 – 3.96 (m, 3H), 1.84 – 1.59 (m, 3H), 1.51 (dt, J = 18.8, 6.2 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 513.3 [M+H] + . Example 25: (S)-6-(7-fluoro-1-oxo-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-d ihydropyridazin-4- yl)amino)pentyl)-1,2-dihydroisoquinolin-6-yl)nicotinonitrile [0289] The title compound was synthesized as described in Example 5, with the following changes: Step 3.6-bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 4. The reaction was allowed to proceed for 3 hours rather than 1 hour. The reaction was filtered through Celite ® and the filtrate was used directly in the next step. Step 5.6-bromopyridine-3-carbonitrile was used instead of 2-iodo-5-(trifluoromethyl)pyrimidine and the aqueous workup was omitted.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.22 (dd, J = 2.2, 0.9 Hz, 1H), 8.50 (dd, J = 8.3, 2.2 Hz, 1H), 8.31 (d, J = 7.4 Hz, 1H), 8.12 – 8.08 (m, 1H), 8.03 (d, J = 11.7 Hz, 1H), 7.91 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 7.3 Hz, 1H), 6.39 – 6.31 (m, 1H), 4.04 – 3.91 (m, 3H), 1.82 – 1.59 (m, 3H), 1.56 – 1.45 (m, 1H), 1.16 (d, J = 6.3 Hz, 3H). ES/MS m/z: 513.3 [M+H] + . Example 26: (S)-6-(2,3-dihydrobenzofuran-7-yl)-7-fluoro-2-(4-((6-oxo-5-( trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0290] The title compound was synthesized as described in Example 1, with the following changes: Step 1.6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 2.2,3-dihydrobenzofuran-7-ylboronic acid was used instead of [5-(trifluoromethyl)-2- pyridyl]boronic acid. Example 27: (S)-6-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-7-fluoro-2-(4-(( 6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0291] The title compound was synthesized as described in Example 1, with the following changes: Step 2.6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 3.2,3-Dihydro-1,4-benzodioxin-5-ylboronic acid was used instead of [5-(trifluoromethyl)-2- pyridyl]boronic acid.1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 7.95 – 7.87 (m, 2H), 7.71 (d, J = 6.9 Hz, 1H), 7.47 (d, J = 7.4 Hz, 1H), 6.98 (dd, J = 8.1, 2.1 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.88 (dd, J = 7.2, 2.1 Hz, 1H), 6.68 (d, J = 7.3 Hz, 1H), 6.40 – 6.30 (m, 1H), 4.31 – 4.18 (m, 4H), 4.04 – 3.93 (m, 3H), 1.82 – 1.58 (m, 3H), 1.57 – 1.43 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 545.3 [M+H] + . Example 28: (S)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-2-(4-(( 6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0292] The title compound was synthesized as described in Example 1, with the following changes: Step 2.6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 3.2-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane was used instead of [5-(trifluoromethyl)-2-pyridyl]boronic acid.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 7.91 (t, J = 5.7 Hz, 2H), 7.83 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.15 (t, J = 1.9 Hz, 1H), 7.12 (dt, J = 8.3, 1.9 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 7.4 Hz, 1H), 6.39 – 6.30 (m, 1H), 4.35 – 4.26 (m, 4H), 4.04 – 3.94 (m, 3H), 1.80 – 1.58 (m, 3H), 1.55 – 1.42 (m, 1H), 1.16 (d, J = 6.3 Hz, 3H). ES/MS m/z: 545.3 [M+H] + . Example 29: (S)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyr idazin-4- yl)amino)pentyl)-7-(5-(trifluoromethyl)pyrimidin-2-yl)quinaz olin-4(3H)-one [0293] The title compound was synthesized as described in Example 5, using 7-bromo-6- fluoro-1H-quinazolin-4-one instead of 6-bromoisoquinolin-1(2H)-one to give (S)-6-fluoro-3-(4-((6-oxo- 5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)- 7-(5-(trifluoromethyl)pyrimidin-2- yl)quinazolin-4(3H)-one as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.50 (d, J = 1.0 Hz, 2H), 8.46 (s, 1H), 8.35 (d, J = 6.7 Hz, 1H), 8.01 (d, J = 10.6 Hz, 1H), 7.92 (s, 1H), 6.41 – 6.26 (m, 1H), 4.11 – 3.88 (m, 3H), 1.83 – 1.62 (m, 3H), 1.62 – 1.42 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 558.20 [M+H] + . Example 30 Preparation of 6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4- yl]amino]pentyl]-7-[5-(trifluoromethyl)pyrimidin-2-yl]-1H-qu inazoline-2,4-dione [0294] Step 1. Phthalimide potassium salt (0.995 g, 5.37 mmol) was added to a solution of [(4S)-4-(tert-butoxycarbonylamino)pentyl] 4-methylbenzenesulfonate (1.60 g, 4.48 mmol) in DMF (17.8 mL) and the resulting solution was heated to 80 °C for 2.5 hr. The reaction mixture was then diluted with water (ca.100 mL) and the resulting white precipitate was collected by filtration to afford tert-butyl N- [(1S)-4-(1,3-dioxoisoindolin-2-yl)-1-methyl-butyl]carbamate. ES/MS m/z: 333.08 [M+H] + . [0295] Step 2. Hydrazine (0.378 mL, 12.0 mmol) was added slowly to a solution of tert-butyl N-[(1S)-4-(1,3-dioxoisoindolin-2-yl)-1-methyl-butyl]carbamat e (0.8 g, 2.41 mmol) in EtOH (11.0 mL) and the resulting solution was heated to 80 °C for 45 min, at which time the formation of a significant amount of white precipitate hindered stirring. The suspension was then diluted with MeOH (10.0 mL) and a large excess of Et2O, and the white precipitate was removed by filtration. The filtrate was concentrated in vacuo to afford tert-butyl (S)-(5-aminopentan-2-yl)carbamate. ES/MS m/z: 203.15 [M+H] + . [0296] Step 3. Triethylamine (1.75 mL, 12.6 mmol) was added to a solution of triphosgene (0.822 g, 2.77 mmol) and methyl 2-amino-4-bromo-5-fluoro-benzoate (624 mg, 2.52 mmol) in DCM (20.0 mL). The resulting solution was stirred at room temperature for 2 hr, followed by the addition of tert-butyl N-[(1S)-4-amino-1-methyl-butyl]carbamate (390 mg, 1.93 mmol) as a solution in DCM (20.0 mL). The reaction mixture was stirred at room temperature for 3.5 hr, followed by the addition of NaOMe (1.67 mL, 25% in MeOH, 7.29 mmol). After an additional 30 minutes of stirring at room temperature the reaction mixture was poured into saturated aqueous NH 4 Cl, extracted with EtOAc, washed with brine, dried (MgSO 4 ), and concentrated in vacuo. To the crude oil was added DCM (2.00 mL) and PhMe (20 mL), and the resulting white precipitate was collected by filtration to afford tert-butyl N-[(1S)-4-(7-bromo-6-fluoro-2,4-dioxo-1H-quinazolin-3-yl)-1- methyl-butyl]carbamate. ES/MS m/z: 444.033 [M+H] + . [0297] Step 4. Dioxane (5.00 mL) was added to a vial charged with tert-butyl N-[(1S)-4-(7- bromo-6-fluoro-2,4-dioxo-1H-quinazolin-3-yl)-1-methyl-butyl] carbamate (124 mg, 0.279 mmol), potassium acetate (82 mg, 0.837 mmol), bis(pinacolato)diboron (106 mg, 0.419 mmol), and (1,1'- bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (20.4 mg, 0.028 mmol). The resulting suspension was sparged with nitrogen for 5 minutes, then heated to 80 °C for 16 hr. To the reaction mixture was then added 2-iodo-5-(trifluoromethyl)pyrimidine (153 mg, 0.558 mmol) and Na 2 CO 3 (0.419 mL, 2N in H 2 O, 0.837 mmol) and the resulting solution was then heated to 80 °C for 2 hr, then cooled to room temperature, filtered through a pad of Celite ® , concentrated in vacuo, and purified by flash chromatography (100% hexanes to 100% EtOAc) to afford tert-butyl N-[(1S)-4-[6-fluoro-2,4-dioxo-7- [5-(trifluoromethyl)pyrimidin-2-yl]-1H-quinazolin-3-yl]-1-me thyl-butyl]carbamate. ES/MS m/z: 512.11 [M+H] + . [0298] Step 5. In a vial were placed tert-butyl N-[(1S)-4-[6-fluoro-2,4-dioxo-7-[5- (trifluoromethyl)pyrimidin-2-yl]-1H-quinazolin-3-yl]-1-methy l-butyl]carbamate (135 mg, 0.264 mmol), and trifluoroacetic acid (2.00 mL) in DCM (10.0 mL). After the mixture was allowed to stir for 1 hr, it was concentrated under vacuum to give 3-[(4S)-4-aminopentyl]-6-fluoro-7-[5- (trifluoromethyl)pyrimidin-2-yl]-1H-quinazoline-2,4-dione. ES/MS m/z: 412.119 [M+H] + . [0299] Step 6. In a vial were placed 5-chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one (138 mg, 0.419 mmol), 3-[(4S)-4-aminopentyl]-6-fluoro-7- [5-(trifluoromethyl)pyrimidin-2-yl]-1H-quinazoline-2,4-dione (115 mg, 0.279 mmol), and N,N- Diisopropylethylamine (0.486 mL, 2.79 mmol) in DMF (10.0 mL). After the mixture was stirred at room temperature for 16 h, it was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give 6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-7-[5 -(trifluoromethyl)pyrimidin-2-yl]-1H- quinazoline-2,4-dione. ES/MS m/z: 704.29 [M+H] + . [0300] Step 7. In a vial were placed 6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazine-4-yl]amino]pentyl]-7-[ 5-(trifluoromethyl)pyrimidin-2-yl]-1H- quinazoline-2,4-dione (136 mg, 0.193 mmol), and trifluoroacetic acid (1.48 mL, 19.3 mmol) in DCM (10.0 mL). After the mixture was allowed to stir for 1 hr, it was concentrated in vacuo. The resulting crude product was dissolved in methanol (5.00 mL) and ethylenediamine (0.258 mL, 3.86 mmol) was added. The resulting solution was stirred at room temperature for 10 minutes, then concentrated in vacuo. The resulting crude product was purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4- yl]amino]pentyl]-7-[5-(trifluoromethyl)pyrimidin-2-yl]-1H-qu inazoline-2,4-dione. 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 11.68 (s, 1H), 9.48 (d, J = 0.9 Hz, 2H), 7.98 – 7.88 (m, 2H), 7.81 (d, J = 10.5 Hz, 1H), 6.41 – 6.28 (m, 1H), 4.03 – 3.95 (m, 1H), 3.92 (t, J = 6.8 Hz, 2H), 1.76 – 1.56 (m, 3H), 1.59 – 1.47 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z : 574.20 [M+H] + . Example 31: 7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]-6-(2- pyridyl)isoquinolin-1-one [0301] The title compound was synthesized as described in Example 5, using 2- bromopyridine in place of 6-bromoisoquinolin-1(2H)-one to give 7-fluoro-2-[(4S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-(2-pyrid yl)isoquinolin-1-one (15mg, 48%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.78 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 8.24 (d, J = 7.4 Hz, 1H), 8.04 – 7.95 (m, 2H), 7.94 – 7.86 (m, 2H), 7.54 – 7.46 (m, 2H), 6.79 (d, J = 7.3 Hz, 1H), 6.35 (dd, J = 8.6, 3.7 Hz, 1H), 3.99 (t, J = 6.2 Hz, 3H), 1.71 (ddq, J = 24.2, 15.8, 8.8, 7.7 Hz, 3H), 1.50 (dq, J = 12.9, 6.7, 6.3 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z : 488.2 [M+H] + . Example 32: 7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]-6-[5- (trifluoromethoxy)-2-pyridyl]isoquinolin-1-one [0302] The title compound was synthesized as described in Example 8, using 2-bromo-5- (trifluoromethoxy)pyridine in place of 2-iodo-5-(trifluoromethyl)pyrimidine to give 7-fluoro-2-[(4S)-4- [[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]- 6-[5-(trifluoromethoxy)-2- pyridyl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.88 (dt, J = 2.8, 0.8 Hz, 1H), 8.25 (d, J = 7.4 Hz, 1H), 8.13 – 7.97 (m, 3H), 7.91 (s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.35 (dd, J = 8.7, 3.8 Hz, 1H), 3.99 (t, J = 6.7 Hz, 3H), 1.70 (ddt, J = 24.5, 15.7, 7.3 Hz, 3H), 1.55 – 1.45 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z : 572.2 [M+H] + . Example 33: 6-[5-(difluoromethyl)-2-pyridyl]-7-fluoro-2-[(4S)-4-[[6-oxo- 5-(trifluoromethyl)-1H- pyridazin-4-yl]amino]pentyl]isoquinolin-1-one [0303] The title compound was synthesized as described in Example 8, using 2-bromo-5- (difluoromethyl)pyridine in place of 2-iodo-5-(trifluoromethyl)pyrimidine to give 6-[5-(difluoromethyl)- 2-pyridyl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H -pyridazin-4- yl]amino]pentyl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.98 (p, J = 1.2 Hz, 1H), 8.28 (d, J = 7.4 Hz, 1H), 8.20 (ddd, J = 8.3, 2.4, 1.3 Hz, 1H), 8.07 – 7.99 (m, 2H), 7.91 (s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.25 (t, J = 55.2 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.35 (dq, J = 6.7, 3.3 Hz, 1H), 3.99 (q, J = 6.4 Hz, 3H), 1.82 – 1.58 (m, 3H), 1.51 (dt, J = 8.9, 6.1 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z : 538.2 [M+H] + . Example 34: 7-fluoro-6-(5-fluoropyrimidin-2-yl)-2-[(4S)-4-[[6-oxo-5-(tri fluoromethyl)-1H- pyridazin-4-yl]amino]pentyl]isoquinolin-1-one [0304] The title compound was synthesized as described in Example 8, using 2-bromo-5- fluoro-pyrimidine in place of 2-iodo-5-(trifluoromethyl)pyrimidine to give 7-fluoro-6-(5- fluoropyrimidin-2-yl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)- 1H-pyridazin-4- yl]amino]pentyl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.11 (d, J = 0.8 Hz, 2H), 8.32 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 11.3 Hz, 1H), 7.92 (s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 7.3 Hz, 1H), 6.35 (dd, J = 8.7, 3.7 Hz, 1H), 3.99 (t, J = 6.4 Hz, 3H), 1.71 (dtd, J = 22.2, 14.8, 13.7, 7.1 Hz, 3H), 1.50 (dq, J = 12.9, 6.3 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z : 507.2 [M+H] + . Example 35: 7-fluoro-6-(5-fluoro-2-pyridyl)-2-[(4S)-4-[[6-oxo-5-(trifluo romethyl)-1H-pyridazin-4- yl]amino]pentyl]isoquinolin-1-one [0305] The title compound was synthesized as described in Example 8, using 2-bromo-5- fluoro-pyridine in place of 2-iodo-5-(trifluoromethyl)pyrimidine to give 7-fluoro-6-(5-fluoro-2- pyridyl)-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.79 (d, J = 2.9 Hz, 1H), 8.21 (d, J = 7.4 Hz, 1H), 8.05 – 7.87 (m, 4H), 7.49 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.46 – 6.22 (m, 1H), 3.99 (t, J = 6.1 Hz, 3H), 1.69 (ddp, J = 22.3, 15.6, 6.7 Hz, 3H), 1.50 (dq, J = 13.0, 6.2 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z : 506.2 [M+H] + . Example 36: 2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyrid azin-4-yl]amino]butyl]- 7-fluoro-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1- one [0306] Step 1. In a vial were placed methyl (2S)-2-(tert-butoxycarbonylamino)-2- cyclopropyl-acetate (500 mg, 2.18 mmol) and 1N lithium hydroxide solution (aq.) (5.45 mL, 5.45 mmol) in THF (17 mL). The mixture was stirred at room temperature for 4 h. Upon completion, the reaction was diluted with ethyl acetate, washed with 1 N HCl solution (aq.), washed with brine, dried over Na 2 SO 4 and concentrated to give (2S)-2-(tert-butoxycarbonylamino)-2-cyclopropyl-acetic acid. ES/MS m/z 159.701 [M-tert-butyl]-. [0307] Step 2. In a vial were placed (2S)-2-(tert-butoxycarbonylamino)-2-cyclopropyl-acetic acid (468 mg, 2.17 mmol), triethylamine (0.303 mL, 2.17 mmol), and THF (21.0 mL). The mixture was cool to 0 °C and placed under nitrogen atmosphere. To this solution was added ethyl chloroformate (0.208 mL, 2.17 mmol) and stirred for 30 min at 0 °C. The reaction was then filtered to remove the precipitated triethylamine hydrochloride. The filtrate containing the mixed anhydride was slowly added to a stirred suspension of sodium borohydride (247 mg, 6.52 mmol) in 20% aqueous THF (10.0 mL) maintained at 10 °C. After mixture stirred for 30 minutes, it was acidified with 1N HCl to pH ~ 4. The mixture was then extracted with EtOAc (x3), washed with 2M NaOH solution, washed with brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N- [(1S)-1-cyclopropyl-2-hydroxy-ethyl]carbamate. ES/MS: m/z 145.8 [M-tert-butyl]-. [0308] Step 3. In a vial was placed tert-butyl N-[(1S)-1-cyclopropyl-2-hydroxy- ethyl]carbamate (378 mg, 1.88 mmol) in DCM (16.0 mL). The mixture was cooled to 0 °C and Dess- Martin Periodinane (1590 mg, 3.76 mmol) was added. Reaction was warmed to room temperature and stirred for 1 h. Upon complete conversion the reaction mixture was diluted with DCM, washed with saturated sodium bicarbonate solution, washed with brine, dried over Na 2 SO 4 and concentrated to give tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate. ES/MS: m/z 143.8 [M-tert-butyl]-. [0309] Step 4. In a vial were placed tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate (374 mg, 1.88 mmol), and methyl(triphenylphosphoranylidene)acetate (941 mg, 2.82 mmol) in THF (15.0 mL). Reaction was stirred at room temperature for 12h, concentrated in vacuo, and purified via flash chromatography (100% hexanes to 100% EtOAc) to give methyl (E,4S)-4-(tert- butoxycarbonylamino)-4-cyclopropyl-but-2-enoate. ES/MS: m/z 278.2 [M+Na] + . [0310] Step 5. In a pressure vial were placed methyl (E,4S)-4-(tert-butoxycarbonylamino)-4- cyclopropyl-but-2-enoate (255 mg, 0.999 mmol), p-toluenesulfonhydrazide (2790 mg, 15 mmol), and sodium acetate trihydrate (2718 mg, 20 mmol) in THF:H 2 O (1:1, 12.9 mL). Mixture was heated to 80 °C and stirred for 8 h. Upon complete conversion the reaction was diluted with EtOAc, washed with saturated sodium bicarbonate solution, washed with brine, dried over Na 2 SO 4 , and purified via flash chromatography (100% hexanes to 100% EtOAc) to give methyl (4R)-4-(tert-butoxycarbonylamino)- 4-cyclopropyl-butanoate. ES/MS: m/z 257.6 [M+H] + . [0311] Step 6. In a vial were placed methyl (4R)-4-(tert-butoxycarbonylamino)-4- cyclopropyl-butanoate (233 mg, 0.905 mmol), and 1N lithium hydroxide solution (aq.) (2.26 mL, 2.26 mmol) in THF (7.06 mL). The mixture was stirred at room temperature for 4 h. Upon complete conversion reaction diluted with ethyl acetate, washed with 1N HCl solution (aq.), washed with brine, organic layer was dried over Na 2 SO 4 and concentrated to give (4R)-4-(tert-butoxycarbonylamino)-4- cyclopropyl-butanoic acid. ES/MS m/z 187.761 [M-tert-butyl]-. [0312] Step 7. In a vial were placed (4R)-4-(tert-butoxycarbonylamino)-4-cyclopropyl- butanoic acid (220 mg, 0.904 mmol), and triethylamine (0.126 mL, 0.904 mmol) in THF (8.73 mL). The mixture was cool to 0 °C and placed under nitrogen atmosphere. To this solution was added ethyl chloroformate (0.087 mL, 0.904 mmol). After mixture stirred for 30 min at 0 °C, it was filtered to remove the precipitated triethylamine hydrochloride. The filtrate containing the mixed anhydride was slowly added to a stirred suspension of sodium borohydride (103 mg, 2.71 mmol) in 20% aqueous THF (10.0 mL) maintained at 10 °C. After mixture was stirred for 30 minutes, it was acidified with 1N HCl to pH ~ 4. The mixture was then extracted with EtOAc, washed with 2M NaOH solution, washed with brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[(1R)-1-cyclopropyl-4-hydroxy-butyl]carbamate. ES/MS: m/z 229.6 [M+H] + . [0313] Step 8. In a vial were placed tert-butyl N-[(1R)-1-cyclopropyl-4-hydroxy- butyl]carbamate (193 mg, 0.842 mmol), and triethylamine (0.235 mL, 1.68 mmol) in DCM (3.85 mL). The mixture was cooled to 0 °C and p-toluenesulfonyl chloride (160 mg, 0.842 mmol) was added. The mixture was warmed to room temperature and stirred for 2h and was then quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give [(4R)-4-(tert- butoxycarbonylamino)-4-cyclopropyl-butyl] 4-methylbenzenesulfonate. ES/MS m/z: 406.1 [M+Na] +. [0314] Step 9. In a vial were placed 6-bromo-7-fluoro-2H-isoquinolin-1-one (110 mg, 0.454 mmol), [(4R)-4-(tert-butoxycarbonylamino)-4-cyclopropyl-butyl] 4-methylbenzenesulfonate (209 mg, 0.545 mmol), and cesium carbonate (296 mg, 0.909 mmol) in DMF (2.20 mL). After mixture was stirred at room temperature for 16 h, it was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[(1R)-4-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)- 1-cyclopropyl-butyl]carbamate. ES/MS m/z: 455.0 [M+H] + . [0315] Step 10. In a vial were placed tert-butyl N-[(1R)-4-(6-bromo-7-fluoro-1-oxo-2- isoquinolyl)-1-cyclopropyl-butyl]carbamate (181 mg, 0.399 mmol), 1,1'- Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (33 mg, 0.0399mmol), potassium acetate (118 mg, 1.2 mmol), and bis(pinacolato)diboron (152 mg, 0.599 mmol) in dioxane (1.70 mL). The mixture was heated to 100 °C and stirred for 1 h. Upon completion, the reaction was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), filtered through Celite ® , and concentrated to give tert- butyl N-[(1R)-1-cyclopropyl-4-[7-fluoro-1-oxo-6-(4,4,5,5-tetrameth yl-1,3,2-dioxaborolan-2-yl)-2- isoquinolyl]butyl]carbamate. ES/MS: m/z 501.3 [M+H] + . [0316] Step 11. In a vial were placed tert-butyl N-[(1R)-1-cyclopropyl-4-[7-fluoro-1-oxo-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-isoquinolyl] butyl]carbamate (200 mg, 0.4 mmol), 2- iodo-5-(trifluoromethyl)pyrimidine (164 mg, 0.6 mmol), [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (13 mg, 0.02 mmol), and 2M aqueous sodium carbonate (0.6 mL, 1.2 mmol) in dioxane (3.61 mL). After the mixture was heated to 80 °C and allowed to stir for 2 h, it was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[(1R)-1-cyclopropyl-4-[7-fluoro-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]butyl]carbama te. ES/MS: m/z 521.2 [M+H] + . [0317] Step 12. In a vial were placed tert-butyl N-[(1R)-1-cyclopropyl-4-[7-fluoro-1-oxo-6- [5-(trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]butyl]carb amate (196 mg, 0.377 mmol), and trifluoroacetic acid (0.288 mL, 3.77 mmol) in DCM (3.30 mL). After the mixture was allowed to stir for 1 h, it was concentrated under vacuum to give 2-[(4R)-4-amino-4-cyclopropyl-butyl]-7-fluoro-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. ES/MS: m/z 421.1 [M+H] + . [0318] Step 13. In a vial were placed 5-chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one (185 mg, 0.564 mmol), 2-[(4R)-4-amino-4-cyclopropyl- butyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquin olin-1-one (158 mg, 0.376 mmol), and N,N- Diisopropylethylamine (0.327 mL, 1.88 mmol) in DMF (1.10 mL). After the mixture was heated to 80 °C and allowed to stir for 1 h, it was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give 2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]butyl]-7-flu oro-6-[5-(trifluoromethyl)pyrimidin- 2-yl]isoquinolin-1-one. ES/MS m/z: 713.3 [M+H] + . [0319] Step 14. In a vial were placed 2-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1- (2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]butyl]-7- fluoro-6-[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (169 mg, 0.237 mmol), and trifluoroacetic acid (0.181 mL, 2.7 mmol) in DCM (10.4 mL). After the mixture was allowed to stir for 1 h, it was concentrated under vacuum. The resulting crude product was dissolved in methanol (4.0 mL) and ethylenediamine (0.159 mL, 2.437 mmol) was added. The mixture was stirred for 15 minutes and was concentrated under vacuum. The resulting crude product was purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 2- [(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridaz in-4-yl]amino]butyl]-7-fluoro-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.48 (d, J = 1.0 Hz, 2H), 8.44 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 11.4 Hz, 1H), 7.89 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 7.3 Hz, 1H), 6.51 (dd, J = 9.0, 3.8 Hz, 1H), 4.01 (t, J = 6.3 Hz, 2H), 3.36 (s, 1H), 1.72 (d, J = 40.1 Hz, 4H), 1.10 (tt, J = 8.2, 3.4 Hz, 1H), 0.50 (dp, J = 8.4, 4.2 Hz, 1H), 0.38 (tt, J = 8.9, 4.1 Hz, 1H), 0.25 (ddq, J = 18.6, 9.3, 4.6 Hz, 2H). ES/MS m/z : 508.3 [M+H] + . Example 37: 7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]hexyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one [0320] The title compound was synthesized as described in Example 6, using tert-butyl N- [(1S)-1-formylpropyl]carbamate in place of tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate to give 7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]hexyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.48 (d, J = 0.9 Hz, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.96 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.28 (dd, J = 9.1, 3.9 Hz, 1H), 4.00 (t, J = 6.8 Hz, 2H), 3.85 (d, J = 7.7 Hz, 1H), 1.83 – 1.66 (m, 2H), 1.57 (tt, J = 14.4, 8.0 Hz, 4H), 0.82 (t, J = 7.3 Hz, 3H). ES/MS m/z : 571.3 [M+H] + . Example 38: 1-[6-[8-fluoro-1-oxo-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1 H-pyridazin-4- yl]amino]pentyl]-6-isoquinolyl]-3-pyridyl]cyclopropanecarbon itrile [0321] Step 1. In a vial were placed 6-bromo-8-fluoro-2H-isoquinolin-1-one (500 mg, 2.48 mmol), [(4S)-4-(tert-butoxycarbonylamino)pentyl] 4-methylbenzenesulfonate (886 mg, 2.48 mmol), and cesium carbonate (1346 mg, 4.13 mmol) in DMF (9.76 mL). After mixture was stirred at room temperature for 16 h, it was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried over Na 2 SO 4 , and purified via flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[(1S)-4-(6-bromo-8-fluoro-1-oxo-2-isoquinolyl)- 1-methyl-butyl]carbamate. ES/MS m/z: 429.047 [M+2+H] ++ . [0322] Step 2. In a vial were placed tert-butyl N-[(1S)-4-(6-bromo-8-fluoro-1-oxo-2- isoquinolyl)-1-methyl-butyl]carbamate (100 mg, 0.234 mmol), tetrahydroxydiboron (62.9 mg, 0.702 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1 ,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) (9.21 mg, 0.0117 mmol), 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (11.2 mg, 0.0234 mmol), and potassium acetate (68.9 mg, 0.702 mmol) in EtOH (3.9 mL). Mixture was purged with nitrogen gas for 5 minutes and stirred at 80°C until full conversion to boronic acid was observed. Following full conversion to the boronic acid, 1.8 M aqueous potassium carbonate solution (0.39 mL, 0.702 mmol) was added followed by 1-(6-bromo-3-pyridyl)cyclopropanecarbonitrile (57.4 mg, 0.257 mmol). Reaction was stirred at 80°C for 3 h. Upon completion, it was diluted with EtOAc, washed with water, washed with brine, dried over Na 2 SO 4 , concentrated and purified via flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[(1S)-4-[6-[5-(1- cyanocyclopropyl)-2-pyridyl]-8-fluoro-1-oxo-2-isoquinolyl]-1 -methyl-butyl]carbamate. ES/MS m/z: 491.249 [M+H] + . [0323] Step 3. In a vial were placed tert-butyl N-[(1S)-4-[6-[5-(1-cyanocyclopropyl)-2- pyridyl]-8-fluoro-1-oxo-2-isoquinolyl]-1-methyl-butyl]carbam ate (34 mg, 0.069 mmol), and trifluoroacetic acid (0.053 mL, 0.69 mmol) in DCM (0.89 mL). After the mixture was allowed to stir for 1 h, it was concentrated under vacuum to give 1-[6-[2-[(4S)-4-aminopentyl]-8-fluoro-1-oxo-6- isoquinolyl]-3-pyridyl]cyclopropanecarbonitrile. ES/MS: m/z 391.1 [M+H] + . [0324] Step 4. In a vial were placed 5-chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one (34.1 mg, 0.104 mmol), 1-[6-[2-[(4S)-4-aminopentyl]-8- fluoro-1-oxo-6-isoquinolyl]-3-pyridyl]cyclopropanecarbonitri le (27 mg, 0.069 mmol), and N,N- Diisopropylethylamine (0.06 mL, 0.35 mmol) in DMF (2.04 mL). After the mixture was heated to 80 °C and allowed to stir for 1 h, it was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give 1-[6-[8-fluoro-1-oxo-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1 -(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-is oquinolyl]-3- pyridyl]cyclopropanecarbonitrile. ES/MS m/z: 683.4 [M+H] + . [0325] Step 5. In a vial were placed 1-[6-[8-fluoro-1-oxo-2-[(4S)-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]pentyl]-6-isoquinolyl]-3- pyridyl]cyclopropanecarbonitrile (34 mg, 0.05 mmol), and trifluoroacetic acid (0.038 mL, 0.5 mmol) in DCM (2.2 mL). After the mixture was allowed to stir for 1 h, it was concentrated under vacuum. The resulting crude product was dissolved in methanol (4.0 mL) and ethylenediamine (0.033 mL, 0.5 mmol) was added. After the mixture was allowed to stir for 15 min, it was concentrated under vacuum. The resulting oil was purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 1-[6-[8-fluoro-1-oxo-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1 H-pyridazin-4-yl]amino]pentyl]-6- isoquinolyl]-3-pyridyl]cyclopropanecarbonitrile.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.73 (dd, J = 2.5, 0.8 Hz, 1H), 8.34 – 8.08 (m, 2H), 8.02 – 7.81 (m, 3H), 7.54 (d, J = 7.4 Hz, 1H), 6.74 (dd, J = 7.4, 2.0 Hz, 1H), 6.36 (dt, J = 8.5, 3.5 Hz, 1H), 4.03 – 3.91 (m, 3H), 1.93 – 1.84 (m, 2H), 1.79 – 1.60 (m, 4H), 1.50 (dq, J = 12.7, 6.5 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z : 553.3 [M+H] + . Example 39: 8-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]-6-[5- [1-(trifluoromethyl)cyclopropyl]-2-pyridyl]isoquinolin-1-one [0326] The title compound was synthesized as described in Example 8, using 2-chloro-5-[1- (trifluoromethyl)cyclopropyl]pyridine in place of 1-(6-bromo-3-pyridyl)cyclopropanecarbonitrile to give 8-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]-6-[5-[1- (trifluoromethyl)cyclopropyl]-2-pyridyl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.81 (d, J = 2.2 Hz, 1H), 8.23 (d, J = 1.6 Hz, 1H), 8.18 (dd, J = 8.3, 0.8 Hz, 1H), 8.05 (dd, J = 8.2, 2.3 Hz, 1H), 7.90 (dd, J = 13.3, 1.5 Hz, 2H), 7.55 (d, J = 7.4 Hz, 1H), 6.74 (dd, J = 7.4, 2.0 Hz, 1H), 6.36 (dt, J = 8.5, 3.6 Hz, 1H), 3.96 (dt, J = 13.2, 7.1 Hz, 3H), 1.69 (tt, J = 16.3, 7.4 Hz, 3H), 1.51 (dt, J = 11.4, 6.1 Hz, 1H), 1.43 (t, J = 3.5 Hz, 2H), 1.31 – 1.25 (m, 2H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z : 596.3 [M+H] + . Example 40: 8-fluoro-6-[5-(methylsulfonimidoyl)-2-pyridyl]-2-[(4S)-4-[[6 -oxo-5-(trifluoromethyl)- 1H-pyridazin-4-yl]amino]pentyl]isoquinolin-1-one [0327] The title compound was synthesized as described in Example 8, using Intermediate 2 in place of 1-(6-bromo-3-pyridyl)cyclopropanecarbonitrile to give 8-fluoro-6-[5-(methylsulfonimidoyl)- 2-pyridyl]-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazi n-4-yl]amino]pentyl]isoquinolin-1-one. NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.19 (dd, J = 2.4, 0.8 Hz, 1H), 8.45 (dd, J = 8.4, 2.3 Hz, 1H), 8.40 (dd, J = 8.4, 0.9 Hz, 1H), 8.32 (d, J = 1.6 Hz, 1H), 7.97 (dd, J = 13.1, 1.7 Hz, 1H), 7.92 (s, 1H), 7.58 (d, J = 7.3 Hz, 1H), 6.77 (dd, J = 7.4, 2.0 Hz, 1H), 6.35 (dd, J = 8.7, 3.7 Hz, 1H), 3.95 (t, J = 6.5 Hz, 2H), 3.31 (s, 3H), 1.68 (td, J = 13.8, 6.9 Hz, 3H), 1.51 (dt, J = 11.5, 6.2 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z : 565.3 [M+H] + . Intermediate 2: Preparation of tert-butyl N-[(6-chloro-3-pyridyl)-methyl-oxo-lambda6- sulfanylidene]carbamate [0328] Step 1. In a vial were placed (6-chloro-3-pyridyl)-imino-methyl-oxo-lambda6-sulfane (300 mg, 1.57 mmol), and 1M potassium t-butoxide (THF solution, 1.89 mL, 1.89 mmol) in THF (3.65 mL). Reaction allowed to stir at room temperature for 30 min. After stirring, di-tert-butyl decarbonate (687 mg, 3.15 mmol) was added. Reaction allowed to stir for 4 h, diluted with EtOAc, washed with water, washed with brine, dried over Na 2 SO 4 , and purified via flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[(6-chloro-3-pyridyl)-methyl-oxo-lambda6- sulfanylidene]carbamate. ES/MS m/z: 290.965 [M+H] + . Example 41: 8-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]-6-[5- (2,2,2-trifluoroethyl)-2-pyridyl]isoquinolin-1-one [0329] The title compound was synthesized as described in Example 8, using 2-chloro-5- (2,2,2-trifluoroethyl)pyridine in place of 1-(6-bromo-3-pyridyl)cyclopropanecarbonitrile to give 8- fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4- yl]amino]pentyl]-6-[5-(2,2,2- trifluoroethyl)-2-pyridyl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.26 – 8.15 (m, 2H), 8.02 – 7.95 (m, 1H), 7.94 – 7.86 (m, 2H), 7.55 (d, J = 7.4 Hz, 1H), 6.73 (dd, J = 7.5, 2.0 Hz, 1H), 6.35 (d, J = 8.6 Hz, 1H), 3.95 (q, J = 9.4, 6.8 Hz, 3H), 3.84 (q, J = 11.5 Hz, 2H), 1.79 – 1.59 (m, 3H), 1.59 – 1.44 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z : 570.3 [M+H] + . Example 42: 6-[5-(difluoromethoxy)pyrimidin-2-yl]-7-fluoro-2-[(4S)-4-[[6 -oxo-5-(trifluoromethyl)- 1H-pyridazin-4-yl]amino]pentyl]isoquinolin-1-one [0330] The title compound was synthesized as described in Example 8, using 2-chloro-5- (difluoromethoxy)pyrimidine in place of 2-iodo-5-(trifluoromethyl)pyrimidine to give 6-[5- (difluoromethoxy)pyrimidin-2-yl]-7-fluoro-2-[(4S)-4-[[6-oxo- 5-(trifluoromethyl)-1H-pyridazin-4- yl]amino]pentyl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.99 (s, 2H), 8.33 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 11.3 Hz, 1H), 7.92 (s, 1H), 7.70 – 7.29 (m, 2H), 6.82 (d, J = 7.4 Hz, 1H), 6.35 (dd, J = 8.6, 3.9 Hz, 1H), 3.99 (t, J = 6.3 Hz, 3H), 1.83 – 1.62 (m, 3H), 1.52 (q, J = 5.2, 4.5 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z : 555.3 [M+H] + . Example 43: 6-[5-(difluoromethoxy)-2-pyridyl]-7-fluoro-2-[(4S)-4-[[6-oxo -5-(trifluoromethyl)-1H- pyridazin-4-yl]amino]pentyl]isoquinolin-1-one [0331] The title compound was synthesized as described in Example 8, using 2-bromo-5- (difluoromethoxy)pyridine in place of 2-iodo-5-(trifluoromethyl)pyrimidine to give 6-[5- (difluoromethoxy)-2-pyridyl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(t rifluoromethyl)-1H-pyridazin-4- yl]amino]pentyl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.69 (d, J = 2.9 Hz, 1H), 8.23 (d, J = 7.5 Hz, 1H), 8.03 – 7.95 (m, 2H), 7.91 (s, 1H), 7.85 (dd, J = 8.7, 2.9 Hz, 1H), 7.63 – 7.23 (m, 2H), 6.79 (d, J = 7.3 Hz, 1H), 6.35 (dd, J = 8.9, 3.7 Hz, 1H), 3.99 (t, J = 6.2 Hz, 3H), 1.85 – 1.58 (m, 3H), 1.56 – 1.38 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z : 554.3 [M+H] + . Example 44: Preparation of 7-chloro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4- yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoqui nolin-1-one [0332] The title compound was synthesized as described in Example 5, using 6-bromo-7- chloroisoquinolin-1(2H)-one instead of 6-bromoisoquinolin-1(2H)-one to give 7-chloro-2-[(4S)-4-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.53 – 9.48 (m, 3H), 8.33 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.59 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 6.41 – 6.30 (m, 1H), 4.06 – 3.93 (m, 3H), 1.80 – 1.61 (m, 3H), 1.58 – 1.46 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z : 573.3 [M+H] + . Example 45: Preparation of 3-methyl-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4- yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoqui nolin-1-one [0333] The title compound was synthesized as described in Example 5, using 6-bromo-3- methylisoquinolin-1(2H)-one instead of 6-bromoisoquinolin-1(2H)-one to give 3-methyl-2-[(4S)-4-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.42 (d, J = 1.0 Hz, 2H), 8.62 (d, J = 1.6 Hz, 1H), 8.43 (dd, J = 8.5, 1.7 Hz, 1H), 8.33 (d, J = 8.5 Hz, 1H), 7.94 (s, 1H), 6.73 (s, 1H), 6.44 – 6.37 (m, 1H), 4.13 – 3.95 (m, 3H), 2.46 (s, 3H), 1.80 – 1.54 (m, 4H), 1.19 (d, J = 6.3 Hz, 3H). ES/MS m/z : 553.3 [M+H] + . Example 46: Preparation of 4-methyl-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4- yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoqui nolin-1-one [0334] Step 1. tert-butyl N-[(1S)-1-methyl-4-[1-oxo-6-[5-(trifluoromethyl)pyrimidin-2- yl]-2- isoquinolyl]butyl]carbamate (300 mg, 0.60 mmol) was dissolved in THF (3.0 mL) and the solution stirred at ambient temperature. N-bromosuccinimide (160 mg, 0.9 mmol) was added and the reaction stirred for 1h. The solvent was removed in vacuo and the residue purified via column chromatography eluting with EtOAc in hexanes 0-70% to provide tert-butyl N-[(1S)-4-[4-bromo-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]-1-methyl-but yl]carbamate. ES/MS: m/z 555.13/557.08 [M+H] + . [0335] Step 2. To a vial was charged tert-butyl N-[(1S)-4-[4-bromo-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]-1-methyl-but yl]carbamate (102 mg, 0.17 mmol) and [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) (6.0 mg, 0.009 mmol). The vial was purged with dry nitrogen and charged with dioxane (1.0 mL), 1.8 M aqueous potassium carbonate (0.19 mL, 0.35 mmol), and trimethylboroxine (0.05 mL, 0.35 mmol). The reaction was then stirred at 100°C for 16 hours before being diluted with EtOAc and filtered through a plug of Celite. The filtrate was evaporated and purified twice using column chromatography eluting with EtOAc in hexanes 0-70% then MeCN in hexanes 0-35% to yield tert-butyl N-[(1S)-1-methyl-4-[4-methyl-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]butyl]carbama te. ES/MS: m/z 491.2 [M+H] + . [0336] Step 3. In a vial were placed tert-butyl N-[(1S)-1-methyl-4-[4-methyl-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]butyl]carbama te (61 mg, 0.12 mmol), and trifluoroacetic acid (0.09 mL, 1.2 mmol) in DCM (2.0 mL). After the mixture was allowed to stir for 1 h, it was concentrated under vacuum to give 2-[(4S)-4-aminopentyl]-4-methyl-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one that was used directly in the next step. [0337] Step 4. In a vial were placed 5-chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one (46 mg, 0.14 mmol), 2-[(4S)-4-aminopentyl]-4-methyl-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one (46 mg, 0.12 mmol), and N,N-Diisopropylethylamine (0.13 mL, 0.73 mmol) in ACN (0.50 mL). After the mixture was heated to 60 °C and allowed to stir for 18 h, it was quenched with 10% aqueous potassium hydrogensulfate and extracted with EtOAc. The combined organic layers were dried (Na 2 SO 4 ), filtered, and the solvent removed in vacuo to give 4- methyl-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethyls ilylethoxymethyl)pyridazin-4- yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoqui nolin-1-one that was used directly in the next step. [0338] Step 5. In a vial were placed 4-methyl-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (80 mg, 0.12 mmol) and trifluoroacetic acid (0.09 mL, 1.2 mmol) in DCM (2.0 mL). After the mixture was allowed to stir for 1 hr, it was concentrated under vacuum. The resulting oil was dissolved in methanol (1.0 mL) and ethylenediamine (0.08 mL, 1.2 mmol) was added. After the mixture was allowed to stir for 1 hr, it was concentrated under vacuum. The resulting crude product was purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 4-methyl-2-[(4S)-4-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.45 (d, J = 0.9 Hz, 2H), 8.73 (d, J = 1.6 Hz, 1H), 8.55 (dd, J = 8.5, 1.6 Hz, 1H), 8.44 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.42 (d, J = 1.3 Hz, 1H), 6.40 – 6.32 (m, 1H), 4.06 – 3.92 (m, 3H), 2.34 (s, 3H), 1.81 – 1.61 (m, 3H), 1.58 – 1.46 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z : 553.3 [M+H] + .
Intermediate 3: Preparation of tert-butyl (1R,2R,5S)-2-[3-(p-tolylsulfonyloxy)propyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate [0339] Step 1. tert-butyl (1R,2S,5S)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (750 mg, 3.5 mmol) was dissolved in DCM (18.0 mL) and the solution was stirred at 0 °C. DMP (2.99 g, 7.0 mmol) was added and the reaction was allowed to warm to ambient temperature and stir for 2.5 hr at which point saturated aqueous sodium bicarbonate was added. The mixture was stirred for 10 minutes and the solids were removed via filtration. The phases were then separated, and the aqueous layer extracted twice more with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered, and evaporated to a white solid. The crude was purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl (1R,2S,5S)-2-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate. ES/MS m/z: 156.28 [M-tBu]-. [0340] Step 2. tert-butyl (1R,2S,5S)-2-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (580 mg, 2.6 mmol) was dissolved in DCM (15.0 mL) and the solution was stirred at ambient temperature. Ethyl (triphenylphosphoranylidene)acetate (1.37 g, 3.90 mmol) was added and the reaction was stirred for 24 h at which point saturated aqueous ammonium chloride was added and the mixture was extracted three times with DCM. The combined organic layers were dried over MgSO 4 , filtered, and evaporated to a provide the crude product. The crude product was purified by flash chromatography (100% hexanes to 70% EtOAc) to give tert-butyl (1R,2R,5S)-2-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate. ES/MS m/z: 282.12 [M+H] + . [0341] Step 3. tert-butyl (1R,2R,5S)-2-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (710 mg, 2.4 mmol) and 10% Pd/C (wet, 70 mg) were carefully flushed with nitrogen and then suspended in EtOH (10.0 mL). The reaction was purged with nitrogen and then stirred under a balloon of hydrogen at ambient temperature. After 1.5 h, the reaction was purged with nitrogen and filtered through a plug of Celite ® . The filtrate was evaporated to yield a grey oil. The crude was purified by flash chromatography (100% hexanes to 30% EtOAc) to give tert-butyl (1R,2R,5S)-2-(3-ethoxy-3-oxo-propyl)-3-azabicyclo[3.1.0]hexa ne-3-carboxylate. ES/MS m/z: 306.20 [M+H+Na] + . [0342] Step 4. tert-butyl (1R,2R,5S)-2-(3-ethoxy-3-oxo-propyl)-3-azabicyclo[3.1.0]hexa ne-3- carboxylate (440 mg, 1.5 mmol) was dissolved in THF (8.0 mL) and MeOH (0.06 mL, 1.5 mmol) was added. The solution was then cooled to 0°C and a suspension of lithium borohydride (94.0 mg, 4.5 mmol) in THF (8.0 mL) was added slowly. The reaction was stirred at ambient temperature for 4 h at which point an additional portion of solid lithium borohydride (160 mg, 7.4 mmol) was added. The reaction was stirred for an additional 16 h and was then quenched by the careful addition of 10% aqueous potassium hydrogen sulfate. The mixture was extracted three times with EtOAc, and the combined organic layers were dried over MgSO 4 . The organic layers were filtered and evaporated and the crude product was purified by flash chromatography (100% hexanes to 60% EtOAc) to give tert-butyl (1R,2R,5S)-2-(3-hydroxypropyl)-3-azabicyclo[3.1.0]hexane-3-c arboxylate. ES/MS m/z: 242.10 [M+H] + . [0343] Step 5. tert-butyl (1R,2R,5S)-2-(3-hydroxypropyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (170 mg, 0.70 mmol) was dissolved in DCM (5.0 mL) and treated with TEA (0.22 mL, 1.6 mmol). The solution was cooled to 0°C and then p-toluenesulfonyl chloride (160 mg, 0.84 mmol) was added. The reaction was left to stir at ambient temperature for 20 h at which point 10% aqueous potassium hydrogen sulfate was added and the mixture extracted three times with DCM. The combined organics were washed with brine, dried over MgSO 4 , filtered, and evaporated to yield an amber oil. The crude product was purified by flash chromatography (100% hexanes to 60% EtOAc) to give tert-butyl (1R,2R,5S)-2-[3-(p-tolylsulfonyloxy)propyl]-3-azabicyclo[3.1 .0]hexane-3-carboxylate. ES/MS m/z: 396.15 [M+H] + . Example 47: Preparation of 6-[3-[(1R,2R,5S)-3-[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4 -yl]-3- azabicyclo[3.1.0]hexan-2-yl]propyl]-2-[5-(trifluoromethyl)-2 -pyridyl]-1,6-naphthyridin-5-one [0344] The title compound was synthesized as described in Example 1 using 2-bromo-6H-1,6- naphthyridin-5-one instead of 6-bromo-2H-isoquinolin-1-one and tert-butyl (1R,2R,5S)-2-[3-(p- tolylsulfonyloxy)propyl]-3-azabicyclo[3.1.0]hexane-3-carboxy late instead of 4-(tert- butoxycarbonylamino)pentyl 4-methylbenzenesulfonate (Intermediate 3) to give 6-[3-[(1R,2R,5S)-3-[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]-3-azabicyclo[3.1. 0]hexan-2-yl]propyl]-2-[5- (trifluoromethyl)-2-pyridyl]-1,6-naphthyridin-5-one.1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 9.19 – 9.13 (m, 1H), 8.74 (d, J = 8.4 Hz, 1H), 8.71 (d, J = 8.3 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.45 (dd, J = 8.6, 2.4 Hz, 1H), 7.93 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 4.37 – 4.26 (m, 1H), 4.18 – 4.06 (m, 1H), 4.06 – 3.95 (m, 1H), 3.68 (d, J = 10.2 Hz, 1H), 3.37 (dd, J = 10.4, 4.6 Hz, 1H), 2.01 – 1.79 (m, 3H), 1.79 – 1.64 (m, 2H), 1.30 – 1.16 (m, 1H), 0.68 – 0.58 (m, 1H), 0.40 – 0.30 (m, 1H). ES/MS m/z : 577.3 [M+H] + . Example 48: 8-fluoro-2-[3-[(1R,2R,5S)-3-[6-oxo-5-(trifluoromethyl)-1H-py ridazin-4-yl]-3- azabicyclo[3.1.0]hexan-2-yl]propyl]-6-[5-(trifluoromethyl)-2 -pyridyl]isoquinolin-1-one [0345] The title compound was synthesized as described in Example 8, using 2-bromo-5- (trifluoromethyl)pyridine in place of 1-(6-bromo-3-pyridyl)cyclopropanecarbonitrile and tert-butyl (1R,2R,5S)-2-[3-(p-tolylsulfonyloxy)propyl]-3-azabicyclo[3.1 .0]hexane-3-carboxylate (Intermediate 3) in place of [(4S)-4-(tert-butoxycarbonylamino)pentyl] 4-methylbenzenesulfonate to give 8-fluoro-2-[3- [(1R,2R,5S)-3-[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]- 3-azabicyclo[3.1.0]hexan-2-yl]propyl]- 6-[5-(trifluoromethyl)-2-pyridyl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 9.12 (dt, J = 2.1, 1.1 Hz, 1H), 8.45 – 8.36 (m, 2H), 8.32 (d, J = 1.6 Hz, 1H), 8.01 – 7.89 (m, 2H), 7.61 (d, J = 7.4 Hz, 1H), 6.77 (dd, J = 7.4, 2.0 Hz, 1H), 4.31 (dt, J = 8.9, 3.9 Hz, 1H), 4.09 – 3.87 (m, 3H), 3.68 (d, J = 10.2 Hz, 1H), 3.37 (dd, J = 10.3, 4.5 Hz, 1H), 1.86 (tt, J = 8.0, 4.4 Hz, 2H), 1.70 (td, J = 9.0, 8.6, 4.6 Hz, 2H), 1.22 (qd, J = 10.5, 4.8 Hz, 1H), 0.63 (td, J = 7.8, 4.8 Hz, 1H), 0.35 (q, J = 4.3 Hz, 1H). ES/MS m/z : 594.3 [M+H] + . Example 49: 6-[4-amino-5-(trifluoromethyl)-2-pyridyl]-7-fluoro-2-[(4S)-4 -[[6-oxo-5 (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one [0346] The title compound was synthesized as described in Example 5, using 6-bromo-7- fluoroisoquinolin-1(2H)-one instead of 6-bromoisoquinolin-1(2H)-one and 2-chloro-5- (trifluoromethyl)pyridin-4-amine instead of 2-iodo-5-(trifluoromethyl)pyrimidine to give 6-[4-amino-5- (trifluoromethyl)-2-pyridyl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(t rifluoromethyl)-1H-pyridazin-4- yl]amino]pentyl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.60 (s, 1H), 8.21 – 8.11 (m, 1H), 8.02 (d, J = 11.5 Hz, 1H), 7.93 (d, J = 12.4 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.28 (s, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.35 (dd, J = 9.2, 3.9 Hz, 1H), 4.00 (t, J = 6.7 Hz, 4H), 1.84 – 1.41 (m, 5H), 1.18 (t, J = 6.4 Hz, 4H). ES/MS: m/z 571.3 [M+H] + . Example 50: 6-[5-(1-amino-2,2,2-trifluoro-ethyl)-2-pyridyl]-7-fluoro-2-[ (4S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one [0347] The title compound was synthesized as described in Example 5, using 6-bromo-7- fluoroisoquinolin-1(2H)-one instead of 6-bromoisoquinolin-1(2H)-one and 1-(6-chloro-3-pyridyl)-2,2,2- trifluoro-ethanamine instead of 2-iodo-5-(trifluoromethyl)pyrimidine to give 6-[5-(1-amino-2,2,2- trifluoro-ethyl)-2-pyridyl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(tr ifluoromethyl)-1H-pyridazin-4- yl]amino]pentyl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.26 (d, J = 7.4 Hz, 1H), 8.20 – 8.10 (m, 1H), 8.02 (dd, J = 10.2, 7.0 Hz, 2H), 7.91 (s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.35 (dd, J = 8.6, 3.8 Hz, 1H), 4.00 (t, J = 6.7 Hz, 4H), 1.83 – 1.41 (m, 5H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 585.3 [M+H] + . Example 51 (S)-6-(5-(difluoromethyl)pyridin-2-yl)-7,8-difluoro-2-(4-((6 -oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0348] The title compound was synthesized as described in Example 17, 2-iodo-5- (trifluoromethyl)pyrimidine instead of 2-bromo-5-(difluoromethyl)pyridine and 2-bromo-7,8- difluoroisoquinolin-1(2H)-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one to give (S)-6- (5-(difluoromethyl)pyridin-2-yl)-7,8-difluoro-2-(4-((6-oxo-5 -(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.02 – 8.96 (m, 1H), 8.26 – 8.17 (m, 1H), 8.10 – 8.01 (m, 2H), 7.91 (s, 1H), 7.56 – 7.50 (m, 1H), 7.26 (t, J = 55.2 Hz, 1H), 6.81 – 6.74 (m, 1H), 6.44 – 6.26 (m, 1H), 2.48-2.51 (m, 3H), 1.82 – 1.60 (m, 2H), 1.60 – 1.42 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 556.1 [M+H] + . Example 52 (S)-7,8-difluoro-6-(5-fluoropyridin-2-yl)-2-(4-((6-oxo-5-(tr ifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0349] The title compound was synthesized as described in Example 17, using 2-iodo-5- (trifluoromethyl)pyrimidine instead of 2-bromo-5-fluoropyridine and 2-bromo-7,8-difluoroisoquinolin- 1(2H)-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one to give (S)-7,8-difluoro-6-(5- fluoropyridin-2-yl)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dih ydropyridazin-4- yl)amino)pentyl)isoquinolin-1(2H)-one.1H NMR (400 MHz, DMSO-d6) δ12.43 (s, 1H), 8.89 – 8.71 (m, 1H), 8.08 – 7.78 (m, 5H), 7.51 (d, J = 7.4 Hz, 1H), 6.85 – 6.67 (m, 1H), 6.43 – 6.25 (m, 1H), 4.04 – 3.91 (m, 2H), 3.13 – 2.98 (m, 1H), 1.79 – 1.60 (m, 3H), 1.59 – 1.44 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 524.2 [M+H] + . Example 53 (S)-6-(5-(difluoromethyl)pyrimidin-2-yl)-7,8-difluoro-2-(4-( (6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0350] The title compound was synthesized as described in Example 17 using 2-iodo-5- (trifluoromethyl)pyrimidine instead of 2-chloro-5-(difluoromethyl)pyrimidine and 2-bromo-7,8- difluoroisoquinolin-1(2H)-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one to give (S)-6- (5-(difluoromethyl)pyrimidin-2-yl)-7,8-difluoro-2-(4-((6-oxo -5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.35 – 9.20 (m, 2H), 8.25 – 8.17 (m, 1H), 7.92 (s, 1H), 7.84 (s, 1H), 7.58 – 7.51 (m, 1H), 7.31 (t, J = 54.7 Hz, 1H), 6.86 – 6.77 (m, 1H), 6.47 – 6.27 (m, 1H), 3.96 (t, J = 6.4 Hz, 2H), 3.08 – 2.96 (m, 1H), 1.79 – 1.61 (m, 3H), 1.57 – 1.46 (m, 1H), 1.18 (d, J = 6.3 Hz, 3H). ES/MS: m/z 557.1 [M+H] + . Example 54 (S)-7,8-difluoro-6-(5-fluoropyrimidin-2-yl)-2-(4-((6-oxo-5-( trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0351] The title compound was synthesized as described in Example 17, using 2-iodo-5- (trifluoromethyl)pyrimidine instead of 2-bromo-5-fluoropyrimidine and 2-bromo-7,8- difluoroisoquinolin-1(2H)-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one to give (S)- 7,8-difluoro-6-(5-fluoropyrimidin-2-yl)-2-(4-((6-oxo-5-(trif luoromethyl)-1,6-dihydropyridazin-4- yl)amino)pentyl)isoquinolin-1(2H)-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.13 (s, 1H), 8.15 – 8.10 (m, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.53 (d, J = 7.4 Hz, 1H), 6.84 – 6.74 (m, 1H), 6.40 – 6.27 (m, 1H), 4.04 – 3.90 (m, 2H), 3.06 – 2.97 (m, 1H), 1.79 – 1.60 (m, 3H), 1.51 (dt, J = 11.1, 6.3 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 523.5 [M+H] + . Example 55 (S)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydr opyridazin-4- yl)amino)pentyl)-6-(5-(trifluoromethyl)pyridin-2-yl)isoquino lin-1(2H)-one [0352] The title compound was synthesized as described in Example 17 using 2-iodo-5- (trifluoromethyl)pyrimidine instead of 2-bromo-5-(trifluoromethyl)pyridine and 2-bromo-7,8- difluoroisoquinolin-1(2H)-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one to give 56 (S)- 7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyr idazin-4-yl)amino)pentyl)-6-(5- (trifluoromethyl)pyridin-2-yl)isoquinolin-1(2H)-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.24 – 9.09 (m, 1H), 8.49 – 8.38 (m, 1H), 8.18 – 8.11 (m, 1H), 8.09 – 8.02 (m, 1H), 7.91 (s, 1H), 7.56 – 7.51 (m, 1H), 6.82 – 6.71 (m, 1H), 6.41 – 6.26 (m, 1H), 4.02 – 3.91 (m, 2H), 3.08 – 2.99 (m, 1H), 1.80 – 1.60 (m, 3H), 1.58 – 1.45 (m, 1H), 1.18 (d, J = 6.3 Hz, 3H). ES/MS: m/z 574.2 [M+H] + . Example 56 (S)-6-(5-(difluoromethoxy)pyrimidin-2-yl)-7,8-difluoro-2-(4- ((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)iso quinolin-1(2H)-one [0353] The title compound was synthesized as described in Example 17, 2-chloro-5- (difluoromethoxy)pyrimidine instead of 2-iodo-5-(trifluoromethyl)pyrimidine and 2-bromo-7,8- difluoroisoquinolin-1(2H)-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one to give (S)-6- (5-(difluoromethoxy)pyrimidin-2-yl)-7,8-difluoro-2-(4-((6-ox o-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.01 (s, 2H), 8.20 – 8.08 (m, 1H), 7.92 (s, 1H), 7.56 – 7.51 (m, 1H), 7.50 (t, J = 72.6 Hz, 1H), 6.83 – 6.73 (m, 1H), 6.40 – 6.29 (m, 1H), 4.04 – 3.90 (m, 3H), 1.78 – 1.59 (m, 3H), 1.58 – 1.45 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 573.3 [M+H] + . Example 57: (S)-6-(5-(difluoromethoxy)pyridin-2-yl)-7,8-difluoro-2-(4-(( 6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0354] The title compound was synthesized as described in Example 17, using 2-bromo-5- (difluoromethoxy)pyridine instead of 2-bromo-5-(trifluoromethyl)pyridine and 2-bromo-7,8- difluoroisoquinolin-1(2H)-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one to give (S)-6- (5-(difluoromethoxy)pyridin-2-yl)-7,8-difluoro-2-(4-((6-oxo- 5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.70 (d, J = 2.9 Hz, 1H), 8.04 – 7.96 (m, 2H), 7.95 – 7.82 (m, 2H), 7.55 – 7.48 (m, 1H), 7.44 (t, J = 73.1 Hz, 1H), 6.81 – 6.65 (m, 1H), 6.48 – 6.22 (m, 1H), 4.10 – 3.80 (m, 3H), 1.79 – 1.59 (m, 3H), 1.57 – 1.44 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 572.3 [M+H] + . Example 58: (S)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyr idazin-4- yl)amino)pentyl)-7-(5-(trifluoromethyl)pyridin-2-yl)quinazol in-4(3H)-one [0355] The title compound was synthesized as described in Example 17, using 2-bromo-5- (trifluoromethyl)pyridine instead of 2-bromo-5-(difluoromethoxy)pyridine and 7-bromo-6-fluoro-1H- quinazolin-4-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one to give (S)-6-fluoro-3-(4- ((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) pentyl)-7-(5-(trifluoromethyl)pyridin- 2-yl)quinazolin-4(3H)-one.1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.19 (dd, J = 2.4, 1.2 Hz, 1H), 8.45 (s, 1H), 8.42 (dd, J = 8.5, 2.4 Hz, 1H), 8.24 (d, J = 6.9 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 10.8 Hz, 1H), 7.92 (s, 1H), 6.43 – 6.24 (m, 1H), 4.04 – 3.99 (m, 3H), 1.83 – 1.61 (m, 3H), 1.59 – 1.46 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 557.30 [M+H] + . Example 59: (S)-6-fluoro-7-(5-fluoropyridin-2-yl)-3-(4-((6-oxo-5-(triflu oromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)quinazolin-4(3H)-one [0356] The title compound was synthesized as described in Example 17, using 2-bromo-5- fluoro-pyridine instead of 2-bromo-5-(difluoromethoxy)pyridine and 7-bromo-6-fluoro-1H-quinazolin-4- one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one to give (S)-6-fluoro-7-(5-fluoropyridin- 2-yl)-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin- 4-yl)amino)pentyl)quinazolin-4(3H)- one.1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.80 (d, J = 2.9 Hz, 1H), 8.43 (s, 1H), 8.15 (d, J = 7.0 Hz, 1H), 8.00 (ddd, J = 8.9, 4.6, 1.8 Hz, 1H), 7.98 – 7.89 (m, 3H), 6.40 – 6.28 (m, 1H), 4.05 – 3.94 (m, 3H), 1.80 – 1.62 (m, 3H), 1.59 – 1.45 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 507.30 [M+H] + . Example 60: 6-fluoro-7-(5-fluoropyrimidin-2-yl)-3-[(4S)-4-[[6-oxo-5-(tri fluoromethyl)-1H- pyridazin-4-yl]amino]pentyl]quinazolin-4-one [0357] The title compound was synthesized as described in Example 17, using 2-bromo-5- fluoro-pyrimidine instead of 2-bromo-5-(difluoromethoxy)pyridine and 7-bromo-6-fluoro-1H- quinazolin-4-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one to give 6-fluoro-7-(5- fluoropyrimidin-2-yl)-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)- 1H-pyridazin-4- yl]amino]pentyl]quinazolin-4-one.1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.12 (d, J = 0.7 Hz, 2H), 8.44 (s, 1H), 8.24 (d, J = 6.8 Hz, 1H), 7.97 (d, J = 10.6 Hz, 1H), 7.92 (s, 1H), 6.40 – 6.28 (m, 1H), 4.05 – 3.93 (m, 3H), 1.84 – 1.62 (m, 3H), 1.59 – 1.46 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 508.20 [M+H] + . Intermediate 4: Preparation of tert-butyl (1-(3-(7-fluoro-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoquinolin-2(1H)-yl)propyl)cyclopropyl)ca rbamate [0358] The title compound was synthesized as described in Example 5, using tert-butyl (1-(3- hydroxypropyl)cyclopropyl)carbamate and 6-bromo-7-fluoroisoquinolin-1(2H)-one instead of tert-butyl N-[(1S)-4-hydroxy-1-methyl-butyl]carbamate in step 2 and 6-bromoisoquinolin-1(2H)-one in step 3, respectively, to give tert-butyl (1-(3-(7-fluoro-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2- yl)isoquinolin-2(1H)-yl)propyl)cyclopropyl)carbamate. ES/MS: m/z 487.2 [M+H] + . Intermediate 5: Preparation of tert-butyl (1-(3-(7-fluoro-1-oxo-6-(5-(trifluoromethyl)pyrimidin-2- yl)isoquinolin-2(1H)-yl)propyl)cyclopropyl)carbamate [0359] In a vial were placed tert-butyl (1-(3-(7-fluoro-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoquinolin-2(1H)-yl)propyl)cyclopropyl)ca rbamate (66 mg, 0.14 mmol), 2-chloro-5- (trifluoromethyl)pyrimidine (37 mg, 0.20 mmol), and Pd(PPh 3 ) 4 (16 mg, 0.014 mmol) in dioxane (1.0 mL) and Na 2 CO 3 aq. (2M, 0.3 mL). The mixture was sonicated for 20 seconds, purged with N 2 for 20 seconds, and stirred at 110 °C for 16 h. Upon completion, the mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified using silica flash chromatography (100% hexanes to 10% EtOAc) to give tert-butyl (1-(3-(7-fluoro-1-oxo-6-(5-(trifluoromethyl)pyrimidin-2- yl)isoquinolin-2(1H)-yl)propyl)cyclopropyl)carbamate (45 mg, 66%). ES/MS: m/z 507.2 [M+H] + . Example 61: 7-fluoro-2-(3-(1-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyri dazin-4- yl)amino)cyclopropyl)propyl)-6-(5-(trifluoromethyl)pyrimidin -2-yl)isoquinolin-1(2H)-one [0360] The title compound was synthesized as described in Example 5, using tert-butyl (1-(3- (7-fluoro-1-oxo-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquin olin-2(1H)- yl)propyl)cyclopropyl)carbamate instead of tert-butyl N-[(1S)-1-methyl-4-[1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]butyl]carbama te to give 7-fluoro-2-(3-(1-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclopropy l)propyl)-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one. 1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 9.48 (s, 2H), 8.43 (d, J = 7.2 Hz, 1H), 8.24 – 7.92 (m, 2H), 7.54 (d, J = 7.4 Hz, 1H), 7.34 (m, 1H), 6.84 (d, J = 7.4 Hz, 1H), 3.99 (t, J = 7.1 Hz, 2H), 1.92 – 1.33 (m, 4H), 0.85 (m, 4H). ES/MS: m/z 569.1 [M+H] + . Example 62: 6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]-7-(7H- pyrrolo[2,3-d]pyrimidin-2-yl)quinazolin-4-one [0361] The title compound was synthesized as described in Example 17 with the following changes: Step 1.6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 3.2-Chloro-7H-pyrrolo[2,3-d]pyrimidine is used instead of 2-bromo-5-(difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.55 – 12.27 (m, 2H), 9.22 (s, 1H), 8.43 (s, 1H), 8.32 (d, J = 6.9 Hz, 1H), 7.99 – 7.87 (m, 2H), 7.77 – 7.69 (m, 1H), 6.77 – 6.64 (m, 1H), 6.40 – 6.31 (m, 1H), 4.07 – 3.92 (m, 3H), 1.85 – 1.62 (m, 3H), 1.60 – 1.43 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 529.2 [M+H] + . Example 63: 6-fluoro-7-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3-[(4S )-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quinazolin- 4-one [0362] The title compound was synthesized as described in Example 17 with the following changes: Step 1.6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 3.2-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine is used instead of 2-bromo-5- (difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 12.15 (s, 1H), 9.20 (s, 1H), 8.43 (s, 1H), 8.30 (d, J = 6.8 Hz, 1H), 8.07 – 7.81 (m, 2H), 7.55 – 7.40 (m, 1H), 6.40 – 6.31 (m, 1H), 4.06 – 3.95 (m, 3H), 2.37 (s, 3H), 1.82 – 1.61 (m, 3H), 1.59 – 1.47 (m, 1H), 1.18 (d, J = 6.3 Hz, 3H). ES/MS m/z: 543.2 [M+H] + .
Example 64: 6-fluoro-7-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3-[(4S )-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quinazolin- 4-one [0363] The title compound was synthesized as described in Example 17 with the following changes: Step 1.6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 3. -chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine is used instead of 2-bromo-5- (difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 12.32 (s, 1H), 9.30 (s, 1H), 8.43 (s, 1H), 8.32 (d, J = 6.9 Hz, 1H), 7.98 – 7.90 (m, 2H), 7.72 (t, J = 2.5 Hz, 1H), 6.39 – 6.32 (m, 1H), 4.05 – 3.98 (m, 3H), 1.79 – 1.65 (m, 3H), 1.58 – 1.50 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 547.2 [M+H] + . Example 65: 7-(4-amino-5-cyclopropyl-pyrimidin-2-yl)-6-fluoro-3-[(4S)-4- [[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quinazolin- 4-one [0364] The title compound was synthesized as described in Example 17 with the following changes: Step 1.6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 3.2-chloro-5-cyclopropyl-pyrimidin-4-amine is used instead of 2-bromo-5- (difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.46 (s, 1H), 8.13 (d, J = 6.5 Hz, 1H), 8.09 (d, J = 1.0 Hz, 1H), 8.00 (d, J = 10.2 Hz, 1H), 7.92 (s, 1H), 6.38 – 6.27 (m, 1H), 4.03 – 3.97 (m, 2H), 1.81 – 1.63 (m, 4H), 1.60 – 1.45 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H), 1.02 – 0.94 (m, 2H), 0.84 – 0.69 (m, 2H). ES/MS m/z: 545.2 [M+H] + . Example 66: 7-(4-amino-5-methoxy-pyrimidin-2-yl)-6-fluoro-3-[(4S)-4-[[6- oxo-5-(trifluoromethyl)- 1H-pyridazin-4-yl]amino]pentyl]quinazolin-4-one [0365] The title compound was synthesized as described in Example 17 with the following changes: Step 1.6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 3.2-chloro-5-methoxy-pyrimidin-4-amine is used instead of 2-bromo-5-(difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.44 (s, 1H), 8.11 (d, J = 6.6 Hz, 1H), 8.08 (s, 1H), 7.97 (d, J = 10.2 Hz, 1H), 7.92 (s, 1H), 6.40 – 6.28 (m, 1H), 4.03 – 3.98 (m, 2H), 3.96 (s, 3H), 1.91 – 1.62 (m, 3H), 1.61 – 1.44 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 535.2 [M+H] + . Example 67: 7-(4-amino-5-fluoro-pyrimidin-2-yl)-6-fluoro-3-[(4S)-4-[[6-o xo-5-(trifluoromethyl)- 1H-pyridazin-4-yl]amino]pentyl]quinazolin-4-one [0366] The title compound was synthesized as described in Example 17 with the following changes: Step 1.6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 3.2-chloro-5-fluoro-pyrimidin-4-amine is used instead of 2-bromo-5-(difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.41 (s, 1H), 8.36 (d, J = 3.7 Hz, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J = 10.4 Hz, 1H), 7.58 (s, 2H), 6.39 – 6.31 (m, 1H), 4.03 – 3.97 (m, 2H), 1.84 – 1.60 (m, 3H), 1.59 – 1.42 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 523.2 [M+H] + . Example 68: Preparation of 7-fluoro-2-[[(1R,2R)-2-[(1S)-1-[[6-oxo-5-(trifluoromethyl)-1 H- pyridazin-4-yl]amino]ethyl]cyclopropyl]methyl]-6-[5-(trifluo romethyl)pyrimidin-2-yl]isoquinolin- 1-one [0367] Step 1. To a stirred solution of [(1R,2R)-2-[[tert- butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methanol (2.08 g, 6.11 mmol) and sodium carbonate (646 mg, 7.33 mmol) in dichloromethane (61.0 mL) at 0 °C was added Dess Martin periodinane (3.11 g, 7.33 mmol) and the mixture was warmed to room temperature and stirred for 2 hr. Upon completion, the mixture was filtered through Celite ® and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0-100% to afford (1R,2R)-2-[[tert butyl(diphenyl)silyl]oxymethyl]cyclopropanecarbaldehyde ES/MS: m/z 339.4 [M+H] + . [0368] Step 2. To a stirred solution (1R,2R)-2-[[tert- butyl(diphenyl)silyl]oxymethyl]cyclopropanecarbaldehyde (2.15 g, 6.36 mmol) and anhydrous copper sulfate (4.06 g, 25.5 mmol) in dichloromethane (61.0 mL) was added (R)-2-methylpropane-2-sulfinamide (1.16 g, 9.54 mmol) and the mixture was stirred for 18 h. Upon completion, the mixture was filtered through Celite ® and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0-100% to afford (NE,R)-N-[[(1R,2R)-2-[[tert- butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methylene]-2-meth yl-propane-2-sulfinamide ES/MS: m/z 447.1 [M+H] + . [0369] Step 3. To a mixture of (NE,R)-N-[[(1R,2R)-2-[[tert- butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methylene]-2-meth yl-propane-2-sulfinamide (2.59 g, 5.87 mmol) in dichloromethane (28.0 mL) cooled to -78 °C was added 3.0 M Methyl magnesium bromide in diethyl ether (2.15 ml, 6.46 mmol). The solution was stirred at -78 °C for 1 hr then warmed to room temperature and stirred for an additional 2 hr. Reaction mixture was quenched by the addition of saturated aqueous ammonium chloride and extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO 4 and concentrated in vacuo to give the crude product (R)-N- [(1S)-1-[(1R,2R)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]cyc lopropyl]ethyl]-2-methyl-propane-2- sulfinamide ES/MS: m/z 458.2 [M+H] + . [0370] Step 4. To a stirred solution (R)-N-[(1S)-1-[(1R,2R)-2-[[tert- butyl(diphenyl)silyl]oxymethyl]cyclopropyl]ethyl]-2-methyl-p ropane-2-sulfinamide (2.75 g, 6.01 mmol) in tetrahydrofuran was added 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (10.5 ml, 10.5 mmol) and the mixture was stirred for 2 hr. Upon completion the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO 4 and concentrated in vacuo to give the crude product (R)-N- [(1S)-1-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]ethyl]-2-methy l-propane-2-sulfinamide ES/MS: m/z 220.4 [M+H] + . [0371] Step 5. To a stirred solution of (R)-N-[(1S)-1-[(1R,2R)-2- (hydroxymethyl)cyclopropyl]ethyl]-2-methyl-propane-2-sulfina mide (345 mg, 1.57 mmol) and triethylamine (477 mg, 4.72 mmol) in dichloromethane (15 mL) at 0 °C was added p-Toluenesulfonyl chloride (480 mg, 2.52 mmol) and the mixture was warmed to room temperature and stirred for 18 hr. Upon completion, the mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO 4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with MeOH in DCM 0- 20% to afford [(1R,2R)-2-[(1S)-1-[[(R)-tert-butylsulfinyl]amino]ethyl]cycl opropyl]methyl 4- methylbenzenesulfonate ES/MS: m/z 374.4 [M+H] + . [0372] Step 6. To a mixture of 6-bromo-7-fluoro-2H-isoquinolin-1-one (95.7 mg, 0.396 mmol) and [(1R,2R)-2-[(1S)-1-[[(R)-tert-butylsulfinyl]amino]ethyl]cycl opropyl]methyl 4- methylbenzenesulfonate (98.5 mg, 0.264 mmol) in DMF (7.0 mL) was added Cs 2 CO 3 (172 mg, 0.527 mmol) and the reaction was stirred at room temperature for 18 hr. Upon completion, the mixture was diluted with EtOAc, washed with water, washed with brine, dried over MgSO 4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with MeOH in DCM 0-20% to afford (R)-N-[(1S)-1-[(1R,2R)-2-[(6-bromo-7-fluoro-1-oxo-2- isoquinolyl)methyl]cyclopropyl]ethyl]-2-methyl-propane-2-sul finamide ES/MS: m/z 444.9 [M+H] + . [0373] Step 7. To a solution of (R)-N-[(1S)-1-[(1R,2R)-2-[(6-bromo-7-fluoro-1-oxo-2- isoquinolyl)methyl]cyclopropyl]ethyl]-2-methyl-propane-2-sul finamide (93.8 mg, 0.212 mmol) in methanol (2.50 mL) was added a solution of 4.0 M hydrogen chloride in dioxane (0.212 mL, 0.846 mmol) at room temperature and the mixture was stirred for 10 min. Upon completion, the solvent was removed under reduced pressure to afford 2-(((1R,2R)-2-((S)-1-aminoethyl)cyclopropyl)methyl)-6- bromo-7-fluoroisoquinolin-1(2H)-one hydrochloride. ES/MS: m/z 340.9 [M+H] + . [0374] Step 8. A mixture of 2-(((1R,2R)-2-((S)-1-aminoethyl)cyclopropyl)methyl)-6-bromo- 7-fluoroisoquinolin-1(2H)-one hydrochloride (79.5 mg, 2.12 mmol), 5-chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one (186 mg, 0.565 mmol), and N,N-diisopropylethylamine (0.435 mL, 2.50 mmol) in DMF (2.0 mL) was stirred at room temperature for 4hr. Upon completion, the reaction was diluted with EtOAc, washed with water, washed with brine, dried over MgSO 4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0-100% to afford 6-bromo-7-fluoro-2-[[(1R,2R)-2- [(1S)-1-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethox ymethyl)pyridazin-4- yl]amino]ethyl]cyclopropyl]methyl]isoquinolin-1-one. ES/MS: m/z 633.0 [M+H] + . [0375] Step 9. In a vial were placed 6-bromo-7-fluoro-2-[[(1R,2R)-2-[(1S)-1-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4- yl]amino]ethyl]cyclopropyl]methyl]isoquinolin-1-one (123 mg, 0.195 mmol), 1,1'- Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (16.1 mg, 0.0195 mmol), potassium acetate (57.3 mg, 0.584 mmol), and bis(pinacolato)diboron (74.2 mg, 0.292 mmol) in dioxane (1.84 mL). The mixture was heated to 80 °C and stirred for 16 hr, followed by the addition of 2 M aqueous sodium carbonate (0.21 mL, 0.427 mmol) and2-iodo-5-(trifluoromethyl)pyrimidine (80.1 mg, 0.292 mmol). The reaction was then stirred for an additional hour at 80 °C. Upon completion, the mixture was filtered through Celite ® and concentrated under vacuum to afford the crude product which was then taken up in a solution of trifluoroacetic acid (1.5 mL) in dichloromethane (5 ml) and stirred for 1 hr at room temperature. Upon completion, the reaction was concentrated under vacuum and the resulting product was dissolved in methanol (5.0 mL) and ethylenediamine (0.16 mL, 2.42 mmol) was added and stirred for 15 minutes, and then concentrated under vacuum. The crude product was purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 7-fluoro-2-[[(1R,2R)-2- [(1S)-1-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino] ethyl]cyclopropyl]methyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.60 – 9.31 (m, 2H), 8.41 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 11.5 Hz, 1H), 7.74 (s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 6.73 (d, J = 7.4 Hz, 1H), 6.49 – 6.18 (m, 2H), 3.68 – 3.57 (m, 1H), 3.47 – 3.34 (m, 1H), 1.44 – 1.27 (m, 2H), 1.21 (d, J = 6.3 Hz, 3H), 0.75 – 0.62 (m, 1H), 0.58 – 0.45 (m, 1H). ES/MS: m/z 569.1 [M+H] + . Intermediate 6: Preparation of 6-(5-chloropyrimidin-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]pentyl]isoquinolin-1-one [0376] The title compound was synthesized as described in Example 17 with the following changes: Step 1.6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. Step 3.5-chloro-2-iodo-pyrimidine is used instead of 2-bromo-5-(difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. Example 69: Preparation of 7-fluoro-6-[5-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]py rimidin-2- yl]-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl] amino]pentyl]isoquinolin-1-one [0377] Step 1. In a vial were placed 6-(5-chloropyrimidin-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]pentyl]isoquinolin-1-one Intermdiate 6 (73 mg, 0.115 mmol), RuPhos Pd G4 (9.5 mg, 0.0112 mmol), cesium carbonate(146 mg, 0.447 mmol), and 3-(trifluoromethyl)azetidin-3-ol hydrochloride (21.8 mg, 0.123 mmol) in toluene (2.00 mL). The mixture was heated to 70 °C and stirred for 16 hr. Upon completion, the mixture was filtered through Celite ® and concentrated under vacuum to afford the crude product which was then purified using column chromatography eluting with EtOAc in hexanes 0-100% to afford 7-fluoro-6-[5-[3- hydroxy-3-(trifluoromethyl)azetidin-1-yl]pyrimidin-2-yl]-2-[ (4S)-4-[[6-oxo-5-(trifluoromethyl)-1- (2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]is oquinolin-1-one. ES/MS: m/z 758.2 [M+H] + . [0378] Step 2. In a vial containing 7-fluoro-6-[5-[3-hydroxy-3-(trifluoromethyl)azetidin-1- yl]pyrimidin-2-yl]-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1-( 2-trimethylsilylethoxymethyl)pyridazin-4- yl]amino]pentyl]isoquinolin-1-one (20.5 mg, 0.0271 mmol was added a solution of trifluoroacetic acid (1.5 mL) in dichloromethane (5 ml) which was stirred for 1 hr at room temperature. Upon completion, the mixture was concentrated under vacuum the resulting product was dissolved in methanol (5.0 mL) and ethylenediamine (0.06 mL, 0.947 mmol) was added and stirred for 15 minutes, and then was concentrated under vacuum. The crude product was purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 7-fluoro-6-[5-[3-hydroxy-3-(trifluoromethyl)azetidin-1- yl]pyrimidin-2-yl]-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H- pyridazin-4- yl]amino]pentyl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.33 (s, 1H), 8.25 (d, J = 7.4 Hz, 1H), 8.01 – 7.86 (m, 2H), 7.56 – 7.36 (m, 2H), 6.78 (d, J = 7.3 Hz, 1H), 6.43 – 6.21 (m, 1H), 4.42 – 4.34 (m, 3H), 4.11 – 4.03 (m, 2H), 3.98 (t, J = 6.5 Hz, 3H), 1.88 – 1.58 (m, 3H), 1.56 – 1.44 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 628.1 [M+H] + . Example 70: 4-amino-2-[7-fluoro-1-oxo-2-[(4S)-4-[[6-oxo-5-(trifluorometh yl)-1H-pyridazin-4- yl]amino]hexyl]-6-isoquinolyl]pyrimidine-5-carbonitrile [0379] The title compound was synthesized as described in Example 37 with the following changes: Step 5. 4-amino-2-chloro-pyrimidine-5-carbonitrile was used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were used to afford 4-amino-2-[7-fluoro-1-oxo-2-[(4S)-4-[[6-oxo-5-(trifluorometh yl)-1H- pyridazin-4-yl]amino]hexyl]-6-isoquinolyl]pyrimidine-5-carbo nitrile. 1 H NMR (400 MHz, DMSO- d6) δ 12.41 (s, 1H), 8.80 (s, 1H), 8.21 (d, J = 7.1 Hz, 1H), 8.03 – 7.84 (m, 2H), 7.49 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.28 (dd, J = 8.9, 3.9 Hz, 1H), 3.98 (t, J = 6.8 Hz, 2H), 3.85 (d, J = 7.3 Hz, 1H), 1.85 – 1.39 (m, 4H), 0.81 (t, J = 7.3 Hz, 3H). ES/MS: m/z 543.3 [M+H] + . Example 71: 6-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-7-fluoro-2-[(4 S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]hexyl]isoquinolin- 1-one [0380] The title compound was synthesized as described in Example 37 with the following changes: Step 5. 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine was used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were used to afford 6-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-7-fluoro-2-[(4 S)-4-[[6-oxo- 5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]hexyl]isoquinoli n-1-one. 1 H NMR (400 MHz, DMSO- d6) δ 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.64 (d, J = 1.1 Hz, 1H), 8.19 (d, J = 7.0 Hz, 1H), 8.06 – 7.85 (m, 2H), 7.49 (d, J = 7.4 Hz, 1H), 6.76 (d, J = 7.3 Hz, 1H), 6.28 (dd, J = 8.5, 3.9 Hz, 1H), 3.98 (t, J = 6.8 Hz, 2H), 3.85 (d, J = 8.8 Hz, 1H), 1.87 – 1.41 (m, 5H), 0.82 (t, J = 7.3 Hz, 3H). ES/MS: m/z 586.3 [M+H] + .
Example 72: 7-fluoro-2-[3-[1-[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-y l]azetidin-2-yl]propyl]-6- [5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one [0381] The title compound was synthesized as described in Example 5 with the following changes: Step 1. 3-(1-tert-butoxycarbonylazetidin-2-yl)propanoic acid was used instead of (4S)-4-(tert- butoxycarbonylamino)pentanoic acid. Step 5.20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were used to give 7-fluoro-2-[3-[1-[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-y l]azetidin-2-yl]propyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.48 (d, J = 0.9 Hz, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.04 (d, J = 11.4 Hz, 1H), 7.56 (d, J = 7.9 Hz, 2H), 6.86 (d, J = 7.4 Hz, 1H), 4.70 (s, 1H), 4.43 – 4.20 (m, 1H), 4.19 – 3.82 (m, 3H), 2.06 – 1.63 (m, 6H). ES/MS: m/z 569.3 [M+H] + . Example 73: 7-fluoro-2-[(4R)-5-hydroxy-5-methyl-4-[[6-oxo-5-(trifluorome thyl)-1H-pyridazin-4- yl]amino]hexyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquin olin-1-one [0382] The title compound was synthesized as described in Example 36, beginning at Step 2, with the following changes: Step 2. tert-Butyl N-[(1R)-2-hydroxy-1-(hydroxymethyl)-2-methyl-propyl]carbamat e was used instead of (2S)-2-(tert-butoxycarbonylamino)-2-cyclopropyl-acetic acid. Step 11. 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step to give 7-fluoro-2-[(4R)-5-hydroxy-5-methyl-4-[[6-oxo- 5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]hexyl]-6-[5-(tri fluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.48 (d, J = 1.0 Hz, 2H), 8.43 (d, J = 7.1 Hz, 1H), 8.10 – 7.91 (m, 2H), 7.53 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.02 (dt, J = 10.0, 4.8 Hz, 1H), 4.00 (tt, J = 9.5, 4.6 Hz, 2H), 3.86 (t, J = 9.9 Hz, 1H), 1.87 – 1.63 (m, 3H), 1.56 (dd, J = 14.4, 9.1 Hz, 1H), 1.09 (d, J = 16.6 Hz, 6H). ES/MS: m/z 601.3 [M+H] + . Example 74: 7-fluoro-6-[5-(1-hydroxy-1-methyl-ethyl)pyrimidin-2-yl]-2-[( 4S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one [0383] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 2-(2-chloropyrimidin-5-yl)propan-2-ol was used instead of 2-iodo-5-(trifluoromethyl)pyrimidine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step to give 7-fluoro-6-[5-(1-hydroxy-1-methyl- ethyl)pyrimidin-2-yl]-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)- 1H-pyridazin-4- yl]amino]pentyl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.06 (s, 2H), 8.32 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 11.3 Hz, 1H), 7.92 (s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.36 (dd, J = 8.8, 3.8 Hz, 1H), 3.99 (t, J = 5.9 Hz, 3H), 1.80 – 1.60 (m, 3H), 1.55 (s, 7H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 547.3 [M+H] + . Intermediate 7: Preparation of 2-(6-chloro-3-pyridyl)-2,2-difluoro-ethanol [0384] To a stirred solution of 2-(6-chloro-3-pyridyl)-2,2-difluoro-acetic acid (565 mg, 2.72 mmol) and triethylamine (0.379 mL, 2.72 mmol) in THF (26.3 mL) at 0°C under N 2 atmosphere was added ethyl chloroformate (0.261 mL, 2.72 mmol). The solution was allowed to stir for 30 min at 0 °C and then was filtered to remove precipitated triethylamine hydrochloride. The filtrate containing the mixed anhydride was slowly added to a stirred suspension of NaBH4 (309 mg, 8.17 mmol) in 20% aqueous THF (10.0 mL) maintained at 10°C and allowed to stir for 30 min, then acidified with a aqueous solution of 1N HCl to pH ~ 4. The mixture was extracted with EtOAc, washed with a solution of 2M NaOH, washed with brine, dried over Na 2 SO 4 and concentrated. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0-100% to afford of 2-(6-chloro-3-pyridyl)-2,2- difluoro-ethanol. ES/MS m/z: 193.97 [M+H] ++ . Example 75: 6-[5-(1,1-difluoro-2-hydroxy-ethyl)-2-pyridyl]-7-fluoro-2-[( 4S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one [0385] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 2-(6-chloro-3-pyridyl)-2,2-difluoro-ethanol was used instead of 2-iodo-5- (trifluoromethyl)pyrimidine to give and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step to give 6-[5-(1,1- difluoro-2-hydroxy-ethyl)-2-pyridyl]-7-fluoro-2-[(4S)-4-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.95 – 8.88 (m, 1H), 8.27 (d, J = 7.4 Hz, 1H), 8.13 (dd, J = 8.4, 2.4 Hz, 1H), 8.07 – 7.97 (m, 2H), 7.91 (s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 7.3 Hz, 1H), 6.35 (d, J = 7.2 Hz, 1H), 4.11 – 3.87 (m, 6H), 1.69 (d, J = 26.8 Hz, 3H), 1.52 (d, J = 9.3 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 568.3 [M+H] + . Example 76: 6-[5-(difluoromethyl)pyrimidin-2-yl]-7-fluoro-2-[(4S)-4-[[6- oxo-5-(trifluoromethyl)- 1H-pyridazin-4-yl]amino]pentyl]isoquinolin-1-one [0386] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 2-Chloro-5-(difluoromethyl)pyrimidine used instead of 2-iodo-5-(trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 6-[5-(difluoromethyl)pyrimidin-2-yl]-7-fluoro- 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amin o]pentyl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.33 (s, 1H), 8.25 (d, J = 7.4 Hz, 1H), 8.01 – 7.86 (m, 2H), 7.56 – 7.36 (m, 2H), 6.78 (d, J = 7.3 Hz, 1H), 6.43 – 6.21 (m, 1H), 4.42 – 4.34 (m, 3H), 4.11 – 4.03 (m, 2H), 3.98 (t, J = 6.5 Hz, 3H), 1.88 – 1.58 (m, 3H), 1.56 – 1.44 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 539.1 [M+H] + . Example 77: (S)-6-(4-amino-5-methylpyrimidin-2-yl)-7,8-difluoro-2-(4-((6 -oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0387] The title compound was synthesized as described in Example 17 with the following changes: Step 1.2-bromo-7,8-difluoroisoquinolin-1(2H)-one was used instead of 6-bromo-8-fluoro-1,2- dihydroisoquinolin-1-one Step 3.2-Chloro-5-methylpyrimidin-4-amine was used instead of 2-bromo-5-(difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.22 (s, 1H), 7.94 – 7.89 (m, 2H), 7.53 (d, J = 7.4 Hz, 1H), 6.72 (dd, J = 7.6, 1.9 Hz, 1H), 6.35 (d, J = 5.3 Hz, 1H), 4.03 – 3.88 (m, 2H), 2.10 (s, 3H), 1.79 – 1.59 (m, 3H), 1.53 (d, J = 9.5 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 536.3 [M+H] + . Example 78: (S)-7-(4-amino-5-methylpyrimidin-2-yl)-6-fluoro-3-(4-((6-oxo -5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)quinazolin-4(3H)-one [0388] The title compound was synthesized as described in Example 17 with the following changes: Step 1.7-bromo-6-fluoro-1H-quinazolin-4-one was used instead of 6-bromo-8-fluoro-1,2- dihydroisoquinolin-1-one Step 3.2-chloro-5-methylpyrimidin-4-amine was used instead of 2-bromo-5-(difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 8.14 (d, J = 6.6 Hz, 1H), 8.00 (d, J = 10.2 Hz, 1H), 7.92 (s, 1H), 6.42 – 6.26 (m, 2H), 4.07 – 3.89 (m, 2H), 2.12 (s, 3H), 1.83 – 1.64 (m, 3H), 1.60 – 1.46 (m, 1H), 1.17 (d, J = 6.3 Hz, 4H). ES/MS: m/z 519.3 [M+H] + . Example 79: (S)-7-(2-amino-5-methylpyrimidin-4-yl)-6-fluoro-3-(4-((6-oxo -5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)quinazolin-4(3H)-one [0389] The title compound was synthesized as described in Example 17 with the following changes: Step 1.7-bromo-6-fluoro-1H-quinazolin-4-one was used instead of 6-bromo-8-fluoro-1,2- dihydroisoquinolin-1-one. Step 3.4-bromo-5-methylpyrimidin-2-amine was used instead of 2-bromo-5-(difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 7.94 (d, J = 9.5 Hz, 1H), 7.92 (s, 1H), 7.72 (d, J = 6.4 Hz, 1H), 6.62 (s, 2H), 6.39 – 6.31 (m, 1H), 4.05 – 3.92 (m, 3H), 1.94 (s, 3H), 1.82 – 1.60 (m, 3H), 1.60 – 1.46 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 519.3 [M+H] + . Example 80: (S)-6-(2-amino-5-methylpyrimidin-4-yl)-7,8-difluoro-2-(4-((6 -oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0390] The title compound was synthesized as described in Example 17 with the following changes: Step 1.2-bromo-7,8-difluoroisoquinolin-1(2H)-one was used instead of 6-bromo-8-fluoro-1,2- dihydroisoquinolin-1-one Step 3.4-Bromo-5-methylpyrimidin-2-amine was used instead of 2-bromo-5-(difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.28 (s, 1H), 7.92 (s, 1H), 7.56 (d, J = 6.2 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 7.3 Hz, 1H), 6.35 (d, J = 5.3 Hz, 1H), 4.02 – 3.90 (m, 3H), 1.96 (s, 3H), 1.77 – 1.62 (m, 3H), 1.57 – 1.46 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 536.3 [M+H] + . Example 81: (S)-6-(4-amino-5-(trifluoromethyl)pyrimidin-2-yl)-7,8-difluo ro-2-(4-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)iso quinolin-1(2H)-one [0391] The title compound was synthesized as described in Example 17 with the following changes: Step 1.2-bromo-7,8-difluoroisoquinolin-1(2H)-one was used instead of 6-bromo-8-fluoro-1,2- dihydroisoquinolin-1-one Step 3.2-chloro-5-(trifluoromethyl)pyrimidin-4-amine was used instead of 2-bromo-5- (difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.71 – 8.60 (m, 1H), 8.06 – 7.95 (m, 1H), 7.92 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.79 – 6.68 (m, 1H), 6.42 – 6.26 (m, 1H), 4.06 – 3.86 (m, 3H), 1.80 – 1.60 (m, 3H), 1.59 – 1.45 (m, 1H), 1.21 – 1.14 (m, 3H). ES/MS: m/z 590.3 [M+H] + . Example 82: (S)-7-(5-(difluoromethyl)pyrimidin-2-yl)-6-fluoro-3-(4-((6-o xo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)quinazolin-4(3H)-one [0392] The title compound was synthesized as described in Example 17 with the following changes: Step 1.7-bromo-6-fluoro-1H-quinazolin-4-one was used instead of 6-bromo-8-fluoro-1,2- dihydroisoquinolin-1-one Step 3.2-chloro-5-(difluoromethyl)pyrimidine was used instead of 2-bromo-5- (difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.26 (s, 2H), 8.45 (s, 1H), 8.32 (d, J = 6.8 Hz, 1H), 7.99 (d, J = 10.5 Hz, 1H), 7.92 (s, 1H), 7.31 (t, J = 54.7 Hz, 1H), 6.43 – 6.27 (m, 1H), 4.07 – 3.91 (m, 3H), 1.82 – 1.62 (m, 3H), 1.59 – 1.48 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 540.3 [M+H] + . Example 83: (S)-7-(5-cyclopropylpyrimidin-2-yl)-6-fluoro-3-(4-((6-oxo-5- (trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)quinazolin-4(3H)-one [0393] The title compound was synthesized as described in Example 17 with the following changes: Step 1.7-bromo-6-fluoro-1H-quinazolin-4-one was used instead of 6-bromo-8-fluoro-1,2- dihydroisoquinolin-1-one Step 3.2-bromo-5-cyclopropylpyrimidine was used instead of 2-bromo-5-(difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.78 (s, 2H), 8.43 (s, 1H), 8.23 (d, J = 6.8 Hz, 1H), 7.94 (d, J = 10.8 Hz, 2H), 6.39 – 6.31 (m, 1H), 4.01 (t, J = 6.6 Hz, 3H), 2.10 – 1.99 (m, 1H), 1.82 – 1.61 (m, 3H), 1.59 – 1.46 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H), 1.15 – 1.08 (m, 2H), 1.00 – 0.92 (m, 2H). ES/MS: m/z 530.3 [M+H] + . Example 84: (S)-7-fluoro-6-(5-(methylsulfonyl)pyrimidin-2-yl)-2-(4-((6-o xo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0394] The title compound was synthesized as described in Example 17 with the following changes: Step 1.6-bromo-7-fluoro-1,2-dihydroisoquinolin-1-one was used instead of 6-bromo-8-fluoro-1,2- dihydroisoquinolin-1-one Step 3.2-chloro-5-(methylsulfonyl)pyrimidine was used instead of 2-bromo-5- (difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.46 (s, 2H), 8.46 (d, J = 7.1 Hz, 1H), 8.04 (d, J = 11.4 Hz, 1H), 7.92 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 7.4 Hz, 1H), 6.43 – 6.27 (m, 1H), 4.05 – 3.97 (m, 3H), 3.49 (s, 3H), 1.80 – 1.59 (m, 3H), 1.58 – 1.45 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 567.3 [M+H] + . Intermediate 8: Preparation of 7,8-difluoro-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquinoli n- 1(2H)-one [0395] Step 1. To a vial was added 6-bromo-7,8-difluoroisoquinolin-1(2H)-one (1.00 g, 3.85 mmol), bis(pinocolato)diboron (1.47 g, 5.77 mmol), 1,1'-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (314 mg, 0.385 mmol), potassium acetate (1.13 g, 11.5 mmol), and 1,4-dioxane (39.0 mL). The reaction was stirred at 90 °C for 1 hr, cooled to room temperature, and then 2-iodo-5-(trifluoromethyl)pyrimidine (0.983 g, 3.59 mmol), cataCXium Pd G4 (0.533 g, 0.72 mmol), and aqueous sodium carbonate solution (5.38 mL, 2.0 M) were added. The reaction was stirred at 90 °C for 1 hour, cooled, and filtered over a fritted funnel to give 7,8-difluoro-6- (5-(trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one which was sufficiently pure for the next step. ES/MS m/z: 327.93 [M+H] + . Example 85: 7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyr idazin-4-yl)amino)butyl)- 6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one [0396] The title compound was synthesized as described in Example 1 with the following changes: Step 1. Omitted Step 2.7,8-Difluoro-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquino lin-1(2H)-one (Intermediate 8) was used instead of 6-bromo-7-fluoro-1,2-dihydroisoquinolin-1-one and 4-((tert-butoxycarbonyl)amino)butyl 4-methylbenzenesulfonate was used instead of 4-(tert-butoxycarbonylamino)pentyl 4- methylbenzenesulfonate Step 3. Omitted Step 4. tert-Butyl (4-(7,8-difluoro-1-oxo-6-(5-(trifluoromethyl)pyrimidin-2-yl) isoquinolin-2(1H)- yl)butyl)carbamate was used instead of tert-butyl N-[1-methyl-4-[1-oxo-6-[5-(trifluoromethyl)-2- pyridyl]-2-isoquinolyl]butyl]carbamate Step 5.2-(4-Aminobutyl)-7,8-difluoro-6-(5-(trifluoromethyl)pyrimi din-2-yl)isoquinolin-1(2H)-one hydrochloride was used instead of 2-(4-aminopentyl)-6-[5-(trifluoromethyl)-2-pyridyl]isoquinol in-1-one hydrochloride. Step 6.7,8-Dluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1-((2-(trimeth ylsilyl)ethoxy)methyl)-1,6- dihydropyridazin-4-yl)amino)butyl)-6-(5-(trifluoromethyl)pyr imidin-2-yl)isoquinolin-1(2H)-one was used instead of 2-[4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxyme thyl)pyridazin-4- yl]amino]pentyl]-6-[5-(trifluoromethyl)-2-pyridyl]isoquinoli n-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.51 (s, 2H), 8.30 – 8.18 (m, 1H), 7.89 (s, 1H), 7.57 (d, J = 7.4 Hz, 1H), 7.17 – 7.07 (m, 1H), 6.87 – 6.77 (m, 1H), 4.04 – 3.92 (m, 3H), 1.78 – 1.65 (m, 3H), 1.63 – 1.48 (m, 3H). ES/MS: m/z 561.2 [M+H] + .
Examples 86 and Example 87: (S)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl-4-d)-6-(5-(trifluoromethy l)pyrimidin-2-yl)isoquinolin-1(2H)- one and (R)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydr opyridazin-4-yl)amino)pentyl- 4-d)-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)- one [0397] Step 1. In a vial were placed 6-bromo-7,8-difluoro-2H-isoquinolin-1-one (2.00 g, 7.69 mmol), 5-bromo-pentan-2-one (1.52 g, 9.23 mmol), and cesium carbonate (5.01 g, 15.4 mmol) in DMF (40.0 mL). After the mixture was stirred at room temperature for 16 h, it was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give 6-bromo-7,8- difluoro-2-(4-oxopentyl)isoquinolin-1-one. ES/MS m/z: 343.886 [M+H]. [0398] Step 2. In a vial were placed 6-bromo-7,8-difluoro-2H-isoquinolin-1-one (685 mg, 1.99 mmol), (S)-(-)-2-methyl-2-propanesulfinamide (265 mg, 2.19 mmol), titanium(IV) ethoxide (0.835 mL, 3.98 mmol), and THF (20.0 mL). The reaction is heated to 65 °C for 8 h and afterward it was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (MgSO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give (S)-N-[4-(6-bromo-7,8-difluoro-1-oxo-2-isoquinolyl)-1-methyl -butylidene]-2-methyl- propane-2-sulfinamide. ES/MS m/z: 446.985 [M+H]. [0399] Step 3. In a vial were placed (S)-N-[4-(6-bromo-7,8-difluoro-1-oxo-2-isoquinolyl)-1- methyl-butylidene]-2-methyl-propane-2-sulfinamide (300 mg, 0.671 mmol) and methanol (6.70 mL). The reaction mixture was cooled to 0 °C and then sodium borodeuteride (28.1 mg, 0.671 mmol) was added in one portion. The reaction was stirred until completed by LCMS and then quenched with saturated ammonium chloride solution and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (MgSO 4 ), and concentrated. A solution of HCl (4N in dioxane, 0.671 mmol) was added and stirred for 1 h and concentrated to give 2-(4-amino-4-deuterio-pentyl)-6- bromo-7,8-difluoro-isoquinolin-1-one. ES/MS m/z: 345.937 [M+H]. [0400] Step 4. In a vial were placed 2-(4-amino-4-deuterio-pentyl)-6-bromo-7,8-difluoro- isoquinolin-1-one (232 mg, 0.670 mmol), 5-chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one (331 mg, 1.01 mmol) and N,N-diisopropylethylamine (0.584 mL, 3.35 mmol) in DMF (7.00 mL). The mixture was heated to 80 °C and stirred for 1 hr, and then quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (MgSO4), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give 6-bromo-2-[4-deuterio-4-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-7,8- difluoro-isoquinolin-1-one. ES/MS m/z: 638.061 [M+H]. [0401] Step 5. In a vial were placed 6-bromo-2-[4-deuterio-4-[[6-oxo-5-(trifluoromethyl)-1- (2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-7 ,8-difluoro-isoquinolin-1-one (171 mg, 0.268 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (43.7 mg, 0.054 mmol), potassium acetate (78.8 mg, 0.803 mmol), and bis(pinacolato)diboron (102 mg, 0.402 mmol) in dioxane (3.0 mL). The mixture was heated to 80 °C and stirred for 1 h, cooled, and then followed by the addition of 2 M aqueous sodium carbonate (0.403 mL, 0.805 mmol), cataCXium Pd G4 (39.8 mg, 0.054 mmol) and 2-iodo-5-(trifluoromethyl)pyrimidine (110 mg, 0.403 mmol). The reaction was then stirred for an additional hour at 80 °C. Upon completion, the mixture was filtered through Celite ® and concentrated under vacuum and then purified by flash chromatography (100% hexanes to 100% EtOAc) to give 2-[4-deuterio-4-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-7,8- difluoro-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. ES/MS m/z: 706.137 [M+H]. [0402] Step 6. In a vial was placed 2-[4-deuterio-4-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-7,8- difluoro-6-[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (135 mg, 0.191 mmol), trifluoroacetic acid (0.366 mL, 4.78 mmol), and methylene chloride (5.0 mL). The reaction was stirred until completion as indicated by LCMS, concentrated, and purified by flash chromatography (100% DCM to 100% MeCN) to give 7,8-difluoro-2-(4-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl-4-d )-6-(5-(trifluoromethyl)pyrimidin-2- yl)isoquinolin-1(2H)-one. ES/MS m/z: 576.2 [M+H]. [0403] Step 7. Examples 86 and Example 87 were separated via chiral SFC (AD-H, 5 um, 21x250 mm column; 40% EtOH as co-solvent; 100 bar; 40 °C). The first eluting peak was assigned as the (S)-configuration (Example 2) , and the second eluting peak was assigned as the (R)-configuration (Example 3). The final compounds were free of TFA. [0404] Example 86: 2-[(4R)-4-deuterio-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazi n-4- yl]amino]pentyl]-7,8-difluoro-6-[5-(trifluoromethyl)pyrimidi n-2-yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.57 – 9.42 (m, 2H), 8.26 – 8.21 (m, 1H), 7.92 (s, 1H), 7.56 (d, J = 7.4 Hz, 1H), 6.85 – 6.78 (m, 1H), 6.35 (d, J = 3.7 Hz, 1H), 4.01 – 3.90 (m, 2H), 1.80 – 1.60 (m, 3H), 1.57 – 1.43 (m, 1H), 1.17 (s, 3H). ES/MS: m/z 576.2 [M+H] + . [0405] Example 87: 2-[(4S)-4-deuterio-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazi n-4- yl]amino]pentyl]-7,8-difluoro-6-[5-(trifluoromethyl)pyrimidi n-2-yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.57 – 9.42 (m, 2H), 8.26 – 8.21 (m, 1H), 7.92 (s, 1H), 7.56 (d, J = 7.4 Hz, 1H), 6.85 – 6.78 (m, 1H), 6.35 (d, J = 3.7 Hz, 1H), 4.01 – 3.90 (m, 2H), 1.80 – 1.60 (m, 3H), 1.57 – 1.43 (m, 1H), 1.17 (s, 3H). ES/MS: m/z 576.2 [M+H] + . Intermediate 9: Preparation of methyl (2R)-5-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-2-(tert- butoxycarbonylamino)pentanoate [0406] The title compound was synthesized as described in Steps 1-3 of Example 5 with the following changes: Step 1. (4R)-4-(tert-butoxycarbonylamino)-5-methoxy-5-oxo-pentanoic acid was utilized as the starting material. Step 3.6-bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-bromo-2H-isoquinolin-1-one. ES/MS m/z: 470.2 [M+H] + . Example 88: Preparation of 7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H- pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin -2-yl]isoquinolin-1-one [0407] Step 1. In a vial were placed methyl (2R)-5-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-2- (tert-butoxycarbonylamino)pentanoate (782 mg, 1.6 mmol), 1,1'-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (58 mg, 0.07 mmol), potassium acetate (464 mg, 4.7 mmol), and bis(pinacolato)diboron (1.2 g, 4.7 mmol) in dioxane (14.0 mL). The mixture was bubbled with dry Nitrogen and stirred at 100°C for 18 hr at which point LC/MS indicated complete conversion of the bromide. The reaction was cooled to ambient and 2 M aqueous sodium carbonate (2.4 mL, 4.7 mmol), 2-iodo-5-(trifluoromethyl)pyrimidine (518 mg, 1.9 mmol), and CataCXIum Pd G4 (59 mg, 0.079 mmol) were added. The mixture was bubbled with dry nitrogen gas and stirred at 80°C 1 hr before additional 2-iodo-5-(trifluoromethyl)pyrimidine (108 mg, 0.39 mmol) was added. Stirred for 2 hr at 80°C. The rection was then cooled, diluted with EtOAc and filtered through a plug of Celite ® . The volatiles were evaporated in vacuo and the residue purified via flash chromatography (100% hexanes to 100% EtOAc) to give methyl (2R)-2-(tert-butoxycarbonylamino)-5-[7-fluoro-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]pentanoate. ES/MS m/z: 539.2 [M+H] + . [0408] Step 2. Methyl (2R)-2-(tert-butoxycarbonylamino)-5-[7-fluoro-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]pentanoate (758 mg, 1.1 mmol) was dissolved in THF (5.0 mL), MeOH (2.0 mL), and Water (1.0 mL). This was stirred rapidly at ambient temperature and treated with lithium hydroxide (33 mg, 1.4 mmol). After 90 minutes, LC/MS indicated partial conversion and additional Lithium hydroxide (17 mg, 0.70 mmol) was added. The reaction was stirred for an additional 90 minutes and then quenched with 10% aq. KHSO 4 and extracted 3x with EtOAc. The organics were washed with brine, dried over MgSO 4 , filtered, and evaporated to yield (2R)-2-(tert- butoxycarbonylamino)-5-[7-fluoro-1-oxo-6-[5-(trifluoromethyl )pyrimidin-2-yl]-2- isoquinolyl]pentanoic acid which was used directly in the next step. [0409] Step 3. (2R)-2-(tert-butoxycarbonylamino)-5-[7-fluoro-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]pentanoic acid (319 mg, 0.55 mmol) was dissolved in THF (6.4 mL) and was treated with TEA (0.15 mL, 1.1 mmol). The solution was then cooled to 0°C and stirred rapidly. Isobutyl chloroformate (85 µL, 0.66 mmol) was added and the reaction maintained at 0°C for 30 minutes at which point precipitated solids were filtered off and rinsed with minimal THF. The filtrate was slowly added to a rapidly stirred mixture of sodium borohydride (41 mg, 1.1 mmol) in THF (6.4 mL) and water (3.2 mL) that was held at 0°C. The reaction was stirred for a further hour at 0°C and then was quenched with 10% aq. KHSO 4 and extracted 3x with EtOAc. The organics were dried over MgSO 4 , filtered, and evaporated to yield crude material which was purified via flash column chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[(1R)-4-[7-fluoro-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]-1-(hydroxyme thyl)butyl]carbamate. ES/MS m/z: 511.1 [M+H] + . [0410] Step 4. tert-butyl N-[(1R)-4-[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2- yl]-2- isoquinolyl]-1-(hydroxymethyl)butyl]carbamate (124 mg, 0.22 mmol) was dissolved in DCM (2.0 mL) and stirred at ambient temperature. TFA (0.17 mL, 2.2 mmol) was added and the reaction stirred for 90 minutes before removing the volatiles in vacuo. This gave crude 2-[(4R)-4-amino-5-hydroxy-pentyl]-7- fluoro-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-on e which was carried forward directly into the next step assuming quantitative yield. [0411] Step 5.2-[(4R)-4-amino-5-hydroxy-pentyl]-7-fluoro-6-[5-(trifluoro methyl)pyrimidin- 2-yl]isoquinolin-1-one (90 mg, 0.22 mmol) and 5-chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one (79 mg, 0.24 mmol) were dissolved in ACN (2.0 mL) and treated with DIPEA (0.38 mL, 2.2 mmol). The reaction was then stirred at 60°C for 1 hour before cooling.10% aq. KHSO 4 was added and the mixture extracted 3x with EtOAc. The organics were dried over Na 2 SO 4 , filtered, and evaporated to yield crude material which was purified via flash column chromatography (100% hexanes to 100% EtOAc) to give 7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]pentyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. ES/MS m/z: 703.2 [M+H] + . [0412] Step 6.7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1 -(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (65 mg, 0.093 mmol) was dissolved in DCM (2.0 mL) and stirred at ambient temperature. TFA (71 µL, 0.93 mmol) was added and the reaction stirred for 1 hour before being evaporated to dryness. The residue was then dissolved in MeOH (1.0 mL) and treated with ethylenediamine (62 µL, 0.93 mmol). After 30 minutes, the reaction was evaporated and the residue purified via reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 7-fluoro-2-[(4R)- 5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]am ino]pentyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.48 (d, J = 1.0 Hz, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.94 (s, 1H), 7.53 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.30 – 6.22 (m, 1H), 4.00 (t, J = 6.9 Hz, 2H), 3.96 – 3.87 (m, 1H), 3.46 (d, J = 4.9 Hz, 2H), 1.83 – 1.69 (m, 2H), 1.63 – 1.54 (m, 2H). ES/MS m/z: 573.3 [M+H] + . Example 89: Preparation of 2-[(4S)-2,2-difluoro-4-[[6-oxo-5-(trifluoromethyl)-1H-pyrida zin-4- yl]amino]pentyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one [0413] Step 1. In a vial were placed 6-bromo-7-fluoro-2H-isoquinolin-1-one (900 mg, 3.72 mmol), tert-butyl N-[(1S)-4-bromo-1-methyl-3-oxo-butyl]carbamate (1.04 g, 3.72 mmol), and cesium carbonate (2.42 g, 7.44 mmol) in DMF (20.0 mL). After mixture was stirred at room temperature for 16 hr, it was filtered through a pad of celite with EtOAc and concentrated. Purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[(1S)-4-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)- 1-methyl-3-oxo-butyl]carbamate, intermediate 10. ES/MS m/z: 442.9 [M+H] + . [0414] Step 2. In a vial were placed intermediate 10 (982 mg, 2.23 mmol), trifluoroacetic acid (4.40 mL) and DCM (4.40 mL). The mixture was stirred at room temperature for 2 hours before being concentrated to give 2-[(4S)-4-amino-2-oxo-pentyl]-6-bromo-7-fluoro-isoquinolin-1 -one. ES/MS m/z: 342.8 [M+H] + .p [0415] Step 3. In a vial were placed 2-[(4S)-4-amino-2-oxo-pentyl]-6-bromo-7-fluoro- isoquinolin-1-one (759 mg, 2.22 mmol), 5-chloro-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)pyridazin-3-one (1.06 g, 3.34 mmol), triethylamine (1.55 mL, 11.1 mmol) and DMF (8.80 mL). The mixture was heated to 85 °C and stirred for 3 hours before being concentrated. Purified by flash chromatography (100% hexanes to 100% EtOAc) to give 6-bromo-7-fluoro-2-[(4S)-4-[[1-[(4- methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)pyridazin-4-y l]amino]-2-oxo-pentyl]isoquinolin- 1-one. ES/MS m/z: 624.9 [M+H] + . [0416] Step 4. In a vial were placed 6-bromo-7-fluoro-2-[(4S)-4-[[1-[(4- methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)pyridazin-4-y l]amino]-2-oxo-pentyl]isoquinolin-1-one (100 mg, 0.16 mmol) and diethylaminosulfur trifluoride (0.06 mL, 0.48 mmol) in DCM (1.6 mL) at 0 °C. After stirring overnight, the reaction is cooled to 0 °C and diethylaminosulfur trifluoride (0.11 mL, 0.80 mmol) is added dropwise. After 1 hour, the reaction is heated to 40 °C. After stirring overnight, the reaction is purified by flash chromatography (100% hexanes to 100% EtOAc) to give 6-bromo-2-[(4S)- 2,2-difluoro-4-[[1-[(4-methoxyphenyl)methyl]-6-oxo-5-(triflu oromethyl)pyridazin-4- yl]amino]pentyl]-7-fluoro-isoquinolin-1-one. ES/MS m/z: 646.9 [M+H] + . [0417] Step 5. In a vial were placed 6-bromo-2-[(4S)-2,2-difluoro-4-[[1-[(4- methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)pyridazin-4-y l]amino]pentyl]-7-fluoro-isoquinolin-1- one (35 mg, 0.05 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8.8 mg, 0.01 mmol), potassium acetate (16 mg, 0.16 mmol), and bis(pinacolato)diboron (41 mg, 0.16 mmol) in dioxane (1.0 mL). The mixture was heated to 100 °C and stirred for 3 hours, followed by the addition of cesium carbonate (52 mg, 0.16 mmol), cataCXium Pd G4 (4 mg, 0.005 mmol), 2-iodo- 5-(trifluoromethyl)pyrimidine (22 mg, 0.08 mmol), and water (0.2 mL). The reaction was then stirred for an additional hour at 90 °C. Upon completion, the mixture was directly purified by flash chromatography (100% hexanes to 100% EtOAc) to give 2-[(4S)-2,2-difluoro-4-[[1-[(4-methoxyphenyl)methyl]-6-oxo- 5-(trifluoromethyl)pyridazin-4-yl]amino]pentyl]-7-fluoro-6-[ 5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. ES/MS m/z: 713.7 [M+H] + . [0418] Step 6. In a vial were placed 7-fluoro-2-[(4S)-4-[[1-[(4-methoxyphenyl)methyl]-6- oxo-5-(trifluoromethyl)pyridazin-4-yl]amino]-2-oxo-pentyl]-6 -[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (50 mg, 0.72 mmol), trifluoroacetic acid (1.0 mL), and sulfuric acid (0.2 mL). The reaction was heated to 50 °C and stirred for 5 hours and purified by prep HPLC to give 2-[(4S)-2,2- difluoro-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]ami no]pentyl]-7-fluoro-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.49 (d, J = 1.0 Hz, 2H), 8.46 (d, J = 7.1 Hz, 1H), 8.07 (d, J = 11.3 Hz, 1H), 7.96 (s, 1H), 7.43 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 6.67 – 6.53 (m, 1H), 4.70 – 4.46 (m, 2H), 4.40 (s, 1H), 2.58 (dq, J = 15.1, 8.2, 7.3 Hz, 1H), 2.37 – 2.13 (m, 1H), 1.25 (d, J = 6.4 Hz, 3H). ES/MS m/z: 593.3 [M+H] + . Example 90: Preparation of 7-fluoro-2-[(4S)-2-oxo-4-[[6-oxo-5-(trifluoromethyl)-1H-pyri dazin-4- yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoqui nolin-1-one [0419] Step 1. In a vial were placed 6-bromo-7-fluoro-2H-isoquinolin-1-one (900 mg, 3.72 mmol), tert-butyl N-[(1S)-4-bromo-1-methyl-3-oxo-butyl]carbamate (1.04 g, 3.72 mmol), and cesium carbonate (2.42 g, 7.44 mmol) in DMF (20.0 mL). After mixture was stirred at room temperature for 16 hr, it was filtered through a pad of Celite ® with EtOAc and concentrated. Purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[(1S)-4-(6-bromo-7-fluoro-1- oxo-2-isoquinolyl)-1-methyl-3-oxo-butyl]carbamate. ES/MS m/z: 442.9 [M+H] + . [0420] Step 2. In a vial were placed tert-butyl N-[(1S)-4-(6-bromo-7-fluoro-1-oxo-2- isoquinolyl)-1-methyl-3-oxo-butyl]carbamate (982 mg, 2.23 mmol), trifluoroacetic acid (4.40 mL) and DCM (4.40 mL). The mixture was stirred at room temperature for 2 hours before being concentrated to give 2-[(4S)-4-amino-2-oxo-pentyl]-6-bromo-7-fluoro-isoquinolin-1 -one. ES/MS m/z: 342.8 [M+H] + .p [0421] Step 3. In a vial were placed 2-[(4S)-4-amino-2-oxo-pentyl]-6-bromo-7-fluoro- isoquinolin-1-one (759.0 mg, 2.22 mmol), 5-chloro-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)pyridazin-3-one (1.06 g, 3.34 mmol), triethylamine (1.55 mL, 11.1 mmol) and DMF (8.80 mL). The mixture was heated to 85 °C and stirred for 3 hrs before being concentrated. Purified by flash chromatography (100% hexanes to 100% EtOAc) to give 6-bromo-7-fluoro-2-[(4S)-4-[[1-[(4- methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)pyridazin-4-y l]amino]-2-oxo-pentyl]isoquinolin- 1-one. ES/MS m/z: 624.9 [M+H] + . [0422] Step 4. In a vial were placed 6-bromo-7-fluoro-2-[(4S)-4-[[1-[(4- methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)pyridazin-4-y l]amino]-2-oxo-pentyl]isoquinolin-1-one (662 mg, 1.06 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (173 mg, 0.21 mmol), potassium acetate (313 mg, 3.19 mmol), and bis(pinacolato)diboron (809 mg, 3.19 mmol) in dioxane (10.0 mL). The mixture was heated to 100 °C and stirred for 3 hours, followed by the addition of cesium carbonate (1.04 g, 3.19 mmol), cataCXium Pd G4 (79 mg, 0.11 mmol), 2-iodo-5-(trifluoromethyl)pyrimidine (436 mg, 1.59 mmol), and water (2.5 mL). The reaction was then stirred for an additional hour at 80 °C. Upon completion, the mixture was directly purified by flash chromatography (100% hexanes to 100% EtOAc) to give 7-fluoro-2-[(4S)-4-[[1-[(4- methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)pyridazin-4-y l]amino]-2-oxo-pentyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. ES/MS m/z: 691.1 [M+H] + . [0423] Step 5. In a vial were placed 7-fluoro-2-[(4S)-4-[[1-[(4-methoxyphenyl)methyl]-6- oxo-5-(trifluoromethyl)pyridazin-4-yl]amino]-2-oxo-pentyl]-6 -[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (50 mg, 0.72 mmol), trifluoroacetic acid (1.0 mL), and sulfuric acid (0.2 mL). The reaction was heated to 50 °C and stirred for 4 hours and purified by prep HPLC to give 7-fluoro-2-[(4S)- 2-oxo-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino] pentyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.49 (s, 2H), 8.46 (d, J = 7.1 Hz, 1H), 8.08 – 7.89 (m, 2H), 7.38 (d, J = 7.3 Hz, 1H), 6.86 (d, J = 7.4 Hz, 1H), 6.57 (dd, J = 9.0, 4.2 Hz, 1H), 4.40 (q, J = 7.1, 6.6 Hz, 1H), 3.00 (ddd, J = 98.8, 17.5, 6.1 Hz, 2H), 1.23 (dd, J = 13.3, 6.4 Hz, 3H). ES/MS m/z: 571.3 [M+H] + . Example 91: Preparation of 7-fluoro-2-[[3-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4- yl]amino]phenyl]methyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl ]isoquinolin-1-one [0424] Step 1. In a vial were placed 6-Bromo-7-fluoro-1,2-dihydroisoquinolin-1-one (300 mg, 1.24 mmol), tert-butyl N-[3-(bromomethyl)phenyl]carbamate (355 mg, 1.24 mmol), and cesium carbonate (1.21 g, 3.72 mmol) in DMF (10.0 mL). After mixture was stirred at room temperature for 16 hr, it was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[3-[(6-bromo-7-fluoro-1-oxo-2- isoquinolyl)methyl]phenyl]carbamate. ES/MS m/z: 448.2 [M+H] + . [0425] Step 2. In a vial were placed tert-butyl N-[3-[(6-bromo-7-fluoro-1-oxo-2- isoquinolyl)methyl]phenyl]carbamate (500 mg, 1.12 mmol), 1,1'-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (91.0 mg, 0.112 mmol), potassium acetate (329 mg, 3.35 mmol), and bis(pinacolato)diboron (426.0 mg, 1.68 mmol) in dioxane (7.00 mL). The mixture was heated to 100 °C and stirred for 2 hrs, followed by the addition of 2 M aqueous sodium carbonate (1.68 mL, 3.36 mmol) and 2-iodo-5-(trifluoromethyl)pyrimidine (46 mg, 1.68 mmol), and 1,1'- Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (91 mg, 0.112 mmol). The reaction was then stirred for an additional hour at 100 °C. Upon completion, the mixture was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[3-[[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl]- 2- isoquinolyl]methyl]phenyl]carbamate. ES/MS m/z: 515.0 [M+H] + . [0426] Step 3. In a vial were placed tert-butyl N-[3-[[7-fluoro-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]methyl]phenyl ]carbamate (482 mg, 0.937 mmol), and trifluoroacetic acid (1.06 mL, 18.7 mmol) in DCM (5.0 mL). After the mixture was stirred for 1 hr, it was concentrated under vacuum. The resulting material was partitioned between EtOAc and water. The organic layer was separated and washed with brine, dried (Na 2 SO 4 ), and concentrated to afford 2-[(3- aminophenyl)methyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidin -2-yl]isoquinolin-1-one. ES/MS m/z: 415.0 [M+H] + . In a vial were placed 2-[(3-aminophenyl)methyl]-7-fluoro-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one (100 mg, 0.24 mmol), 5-chloro-4-(trifluoromethyl)-2- (2-trimethylsilylethoxymethyl)pyridazin-3-one (95 mg, 0.29 mmol), RuPhos Pd G4 (40 mg, 0.048 mmol) and Cesium carbonate (236 mg, 0.72 mmol) in toluene (2.00 mL). The mixture was heated to 80 °C and stirred for 5 mins, and then quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (MgSO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give 7-fluoro-2-[[3-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]phenyl]methy l]-6-[5-(trifluoromethyl)pyrimidin- 2-yl]isoquinolin-1-one. ES/MS m/z: 707.12 [M+H] + . [0427] Step 4. In a vial were placed 7-fluoro-2-[[3-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]phenyl]methy l]-6-[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (120 mg, 0.17 mmol) and trifluoroacetic acid (0.79 mL) in DCM (2.00 mL) and the mixture was stirred for 1 hr at room temperature and concentrated under vacuum. The resulting product was dissolved in methanol (2.0 mL) and ethylenediamine (0.11 mL, 1.7 mmol) was added and stirred for 15 minutes, and then was concentrated under vacuum. The crude product was purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 7-fluoro-2-[[3-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]phenyl]methyl]-6-[ 5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 9.48 (d, J = 0.9 Hz, 2H), 9.00 (d, J = 2.4 Hz, 1H), 8.46 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 11.3 Hz, 1H), 7.68 (d, J = 7.4 Hz, 1H), 7.56 – 7.30 (m, 2H), 7.34 – 7.19 (m, 3H), 6.90 (d, J = 7.4 Hz, 1H), 5.23 (s, 2H). ES/MS m/z: 577.2105 [M+H] + . Example 92: (S)-6-(5-(dimethylamino)pyrimidin-2-yl)-7-fluoro-2-(4-((6-ox o-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0428] The title compound was synthesized as described in Example 17, using 6-bromo-7- fluoroisoquinolin-1(2H)-one instead of 6-bromoisoquinolin-1(2H)-one in Step 1, and using 2-chloro- N,N-dimethyl-pyrimidin-5-amine instead of 2-iodo-5-(trifluoromethyl)pyrimidine in Step 3. In Step 3, XPhos Pd G4 (0.1 equiv) was added along with the aryl halide and the resulting penultimate material was purified by flash chromatography. Final deprotection gave (S)-6-(5-(dimethylamino)pyrimidin-2-yl)-7- fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin -4-yl)amino)pentyl)isoquinolin-1(2H)- one. 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.45 (s, 2H), 8.26 (d, J = 7.4 Hz, 1H), 7.97 – 7.89 (m, 2H), 7.46 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.40 – 6.32 (m, 1H), 4.05 – 3.95 (m, 3H), 3.06 (s, 6H), 1.59 – 1.82 (m, 3H), 1.57 – 1.46 (m, 1H), 1.18 (d, J = 6.3 Hz, 3H). ES/MS: m/z 532.2 [M+H] + . Example 93: (S)-7-fluoro-6-(5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3 -yl)pyrimidin-2-yl)-2-(4- ((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) pentyl)isoquinolin-1(2H)-one [0429] The title compound was synthesized as described in Example 17, using 6-bromo-7- fluoroisoquinolin-1(2H)-one instead of 6-bromoisoquinolin-1(2H)-one in Step 1, and using 3-chloro-1- methyl-5-(trifluoromethyl)pyrazole instead of 2-iodo-5-(trifluoromethyl)pyrimidine in Step 3. In Step 3, XPhos Pd G4 (0.1 equiv) was added along with the aryl halide and the resulting penultimate material was purified by flash chromatography. Final deprotection gave (S)-7-fluoro-6-(5-(1-methyl-5- (trifluoromethyl)-1H-pyrazol-3-yl)pyrimidin-2-yl)-2-(4-((6-o xo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.26 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 11.7 Hz, 1H), 7.92 (s, 1H), 7.47 (d, J = 7.4 Hz, 1H), 7.31 (d, J = 3.2 Hz, 1H), 6.76 (d, J = 7.4 Hz, 1H), 6.39 – 6.30 (m, 1H), 4.09 (s, 3H), 3.98 (t, J = 6.7 Hz, 3H), 1.81 – 1.60 (m, 3H), 1.58 – 1.44 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 559.3 [M+H] + . Example 94: (S)-6-(6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-7-fluoro- 2-(4-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)iso quinolin-1(2H)-one [0430] The title compound was synthesized as described in Example 17, using 6-bromo-7- fluoroisoquinolin-1(2H)-one instead of 6-bromoisoquinolin-1(2H)-one in Step 1, and using 2-chloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine instead of 2-iodo-5-(trifluoromethyl)pyrimidine in Step 3. In Step 3, XPhos Pd G4 (0.1 equiv) was added along with the aryl halide and the resulting penultimate material was purified by flash chromatography. Final deprotection gave (S)-6-(6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(triflu oromethyl)-1,6-dihydropyridazin-4- yl)amino)pentyl)isoquinolin-1(2H)-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.80 – 8.75 (m, 1H), 8.28 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 11.3 Hz, 1H), 7.93 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.41 – 6.31 (m, 1H), 4.05 – 3.94 (m, 3H), 3.07 – 2.96 (m, 4H), 2.14 (p, J = 7.7 Hz, 2H), 1.82 – 1.60 (m, 3H), 1.59 – 1.45 (m, 1H), 1.18 (d, J = 6.3 Hz, 3H). ES/MS: m/z 529.3 [M+H] + . Example 95: (S)-6-fluoro-7-(5-methylpyrimidin-2-yl)-3-(4-((6-oxo-5-(trif luoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)quinazolin-4(3H)-one [0431] The title compound was synthesized as described in Example 17, using 7-bromo-6- fluoroquinazolin-4(3H)-one instead of 6-bromoisoquinolin-1(2H)-one in Step 1, and using 2-bromo-5- methyl-pyrimidine instead of 2-iodo-5-(trifluoromethyl)pyrimidine in Step 3. In Step 3, XPhos Pd G4 (0.1 equiv) was added along with the aryl halide and the resulting penultimate material was purified by flash chromatography. Final deprotection gave (S)-6-fluoro-7-(5-methylpyrimidin-2-yl)-3-(4-((6-oxo- 5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)q uinazolin-4(3H)-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.90 – 8.84 (m, 2H), 8.43 (s, 1H), 8.23 (d, J = 6.8 Hz, 1H), 7.94 (d, J = 10.5 Hz, 1H), 7.92 (s, 1H), 6.39 – 6.31 (m, 1H), 4.05 – 3.93 (m, 3H), 2.37 (s, 3H), 1.82 – 1.61 (m, 3H), 1.53 (t, J = 11.6 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 504.3 [M+H] + . Example 96: (S)-6-(5-amino-4-fluoropyridin-2-yl)-7-fluoro-2-(4-((6-oxo-5 -(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0432] The title compound was synthesized as described in Example 17, using 6-bromo-7- fluoroisoquinolin-1(2H)-one instead of 6-bromoisoquinolin-1(2H)-one in Step 1, and using tert-butyl N- (6-chloro-4-fluoro-3-pyridyl)carbamate instead of 2-iodo-5-(trifluoromethyl)pyrimidine in Step 3. In Step 3, XPhos Pd G4 (0.1 equiv) was added along with the aryl halide and the resulting penultimate material was purified by flash chromatography. Final deprotection gave (S)-6-(5-amino-4- fluoropyridin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl )-1,6-dihydropyridazin-4- yl)amino)pentyl)isoquinolin-1(2H)-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.29 (d, J = 11.3 Hz, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.97 – 7.89 (m, 2H), 7.65 (dd, J = 12.7, 1.3 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.74 (d, J = 7.4 Hz, 1H), 6.40 – 6.26 (m, 1H), 4.04 – 3.92 (m, 3H), 1.81 – 1.59 (m, 3H), 1.56 – 1.45 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 523.1 [M+H] + . Example 97: (S)-6-(5-amino-4-(trifluoromethyl)pyridin-2-yl)-7-fluoro-2-( 4-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)iso quinolin-1(2H)-one [0433] The title compound was synthesized as described in Example 17, using 6-bromo-7- fluoroisoquinolin-1(2H)-one instead of 6-bromoisoquinolin-1(2H)-one in Step 1, and using 6-chloro-4- (trifluoromethyl)pyridin-3-amine instead of 2-iodo-5-(trifluoromethyl)pyrimidine in Step 3. In Step 3, XPhos Pd G4 (0.1 equiv) was added along with the aryl halide and the resulting penultimate material was purified by flash chromatography. Final deprotection gave (S)-6-(5-amino-4-(trifluoromethyl)pyridin- 2-yl)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydrop yridazin-4-yl)amino)pentyl)isoquinolin- 1(2H)-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.43 (s, 1H), 8.24 (d, J = 7.7 Hz, 1H), 7.97 – 7.89 (m, 2H), 7.79 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 6.76 (d, J = 7.4 Hz, 1H), 6.54 – 6.39 (m, 2H), 6.40 – 6.31 (m, 1H), 4.02 – 3.93 (m, 3H), 1.79 – 1.58 (m, 3H), 1.56 – 1.45 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 571.3 [M+H] + .
Example 98: Preparation of (S)-6-(5-chloropyrimidin-2-yl)-7-fluoro-2-(4-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)iso quinolin-1(2H)-one [0434] The title compound was synthesized as described in Example 17, using 6-bromo-7- fluoroisoquinolin-1(2H)-one instead of 6-bromoisoquinolin-1(2H)-one in Step 1, and using 5-chloro-2- iodo-pyrimidine instead of 2-iodo-5-(trifluoromethyl)pyrimidine in Step 3. In step 3, XPhos Pd G4 (0.1 equiv) was added along with the aryl halide and the resulting penultimate material Intermediate 11, which was purified by flash chromatography (100% hexanes to 100% EtOAc). Final deprotection gave (S)-6-(5-chloropyrimidin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trif luoromethyl)-1,6-dihydropyridazin-4- yl)amino)pentyl)isoquinolin-1(2H)-one.1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.15 (s, 2H), 8.36 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 11.4 Hz, 1H), 7.92 (s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.39 – 6.31 (m, 1H), 4.04 – 3.95 (m, 3H), 1.80 – 1.59 (m, 3H), 1.56 – 1.44 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 523.2 [M+H] + . Example 99: (S)-6-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl)-7 -fluoro-2-(4-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)iso quinolin-1(2H)-one [0435] Step 1. (S)-6-(5-chloropyrimidin-2-yl)-7-fluoro-2-(4-((6-oxo-5-(trif luoromethyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl )amino)pentyl)isoquinolin-1(2H)-one Intermediate 11 (51 mg, 0.078 mmol) was combined with 2-oxa-6-azaspiro[3.3]heptane (14 mg, 0.14 mmol), RuPhos Pd G4 (6 mg, 0.008 mmol), and cesium carbonate (52 mg, 0.16 mmol) in toluene. The mixture was sonicated, degassed with nitrogen gas, and heated to 60 o C for 12 hr. The reaction was concentrated in vacuo and the residue purified by flash chromatography (0 – 100% 3:1 EtOAc/EtOH in heptane) to give (S)-6-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl)-7 -fluoro-2-(4-((6-oxo-5- (trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-d ihydropyridazin-4- yl)amino)pentyl)isoquinolin-1(2H)-one. ES/MS m/z: 716.3 [M+H] + . [0436] Step 2. (S)-6-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl)-7 -fluoro-2-(4-((6- oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1,6-dihydropyridazin-4- yl)amino)pentyl)isoquinolin-1(2H)-one was treated according to Example 5, step 8 to give (S)-6-(5-(2- oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl)-7-fluoro-2-(4 -((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.27 – 8.16 (m, 3H), 7.96 – 7.88 (m, 2H), 7.46 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.39 – 6.31 (m, 1H), 4.75 (s, 4H),4.22 (s, 4H), 4.02 – 3.94 (m, 3H), 1.79 – 1.59 (m, 3H), 1.56 – 1.43 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 586.3 [M+H] + . Example 100: 6-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-7-fluoro-2-[(4 S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one [0437] The title compound was synthesized as described in Example 9 with the following changes: Step5. 2-Chloro-5-(trifluoromethyl)pyrimidin-4-amine used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 6-[4-amino-5-(trifluoromethyl)pyrimidin-2- yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyrida zin-4-yl]amino]pentyl]isoquinolin-1- one. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.65 (d, J = 1.1 Hz, 1H), 8.20 (d, J = 7.1 Hz, 1H), 8.03 – 7.88 (m, 2H), 7.50 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 7.3 Hz, 1H), 6.35 (dd, J = 8.5, 3.9 Hz, 1H), 3.99 (t, J = 6.6 Hz, 3H), 1.70 (ddt, J = 20.0, 13.0, 6.3 Hz, 3H), 1.50 (dq, J = 12.8, 6.4 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 572.3. Example 101: 4-amino-2-[7-fluoro-1-oxo-2-[(4S)-4-[[6-oxo-5-(trifluorometh yl)-1H-pyridazin-4- yl]amino]pentyl]-6-isoquinolyl]pyrimidine-5-carbonitrile [0438] The title compound was synthesized as described in Example 9 with the following changes: Step5. 4-amino-2-chloro-pyrimidine-5-carbonitrile used instead of 2-iodo-5-(trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 4-amino-2-[7-fluoro-1-oxo-2-[(4S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-isoquino lyl]pyrimidine-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.80 (s, 1H), 8.22 (d, J = 7.1 Hz, 1H), 8.06 – 7.86 (m, 2H), 7.50 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.35 (dd, J = 9.0, 3.6 Hz, 1H), 3.98 (t, J = 6.6 Hz, 3H), 1.69 (ddt, J = 21.5, 14.4, 7.3 Hz, 3H), 1.51 (dd, J = 10.6, 5.8 Hz, 1H), 1.16 (d, J = 6.3 Hz, 3H). ES/MS: m/z 529.3. Example 102: 6-(4-amino-5-methoxy-pyrimidin-2-yl)-7-fluoro-2-[(4S)-4-[[6- oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one [0439] The title compound was synthesized as described in Example 9 with the following changes: Step5. 2-Chloro-5-methoxy-pyrimidin-4-amine used instead of 2-iodo-5-(trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 6-(4-amino-5-methoxy-pyrimidin-2-yl)-7- fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4- yl]amino]pentyl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.21 – 7.83 (m, 4H), 7.52 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 7.3 Hz, 1H), 6.35 (dd, J = 8.0, 3.8 Hz, 1H), 3.98 (d, J = 12.7 Hz, 6H), 1.70 (ddt, J = 20.6, 13.7, 7.1 Hz, 3H), 1.51 (q, J = 6.4 Hz, 1H), 1.17 (d, J = 6.2 Hz, 3H). ES/MS: m/z 534.3. Example 103: 6-(4-amino-5-fluoro-pyrimidin-2-yl)-7-fluoro-2-[(4S)-4-[[6-o xo-5-(trifluoromethyl)- 1H-pyridazin-4-yl]amino]pentyl]isoquinolin-1-one [0440] The title compound was synthesized as described in Example 9 with the following changes: Step5. 2-chloro-5-fluoro-pyrimidin-4-amine used instead of 2-iodo-5-(trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) to give 6-(4-amino-5-fluoro-pyrimidin-2-yl)-7-fluoro-2-[(4S)-4-[[6-o xo-5-(trifluoromethyl)-1H- pyridazin-4-yl]amino]pentyl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.36 (d, J = 3.7 Hz, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.99 – 7.83 (m, 2H), 7.60 (s, 2H), 7.48 (d, J = 7.4 Hz, 1H), 6.75 (d, J = 7.4 Hz, 1H), 6.36 (dt, J = 8.5, 3.6 Hz, 1H), 3.98 (t, J = 6.8 Hz, 3H), 1.83 – 1.58 (m, 3H), 1.51 (q, J = 6.8, 6.4 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 522.3. Example 104: 6-[4-amino-5-(difluoromethyl)pyrimidin-2-yl]-7-fluoro-2-[(4S )-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one [0441] The title compound was synthesized as described in Example 9 with the following changes: Step5. 2-Chloro-5-(difluoromethyl)pyrimidin-4-amine used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 6-[4-amino-5-(difluoromethyl)pyrimidin-2- yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyrida zin-4-yl]amino]pentyl]isoquinolin-1- one. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.17 (d, J = 7.1 Hz, 1H), 8.01 – 7.85 (m, 2H), 7.49 (d, J = 7.4 Hz, 2H), 7.10 (t, J = 54.1 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.36 (dt, J = 8.9, 3.5 Hz, 1H), 3.99 (t, J = 6.7 Hz, 3H), 1.84 – 1.58 (m, 3H), 1.51 (dt, J = 12.0, 6.3 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 554.3. Example 105: 6-[2-amino-5-(difluoromethyl)pyrimidin-4-yl]-7-fluoro-2-[(4S )-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one [0442] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 4-chloro-5-(difluoromethyl)pyrimidin-2-amine used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 6-[2-amino-5-(difluoromethyl)pyrimidin-4- yl]-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyrida zin-4-yl]amino]pentyl]isoquinolin-1- one. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.60 (s, 1H), 8.02 – 7.86 (m, 2H), 7.79 (d, J = 6.8 Hz, 1H), 7.59 – 7.28 (m, 3H), 6.92 – 6.53 (m, 2H), 6.36 (dq, J = 6.9, 3.3 Hz, 1H), 3.99 (t, J = 6.3 Hz, 4H), 1.69 (ddt, J = 22.8, 9.1, 4.6 Hz, 3H), 1.51 (dt, J = 9.0, 6.4 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 554.3. Example 106: 7-fluoro-6-[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-y l]-2-[(4S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one [0443] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 7-fluoro-6-[4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl]-2-[(4S)-4-[[6-oxo-5-(triflu oromethyl)-1H-pyridazin-4- yl]amino]pentyl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.62 (d, J = 1.1 Hz, 1H), 8.35 (d, J = 7.1 Hz, 1H), 7.97 (d, J = 11.3 Hz, 1H), 7.91 (d, J = 5.8 Hz, 1H), 7.68 (q, J = 4.5 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 7.4 Hz, 1H), 6.35 (dd, J = 8.5, 3.9 Hz, 1H), 3.98 (q, J = 8.5, 7.2 Hz, 3H), 3.01 (d, J = 4.4 Hz, 3H), 1.83 – 1.59 (m, 2H), 1.50 (dq, J = 12.9, 6.9, 6.4 Hz, 1H), 1.16 (dd, J = 6.5, 3.6 Hz, 3H). ES/MS: m/z 586.3. Example 107: 6-(4-amino-5-cyclopropyl-pyrimidin-2-yl)-7-fluoro-2-[(4S)-4- [[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one [0444] The title compound was synthesized as described in Example 9 with the following changes: Step5. 2-chloro-5-cyclopropyl-pyrimidin-4-amine used instead of 2-iodo-5-(trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 6-(4-amino-5-cyclopropyl-pyrimidin-2-yl)-7- fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4- yl]amino]pentyl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.50 (s, 2H), 8.21 – 7.97 (m, 3H), 7.91 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.35 (dd, J = 8.7, 3.8 Hz, 1H), 4.00 (t, J = 6.7 Hz, 3H), 1.80 – 1.60 (m, 4H), 1.51 (dt, J = 11.9, 6.1 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H), 1.04 – 0.94 (m, 2H), 0.80 – 0.66 (m, 2H). ES/MS: m/z 544.3. Example 108: 7-[4-amino-5-(difluoromethyl)pyrimidin-2-yl]-6-fluoro-3-[(4S )-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quinazolin- 4-one [0445] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 2-Chloro-5-(difluoromethyl)pyrimidin-4-amine used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 7-[4-amino-5-(difluoromethyl)pyrimidin-2- yl]-6-fluoro-3-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyrida zin-4-yl]amino]pentyl]quinazolin-4- one. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.52 (d, J = 1.5 Hz, 1H), 8.43 (s, 1H), 8.15 (d, J = 6.7 Hz, 1H), 7.96 – 7.85 (m, 2H), 7.65 (s, 1H), 7.10 (t, J = 54.1 Hz, 1H), 6.39 – 6.30 (m, 1H), 3.99 (q, J = 10.6, 8.4 Hz, 3H), 1.83 – 1.59 (m, 3H), 1.52 (dq, J = 12.9, 6.2 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 555.3. Example 109: 6-(4-amino-5-methoxy-pyrimidin-2-yl)-7,8-difluoro-2-[(4S)-4- [[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one [0446] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 2-chloro-5-methoxy-pyrimidin-4-amine used instead of 2-iodo-5-(trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 6-(4-amino-5-methoxy-pyrimidin-2-yl)-7,8- difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]pentyl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.04 (s, 1H), 7.96 – 7.85 (m, 2H), 7.62 (s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 6.70 (dd, J = 7.5, 1.9 Hz, 1H), 6.39 – 6.29 (m, 1H), 4.04 – 3.85 (m, 6H), 2.77 (s, 1H), 1.78 – 1.40 (m, 6H), 1.18 (dd, J = 6.3, 3.8 Hz, 4H). ES/MS: m/z 552.3.
Example 110: 4-amino-2-[7,8-difluoro-1-oxo-2-[(4S)-4-[[6-oxo-5-(trifluoro methyl)-1H-pyridazin-4- yl]amino]pentyl]-6-isoquinolyl]pyrimidine-5-carbonitrile [0447] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 4-amino-2-chloro-pyrimidine-5-carbonitrile used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 4-amino-2-[7,8-difluoro-1-oxo-2-[(4S)-4-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-is oquinolyl]pyrimidine-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.81 (s, 1H), 8.01 (dd, J = 6.6, 1.7 Hz, 1H), 7.92 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.74 (dd, J = 7.5, 1.9 Hz, 1H), 6.35 (dd, J = 8.4, 3.8 Hz, 1H), 3.94 (t, J = 6.7 Hz, 2H), 1.68 (tt, J = 15.4, 6.9 Hz, 3H), 1.51 (dt, J = 11.0, 6.1 Hz, 1H), 1.17 (d, J = 6.2 Hz, 3H). ES/MS: m/z 547.3. Example 111: 6-(4-amino-5-nitro-pyrimidin-2-yl)-7-fluoro-2-[(4S)-4-[[6-ox o-5-(trifluoromethyl)- 1H-pyridazin-4-yl]amino]pentyl]isoquinolin-1-one [0448] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 2-Chloro-5-nitro-pyrimidin-4-amine used instead of 2-iodo-5-(trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) to give 6-(4-amino-5-nitro-pyrimidin-2-yl)-7-fluoro-2-[(4S)-4-[[6-ox o-5-(trifluoromethyl)-1H- pyridazin-4-yl]amino]pentyl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.26 (s, 1H), 8.96 (s, 1H), 8.44 (s, 1H), 8.28 (d, J = 7.1 Hz, 1H), 7.98 (d, J = 11.2 Hz, 1H), 7.92 (s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 7.4 Hz, 1H), 6.35 (dd, J = 8.6, 4.0 Hz, 1H), 3.99 (t, J = 6.5 Hz, 3H), 1.70 (ddd, J = 22.5, 13.3, 4.5 Hz, 2H), 1.51 (dt, J = 8.9, 6.2 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 549.3. Example 112: 6-(5,5-dimethyl-6,7-dihydropyrrolo[2,3-d]pyrimidin-2-yl)-7-f luoro-2-[(4S)-4-[[6-oxo- 5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinol in-1-one [0449] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 2-chloro-5,5-dimethyl-6,7-dihydropyrrolo[2,3-d]pyrimidine used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 6-(5,5-dimethyl-6,7-dihydropyrrolo[2,3- d]pyrimidin-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromet hyl)-1H-pyridazin-4- yl]amino]pentyl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.25 (s, 1H), 8.29 – 8.11 (m, 2H), 8.04 (d, J = 11.0 Hz, 1H), 7.93 (d, J = 11.3 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.35 (dd, J = 8.6, 3.9 Hz, 1H), 3.99 (q, J = 9.2, 7.8 Hz, 3H), 3.55 (s, 2H), 1.84 – 1.45 (m, 4H), 1.39 (s, 6H), 1.17 (d, J = 6.1 Hz, 3H). ES/MS: m/z 558.4. Example 113: 6-[4-amino-5-(difluoromethyl)pyrimidin-2-yl]-7,8-difluoro-2- [(4S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one [0450] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 2-Chloro-5-(difluoromethyl)pyrimidin-4-amine used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 6-[4-amino-5-(difluoromethyl)pyrimidin-2- yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-py ridazin-4-yl]amino]pentyl]isoquinolin- 1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.51 (d, J = 1.5 Hz, 1H), 8.03 – 7.79 (m, 2H), 7.51 (d, J = 7.4 Hz, 1H), 7.10 (t, J = 54.1 Hz, 1H), 6.73 (dd, J = 7.5, 1.9 Hz, 1H), 6.35 (dd, J = 8.7, 3.8 Hz, 1H), 3.96 (dt, J = 13.3, 7.2 Hz, 3H), 1.68 (td, J = 14.6, 14.0, 7.1 Hz, 3H), 1.50 (dq, J = 12.7, 6.6 Hz, 1H), 1.17 (d, J = 6.2 Hz, 3H). ES/MS: m/z 572.3. Example 114: 6-[2-amino-5-(difluoromethyl)pyrimidin-4-yl]-7,8-difluoro-2- [(4S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one [0451] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 4-Chloro-5-(difluoromethyl)pyrimidin-2-amine used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 6-[2-amino-5-(difluoromethyl)pyrimidin-4- yl]-7,8-difluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-py ridazin-4-yl]amino]pentyl]isoquinolin- 1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.63 (s, 1H), 7.93 (s, 1H), 7.63 – 7.45 (m, 4H), 6.98 – 6.55 (m, 2H), 6.35 (dd, J = 8.7, 3.8 Hz, 1H), 3.97 (dt, J = 13.4, 6.7 Hz, 3H), 1.69 (qt, J = 8.7, 4.4 Hz, 3H), 1.59 – 1.42 (m, 1H), 1.18 (d, J = 6.3 Hz, 3H). ES/MS: m/z 572.3. Example 115: 6-fluoro-7-[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-y l]-3-[(4S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quinazolin- 4-one [0452] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 2-Chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 6-fluoro-7-[4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl]-3-[(4S)-4-[[6-oxo-5-(triflu oromethyl)-1H-pyridazin-4- yl]amino]pentyl]quinazolin-4-one. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.71 – 8.60 (m, 1H), 8.44 (s, 1H), 8.30 (d, J = 6.7 Hz, 1H), 8.00 – 7.85 (m, 2H), 7.71 (d, J = 4.6 Hz, 1H), 6.35 (dq, J = 7.0, 3.3 Hz, 1H), 4.01 (q, J = 6.2 Hz, 3H), 3.00 (d, J = 4.4 Hz, 3H), 1.85 – 1.44 (m, 5H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 587.3. Example 116: 7-[4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-yl]-6 -fluoro-3-[(4S)-4-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quina zolin-4-one [0453] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 2-Chloro-N-cyclopropyl-5-(trifluoromethyl)pyrimidin-4-amine used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 7-[4-(cyclopropylamino)-5- (trifluoromethyl)pyrimidin-2-yl]-6-fluoro-3-[(4S)-4-[[6-oxo- 5-(trifluoromethyl)-1H-pyridazin-4- yl]amino]pentyl]quinazolin-4-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.66 (d, J = 1.1 Hz, 1H), 8.43 (s, 1H), 8.33 (d, J = 6.7 Hz, 1H), 7.99 – 7.83 (m, 2H), 7.70 (d, J = 3.4 Hz, 1H), 6.35 (dd, J = 8.8, 3.8 Hz, 1H), 4.01 (t, J = 6.6 Hz, 2H), 3.01 (tq, J = 7.3, 3.8 Hz, 1H), 1.72 (td, J = 15.7, 6.6 Hz, 3H), 1.52 (dt, J = 12.4, 6.4 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H), 0.85 – 0.64 (m, 4H). ES/MS: m/z 613.3. Example 117: 7-[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]-6-fluor o-3-[(4S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quinazolin- 4-one [0454] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 2-Chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 7-[4-(ethylamino)-5- (trifluoromethyl)pyrimidin-2-yl]-6-fluoro-3-[(4S)-4-[[6-oxo- 5-(trifluoromethyl)-1H-pyridazin-4- yl]amino]pentyl]quinazolin-4-one. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.63 (d, J = 1.1 Hz, 1H), 8.43 (s, 1H), 8.27 (d, J = 6.7 Hz, 1H), 8.02 – 7.87 (m, 2H), 7.75 (t, J = 5.7 Hz, 1H), 6.35 (dd, J = 8.9, 3.7 Hz, 1H), 4.00 (q, J = 11.3, 8.8 Hz, 3H), 3.64 – 3.49 (m, 2H), 1.86 – 1.61 (m, 3H), 1.53 (dd, J = 10.7, 5.7 Hz, 1H), 1.24 – 1.11 (m, 6H). ES/MS: m/z 601.3. Example 118: 6-(7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-7-fluoro- 2-[(4S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin -1-one [0455] The title compound was synthesized as described in Example 9 with the following changes: Step 5. 2-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine used instead of 2-iodo-5- (trifluoromethyl)pyrimidine and 20 mol % of cataCXium Pd G4 was used instead of [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) to give 6-(7,8-dihydro-6H-pyrimido[5,4- b][1,4]oxazin-2-yl)-7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluorom ethyl)-1H-pyridazin-4- yl]amino]pentyl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.63 (s, 1H), 8.21 – 7.78 (m, 4H), 7.49 (d, J = 7.4 Hz, 1H), 6.75 (d, J = 7.4 Hz, 1H), 6.35 (q, J = 3.3 Hz, 1H), 4.23 (t, J = 4.5 Hz, 2H), 3.98 (t, J = 6.7 Hz, 4H), 3.56 (q, J = 3.8 Hz, 2H), 1.70 (ddt, J = 28.3, 15.0, 7.3 Hz, 3H), 1.51 (dd, J = 10.2, 5.9 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS: m/z 546.3. Intermediate 12: Preparation of 1-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)azetidine-3- carbonitrile [0456] N,N-Diisopropylethylamine (0.722 mL, 4.15 mmol) was added to a solution of 2,4- dichloro-5-(trifluoromethyl)pyrimidine (300 mg, 1.38 mmol) and azetidine-3-carbonitrile hydrochloride (164 mg, 1.38 mmol) in DMF (2.5 mL). The resulting solution was stirred at room temperature for 2 h then diluted with water and extracted two times with EtOAc. The combined organic layers were washed three time with water, then washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude residue was purified via prep. HPLC and lyophilized to afford 177 mg (49%) of 1-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)azetidine-3-ca rbonitrile. ES/MS: m/z 262.9 [M+H] + . Example 119: (S)-1-(2-(7-fluoro-1-oxo-2-(4-((6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4- yl)amino)pentyl)-1,2-dihydroisoquinolin-6-yl)-5-(trifluorome thyl)pyrimidin-4-yl)azetidine-3- carbonitrile [0457] The title compound was synthesized as described in Example 17 with the following changes: Step 1.2-bromo-7,8-difluoroisoquinolin-1(2H)-one was used instead of 6-bromo-8-fluoro-1,2- dihydroisoquinolin-1-one Step 3.1-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)azetidine-3- carbonitrile was used instead of 2- bromo-5-(difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step to give (S)-1-(2-(7- fluoro-1-oxo-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyr idazin-4-yl)amino)pentyl)-1,2- dihydroisoquinolin-6-yl)-5-(trifluoromethyl)pyrimidin-4-yl)a zetidine-3-carbonitrile. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.78 (s, 1H), 8.35 (d, J = 7.1 Hz, 1H), 7.98 (d, J = 11.3 Hz, 1H), 7.92 (s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 7.4 Hz, 1H), 6.42 – 6.27 (m, 1H), 4.63 – 4.53 (m, 2H), 4.50 – 4.43 (m, 2H), 4.01 – 3.97 (m, 4H), 1.80 – 1.59 (m, 3H), 1.57 – 1.43 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H).. ES/MS: m/z 637.3 [M+H] + . Intermediate 13: Preparation of tert-butyl (S)-2-(3-(tosyloxy)propyl)pyrrolidine-1-carboxylate [0458] The title compound was synthesized as described in Intermediate 3, using tert-butyl (S)-2-formylpyrrolidine-1-carboxylate instead of tert-butyl (1R,2S,5S)-2-formyl-3- azabicyclo[3.1.0]hexane-3-carboxylate to give tert-butyl (S)-2-(3-(tosyloxy)propyl)pyrrolidine-1- carboxylate. ES/MS m/z: 156.28 [M+H] + . Example 120: (S)-7-fluoro-2-(3-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydrop yridazin-4-yl)pyrrolidin- 2-yl)propyl)-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquinoli n-1(2H)-one [0459] The title compound was synthesized as described in Example 17, using 2-iodo-5- (trifluoromethyl)pyrimidine instead of 2-bromo-5-(difluoromethoxy)pyridine and 7-bromo-6-fluoro-1H- quinazolin-4-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one and tert-butyl (S)-2-(3- (tosyloxy)propyl)pyrrolidine-1-carboxylate instead of (S)-4-((tert-butoxycarbonyl)amino)pentyl 4- methylbenzenesulfonate. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.48 (s, 2H), 8.43 (d, J = 7.1 Hz, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.98 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.3 Hz, 1H), 4.28 (q, J = 8.3 Hz, 1H), 4.10 – 3.91 (m, 2H), 3.59 – 3.45 (m, 1H), 3.20 (dd, J = 10.9, 6.4 Hz, 1H), 2.22 – 2.11 (m, 1H), 1.95 – 1.52 (m, 6H), 1.51 – 1.38 (m, 1H). ES/MS m/z: 583.30 [M+H]. Example 121: (S)-6-(4-amino-5-(trifluoromethyl)pyrimidin-2-yl)-7-fluoro-2 -(3-(1-(6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl) propyl)isoquinolin-1(2H)-one [0460] The title compound was synthesized as described in Example 17, using 2-chloro-5- (trifluoromethyl)pyrimidin-4-amine instead of 2-bromo-5-(difluoromethoxy)pyridine and 7-bromo-6- fluoro-1H-quinazolin-4-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one and tert-butyl (S)-2-(3-(tosyloxy)propyl)pyrrolidine-1-carboxylate instead of (S)-4-((tert-butoxycarbonyl)amino)pentyl 4-methylbenzenesulfonate. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.65 (d, J = 1.1 Hz, 1H), 8.20 (d, J = 7.1 Hz, 1H), 8.00 – 7.92 (m, 2H), 7.51 (d, J = 7.4 Hz, 1H), 6.76 (d, J = 7.3 Hz, 1H), 4.33 – 4.21 (m, 1H), 4.08 – 3.91 (m, 2H), 3.58 – 3.45 (m, 1H), 3.24 – 3.13 (m, 1H), 2.22 – 2.09 (m, 1H), 1.95 – 1.86 (m, 1H), 1.85 – 1.50 (m, 5H), 1.50 – 1.37 (m, 1H). ES/MS m/z: 598.30 [M+H]. Example 122: (S)-6-(4-amino-5-methoxypyrimidin-2-yl)-7-fluoro-2-(3-(1-(6- oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl) propyl)isoquinolin-1(2H)-one [0461] The title compound was synthesized as described in Example 17, using 2-chloro-5- methoxypyrimidin-4-amine instead of 2-bromo-5-(difluoromethoxy)pyridine and 7-bromo-6-fluoro-1H- quinazolin-4-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one and tert-butyl (S)-2-(3- (tosyloxy)propyl)pyrrolidine-1-carboxylate instead of (S)-4-((tert-butoxycarbonyl)amino)pentyl 4- methylbenzenesulfonate. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.11 (d, J = 7.0 Hz, 1H), 8.07 (s, 1H), 8.00 (d, J = 11.0 Hz, 1H), 7.97 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.76 (d, J = 7.4 Hz, 1H), 4.31 – 4.25 (m, 1H), 3.51 (s, 1H), 3.24 – 3.14 (m, 1H), 2.22 – 2.10 (m, 1H), 1.95 – 1.85 (m, 1H), 1.84 – 1.51 (m, 5H), 1.50 – 1.37 (m, 1H). One methylene peak is obstructed by water signal. ES/MS m/z: 560.30 [M+H].
Intermediate 14: Preparation of 2-((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclobutyl)ethyl 4- methylbenzenesulfonate [0462] Step 1. In a vial were placed (1S,2S)-2-((tert-butoxycarbonyl)amino)cyclobutane-1- carboxylic acid (2.40 g, 11.2 mmol), and triethylamine (1.55 mL, 11.2 mmol) in THF (100 mL). The mixture was cooled to 0 °C and placed under nitrogen atmosphere. To this solution was added ethyl chloroformate (1.07 mL, 11.2 mmol) and the reaction was stirred for 30 minutes at 0 °C. The mixture was then filtered to remove the precipitated triethylamine hydrochloride. The filtrate containing the mixed anhydride was slowly added to a stirred suspension of sodium borohydride (633 mg, 16.7 mmol) in 20% aqueous THF (100 mL) maintained at 0 °C. The reaction mixture was then warmed to room temperature and stirred for 30 minutes, diluted with sat. aq. NH 4 Cl, extracted with EtOAc, washed water, then brine, dried (MgSO 4 ), and concentrated. Purification via flash chromatography (elution with 0-100% v/v ethyl acetate in hexanes) afforded 1.21 g (54%) of tert-butyl ((1S,2S)-2- (hydroxymethyl)cyclobutyl) carbamate. ES/MS: m/z 223.967 [M+Na]. [0463] Step 2. In a vial were placed give tert-butyl ((1S,2S)-2-(hydroxymethyl)cyclobutyl) carbamate (1.21 g, 6.01 mmol), and N,N-diisopropylethylamine base (3.14 mL, 18.0 mmol) in DCM (45.0 mL). The mixture was cooled to 0 °C followed by the addition of p-toluenesulfonyl chloride (1.72 g, 9.02 mmol) and DMAP (147 mg, 1.20 mmol). The resulting mixture was warmed to room temperature and stirred for 64 h, then diluted with water and extracted with EtOAc, washed with brine, dried (MgSO 4 ), and concentrated. Purification via flash (elution with 0-100% v/v ethyl acetate in hexanes) afforded 756 mg (35%) of ((1S,2S)-2-((tert-butoxycarbonyl)amino)cyclobutyl)methyl 4- methylbenzenesulfonate. ES/MS m/z: 356.042 [M+H]. [0464] Step 3. To a solution of [(1S,2S)-2-(tert-butoxycarbonylamino)cyclobutyl]methyl 4- methylbenzenesulfonate (756 mg, 2.13 mmol) in DMSO (5 mL) was added NaCN (1.04 g, 21.3 mmol). The resulting mixture was then stirred at 35 °C for 72 h, then diluted with water and sat. aq. NaHCO 3 , then extracted with EtOAc (2x) and the combined organic fractions were then washed with water (2x) and brine, dried (MgSO 4 ), and concentrated. Purification via flash chromatography (elution with 0-100% v/v ethyl acetate in hexanes) afforded 373 mg (83%) of tert-butyl-((1S,2R)-2- (cyanomethyl)cyclobutyl]carbamate. ES/MS m/z: 211.1 [M+H] + . [0465] Step 4. To a solution of tert-butyl N-[(1S,2R)-2-(cyanomethyl)cyclobutyl]carbamate (373 mg, 1.77 mmol) in EtOH (7.0 mL) was added NaOH (7.0 mL, 6.0 M, 42 mmol). The resulting mixture was then heated to 80 °C for 16 h, then cooled to room temperature and acidified to pH 4-5 with 6 M HCl. The resulting solution was extracted with EtOAc (2x), then dried (MgSO 4 ), and concentrated to afford 373.0 mg (92%) of 2-[(1R,2S)-2-(tert-butoxycarbonylamino)cyclobutyl]acetic acid. The crude material was used in the subsequent step without further purification. [0466] Step 5. In a vial were placed 2-[(1R,2S)-2-(tert- butoxycarbonylamino)cyclobutyl]acetic acid (290 mg, 1.26 mmol), and triethylamine (0.53 mL, 3.79 mmol) in THF (15.0 mL). The mixture was cooled to 0 °C and placed under nitrogen atmosphere. To this solution was added ethyl chloroformate (0.182 mL, 1.90 mmol) and the reaction was stirred for 30 minutes at 0 °C. The mixture was then filtered to remove the precipitated triethylamine hydrochloride. The filtrate containing the mixed anhydride was slowly added to a stirred suspension of sodium borohydride (144 mg, 3.79 mmol) in 20% aqueous THF (15.0 mL) maintained at 0 °C. The reaction mixture was then warmed to room temperature and stirred for 30 minutes, diluted with sat. aq. NH4Cl, extracted with EtOAc, washed water, then brine, dried (MgSO 4 ), and concentrated. Purification via flash chromatography (elution with 0-100% v/v ethyl acetate in hexanes) aforded 183 mg (67%) of tert-butyl N-[(1S,2R)-2-(2-hydroxyethyl)cyclobutyl]carbamate. ES/MS: m/z 216.012 [M+NH]. [0467] Step 6. In a vial were placed tert-butyl N-[(1S,2R)-2-(2- hydroxyethyl)cyclobutyl]carbamate (183 mg, 0.85 mmol), and N,N-diisopropylethylamine (0.592 mL, 3.40 mmol) in DCM (10.0 mL). The mixture was cooled to 0 °C followed by the addition of p- toluenesulfonyl chloride (324 mg, 1.70 mmol) and DMAP (20.8 mg, 0.17 mmol). The resulting mixture was warmed to room temperature and stirred for 16 h, then diluted with water and extracted with EtOAc, washed with brine, dried (MgSO 4 ), and concentrated. Purification via flash (elution with 0-100% v/v ethyl acetate in hexanes) afforded 103 mg (33%) of 2-[(1R,2S)-2-(tert- butoxycarbonylamino)cyclobutyl]ethyl 4-methylbenzenesulfonate. ES/MS m/z: 370.099 [M+H]. Example 123: 6-(4-amino-5-(trifluoromethyl)pyrimidin-2-yl)-7-fluoro-2-(2- ((1R,2S)-2-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclobutyl )ethyl)isoquinolin-1(2H)-one [0468] The title compound was synthesized as described in Example 17, using 2-chloro-5- (trifluoromethyl)pyrimidin-4-amine instead of 2-bromo-5-(difluoromethoxy)pyridine and 7-bromo-6- fluoro-1H-quinazolin-4-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one and 2-((1R,2S)- 2-((tert-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonate instead of (S)-4-((tert- butoxycarbonyl)amino)pentyl 4-methylbenzenesulfonate. 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.65 (d, J = 1.0 Hz, 1H), 8.19 (d, J = 7.1 Hz, 1H), 7.95 (d, J = 11.1 Hz, 1H), 7.80 (s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 6.97 – 6.88 (m, 1H), 6.77 (d, J = 7.4 Hz, 1H), 4.08 – 3.94 (m, 2H), 3.91 – 3.79 (m, 1H), 2.26 (q, J = 8.8 Hz, 1H), 2.04 – 1.91 (m, 1H), 1.90 – 1.75 (m, 3H), 1.36 – 1.23 (m, 1H). One proton appears to overlap with the DMSO signal. ES/MS m/z: 584.30 [M+H]. Intermediate 15: Preparation of 4-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-iodo-5- (trifluoromethyl)pyrimidine [0469] Step 1. To a solution of 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (500 mg, 2.53 mmol) and azetidin-3-ol hydrochloride (277 mg, 2.53 mmol) in DMF (16.0 mL) was added N,N- diisopropylethylamine (4.41 mL, 25.3 mmol). The resulting mixture was heated to 80 °C for 1 h, then cooled to room temperature followed by the addition of tert-butyldimethylsilyl chloride (763 mg, 5.06 mmol) and imidazole (379 mg, 5.57 mmol). The resulting solution was heated to 80 °C for 3 h, then diluted with sat. aq. NH 4 Cl, extracted with EtOAc, washed with brine, dried (MgSO 4 ), and concentrated. Purification via flash (elution with 0-100% v/v ethyl acetate in hexanes) afforded 565 mg (64%) of 4-[3- [tert-butyl(dimethyl)silyl]oxyazetidin-1-yl]-5-(trifluoromet hyl)pyrimidin-2-amine ES/MS m/z: 350.196 [M+H]. [0470] Step 2. A solution of 4-[3-[tert-butyl(dimethyl)silyl]oxyazetidin-1-yl]-5- (trifluoromethyl)pyrimidin-2-amine (465 mg, 1.33 mmol), di-iodomethane (4.30 mL, 53.4 mmol), tert- Butylnitrite (0.635 mL, 5.34 mmol), and CuI (50.8 mg, 0.267 mmol) in MeCN (5.0 mL) was heated to 80 °C for 3 h, then poured into Na 2 S 2 O 3 , extracted with EtOAc, washed with brine, dried (MgSO 4 ) and concentrated. Purification via flash (elution with 0-100% v/v ethyl acetate in hexanes) afforded 40 mg (7%) of tert-butyl-[1-[2-iodo-5-(trifluoromethyl)pyrimidin-4-yl]azet idin-3-yl]oxy-dimethyl-silane ES/MS m/z: 459.340 [M+H]. Example 124: (S)-6-fluoro-7-(4-(3-hydroxyazetidin-1-yl)-5-(trifluoromethy l)pyrimidin-2-yl)-3-(4- ((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) pentyl)quinazolin-4(3H)-one [0471] The title compound was synthesized as described in Example 17, using 4-(3-((tert- butyldimethylsilyl)oxy)azetidin-1-yl)-2-iodo-5-(trifluoromet hyl)pyrimidine instead of 2-bromo-5- (difluoromethoxy)pyridine and 7-bromo-6-fluoroquinazolin-4(1H)-one instead of 6-Bromo-8-fluoro-1,2- dihydroisoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.72 (s, 1H), 8.43 (s, 1H), 8.26 (d, J = 6.7 Hz, 1H), 7.96 – 7.88 (m, 2H), 6.41 – 6.27 (m, 1H), 5.87 (s, 1H), 4.65 – 4.55 (m, 1H), 4.55 – 4.44 (m, 2H), 4.04 – 3.98 (m, 4H), 1.83 – 1.62 (m, 3H), 1.58 – 1.46 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 629.30 [M+H]. Example 125: (S)-4-amino-2-(6-fluoro-4-oxo-3-(4-((6-oxo-5-(trifluoromethy l)-1,6-dihydropyridazin- 4-yl)amino)pentyl)-3,4-dihydroquinazolin-7-yl)pyrimidine-5-c arbonitrile [0472] The title compound was synthesized as described in Example 17, using 4-amino-2- chloropyrimidine-5-carbonitrile instead of 2-bromo-5-(difluoromethoxy)pyridine and 7-bromo-6- fluoroquinazolin-4(1H)-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.81 (s, 1H), 8.43 (s, 1H), 8.19 (d, J = 6.7 Hz, 1H), 7.95 – 7.87 (m, 2H), 6.39 – 6.28 (m, 1H), 4.03 – 3.93 (m, 3H), 1.81 – 1.61 (m, 3H), 1.58 – 1.48 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 530.30 [M+H] + . Example 126: (S)-6-fluoro-7-(5-(methylsulfonyl)pyrimidin-2-yl)-3-(4-((6-o xo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)pentyl)quinazolin-4(3H)-one [0473] The title compound was synthesized as described in Example 17, using 2-chloro-5- (methylsulfonyl)pyrimidine instead of 2-bromo-5-(difluoromethoxy)pyridine and 7-bromo-6- fluoroquinazolin-4(1H)-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.48 (s, 2H), 8.47 (s, 1H), 8.36 (d, J = 6.8 Hz, 1H), 8.01 (d, J = 10.5 Hz, 1H), 7.92 (s, 1H), 6.40 – 6.28 (m, 1H), 4.06 – 3.93 (m, 3H), 3.49 (s, 3H), 1.82 – 1.62 (m, 3H), 1.59 – 1.46 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 568.30 [M+H]. Example 127: (S)-6-fluoro-7-(5-(2-hydroxyethoxy)pyrimidin-2-yl)-3-(4-((6- oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)pentyl)quinazolin-4(3H)-one [0474] The title compound was synthesized as described in Example 17, using 5-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-2-chloropyrimidine instead of 2-bromo-5-(difluoromethoxy)pyridine and 7-bromo-6-fluoroquinazolin-4(1H)-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.77 (s, 2H), 8.42 (s, 1H), 8.23 (d, J = 7.0 Hz, 1H), 7.95 – 7.89 (m, 2H), 6.35 (dd, J = 8.8, 3.8 Hz, 1H), 4.30 – 4.24 (m, 2H), 4.03 – 3.95 (m, 3H), 3.80 – 3.77 (m, 2H), 1.84 – 1.61 (m, 3H), 1.59 – 1.47 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 550.30 [M+H]. Example 128: (S)-6-(4-amino-5-(trifluoromethyl)pyrimidin-2-yl)-7-fluoro-2 -(4-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)iso quinolin-1(2H)-one [0475] The title compound was synthesized as described in Example 17, using 2-chloro-5- (trifluoromethyl)pyrimidin-4-amine instead of 2-bromo-5-(difluoromethoxy)pyridine and 7-bromo-6- fluoroquinazolin-4(1H)-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.66 (d, J = 1.0 Hz, 1H), 8.43 (s, 1H), 8.18 (d, J = 6.7 Hz, 1H), 7.95 – 7.90 (m, 2H), 6.40 – 6.28 (m, 1H), 4.04 – 3.92 (m, 3H), 1.81 – 1.60 (m, 3H), 1.60 – 1.45 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 573.30 [M+H]. Example 129: (S)-7-fluoro-6-(5-(2-hydroxyethoxy)pyrimidin-2-yl)-2-(4-((6- oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one [0476] The title compound was synthesized as described in Example 17, using 5-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-2-chloropyrimidine instead of 2-bromo-5-(difluoromethoxy)pyridine and 6-bromo-7-fluoroisoquinolin-1(2H)-one instead of 6-Bromo-8-fluoro-1,2-dihydroisoquinolin-1-one.1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.77 (s, 2H), 8.42 (s, 1H), 8.23 (d, J = 7.0 Hz, 1H), 7.95 – 7.89 (m, 2H), 6.35 (dd, J = 8.8, 3.8 Hz, 1H), 4.30 – 4.24 (m, 2H), 4.03 – 3.95 (m, 3H), 3.80 – 3.77 (m, 2H), 1.84 – 1.61 (m, 3H), 1.59 – 1.47 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 550.30 [M+H]. Example 130: 7,8-difluoro-2-(((1R,3R)-3-(((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4- yl)amino)methyl)cyclobutyl)methyl)-6-(5-(trifluoromethyl)pyr imidin-2-yl)isoquinolin-1(2H)-one [0477] Step 1. 5-((((1R,3R)-3-(hydroxymethyl)cyclobutyl)methyl)amino)-4- (trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyrida zin-3(2H)-one was synthesized as described in Example 5 (step 7) using ((1R,3R)-3-(aminomethyl)cyclobutyl)methanol (HCl salt) instead of 2-[(4S)- 4-aminopentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquino lin-1-one. ES/MS m/z: 408.14 [M+H] + . [0478] Step 2. ((1R,3R)-3-(((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsily l)ethoxy)methyl)- 1,6-dihydropyridazin-4-yl)amino)methyl)cyclobutyl)methyl 4-methylbenzenesulfonate was synthesized as described in Example 5 (step 2) using 5-((((1R,3R)-3-(hydroxymethyl)cyclobutyl)methyl)amino)-4- (trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyrida zin-3(2H)-one instead of tert-butyl N-[(1S)- 4-hydroxy-1-methyl-butyl]carbamate. ES/MS m/z: 562.10 [M+H] + . [0479] Step 3. 7,8-difluoro-2-(((1R,3R)-3-(((6-oxo-5-(trifluoromethyl)-1-(( 2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)ami no)methyl)cyclobutyl)methyl)-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one was synthesized as described in Example 5 (step 3) using ((1R,3R)-3-(((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsily l)ethoxy)methyl)-1,6- dihydropyridazin-4-yl)amino)methyl)cyclobutyl)methyl 4-methylbenzenesulfonate instead of [(4S)-4- (tert-butoxycarbonylamino)pentyl] 4-methylbenzenesulfonate and 7,8-difluoro-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one instead of 6-bromo-2H-isoquinolin-1-one. ES/MS m/z: 717.12 [M+H] + . [0480] Step 4. 7,8-difluoro-2-(((1R,3R)-3-(((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin- 4-yl)amino)methyl)cyclobutyl)methyl)-6-(5-(trifluoromethyl)p yrimidin-2-yl)isoquinolin-1(2H)-one was synthesized as described in Example 5 (step 8) using 7,8-difluoro-2-(((1R,3R)-3-(((6-oxo-5- (trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-d ihydropyridazin-4- yl)amino)methyl)cyclobutyl)methyl)-6-(5-(trifluoromethyl)pyr imidin-2-yl)isoquinolin-1(2H)-one instead of 2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilyleth oxymethyl)pyridazin-4-yl]amino]pentyl]- 6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.50 (d, J = 1.0 Hz, 2H), 8.24 (dd, J = 6.5, 1.7 Hz, 1H), 7.89 (s, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.80 (dd, J = 7.4, 1.9 Hz, 1H), 4.04 (d, J = 7.6 Hz, 2H), 3.49 - 3.42 (m, 2H), 2.79 (p, J = 7.5 Hz, 1H), 2.63 - 2.54 (m, 1H), 1.95 - 1.86 (m, 2H), 1.84 - 1.75 (m, 2H). ES/MS m/z: 587.30 [M+H] +. Intermediates 16 and 17: (R)-N-((R,Z)-5-((tert-butyldiphenylsilyl)oxy)-3-fluoropent-3 -en-2-yl)-2- methylpropane-2-sulfinamide (16) and (R)-N-((S,Z)-5-((tert-butyldiphenylsilyl)oxy)-3-fluoropent-3 - en-2-yl)-2-methylpropane-2-sulfinamide (17) [0481] (Z)-4-((tert-butyldiphenylsilyl)oxy)-2-fluorobut-2-en-1-ol was prepared as described in Nucleosides, Nucleotides & Nucleic Acids, 22 (5-8), 659-661; 2003. [0482] Step 1. A suspension of (Z)-4-((tert-butyldiphenylsilyl)oxy)-2-fluorobut-2-en-1-ol (585 mg, 1.7 mmol) and IBX (45%, 3.17 g, 5.1 mmol) in ethyl acetate (15.0 mL) was heated at reflux for 3h. Upon cooling, the solid was filtered. The filtrate was concentrated and purified using column chromatography eluting with EtOAc in hexanes 0-25% to afford (Z)-4-((tert-butyldiphenylsilyl)oxy)-2- fluorobut-2-enal. ES/MS m/z: 365.20 [M+Na] + . [0483] Step 2. To solution of (Z)-4-((tert-butyldiphenylsilyl)oxy)-2-fluorobut-2-enal (265 mg, 0.774 mmol) in THF (15.0 mL) was added Ti(OET)4 (0.41 mL, 1.93 mmol) and (R)-tert- butylsulfinylamine (234 mg, 1.93 mmol). The reaction mixture was stirred at reflux for 2 h. Upon cooling, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0-50% to afford (R)-N-((1E,2Z)-4-((tert-butyldiphenylsilyl)oxy)-2-fluorobut- 2-en-1-ylidene)-2-methylpropane-2- sulfinamide. ES/MS m/z: 446.12 [M+H] + . [0484] Step 3. To solution of (R)-N-((1E,2Z)-4-((tert-butyldiphenylsilyl)oxy)-2-fluorobut- 2- en-1-ylidene)-2-methylpropane-2-sulfinamide (282 mg, 0.633 mmol) in PhMe (3.0 mL) at 0 °C was added a 3.0 M solution of MeMgBr in Et2O (0.548 mL, 1.65 mmol). The reaction mixture was stirred at ambient temperature for 16 h. Upon cooling, the mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0-80% to afford (R)-N-((R,Z)-5-((tert- butyldiphenylsilyl)oxy)-3-fluoropent-3-en-2-yl)-2-methylprop ane-2-sulfinamide (X) and (R)-N- ((S,Z)-5-((tert-butyldiphenylsilyl)oxy)-3-fluoropent-3-en-2- yl)-2-methylpropane-2-sulfinamide (Y). ES/MS m/z: 484.30 [M+Na] + . Example 131: Preparation of (R,Z)-7,8-difluoro-2-(3-fluoro-4-((6-oxo-5-(trifluoromethyl) -1,6- dihydropyridazin-4-yl)amino)pent-2-en-1-yl)-6-(5-(trifluorom ethyl)pyrimidin-2-yl)isoquinolin- 1(2H)-one [0485] Step 1. To a solution of (R)-N-((R,Z)-5-((tert-butyldiphenylsilyl)oxy)-3-fluoropent-3 - en-2-yl)-2-methylpropane-2-sulfinamide (intermediate 16, 100 mg, 0.22 mmol) in MeOH (2.00 mL) was added 4N HCl in dioxane (0.325 mL, 1.30 mmol). The reaction mixture was stirred at ambient temperature for 1 h. Upon concentration, crude (R,Z)-4-amino-3-fluoropent-2-en-1-ol (HCl salt) was used in the next step. [0486] Step 2. (R,Z)-5-((3-fluoro-5-hydroxypent-3-en-2-yl)amino)-4- (trifluoromethyl)pyridazin-3(2H)-one was synthesized as described in Example 5 (step 7) using (R,Z)-4- amino-3-fluoropent-2-en-1-ol (HCl salt) instead of 2-[(4S)-4-aminopentyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. ES/MS m/z: 434.20 [M+Na] + . [0487] Step 3. (R,Z)-3-fluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyri dazin-4- yl)amino)pent-2-en-1-yl 4-methylbenzenesulfonate was synthesized as described in Example 5 (step 2) using (R,Z)-5-((3-fluoro-5-hydroxypent-3-en-2-yl)amino)-4-(trifluo romethyl)pyridazin-3(2H)-one instead of tert-butyl N-[(1S)-4-hydroxy-1-methyl-butyl]carbamate. ES/MS m/z: 566.10 [M+H] + . [0488] Step 4. (R,Z)-7,8-difluoro-2-(3-fluoro-4-((6-oxo-5-(trifluoromethyl) -1-((2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)ami no)pent-2-en-1-yl)-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one was synthesized as described in Example 5 (step 3) using (R,Z)-3-fluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyri dazin-4-yl)amino)pent-2-en-1-yl 4- methylbenzenesulfonate instead of [(4S)-4-(tert-butoxycarbonylamino)pentyl] 4-methylbenzenesulfonate and 7,8-difluoro-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquinoli n-1(2H)-one instead of 6-bromo-2H- isoquinolin-1-one. ES/MS m/z: 721.12 [M+H] + . [0489] Step 5. (R,Z)-7,8-difluoro-2-(3-fluoro-4-((6-oxo-5-(trifluoromethyl) -1,6- dihydropyridazin-4-yl)amino)pent-2-en-1-yl)-6-(5-(trifluorom ethyl)pyrimidin-2-yl)isoquinolin-1(2H)- one was synthesized as described in Example 5 (step 8) using (R,Z)-7,8-difluoro-2-(3-fluoro-4-((6-oxo-5- (trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-d ihydropyridazin-4-yl)amino)pent-2-en-1-yl)- 6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one instead of 2-[(4S)-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]pentyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 9.51 (s, 2H), 8.25 (dd, J = 6.6, 1.7 Hz, 1H), 7.92 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.83 (dd, J = 7.5, 1.9 Hz, 1H), 6.58 (dt, J = 8.1, 3.5 Hz, 1H), 5.32 (dt, J = 37.3, 7.0 Hz, 1H), 4.79 (dt, J = 13.0, 6.9 Hz, 1H), 4.70 – 4.56 (m, 2H), 1.42 (d, J = 6.7 Hz, 3H). ES/MS m/z: 591.20 [M+H] + . Example 132: (S,Z)-7,8-difluoro-2-(3-fluoro-4-((6-oxo-5-(trifluoromethyl) -1,6-dihydropyridazin-4- yl)amino)pent-2-en-1-yl)-6-(5-(trifluoromethyl)pyrimidin-2-y l)isoquinolin-1(2H)-one [0490] (S,Z)-7,8-difluoro-2-(3-fluoro-4-((6-oxo-5-(trifluoromethyl) -1,6-dihydropyridazin-4- yl)amino)pent-2-en-1-yl)-6-(5-(trifluoromethyl)pyrimidin-2-y l)isoquinolin-1(2H)-one was synthesized as described in Example 132 using intermediate 17 instead intermediate 16. 1 H NMR (400 MHz, DMSO- d6) δ 12.60 (s, 1H), 9.51 (s, 2H), 8.25 (dd, J = 6.6, 1.7 Hz, 1H), 7.92 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.83 (dd, J = 7.5, 1.9 Hz, 1H), 6.58 (dt, J = 8.1, 3.5 Hz, 1H), 5.32 (dt, J = 37.3, 7.0 Hz, 1H), 4.79 (dt, J = 13.0, 6.9 Hz, 1H), 4.70 – 4.56 (m, 2H), 1.42 (d, J = 6.7 Hz, 3H). ES/MS m/z: 591.24 [M+H] + .
Example 133: (S,E)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihy dropyridazin-4- yl)amino)pent-2-en-1-yl)-6-(5-(trifluoromethyl)pyrimidin-2-y l)isoquinolin-1(2H)-one [0491] (S,E)-7,8-difluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihy dropyridazin-4- yl)amino)pent-2-en-1-yl)-6-(5-(trifluoromethyl)pyrimidin-2-y l)isoquinolin-1(2H)-one was synthesized as described in Example 132 using tert-butyl (S,E)-(5-hydroxypent-3-en-2-yl)carbamate (Chem. Lett.1986, 5, 815-18) instead of intermediate 16. 1 H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 9.51 (s, 2H), 8.25 (dd, J = 6.6, 1.7 Hz, 1H), 7.92 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.83 (dd, J = 7.5, 1.9 Hz, 1H), 6.58 (dt, J = 8.1, 3.5 Hz, 1H), 5.32 (dt, J = 37.3, 7.0 Hz, 1H), 4.79 (dt, J = 13.0, 6.9 Hz, 1H), 4.70 – 4.56 (m, 2H), 1.42 (d, J = 6.7 Hz, 3H). ES/MS m/z: 572.4 [M+H] + . Example 134: Preparation of (S,E)-6-(4-amino-5-methoxypyrimidin-2-yl)-7-fluoro-2-(4-((6- oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pent-2-en- 1-yl)isoquinolin-1(2H)-one [0492] Step 1. (S,E)-6-bromo-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pent-2-en-1-yl)isoquinolin-1(2H) -one was synthesized as described in Example 132 (Steps 1-4) using tert-butyl (S,E)-(5-hydroxypent-3-en-2-yl)carbamate (Chem. Lett.1986, 5, 815-18) instead intermediate 16 and 6-bromo-7-fluoroisoquinolin-1(2H)-one instead of 7,8-difluoro-6- (5-(trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one. ES/MS m/z: 617.06 [M+H] + . [0493] Step 2. (S,E)-6-(4-amino-5-methoxypyrimidin-2-yl)-7-fluoro-2-(4-((6- oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pent-2-en- 1-yl)isoquinolin-1(2H)-one was synthesized as described in Example 17 (step 3) using 2-chloro-5-methoxypyrimidin-4-amine instead of 2-bromo-5-(difluoromethoxy)pyridine. 1 H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 0.35H), 12.49 (s, 0.65H), 9.34 (d, J = 8.1 Hz, 0.35H), 8.15 (s, 0.35H), 8.11 (d, J = 7.1 Hz, 1H), 8.05 (s, 1H), 7.97 (d, J = 11.0 Hz, 1H), 7.81 (s, 0.65H), 7.43 (dd, J = 7.4, 1.8 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.50 (dd, J = 7.8, 3.8 Hz, 1H), 5.92 – 5.69 (m, 2H), 4.71 – 4.50 (m, 3H), 3.94 (s, 3H), 1.33 (d, J = 6.6 Hz, 1H), 1.28 (d, J = 6.6 Hz, 2H). ES/MS m/z: 532.3 [M+H] + . Example 135: Preparation of (R)-7-fluoro-2-(5-methoxy-4-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)py rimidin-2-yl)isoquinolin-1(2H)-one [0494] Step 1. To a solution of (2R)-2-(tert-butoxycarbonylamino)-5-[7-fluoro-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]pentanoic acid (synthesized as described in Example 88, Steps 1-3) (39.3 mg, mmol) in anhydrous acetonitrile (1.00 mL) was added Silver oxide (76.3 mg, 0.329 mmol) and iodomethane (104 mg, 0.731 mmol). The heterogenous mixture was protected from light and stirred at room temperature for 12 hrs. Upon completion, the solid was filtered off and the filtrate was concentrated in vacuo. The crude product was purified using flash chromatography eluting with EtOAc in hexanes 0-100% to afford tert-butyl N-[(1R)-4-[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2- yl]- 2-isoquinolyl]-1-(methoxymethyl)butyl]carbamate. ES/MS m/z: 525.2 [M+H] + . [0495] Step 2.2-[(4R)-4-amino-5-methoxy-pentyl]-7-fluoro-6-[5-(trifluoro methyl)pyrimidin- 2-yl]isoquinolin-1-one was synthesized as described in Example 88 (step 4) using tert-butyl N-[(1R)-4- [7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl]-2-isoq uinolyl]-1- (methoxymethyl)butyl]carbamate. ES/MS m/z: 425.2 [M+H] + . [0496] Step 3.7-fluoro-2-[(4R)-5-methoxy-4-[[6-oxo-5-(trifluoromethyl)-1 -(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one was synthesized as described in Example 88 (step 5) using 2-[(4R)-4-amino-5- methoxy-pentyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidin-2-y l]isoquinolin-1-one. ES/MS m/z: 717.2 [M+H] + . [0497] Step 4.7-fluoro-2-[(4R)-5-methoxy-4-[[6-oxo-5-(trifluoromethyl)-1 H-pyridazin-4- yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoqui nolin-1-one (was synthesized as described in Example 88 (step 6) using 7-fluoro-2-[(4R)-5-methoxy-4-[[6-oxo-5-(trifluoromethyl)-1-( 2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.48 (s, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.95 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.29 (dd, J = 10.4, 2.3 Hz, 1H), 4.18 – 4.07 (m, 1H), 4.00 (t, J = 6.8 Hz, 2H), 3.24 (s, 3H), 1.81 – 1.70 (m, 2H), 1.62 – 1.52 (m, 2H). ES/MS m/z: 587.2 [M+H] + . Example 136: Preparation of 7-fluoro-2-[4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4- yl]oxy]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquino lin-1-one [0498] Step 1. To a solution of 5-bromopentan-2-one (375 mg, 2.27 mmol) and 6-bromo-7- fluoro-2H-isoquinolin-1-one (250 mg, 1.03 mmol) in DMF (11.0 mL) was added Cs 2 CO 3 (1.20 g, 3.62 mmol) and the heterogeneous mixture was stirred for 4 hrs. Upon completion, the mixture was diluted with EtOAc and the solid was filtered off and the filtrate was concentrated in vacuo. The crude product was purified using flash chromatography eluting with EtOAc in hexanes 0-100% to afford 6-bromo-7- fluoro-2-(4-oxopentyl)isoquinolin-1-one. ES/MS m/z: 327.9 [M+H] + . [0499] Step 2. To a solution of 6-bromo-7-fluoro-2-(4-oxopentyl)isoquinolin-1-one (224 mg, 0.687 mmol) in EtOH (7.0 mL) was added NaBH4 (52.0 mg, 1.37 mmol) at 0°C and the mixture was stirred at room temperature for 2 hrs. Upon completion, the mixture was acidified using 1 N HCl(aq) (pH ~3) at 0°C and concentrated in vacuo. The residue was diluted with EtOAc, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo and used without no further purification. ES/MS m/z: 329.2 [M+H] + . [0500] Step 3. A solution of 6-bromo-7-fluoro-2-(4-hydroxypentyl)isoquinolin-1-one (124 mg, 0.378 mmol), 5-chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl )pyridazin-3-one (248 mg, 0.756 mmol) and N,N-Diisopropylethylamine (293 mg, mmol) in DMF (3.8 mL) was heated at 80 °C for 1 hr. Upon completion, the mixture was diluted with EtOAc and water and the aqueous layer was extracted with EtOAc. Combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo and the crude product was purified using flash chromatography eluting with EtOAc in hexanes 0- 100% to afford 6-bromo-7-fluoro-2-[4-[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]oxypentyl]isoquino lin-1-one. ES/MS m/z: 622.2 [M+H] + . [0501] Step 4. A mixture of 6-bromo-7-fluoro-2-[4-[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]oxypentyl]isoquino lin-1-one (160.0 mg, 0.258 mmol), Bis (Pinacolato) Diboron (98.2 mg, 0.387 mmol), KOAc (75.9 mg, 0.774 mmol), dichloro 1,1'- bis(diphenylphosphino)ferrocene palladium (II) dichloromethane (21.1 mg, 0.026 mmol) in dioxane (2.0 mL) was purged with nitrogen gas and heated at 100° C for 1 hr. Upon completion, the mixture was diluted with EtOAc, filtered through a pad of Celite ® and concentrated in vacuo to afford the corresponding boronic ester. A mixture of 7-fluoro-2-[4-[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]oxypentyl]-6-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoquinolin-1-one (172 mg, 0.258 mmol), 2-iodo-5-(trifluoromethyl)pyrimidine (212 mg, 0.773 mmol), cataCXium A Pd G4 (37.5 mg, 0.051 mmol), and 2M Na 2 CO 3 (aq) (0.39 mL) in dioxane (1.00 mL) was purged with nitrogen gas and heated at 95 °C for 20 minutes. Upon completion, the mixture was diluted with EtOAc and filtered through a pad of Celite ® and concentrated in vacuo to afford the crude product. The crude product was purified using flash chromatography eluting with EtOAc in hexanes 0- 100% to afford 7-fluoro-2-[4-[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilyl ethoxymethyl)pyridazin-4- yl]oxypentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinol in-1-one. ES/MS m/z: 688.1 [M+H] + . [0502] Step 5.7-fluoro-2-[4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-y l]oxy]pentyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one was synthesized as described in Example 5 (step 8) using 7-fluoro-2-[4-[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilyl ethoxymethyl)pyridazin-4- yl]oxypentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinol in-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 9.48 (s, 2H), 8.44 (d, J = 7.2 Hz, 1H), 8.26 (s, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.54 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 5.08 – 4.96 (m, 1H), 4.02 (t, J = 6.7 Hz, 2H), 1.88 – 1.61 (m, 4H), 1.29 (d, J = 6.0 Hz, 3H). ES/MS m/z: 558.20 [M+H] + . Example 137: 6-(4-amino-5-(trifluoromethyl)pyrimidin-2-yl)-7-fluoro-2-(4- methyl-4-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)iso quinolin-1(2H)-one [0503] The title compound was synthesized as described in Example 5 with the following changes: Step 1: tert-butyl (5-hydroxy-2-methylpentan-2-yl)carbamate was used instead of tert-butyl N-[(1S)-4- hydroxy-1-methyl-butyl]carbamate. Step 4: tert-butyl (5-(6-bromo-7-fluoro-1-oxoisoquinolin-2(1H)-yl)-2-methylpent an-2-yl)carbamate was used instead of tert-butyl N-[(1S)-4-(6-bromo-1-oxo-2-isoquinolyl)-1-methyl-butyl]carba mate Step 5: tert-butyl (5-(7-fluoro-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)isoquinolin-2(1H)- yl)-2-methylpentan-2-yl)carbamate, 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine, and CataCXium Pd G4 were used instead of tert-butyl N-[(1S)-1-methyl-4-[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan- 2-yl)-2-isoquinolyl]butyl]carbamate, 2-iodo-5-(trifluoromethyl)pyrimidine, and [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II), respectively. 1 H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 8.65 (s, 1H), 8.19 (d, J = 7.1 Hz, 1H), 8.01 – 7.82 (m, 2H), 7.50 (d, J = 7.4 Hz, 1H), 6.75 (d, J = 7.4 Hz, 1H), 5.76 (m, 1H), 3.91 (m, 3H), 1.75 (m, 5H), 1.38 (s, 6H). ES/MS m/z: 586.1 [M+H] + . Intermediate 18: Preparation of tert-butyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(3- (tosyloxy)propyl)pyrrolidine-1-carboxylate [0504] The title compound was synthesized as described in Intermediate 3, using tert-butyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)py rrolidine-1-carboxylate instead of tert- butyl (1R,2S,5S)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-car boxylate. ES/MS m/z: 514.1 [M+H] + . [0505] The following intermediates were synthesized using the procedure used above or a modification of the procedure above from the corresponding starting materials. Example 138: Preparation of 7-fluoro-2-(3-((2R,4S)-4-hydroxy-1-(6-oxo-5-(trifluoromethyl )-1,6- dihydropyridazin-4-yl)pyrrolidin-2-yl)propyl)-6-(5-(trifluor omethyl)pyrimidin-2-yl)isoquinolin- 1(2H)-one [0506] The title compound was synthesized as described in Example 5, using tert-butyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(3-(tosyloxy)prop yl)pyrrolidine-1-carboxylate instead of [(4S)-4-(tert-butoxycarbonylamino)pentyl] 4-methylbenzenesulfonate to afford 7-fluoro-2-(3-((2R,4S)- 4-hydroxy-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin- 4-yl)pyrrolidin-2-yl)propyl)-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 9.48 (s, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.13 – 7.91 (m, 2H), 7.54 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 4.33 (m, 1H), 4.16 – 3.86 (m, 3H), 3.74 – 3.15 (m, 3H), 2.35 – 2.23 (m, 1H), 1.94 – 1.59 (m, 3H), 1.51 (m, 2H). ES/MS m/z: 599.1 [M+H]. [0507] The following Examples were synthesized using the procedure used above or a modification of the procedure above from the corresponding starting materials. Example 144: 6-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-2-[(4R)-4-cycl opropyl-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]butyl]-7-fluoro-is oquinolin-1-one (GS-1297284) [0508] The title compound was synthesized as described in Example 17, with the following changes: Step 1. 6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-Bromo-8-fluoro-1,2- dihydroisoquinolin-1-one and [(4R)-4-(tert-butoxycarbonylamino)-4-cyclopropyl-butyl] 4- methylbenzenesulfonate was used instead of 4-(tert-butoxycarbonylamino)pentyl] 4- methylbenzenesulfonate. Step 3. 2-Chloro-5-(trifluoromethyl)pyrimidin-4-amine was used instead of 2-bromo-5- (difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.64 (d, J = 1.0 Hz, 1H), 8.20 (d, J = 7.1 Hz, 1H), 7.96 (d, J = 11.1 Hz, 1H), 7.89 (s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.51 (dd, J = 9.1, 3.8 Hz, 1H), 3.98 (d, J = 6.7 Hz, 2H), 3.35 (s, 1H), 1.71 (d, J = 38.7 Hz, 4H), 1.09 (dd, J = 8.7, 4.6 Hz, 1H), 0.49 (dt, J = 9.1, 4.8 Hz, 1H), 0.38 (td, J = 8.8, 4.1 Hz, 1H), 0.24 (ddq, J = 18.5, 9.4, 4.7 Hz, 2H). ES/MS m/z: 598.3 [M+H]. [0509] The following Examples were synthesized using the procedure used above for the synthesis of Example 144 or a modification of the procedure above from the corresponding starting materials. Example 148 and Example 149: 7-fluoro-2-[3-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1H-pyridazi n-4- yl]azetidin-2-yl]propyl]-6-[5-(trifluoromethyl)pyrimidin-2-y l]isoquinolin-1-one and 7-fluoro-2-[3- [(2R)-1-[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]azetidi n-2-yl]propyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one [0510] Step 1. The racemic mixture was synthesized as described in Example 17 and separated via chiral SFC (AD-H, 5um, 21x250 mm column; 40% EtOH as co-solvent; 100 bar; 40 °C). The first eluting peak was assigned as the (S)-configuration (Example 149) 1 H NMR (400 MHz, DMSO- d6) δ 12.35 (s, 1H), 9.65 – 9.39 (m, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.04 (d, J = 11.4 Hz, 1H), 7.56 (d, J = 7.7 Hz, 2H), 6.86 (d, J = 7.4 Hz, 1H), 4.70 (s, 1H), 4.43 – 4.20 (m, 1H), 4.20 – 3.78 (m, 3H), 2.07 – 1.66 (m, 6H), and the second eluting peak was assigned as the (R)-configuration (Example 150) 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.48 (d, J = 0.9 Hz, 2H), 8.44 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 11.4 Hz, 1H), 7.56 (d, J = 7.7 Hz, 2H), 6.86 (d, J = 7.4 Hz, 1H), 4.70 (s, 1H), 4.32 (s, 1H), 4.17 – 3.79 (m, 3H), 2.09 – 1.66 (m, 6H). ES/MS m/z: 569.3 [M+H]. Example 150: 6-fluoro-3-[3-[1-[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-y l]azetidin-2-yl]propyl]- 7-[5-(trifluoromethyl)pyrimidin-2-yl]quinazolin-4-one [0511] The title compound was synthesized as described in Example 73, using 7-bromo-6- fluoro-3H-quinazolin-4-one instead of 6-Bromo-7-fluoro-2H-isoquinolin-1-one to give 6-fluoro-3-[3-[1- [6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]azetidin-2-yl]p ropyl]-7-[5- (trifluoromethyl)pyrimidin-2-yl]quinazolin-4-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.50 (d, J = 1.0 Hz, 2H), 8.47 (s, 1H), 8.35 (d, J = 6.8 Hz, 1H), 8.01 (d, J = 10.6 Hz, 1H), 7.57 (s, 1H), 4.68 (s, 1H), 4.32 (d, J = 9.8 Hz, 1H), 4.13 – 3.99 (m, 2H), 3.91 (s, 1H), 2.12 – 1.61 (m, 6H). ES/MS m/z: 570.3. Example 151 and Example 152: 6-fluoro-3-[3-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1H-pyridazi n-4- yl]azetidin-2-yl]propyl]-7-[5-(trifluoromethyl)pyrimidin-2-y l]quinazolin-4-one and 6-fluoro-3-[3- [(2R)-1-[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]azetidi n-2-yl]propyl]-7-[5- (trifluoromethyl)pyrimidin-2-yl]quinazolin-4-one [0512] Step 1. Examples 151 and Example 152 were separated from Example 150 via chiral SFC (AD-H, 5um, 21x250 mm column; 40% EtOH as co-solvent; 100 bar; 40 °C). The first eluting peak was assigned as the (S)-configuration (Example 152) 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.50 (d, J = 1.0 Hz, 2H), 8.47 (s, 1H), 8.35 (d, J = 6.7 Hz, 1H), 8.01 (d, J = 10.5 Hz, 1H), 7.57 (s, 1H), 4.69 (d, J = 8.8 Hz, 1H), 4.32 (d, J = 10.1 Hz, 1H), 4.15 – 3.97 (m, 2H), 3.91 (d, J = 5.6 Hz, 1H), 2.04 – 1.65 (m, 5H), and the second eluting peak was assigned as the (R)-configuration (Example 153) 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.50 (d, J = 0.9 Hz, 2H), 8.47 (s, 1H), 8.35 (d, J = 6.8 Hz, 1H), 8.01 (d, J = 10.5 Hz, 1H), 7.57 (s, 1H), 4.68 (s, 1H), 4.32 (d, J = 3.0 Hz, 0H), 4.06 (d, J = 5.4 Hz, 2H), 3.91 (s, 1H), 2.02 – 1.69 (m, 5H).ES/MS m/z: 570.3 [M+H]. Example 153: 6-(4-amino-5-methoxy-pyrimidin-2-yl)-7-fluoro-2-[3-[1-[6-oxo -5-(trifluoromethyl)- 1H-pyridazin-4-yl]azetidin-2-yl]propyl]isoquinolin-1-one [0513] The title compound was synthesized as described in Example 17, with the following changes: Step 1. tert-butyl 2-[3-(p-tolylsulfonyloxy)propyl]azetidine-1-carboxylate was used instead of tert-butyl 2-[3-(p-tolylsulfonyloxy)propyl]azetidine-1-carboxylate[(4S) -4-(tert-butoxycarbonylamino)pentyl] 4- methylbenzenesulfonate and 6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-Bromo-8- fluoro-1,2-dihydroisoquinolin-1-one. Step 3. 2-chloro-5-methoxy-pyrimidin-4-amine was used instead of 2-bromo-5- (difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.11 (d, J = 7.1 Hz, 1H), 8.05 (s, 1H), 7.98 (d, J = 11.0 Hz, 1H), 7.60 – 7.49 (m, 2H), 6.77 (d, J = 7.4 Hz, 1H), 4.70 (s, 1H), 4.31 (d, J = 8.5 Hz, 1H), 3.94 (s, 6H), 2.00 – 1.66 (m, 6H). ES/MS m/z: 546.3 [M+H]. Example 154: 7-fluoro-2-[3-[2-[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-y l]pyrazolidin-1- yl]propyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin- 1-one [0514] Step 1. In a vial were placed 6-bromo-7-fluoro-2H-isoquinolin-1-one (500 mg, 2.07 mmol), 1,3-dibromopropane (4.21 mL, 41.3 mmol), and cesium carbonate (1.35 g, 4.13 mmol) in DMF (13.9 mL). After mixture was stirred at room temperature for 16 hr, it was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give 6-bromo-2-(3- bromopropyl)-7-fluoro-isoquinolin-1-one. ES/MS m/z: 363.8 [M+H]. [0515] Step 2. In a vial were placed 6-bromo-2-(3-bromopropyl)-7-fluoro-isoquinolin-1-one (226 mg, 0.62 mmol), tert-butyl pyrazolidine-1-carboxylate (129 mg, 0.75 mmol), cesium carbonate (406 mg, 1.25 mmol), and sodium iodide (93 mg, 0.62 mmol). Mixture was heated to 60 °C and allowed to stir 2 hr. After mixture was stirred at 60 °C, it was quenched with saturated sodium thiosulfate solution, diluted with water, and extracted with EtOAc (3x). The combined layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl 2-[3-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)propyl]pyrazolidi ne-1-carboxylate. ES/MS m/z: 455.9 [M+H]. [0516] Step 3. In a vial were placed tert-butyl 2-[3-(6-bromo-7-fluoro-1-oxo-2- isoquinolyl)propyl]pyrazolidine-1-carboxylate (169 mg, 0.37 mmol) and trifluoroacetic acid (0.29 mL, 3.7 mmol) in DCM (5.9 mL). After the mixture was stirred for 1 hr, it was concentrated under vacuum. To the same vial was then added 5-chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl )pyridazin- 3-one (135 mg, 0.41 mmol) and N,N-Diisopropylethylamine (0.33 mL, 1.86 mmol) in DMF (1.5 mL). The mixture was heated to 60 °C and stirred for 1 hr, then quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give 6-bromo-7-fluoro-2-[3-[2-[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]pyrazolidin-1- yl]propyl]isoquinolin-1-one. ES/MS m/z: 648.06 [M+H]. [0517] Step 4. In a vial were placed 6-bromo-7-fluoro-2-[3-[2-[6-oxo-5-(trifluoromethyl)-1- (2-trimethylsilylethoxymethyl)pyridazin-4-yl]pyrazolidin-1-y l]propyl]isoquinolin-1-one (82 mg, 0.13 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (11 mg, 0.013 mmol), potassium acetate (37 mg, 0.38 mmol), and bis(pinacolato)diboron (48 mg, 0.19 mmol) in dioxane (1.5 mL). The mixture was heated to 100 °C and stirred for 1 hr, followed by the addition of 2 M aqueous sodium carbonate (0.19 mL, 0.38 mmol) and 2-iodo-5-(trifluoromethyl)pyrimidine (52 mg, 0.19 mmol). The reaction was then stirred for an addition hour at 80 °C. Upon completion, the mixture was filtered through Celite ® , concentrated under vacuum, and purified by flash chromatography (100% hexanes to 100% EtOAc) to give 7-fluoro-2-[3-[2-[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]pyrazolidin-1-yl]p ropyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. ES/MS m/z: 714.3 [M+H]. [0518] Step 5. In a vial were placed 7-fluoro-2-[3-[2-[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]pyrazolidin-1-yl]p ropyl]-6-[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (43 mg, 0.06 mmol), trifluoroacetic acid (0.05 mL, 0.6 mmol), and DCM (2.6 mL). Mixture stirred at room temperature and concentrated under vacuum. The resulting product was dissolved in methanol (2.6 mL) and ethylenediamine (0.04 mL, 0.6 mmol) was added and stirred for 15 minutes, and then was concentrated under vacuum. The crude product was purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 7-fluoro-2-[3-[2-[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]pyrazolidin-1-yl]propyl] -6-[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 9.48 (d, J = 1.0 Hz, 2H), 8.43 (d, J = 7.2 Hz, 1H), 8.38 (s, 1H), 8.02 (d, J = 11.4 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 4.12 – 4.00 (m, 2H), 3.74 (s, 1H), 3.08 (d, J = 53.5 Hz, 2H), 2.91 – 2.56 (m, 3H), 2.13 (d, J = 54.4 Hz, 2H), 1.84 (t, J = 7.2 Hz, 2H). ES/MS m/z: 584.3 [M+H]. Example 155: (S)-6-fluoro-3-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyr idazin-4- yl)amino)hexyl)-7-(5-(trifluoromethyl)pyrimidin-2-yl)quinazo lin-4(3H)-one [0519] The title compound was synthesized as described in Example 37, using 7-bromo-6- fluoro-3H-quinazolin-4-one instead of 6-Bromo-7-fluoro-2H-isoquinolin-1-one to give (S)-6-fluoro-3- (4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)ami no)hexyl)-7-(5- (trifluoromethyl)pyrimidin-2-yl)quinazolin-4(3H)-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.50 (d, J = 0.9 Hz, 2H), 8.46 (s, 1H), 8.35 (d, J = 6.7 Hz, 1H), 8.00 (d, J = 10.5 Hz, 1H), 7.96 (s, 1H), 6.39 – 6.17 (m, 1H), 4.01 (t, J = 6.9 Hz, 2H), 3.85 (d, J = 7.8 Hz, 1H), 1.90 – 1.41 (m, 5H), 0.82 (t, J = 7.3 Hz, 3H). ES/MS m/z: 572.3 [M+H]. [0520] [0521] The following Examples were synthesized using the procedure used above or a modification of the procedure above from the corresponding starting materials. Intermediate 23: Preparation of 2-chloro-N-(2,2-difluoroethyl)-5-methoxy-pyrimidin-4-amine [0522] Step 1. To a vial was added 2-chloro-5-methoxy-pyrimidin-4-amine (250.0 mg, 1.57 mmol) and DMF (5.41 mL) and the reaction mixture was cooled to 0°C and sodium hydride was added (72.0 mg, 1.88 mmol). The mixture was stirred at 0°C and 2,2-difluoroethyl trifluoromethanesulfonate (0.229 mL, 1.72 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 1 hr. Upon complete conversion, reaction was quenched with saturated aqueous ammonium chloride solution, diluted with water, and extracted with EtOAc (x3). The combined organic layers were dried (Na 2 SO 4 ), concentrated, and purified by flash chromatography (100% hexanes to 100% EtOAc) to give 2-chloro-N-(2,2-difluoroethyl)-5-methoxy-pyrimidin-4-amine. ES/MS m/z: 337.9 [M+H]. Example 158: 6-[4-(2,2-difluoroethylamino)-5-methoxy-pyrimidin-2-yl]-7-fl uoro-2-[(4S)-4-[[6-oxo- 5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinol in-1-one [0523] The title compound was synthesized as described in Example 17, with the following changes: Step 1. 6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-Bromo-8-fluoro-1,2- dihydroisoquinolin-1-one. Step 3. 2-chloro-N-(2,2-difluoroethyl)-5-methoxy-pyrimidin-4-amine was used instead of 2-bromo-5- (difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.24 (d, J = 7.2 Hz, 1H), 8.11 (s, 2H), 7.98 (d, J = 11.3 Hz, 1H), 7.92 (s, 1H), 7.54 – 7.44 (m, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.42 – 6.08 (m, 2H), 3.88 (m, J = 15.0, 6.2, 4.3 Hz, 5H), 1.79 – 1.43 (m, 4H), 1.17 (d, J = 6.2 Hz, 3H). ES/MS m/z: 598.3 [M+H]. Example 159: 7-[4-(2,2-difluoroethylamino)-5-methoxy-pyrimidin-2-yl]-6-fl uoro-3-[(4S)-4-[[6-oxo- 5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazi n-4-yl]amino]pentyl]quinazolin-4-one [0524] The title compound was synthesized as described in Example 29, using 2-chloro-N- (2,2-difluoroethyl)-5-methoxy-pyrimidin-4-amine instead of 2-iodo-5-(trifluoromethyl)pyrimidine to give 7-[4-(2,2-difluoroethylamino)-5-methoxy-pyrimidin-2-yl]-6-fl uoro-3-[(4S)-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]quinazolin- 4-one. 1 H NMR (400 MHz, DMSO- d6) δ 12.44 (s, 1H), 8.41 (s, 1H), 8.22 (d, J = 6.9 Hz, 1H), 8.11 (s, 1H), 7.95 – 7.86 (m, 2H), 7.76 (d, J = 11.2 Hz, 1H), 6.42 – 6.05 (m, 2H), 3.98 (d, J = 16.4 Hz, 5H), 3.84 (dtt, J = 19.3, 9.3, 4.8 Hz, 2H), 1.82 – 1.43 (m, 4H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 599.3. Intermediate 24: Preparation of tert-butyl N-[(1R)-1-(cyanomethyl)-4-hydroxy-butyl]carbamate [0525] Step 1.2-[(2R)-5-oxopyrrolidin-2-yl]acetonitrile (620 mg, 5.0 mmol) was taken up in 1N HCl (25.0 mL) and the mixture was stirred at 100°C for 2.5 hrs. After cooling, the reaction was evaporated to dryness and the residue taken up in PhMe and evaporated twice more. The residue was then dissolved in THF (15.0 mL) and water (15.0 mL) and stirred at ambient temperature. Sodium bicarbonate (2.1 g, 25 mmol) was added followed by di-tert-butyl decarbonate (2.20 g, 10 mmol) and the reaction was stirred for 16 hrs. The pH was then adjusted to 3 with 10% KHSO 4 and the mixture extracted with DCM (3x). The combined organic layers were dried over Na 2 SO 4 , filtered, and evaporated to afford (4R)-4-(tert-butoxycarbonylamino)-5-cyano-pentanoic acid which was carried forward without purification assuming quantitative conversion. [0526] Step 2. The crude (4R)-4-(tert-butoxycarbonylamino)-5-cyano-pentanoic acid was dissolved in THF (20 mL) and TEA (0.77 mL, 5.5 mmol) was added. The solution was cooled to 0°C and stirred rapidly. Ethyl chloroformate (0.53 mL, 5.5 mmol) was then added and the reaction was stirred for an additional hour before the precipitated triethylamine hydrochloride was filtered off and washed with a small amount of THF. The filtrate was then added slowly to a 0°C solution of sodium borohydride (570 mg, 15 mmol) in THF (20 mL) and water (6 mL). After 2 hrs, 10% KHSO 4 was carefully added and the mixture extracted 3x with EtOAc. The combined organics were dried over MgSO 4 , filtered, and evaporated. The crude was purified via flash chromatography (100% hexanes → 100% EtOAc) to afford tert-butyl N-[(1R)-1-(cyanomethyl)-4-hydroxy-butyl]carbamate. ES/MS m/z: 229.0 [M+H] + . Example 160: (3R)-6-[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl] -2-isoquinolyl]-3-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]hexanenitril e [0527] The title compound was synthesized as described in Example 5 Steps 2-8 with the following changes: Step 2. tert-butyl N-[(1R)-1-(cyanomethyl)-4-hydroxy-butyl]carbamate was used instead of tert-butyl N- [(1S)-4-hydroxy-1-methyl-butyl]carbamate. Step 5.20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step give (3R)-6-[7-fluoro-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]-3-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4- yl]amino]hexanenitrile. 1 H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 9.48 (d, J = 0.9 Hz, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.08 (s, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.53 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 7.3 Hz, 1H), 6.65 – 6.54 (m, 1H), 4.48 – 4.35 (m, 1H), 4.05 – 3.96 (m, 2H), 2.95 – 2.79 (m, 2H), 1.80 – 1.55 (m, 4H). ES/MS: m/z 582.2 [M+H] + .
Example 161: Preparation of 7,8-difluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyrida zin-4- yl]amino]hept-5-ynyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]i soquinolin-1-one [0528] Step 1.6-bromo-7,8-difluoro-2H-isoquinolin-1-one (750 mg, 2.9 mmol) and 2-(3- bromopropyl)-1,3-dioxolane (0.43 mL, 3.2 mmol) were dissolved in DMF (10 mL) and stirred at ambient temperature. Cs 2 CO 3 (1.9 g, 5.8 mmol) was then added and the reaction maintained for 3.5 hours at which point it was diluted with water and EtOAc. Solids crashed out and were filtered off to give pure product. The filtrate was then extracted 3x with EtOAc. The combined organics were dried over MgSO 4 , filtered, and evaporated to give a yellow residue. Diethyl ether was added to this and the mixture sonicated to produce a white solid which was collected via filtration to give a second crop of 6-bromo- 2-[3-(1,3-dioxolan-2-yl)propyl]-7,8-difluoro-isoquinolin-1-o ne. ES/MS: m/z 373.9/375.9 [M] + . [0529] Step 2. A vial was charged with 6-bromo-2-[3-(1,3-dioxolan-2-yl)propyl]-7,8- difluoro-isoquinolin-1-one (700 mg, 1.8 mmol), 1,1'-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride (65 mg, 0.089 mmol), potassium acetate (530 mg, 5.4 mmol), and bis(pinacolato)diboron (1.4 g, 5.4 mmol) and flushed with dry nitrogen. Dioxane (12 mL) was added and the reaction heated to 100°C for 4.5 hours. After cooling, 2-iodo-5-(trifluoromethyl)pyrimidine (590 mg, 2.1 mmol), CataCXium Pd G4 (66 mg, 0.089 mmol), and aqueous sodium carbonate (2.0 M, 2.7 mL) were added and the mixture bubbled with dry nitrogen briefly. The reaction was then stirred at 80°C for 1 hour before being diluted with EtOAc and filtered through a plug of Celite. The filtrate was evaporated and the crude purified via flash chromatography to afford 2-[3-(1,3-dioxolan-2-yl)propyl]-7,8-difluoro- 6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one as a yellow solid. ES/MS: m/z 441.7 [M] + . [0530] Step 3.2-[3-(1,3-dioxolan-2-yl)propyl]-7,8-difluoro-6-[5-(trifluo romethyl)pyrimidin- 2-yl]isoquinolin-1-one (700 mg, 1.5 mmol) was taken up in acetone (20 mL) and aqueous hydrochloric acid (1N, 14 mL). The reaction was stirred at 60°C for 75 minutes before being cooled to ambient temperature and diluted with water. The precipitated solids were collected via filtration, washed with minimal water and heptanes, and dried to provide 4-[7,8-difluoro-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]butanal which was used without purification. m/z 398.0 [M+H] + . [0531] Step 4. Crude 4-[7,8-difluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl]- 2- isoquinolyl]butanal (600 mg, 1.5 mmol), (R)-2-methylpropane-2-sulfinamide (270 mg, 2.3 mmol), and Cupric sulfate (960 mg, 6.0 mmol) were suspended in DCM (14.0 mL) and stirred at ambient temperature. After 16 hours, the solids were removed via filtration, washed with additional DCM, and the filtrate evaporated. The residue was purified via flash chromatography (100% hexanes → 100% EtOAc) to afford (NE,R)-N-[4-[7,8-difluoro-1-oxo-6-[5-(trifluoromethyl)pyrimi din-2-yl]-2- isoquinolyl]butylidene]-2-methyl-propane-2-sulfinamide as a yellow solid. m/z 501.0 [M+H] + . [0532] Step 5. (NE,R)-N-[4-[7,8-difluoro-1-oxo-6-[5-(trifluoromethyl)pyrimi din-2-yl]-2- isoquinolyl]butylidene]-2-methyl-propane-2-sulfinamide (350 mg, 0.66 mmol) was dissolved in DCM (14.0 mL) and the resultant solution was cooled to -78°C.1-propynylmagnesium bromide (0.5 M in THF, 1.6 mL) was then added slowly and the reaction maintained at -78°C for 30 minutes before warming to ambient temperature and stirring a further 1 hour. The solution was cooled to 0°C, quenched via addition of 10% KHSO 4 , and extracted 3x with EtOAc. The combined organics were dried over MgSO 4 , filtered, and evaporated. The residue was purified via flash chromatography (100% DCM → 100% ACN) to provide (R)-N-[(1R)-1-[3-[7,8-difluoro-1-oxo-6-[5-(trifluoromethyl)p yrimidin-2-yl]-2- isoquinolyl]propyl]but-2-ynyl]-2-methyl-propane-2-sulfinamid e as a yellow residue. m/z 541.1 [M+H] + . [0533] Step 6. (R)-N-[(1R)-1-[3-[7,8-difluoro-1-oxo-6-[5-(trifluoromethyl)p yrimidin-2-yl]-2- isoquinolyl]propyl]but-2-ynyl]-2-methyl-propane-2-sulfinamid e (78 mg, 0.14 mmol) was dissolved in MeOH (1.0 mL) and the solution stirred at ambient temperature. Hydrochloric acid (4 M in dioxane, 0.14 mL) was then added. After 1 hour, the solvent was evaporated to afford 2-[(4R)-4-aminohept-5-ynyl]- 7,8-difluoro-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinoli n-1-one. m/z 438.3 [M+2H] + . [0534] Step 7.2-[(4R)-4-aminohept-5-ynyl]-7,8-difluoro-6-[5-(trifluorome thyl)pyrimidin-2- yl]isoquinolin-1-one (60 mg, 0.14 mmol) was dissolved in DMF (1.0 mL) before being treated with 5- chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)p yridazin-3-one (90 mg, 0.28 mmol) and DIPEA (0.24 mL, 1.4 mmol). The reaction was stirred at 65°C for 1 hour before cooling to ambient temperature.10% aq. KHSO 4 was added and the mixture extracted 3x with EtOAc. The combined organics were washed with brine, dried over MgSO 4 , filtered, and evaporated. The residue was then purified via column chromatography (100% hexanes → 100% EtOAc) to afford 7,8-difluoro-2-[(4R)-4- [[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl) pyridazin-4-yl]amino]hept-5-ynyl]-6- [5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. m/z 729.2 [M+H] + . [0535] Step 8. To a solution of 7,8-difluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]hept-5-ynyl] -6-[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (87 mg, 0.11 mmol) in DCM (2.0 mL) stirred at ambient temperature was added TFA (0.10 mL, 1.1 mmol). The reaction was stirred for one hour then the volatiles were removed under vacuum. The resultant residue was dissolved in MeOH (1.0 mL), stirred at ambient temp, and treated with ethylenediamine (0.076 mL, 1.1 mmol). After 30 minutes, the reaction was concentrated and the residue purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 7,8- difluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]hept-5-ynyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 9.51 (d, J = 1.0 Hz, 2H), 8.25 (dd, J = 6.7, 1.7 Hz, 1H), 7.95 (s, 1H), 7.56 (d, J = 7.4 Hz, 1H), 6.84 (dd, J = 7.5, 1.8 Hz, 1H), 6.81 – 6.74 (m, 1H), 4.69 – 4.59 (m, 1H), 4.04 – 3.95 (m, 2H), 1.91 – 1.75 (m, 7H). ES/MS: m/z 599.3 [M+H] + . Intermediate 25: 6-bromo-7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromet hyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]isoqu inolin-1-one [0536] Step 1. benzyl N-[(1R)-4-hydroxy-1-(hydroxymethyl)butyl]carbamate (17 g, 67 mmol) was dissolved in DCM (147 mL) and 2,2-Dimethoxypropane (100 mL). The solution was stirred at ambient temperature and p-toluenesulfonic acid (1.3 g, 6.7 mmol) was added. After stirring for 4 hours, saturated aqueous Na 2 HCO 3 was added. The phases were separated and the aqueous was extracted 2x with DCM. Combined organics were dried over Na 2 SO 4 , filtered, and evaporated. The residue was then purified via flash chromatography (100% hexanes → 60% EtOAc) to afford benzyl (4R)-4-(3- hydroxypropyl)-2,2-dimethyl-oxazolidine-3-carboxylate. ES/MS: m/z 294.1 [M+H] + . [0537] Step 2. benzyl (4R)-4-(3-hydroxypropyl)-2,2-dimethyl-oxazolidine-3-carboxyl ate (15.6 g, 51 mmol) was dissolved in DCM (200 mL) and treated with TEA (14 mL, 100 mmol) before cooling to 0°C. DMAP (620 mg, 0.51 mmol) and p-toluenesulfonyl chloride (12 g, 61 mmol) were then added and the reaction was allowed to warm slowly to ambient temperature and stir for 16 hours at which point it was again cooled to 0°C and treated with 10% KHSO 4 solution. This was extracted 3x with DCM and the combined organics were dried over Na 2 SO 4 , filtered, and evaporated. The crude residue was purified via column chromatography (100% hexanes → 60% EtOAc/Hex) to afford benzyl (4R)-2,2- dimethyl-4-[3-(p-tolylsulfonyloxy)propyl]oxazolidine-3-carbo xylate. ES/MS: m/z 448.1 [M+H] + . [0538] Step 3. Benzyl (4R)-2,2-dimethyl-4-[3-(p-tolylsulfonyloxy)propyl]oxazolidin e-3- carboxylate (10.2 g, 22 mmol), 6-bromo-7-fluoro-2H-isoquinolin-1-one (6.0 g, 25 mmol), and Cs 2 CO 3 (14 g, 43 mmol) were suspended in DMF (61 mL) and stirred at ambient temperature for 5 hours. The reaction was then diluted w/ water and extracted 3x with EtOAc. The combined organics were washed with brine, dried over MgSO 4 , filtered, and evaporated. The crude residue was purified via column chromatography (100% hexanes → 60% EtOAc/Hex) to afford benzyl (4R)-4-[3-(6-bromo-7-fluoro-1- oxo-2-isoquinolyl)propyl]-2,2-dimethyl-oxazolidine-3-carboxy late. ES/MS: m/z 517.1/519.0 [M+H] + . [0539] Step 4. Benzyl (4R)-4-[3-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)propyl]-2,2- dimethyl-oxazolidine-3-carboxylate (8.4 g, 15.4 mmol) was suspended in aqueous hydrochloric acid (6 N, 51 mL) and the mixture stirred at 105°C for 2 hours. The reaction was cooled to 0°C and the pH adjusted to ~9-10 with 12 N aqueous NaOH. The suspension was then extracted 8x with a 3:1 mixture of DCM:MeOH while monitoring the pH of the aqueous phase and adjusting with 2N NaOH to maintain a pH ~9-10. The combined organics were dried over Na 2 SO 4 , filtered, and evaporated to provide crude 2- [(4R)-4-amino-5-hydroxy-pentyl]-6-bromo-7-fluoro-isoquinolin -1-one which was used without purification. ES/MS: m/z 343.0/345.0 [M+H] + . [0540] Step 5.2-[(4R)-4-amino-5-hydroxy-pentyl]-6-bromo-7-fluoro-isoquin olin-1-one (15.4 mmol) and 5-chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl )pyridazin-3-one (7.3 g, 20 mmol) were dissolved in DMF (56 mL) and the solution was treated with DIPEA (8.0 mL, 46 mmol) before being warmed to 60°C. After stirring for 75 minutes, the reaction was cooled, diluted with water and aqueous 10% KHSO 4 , and extracted 3x with EtOAc. The combined extracts were washed with brine, dried over MgSO 4 , filtered, and evaporated. The crude residue was purified via column chromatography (100% hexanes → 100% EtOAc) to afford 6-bromo-7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]pentyl]isoquinolin-1-one. ES/MS: m/z 635.2/637.2 [M+H] + . Example 162: (2R)-5-[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl] -2-isoquinolyl]-2-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentanenitri le [0541] Step 1. A vial was charged with 6-bromo-7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]pentyl]isoquinolin-1-one (165 mg, 0.25 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (9.0 mg, 0.012 mmol), potassium acetate (73 mg, 0.74 mmol), and bis(pinacolato)diboron (160 mg, 0.74 mmol) and flushed with dry nitrogen. Dioxane (1.2 mL) was added and the reaction heated to 100°C for 1.5 hours. After cooling, 2-iodo-5-(trifluoromethyl)pyrimidine (81 mg, 0.30 mmol), CataCXium Pd G4 (9.0 mg, 0.012 mmol), and aqueous sodium carbonate (2.0 M, 0.37 mL) were added and the mixture bubbled with dry nitrogen briefly. The reaction was then stirred at 80°C for 1 hour before being diluted with EtOAc and filtered through a plug of Celite. The filtrate was evaporated and the crude purified via flash chromatography to afford 7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1-( 2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. ES/MS: m/z 703.3 [M+H] + . [0542] Step 2.7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1 -(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (120 mg, 0.16 mmol) was dissolved in dioxane (0.43 mL) and water (50 µL) and stirred at ambient temperature. TEMPO (1.3 mg, 8 µmol) and iodobenzene diacetate (115 mg, 0.36 mmol) were then added. After stirring for 1.5 hours, the reaction was diluted with 10% KHSO 4 and extracted 3x with EtOAc. The combined organics were dried over MgSO 4 , filtered, and evaporated to provide (2R)-5-[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl] -2-isoquinolyl]-2-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]pentanoic acid which was used immediately without purification. ES/MS: m/z 717.3 [M+H] + . [0543] Step 3. (2R)-5-[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl] -2-isoquinolyl]-2- [[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl) pyridazin-4-yl]amino]pentanoic acid (0.16 mmol) and HATU (76 mg, 0.32 mmol) were dissolved in DMF (1.6 mL) and DIPEA (85 µL, 0.49 mmol) and the solution stirred at ambient temperature. Ammonia (0.5 M in dioxane, 0.97 mL) was then added and the reaction maintained at ambient temperature. An additional portion of HATU, DIPEA, and ammonia was added after 1 hour and 1.5 hours. After a total of 2 hours, the reaction was diluted with water and extracted 3x with EtOAc. The combined organics were washed with 10% KHSO 4 , brine, dried over MgSO 4 , filtered, and evaporated to afford crude (2R)-5-[7-fluoro-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]-2-[[6-oxo-5- (trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentanamide which was used without purification. m/z 716.3 [M+H] + . [0544] Step 4. (2R)-5-[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl] -2-isoquinolyl]-2- [[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl) pyridazin-4-yl]amino]pentanamide (0.16 mmol) was dissolved in DMF (0.8 mL) and stirred at 0°C. Cyanuric chloride (42 mg, 0.23 mmol) was charged and the reaction stirred for 45 minutes before being diluted with EtOAc. The mixture was washed with saturated sodium bicarbonate, brine, and then dried over MgSO 4 . This was then filtered and concentrated under vacuum. The crude purified via flash chromatography (100% hexanes → 100% EtOAc) to afford (2R)-5-[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl] -2-isoquinolyl]-2-[[6- oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyri dazin-4-yl]amino]pentanenitrile. m/z 698.2 [M+H] + . [0545] Step 5. (2R)-5-[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl] -2-isoquinolyl]-2- [[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl) pyridazin-4-yl]amino]pentanenitrile (75 mg, 0.096 mmol) was dissolved in DCM (2.5 mL) and stirred at ambient temperature. TFA (74 µL, 0.96 mmol) was added and the rection maintained for 1.5 hours at which point ethylenediamine (96 µL, 0.14 mmol) was added directly. After an additional 20 minutes, the reaction was evaporated and the residue purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford (2R)-5-[7-fluoro- 1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]-2 -[[6-oxo-5-(trifluoromethyl)-1H- pyridazin-4-yl]amino]pentanenitrile. 1 H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.48 (d, J = 1.0 Hz, 2H), 8.45 (d, J = 7.1 Hz, 1H), 8.09 – 8.00 (m, 2H), 7.56 (d, J = 7.4 Hz, 1H), 7.30 – 7.21 (m, 1H), 6.88 (d, J = 7.4 Hz, 1H), 5.24 – 5.14 (m, 1H), 4.07 (t, J = 6.8 Hz, 2H), 2.10 – 1.94 (m, 2H), 1.93 – 1.79 (m, 2H). ES/MS: m/z 568.3 [M+H] + . Intermediate 26: benzyl (4R)-4-[3-(6-bromo-7,8-difluoro-1-oxo-2-isoquinolyl)propyl]- 2,2-dimethyl- oxazolidine-3-carboxylate [0546] The title compound was synthesized as described in Steps 1-3 of Intermediate 25, using 6-bromo-7,8-difluoro-2H-isoquinolin-1-one in place of 6-bromo-7-fluoro-2H-isoquinolin-1-one. ES/MS: m/z 535.1/537.0 [M+H] + . Example 163: 7,8-difluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl) -1H-pyridazin-4- yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoqui nolin-1-one [0547] Step 1. A vial was charged with benzyl (4R)-4-[3-(6-bromo-7,8-difluoro-1-oxo-2- isoquinolyl)propyl]-2,2-dimethyl-oxazolidine-3-carboxylate (624 mg, 0.11 mmol), 1,1'- Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (41 mg, 0.055 mmol), potassium acetate (325 mg, 3.3 mmol), and bis(pinacolato)diboron (840 mg, 3.3 mmol) and flushed with dry nitrogen. Dioxane (5.6 mL) was added and the reaction was heated to 100°C for 1.5 hours. After cooling, 2-iodo-5- (trifluoromethyl)pyrimidine (364 mg, 1.3 mmol), CataCXium Pd G4 (41 mg, 0.055 mmol), and aqueous sodium carbonate (2.0 M, 1.7 mL) were added and the mixture bubbled with dry nitrogen briefly. The reaction was then stirred at 80°C for 45 minutes before being diluted with EtOAc and filtered through a plug of Celite. The filtrate was evaporated and the crude purified via flash chromatography (100% hexanes → 80% EtOAc/Hex) to afford benzyl (4R)-4-[3-[7,8-difluoro-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]propyl]-2,2-d imethyl-oxazolidine-3-carboxylate. ES/MS: m/z 603.2 [M+H] + . [0548] Step 2. benzyl (4R)-4-[3-[7,8-difluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidi n-2-yl]-2- isoquinolyl]propyl]-2,2-dimethyl-oxazolidine-3-carboxylate (927 mg, 1.5 mmol) was suspended in aqueous hydrochloric acid (6 N, 4.9 mL) and the mixture stirred at 105°C for 4 hours. The reaction was cooled to 0°C and the pH adjusted to ~9-10 with 2N aqueous NaOH. The precipitate was then collected via filtration, washed with minimal water and heptanes and dried under high-vacuum to afford 2-[(4R)-4- amino-5-hydroxy-pentyl]-7,8-difluoro-6-[5-(trifluoromethyl)p yrimidin-2-yl]isoquinolin-1-one which was used without purification. ES/MS: m/z 429.0 [M+H] + . [0549] Step 3.2-[(4R)-4-amino-5-hydroxy-pentyl]-7,8-difluoro-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one (422 mg, 0.99 mmol) and 5-chloro-4- (trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin- 3-one (602 mg, 1.3 mmol) were dissolved in DMF (4.5 mL) and the solution was treated with DIPEA (0.52 mL, 3.0 mmol) before being warmed to 60°C. After stirring for 75 minutes, the reaction was cooled, diluted with water and aqueous 10% KHSO 4 , and extracted 3x with EtOAc. The combined extracts were washed with brine, dried over MgSO 4 , filtered, and evaporated. The crude residue was purified via column chromatography (100% hexanes → 100% EtOAc) to afford 7,8-difluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl) -1- (2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6 -[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. ES/MS: m/z 721.3 [M+H] + . [0550] Step 4.7,8-difluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethy l)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (75 mg, 0.099 mmol) was dissolved in DCM (1.0 mL) and stirred at ambient temperature. TFA (76 µL, 0.99 mmol) was added and the rection maintained for 30 minutes at which point it was evaporated to dryness. The residue was dissolved in MeOH (1.0 mL) and treated with ethylenediamine (66 µL, 0.99 mmol). After 30 minutes, the reaction was evaporated and the residue purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 7,8-difluoro-2- [(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4 -yl]amino]pentyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.50 (d, J = 1.0 Hz, 2H), 8.24 (dd, J = 6.6, 1.7 Hz, 1H), 7.94 (s, 1H), 7.55 (d, J = 7.4 Hz, 1H), 6.82 (dd, J = 7.4, 1.8 Hz, 1H), 6.31 – 6.20 (m, 1H), 4.00 – 3.86 (m, 3H), 3.52 – 3.42 (m, 2H), 1.82 – 1.67 (m, 2H), 1.64 – 1.51 (m, 2H). ES/MS: m/z 591.3 [M+H] + . Intermediate 26: benzyl (4R)-4-[3-(7-bromo-6-fluoro-4-oxo-quinazolin-3-yl)propyl]-2, 2-dimethyl- oxazolidine-3-carboxylate [0551] The title compound was synthesized as described in Steps 1-3 of Intermediate 25, using 7-bromo-6-fluoro-3H-quinazolin-4-one in place of 6-bromo-7-fluoro-2H-isoquinolin-1-one. ES/MS: m/z 518.1/520.0 [M+H] + . [0552] The following Examples were synthesized as described in Example 163 or a modification of the procedure above from the corresponding intermediates.
Example 168: 2-[(4R)-5-(difluoromethoxy)-4-[[6-oxo-5-(trifluoromethyl)-1H -pyridazin-4- yl]amino]pentyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one [0553] Step 1.6-bromo-7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluorom ethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]isoqu inolin-1-one (250 mg, 0.37 mmol) and potassium acetate (293 mg, 3.0 mmol) were taken up in DCM (2.0 mL) and water (2.0 mL) and stirred very rapidly. (Bromodifluoromethyl)trimethylsilane (0.23 mL, 1.5 mmol) was then added. An additional portion of potassium acetate and (Bromodifluoromethyl)trimethylsilane was added at 7 hours and at 24 hours. After 27 hours total reaction time, water was added, and the reaction extracted 3x with DCM. The combined organics were dried over MgSO 4 , filtered, and evaporated. The crude residue was purified via column chromatography (100% hexanes → 100% EtOAc) to afford 6-bromo-2-[(4R)-5- (difluoromethoxy)-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimeth ylsilylethoxymethyl)pyridazin-4- yl]amino]pentyl]-7-fluoro-isoquinolin-1-one. ES/MS: m/z 685.2/687.1 [M+H] + . [0554] Step 2. A vial was charged with benzyl 6-bromo-2-[(4R)-5-(difluoromethoxy)-4-[[6- oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyri dazin-4-yl]amino]pentyl]-7-fluoro- isoquinolin-1-one (235 mg, 0.33 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (12 mg, 0.016 mmol), potassium acetate (96 mg, 0.98 mmol), and bis(pinacolato)diboron (250 mg, 0.98 mmol) and flushed with dry nitrogen. Dioxane (3.3 mL) was added and the reaction heated to 100°C for 16 hours. After cooling, 2-iodo-5-(trifluoromethyl)pyrimidine (107 mg, 0.39mmol), CataCXium Pd G4 (12 mg, 0.016 mmol), and aqueous sodium carbonate (2.0 M, 0.49 mL) were added and the mixture bubbled with dry nitrogen briefly. The reaction was then stirred at 80°C for 3 hours before being diluted with EtOAc and filtered through a plug of Celite. The filtrate was evaporated and the crude purified via flash chromatography (100% hexanes → 80% EtOAc/Hex) to afford 2-[(4R)-5-(difluoromethoxy)-4- [[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl) pyridazin-4-yl]amino]pentyl]-7-fluoro- 6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one ES/MS: m/z 753.2 [M+H] + . [0555] Step 3.2-[(4R)-5-(difluoromethoxy)-4-[[6-oxo-5-(trifluoromethyl)- 1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-7-fl uoro-6-[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (281 mg, 0.30 mmol) was dissolved in DCM (5.0 mL) and stirred at ambient temperature. TFA (0.45 mL, 6.0 mmol) was added and the rection maintained for 1 hour at which point it was evaporated to dryness. The residue was dissolved in MeOH (2.5 mL) and treated with ethylenediamine (0.20 mL, 3.0 mmol). After 30 minutes, the reaction was evaporated and the residue purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 2-[(4R)-5- (difluoromethoxy)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin -4-yl]amino]pentyl]-7-fluoro-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.48 (d, J = 1.0 Hz, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.98 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.87 – 6.45 (m, 2H), 6.45 – 6.36 (m, 1H), 4.34 – 4.20 (m, 1H), 4.01 (t, J = 6.8 Hz, 2H), 3.96 – 3.87 (m, 2H), 1.86 – 1.70 (m, 2H), 1.69 – 1.51 (m, 2H). ES/MS: m/z 623.3 [M+H] + .
Example 169: 7-fluoro-2-[(4R)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-4-[[6-oxo -5-(trifluoromethyl)-1H- pyridazin-4-yl]amino]butyl]-6-[5-(trifluoromethyl)pyrimidin- 2-yl]isoquinolin-1-one [0556] Step 1.7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1 -(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (75 mg, 0.10 mmol) was dissolved in dioxane (0.27 mL) and water (30 µL) and stirred at ambient temperature. TEMPO (0.80 mg, 5.1 µmol) and iodobenzene diacetate (72.0 mg, 0.22 mmol) were then added. After stirring for 18 hours, the reaction was diluted with 10% KHSO 4 and extracted 3x with EtOAc. The combined organics were dried over MgSO 4 , filtered, and evaporated to provide (2R)-5-[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl] -2-isoquinolyl]-2-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]pentanoic acid which was used immediately without purification. ES/MS: m/z 717.3 [M+H] + . [0557] Step 2. (2R)-5-[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl] -2-isoquinolyl]-2- [[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl) pyridazin-4-yl]amino]pentanoic acid (0.10 mmol), acethydrazide (11 mg, 0.13 mmol), and HATU (48 mg, 0.20 mmol) were dissolved in DMF (1.0 mL) and DIPEA (53 µL, 0.30 mmol) and the solution stirred at ambient temperature. After 2 hours, the reaction was diluted with water and extracted 3x with EtOAc. The combined organics were washed with 10% KHSO 4 , brine, dried over MgSO 4 , filtered, and evaporated to afford crude (2R)-N'-acetyl-5-[7- fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl]-2-isoquin olyl]-2-[[6-oxo-5-(trifluoromethyl)-1- (2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentanehy drazide which was used without purification. m/z 716.3 [M+H] + . [0558] Step 3. (2R)-N'-acetyl-5-[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrim idin-2-yl]-2- isoquinolyl]-2-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsil ylethoxymethyl)pyridazin-4- yl]amino]pentanehydrazide (0.10 mmol) was dissolved in DCM (1.0 mL) and stirred at ambient temperature. Burgess reagent (48 mg, 0.20 mmol) and DIPEA (35 µL, 0.20 mmol) were charged. An additional portion of Burgess reagent and DIPEA were added at 22 hours and 26 hours. After 40 hours total, the reaction was diluted with 10% KHSO 4 and extracted 3x with DCM. The combined organics were dried over MgSO 4 , filtered and, concentrated under vacuum. The crude was then purified via flash chromatography (100% hexanes → 100% EtOAc) to afford 7-fluoro-2-[(4R)-4-(5-methyl-1,3,4- oxadiazol-2-yl)-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethyl silylethoxymethyl)pyridazin-4- yl]amino]butyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquin olin-1-one. m/z 755.3 [M+H] + . [0559] Step 4.7-fluoro-2-[(4R)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-4-[[6-o xo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]butyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one (46 mg, 0.058 mmol) was dissolved in DCM (2.0 mL) and stirred at ambient temperature. TFA (44 µL, 0.58 mmol) was added and the rection maintained for 40 minutes at which point it was evaporated to dryness. The residue was dissolved in MeOH (1.0 mL) and treated with ethylenediamine (39 µL, 0.58 mmol). After 25 minutes, the reaction was evaporated and the residue purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 7-fluoro- 2-[(4R)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-4-[[6-oxo-5-(trifl uoromethyl)-1H-pyridazin-4- yl]amino]butyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquin olin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 9.48 (d, J = 1.0 Hz, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.12 – 7.03 (m, 1H), 6.86 (d, J = 7.4 Hz, 1H), 5.49 – 5.38 (m, 1H), 4.06 (t, J = 6.8 Hz, 2H), 2.47 (s, 3H), 2.19 – 2.03 (m, 2H), 1.96 – 1.77 (m, 2H). ES/MS: m/z 625.3 [M+H] + . Example 170: 7-fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]hex-5-ynyl]- 6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one [0560] Step 1.7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1 -(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (127 mg, 0.17 mmol) was dissolved in DCM (3.5 mL) and stirred at 0°C. DMP (80 mg, 0.19 mmol) was then added. After stirring for 16 hours, DMP (22 mg, 0.051 mmol) was added and the reaction was stirred an additional 6 hours. Saturated aqueous sodium bicarbonate was added, and the mixture extracted 3x with DCM. The combined organics were dried over Na 2 SO 4 , filtered, and evaporated to provide (2R)-5-[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl] -2-isoquinolyl]-2- [[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl) pyridazin-4-yl]amino]pentanal which was used immediately without purification. ES/MS: m/z 733.3 [M+OMe+H] + . [0561] Step 2. (2R)-5-[7-fluoro-1-oxo-6-[5-(trifluoromethyl)pyrimidin-2-yl] -2-isoquinolyl]-2- [[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl) pyridazin-4-yl]amino]pentanal (0.17 mmol) and potassium carbonate (95 mg, 0.69 mmol) were suspended in MeOH (3.0 mL) and the mixture was stirred at ambient temperature. (1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (40 mg, 0.21 mmol) was added in MeOH (0.75 mL) and the reaction stirred for 20 hours before being diluted with EtOAc and the solids filtered off. The filtrate was evaporated to provide crude material which was purified via flash chromatography (100% hexanes → 100% EtOAc) to afford impure 7-fluoro-2-[(4R)-4- [[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl) pyridazin-4-yl]amino]hex-5-ynyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one which was used as is. m/z 697.3 [M+H] + . [0562] Step 3.7-fluoro-2-[(4R)-4-[[6-oxo-5-(trifluoromethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]hex-5-ynyl]- 6-[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (38 mg, 0.054 mmol) was dissolved in DCM (2.0 mL) and stirred at ambient temperature. TFA (41 µL, 0.54 mmol) was added and the rection maintained for 1.5 hours at which point it was evaporated to dryness. The residue was dissolved in MeOH (1.0 mL) and treated with ethylenediamine (36 µL, 0.54 mmol). After 25 minutes, the reaction was evaporated and the residue purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 7-fluoro-2-[(4R)- 4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]hex-5- ynyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 9.48 (d, J = 1.0 Hz, 2H), 8.45 (d, J = 7.1 Hz, 1H), 8.04 (d, J = 11.4 Hz, 1H), 7.96 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 6.91 – 6.80 (m, 2H), 4.77 – 4.66 (m, 1H), 4.11 – 3.99 (m, 2H), 3.46 (d, J = 2.2 Hz, 1H), 1.95 – 1.76 (m, 4H). ES/MS: m/z 567.3[M+H] + . Example 171: 7-fluoro-2-[(4S)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin- 4-yl]amino]hex-5-ynyl]- 6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one [0563] The title compound was synthesized as described in example 170, using 7-fluoro-2- [(4S)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethyl silylethoxymethyl)pyridazin-4- yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoqui nolin-1-one was utilized as starting material instead of 7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1-( 2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. This material was prepared from tert-butyl N-[(1S)-4-hydroxy-1- (hydroxymethyl)butyl]carbamate instead of benzyl N-[(1R)-4-hydroxy-1- (hydroxymethyl)butyl]carbamate. 1 H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 9.51 (d, J = 1.0 Hz, 2H), 8.25 (d, J = 6.3 Hz, 1H), 7.96 (s, 1H), 7.57 (d, J = 7.4 Hz, 1H), 6.90 – 6.79 (m, 2H), 4.77 – 4.66 (m, 1H), 4.04 – 3.96 (m, 2H), 3.46 (d, J = 2.2 Hz, 1H), 1.95 – 1.77 (m, 4H). ES/MS: m/z 585.3 [M+H] + . Example 172: 7-fluoro-2-(3-(1-methyl-2-(6-oxo-5-(trifluoromethyl)-1,6-dih ydropyridazin-4- yl)hydrazineyl)propyl)-6-(5-(trifluoromethyl)pyrimidin-2-yl) isoquinolin-1(2H)-one [0564] Step 1. 1,3-dibromopropane (4.2 mL, 41 mmol) was added to a mixture of 6-bromo-7- fluoroisoquinolin-1-one (500 mg, 2.1 mmol) and cesium carbonate (1.35 g, 4.1 mmol) in DMF (8.0 mL). After stirring at ambient temperature overnight, the reaction was poured into aq. NaHCO 3 and extracted into EtOAc (3x). The combined extracts were washed with brine, concentrated, and purified by flash chromatography (EtOAc/hexane) to provide 6-bromo-2-(3-bromopropyl)-7-fluoro-isoquinolin-1-one. ES/MS m/z: 364.1 [M+H] + . [0565] Step 2. 6-Bromo-2-(3-bromopropyl)-7-fluoro-isoquinolin-1-one (100 mg, 0.28 mmol), methyl hydrazine (0.02 mL, 0.30 mmol), cesium carbonate (180 mg, 0.55 mmol), and sodium iodide (57 mg, 0.38 mmol) were combined in DMF (1.0 mL) and heated to 50 °C. After one hour, the reaction was allowed to cool to ambient temperature. 5-Chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one (279 mg, 0.85 mmol) and DIEA (0.14 mL, 0.83 mmol) were added, and the resulting mixture was heated at 50 °C for 20 minutes, then stirred at ambient temperature for 4 days. The reaction was poured into water and extracted into EtOAc (3x). The combined extracts were washed with brine, concentrated, and purified by flash chromatography (3:1 EtOAc/EtOH in hexane) to provide 6-bromo-7-fluoro-2-[3-[methyl-[[6-oxo-5-(trifluoromethyl)-1- (2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]amino]propyl ]isoquinolin-1-one. ES/MS m/z: 620.1 [M+H] + . [0566] Step 3. 6-Bromo-7-fluoro-2-[3-[methyl-[[6-oxo-5-(trifluoromethyl)-1- (2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]amino]propyl ]isoquinolin-1-one was subjected to conditions in Example 17 step 3, using 2-iodo-5-(trifluoromethyl)pyrimidine instead of 2-bromo-5- (difluoromethoxy)pyridine and adding 10 mol % of XPhos Pd G4 along with the pyrimidine. 1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.48 (d, J = 1.0 Hz, 2H), 8.44 (d, J = 7.2 Hz, 1H), 8.25 (s, 1H), 8.10 – 8.06 (m, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 4.12 – 3.94 (m, 2H), 2.95 – 2.83 (m, 1H), 2.80 – 2.69 (m, 1H), 2.57 (s, 3H), 1.82 (p, J = 7.1 Hz, 2H). ES/MS m/z: 558.3 [M+H] + . Example 173: (S)-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4- yl)amino)pentyl)-6-(4- (trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1(2H)-one [0567] The title compound was synthesized as described in Example 5, with the following changes: Steps 4-5 were replaced with the following conditions. tert-Butyl N-[(1S)-4-(6-bromo-1-oxo-2-isoquinolyl)-1-methyl-butyl]carba mate (90 mg, 0.22 mmol), 4- (trifluoromethyl)-1H-pyrazole (36 mg, 0.26 mmol), tBu-XPhos Pd G3 (15 mg, 0.02 mmol), cesium carbonate (143 mg, 0.44 mmol), and dioxane (.0 mL) were combined and purged with nitrogen gas. The reaction was heated to 100 °C for 20 hours, then adsorbed onto isolute and purified by flash chromatography eluting with EtOAc in hexanes 0-100% to afford tert-butyl N-[(1S)-1-methyl-4-[1-oxo- 6-[4-(trifluoromethyl)pyrazol-1-yl]-2-isoquinolyl]butyl]carb amate. ES/MS m/z: 465.2 [M+H] + . Step 6. HCl in dioxane was used instead of TFA in DCM. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.36 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.31 (s, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8.05 (dd, J = 8.8, 2.2 Hz, 1H), 7.92 (s, 1H), 7.55 (d, J = 7.4 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 6.41 – 6.31 (m, 1H), 4.05 – 3.92 (m, 3H), 1.82 – 1.60 (m, 3H), 1.57 – 1.46 (m, 1H), 1.17 (d, J = 6.3 Hz, 3H). ES/MS m/z: 527.3 [M+H] + . Intermediate 27: Preparation of tert-butyl (2R,4R)-4-methyl-2-(3-(tosyloxy)propyl)pyrrolidine-1- carboxylate [0568] The title compound was synthesized as described in Intermediate 3, using tert-butyl (2S,4R)-2-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate instead of tert-butyl (1R,2S,5S)-2- (hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. ES/MS m/z: 398.1 [M+H] + . Example 174: 7-fluoro-2-(3-((2R,4R)-4-methyl-1-(6-oxo-5-(trifluoromethyl) -1,6-dihydropyridazin- 4-yl)pyrrolidin-2-yl)propyl)-6-(5-(trifluoromethyl)pyrimidin -2-yl)isoquinolin-1(2H)-one [0569] The title compound was synthesized as described in Example 17 with the following changes: Step 16-bromo-7-fluoroisoquinolin-1(2H)-one was used instead of 6-bromo-8-fluoro-1,2- dihydroisoquinolin-1-one and tert-butyl (2R,4R)-4-methyl-2-(3-(tosyloxy)propyl)pyrrolidine-1- carboxylate was used instead of (S)-4-((tert-butoxycarbonyl)amino)pentyl 4-methylbenzenesulfonate Step 3.2-iodo-5-(trifluoromethyl)pyrimidine was used instead of 2-bromo-5-(difluoromethoxy)pyridine and 10 mol% [1,1'-Bis (di-tert-butyl phosphino)ferrocene] dichloropalladium (II) was used for borylation and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.). 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.48 (d, J = 1.0 Hz, 2H), 8.43 (d, J = 7.2 Hz, 1H), 8.07 – 8.00 (m, 2H), 7.54 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 4.48 – 4.29 (m, 1H), 4.09 – 3.91 (m, 2H), 3.78 – 3.65 (m, 1H), 2.83 (d, J = 10.9 Hz, 1H), 2.42 – 2.30 (m, 1H), 1.87 – 1.58 (m, 5H), 1.52 – 1.37 (m, 1H), 0.81 (d, J = 6.9 Hz, 3H). ES/MS: m/z 597.3 [M+H] + . [0570] The following Examples were synthesized as described in Example 174 or a modification of the procedure above from the corresponding intermediates.
Intermediate 28: 2-((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)ethyl 4- methylbenzenesulfonate [0571] 2-((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)ethyl 4- methylbenzenesulfonate was synthesized as described in Intermediate 14 (2-((1R,2S)-2-((tert- butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonate) using (1S,2S)-2-((tert- butoxycarbonyl)amino)cyclopentane-1-carboxylic acid instead (1S,2S)-2-((tert- butoxycarbonyl)amino)cyclobutane-1-carboxylic acid. ES/MS m/z: 406.32 [M+Na] + . Example 178: 6-(4-amino-5-(trifluoromethyl)pyrimidin-2-yl)-7-fluoro-2-(2- ((1R,2S)-2-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclopenty l)ethyl)isoquinolin-1(2H)-one [0572] 6-(4-amino-5-(trifluoromethyl)pyrimidin-2-yl)-7-fluoro-2-(2- ((1R,2S)-2-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclopenty l)ethyl)isoquinolin-1(2H)-one was synthesized as described in Example 17 using 2-((1R,2S)-2-((tert- butoxycarbonyl)amino)cyclopentyl)ethyl 4-methylbenzenesulfonate, 6-bromo-7-fluoroisoquinolin- 1(2H)-one and 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine. 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.65 (s, 1H), 8.19 (d, J = 7.1 Hz, 1H), 7.95 (d, J = 11.2 Hz, 1H), 7.92 (s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 6.76 (d, J = 7.4 Hz, 1H), 6.47 (dd, J = 8.3, 3.7 Hz, 1H), 3.99 (t, J = 7.4 Hz, 2H), 3.85 (p, J = 7.8 Hz, 1H), 2.09 – 1.84 (m, 3H), 1.72 – 1.46 (m, 4H), 1.36 – 1.22 (m, 1H). ES/MS m/z: 598.30 [M+H] + . Example 179: 7-fluoro-2-(2-((1R,2S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dih ydropyridazin-4- yl)amino)cyclopentyl)ethyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one [0573] 7-fluoro-2-(2-((1R,2S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dih ydropyridazin-4- yl)amino)cyclopentyl)ethyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one was synthesized as described in Example 17 using 2-((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)ethyl 4- methylbenzenesulfonate, 6-bromo-7-fluoroisoquinolin-1(2H)-one and 2-iodo-5- (trifluoromethyl)pyrimidine. 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 9.48 (d, J = 1.0 Hz, 2H), 8.43 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 11.4 Hz, 1H), 7.92 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.52 – 6.43 (m, 1H), 4.00 (t, J = 7.4 Hz, 2H), 3.85 (p, J = 7.9 Hz, 1H), 2.10 – 1.86 (m, 4H), 1.73 – 1.46 (m, 4H), 1.36 – 1.22 (m, 1H). ES/MS m/z: 583.30 [M+H] + . Example 180: (R)-2-(5-ethoxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyr idazin-4- yl)amino)pentyl)-7-fluoro-6-(5-(trifluoromethyl)pyrimidin-2- yl)isoquinolin-1(2H)-one [0574] The title compound was synthesized as described in Example 135, using iodoethane instead of iodomethane in step 1 to afford (R)-2-(5-ethoxy-4-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)pentyl)-7-fluoro-6-(5-(trifluoro methyl)pyrimidin-2-yl)isoquinolin- 1(2H)-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.48 (s, 2H), 8.46 – 8.41 (m, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.95 (s, 1H), 7.53 (d, J = 7.4 Hz, 1H), 6.87 – 6.82 (m, 1H), 6.32 – 6.24 (m, 1H), 4.17 – 4.08 (m, 1H), 4.04 – 3.97 (m, 2H), 3.47 – 3.37 (m, 4H), 1.82 – 1.70 (m, 2H), 1.63 – 1.52 (m, 2H), 1.03 (t, J = 7.0 Hz, 3H). ES/MS m/z: 601.3 [M+H]. Example 181: (R)-7-fluoro-2-(5-(methoxy-d3)-4-((6-oxo-5-(trifluoromethyl) -1,6-dihydropyridazin- 4-yl)amino)pentyl)-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoq uinolin-1(2H)-one [0575] The title compound was synthesized as described in Example 135, using iodomethane- d3 instead of iodomethane in step 1 to afford (R)-7-fluoro-2-(5-(methoxy-d3)-4-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-6- (5-(trifluoromethyl)pyrimidin-2- yl)isoquinolin-1(2H)-one. 1 H NMR (400 MHz, Acetonitrile-d3) δ 10.44 (s, 1H), 9.25 (s, 2H), 8.36 (d, J = 7.1 Hz, 1H), 8.10 (d, J = 11.7 Hz, 1H), 7.74 (s, 1H), 7.28 – 7.24 (m, 1H), 6.71 (d, J = 7.4 Hz, 1H), 5.81 – 5.72 (m, 1H), 4.05 – 4.00 (m, 2H), 3.97 (d, J = 8.7 Hz, 1H), 3.48 – 3.41 (m, 2H), 1.82 (s, 2H), 1.72 – 1.58 (m, 2H). ES/MS m/z: 590.1 [M+H]. Intermediate 29: tert-butyl (R)-1-(3-(tosyloxy)propyl)isoindoline-2-carboxylate [0576] The title compound was synthesized as described in Intermediate 3, using tert-butyl (S)-1-(hydroxymethyl)isoindoline-2-carboxylate instead of tert-butyl (1R,2S,5S)-2-(hydroxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate. ES/MS m/z: 432.2 [M+H] + . Example 182: 7-fluoro-2-[3-[(1R)-2-[6-oxo-5-(trifluoromethyl)-1H-pyridazi n-4-yl]isoindolin-1- yl]propyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin- 1-one [0577] The title compound was synthesized as described in Example 5, using tert-butyl (S)-1- (hydroxymethyl)isoindoline-2-carboxylate instead of tert-butyl N-[(1S)-1-cyclopropyl-2-hydroxy- ethyl]carbamate in step 3. 1 H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 9.48 (d, J = 1.0 Hz, 2H), 8.41 (d, J = 7.2 Hz, 1H), 8.21 (s, 1H), 7.98 (d, J = 11.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.42 – 7.22 (m, 4H), 6.79 (d, J = 7.4 Hz, 1H), 5.86 (s, 1H), 5.04 (d, J = 14.9 Hz, 1H), 4.51 (d, J = 14.9 Hz, 1H), 3.94 (dh, J = 19.9, 7.0 Hz, 2H), 1.91 (dq, J = 19.9, 13.6 Hz, 2H), 1.76 – 1.53 (m, 1H), 1.54 – 1.27 (m, 1H). ES/MS m/z: 631.3 [M+H] + . Intermediate 30: [(1R,3S)-3-(tert-butoxycarbonylamino)cyclohexyl]methyl 4- methylbenzenesulfonate [0578] The title compound was synthesized as described in Intermediate 3, using tert-butyl N- [(1S,3R)-3-(hydroxymethyl)cyclohexyl]carbamate instead of tert-butyl (1R,2S,5S)-2-(hydroxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate. ES/MS m/z: 384.2 [M+H] + . Example 183: 7-fluoro-2-[[(1R,3S)-3-[[6-oxo-5-(trifluoromethyl)-1H-pyrida zin-4- yl]amino]cyclohexyl]methyl]-6-[5-(trifluoromethyl)pyrimidin- 2-yl]isoquinolin-1-one [0579] The title compound was synthesized as described in Example 63, using [(1R,3S)-3- (tert-butoxycarbonylamino)cyclohexyl]methyl 4-methylbenzenesulfonate instead of 4-(tert- butoxycarbonylamino)pentyl] 4-methylbenzenesulfonate in step 1, and 2-iodo-5- (trifluoromethyl)pyrimidine instead of 2-bromo-5-(difluoromethoxy)pyridine in step 3. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.48 (d, J = 1.0 Hz, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.91 (s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.37 – 6.25 (m, 1H), 3.89 (d, J = 7.0 Hz, 2H), 3.89 – 3.79 (m, 1H), 2.04 (dd, J = 24.7, 16.4 Hz, 1H), 1.76 (dd, J = 30.0, 10.8 Hz, 3H), 1.57 (d, J = 12.9 Hz, 1H), 1.33 (dp, J = 34.1, 12.2, 11.5 Hz, 3H), 0.94 (t, J = 12.0 Hz, 1H). ES/MS m/z: 583.3 [M+H] + . Example 184: 6-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-7-fluoro-2-[[( 1R,3S)-3-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]cyclohexyl]methyl] isoquinolin-1-one [0580] The title compound was synthesized as described in Example 63, using [(1R,3S)-3- (tert-butoxycarbonylamino)cyclohexyl]methyl 4-methylbenzenesulfonate instead of 4-(tert- butoxycarbonylamino)pentyl] 4-methylbenzenesulfonate in step 1, and 2-chloro-5- (trifluoromethyl)pyrimidin-4-amine instead of 2-bromo-5-(difluoromethoxy)pyridine in step 3. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.64 (s, 1H), 8.20 (d, J = 7.1 Hz, 1H), 8.04 – 7.84 (m, 2H), 7.47 (d, J = 7.4 Hz, 1H), 6.75 (d, J = 7.4 Hz, 1H), 6.32 (dd, J = 8.5, 3.8 Hz, 1H), 3.88 (d, J = 7.0 Hz, 2H), 3.72 (d, J = 10.7 Hz, 1H), 2.01 (s, 1H), 1.90 – 1.64 (m, 3H), 1.56 (d, J = 12.7 Hz, 1H), 1.33 (dp, J = 34.6, 12.2, 11.8 Hz, 3H), 0.95 (q, J = 12.4, 11.9 Hz, 1H). ES/MS m/z: 593.3 [M+H] + . Intermediate 31: Preparation of 4-(azetidin-1-yl)-2-chloro-5-methoxypyrimidine [0581] N,N-Diisopropylethylamine (1.95 mL, 11.2 mmol) was added to a solution of 2,4- dichloro-5-(trifluoromethyl)pyrimidine (200 mg, 1.12 mmol) and azetidine (64 mg, 1.12 mmol) in DMF (7.8 mL). The resulting solution was stirred at room temperature for 2 hr and then diluted with water and extracted with EtOAc (x2). The combined organic layers were washed with water (x3), then washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure afford 4- (azetidin-1-yl)-2-chloro-5-methoxypyrimidine ES/MS: m/z 200.3 [M+H] + . [0582] The following intermediates were synthesized using the procedure as described in Intermediate 12 from the corresponding starting materials.
Intermediate 37: Preparation of 2-chloro-5-ethoxypyrimidin-4-amine [0583] Bromoethane (0.580 mL, 0.78 mmol) was added to a solution of 4-amino-2-chloro- pyrimidin-5-ol (104 mg, 0.71 mmol) and potassium carbonate (148 mg, 1.07 mmol) in DMF (1.40 mL). The resulting solution was stirred at room temperature for 16 hr, and then diluted with water and extracted two times with EtOAc. The combined organic layers were washed three time with water, then washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 2-chloro-5-ethoxypyrimidin-4-amine. ES/MS: m/z 175.9 [M+H] + . Intermediate 38: 2-Chloro-5-(trideuteriomethoxy)pyrimidin-4-amine) [0584] 4-Amino-2-chloro-pyrimidin-5-ol (250 mg, 1.7 mmol) and potassium carbonate (240 mg, 1.7 mmol) were suspended in DMF (2.0 mL) and stirred at ambient temperature. Iodomethane-d3 (54.0 µl, 0.86 mmol) was added via syringe. After stirring for 1 hour and 45 minutes, the reaction was diluted with water and extracted with EtOAc (x3). The combined organic layers were dried over Na 2 SO 4 , filtered and evaporated. The crude residue was purified via flash chromatography (100% DCM → 50% ACN/DCM) to afford 2-chloro-5-(trideuteriomethoxy)pyrimidin-4-amine. ES/MS m/z: 162.9 [M+H] +. Intermediate 39: 4-[2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl]morpholine [0585] 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (400 mg, 1.84 mmol), morpholine (0.16 mL, 1.84 mmol), and potassium carbonate (510 mg, 3.69 mmol) were combined in EtOH (18.0 mL) and stirred at ambient temperature overnight. The reaction was poured into water and extracted into DCM (3x). The combined extracts were concentrated and purified by flash chromatography using 3:1 EtOAc/EtOH in heptane as eluent.4-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]morphol ine was isolated as the minor regioisomer, ES/MS m/z: 268.1 [M+H] + . Intermediate 40: 3-Chloro-7,7-difluoro-5,6-dihydrocyclopenta[c]pyridine [0586] 3-Chloro-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one (1.0 g, 5.97 mmol) was cooled in an autoclave to -78 °C. HF was added, followed by SF4. The autoclave was warmed to 20 °C and the reaction stirred for 14 hours. Cold aqueous NaOH (3M, 20.0 mL) was added, followed by EtOAc (15.0 mL). The organic phase was separated and washed with brine (5.0 mL), dried over Na 2 SO 4 , filtered, and concentrated. Purification by flash chromatography using EtOAc in petroleum ether (0-100%) provided 3-chloro-7,7-difluoro-5,6-dihydrocyclopenta[c]pyridine. ES/MS m/z: 189.9 [M+H] + . Intermediate 41: Preparation of 2-chloro-N-ethyl-5-methoxy-pyrimidin-4-amine [0587] N,N-Diisopropylethylamine (0.36 mL, 2.09 mmol) was added to a solution of 2,4- dichloro-5-methoxy-pyrimidine (250 mg, 1.40 mmol) and ethylamine 2.0 M in THF (1.05 mL, 2.09 mmol) in MeOH (0.7 mL) and EtOAc (0.7 mL). The resulting solution was stirred at room temperature for 15 minutes and purified via prep. HPLC. The fractions are basified with sat. NaHCO3 and extracted with DCM. The organic layer is concentrated to afford 119 mg (45%) of 2-chloro-N-ethyl-5-methoxy- pyrimidin-4-amine ES/MS: m/z 189.5 [M+2+H] ++ . [0588] The following intermediates were synthesized using the procedure as described in Intermediate 41 from the corresponding starting materials [0589] The Following compounds were synthesized using the procedure as described in Example 17, with the following modification: 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. Example 226: 7-fluoro-2-(3-(1-methyl-2-(6-oxo-5-(trifluoromethyl)-1,6-dih ydropyridazin-4- yl)hydrazineyl)propyl)-6-(5-(trifluoromethyl)pyrimidin-2-yl) isoquinolin-1(2H)-one [0590] Step 1. To a stirred solution of tert-butyl N-[(1S,3R)-3- (hydroxymethyl)cyclohexyl]carbamate (1500 mg, 6.54 mmol) and triethylamine (1.82 mL, 13.1 mmol), in dichloromethane (10 mL) was added p-Toluenesulfonyl chloride (1434 mg, 7.52mmol) dropwise, followed by DMAP (20 mg). The mixture was stirred at room temperature and stirred for 16h. Upon completion, the mixture was diluted with water and extracted with dicholoromethane. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0- 100% to afford [(1R,3S)-3-(tert-butoxycarbonylamino)cyclohexyl]methyl 4-methylbenzenesulfonate ES/MS: m/z 384.1 [M+H] + . [0591] Step 2. To a mixture of 6-bromo-2H-isoquinolin-1-one (694 mg, 2.87 mmol) and [(1R,3S)-3-(tert-butoxycarbonylamino)cyclohexyl]methyl 4-methylbenzenesulfonate (1000 mg, 2.61 mmol) in DMF (12 mL) was added Cs 2 CO 3 (2550 mg, 7.82 mmol) and the reaction was stirred at room temperature for 18 h. Upon completion, the mixture was diluted with EtOAc, washed with water, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EA in hexanes 0-100% to afford tert-butyl N- [(1S,3R)-3-[(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)methyl]cyc lohexyl]carbamate. ES/MS: m/z 455.1 [M+H] + . [0592] Step 3. In a vial were placed tert-butyl N-[(1S,3R)-3-[(6-bromo-7-fluoro-1-oxo-2- isoquinolyl)methyl]cyclohexyl]carbamate (230 mg, 0.57 mmol), trifluoroacetic acid (0.51 mL) and DCM (4 mL). The mixture was stirred at room temperature for 1 hour. Upon completion, the mixture was concentrated in vacuo, the resultant was partitioned between EtOAc and sat. aq. Sodium bicarbonate solution. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give 2-[[(1R,3S)-3-aminocyclohexyl]methyl]-6-bromo-7-fluoro-isoqu inolin-1-one ES/MS m/z: 355.5[M+H] + . [0593] Step 4. A mixture of 2-[[(1R,3S)-3-aminocyclohexyl]methyl]-6-bromo-7-fluoro- isoquinolin-1-one (170 mg, 0.48 mmol), 5-chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one (237 mg, 0.722 mmol), and N,N-diisopropylethylamine (0.5 mL, 2.9 mmol) in DMF (5.0 mL) was heated at 80 °C for 1 hour. Upon completion, the reaction was diluted with EtOAc, washed with water, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0-100% to provide 6-bromo-7-fluoro-2-[[(1R,3S)-3-[[6-oxo-5-(trifluoromethyl)-1 - (2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]cyclohexy l]methyl]isoquinolin-1-one. ES/MS: m/z 647.1 [M+H] + . [0594] Step 5. A vial was charged with 6-bromo-7-fluoro-2-[[(1R,3S)-3-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]cyclohexyl]methyl]isoquinolin- 1-one (118 mg, 0.18 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (15 mg, 0.018 mmol), potassium acetate (54 mg, 0.54 mmol), and bis(pinacolato)diboron (70 mg, 0.27 mmol) and flushed with dry nitrogen. Dioxane (5 mL) was added and the reaction heated to 100°C for 2 hours. After cooling, 2-chloro-5-(difluoromethyl)pyrimidine (45 mg, 0.28 mmol), CataCXium Pd G4 (14 mg, 0.018 mmol), and aqueous sodium carbonate (2.0 M, 0.28 mL) were added and the mixture bubbled with dry nitrogen briefly. The reaction was then stirred at 100°C for 1 hour before being diluted with EtOAc and filtered through a plug of Celite. The filtrate was evaporated and the crude purified via chromatography eluting with EtOAc in hexanes 0-100% to provide 6-[5-(difluoromethyl)pyrimidin-2-yl]-7-fluoro-2- [[(1R,3S)-3-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilyle thoxymethyl)pyridazin-4- yl]amino]cyclohexyl]methyl]isoquinolin-1-one ES/MS: m/z 695.3 [M+H] + . [0595] Step 6. To a solution of 6-[5-(difluoromethyl)pyrimidin-2-yl]-7-fluoro-2-[[(1R,3S)-3- [[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl) pyridazin-4- yl]amino]cyclohexyl]methyl]isoquinolin-1-one (73 mg, 0.11 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.5 mL, 6.41 mmol) at room temperature and the mixture was stirred for 1 hour. The excess trifluoroacetic acid and solvent was removed under reduced pressure and the residue was dissolved in MeOH (1.0 mL). To this was added ethylenediamine (0.072 mL, 1.05 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. Upon completion, the mixture was concentrated in vacuo and purified via reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 6-[5-(difluoromethyl)pyrimidin-2-yl]-7-fluoro-2-[[(1R,3S)-3- [[6-oxo-5-(trifluoromethyl)- 1H-pyridazin-4-yl]amino]cyclohexyl]methyl]isoquinolin-1-one 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.25 (s, 1H), 8.41 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 11.4 Hz, 1H), 7.91 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.31 (t, J = 54.8 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.32 (dd, J = 8.6, 3.9 Hz, 1H), 3.89 (d, J = 7.0 Hz, 2H), 3.73 (s, 1H), 2.03 (s, 1H), 1.80 (d, J = 10.2 Hz, 2H), 1.75 – 1.67 (m, 1H), 2.11 – 1.92 (m, 1H), 1.57 (d, J = 12.5 Hz, 1H), 1.44 – 1.33 (m, 2H), 1.27 (q, J = 11.1 Hz, 2H), 0.96 (q, J = 12.8, 12.0 Hz, 1H). ES/MS m/z = 565.3 [M+H] + . Intermediate 48: 2,5-dichloro-6-methylpyrimidin-4-amine [0596] 2,4,5-Trichloro-6-methyl-pyrimidine (300 mg, 1.52 mmol) was dissolved in THF (5 mL) and treated with ammonia (7M in MeOH, 0.65 mL, 4.56 mmol). The reaction was allowed to stir at ambient temperature overnight, then was poured into water . The resulting precipitate was collected and dried to afford the title compound as a white crystalline solid. ES/MS m/z: 177.9 [M+H] + . Intermediate 49: 2-chloro-6-methyl-5-(trifluoromethyl)pyrimidin-4-amine [0597] 2,4-Dichloro-6-methyl-5-(trifluoromethyl)pyrimidine (250 mg, 1.08 mmol) was dissolved in THF (3 mL) and treated with ammonia (7M in MeOH, 0.46 mL, 3.25 mmol). The reaction was allowed to stir at ambient temperature overnight, then was poured into water and extracted 3x into EtOAc. The combined extracts were washed with brine, concentrated and purified by flash chromatography using 3:1 EtOAc/EtOH in heptane as eluent to give a mixture of isomers. The first- eluting minor isomer was isolated to give the title compound as a white solid. ES/MS m/z: 211.9 [M+H] + . Intermediate 50: tert-butyl (tert-butoxycarbonyl)(2,5-dichloro-6-cyclopropylpyrimidin-4- yl)carbamate [0598] Step 1. 2,4,5-trichloro-6-cyclopropyl-pyrimidine (115 mg, 0.52 mmol) and DIEA (0.18 mL, 1.0 mmol) were dissolved in DMF (1 mL) and treated with ammonia (7M in MeOH, 0.10 mL, 0.67 mmol). After stirring at ambient temperature 18 hours, the reaction was poured into water and extracted 3x into EtOAc. The combined extracts were washed with brine, concentrated and purified by flash chromatography using 3:1 EtOAc/EtOH in heptane as eluent to give 2,5-dichloro-6- cyclopropylpyrimidin-4-amine as a white solid. ES/MS m/z: 203.9 [M+H] + . [0599] Step 2. DIEA (0.11 mL, 0.65 mmol), di-tert-butyldicarbonate (490 mg, 2.25 mmol), and DMAP (2.5 mg, 0.021 mmol) were added to a suspension of 2,5-dichloro-6-cyclopropylpyrimidin-4- amine (126 mg, 0.62 mmol) in DCM (3 mL). The resulting solution was allowed to stir at ambient temperature. Upon completion, the reaction was poured into aq. NaHCO 3 and extracted 3x into DCM. The combined extracts were concentrated and purified by flash chromatography using EtOAc in hexane as eluent to give the title compound as a colorless oil. ES/MS m/z: 426.0 [M+Na] + . [0600] The Following compounds were synthesized using the procedure as described in Example 226 from the corresponding starting materials.
[0601] The following intermediates were synthesized using the procedure as described in Intermediate 41 from the corresponding starting materials. Intermediate 58: 3-[2- chloro-5- (trifluoromethyl)pyrimidin-4-yl]-1,3-thiazolidine 1,1-dioxide [0602] Step 1.2,4-dichloro-5-(trifluoromethyl)pyrimidine (656 mg, 3.02 mmol), thiazolidine (0.239 ml, 3.02 mmol), and triethylamine (1.26 ml, 9.0 mmol) were stirred in DMF at room temperature for 18 hr. Reaction was then poured into water and extracted with Et 2 O. The organic layer was washed with brine and dried over MgSO 4 . The crude product was purified via prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to provide 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]thiazolidine. ES/MS: m/z 270.50 [M+H] + . [0603] Step 2.3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]thiazolidine (125 mg, 0.464 mmol), NaHCO 3 (195 mg, 2.32 mmol), and 3-Chloroperoxybenzoic acid (260 mg, 1.16 mmol) was stirred in DCM (5.0 ml) at room temperature for 18 hr. Reaction was then poured into sat. aq. NaHCO 3 and extracted with DCM, washed with brine and dried over MgSO 4 . The crude product was purified with column chromatography eluting with EtOAc in hexanes 0-100% to provide 3-[2-chloro-5- (trifluoromethyl)pyrimidin-4-yl]-1,3-thiazolidine 1,1-dioxide. ES/MS: m/z 301.9 [M+H] + . Intermediate 59: Preparation of 2-chloro-5-(3-fluorooxetan-3-yl)pyrimidin-4-amine [0604] Step 1. In a flask were placed 5-bromo-2,4-dichloro-pyrimidine (800 mg, 3.51 mmol) and THF (18 mL). The solution was sparged with nitrogen gas and cooled to -78 °C.2.0 M Isopropylmagnesium chloride in THF (1.93 mL, 3.86 mmol) was added dropwise. After 15 minutes, 3- oxetanone (0.25 mL, 3.86 mmol) was added dropwise and the reaction was warmed to 0 °C. After 1 hour the reaction is quenched with saturated NH4Cl, diluted with water and extracted with EtOAc. The organic layer is concentrated and purified by flash chromatography to give 3-(2,4-dichloropyrimidin-5- yl)oxetan-3-ol.1H NMR (400 MHz, Chloroform-d) δ 8.54 (s, 1H), 5.19 (dd, J = 7.7, 1.0 Hz, 2H), 4.90 (dd, J = 7.7, 1.0 Hz, 2H), 3.50 (s, 1H). [0605] Step 2. In a vial were placed 3-(2,4-dichloropyrimidin-5-yl)oxetan-3-ol (114 mg, 0.52 mmol) and XtalFluor-M (251 mg, 1.03 mmol) in DCE (5.0 mL). The mixture was heated at 75 °C and stirred overnight. The mixture was then cooled to room temperature and purified by column chromatography (Hex/EtOAc) to give 2,4-dichloro-5-(3-fluorooxetan-3-yl)pyrimidine. 1H NMR (400 MHz, Chloroform-d) δ 8.59 (d, J = 1.9 Hz, 1H), 5.29 – 5.04 (m, 4H).19F NMR (376 MHz, Chloroform- d) δ -141.21 (m, 1F). [0606] Step 3. In a vial were placed 2,4-dichloro-5-(3-fluorooxetan-3-yl)pyrimidine (32 mg, 0.14 mmol) and 0.4 M ammonia in dioxane (1.08 mL, 0.43 mmol). The mixture was stirred at room temperature for 4 hours and concentrated to give 2-chloro-5-(3-fluorooxetan-3-yl)pyrimidin-4-amine. ES/MS m/z = 203.9 [M+H]. [0607] The Following compounds were synthesized using the procedure as described in Example 17, with the following modification: 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step.
The Following compounds were synthesized using the procedure as described in Example 168 from the corresponding starting materials.
[0608] The Following compounds were synthesized using the procedure as described in Example 181 from the corresponding starting materials. Example 435: (R)-7-fluoro-2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyr idazin-4-yl)amino)-5- (trifluoromethoxy)pentyl)-6-(5-(trifluoromethyl)pyrimidin-2- yl)isoquinolin-1(2H)-one [0609] The title compound was synthesized as described in Example 135 with the following modification in step 1. 1 H NMR (400 MHz, Acetonitrile-d3) δ 10.44 (s, 1H), 9.15 (s, 2H), 8.27 (d, J = 7.1 Hz, 1H), 8.00 (d, J = 11.6 Hz, 1H), 7.66 (s, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.62 (d, J = 7.4 Hz, 1H), 5.60 – 5.52 (m, 1H), 4.16 – 4.07 (m, 1H), 4.06 – 4.02 (m, 1H), 3.99 – 3.90 (m, 3H), 1.78 – 1.72 (m, 2H), 1.60 (d, J = 4.9 Hz, 2H). ES/MS m/z: 641.2 [M+H] + . [0610] Step 1. To a mixture of (2R)-2-(tert-butoxycarbonylamino)-5-[7-fluoro-1-oxo-6-[5- (trifluoromethyl)pyrimidin-2-yl]-2-isoquinolyl]pentanoic acid (synthesized as described in Example 89, Steps 1-3) (40.0 mg, 0.09 mmol), Silver trifluoromethanesulfonate (70.0 mg, 0.27 mmol), Selectfluor (48.0 mg, 0.14 mmol), potassium fluoride (21.0 mg, 0.36 mmol) in anhydrous EtOAc (1.0 mL) under an atmosphere of nitrogen was added Trifluoromethyltrimethylsilane (38.0 mg, 0.27 mmol) and 2- fluoropyridine (26.0 mg, 0.27 mmol) and the mixture was stirred at room temperature for 12 hr. The mixture was then filtered through a pad of Celite ® and the filtrate was concentrated under reduced pressure. The crude product was purified using flash chromatography eluting with EtOAc in hexanes 0- 100% to afford tert-butyl N-[(1R)-4-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-1- (trifluoromethoxymethyl)butyl]carbamate. ES/MS m/z: 512.9 [M+H] ++ .
Example 436: (rac)-7-fluoro-2-(2-((1S,2S)-2-((6-oxo-5-(trifluoromethyl)-1 ,6-dihydropyridazin-4- yl)amino)cyclohexyl)ethyl)-6-(5-(trifluoromethyl)pyrimidin-2 -yl)isoquinolin-1(2H)-one [0611] Step 1: 2-(2-(1,4-dioxaspiro[4.5]decan-6-yl)ethyl)-6-bromo-7-fluoroi soquinolin- 1(2H)-one was synthesized as described in step 2 of Example 1 using 6-bromo-7-fluoroisoquinolin- 1(2H)-one and 2-(1,4-dioxaspiro[4.5]decan-6-yl)ethyl 4-methylbenzenesulfonate. ES/MS m/z: 410.2 [M+H] + . [0612] Step 2: A solution of 2-(2-(1,4-dioxaspiro[4.5]decan-6-yl)ethyl)-6-bromo-7- fluoroisoquinolin-1(2H)-one (644 mg, 1.57 mmol) and pyridinium p-toluenesulfonate (237 mg, 0.942 mmol) in toluene (15.0 mL) was stirred under reflux for 2 hr. Upon cooling, saturated NaHCO 3 and ethyl acetate were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure. The solid was triturated with a small amount of ethyl acetate and filtered to afford 6-bromo-7-fluoro-2-(2-(2- oxocyclohexyl)ethyl)isoquinolin-1(2H)-one. ES/MS m/z: 366.2 [M+H] + . [0613] Step 3: A solution of 6-bromo-7-fluoro-2-(2-(2-oxocyclohexyl)ethyl)isoquinolin- 1(2H)-one (550 mg, 1.50 mmol) and ammonium formate (947 mg, 15 mmol) in EtOH (15 mL) was stirred at 60 °C for 1 hr. Upon cooling, sodium cyanoborohydride (472 mg, 7.5 mmol) was added and the reaction mixture was stirred at room temperature for 24 hr. The mixture was concentrated under reduced pressure. Ethyl acetate and saturated NaHCO 3 were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure. Crude 2-(2-(2-aminocyclohexyl)ethyl)-6-bromo-7- fluoroisoquinolin-1(2H)-one was used without further purification in the next step. ES/MS m/z: 367.2 [M+H] + . [0614] Step 4: 6-Bromo-7-fluoro-2-(2-(2-((6-oxo-5-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)ami no)cyclohexyl)ethyl)isoquinolin-1(2H)-one was synthesized as described in step 7 of Example 5 using 2-(2-(2-aminocyclohexyl)ethyl)-6-bromo-7- fluoroisoquinolin-1(2H)-one. ES/MS m/z: 659.2 [M+H] + . [0615] Step 5: 7-fluoro-2-(2-(2-((6-oxo-5-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)ami no)cyclohexyl)ethyl)-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one was synthesized as described in step 2 of Example 168 using 6-bromo-7-fluoro-2-(2-(2-((6-oxo-5-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)ami no)cyclohexyl)ethyl)isoquinolin-1(2H)- one. ES/MS m/z: 727.3 [M+H] + . [0616] Step 6: (rac)-7-fluoro-2-(2-((1S,2S)-2-((6-oxo-5-(trifluoromethyl)-1 ,6- dihydropyridazin-4-yl)amino)cyclohexyl)ethyl)-6-(5-(trifluor omethyl)pyrimidin-2-yl)isoquinolin-1(2H)- one was synthesized as described in step 3 of Example 168 using 7-fluoro-2-(2-(2-((6-oxo-5- (trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-d ihydropyridazin-4- yl)amino)cyclohexyl)ethyl)-6-(5-(trifluoromethyl)pyrimidin-2 -yl)isoquinolin-1(2H)-one. The cis diastereoisomer was isolated after purification by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA). ES/MS m/z: 597.3; 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 9.48 (s, 2H), 8.42 (d, J = 7.1 Hz, 1H), 8.00 (d, J = 11.4 Hz, 1H), 7.90 (s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 7.4 Hz, 1H), 5.83 - 5.75 (m, 1H), 4.09 - 3.91 (m, 3H), 1.88 – 1.25 (m, 11H). Example 437: (rac)-7-fluoro-2-(2-((1S,2S)-2-((6-oxo-5-(trifluoromethyl)-1 ,6-dihydropyridazin-4- yl)amino)cyclopentyl)ethyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one [0617] (rac)-7-fluoro-2-(2-((1S,2S)-2-((6-oxo-5-(trifluoromethyl)-1 ,6-dihydropyridazin-4- yl)amino)cyclopentyl)ethyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one was synthesized as described in Example 436 using 2-(1,4-dioxaspiro[4.4]nonan-6-yl)ethyl 4-methylbenzenesulfonate instead of 2-(1,4-dioxaspiro[4.5]decan-6-yl)ethyl 4-methylbenzenesulfonate. ES/MS m/z: 583.3; 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.48 (s, 2H), 8.42 (d, J = 7.1 Hz, 1H), 8.00 (d, J = 11.4 Hz, 1H), 7.88 (s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.08 - 5.98 (m, 1H), 4.28 – 4.18 (m, 1H), 4.11 – 3.89 (m, 2H), 2.16 – 1.43 (m, 9H). Example 438: 6-(4-amino-5-(trifluoromethyl)pyrimidin-2-yl)-7-fluoro-2-(3- ((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)benzyl)iso quinolin-1(2H)-one [0618] The title compound was synthesized as described in Example 91, using 2-chloro-5- (trifluoromethyl)pyrimidin-4-amine instead of 2-iodo-5-(trifluoromethyl)pyrimidine in step 2. 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 9.00 (s, 1H), 8.65 (s, 1H), 8.22 (d, J = 7.0 Hz, 1H), 7.98 (d, J = 11.1 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.47 (s, 1H), 7.41 (m, 1H), 7.33 – 7.19 (m, 3H), 6.82 (d, J = 7.4 Hz, 1H), 5.22 (s, 2H). ES/MS m/z: 591.7 [M+H]. Example 439: (R)-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6 -dihydropyridazin-4- yl)amino)pentyl)-7-fluoro-6-(5,6,7,8-tetrahydro-[1,2,4]triaz olo[1,5-a]pyrazin-2-yl)isoquinolin- 1(2H)-one [0619] The title compound was synthesized as described in Example 168, using tert-butyl 2- bromo-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazine-7(8H)-carbo xylate instead of 2-iodo-5- (trifluoromethyl)pyrimidine in step 2. 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.64 (s, 2H), 8.34 (d, J = 7.0 Hz, 1H), 7.99 (m, 2H), 7.49 (d, J = 7.4 Hz, 1H), 6.89 – 6.45 (m, 2H), 6.44 – 6.34 (m, 1H), 4.65 (s, 2H), 4.49 (m, 2H), 4.26 (m, 1H), 4.05 – 3.90 (m, 4H), 3.79 (m, 2H), 1.87 – 1.45 (m, 4H). ES/MS m/z: 598.5 [M+H]. Example 440: Preparation of (S)-6-(5-(difluoromethoxy)pyridin-2-yl)-8-fluoro-2-(4-((6-ox o-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)iso quinolin-1(2H)-one [0620] Step 1. In a 100 mL round bottomed single necked flask were placed 1-(tert-butyl) 2- methyl (2S,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate (3.0 g, 12.0 mmol) and PPh 3 (4.8 g, 18.0 mmol) in THF (20.0 mL). The mixture was cooled to 0 °C and to this mixture were added a solution of diisopropyl azodicarboxylate (3.6 mL, 18.0 mmol) in THF (3.0 mL) followed by the solution of diphenylphosphoryl azide (3.9 mL, 18.0 mmol) in THF (3.0 mL). The resulting mixture was warmed to room temperature and stirred for 16 hr. The reaction was then concentrated and purified by flash chromatography (100% Hexane to 100% EtOAc then 100% DCM to 100% MeOH) to give 1-(tert-butyl) 2-methyl (2S,3S)-3-azidopyrrolidine-1,2-dicarboxylate. [0621] Step 2. In a 100 mL round bottomed single necked flask was placed 1-(tert-butyl) 2- methyl (2S,3S)-3-azidopyrrolidine-1,2-dicarboxylate (2.9 g, 11.0 mmol) in MeOH (15.0 mL). The solution was purged with N 2 followed by the addition of Pd/C (10 %, 340 mg, 0.320 mmol). The mixture was stirred at room temperature under H 2 at 1 ATM for 16 hr, and filtered through a pad of Celite ® . The filtrate was concentrated and carried onto the next step without further purification. ES/MS m/z: 245.1 [M+H]. [0622] Step 3. To a mixture of 1-(tert-butyl) 2-methyl (2S,3S)-3-aminopyrrolidine-1,2- dicarboxylate (660 mg, 2.7 mmol) and DIPEA (0.94 mL, 5.4 mmol) was added THF (3.0 mL). The mixture was cooled to 0 °C followed by the addition of benzyl chloroformate (50% in xylene (v/v), 1.2 mL, 4.1 mmol). The mixture was slowly warmed to room temperature and stirred at this temperature for 16 h. Upon completion, the mixture was loaded onto the Silica pre-packed cartridge and purified by flash chromatography (100% Hexane to 100% EtOAc then 100% DCM to 100% MeOH) to give 1-(tert- butyl) 2-methyl (2S,3S)-3-(((benzyloxy)carbonyl)amino)pyrrolidine-1,2-dicarb oxylate. ES/MS m/z: 379.1 [M+H]. [0623] Step 4. In a 100 mL round bottomed single necked flask was placed 1-(tert-butyl) 2- methyl (2S,3S)-3-(((benzyloxy)carbonyl)amino)pyrrolidine-1,2-dicarb oxylate (2.7 g, 7.1 mmol) in THF (30 mL), and the solution was cooled to 0 o C. To this was added lithium borohydride (2.0 M in THF, 8.9 mL, 18 mmol). The mixture was warmed to room temperature and stirred for 3 h. Then, it was quenched with sat. NaHCO 3 and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% Hexane to 100% EtOAc then 100% DCM to 100% MeOH) to give tert-butyl (2S,3S)-3-(((benzyloxy)carbonyl)amino)-2- (hydroxymethyl)pyrrolidine-1-carboxylate. ES/MS m/z: 351.1 [M+H]. [0624] Step 5. In a 100 mL round bottomed single necked flask were placed tert-butyl (2S,3S)-3-(((benzyloxy)carbonyl)amino)-2-(hydroxymethyl)pyrr olidine-1-carboxylate (2.2 g, 6.3 mmol), triethylamine (8.8 mL, 62 mmol), p-toluenesulfonyl chloride (2.4 g, 13 mmol), and 4- dimethylaminopyridine (77 mg, 0.63 mmol)) in DCM (30 mL). The mixture was stirred at room temperature for 2 hr. The mixture was concentrated and purified by flash chromatography (100% Hexane to 100% EtOAc then 100% DCM to 100% MeOH) to give tert-butyl (2S,3S)-3- (((benzyloxy)carbonyl)amino)-2-((tosyloxy)methyl)pyrrolidine -1-carboxylate. ES/MS m/z: 505.2 [M+H]. [0625] Step 6. In a 100 mL round bottomed single necked flask was placed tert-butyl (2S,3S)- 3-(benzyloxycarbonylamino)-2-(p-tolylsulfonyloxymethyl)pyrro lidine-1-carboxylate (2.7 g, 5.4 mmol) in DMSO (35 mL). To this was added sodium cyanide (1.0 g, 21 mmol). The mixture was stirred at room temperature for 7 days. Then, it was quenched with sat. NaHCO 3 and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% Hexane to 100% EtOAc then 100% DCM to 100% MeOH) to give tert-butyl (2R,3S)-3-(((benzyloxy)carbonyl)amino)-2-(cyanomethyl)pyrrol idine-1-carboxylate. ES/MS m/z: 360.1 [M+H]. [0626] Step 7. In a 100 mL round bottomed single necked flask was placed tert-butyl (2R,3S)-3-(benzyloxycarbonylamino)-2-(cyanomethyl)pyrrolidin e-1-carboxylate (1.5 g, 4.2 mmol) in DCM (30 mL), and the mixture was cooled to 0 °C. To this was added diisobutylaluminum hydride (1.0 M in DCM, 17 mL, 17 mmol), and the resulting mixture was stirred at 0 °C for 2 hr. The mixture was quenched with potassium sodium tartrate salt solution and filtered through a pad of Celite ® . The filtrate was extracted with DCM, and the combined organic layers were washed with water, dried (Na 2 SO 4 ), concentrated, and carried onto the next step without further purification. ES/MS m/z: 363.1 [M+H]. [0627] Step 8. In a 100 mL, round bottomed, single necked flask was placed tert-butyl (2R,3S)-3-(((benzyloxy)carbonyl)amino)-2-(2-oxoethyl)pyrroli dine-1-carboxylate (1.3 g, 3.6 mmol) in MeOH (15 mL), and the solution was cooled to 0 °C. To this was added sodium borohydride (0.27 g, 7.2 mmol). The mixture was warmed to room temperature and stirred for 2 hr. Then, it was cooled to 0 °C and quenched with sat. NaHCO 3 and extracted with DCM. The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), and purified by flash chromatography (100% Hexane to 100% EtOAc then 100% DCM to 100% MeOH) to give tert-butyl (2R,3S)-3-(((benzyloxy)carbonyl)amino)- 2-(2-hydroxyethyl)pyrrolidine-1-carboxylate. ES/MS m/z: 365.1 [M+H]. [0628] Step 9. In a vial were placed tert-butyl (2R,3S)-3-(((benzyloxy)carbonyl)amino)-2-(2- hydroxyethyl)pyrrolidine-1-carboxylate (30 mg, 0.082 mmol), triethylamine (83 mg, 0.82 mmol), 4- dimethylaminopyridine (0.50 mg, 0.0041 mmol), and p-toluenesulfonyl chloride (19 mg, 0.099 mmol) in DCM (2.0 mL). After the mixture was stirred at room temperature for 24 hr, it was loaded onto the Silica pre-packed cartridge and purified by flash chromatography (100% Hexane to 100% EtOAc then 100% DCM to 100% MeOH) to give tert-butyl (2R,3S)-3-(((benzyloxy)carbonyl)amino)-2-(2- (tosyloxy)ethyl)pyrrolidine-1-carboxylate. ES/MS m/z: 519.2 [M+H]. [0629] Step 10. In a vial were placed tert-butyl (2R,3S)-3-(benzyloxycarbonylamino)-2-[2-(p- tolylsulfonyloxy)ethyl]pyrrolidine-1-carboxylate (15 mg, 0.029 mmol), 7-fluoro-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one (18 mg, 0.058 mmol), and cesium carbonate (28 mg, 0.087 mmol) in DMF (2.0 mL). The mixture was stirred at room temperature for 72 hr and was loaded onto the Silica pre-packed cartridge and purified by flash chromatography (100% DCM to 100% MeOH) to give tert-butyl (2R,3S)-3-(((benzyloxy)carbonyl)amino)-2-(2-(7-fluoro-1-oxo- 6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-2(1H)-yl)ethyl)p yrrolidine-1-carboxylate. ES/MS m/z: 656.4 [M+H]. [0630] Step 11. In a vial was placed tert-butyl (2R,3S)-3-(((benzyloxy)carbonyl)amino)-2-(2- (7-fluoro-1-oxo-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquin olin-2(1H)-yl)ethyl)pyrrolidine-1- carboxylate (9.0 mg, 0.014 mmol) in MeOH (2.0 mL). The solution purged with N 2 followed by the addition of Pd/C (10 %, 2.5 mg, 0.0023 mmol). Then, the mixture was stirred at room temperature under H 2 at 1 ATM for 16 h and filtered through a pad of Celite. The filtrate was concentrated and carried onto the next step without further purification. ES/MS m/z: 656.4 [M+H]. [0631] Step 12. In a vial were placed tert-butyl (2R,3S)-3-amino-2-(2-(7-fluoro-1-oxo-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-2(1H)-yl)ethyl)p yrrolidine-1-carboxylate (8.0 mg, 0.015 mmol), 5-chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl )pyridazin-3-one (6.1 mg, 0.018 mmol), and N,N-diisopropylethylamine (0.027 mL, 0.15 mmol) in DMF (1.0 mL). After the mixture was stirred at 80 °C for 2 hr, it was loaded onto the Silica pre-packed cartridge and purified by flash chromatography (100% Hexane to 100% EtOAc then 100% DCM to 100% MeOH) to give tert-butyl (2R,3S)-2-(2-(7-fluoro-1-oxo-6-(5-(trifluoromethyl)pyrimidin -2-yl)isoquinolin-2(1H)-yl)ethyl)-3-((6- oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1,6-dihydropyridazin-4- yl)amino)pyrrolidine-1-carboxylate. ES/MS m/z: 814.3 [M+H]. [0632] Step 13. In a vial was placed tert-butyl (2R,3S)-2-(2-(7-fluoro-1-oxo-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-2(1H)-yl)ethyl)- 3-((6-oxo-5-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)ami no)pyrrolidine-1-carboxylate (5.0 mg, 0.0061 mmol) in DCM (1 mL). To this was added TFA (0.0093 mL, 0.12 mmol) and the mixture was stirred at room temperature for 1 hr. The reaction was concentrated and re-dissolved in MeOH (1.0 mL) followed by the addition of ethylenediamine (0.0087 mL, 0.13 mmol). After the mixture was stirred at room temperature for 1 hr, it was concentrated and purified by reverse phase chromatography to give 7- fluoro-2-(2-((2R,3S)-3-((6-oxo-5-(trifluoromethyl)-1,6-dihyd ropyridazin-4-yl)amino)pyrrolidin-2- yl)ethyl)-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquinolin-1 (2H)-one. 1 H NMR (400 MHz, Methanol-d4) δ 9.30 (s, 2H), 8.46 (d, J = 7.0 Hz, 1H), 8.16 (d, J = 11.3 Hz, 1H), 7.92 (s, 1H), 7.44 (d, J = 7.4 Hz, 1H), 6.88 (d, J = 7.4 Hz, 1H), 4.41 (m, 2H), 4.09 (m, 1H), 3.77 – 3.63 (m, 1H), 3.60 – 3.39 (m, 2H), 2.59 – 2.50 (m, 1H), 2.42 – 2.28 (m, 1H), 2.24 – 2.13 (m, 1H), 2.01 (m, 1H). ES/MS m/z: 584.1 [M+H].
Intermediate 60: (rac) 2-((3R,4R)-4-((tert-butoxycarbonyl)amino)tetrahydrofuran-3-y l)ethyl 4- methylbenzenesulfonate [0633] Step 1. (rac)tert-Butyl ((3R,4S)-4-(hydroxymethyl)tetrahydrofuran-3-yl)carbamate (2.0 g, 9.2 mmol) was dissolved in DCM (30 mL) in a flask and cooled to 0 °C under N 2 . DMSO was added (1.96 mL, 27.6 mmol), followed by triethylamine (3.85 mL, 27.6 mmol), then sulfur trioxide pyridine complex (2.93 g, 18.4 mmol). The N 2 line was removed and the reaction was allowed to gradually reach to ambient temperature and stirred overnight. Upon completion, water was added and the reaction was poured into aq. NH4Cl and extracted 3x into DCM. The combined extracts were concentrated and purified by flash chromatography using EtOAc in hexane as eluent and ELS detection to give (rac) tert-butyl ((3R,4R)-4-formyltetrahydrofuran-3-yl)carbamate as a colorless oil. ES/MS m/z: 238.1 [M+Na] + . [0634] Step 2. Methyl(triphenyl)phosphonium bromide (1.08 g, 3.02 mmol) was suspended in THF (6.0 mL) and cooled in an ice bath under N 2 . NaHMDS (1M solution in THF; 3.48 mL, 3.48 mmol) was added gradually. The resulting yellow suspension was stirred at ambient temperature for one hour, then was cooled again to 0 °C. A solution of (rac) tert-butyl ((3R,4R)-4-formyltetrahydrofuran-3- yl)carbamate (500 mg, 2.32 mmol) in THF (3 mL) was added portionwise. Following addition, the N 2 line was removed and the reaction was allowed to reach ambient temperature and stirred overnight. Upon completion, water was added and the reaction was poured into aq. NH 4 Cl and extracted 3x into EtOAc. The combined extracts were washed with brine, concentrated and purified by flash chromatography using EtOAc in hexane as eluent and ELS detection to give (rac) tert-butyl ((3R,4R)-4- vinyltetrahydrofuran-3-yl)carbamate as a colorless oil. ES/MS m/z: 236.2 [M+Na] + . [0635] Step 3. (rac) tert-butyl ((3R,4R)-4-vinyltetrahydrofuran-3-yl)carbamate (370 mg, 1.73 mmol) was combined with chlorotris(triphenylphosphine)rhodium(I) (80 mg, 0.089 mmol) in THF (6 mL) in a vial and cooled to 0 °C under N 2 . Catecholborane (1M solution in THF; 3.47 mL, 3.47 mmol) was added dropwise. Following addition, the N 2 line was removed and the reaction was allowed to attain ambient temperature and stir overnight. The reaction was cooled again to 0 o C, then treated with aq. NaHCO 3 (3 mL), H 2 O2 (30% aqueous; 1.0 mL), and water (3 mL). The reaction was allowed to attain ambient temperature. Upon completion, the reaction was poured into aq. NaHCO 3 and extracted 3x into EtOAc. The combined extracts were washed with brine, concentrated and purified by flash chromatography using EtOAc in hexane as eluent and ELS detection to give (rac) tert-butyl ((3R,4R)-4- (2-hydroxyethyl)tetrahydrofuran-3-yl)carbamate as an amber oil. ES/MS m/z: 254.2 [M+Na] + . [0636] Step 4. (rac) tert-butyl ((3R,4R)-4-(2-hydroxyethyl)tetrahydrofuran-3-yl)carbamate was treated following Example 1, Step 1 to provide (rac) 2-((3R,4R)-4-((tert- butoxycarbonyl)amino)tetrahydrofuran-3-yl)ethyl 4-methylbenzenesulfonate, ES/MS m/z: 408.3 [M+Na] + . Example 441: (rac) 6-(4-amino-5-(trifluoromethyl)pyrimidin-2-yl)-7-fluoro-2-(2- ((3R,4R)-4-((6- oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)tetr ahydrofuran-3-yl)ethyl)isoquinolin- 1(2H)-one [0637] The title compound was synthesized as described in Example 17, using (rac) 2- ((3R,4R)-4-((tert-butoxycarbonyl)amino)tetrahydrofuran-3-yl) ethyl 4-methylbenzenesulfonate and 6- bromo-7-fluoro-2H-isoquinolin-1-one in Step 1, and 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine instead of 2-bromo-5-(difluoromethoxy)pyridine in Step 3. 1 H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.65 (s, 1H), 8.19 (d, J = 7.0 Hz, 1H), 7.95 (d, J = 11.1 Hz, 1H), 7.91 (s, 1H), 8.09 – 6.83 (m, 2H), 7.53 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.65 – 6.58 (m, 1H), 4.24 (p, J = 6.2 Hz, 1H), 4.09 – 3.91 (m, 4H), 3.55 (dd, J = 8.9, 5.4 Hz, 1H), 3.46 (dd, J = 8.7, 6.9 Hz, 1H), 2.38 (td, J = 13.2, 6.4 Hz, 1H), 1.96 (dq, J = 13.3, 7.0 Hz, 1H), 1.85 – 1.71 (m, 1H). ES/MS m/z: 600.1 [M+H] + .
Example 442: 7-fluoro-2-((3S,4S)-3-hydroxy-4-((6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4- yl)amino)pentyl)-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoqui nolin- [0638] Step 1. Benzyl (3-hydroxypent-4-en-2-yl)carbamate, isolated as a mixture of isomers from a literature preparation (17 g, 72.2 mmol), was dissolved in THF (119 mL). Imidazole (9.84 g, 144 mmol) was added, followed by TBSCl (13.0 g, 86.7 mmol). After stirring for 2 hours, the reaction was poured into water (100 mL) and extracted with DCM (2 x 100 mL). The combined extracts were washed with brine (100 mL), dried over Na 2 SO 4 , filtered, and concentrated. Purification by flash chromatography using EtOAc in petroleum ether as eluent and ELS detection provided benzyl (3-((tert- butyldimethylsilyl)oxy)pent-4-en-2-yl)carbamate as a mixture of isomers. ES/MS m/z: 350.2 [M+H] + . [0639] Step 2. Benzyl (3-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)carbamate was separated by reverse phase chiral prep-SFC (Chiralpak AD, 0.1%NH 3 H 2 O in MeOH) to give benzyl ((2S,3S)-3-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)carb amate, ES/MS m/z: 350.2 [M+H] + . [0640] Step 3. Benzyl ((2S,3S)-3-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)carb amate was treated following the method used in Intermediate 60, Step 3 to provide benzyl ((2S,3S)-3-((tert- butyldimethylsilyl)oxy)-5-hydroxypentan-2-yl)carbamate, ES/MS m/z: 368.3 [M+H] + . [0641] Step 4. Benzyl ((2S,3S)-3-((tert-butyldimethylsilyl)oxy)-5-hydroxypentan-2- yl)carbamate was treated following the method used in Example 1, Step 1 to provide (3S,4S)-4- (((benzyloxy)carbonyl)amino)-3-((tert-butyldimethylsilyl)oxy )pentyl 4-methylbenzenesulfonate, ES/MS m/z: 522.2 [M+H] + . [0642] Step 5. (3S,4S)-4-(((Benzyloxy)carbonyl)amino)-3-((tert- butyldimethylsilyl)oxy)pentyl 4-methylbenzenesulfonate was treated following the method used in Example 1, Step 2 using 6-bromo-7-fluoro-2H-isoquinolin-1-one instead of 6-bromo-2H-isoquinolin-1- one to provide benzyl ((2S,3S)-5-(6-bromo-7-fluoro-1-oxoisoquinolin-2(1H)-yl)-3-(( tert- butyldimethylsilyl)oxy)pentan-2-yl)carbamate, ES/MS m/z: 591.2 [M+H] + . [0643] Step 6. Benzyl ((2S,3S)-5-(6-bromo-7-fluoro-1-oxoisoquinolin-2(1H)-yl)-3-(( tert- butyldimethylsilyl)oxy)pentan-2-yl)carbamate was treated following the method used in Example 17, Step 3, using 2-Iodo-5-(trifluoromethyl)pyrimidine instead of 2-bromo-5-(difluoromethoxy)pyridine. XPhos Pd G4 (0.1 equiv) was added along with the aryl halide and the reaction was purified by flash chromatography to give benzyl ((2S,3S)-3-((tert-butyldimethylsilyl)oxy)-5-(7-fluoro-1-oxo- 6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-2(1H)-yl)pentan- 2-yl)carbamate. ES/MS m/z: 659.3 [M+H] + . [0644] Step 7. A solution of benzyl ((2S,3S)-3-((tert-butyldimethylsilyl)oxy)-5-(7-fluoro-1- oxo-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquinolin-2(1H)-y l)pentan-2-yl)carbamate (80 mg, 0.121 mmol) in EtOH (2 mL) and EtOAc (2 mL) was added to 10% Pd/C in a flask purged with N 2 . The flask was evacuated and purged with N 2 , then fitted with a balloon filled with H 2 and stirred under an H 2 atmosphere. Upon completion, the reaction was evacuated and purged with N 2 , then filtered through a celite plug. The filtrate was concentrated to give 2-((3S,4S)-4-amino-3-((tert- butyldimethylsilyl)oxy)pentyl)-7-fluoro-6-(5-(trifluoromethy l)pyrimidin-2-yl)isoquinolin-1(2H)- one, which was used in the next step without purification. ES/MS m/z: 525.3 [M+H] + . [0645] Step 8. 2-((3S,4S)-4-amino-3-((tert-butyldimethylsilyl)oxy)pentyl)-7 -fluoro-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one was treated following the method used in Example 1, Step 5 to give 2-((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-((6-oxo-5-(tri fluoromethyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4- yl)amino)pentyl)-7-fluoro-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one, ES/MS m/z: 817.3 [M+H] + . [0646] Step 9. 2-((3S,4S)-3-((tert-Butyldimethylsilyl)oxy)-4-((6-oxo-5-(tri fluoromethyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl )amino)pentyl)-7-fluoro-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one was subjected to the conditions in Example 1, Step 6. After concentration, the residue was subjected to aqueous workup to give crude 2-((3S,4S)-3- ((tert-butyldimethylsilyl)oxy)-4-((6-oxo-5-(trifluoromethyl) -1,6-dihydropyridazin-4- yl)amino)pentyl)-7-fluoro-6-(5-(trifluoromethyl)pyrimidin-2- yl)isoquinolin-1(2H)-one, which was used directly in the subsequent step. ES/MS m/z: 687.3 [M+H] + . [0647] Step 10. 2-((3S,4S)-3-((tert-Butyldimethylsilyl)oxy)-4-((6-oxo-5-(tri fluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)pentyl)-7-fluoro-6-(5-(trifl uoromethyl)pyrimidin-2-yl)isoquinolin- 1(2H)-one (43 mg, 0.062 mmol) was dissolved in THF (0.6 mL) and treated with TBAF (1M solution in THF; 0.081 mL, 0.081 mmol). After 1 hour, the reaction was poured into aq. NaHCO 3 and extracted 3x into EtOAc. The combined extracts were washed with brine, concentrated, and purified via reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford the title compound, 7-fluoro-2-((3S,4S)-3- hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4 -yl)amino)pentyl)-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.48 (s, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.91 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.27 – 6.17 (m, 1H), 4.22 – 4.10 (m, 2H), 4.08 – 3.90 (m, 2H), 3.57 (dt, J = 9.5, 3.4 Hz, 1H), 1.95 – 1.82 (m, 1H), 1.81 – 1.67 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H). ES/MS m/z: 573.3 [M+H] + . Example 443: 7-fluoro-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1,6-dihyd ropyridazin-4- yl)amino)cyclopentyl)methyl)-6-(5-(trifluoromethyl)pyrimidin -2-yl)isoquinolin-1(2H)-one [0648] The title compound was prepared following the method used for Example 17, starting with ((1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)methyl 4-methylbenzenesulfonate and 6- bromo-7-fluoro-2H-isoquinolin-1-one in Step 1 and using 2-iodo-5-(trifluoromethyl)pyrimidine instead of 2-bromo-5-(difluoromethoxy)pyridine in Step 3. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.48 (s, 2H), 8.45 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 11.4 Hz, 1H), 7.89 (s, 1H), 7.55 (d, J = 7.3 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.58 – 6.50 (m, 1H), 4.18 (dt, J = 15.5, 7.2 Hz, 1H), 4.06 (dd, J = 13.0, 7.2 Hz, 1H), 3.97 (dd, J = 13.0, 7.6 Hz, 1H), 2.50 – 2.37 (m, 1H), 2.16 – 1.95 (m, 2H), 1.78 – 1.61 (m, 2H), 1.60 – 1.41 (m, 2H). ES/MS m/z: 569.3 [M+H] + . Intermediate 61: ((1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)methyl 4- methylbenzenesulfonate [0649] The title compound was prepared following Example 1, Step 1, starting with tert-butyl N-[(1S,3R)-3-(hydroxymethyl)cyclopentyl]carbamate to provide ((1R,3S)-3-((tert- butoxycarbonyl)amino)cyclopentyl)methyl 4-methylbenzenesulfonate. ES/MS m/z: 392.2 [M+Na] + . Example 444: 6-(4-amino-5-(trifluoromethyl)pyrimidin-2-yl)-7-fluoro-2-((( 1R,3S)-3-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclopenty l)methyl)isoquinolin-1(2H)-one [0650] The title compound was prepared following the method used for Example 17, starting with ((1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)methyl 4-methylbenzenesulfonate and 6- bromo-7-fluoro-2H-isoquinolin-1-one in Step 1 and using 2-chloro-5-(trifluoromethyl)pyrimidin-4- amine instead of 2-bromo-5-(difluoromethoxy)pyridine in Step 3. 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.65 (s, 1H), 8.21 (d, J = 7.0 Hz, 1H), 7.97 (d, J = 11.1 Hz, 1H), 7.89 (s, 1H), 8.37 – 7.21 (br. m, 2H), 7.52 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.59 – 6.50 (m, 1H), 4.17 (h, J = 7.7 Hz, 1H), 4.05 (dd, J = 13.0, 7.2 Hz, 1H), 3.96 (dd, J = 13.0, 7.6 Hz, 1H), 2.42 (dt, J = 14.7, 7.3 Hz, 1H), 2.16 – 1.95 (m, 2H), 1.78 – 1.60 (m, 2H), 1.60 – 1.40 (m, 2H). ES/MS m/z: 584.3 [M+H] + . Example 445: 7-fluoro-2-((3R,4S)-3-hydroxy-4-((6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4- yl)amino)pentyl)-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoqui nolin-1(2H)-one [0651] The title compound was prepared according to the procedure of Example 442, using benzyl ((2S,3R)-3-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)carb amate isolated from Step 2. 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.48 (s, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.04 (d, J = 11.4 Hz, 1H), 7.92 (s, 1H), 7.53 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 7.4 Hz, 1H), 6.32 – 6.21 (m, 1H), 4.17 (ddd, J = 13.3, 8.2, 5.2 Hz, 1H), 4.08 – 3.93 (m, 2H), 3.68 – 3.59 (m, 2H), 1.96 – 1.83 (m, 1H), 1.80 – 1.66 (m, 1H), 1.11 (d, J = 6.4 Hz, 3H). ES/MS m/z: 573.3 [M+H] + . Example 446: 7-fluoro-2-(((1S,3R)-3-((6-oxo-5-(trifluoromethyl)-1,6-dihyd ropyridazin-4- yl)amino)cyclopentyl)methyl)-6-(5-(trifluoromethyl)pyrimidin -2-yl)isoquinolin-1(2H)-one [0652] The title compound was prepared following the method used for Example 17, starting with ((1S,3R)-3-((tert-butoxycarbonyl)amino)cyclopentyl)methyl 4-methylbenzenesulfonate and 6- bromo-7-fluoro-2H-isoquinolin-1-one in Step 1 and using 2-iodo-5-(trifluoromethyl)pyrimidine instead of 2-bromo-5-(difluoromethoxy)pyridine in Step 3. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.48 (s, 2H), 8.45 (d, J = 7.1 Hz, 1H), 8.04 (d, J = 11.4 Hz, 1H), 7.89 (s, 1H), .55 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.59 – 6.51 (m, 1H), 4.18 (h, J = 7.7 Hz, 1H), 4.06 (dd, J = 13.0, 7.2 Hz, 1H), 3.97 (dd, J = 12.8, 7.6 Hz, 1H), 2.50 – 2.37 (m, 1H), 2.16 – 1.95 (m, 2H), 1.89 – 1.61 (m, 2H), 1.60 – 1.38 (m, 2H). ES/MS m/z: 569.3 [M+H] + . Intermediate 62: ((1S,3R)-3-((tert-butoxycarbonyl)amino)cyclopentyl)methyl 4- methylbenzenesulfonate [0653] The title compound was prepared following Example 1, Step 1, starting with tert- butyl N-[(1R,3S)-3-(hydroxymethyl)cyclopentyl]carbamate to provide ((1S,3R)-3-((tert- butoxycarbonyl)amino)cyclopentyl)methyl 4-methylbenzenesulfonate. ES/MS m/z: 392.1 [M+Na] + . Example 447: 6-(4-amino-5-(trifluoromethyl)pyrimidin-2-yl)-7-fluoro-2-((( 1S,3R)-3-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclopenty l)methyl)isoquinolin-1(2H)-one [0654] The title compound was prepared following the method used for Example 17, starting with ((1S,3R)-3-((tert-butoxycarbonyl)amino)cyclopentyl)methyl 4-methylbenzenesulfonate and 6- bromo-7-fluoro-2H-isoquinolin-1-one in Step 1 and using 2-chloro-5-(trifluoromethyl)pyrimidin-4- amine instead of 2-bromo-5-(difluoromethoxy)pyridine in Step 3. 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.65 (s, 1H), 8.21 (d, J = 7.0 Hz, 1H), 7.97 (d, J = 11.1 Hz, 1H), 7.89 (s, 1H), 8.10 – 7.37 (m, 3H), 7.52 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.59 – 6.51 (m, 1H), 4.21 – 4.14 (m, 1H), 4.05 (dd, J = 13.0, 7.2 Hz, 1H), 3.96 (dd, J = 13.0, 7.6 Hz, 1H), 2.48 – 2.36 (m, 1H), 2.16 – 1.95 (m, 2H), 1.88 – 1.60 (m, 2H), 1.60 – 1.38 (m, 2H). ES/MS m/z: 584.3 [M+H] + .
Example 448: 7-(5-chloropyrimidin-2-yl)-6-fluoro-3-(2-((1R,2S)-2-((6-oxo- 5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)cyclopentyl)ethyl)quinazolin-4(3 H)-one [0655] The title compound was synthesized as described in Example 17, using 2-((1R,2S)-2- ((tert-butoxycarbonyl)amino)cyclopentyl)ethyl 4-methylbenzenesulfonate and 7-bromo-6-fluoro-1H- quinazolin-4-one in Step 1, and 2,5-dichloropyrimidine instead of 2-bromo-5-(difluoromethoxy)pyridine in Step 3. 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 9.16 (s, 2H), 8.46 (s, 1H), 8.27 (d, J = 6.8 Hz, 1H), 7.96 (d, J = 10.5 Hz, 1H), 7.94 – 7.88 (m, 1H), 6.52 – 6.43 (m, 1H), 4.09 – 3.93 (m, 2H), 3.85 (p, J = 7.9 Hz, 1H), 2.10 – 1.85 (m, 4H), 1.73 – 1.58 (m, 3H), 1.57 – 1.44 (m, 1H), 1.29 (dq, J = 12.0, 8.6, 8.2 Hz, 1H). ES/MS m/z: 550.1 [M+H] + . Example 449: 7-(4-amino-5-chloropyrimidin-2-yl)-6-fluoro-3-(2-((1R,2S)-2- ((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclopenty l)ethyl)quinazolin-4(3H)-one [0656] The title compound was synthesized as described in Example 17, using 2-((1R,2S)-2- ((tert-butoxycarbonyl)amino)cyclopentyl)ethyl 4-methylbenzenesulfonate and 7-bromo-6-fluoro-1H- quinazolin-4-one in Step 1, and tert-butyl N-tert-butoxycarbonyl-N-(2,5-dichloropyrimidin-4- yl)carbamate instead of 2-bromo-5-(difluoromethoxy)pyridine in Step 3. 1H NMR (400 MHz, DMSO- d6) δ 12.45 (s, 1H), 8.44 (s, 1H), 8.43 (s, 1H), 8.13 (d, J = 6.7 Hz, 1H), 7.92 (s, 1H), 7.89 (d, J = 10.4 Hz, 1H), 7.84 – 7.19 (m, 2H), 6.56 – 6.41 (m, 1H), 4.09 – 3.94 (m, 3H), 2.06 – 1.86 (m, 4H), 1.74 – 1.58 (m, 3H), 1.57 – 1.45 (m, 1H), 1.35 – 1.21 (m, 1H). ES/MS m/z: 565.1 [M+H] + . Example 450: Preparation of 7-fluoro-2-[2-[(1R,2S)-2-[[6-oxo-5-(trifluoromethyl)-1H-pyri dazin-4- yl]amino]cyclohexyl]ethyl]-6-[5-(trifluoromethyl)pyrimidin-2 -yl]isoquinolin-1-one [0657] Step 1. In a flask was placed (1S,2S)-2-(tert- butoxycarbonylamino)cyclohexanecarboxylic acid (2000 mg, 8.2 mmol), and triethylamine (3.4 mL, 24.7 mmol) in THF (40 mL). The mixture was cool to 0 °C and placed under nitrogen atmosphere. To this solution was added ethyl chloroformate (1.2 mL, 12.3 mmol) and the reaction was stirred for 30 minutes at 0 °C. The mixture was then filtered to remove the precipitated triethylamine hydrochloride. The filtrate containing the mixed anhydride was slowly added to a stirred suspension of sodium borohydride (933 mg, 24.7 mmol) in 20% aqueous THF (10.0 mL) maintained at 10 °C. After the mixture was stirred for 30 minutes, it was quenched by the slow addition of sat. aq. NH4Cl. The mixture was then extracted with EtOAc, washed with 2M NaOH solution, washed with brine, dried (MgSO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[(1S,2S)-2- (hydroxymethyl)cyclohexyl]carbamate. ES/MS: m/z 230.08 [M+H] + . [0658] Step 2. Iodine (2.02 g, 7.96 mmol) was added to a solution of triphenylphosphine (2.09 g, 7.96 mmol) and imidazole (0.542 g, 7.96 mmol) in DCM (27 ml). The mixture is stirred at room temperature until a solution forms (30 minutes) then tert-butyl N-[(1S,2S)-2- (hydroxymethyl)cyclohexyl]carbamate (1.522 g, 6.64 mmol) is added. After stirring the mixture at room temperature for 18 h the mixture is filtered, and the filtrate evaporated. The residue is dissolved in EtOAc and washed with sat. aq. sodium bisulfite and then brine. The organic phase is dried over MgSO 4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography using a gradient of EtOAc/hexane (0 to 100%) as eluent to give tert-butyl N-[(1S,2S)-2- (iodomethyl)cyclohexyl]carbamate. ES/MS: m/z 340.02 [M+H] + . [0659] Step 3. To a suspension of tert-butyl N-[(1S,2S)-2-(iodomethyl)cyclohexyl]carbamate (1841 mg, 5.43 mmol) in acetonitrile (53.0 ml) was added n-Bu 4 NCN at RT and was stirred for 2 hr. The reaction was then diluted with water and the mixture was extracted with EtOAc. Organic phases were washed with water and brine then dried (MgSO 4 ) and concentrated to afford tert-butyl N-[(1S,2R)- 2-(cyanomethyl)cyclohexyl]carbamate which was used without further purification ES/MS: m/z 239.09 [M+H] + . [0660] Step 4. Aqueous NaOH (5.12 g, 128 mmol, 6 M) was added to a solution of tert-butyl N-[(1S,2R)-2-(cyanomethyl)cyclohexyl]carbamate (1290 mg, 5.41 mmol) in EtOH (21 ml). The suspension was heated at 80 °C ON. Upon completion the reaction was diluted with EtOAc and extracted. Aqueous phase was then acidified with 6 M HCl to pH 4-5 and extracted with EtOAc (2x100 mL), dried (MgSO 4 ), and concentrated to afford 2-[(1R,2S)-2-(tert- butoxycarbonylamino)cyclohexyl]acetic acid which was used without further purification. ES/MS: m/z 258.09 [M+H] + . [0661] Step 5. In a flask was placed 2-[(1R,2S)-2-(tert- butoxycarbonylamino)cyclohexyl]acetic acid (833 mg, 3.24 mmol), and triethylamine (1.35 mL, 9.71 mmol) in THF (16.0 mL). The mixture was cool to 0 °C and placed under nitrogen atmosphere. To this solution was added ethyl chloroformate (0.47 mL, 4.86 mmol) and the reaction was stirred for 30 minutes at 0 °C. The mixture was then filtered to remove the precipitated triethylamine hydrochloride. The filtrate containing the mixed anhydride was slowly added to a stirred suspension of sodium borohydride (367 mg, 9.71 mmol) in 20% aqueous THF (10.0 mL) maintained at 10 °C. After the mixture was stirred for 30 minutes, it was acidified with 1N HCl to pH ~ 4. The mixture was then extracted with EtOAc, washed with 2M NaOH solution, washed with brine, dried (MgSO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl N-[(1S,2R)-2-(2- hydroxyethyl)cyclohexyl]carbamate. ES/MS: m/z 244.14 [M+H] + . [0662] Step 6. To a stirred solution of tert-butyl N-[(1S,2R)-2-(2- hydroxyethyl)cyclohexyl]carbamate (445 mg, 1.83 mmol) and triethylamine (0.7 ml, 5.49 mmol) in dichloromethane (18 mL) at 0 °C was added p-toluenesulfonyl chloride (558 mg, 2.93 mmol), DMAP (13.2 mg, 0.1 mmol) and the mixture was warmed to room temperature and stirred overnight. Upon completion, the mixture was diluted with water and extracted with dicholoromethane. The combined organic layers were washed with brine, dried over MgSO 4 and concentrated in vacuo to give the crude product. The residue was purified using column chromatography eluting with EtOAc in hexanes 0-100% to afford 2-[(1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl]ethyl 4-methylbenzenesulfonate. ES/MS: m/z 398.18 [M+H] + . [0663] Step 7. To a mixture of 6-bromo-2H-isoquinolin-1-one (360.0 mg, 1.49mmol) and 2- [(1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl]ethyl 4-methylbenzenesulfonate (537 mg, 1.35 mmol) in DMF (12 mL) was added Cs 2 CO 3 (880 mg, 2.70 mmol) and the reaction was stirred at room temperature for 18 hr. Upon completion, the mixture was diluted with EtOAc, washed with water, washed with brine, dried over MgSO 4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EA in hexanes 0-100% to afford tert- butyl N-[(1S,2R)-2-[2-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)ethyl] cyclohexyl]carbamate. ES/MS: m/z 469.10 [M+H] + . [0664] Step 8. To a solution of tert-butyl N-[(1S,2R)-2-[2-(6-bromo-7-fluoro-1-oxo-2- isoquinolyl)ethyl]cyclohexyl]carbamate (207 mg, 0.443 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.67 mL, 8.86 mmol) at room temperature and the mixture was stirred for 1hr. Upon completion, the solvent was removed under reduced pressure to afford 2-(2-((1R,2S)-2- aminocyclohexyl)ethyl)-6-bromo-7-fluoroisoquinolin-1(2H)-one which was used without further purification. ES/MS: m/z 369.67 [M+H] + . [0665] Step 9. A mixture of 2-(2-((1R,2S)-2-aminocyclohexyl)ethyl)-6-bromo-7- fluoroisoquinolin-1(2H)-one (213 mg, 0.443 mmol), 5-chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one (432 mg, 1.18 mmol), and N,N-diisopropylethylamine (0.90 mL, 5.22 mmol) in DMF (4.0 mL) was stirred at RT for 2 h. Upon completion, the reaction was diluted with EtOAc, washed with water, washed with brine, dried over MgSO 4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0-100% to provide 6-bromo-7-fluoro-2-[2-[(1R,2S)-2-[[6-oxo-5-(trifluoromethyl) -1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]cyclohexyl]e thyl]isoquinolin-1-one ES/MS: m/z 660.33 [M+H] + . [0666] Step 10. In a vial were placed methyl 6-bromo-7-fluoro-2-[2-[(1R,2S)-2-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]cyclohexyl]ethyl]isoquinolin-1- one (75 mg, 0.114 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.014 mmol), potassium acetate (33.5 mg, 0.341 mmol), and bis(pinacolato)diboron (43.3 mg, 0.171 mmol) in dioxane (2 mL). The mixture was bubbled with dry Nitrogen and stirred at 80°C for 18 hr. The reaction was cooled to ambient temperature and 2 M aqueous sodium carbonate (0.125 mL, 0.249 mmol), 2-iodo-5-(trifluoromethyl)pyrimidine (46.7 mg, 0.171 mmol), and CataCXIum Pd G4 (8 mg, 0.011 mmol) were added. The mixture was bubbled with dry nitrogen gas and stirred at 80°C for 3 hr. The rection was then cooled, diluted with EtOAc and filtered through a plug of Celite ® . The volatiles were evaporated in vacuo and the residue purified via flash chromatography (100% hexanes to 100% EtOAc) to give 7-fluoro-2-[2-[(1R,2S)-2-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]cyclohexyl]ethyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. ES/MS m/z: 727.21 [M+H] + . [0667] Step 11. In a vial were placed 7-fluoro-2-[2-[(1R,2S)-2-[[6-oxo-5-(trifluoromethyl)-1- (2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]cyclohexy l]ethyl]-6-[5-(trifluoromethyl)pyrimidin- 2-yl]isoquinolin-1-one (82.6 mg, 0.114 mmol), and trifluoroacetic acid (0.3 mL, 3.98 mmol) in DCM (5 mL). The mixture was stirred for 1 hr, and then was concentrated under vacuum. The resulting crude product was dissolved in methanol (5 mL) and ethylenediamine (0.266 mL, 3.98 mmol) was added and the mixture was stirred for 15 minutes and then concentrated under vacuum. The resulting crude product was purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 7-fluoro-2- [2-[(1R,2S)-2-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl] amino]cyclohexyl]ethyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 9.48 (s, 2H), 8.42 (d, J = 7.1 Hz, 1H), 8.01 (d, J = 11.4 Hz, 1H), 7.93 (s, 1H), 7.44 (d, J = 7.4 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 6.41 – 6.26 (m, 1H), 4.02 – 3.99 (m, 2H), 3.63 – 3.45 (m, 1H), 2.03 (d, J = 10.0 Hz, 1H), 1.98 – 1.84 (m, 1H), 1.78 (d, J = 8.7 Hz, 1H), 1.72 – 1.56 (m, 3H), 1.55 – 1.44 (m, 1H), 1.44 – 1.30 (m, 2H), 1.25 – 1.01 (m, 2H). ES/MS m/z : 597.3 [M+H] + . Example 451: 6-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-7-fluoro-2-[2- [(1R,2S)-2-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]cyclohexyl]ethyl]i soquinolin-1-one [0668] The title compound was synthesized as described in Example 450, using 2-chloro-5- (trifluoromethyl)pyrimidin-4-amine instead of 2-iodo-5-(trifluoromethyl)pyrimidine. 1 H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.65 (s, 1H), 8.18 (d, J = 7.0 Hz, 1H), 8.00 – 7.90 (m, 2H), 7.41 (d, J = 7.4 Hz, 1H), 6.75 (d, J = 7.4 Hz, 1H), 6.48 – 6.23 (m, 1H), 4.12 – 3.89 (m, 2H), 3.63 – 3.45 (m, 1H), 2.03 (d, J = 10.1 Hz, 1H), 1.98 – 1.84 (m, 1H), 1.78 (d, J = 8.7 Hz, 1H), 1.73 – 1.56 (m, 3H), 1.53 – 1.30 (m, 3H), 1.23 – 1.04 (m, 2H). ES/MS m/z : 612.3 [M+H] + . Example 452: 6-fluoro-3-[2-[(1R,2S)-2-[[6-oxo-5-(trifluoromethyl)-1H-pyri dazin-4- yl]amino]cyclobutyl]ethyl]-7-[5-(trifluoromethyl)pyrimidin-2 -yl]quinazolin-4-one [0669] The title compound was synthesized as described in Example 450, using (1S,2S)-2- (tert-butoxycarbonylamino)cyclobutanecarboxylic acid instead of (1S,2S)-2-(tert- butoxycarbonylamino)cyclohexanecarboxylic acid and 7-bromo-6-fluoro-3H-quinazolin-4-one instead of 6-bromo-7-fluoro-2H-isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.49 (s, 2H), 8.45 (s, 1H), 8.34 (d, J = 6.7 Hz, 1H), 7.99 (d, J = 10.5 Hz, 1H), 7.80 (s, 1H), 6.92 – 6.77 (m, 1H), 4.08 – 3.86 (m, 3H), 2.66 – 2.52 (m, 1H), 2.34 – 2.19 (m, 1H), 2.08 – 1.97 (m, 1H), 1.94 – 1.77 (m, 3H), 1.40 – 1.21 (m, 1H). ES/MS m/z : 570.3 [M+H] + . Intermediate 63: Preparation of (R)-4-((tert-butoxycarbonyl)amino)-6,6,6-trifluorohexyl 4- methylbenzenesulfonate [0670] Step 1. In a vial were placed (S)-2-((tert-butoxycarbonyl)amino)-4,4,4- trifluorobutanoic acid (2.73 g, 10.6 mmol) and THF (16.0 mL). 1,1’-carbonyldiimidazole (1.70 g, 10.5 mmol) was added portion-wise over 10 minutes. After stirring for 1 hr at room temperature, a solution of N,O-dimethylhydroxylamine hydrochloride (0.932 g, 9.55 mmol) and DIPEA (1.66 mL, 9.55 mmol) in DMF (4.0 mL) was added. The reaction mixture was stirred at room temperature for 15 hr, followed by concentration in vacuo. The residue was diluted with EtOAc (100 mL) and washed with 1 M aq. HCl (2 x 50 mL), saturated aq. NaHCO3 (2 x 50 mL), and brine (50.0 mL). The organic layer was dried over MgSO 4 , filtered, and concentrated in vacuo to give tert-butyl (S)-(4,4,4-trifluoro-1- (methoxy(methyl)amino)-1-oxobutan-2-yl)carbamate. [0671] Step 2. In a 200 mL round bottom flask was added LiAlH4 (0.444 g, 11.7 mmol) in Et2O (30 mL) at 0 °C was added dropwise a solution of tert-butyl (S)-(4,4,4-trifluoro-1- (methoxy(methyl)amino)-1-oxobutan-2-yl)carbamate (2.56 g, 10.6 mmol) in Et 2 O (20 mL) so that the internal temperature did not exceed 5 °C. The reaction mixture was stirred for 30 min at 0 °C and quenched by the dropwise addition of EtOAc (20.0 mL) followed by 5% aq. potassium bisulfate (20 mL), maintaining the internal temperature <5 °C. The reaction mixture was then washed with 1 M aq. HCl (2 x 40 mL), saturated aq. NaHCO 3 (2 x 40 mL), and brine (40 mL). The organic layer was dried over MgSO 4 ,filtered, and concentrated in vacuo to afford tert-butyl (S)-(4,4,4-trifluoro-1-oxobutan-2-yl)carbamate. [0672] Step 3. In a vial was placed methyl (triphenylphosphoranylidene)acetate (4.26 g, 12.7 mmol) and tert-butyl (S)-(4,4,4-trifluoro-1-oxobutan-2-yl)carbamate (2.56 g, 10.6 mmol) in Et2O (45 mL) The reaction mixture was stirred at room temperature for 15 hrs. The solid was removed by filtration and the solution was concentrated in vacuo. Purification via flash column chromatography (0-100% EtOAc/hexanes) afforded methyl (S,E)-4-((tert-butoxycarbonyl)amino)-6,6,6-trifluorohex-2-en oate. [0673] Step 4. In a 200 mL round bottom flask was placed methyl (S,E)-4-((tert- butoxycarbonyl)amino)-6,6,6-trifluorohex-2-enoate (8.11 mg, 2.73 mmol) and 10% Pd on C (290 mg) in EtOH (25 mL). The reaction was placed under a hydrogen balloon and stirred for 6 hrs. The reaction was filtered over Celite ® and rinsed with ethyl acetate (2 x 30 mL) and concentrated give methyl (R)-4- ((tert butoxycarbonyl)amino)-6,6,6-trifluorohexanoate. [0674] Step 5. In a vial was placed methyl (R)-4-((tert-butoxycarbonyl)amino)-6,6,6- trifluorohexanoate. (816 mg, 2.73 mmol) and sodium hydroxide (545 mg, 13.6 mmol) in 5:2 methanol/water (20 mL). The solution was stirred for 1 hr and then diluted with water (100 mL), and washed with DCM (2 x 50 mL). The aqueous solution was acidified to pH = 4 with 1M HCl, and then extracted with DCM (3 x 50 mL). The combined DCM extracts were dried over MgSO 4 , filtered, and concentrated to give (R)-4-((tert-butoxycarbonyl)amino)-6,6,6-trifluorohexanoic acid. [0675] Step 6. In a vial were placed (R)-4-((tert-butoxycarbonyl)amino)-6,6,6- trifluorohexanoic acid (861 mg, 3.02 mmol), triethylamine (0.421 mL, 3.02 mmol), and THF (30.0 mL). The mixture was cooled to 0 °C and placed under nitrogen atmosphere. To this solution was added ethyl chloroformate (0.289 mL, 3.02 mmol) and stirred for 30 min at 0 °C. The reaction was then filtered to remove the precipitated triethylamine hydrochloride. The filtrate containing the mixed anhydride was slowly added to a stirred suspension of sodium borohydride (343 mg, 9.05 mmol) in 20% aqueous THF (10.0 mL) maintained at 10 °C. After mixture stirred for 30 minutes, it was acidified with 1N HCl to pH ~ 4. The mixture was then extracted with EtOAc (x3), washed with 2M NaOH solution, washed with brine, dried (MgSO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give tert-butyl (R)-(1,1,1-trifluoro-6-hydroxyhexan-3-yl)carbamate. ES/MS m/z: 215.9 [M-tBu+1] [0676] Step 7. In a vial were placed tert-butyl (R)-(1,1,1-trifluoro-6-hydroxyhexan-3- yl)carbamate (436 mg, 1.61 mmol), and triethylamine (0.448 mL, 3.21 mmol) in DCM (8.0 mL). The mixture was cooled to 0 °C and p-toluenesulfonyl chloride (337 mg, 1.77 mmol) and a few crystals of DMAP was added. The mixture was warmed to room temperature and stirred for 2h and was then quenched with water and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried (MgSO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give (R)-(1,1,1-trifluoro-6-(tosyloxy)hexan-3-yl)carbamic acid. ES/MS m/z: 370.1 [M+H] Example 453: (R)-7-fluoro-2-(6,6,6-trifluoro-4-((6-oxo-5-(trifluoromethyl )-1,6-dihydropyridazin-4- yl)amino)hexyl)-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquin olin-1(2H)-one [0677] The title compound was synthesized as described in Example 17, with the following changes: Step 1. 6-Bromo-7-fluoro-2H-isoquinolin-1-one was used instead of 6-Bromo-8-fluoro-1,2- dihydroisoquinolin-1-one and (R)-4-((tert-butoxycarbonyl)amino)-6,6,6-trifluorohexyl 4- methylbenzenesulfonate instead of [(4S)-4-(tert-butoxycarbonylamino)pentyl] 4-methylbenzenesulfonate Step 3. 2-iodo-5-(trifluoromethyl)pyrimidine was used instead of 2-bromo-5-(difluoromethoxy)pyridine and 20 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 9.48 (d, J = 1.0 Hz, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.03 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 7.4 Hz, 1H), 6.62 – 6.52 (m, 1H), 4.42 – 4.31 (m, 1H), 4.07 – 3.89 (m, 1H), 2.90 – 2.67 (m, 1H), 2.68 – 2.46 (m, 1H), 1.85 – 1.46 (m, 3H). ES/MS m/z: 625.3 [M+H].
Example 454: Synthesis of 7-fluoro-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1,6-dihyd ropyridazin- 4-yl)oxy)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one [0678] Step 1. In a vial MTBE (1.50 mL) and KOtBu (374 mg, 3.33 mmol) were added at room temperature. A solution of (1R,3S)-3-hydroxycyclohexanecarboxylic acid (200 mg, 1.39 mmol) in DMF (1.50 mL) was added dropwise and stirred for 30 minutes at which point 5-chloro-2-[(4- methoxyphenyl)methyl]-4-(trifluoromethyl)pyridazin-3-one (442 mg, 1.39 mmol) was added in a single portion and stirred for 16 hrs. Upon completion, the reaction is diluted with water(50 mL), and acidified to pH ~ 5 using 1M HCl. The mixture is extracted with EtOAc (3 X 50 mL), and the combined organic extracts are dried over MgSO 4 , filtered, and concentrated by rotary evaporation. Purification by flash chromatography (0-100% EtOAc in Hexane) gave (1R,3S)-3-[1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)pyridazin-4 yl]oxycyclohexanecarboxylic acid. ES/MS m/z: 427.1 [M+1] [0679] Step 2. In a vial were placed (1R,3S)-3-[1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)pyridazin-4 yl]oxycyclohexanecarboxylic acid (515 mg, 1.21 mmol), triethylamine (0.185 mL, 1.33 mmol), and THF (12.0 mL). The mixture was cooled to 0 °C and placed under nitrogen atmosphere. To this solution was added ethyl chloroformate (0.116 mL, 1.21 mmol) and stirred for 30 min at 0 °C. The reaction was then filtered to remove the precipitated triethylamine hydrochloride. The filtrate containing the mixed anhydride was slowly added to a stirred suspension of sodium borohydride (137 mg, 3.62 mmol) in 20% aqueous THF (10.0 mL) maintained at 10 °C. After mixture stirred for 30 minutes, it was acidified with 1N HCl to pH ~ 4. The mixture was then extracted with EtOAc (x3), washed with brine, dried (MgSO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give 5-[(1S,3R)-3-(hydroxymethyl)cyclohexoxy]-2-[(4-methoxyphenyl )methyl]-4- (trifluoromethyl)pyridazin-3-one. ES/MS m/z: 413.1 [M+1] [0680] Step 3. In a vial were placed tert-butyl 5-[(1S,3R)-3-(hydroxymethyl)cyclohexoxy]-2- [(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridazin-3-one (260 mg, 0.63 mmol), and triethylamine (0.176 mL, 1.26 mmol) in DCM (5 mL). The mixture was cooled to 0 °C and p-toluenesulfonyl chloride (144 mg, 0.76 mmol) and a few crystals of DMAP was added. The mixture was warmed to room temperature and stirred for 2h and was then quenched with water and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried (MgSO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give [(1R,3S)-3-[1-[(4-methoxyphenyl)methyl]-6- oxo-5-(trifluoromethyl)pyridazin-4-yl]oxycyclohexyl]methyl 4-methylbenzenesulfonate. ES/MS m/z: 567.1 [M+H] [0681] Step 4. In a vial were placed 6-bromo-7-fluoro-1,2-dihydroisoquinolin-1-one (133 mg, 0.55 mmol), [(1R,3S)-3-[1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluorome thyl)pyridazin-4- yl]oxycyclohexyl]methyl 4-methylbenzenesulfonate (312 mg, 0.55 mmol), and cesium carbonate (358 mg, 1.01 mmol) in DMF (2 mL). After mixture was stirred at room temperature for 16 hr, it was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried (MgSO 4 ), and purified by flash chromatography (100% hexanes to 100% EtOAc) to give 6-bromo-7-fluoro-2-[[(1R,3S)-3-[1-[(4-methoxyphenyl)methyl]- 6-oxo-5- (trifluoromethyl)pyridazin-4-yl]oxycyclohexyl]methyl]isoquin olin-1-one. ES/MS m/z: 638.0 [M+2+H] + . [0682] Step 5. In a vial were placed 6-bromo-7-fluoro-2-[[(1R,3S)-3-[1-[(4- methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)pyridazin-4-y l]oxycyclohexyl]methyl]isoquinolin-1- one (100 mg, 0.157 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (25.7 mg, 0.031 mmol), potassium acetate (46.3 mg, 0.471 mmol), and bis(pinacolato)diboron (60 mg, 0.236 mmol) in dioxane (2 mL). The mixture was degassed for 15 minutes and heated to 80 °C and stirred for 2 hr, cooled to room temperature, and cataCXium Pd G4 (23.3 mg, 0.031 mmol) was added followed by the addition of 2 M aqueous sodium carbonate (0.24 mL, 0.471 mmol) and 2-iodo-5-(trifluoromethyl)pyrimidine (65 mg, 0.236 mmol). The reaction was then stirred for an additional hour at 80 °C. Upon completion, the mixture was filtered through Celite ® and concentrated under vacuum to afford the crude product that was purified by flash chromatography (0- 100% EtOAc in Hexane) to give [2-[7-fluoro-2-[[(1R,3S)-3-[1-[(4-methoxyphenyl)methyl]-6-ox o-5- (trifluoromethyl)pyridazin-4-yl]oxycyclohexyl]methyl]-1-oxo- 6-isoquinolyl]pyrimidin-5-yl]. ES/MS m/z: 704.3 [M+H] [0683] Step 6. In a vial was added [2-[7-fluoro-2-[[(1R,3S)-3-[1-[(4-methoxyphenyl)methyl]- 6-oxo-5-(trifluoromethyl)pyridazin-4-yl]oxycyclohexyl]methyl ]-1-oxo-6-isoquinolyl]pyrimidin-5-yl] (111 mg, 0.18 mmol), trifluoroacetic acid (6 mL), and trifluoromethanesulfonic acid (a few drops). Upon completion reaction is carefully poured into saturated NaHCO 3 solution (50 mL). The mixture is extracted with EtOAc (3 x 25 mL), and the combined organic extracts are dried over MgSO 4 , filtered, and concentrated by rotary evaporation. The crude product was purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 7-fluoro-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)oxy)cyclohexyl)methyl)-6-(5-(trifluoro methyl)pyrimidin-2-yl)isoquinolin- 1(2H)-one. 1 H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 9.48 (s, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.30 (s, 1H), 8.04 (d, J = 11.4 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 4.88 – 4.72 (m, 1H), 2.15 – 1.97 (m, 4H), 1.83 – 1.74 (m, 1H), 1.63 – 1.52 (m, 1H), 1.42 – 1.20 (m, 3H), 1.10 – 0.97 (m, 1H). ES/MS: m/z 584.1 [M+H] + . Example 455: 6-(4-amino-5-(trifluoromethyl)pyrimidin-2-yl)-7-fluoro-2-((( 1R,3S)-3-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)cyclohexyl)m ethyl)isoquinolin-1(2H)-one [0684] The title compound was synthesized as described in Example 454, with the following changes: Step 5. 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine was used instead of 2-iodo-5- (trifluoromethyl)pyrimidine. 1 H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 8.65 (s, 1H), 8.29 (s, 1H), 8.20 (d, J = 7.0 Hz, 1H), 7.96 (d, J = 11.1 Hz, 1H), 7.47 (d, J = 7.4 Hz, 1H), 6.75 (d, J = 7.4 Hz, 1H), 4.89 – 4.72 (m, 1H), 4.01 – 3.78 (m, 2H), 2.15 – 1.96 (m, 4H), 1.83 – 1.70 (m, 1H), 1.62 – 1.48 (m, 1H), 1.43 – 1.18 (m, 3H), 1.11 – 0.94 (m, 1H). ES/MS m/z: 599.1 [M+H].
Example 456: 6-(5-(difluoromethyl)pyrimidin-2-yl)-7-fluoro-2-(((1R,3S)-3- ((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)cyclohexyl)m ethyl)isoquinolin-1(2H)-one [0685] The title compound was synthesized as described in Example 454, with the following changes: Step 5. 2-chloro-5-(difluoromethyl)pyrimidine was used instead of 2-iodo-5- (trifluoromethyl)pyrimidine. H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 9.25 (d, J = 1.6 Hz, 2H), 8.40 (d, J = 7.2 Hz, 1H), 8.29 (s, 1H), 8.02 (d, J = 11.3 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.31 (t, J = 54.8 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 4.86 – 4.71 (m, 1H), 4.00 – 3.83 (m, 2H), 2.13 – 1.97 (m, 4H), 1.85 – 1.71 (m, 1H), 1.63 – 1.48 (m, 1H), 1.43 – 1.17 (m, 3H), 1.11 – 0.93 (m, 1H).. ES/MS m/z: 566.1 [M+H]. Example 457: 7-(5-(difluoromethyl)pyrimidin-2-yl)-6-fluoro-3-(((1R,3S)-3- ((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)cyclohexyl)m ethyl)quinazolin-4(3H)-one [0686] The title compound was synthesized as described in Example 454, with the following changes: Step 4. 7-bromo-6-fluoroquinazolin-4(3H)-one was used instead of 6-Bromo-7-fluoro-2H-isoquinolin-1- one Step 5. 2-chloro-5-(difluoromethyl)pyrimidine was used instead of 2-iodo-5- (trifluoromethyl)pyrimidine. 1 H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 9.26 (d, J = 1.6 Hz, 2H), 8.42 (s, 1H), 8.35 – 8.26 (m, 2H), 7.99 (d, J = 10.5 Hz, 1H), 7.31 (t, J = 54.8 Hz, 1H), 4.06 – 3.81 (m, 2H), 2.08 – 2.01 (m, 3H), 1.87 – 1.72 (m, 1H), 1.66 – 1.54 (m, 1H), 1.45 – 1.18 (m, 3H), 1.12 – 0.95 (m, 1H). ES/MS m/z: 567.1 [M+H]. Example 458: 7-(4-bromo-5-(trifluoromethyl)pyrimidin-2-yl)-6-fluoro-3-((( 1R,3S)-3-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclohexyl )methyl)quinazolin-4(3H)-one [0687] To a suspension of Example 242 (179 mg, 0.30 mmol) in MeCN (3.9 mL) was added CuBr2 (80 mg, 0.36 mmol) and t-butyl nitrite (60 µL, 0.51 mmol). The reaction mixture was then heated to 60 °C for 1 hr, and diluted with EtOAc, washed with sat. aq. Na 2 SO 3 , then brine, dried with anhydrous magnesium sulfate, and concentrated. Purification via flash chromatography (elution with 0-100% v/v ethyl acetate in hexanes) afforded 7-(4-bromo-5-(trifluoromethyl)pyrimidin-2-yl)-6-fluoro-3- (((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin -4- yl)amino)cyclohexyl)methyl)quinazolin-4(3H)-one.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.36 (s, 1H), 8.44 (s, 1H), 8.36 (d, J = 6.7 Hz, 1H), 8.01 (d, J = 10.5 Hz, 1H), 7.92 (s, 1H), 6.37 – 6.26 (m, 1H), 3.91 (d, J = 6.9 Hz, 2H), 3.79 – 3.63 (m, 1H), 2.07 – 1.94 (m, 1H), 1.90 – 1.78 (m, 2H), 1.73 (d, J = 10.9 Hz, 1H), 1.61 (d, J = 12.7 Hz, 1H), 1.46 – 1.19 (m, 3H), 1.03 – 0.87 (m, 1H). ES/MS m/z: 662.0 [M+H]. Example 459: 4-bromo-7-fluoro-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1 ,6-dihydropyridazin-4- yl)amino)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one [0688] To a solution of Example 183 (60.0 mg, 0.103 mmol) in DMSO (3.0 mL) was added NBS (27.5 mg, 0.155 mmol). The reaction mixture was stirred at room temperature for 10 minutes and then purified by reverse phase prep-HPLC (5 - 100% MeCN in water, 0.1% TFA) to afford 4-bromo-7- fluoro-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1,6-dihydro pyridazin-4- yl)amino)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.51 (s, 2H), 8.54 (d, J = 6.8 Hz, 1H), 8.12 (d, J = 11.1 Hz, 1H), 8.01 (s, 1H), 7.92 (s, 1H), 6.44 – 6.20 (m, 1H), 3.96 – 3.85 (m, 2H), 3.73 (d, J = 9.8 Hz, 1H), 2.09 – 1.94 (m, 1H), 1.88 – 1.76 (m, 2H), 1.77 – 1.68 (m, 1H), 1.64 – 1.52 (m, 1H), 1.45 – 1.19 (m, 3H), 1.05 – 0.86 (m, 1H). ES/MS m/z: 661.0 [M+H]. Example 460: (R)-7-(6-amino-5-(trifluoromethyl)pyrazin-2-yl)-3-(4-cyclopr opyl-4-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)butyl)-6-f luoroquinazolin-4(3H)-one [0689] The title compound was synthesized as described in Example 144, with the following changes: Step 1: 7-bromo-6-fluoroquinazolin-4(3H)-one was used instead of 6-Bromo-8-fluoro-1,2- dihydroisoquinolin-1-one. Step 3: tert-butyl (tert-butoxycarbonyl)(6-chloro-3-(trifluoromethyl)pyrazin-2- yl)carbamate was used instead of 2-Chloro-5-(trifluoromethyl)pyrimidin-4-amine and 10 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.45 (s, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.22 (d, J = 6.7 Hz, 1H), 7.99 (d, J = 10.7 Hz, 1H), 7.88 (s, 1H), 7.17 (s, 2H), 6.55 – 6.44 (m, 1H), 3.41 – 3.30 (m, 1H), 1.88 – 1.62 (m, 4H), 1.18 – 1.01 (m, 1H), 0.56 – 0.45 (m, 1H), 0.45 – 0.33 (m, 1H), 0.32 – 0.16 (m, 2H). One methylene peak is obstructed by the water signal. ES/MS m/z: 599.3 [M+H]. Example 461: (R)-7-(4-amino-5-chloropyrimidin-2-yl)-3-(4-cyclopropyl-4-(( 6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)butyl)-6-f luoroquinazolin-4(3H)-one [0690] The title compound was synthesized as described in Example 144, with the following changes: Step 1: 7-bromo-6-fluoroquinazolin-4(3H)-one was used instead of 6-Bromo-8-fluoro-1,2- dihydroisoquinolin-1-one. Step 3: tert-butyl N-tert-butoxycarbonyl-N-(2,5-dichloropyrimidin-4-yl)carbamat e was used instead of 2-Chloro-5-(trifluoromethyl)pyrimidin-4-amine and 10 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step.1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.43 (d, J = 8.4 Hz, 2H), 8.14 (d, J = 6.7 Hz, 1H), 7.90 (d, J = 9.8 Hz, 4H), 6.58 – 6.42 (m, 1H), 4.00 (t, J = 6.4 Hz, 2H), 3.35 (s, 1H), 1.87 – 1.62 (m, 4H), 1.16 – 1.02 (m, 1H), 0.55 – 0.45 (m, 1H), 0.45 – 0.33 (m, 1H), 0.33 – 0.15 (m, 2H). ES/MS m/z: 565.3 [M+H]. Example 462: (R)-7-(4-amino-5-(difluoromethyl)pyrimidin-2-yl)-3-(4-cyclop ropyl-4-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)butyl)-6-f luoroquinazolin-4(3H)-one [0691] The title compound was synthesized as described in Example 144, with the following changes: Step 1: 7-bromo-6-fluoroquinazolin-4(3H)-one was used instead of 6-Bromo-8-fluoro-1,2- dihydroisoquinolin-1-one. Step 3: 2-chloro-5-(difluoromethyl)pyrimidin-4-amine was used instead of 2-Chloro-5- (trifluoromethyl)pyrimidin-4-amine and 10 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step.1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.16 (d, J = 6.7 Hz, 1H), 7.93 (d, J = 10.3 Hz, 1H), 7.89 (s, 1H), 7.66 (s, 2H), 7.10 (t, J = 54.1 Hz, 1H), 6.56 – 6.42 (m, 1H), 4.05 – 3.95 (m, 2H), 3.40 – 3.26 (m, 1H), 1.88 – 1.57 (m, 4H), 1.17 – 1.00 (m, 1H), 0.57 – 0.44 (m, 1H), 0.44 – 0.33 (m, 1H), 0.33 – 0.15 (m, 2H). ES/MS m/z: 581.4 [M+H]. Example 463: 6-fluoro-3-(2-((1R,2S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dih ydropyridazin-4- yl)amino)cyclopentyl)ethyl)-7-(5-(trifluoromethyl)pyrimidin- 2-yl)quinazolin-4(3H)-one [0692] The title compound was synthesized as described in Example 17, with the following changes: Step 1: 2-((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)ethyl 4-methylbenzenesulfonate (intermediate 28) was used instead of [(4S)-4-(tert-butoxycarbonylamino)pentyl] 4- methylbenzenesulfonate and 7-bromo-6-fluoroquinazolin-4(3H)-one was used instead of 6-Bromo-8- fluoro-1,2-dihydroisoquinolin-1-one. Step 3: 2-iodo-5-(trifluoromethyl)pyrimidine was used instead of 2-bromo-5-(difluoromethoxy)pyridine and 10 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step. 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 9.50 (s, 2H), 8.47 (s, 1H), 8.34 (d, J = 6.7 Hz, 1H), 7.99 (d, J = 10.5 Hz, 1H), 7.92 (s, 1H), 6.56 – 6.39 (m, 1H), 4.05 – 3.96 (m, 2H), 3.91 – 3.78 (m, 1H), 2.11 – 1.87 (m, 4H), 1.74 – 1.58 (m, 3H), 1.57 – 1.44 (m, 1H), 1.36 – 1.21 (m, 1H). ES/MS m/z: 584.1 [M+H]. Example 464: 7-(4-amino-5-(trifluoromethyl)pyrimidin-2-yl)-6-fluoro-3-(2- ((1R,2S)-2-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclopenty l)ethyl)quinazolin-4(3H)-one [0693] The title compound was synthesized as described in Example 17, with the following changes: Step 1: 2-((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)ethyl 4-methylbenzenesulfonate (intermediate 28) was used instead of [(4S)-4-(tert-butoxycarbonylamino)pentyl] 4- methylbenzenesulfonate and 7-bromo-6-fluoroquinazolin-4(3H)-one was used instead of 6-Bromo-8- fluoro-1,2-dihydroisoquinolin-1-one. Step 3: 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine was used instead of 2-bromo-5- (difluoromethoxy)pyridine and 10 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step.1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.66 (s, 1H), 8.44 (s, 1H), 8.17 (d, J = 6.7 Hz, 1H), 7.94 – 7.87 (m, 2H), 6.52 – 6.41 (m, 1H), 4.02 – 3.98 (m, 2H), 3.89 – 3.81 (m, 1H), 2.10 – 1.84 (m, 4H), 1.74 – 1.57 (m, 3H), 1.56 – 1.44 (m, 1H), 1.29 (dq, J = 12.2, 8.8, 8.3 Hz, 1H). ES/MS m/z: 599.1 [M+H]. Example 465: 7-(6-amino-5-(trifluoromethyl)pyrazin-2-yl)-6-fluoro-3-(2-(( 1R,2S)-2-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclopenty l)ethyl)quinazolin-4(3H)-one [0694] The title compound was synthesized as described in Example 17, with the following changes: Step 1: 2-((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)ethyl 4-methylbenzenesulfonate (intermediate 28) was used instead of [(4S)-4-(tert-butoxycarbonylamino)pentyl] 4- methylbenzenesulfonate and 7-bromo-6-fluoroquinazolin-4(3H)-one was used instead of 6-Bromo-8- fluoro-1,2-dihydroisoquinolin-1-one. Step 3: tert-butyl (tert-butoxycarbonyl)(6-chloro-3-(trifluoromethyl)pyrazin-2- yl)carbamate was used instead of 2-bromo-5-(difluoromethoxy)pyridine and 10 mol % of cataCXium Pd G4 and 2 M aqueous sodium carbonate (1.9 equiv.) were added following the completion of the borylation step.1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.46 (s, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.21 (d, J = 6.7 Hz, 1H), 7.97 (d, J = 10.7 Hz, 1H), 7.91 (s, 1H), 7.16 (s, 2H), 6.52 – 6.40 (m, 1H), 2.11 – 1.86 (m, 4H), 1.74 – 1.57 (m, 3H), 1.57 – 1.42 (m, 1H), 1.39 – 1.20 (m, 1H). One methylene and one methine peak are obstructed by the water signal." ES/MS m/z: 599.1 [M+H].
Example 466: 2-[(4R)-6-(difluoromethoxy)-4-[[6-oxo-5-(trifluoromethyl)-1H -pyridazin-4- yl]amino]hexyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidin-2-y l]isoquinolin-1-one [0695] Step 1. (3R)-6-benzyloxy-3-(tert-butoxycarbonylamino)-6-oxo-hexanoic acid (1500 mg, 4.27 mmol) and triethylamine (0.60 mL, 4.27 mmol) were taken up in THF (17.5 mL) and cooled to 0°C under N 2 atmosphere. While stirring at 0°C, ethyl chloroformate (0.41 mL, 4.27 mmol) was added and solution allowed to stir for 30 minutes. Solution filtered to remove triethylamine hydrochloride. The filtrate containing the mixed anhydride was slowly added to a stirred suspension of NaBH 4 (484 mg, 12.8 mmol) in 20% aqueous THF (10 mL) maintained at 10 °C and allowed to stir for 30 minutes. Solution was then acidified with 1N HCl to pH 4. Mixture extracted 3x with EtOAc, washed with 2M NaOH solution, washed with brine, dried over Na 2 SO 4 and concentrated. The crude residue was purified via column chromatography (100% hexanes → 100% EtOAc) to afford benzyl (4R)-4-(tert- butoxycarbonylamino)-6-hydroxy-hexanoate. ES/MS: m/z 338.088 [M+H] + . [0696] Step 2. A plastic centrifuge tube was charged with benzyl (4R)-4-(tert- butoxycarbonylamino)-6-hydroxy-hexanoate (500 mg, 1.41 mmol), potassium acetate (1105 mg, 11.3 mmol), and stir bar. DCM (1.5 mL) and water (1.5 mL) added to centrifuge tube and allowed to stir rapidly to thoroughly mix. [bromo(difluoro)methyl]-trimethyl-silane (0.88 mL, 5.63 mmol) was added and solution was allowed to stir overnight. The Solution was then diluted with saturated aqueous sodium bicarbonate solution, extracted (3x) with DCM, dried over Na 2 SO 4 , filtered, concentrated, and purified via column chromatography to (100% hexanes → 100% EtOAc) to afford benzyl (4R)-4-(tert- butoxycarbonylamino)-6-(difluoromethoxy)hexanoate. ES/MS: m/z 388.173 [M+H] + . [0697] Step 3. A vial was charged with benzyl (4R)-4-(tert-butoxycarbonylamino)-6- (difluoromethoxy)hexanoate (338 mg, 0.87 mmol), stir bar, and MeOH (11.2 mL). To this solution was added 10% palladium on carbon (92.8 mg, 0.087 mmol). Vial evacuated and fitted with a gas bag filled with H 2 and solution allowed to stir for 4h. Upon complete conversion, reaction filtered through celite, and concentrated to afford (4R)-4-(tert-butoxycarbonylamino)-6-(difluoromethoxy)hexanoi c acid. ES/MS: m/z 298.003 [M+H] + . [0698] Step 4. (4R)-4-(tert-butoxycarbonylamino)-6-(difluoromethoxy)hexanoi c acid (326 mg, 1.1 mmol) and triethylamine (0.15 mL, 1.1 mmol) were taken up in THF (4.51 mL) and cooled to 0°C under N 2 atmosphere. While stirring at 0°C, ethyl chloroformate (0.11 mL, 1.1 mmol) was added and solution allowed to stir for 30 min. Solution filtered to remove triethylamine hydrochloride. The filtrate containing the mixed anhydride was slowly added to a stirred suspension of NaBH 4 (124 mg, 3.29 mmol) in 20% aqueous THF (5 mL) maintained at 10°C and allowed to stir for 30 min. Solution then acidified with 1N HCl to pH 4. Mixture extracted 3x with EtOAc, washed with 2M NaOH solution, washed with brine, dried over Na 2 SO 4 and concentrated. The crude residue was purified via column chromatography (100% hexanes → 100% EtOAc) to afford tert-butyl N-[(1R)-1-[2- (difluoromethoxy)ethyl]-4-hydroxy-butyl]carbamate. ES/MS: m/z 284.037 [M+H] + . [0699] Step 5. tert-butyl N-[(1R)-1-[2-(difluoromethoxy)ethyl]-4-hydroxy-butyl]carbama te (227 mg, 0.80 mmol), triethylamine (0.22 mL, 1.6 mmol), 4-(dimethylamino)pyridine (1 mg, 0.008 mmol) added to a vial with stir bar and dissolved in DCM. Solution was cooled to 0°C and p- toluenesulfonyl chloride (183 mg, 0.96 mmol) added. Reaction was warmed to room temperature and allowed to stir for 2 hr. Reaction was diluted with water, extracted (3x) with EtOAc, washed with brine, dried over Na 2 SO 4 and concentrated. The crude residue was purified via column chromatography (100% hexanes → 100% EtOAc) to afford [(4R)-4-(tert-butoxycarbonylamino)-6-(difluoromethoxy)hexyl] 4- methylbenzenesulfonate. ES/MS: m/z 438.167 [M+H] + . [0700] Step 6. A vial was charged with [(4R)-4-(tert-butoxycarbonylamino)-6- (difluoromethoxy)hexyl] 4-methylbenzenesulfonate (243 mg, 0.56 mmol), 6-bromo-7-fluoro-2H- isoquinolin-1-one (148 mg, 0.61 mmol), cesium carbonate (362 mg, 1.11 mmol), and DMF (4.12 mL). Reaction allowed to stir overnight at room temperature. Reaction was diluted with water, extracted 3x with EtOAc, washed with brine, dried over Na 2 SO 4 and concentrated. The crude residue was purified via column chromatography (100% hexanes → 100% EtOAc) to afford tert-butyl N-[(1R)-4-(6-bromo-7- fluoro-1-oxo-2-isoquinolyl)-1-[2-(difluoromethoxy)ethyl]buty l]carbamate. ES/MS: m/z 509.006 [M+H] + . [0701] Step 7. A vial was charged with tert-butyl N-[(1R)-4-(6-bromo-7-fluoro-1-oxo-2- isoquinolyl)-1-[2-(difluoromethoxy)ethyl]butyl]carbamate (172 mg, 0.34 mmol) and DCM (5.35 mL). Trifluoroacetic acid (0.26 mL, 3.4 mmol) was then added and the reaction was allowed to stir at room temperature for 1hr. Reaction was concentrated to afford 2-[(4R)-4-amino-6-(difluoromethoxy)hexyl]- 6-bromo-7-fluoro-isoquinolin-1-one. ES/MS: m/z 409.652 [M+H] + . [0702] Step 8. A vial was charged with 5-chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one(191 mg, 0.41 mmol), 2-[(4R)-4-amino-6- (difluoromethoxy)hexyl]-6-bromo-7-fluoro-isoquinolin-1-one (138 mg, 0.34 mmol), N,N- diisopropylethylamine (0.30 mL, 1.69 mmol), and DMF (1.32 mL). Reaction was heated to 60°C and allowed to stir overnight. Reaction was diluted with water, extracted 3x with EtOAc, washed with brine, dried over Na 2 SO 4 and concentrated. The crude residue was purified via column chromatography (100% hexanes → 100% EtOAc) to afford 6-bromo-2-[(4R)-6-(difluoromethoxy)-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]hexyl]-7-fluoro- isoquinolin-1-one. ES/MS: m/z 701.133 [M+H] + . [0703] Step 9. A vial was charged with 6-bromo-2-[(4R)-6-(difluoromethoxy)-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]hexyl]-7-fluoro-isoquinolin-1- one (114 mg, 0.16 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (13.5 mg, 0.016 mmol), potassium acetate (48 mg, 0.49 mmol), bis(pinacolato)diboron (62.1 mg, 0.24 mmol), and dioxane (1.9 mL). The reaction was sparged with N 2 , heated to 100°C, and allowed to stir for 1hr to afford 2-[(4R)-6-(difluoromethoxy)-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]hexyl]-7-fluoro-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one in a dioxane solution to be used in the next step. ES/MS: m/z 747.334 [M+H] + . [0704] Step 10. To the reaction mixture from the previous step was added 2-iodo-5- (trifluoromethyl)pyrimidine (62.1 mg, 0.23 mmol), cataCXium Pd G4 (11.2 mg, 0.015 mmol), and 2M aqueous sodium carbonate solution (0.23 mL, 0.45 mmol). The reaction was sparged with N 2 , heated to 80°C, and allowed to stir for 1hr. Reaction filtered through Celite ® , concentrated, and purified via column (100% hexanes → 100% EtOAc) to afford 2-[(4R)-6-(difluoromethoxy)-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]hexyl]-7-fluoro-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. ES/MS: m/z 767.349 [M+H] + . [0705] Step 11. A vial was charged with 2-[(4R)-6-(difluoromethoxy)-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]hexyl]-7-fluoro-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one (68 mg, 0.089 mmol) and DCM (3.89 mL). Trifluoroacetic acid (0.068 mL, 0.89 mmol) and reaction allowed to stir at room temperature for 1hr. Upon complete conversion, the reaction was concentrated and taken up in MeOH (3.89 mL), and ethylenediamine (0.059 mL, 0.89 mmol) was added. Reaction was allowed to stir for 10 minutes, concentrated, and purified by reverse phase prep-HPLC (5 - 100% MeCN in water, 0.1% TFA) to afford 2-[(4R)-6-(difluoromethoxy)-4-[[6-oxo-5-(trifluoromethyl)-1H -pyridazin-4-yl]amino]hexyl]-7- fluoro-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-on e. 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 9.48 (s, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.92 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 7.3 Hz, 1H), 6.82 – 6.38 (m, 2H), 4.11 – 3.94 (m, 3H), 3.83 (dtt, J = 15.4, 9.9, 5.6 Hz, 2H), 2.03 – 1.48 (m, 4H). ES/MS: m/z 637.33 [M+H] + . Example 467: 6-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-2-[(4R)-6-(dif luoromethoxy)-4-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]hexyl]-7-flu oro-isoquinolin-1-one [0706] The title compound was synthesized as described in Example 466 with the following changes: Step 10 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine was used instead of 2-iodo-5- (trifluoromethyl)pyrimidine. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.64 (s, 1H), 8.19 (d, J = 7.1 Hz, 1H), 8.08 – 7.84 (m, 2H), 7.49 (d, J = 7.4 Hz, 1H), 6.88 – 6.32 (m, 3H), 4.12 – 3.93 (m, 3H), 3.82 (dtd, J = 18.6, 10.2, 5.5 Hz, 2H), 2.01 – 1.46 (m, 4H). ES/MS: m/z 652.3 [M+H] + . Example 468: 3-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyrid azin-4-yl]amino]butyl]- 7-[5-(difluoromethyl)pyrimidin-2-yl]-6-fluoro-quinazolin-4-o ne [0707] The title compound was synthesized as described in Example 144, with the following changes: Step 1 7-bromo-6-fluoro-3H-quinazolin-4-one used instead of 6-bromo-7-fluoro-2H-isoquinolin-1-one and reaction heated to 80C. Step 3 2-chloro-5-(difluoromethyl)pyrimidine used instead of 2-Chloro-5-(trifluoromethyl)pyrimidin-4- amine. 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.26 (d, J = 1.2 Hz, 2H), 8.46 (s, 1H), 8.32 (d, J = 6.8 Hz, 1H), 7.99 (d, J = 10.5 Hz, 1H), 7.89 (s, 1H), 7.31 (t, J = 54.8 Hz, 1H), 6.50 (dd, J = 9.0, 4.1 Hz, 1H), 4.02 (t, J = 6.3 Hz, 2H), 3.35 (s, 1H), 1.73 (d, J = 39.3 Hz, 4H), 1.09 (dt, J = 8.0, 4.9 Hz, 1H), 0.57 – 0.19 (m, 4H). ES/MS: m/z 566.3 [M+H] + . Example 469: 7-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-3-[(4R)-4-cycl opropyl-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]butyl]-6-fluoro-qu inazolin-4-one [0708] The title compound was synthesized as described in example 144, with the following changes: Step 3 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine was used instead of 2-chloro-5- (difluoromethyl)pyrimidine. 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.66 (s, 1H), 8.43 (s, 1H), 8.18 (d, J = 6.7 Hz, 1H), 7.96 – 7.86 (m, 2H), 6.50 (d, J = 8.4 Hz, 1H), 4.01 (s, 2H), 3.40 (s, 1H), 1.73 (d, J = 35.8 Hz, 4H), 1.20 – 0.98 (m, 1H), 0.59 – 0.17 (m, 4H). ES/MS: m/z 599.3 [M+H] + . Example 470: 7-(5-chloropyrimidin-2-yl)-3-[(4R)-4-cyclopropyl-4-[[6-oxo-5 -(trifluoromethyl)-1H- pyridazin-4-yl]amino]butyl]-6-fluoro-quinazolin-4-one [0709] The title compound was synthesized as described in example 144, with the following changes: Step 3 2,5-dichloropyrimidine was used instead of 2-chloro-5-(difluoromethyl)pyrimidine. 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.16 (s, 2H), 8.45 (s, 1H), 8.28 (d, J = 6.8 Hz, 1H), 7.97 (d, J = 10.5 Hz, 1H), 7.89 (s, 1H), 6.50 (s, 1H), 4.01 (d, J = 6.7 Hz, 1H), 3.35 (s, 1H), 1.73 (d, J = 35.2 Hz, 4H), 1.17 – 1.02 (m, 1H), 0.65 – 0.15 (m, 4H). ES/MS: m/z 550.24 [M+H] + . Example 471: 3-[(4R)-4-cyclopropyl-4-[[6-oxo-5-(trifluoromethyl)-1H-pyrid azin-4-yl]amino]butyl]- 6-fluoro-7-[5-(trifluoromethyl)pyrimidin-2-yl]quinazolin-4-o ne [0710] The title compound was synthesized as described in Example 144, with the following changes: Step 3 2-iodo-5-(trifluoromethyl)pyrimidine used instead of 2-chloro-5-(difluoromethyl)pyrimidine. 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.50 (s, 2H), 8.47 (s, 1H), 8.35 (d, J = 6.7 Hz, 1H), 8.01 (d, J = 10.5 Hz, 1H), 7.89 (s, 1H), 6.50 (dd, J = 9.1, 3.9 Hz, 1H), 4.02 (t, J = 6.3 Hz, 2H), 3.35 (s, 1H), 1.73 (d, J = 39.5 Hz, 4H), 1.10 (ddd, J = 13.5, 8.8, 5.1 Hz, 1H), 0.59 – 0.19 (m, 4H). ES/MS: m/z 584.3 [M+H] + . Example 472: 7-[4-amino-5-(difluoromethoxy)pyrimidin-2-yl]-3-[(4R)-4-cycl opropyl-4-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]butyl]-6-fluoro-qu inazolin-4-one [0711] The title compound was synthesized as described in example 144, with the following changes: Step 3 tert-butyl N-tert-butoxycarbonyl-N-[2-chloro-5-(difluoromethoxy)pyrimid in-4-yl]carbamate was used instead of 2-chloro-5-(difluoromethyl)pyrimidine. 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 8.11 (d, J = 6.7 Hz, 1H), 7.94 – 7.85 (m, 2H), 7.48 (s, 2H), 7.21 (t, J = 73.1 Hz, 1H), 6.50 (dd, J = 9.1, 3.7 Hz, 1H), 4.10 – 3.89 (m, 2H), 3.35 (s, 1H), 1.72 (d, J = 38.8 Hz, 5H), 1.08 (dq, J = 13.3, 8.3, 6.7 Hz, 1H), 0.50 (tt, J = 8.5, 4.2 Hz, 1H), 0.38 (tt, J = 8.9, 4.1 Hz, 1H), 0.25 (ddq, J = 19.0, 9.4, 4.7 Hz, 2H). ES/MS: m/z 597.099 [M+H] + . Example 473: 2-[(4R)-5-(dimethylamino)-4-[[6-oxo-5-(trifluoromethyl)-1H-p yridazin-4- yl]amino]pentyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one [0712] Step 1.6-bromo-7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluorom ethyl)-1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]isoqu inolin-1-one (100 mg, 0.15 mmol) and iodobenzene diacetate (48 mg, 0.15 mmol) were dissolved in DCM (1.5 mL) and stirred at ambient temperature. TEMPO (4.7 mg, 0.03 mmol) was then added. After stirring for 20 hours, 2.0 M dimethylamine solution (0.75 ml, 1.5 mmol) and sodium triacetoxyborohydride (63 mg, 0.3 mmol) were added. The reaction was stirred a further 4 hours and quenched with saturated bicarb. Extracted (3x) with DCM and the organics were dried over Na 2 SO 4 , filtered, evaporated and the crude residue was purified via column chromatography (100% heptanes → 100% 3:1 EtOAc:EtOH) to afford 6-bromo-2-[(4R)-5- (dimethylamino)-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethyl silylethoxymethyl)pyridazin-4- yl]amino]pentyl]-7-fluoro-isoquinolin-1-one. ES/MS: m/z 662.3/664.2 [M+H] + . [0713] Step 2. A vial was charged with 6-bromo-2-[(4R)-5-(dimethylamino)-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]pentyl]-7-fluoro-isoquinolin-1- one (33 mg, 0.05 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (1.7 mg, 2 µmol), potassium acetate (14 mg, 0.14 mmol), and bis(pinacolato)diboron (30 mg, 0.12 mmol) and flushed with dry nitrogen. Dioxane (0.75mL) was added and the reaction heated to 100 °C for 8 hours. After cooling, 2-iodo-5-(trifluoromethyl)pyrimidine (15 mg, 0.06 mmol), CataCXium Pd G4 (1.7 mg, 2 µmol), and aqueous sodium carbonate (2.0 M, 0.07 mL) were added and the mixture bubbled with dry nitrogen briefly. The reaction was then stirred at 80 °C for 1 hour before being diluted with EtOAc and filtered through a plug of Celite ® . The filtrate was evaporated and the crude purified via flash chromatography (100% hexanes → 100% EtOAc → 35% MeOH/EtOAc) to afford 2-[(4R)-5- (dimethylamino)-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethyl silylethoxymethyl)pyridazin-4- yl]amino]pentyl]-7-fluoro-6-[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one ES/MS: m/z 730.0 [M+H] + . [0714] Step 3.2-[(4R)-5-(dimethylamino)-4-[[6-oxo-5-(trifluoromethyl)-1- (2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-7-fl uoro-6-[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (32 mg, 0.04 mmol) was dissolved in DCM (2.0 mL) and stirred at ambient temperature. TFA (0.03 mL, 0.42 mmol) was added and the rection maintained for 1.5 hours at which point it was evaporated to dryness. The residue was dissolved in MeOH (1.0 mL) and treated with ethylenediamine (0.03 mL, 0.42 mmol). After 10 minutes, the reaction was evaporated and the residue purified by reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 2-[(4R)-5- (dimethylamino)-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4 -yl]amino]pentyl]-7-fluoro-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 9.49 (s, 2H), 9.12 (br s, 1H), 8.45 (d, J = 7.1 Hz, 1H), 8.10 (s, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 7.4 Hz, 1H), 6.57 – 6.46 (m, 1H), 4.53 – 4.40 (m, 1H), 4.07 – 3.95 (m, 2H), 3.57 – 3.48 (m, 1H), 3.28 – 3.18 (m, 1H), 2.79 (s, 3H), 2.78 (s, 3H), 1.80 – 1.67 (m, 2H), 1.61 – 1.51 (m, 2H). ES/MS: m/z 600.3 [M+H] + . Example 474: 7,8-difluoro-2-[(4R)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-4-[[6 -oxo-5-(trifluoromethyl)- 1H-pyridazin-4-yl]amino]butyl]-6-[5-(trifluoromethyl)pyrimid in-2-yl]isoquinolin-1-one [0715] The title compound was synthesized as described in example 169, using 7,8-difluoro- 2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimeth ylsilylethoxymethyl)pyridazin-4- yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoqui nolin-1-one was utilized as starting material instead of 7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1-( 2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 9.50 (d, J = 1.0 Hz, 2H), 8.25 (dd, J = 6.7, 1.7 Hz, 1H), 7.99 (s, 1H), 7.57 (d, J = 7.4 Hz, 1H), 7.11 – 7.03 (m, 1H), 6.83 (dd, J = 7.5, 1.8 Hz, 1H), 5.43 (q, J = 7.5 Hz, 1H), 4.02 (t, J = 6.8 Hz, 2H), 2.48 (s, 3H), 2.19 – 2.05 (m, 2H), 1.92 – 1.76 (m, 2H). ES/MS: m/z 643.3 [M+H] + . Example 475: 2-[(4R)-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-[[6-oxo-5-( trifluoromethyl)-1H- pyridazin-4-yl]amino]butyl]-7,8-difluoro-6-[5-(trifluorometh yl)pyrimidin-2-yl]isoquinolin-1-one [0716] The title compound was synthesized as described in example 169 with the following modifications: Step 1: 7,8-difluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl) -1-(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one was utilized instead of 7-fluoro-2-[(4R)-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1- (2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6 -[5-(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one. Step 2: Cyclopropanecarbohydrazide was utilized instead of acethydrazide. 1 H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 9.50 (d, J = 1.0 Hz, 2H), 8.24 (dd, J = 6.6, 1.7 Hz, 1H), 8.00 (s, 1H), 7.57 (d, J = 7.4 Hz, 1H), 7.08 – 7.00 (m, 1H), 6.83 (dd, J = 7.5, 1.8 Hz, 1H), 5.39 (q, J = 7.5 Hz, 1H), 4.02 (t, J = 6.8 Hz, 2H), 2.21 (tt, J = 8.4, 4.9 Hz, 1H), 2.16 – 2.04 (m, 2H), 1.93 – 1.74 (m, 2H), 1.15 – 1.08 (m, 2H), 0.96 – 0.90 (m, 2H). ES/MS: m/z 669.3 [M+H] + . Example 476: 2-[(4R)-4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-[[6-oxo-5-( trifluoromethyl)-1H- pyridazin-4-yl]amino]butyl]-7-fluoro-6-[5-(trifluoromethyl)p yrimidin-2-yl]isoquinolin-1-one [0717] The title compound was synthesized as described in example 169, using cyclopropanecarbohydrazide instead of acethydrazide. 1 H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 9.48 (s, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.07 – 7.97 (m, 2H), 7.54 (d, J = 7.4 Hz, 1H), 7.09 – 7.00 (m, 1H), 6.86 (d, J = 7.4 Hz, 1H), 5.39 (q, J = 7.5 Hz, 1H), 4.06 (t, J = 6.8 Hz, 2H), 2.20 (tt, J = 8.4, 4.9 Hz, 1H), 2.16 – 2.03 (m, 2H), 1.94 – 1.76 (m, J = 6.8 Hz, 2H), 1.15 – 1.07 (m, 2H), 0.96 – 0.88 (m, 2H). ES/MS: m/z 651.3 [M+H] + . Example 477: 2-[(4R)-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-4-[[6-ox o-5-(trifluoromethyl)-1H- pyridazin-4-yl]amino]butyl]-7-fluoro-6-[5-(trifluoromethyl)p yrimidin-2-yl]isoquinolin-1-one [0718] The title compound was synthesized as described in example 169, using 2,2- difluoroacetohydrazide instead of acethydrazide. 1 H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 9.48 (s, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.08 – 7.99 (m, 2H), 7.55 (d, J = 7.4 Hz, 1H), 7.49 (t, J = 51.3 Hz, 1H), 7.20 – 7.13 (m, 1H), 6.86 (d, J = 7.4 Hz, 1H), 5.63 – 5.52 (m, 1H), 4.08 (t, J = 6.8 Hz, 2H), 2.23 – 2.13 (m, 2H), 1.96 – 1.84 (m, 2H). ES/MS: m/z 661.3 [M+H] + . Example 478: Preparation of 7-fluoro-2-[(4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H- pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin -2-yl]isoquinolin-1-one [0719] Step 1. In a flask were placed 6-bromo-7-fluoro-2H-isoquinolin-1-one (2.10 g, 8.68 mmol), tert-butyl N-[(1S)-4-bromo-1-methyl-3-oxo-butyl]carbamate (2.55 g, 9.11 mmol), cesium carbonate (5.65 g, 17.4 mmol) in DMF (43.0 mL). The solution was stirred at room temperature overnight, filtered through a pad of Celite ® , concentrated, and purified by flash chromatography (Hex/EtOAc) to give tert-butyl N-[(1S)-4-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-1-methyl-3- oxo- butyl]carbamate. ES/MS m/z = 442.9 [M+H]. [0720] Step 2. In a flask were placed tert-butyl N-[(1S)-4-(6-bromo-7-fluoro-1-oxo-2- isoquinolyl)-1-methyl-3-oxo-butyl]carbamate (1.04 g, 2.36 mmol) in THF (23.0 mL) and NaBH 4 (134 mg, 3.54 mmol) is added. After stirring for 90 minutes, the reaction is carefully quenched with water (5.0 mL) and the pH is adjusted to ~4 with 1N HCl. Diluted with water, extracted with EtOAc, and concentrated to give tert-butyl N-[(1S)-4-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-3-hydroxy-1 - methyl-butyl]carbamate. ES/MS m/z = 444.9 [M+H]. [0721] Step 3. In a flask were placed tert-butyl N-[(1S)-4-(6-bromo-7-fluoro-1-oxo-2- isoquinolyl)-3-hydroxy-1-methyl-butyl]carbamate (1.0 g, 2.30 mmol), imidazole (798 mg, 12 mmol), DMAP (86 mg, 0.7 mmol), and TBSCl (1.06 g, 7.0 mmol) in DMF (12 mL). The mixture was stirred at room temperature overnight. Quenched with sat. NH4Cl and extracted with EtOAc. The organic layer is concentrated and purified by flash chromatography (Hex/EtOAc) to give tert-butyl N-[(1S)-4-(6-bromo- 7-fluoro-1-oxo-2-isoquinolyl)-3-[tert-butyl(dimethyl)silyl]o xy-1-methyl-butyl]carbamate. ES/MS m/z = 559.1 [M+H]. [0722] Step 4. In a flask were placed tert-butyl N-[(1S)-4-(6-bromo-7-fluoro-1-oxo-2- isoquinolyl)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-butyl ]carbamate (224 mg, 0.40 mmol) and TFA (4 mL) in DCM (4.0 mL). The mixture was stirred at room temperature for 15 minutes and concentrated to give 2-[(4S)-4-amino-2-[tert-butyl(dimethyl)silyl]oxy-pentyl]-6-b romo-7-fluoro-isoquinolin-1-one. ES/MS m/z = 460.3 [M+2H]. [0723] Step 5. In a vial were placed 2-[(4S)-4-amino-2-[tert-butyl(dimethyl)silyl]oxy-pentyl]- 6-bromo-7-fluoro-isoquinolin-1-one (184 mg, 0.40 mmol), 5-chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one (198 mg, 0.60 mmol), triethylamine (0.28 mL, 2.01 mmol), and DMF (2 mL). The mixture was heated to 85 o C for 3 hours, concentrated, and purified by flash chromatography (Hex/EtOAc) to give 6-bromo-2-[(4S)-2-[tert-butyl(dimethyl)silyl]oxy-4-[[6-oxo-5 - (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]pentyl]-7-fluoro- isoquinolin-1-one. ES/MS m/z = 751.2 [M+H]. [0724] Step 6. A vial was charged with 2-[(4S)-2-[tert-butyl(dimethyl)silyl]oxy-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]pentyl]-7-fluoro-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (166 mg, 0.22 mmol), 1,1'- Bis(diphenylphosphino)ferrocene-palladi [0725] um(II)dichloride (36 mg, 0.04 mmol), potassium acetate (87 mg, 0.89 mmol), and bis(pinacolato)diboron (169 mg, 0.66 mmol) and flushed with dry nitrogen. Dioxane (2.2 mL) was added and the reaction heated to 100°C for 4 hours. After cooling, 2-iodo-5-(trifluoromethyl)pyrimidine (91 mg, 0.33 mmol), CataCXium Pd G4 (8.2 mg, 0.011 mmol), cesium carbonate (216 mg, 0.66 mmol), and water (0.5 mL) were added. The reaction was then stirred at 80°C for 2 hours before being purified by column chromatography (Hex/EtOAc) to give 2-[(4S)-2-[tert-butyl(dimethyl)silyl]oxy-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]pentyl]-7-fluoro-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. ES/MS: m/z 817.3 [M+H] + . [0726] Step 7. A vial was charged with 2-[(4S)-2-[tert-butyl(dimethyl)silyl]oxy-4-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]pentyl]-7-fluoro-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one (180 mg, 0.22 mmol), TFA (2 mL), and DCM (2mL). The reaction was stirred for 1 hour and concentrated. MeOH (2 mL) and ethylenediamine (0.5 mL) was added. The reaction was stirred for 15 minutes before being purified by prep HPLC to give 7-fluoro-2- [(4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4 -yl]amino]pentyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. ES/MS: m/z 573.0 [M+H] + .1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 12.39 (s, 1H), 9.48 (s, 3H), 8.43 (dd, J = 7.1, 1.4 Hz, 2H), 8.04 (dd, J = 11.4, 3.6 Hz, 2H), 7.88 (d, J = 8.6 Hz, 2H), 7.45 (dd, J = 8.8, 7.4 Hz, 2H), 7.04 – 6.88 (m, 1H), 6.81 (d, J = 7.4 Hz, 2H), 6.57 (dd, J = 7.7, 3.8 Hz, 1H), 4.31 – 3.88 (m, 4H), 1.94 – 1.47 (m, 3H), 1.21 (dd, J = 6.4, 3.2 Hz, 6H). Example 479 and Example 480: 7-fluoro-2-[(2S,4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)- 1H- pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin -2-yl]isoquinolin-1-one and 7-fluoro- 2-[(2R, 4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-y l]amino]pentyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one [0727] Examples 479 and Example 480 were separated via chiral SFC (AD-H, 5 ^m, 21x250 mm column; 35% EtOH as co-solvent; 100 bar; 40 °C). The first eluting peak was assigned as the (S)- configuration (Example 479) , and the second eluting peak was assigned as the (R)-configuration (Example 480). The final compounds were free of TFA. [0728] Example 479: 1 H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.48 (s, 2H), 8.44 (d, J = 7.1 Hz, 1H), 8.03 (d, J = 11.4 Hz, 1H), 7.87 (s, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.57 (dd, J = 8.0, 4.0 Hz, 1H), 5.23 (s, 1H), 4.25 – 3.87 (m, 3H), 3.76 (dd, J = 13.0, 8.0 Hz, 1H), 1.69 (t, J = 6.7 Hz, 2H), 1.21 (d, J = 6.2 Hz, 3H). ES/MS: m/z 573.0 [M+H] + . [ 0729] Example 480: 1 H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 9.48 (s, 2H), 8.43 (d, J = 7.1 Hz, 1H), 8.04 (d, J = 11.3 Hz, 1H), 7.89 (s, 1H), 7.44 (d, J = 7.4 Hz, 1H), 6.96 (dt, J = 7.3, 3.7 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 4.32 – 3.95 (m, 3H), 3.79 (dd, J = 12.8, 7.5 Hz, 1H), 1.83 (dd, J = 13.5, 8.3 Hz, 1H), 1.60 (ddd, J = 14.0, 10.4, 3.3 Hz, 1H), 1.21 (d, J = 6.4 Hz, 3H). ES/MS: m/z 573.0 [M+H] + .
Example 481: 4,7-difluoro-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1,6-d ihydropyridazin-4- yl)amino)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one [0730] The title compound was synthesized as described in Example 459, with the following changes: Step 1: N-Fluorobenzenesulfonimide was used instead of NBS and DMF was used instead of DMSO. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.50 (s, 2H), 8.47 (d, J = 6.8 Hz, 1H), 8.11 (dd, J = 11.1, 1.9 Hz, 1H), 7.92 (s, 1H), 7.85 (d, J = 6.8 Hz, 1H), 6.37 – 6.28 (m, 1H), 3.88 – 3.83 (m, 2H), 2.10 – 1.97 (m, 1H), 1.81 (d, J = 11.4 Hz, 2H), 1.73 (d, J = 11.0 Hz, 1H), 1.59 (d, J = 12.2 Hz, 1H), 1.43 – 1.22 (m, 3H), 1.02 – 0.88 (m, 1H). One methine in obstructed by the water signal. ES/MS m/z: 601.10 [M+H]. Example 482: 6-(5-(difluoromethyl)pyrimidin-2-yl)-4,7-difluoro-2-(((1R,3S )-3-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclohexyl )methyl)isoquinolin-1(2H)-one [0731] The title compound was synthesized as described in Example 459, with the following changes: Step 1: N-Fluorobenzenesulfonimide was used instead of NBS and 6-(5-(difluoromethyl)pyrimidin-2- yl)-7-fluoro-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1,6-d ihydropyridazin-4- yl)amino)cyclohexyl)methyl)isoquinolin-1(2H)-one was used instead of 7-fluoro-2-(((1R,3S)-3-((6-oxo- 5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclohex yl)methyl)-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one and DMF was used instead of DMSO. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.27 (s, 2H), 8.43 (d, J = 6.8 Hz, 1H), 8.09 (dd, J = 11.1, 1.9 Hz, 1H), 7.92 (s, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.32 (t, J = 54.8 Hz, 1H), 6.40 – 6.25 (m, 1H), 3.89 – 3.83 (m, 2H), 3.76 – 3.68 (m, 1H), 2.05 (d, J = 17.9 Hz, 1H), 1.86 – 1.76 (m, 2H), 1.76 – 1.68 (m, 1H), 1.63 – 1.53 (m, 1H), 1.46 – 1.20 (m, 3H), 1.03 – 0.88 (m, 1H). ES/MS m/z: 583.10 [M+H]. Example 483: 7-fluoro-1-oxo-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1,6 -dihydropyridazin-4- yl)amino)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)-1,2-dihydroisoquinoline-4- carbonitrile [0732] Step 1. NBS (65.4 mg, 0.368 mmol) was added to a solution of 7-fluoro-2-(((1R,3S)- 3-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)m ethyl)-1,6-dihydropyridazin-4- yl)amino)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one (262 mg, 0.368 mmol) in MeCN (4.0 mL). The resulting solution was stirred at room temperature for 2 hr, then diluted with water, extracted with EtOAc, washed with brine, dried with anhydrous magnesium sulfate, and concentrated. Purification via flash chromatography (gradient solution with 0–100% EtOAc/Hexanes) afforded 4-bromo-7-fluoro-2-[[(1R,3S)-3-[[6-oxo-5-(trifluoromethyl)-1 -(2- trimethylsilylethoxymethyl)pyridazin-4-yl]amino]cyclohexyl]m ethyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. [0733] Step 2. To a solution of 4-bromo-7-fluoro-2-[[(1R,3S)-3-[[6-oxo-5-(trifluoromethyl)- 1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]cyclohe xyl]methyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one (118 mg, 0.149 mmol) in DMF (3 mL) was added zinc cyanide (23.0 mg, 0.194 mmol) and Tetrakis(triphenylphosphine)palladium(0) (17.2 mg, 0.015 mmol). The reaction mixture was then sparged with N 2 for 10 minutes, and heated to 120 °C for 3 hr. No reaction was observed at this time, so cataCXium Pd G4 (11 mg, 0.015 mmol) was added and the reaction mixture was heated to 100 °C for 10 minutes, then cooled to room temperature and diluted with EtOAc, washed with water (3x) then brine, dried with anhydrous magnesium sulfate, and concentrated. Purification via flash chromatography (gradient solution with 0–100% EtOAc/Hexanes) afforded 7-fluoro-1-oxo-2- (((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsily l)ethoxy)methyl)-1,6-dihydropyridazin- 4-yl)amino)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidi n-2-yl)-1,2-dihydroisoquinoline-4- carbonitrile. [0734] Step 3. TFA (1.17 mL, 15.2 mmol) was added to a solution of 7-fluoro-1-oxo-2- (((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsily l)ethoxy)methyl)-1,6-dihydropyridazin-4- yl)amino)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)-1,2-dihydroisoquinoline-4- carbonitrile (75 mg, 0.102 mmol) in DCM (10.0 mL). The resulting solution was stirred at room temperature for 2 hr, then concentrated under reduced pressure. The resulting crude oil was taken up in MeOH (5.0 mL) followed by the addition of ethylenediamine (0.17 mL, 2.54 mmol). After stirring at room temperature for 5 minutes the reaction mixture was concentrated in vacuo and purified via reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 7-fluoro-1-oxo-2-[[(1R,3S)-3-[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]cyclohexyl]m ethyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinoline-4-carbonitrile. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.53 (s, 2H), 8.60 (s, 1H), 8.47 (d, J = 6.7 Hz, 1H), 8.15 (d, J = 10.9 Hz, 1H), 7.92 (s, 1H), 6.42 – 6.26 (m, 1H), 3.75 – 3.67 (m, 1H), 2.10 – 1.93 (m, 1H), 1.89 – 1.77 (m, 2H), 1.74 (d, J = 11.6 Hz, 1H), 1.59 (d, J = 12.0 Hz, 1H), 1.47 – 1.19 (m, 3H), 1.02 – 0.86 (m, 1H). one methylene peak in obstructed by the water signal. ES/MS m/z: 608.10 [M+H]. Example 484: 4-chloro-7-fluoro-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4- yl)amino)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one [0735] Step 1. NCS (28.0 mg, 0.206 mmol) was added to a solution of 7-fluoro-2-(((1R,3S)- 3-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amin o)cyclohexyl)methyl)-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one (60 mg, 0.103 mmol) in DMF (1.5 mL). The resulting solution was stirred at room temperature for 16 hr, at which point bis-chlorination was observed as the sole product (second chlorination site suspected to be the 4-position on the pyridazinone). The reaction mixture was loaded directly onto prep HPLC (5 – 100% MeCN in water, 0.1% TFA; aqueous condition resulted in hydrolysis of the pyridazinone) to afford 2-(((1R,3S)-3-aminocyclohexyl)methyl)- 4-chloro-7-fluoro-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoqu inolin-1(2H)-one. [0736] Step 2. A solution of 5-chloro-4-(trifluoromethyl)-2-(2- trimethylsilylethoxymethyl)pyridazin-3-one (170 mg, 0.515 mmol) in DMF (2.0 mL) was added to a solution of 2-[[(1R,3S)-3-aminocyclohexyl]methyl]-4-chloro-7-fluoro-6-[5 -(trifluoromethyl)pyrimidin-2- yl]isoquinolin-1-one (ca.0.13 mmol) in DMF (3.0 mL). The reaction mixture was stirred at room temperature for 2 hr, then diluted with EtOAc, washed with water (3x) then brine, dried with anhydrous magnesium sulfate, and concentrated. Purification via flash chromatography (gradient solution with 0– 100% EtOAc/Hexanes) afforded 4-chloro-7-fluoro-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)- 1-((2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)ami no)cyclohexyl)methyl)-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one. ES/MS m/z: 747.18 [M+H]. [0737] Step 3. TFA (0.292 mL, 3.81 mmol) was added to a solution of 4-chloro-7-fluoro-2- (((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsily l)ethoxy)methyl)-1,6-dihydropyridazin-4- yl)amino)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one (19.0 mg, 0.025 mmol) in DCM (2.0 mL). The resulting solution was stirred at room temperature for 1 hr, then concentrated under reduced pressure. The resulting crude oil was taken up in MeOH (1.0 mL) followed by the addition of ethylenediamine (0.59 mL, 0.89 mmol). After stirring at room temperature for 5 minutes the reaction mixture was concentrated in vacuo and purified via reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 4-chloro-7-fluoro-2-(((1R,3S)-3-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclohexyl )methyl)-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.51 (s, 2H), 8.57 (d, J = 6.8 Hz, 1H), 8.13 (d, J = 11.0 Hz, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 6.38 – 6.27 (m, 1H), 3.96 – 3.85 (m, 2H), 3.73 (d, J = 10.1 Hz, 1H), 2.03 (qd, J = 7.3, 4.2, 3.7 Hz, 1H), 1.90 – 1.76 (m, 2H), 1.76 – 1.67 (m, 1H), 1.59 (d, J = 12.7 Hz, 1H), 1.46 – 1.20 (m, 3H), 1.03 – 0.88 (m, 1H). ES/MS m/z: 617.00 [M+H]. Example 485: 7-fluoro-4-methyl-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4- yl)amino)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one [0738] Step 1. In a vial was added 4-bromo-7-fluoro-2-[[(1R,3S)-3-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]cyclohexyl]methyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one (120 mg, 0.15 mmol), trimethylboroxine (0.064 mL, 0.45 mmol), 2M aqueous potassium carbonate (0.23 mL, 0.45 mmol), and cataCXium Pd G4 (23 mg, 0.03 mmol) in dioxane (1.50 mL). The mixture was degassed for 15 minutes with nitrogen gas, heated to 80 °C for 1 hr, cooled to room temperature, filtered through Celite ® , and concentrated. The resulting crude material was purified by flash chromatography (0-100% EtOAc in Hexane) to give 7-fluoro-4- methyl-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1-((2-(trim ethylsilyl)ethoxy)methyl)-1,6- dihydropyridazin-4-yl)amino)cyclohexyl)methyl)-6-(5-(trifluo romethyl)pyrimidin-2-yl)isoquinolin- 1(2H)-one. [0739] Step 2. TFA (1.17 mL, 15.2 mmol) was added to a solution of 7-fluoro-4-methyl-2- (((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsily l)ethoxy)methyl)-1,6-dihydropyridazin-4- yl)amino)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one (110 mg, 0.151 mmol) in DCM (5.0 mL). The resulting solution was stirred at room temperature for 1 hr, then concentrated under reduced pressure. The resulting crude oil was taken up in MeOH (5.0 mL) followed by the addition of ethylenediamine (0.17 mL, 2.54 mmol). After stirring at room temperature for 5 minutes the reaction mixture was concentrated in vacuo and purified via reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 7-fluoro-4-methyl-2-(((1R,3S)-3-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclohexyl )methyl)-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.50 (s, 2H), 8.37 (d, J = 7.0 Hz, 1H), 8.08 (d, J = 11.3 Hz, 1H), 7.91 (s, 1H), 7.38 (s, 1H), 6.40 – 6.22 (m, 1H), 3.93 – 3.78 (m, 2H), 3.78 – 3.68 (m, 1H), 2.31 (s, 3H), 2.09 – 1.95 (m, 1H), 1.84 – 1.76 (m, 2H), 1.76 – 1.68 (m, 1H), 1.63 – 1.51 (m, 1H), 1.45 – 1.20 (m, 3H), 1.03 – 0.88 (m, 1H). one methylene peak in obstructed by the water signal. ES/MS m/z: 597.100 [M+H]. Example 486: 4-amino-7-fluoro-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1 ,6-dihydropyridazin-4- yl)amino)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one [0740] Step 1. In a vial is combined 4-bromo-7-fluoro-2-[[(1R,3S)-3-[[6-oxo-5- (trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin- 4-yl]amino]cyclohexyl]methyl]-6-[5- (trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one (111 mg, 0.140 mmol), diphenylmethanimine (0.047 mL, 0.280 mmol), Cs 2 CO 3 (137 mg, 0.42 mmol), XantPhos Pd G4 (13.5 mg, 0.014 mmol), and dioxane (1.0 mL). The suspension is degassed with N 2 gas and heated to 75 °C for 8 hrs. The reaction is cooled, filtered over Celite ® , concentrated, and purified by flash chromatography (0-100% EtOAc in Hexane) to give 4-((diphenylmethylene)amino)-7-fluoro-2-(((1R,3S)-3-((6-oxo- 5-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)ami no)cyclohexyl)methyl)-6-(5- (trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one. [0741] Step 2. In a vial is added 4-((diphenylmethylene)amino)-7-fluoro-2-(((1R,3S)-3-((6- oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1,6-dihydropyridazin-4- yl)amino)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one (125 mg, 0.140 mmol), TFA (1.17 mL, 15.2 mmol), and DCM (5.0 mL). After 2 hrs LCMS shows cleavage of the SEM group, but the benzephenone imine remains. 5 drops of concentrated HCl is added, and the reaction is stirred for 72 hrs. The reaction is concentrated, treated with 2M NH 3 in MeOH (5.0 mL), and concentrated again. Purification via reverse phase prep-HPLC (5 – 100% MeCN in water, 0.1% TFA) to afford 4-amino-7-fluoro-2-(((1R,3S)-3-((6-oxo-5-(trifluoromethyl)-1 ,6-dihydropyridazin-4- yl)amino)cyclohexyl)methyl)-6-(5-(trifluoromethyl)pyrimidin- 2-yl)isoquinolin-1(2H)-one. 1 H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.52 (s, 2H), 8.55 (d, J = 6.9 Hz, 1H), 8.09 (d, J = 11.2 Hz, 1H), 7.92 (s, 1H), 7.03 (s, 1H), 6.33 (s, 1H), 2.08 – 1.89 (m, 1H), 1.87 – 1.78 (m, 2H), 1.78 – 1.69 (m, 1H), 1.65 – 1.54 (m, 1H), 1.47 – 1.21 (m, 3H), 1.02 – 0.88 (m, 1H). ES/MS m/z: 598.100 [M+H]. Example 487: 7-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-6-fluoro-3-(((1R,3S)- 3-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclohexyl )methyl)quinazolin-4(3H)-one [0742] The Following compound was synthesized using the procedure as described in Example 226, using 2-bromo-[1,2,4]triazolo[1,5-a]pyridine instead of 2-chloro-5-trifluoromethyl pyrimidine.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.09 (d, J = 6.9 Hz, 1H), 8.66 – 8.22 (m, 2H), 8.06 – 7.86 (m, 3H), 7.77 (m, 1H), 7.30 (m, 1H), 6.32 (m, 1H), 4.15 – 3.59 (m, 3H), 2.02 (s, 1H), 1.86 – 1.67 (m, 3H), 1.61 (m, 1H), 1.29 (m, 3H), 1.01 – 0.83 (m, 1H). ES/MS m/z: 555.1 [M+H]. Example 488: 6-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-7-fluoro-2-(((1R,3S)- 3-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)cyclohexyl )methyl)isoquinolin-1(2H)-one [0743] The Following compound was synthesized using the procedure as described in Example 226, using 2-bromo-[1,2,4]triazolo[1,5-a]pyridine instead of 2-chloro-5-trifluoromethyl pyrimidine.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.08 (d, J = 6.9 Hz, 1H), 8.58 (d, J = 6.9 Hz, 1H), 8.03 (d, J = 11.3 Hz, 1H), 8.01 – 7.86 (m, 2H), 7.83 – 7.66 (m, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.29 (m, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.33 (m, 1H), 3.89 (m, 3H), 2.02 (m, 1H), 1.77 (m, 3H), 1.58 (m, 1H), 1.32 (m, 3H), 1.11 – 0.86 (m, 1H). ES/MS m/z: 554.1 [M+H]. Example 489: (R)-6-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-(5-(difluoromet hoxy)-4-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7- fluoroisoquinolin-1(2H)-one [0744] The Following compound was synthesized using the procedure as described in Example 168 , using 2-bromo-[1,2,4]triazolo[1,5-a]pyridine instead of 2-chloro-5-trifluoromethyl pyrimidine.1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.08 (d, J = 6.8 Hz, 1H), 8.57 (d, J = 6.9 Hz, 1H), 8.16 – 7.89 (m, 3H), 7.83 – 7.68 (m, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.29 (m, 1H), 7.00 – 6.27 (m, 3H), 4.27 (m, 1H), 4.12 – 3.83 (m, 4H), 1.77 (m, 2H), 1.62 (m, 2H). ES/MS m/z: 594.0 [M+H]. Example 490: (R)-7-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-(5-(difluoromet hoxy)-4-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-6- fluoroquinazolin-4(3H)-one [0745] The Following compound was synthesized using the procedure as described in Example 168 , using 2-bromo-[1,2,4]triazolo[1,5-a]pyridine instead of 2-chloro-5-trifluoromethyl pyrimidine.1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.09 (d, J = 6.9 Hz, 1H), 8.54 – 8.39 (m, 2H), 8.12 – 7.93 (m, 3H), 7.87 – 7.68 (m, 1H), 7.30 (m, 1H), 6.95 – 6.30 (m, 2H), 4.27 (m, 1H), 4.06 – 3.76 (m, 4H), 1.71 (m, 4H). ES/MS m/z: 595.0 [M+H]. Example 491: 7-fluoro-6-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-[[(1 R,3S)-3-[[6-oxo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]cyclohexyl]methyl] isoquinolin-1-one [0746] The Following compound was synthesized using the procedure as described in Example 226 , using 2-3-chloro-1-methyl-5-(trifluoromethyl)pyrazole instead of 2-chloro-5- trifluoromethyl pyrimidine.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.27 (d, J = 7.1 Hz, 1H), 7.97 (d, J = 11.6 Hz, 1H), 7.90 (s, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.32 (d, J = 3.1 Hz, 1H), 6.75 (d, J = 7.4 Hz, 1H), 6.37 – 6.28 (m, 1H), 4.09 (s, 3H), 3.86 (d, J = 7.0 Hz, 2H), 3.79 – 3.66 (m, 1H), 2.08 – 1.93 (m, 1H), 1.85 – 1.67 (m, 3H), 1.56 (d, J = 12.4 Hz, 1H), 1.45 – 1.20 (m, 3H), 1.01 – 0.87 (m, 1H). ES/MS m/z: 585.10 [M+H]. [0747] Example 492: 7-fluoro-6-(5-methoxypyrimidin-2-yl)-2-[[(1R,3S)-3-[[6-oxo-5 - (trifluoromethyl)-1H-pyridazin-4-yl]amino]cyclohexyl]methyl] isoquinolin-1-one [0748] [0749] The Following compound was synthesized using the procedure as described in Example 226, using 2-bromo-5-methoxy-pyrimidine instead of 2-chloro-5-trifluoromethyl pyrimidine.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.75 (s, 2H), 8.28 (d, J = 7.3 Hz, 1H), 7.96 (d, J = 11.4 Hz, 1H), 7.91 (s, 1H), 7.48 – 7.43 (m, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.32 (dd, J = 7.9, 3.5 Hz, 1H), 4.00 (s, 3H), 3.88 (d, J = 6.8 Hz, 2H), 3.78 – 3.68 (m, 1H), 2.09 – 1.98 (m, 1H), 1.76 (dd, J = 30.9, 8.7 Hz, 3H), 1.57 (d, J = 12.6 Hz, 1H), 1.43 – 1.20 (m, 3H), 0.95 (q, J = 12.3, 11.0 Hz, 1H). ES/MS m/z: 545.20 [M+H]. [0750] Example 493: 7,8-difluoro-6-(5-methoxypyrimidin-2-yl)-2-[[(1R,3S)-3-[[6-o xo-5- (trifluoromethyl)-1H-pyridazin-4-yl]amino]cyclohexyl]methyl] isoquinolin-1-one [0751] [0752] The Following compound was synthesized using the procedure as described in Example 226, using 2-bromo-5-methoxy-pyrimidine instead of 2-chloro-5-trifluoromethyl pyrimidine.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.77 (s, 2H), 8.09 (d, J = 6.6 Hz, 1H), 7.92 (s, 1H), 7.48 (d, J = 7.4 Hz, 1H), 6.75 (d, J = 7.3 Hz, 1H), 6.36 – 6.28 (m, 1H), 4.01 (s, 3H), 3.83 (dd, J = 7.2, 3.1 Hz, 2H), 3.73 (d, J = 5.1 Hz, 1H), 2.01 (m, 1H), 1.80 (m, 2H), 1.73 (d, J = 11.0 Hz, 1H), 1.57 (d, J = 12.7 Hz, 1H), 1.31 (m, 4H), 0.94 (m, 1H). ES/MS m/z: 563.20 [M+H]. [0753] Example 494: 7-fluoro-6-(6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-( ((1R,3S)-3- ((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4- yl)amino)cyclohexyl)methyl)isoquinolin-1(2H)-one [0754] [0755] The Following compound was synthesized using the procedure as described in Example 226, using 2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine instead of 2-chloro-5-trifluoromethyl pyrimidine.1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.46 (m, 1H), 8.55 (d, J = 6.9 Hz, 1H), 8.12 – 7.69 (m, 3H), 7.49 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.33 (m, 1H), 3.89 (m, 2H), 2.05 (m, 1H), 1.77 (m, 4H), 1.58 (m, 1H), 1.32 (m, 4H), 0.94 (m, 1H). ES/MS m/z: 572.20 [M+H]. [0756] Example 495: 7-fluoro-6-[5-(2-hydroxyethoxy)pyrimidin-2-yl]-2-[[(1R,3S)-3 -[[6- oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]cyclohexyl]m ethyl]isoquinolin-1-one [0757] [0758] The Following compound was synthesized using the procedure as described in Example 226, using tert-butyl-[2-(2-chloropyrimidin-5-yl)oxyethoxy]-dimethyl-si lane instead of 2-chloro- 5-trifluoromethyl pyrimidine.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.75 (s, 2H), 8.29 (d, J = 7.3 Hz, 1H), 7.96 (d, J = 11.4 Hz, 1H), 7.91 (s, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.32 (dd, J = 8.4, 4.2 Hz, 1H), 4.27 (t, J = 4.8 Hz, 2H), 3.88 (d, J = 7.0 Hz, 2H), 3.78 (t, J = 4.8 Hz, 2H), 2.05 (d, J = 22.9 Hz, 1H), 1.85 – 1.67 (m, 3H), 1.57 (d, J = 12.6 Hz, 1H), 1.31 (dq, J = 34.7, 11.8 Hz, 3H), 0.95 (q, J = 12.0 Hz, 1H). ES/MS m/z: 575.20 [M+H]. [0759] Example 496: 6-(7,7-difluoro-5,6-dihydrocyclopenta[c]pyridin-3-yl)-7-fluo ro-2- [[(1R,3S)-3-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4- yl]amino]cyclohexyl]methyl]isoquinolin-1-one [0760] [0761] The Following compound was synthesized using the procedure as described in Example 226, using 3-chloro-7,7-difluoro-5,6-dihydrocyclopenta[c]pyridine instead of 2-chloro-5- trifluoromethyl pyrimidine.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.00 (s, 1H), 8.25 (d, J = 7.3 Hz, 1H), 8.01 (d, J = 11.6 Hz, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.47 (d, J = 7.4 Hz, 1H), 6.78 (d, J = 7.3 Hz, 1H), 6.37 – 6.28 (m, 1H), 3.89 (d, J = 7.0 Hz, 2H), 3.79 – 3.66 (m, 1H), 3.25 – 3.15 (m, 2H), 2.71 (tt, J = 14.4, 6.8 Hz, 2H), 2.10 – 1.95 (m, 1H), 1.84 – 1.66 (m, 3H), 1.57 (d, J = 12.7 Hz, 1H), 1.46 – 1.20 (m, 3H), 1.03 – 0.88 (m, 1H). ES/MS m/z: 590.2 [M+H]. [0762] Example 497: 6-fluoro-7-(5-methoxypyrimidin-2-yl)-3-[[(1R,3S)-3-[[6-oxo-5 - (trifluoromethyl)-1H-pyridazin-4-yl]amino]cyclohexyl]methyl] quinazolin-4-one [0763] [0764] The Following compound was synthesized using the procedure as described in Example 226, using 2-bromo-5-methoxy-pyrimidine instead of 2-chloro-5-trifluoromethyl pyrimidine.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.76 (s, 2H), 8.39 (s, 2H), 8.22 (d, J = 11.4 Hz, 1H), 7.93 (d, J = 9.4 Hz, 2H), 6.37 - 6.27 (m, 1H), 4.00 (s, 3H), 3.90 (d, J = 6.8 Hz, 2H), 3.71 (s, 1H), 2.09 – 1.95 (m, 1H), 1.82 (d, J = 12.9 Hz, 2H), 1.66 (dd, J = 52.9, 11.6 Hz, 2H), 1.43 – 1.18 (m, 3H), 1.02 - 0.88 (m, 1H). ES/MS m/z: 546.20 [M+H]. [0765] Example 498: 6-fluoro-7-(5-methoxypyrimidin-2-yl)-3-[[(1R,3S)-3-[[6-oxo-5 - (trifluoromethyl)-1H-pyridazin-4-yl]amino]cyclohexyl]methyl] quinazolin-4-one [0766] [0767] The Following compound was synthesized using the procedure as described in Example 226, using 2-bromo-5-methoxy-pyrimidine instead of 2-chloro-5-trifluoromethyl pyrimidine.1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.75 (s, 2H), 8.28 (d, J = 7.3 Hz, 1H), 8.00 – 7.91 (m, 2H), 7.48 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 7.3 Hz, 1H), 6.66 (t, J = 75.5 Hz, 1H), 6.44 – 6.37 (m, 1H), 4.34 – 4.20 (m, 1H), 4.05 – 3.95 (m, 5H), 3.96 – 3.90 (m, 2H), 1.84 – 1.68 (m, 2H), 1.68 – 1.52 (m, 2H). ES/MS m/z: 585.1 [M+H]. a. VII. Compound Table b. The following compounds were prepared according to the Examples and Procedures described herein (and indicated in Table 1 under Example/Procedure) using the appropriate starting material(s) and appropriate protecting group chemistry as needed. VIII. Biological Data Probe Displacement Assay for PARP7 c. Displacement of a biotinylated probe (RBN011147; Wigle et al., Cell Chemical Biology, 2020, pp.877-887) from the PARP7 NAD+-binding site was measured in vitro using a Mesoscale Discovery electrochemiluminescent assay. Twenty microliters of the biotinylated probe (78nM, 2x Kd) in PBS buffer was incubated for 1 hour at room temperature in MSD streptavidin-coated plates (CAT #L21SA). The plates were then washed 3x with PBS and subsequently blocked overnight in PBS buffer containing 1% BSA. The BSA is removed with 3x PBS washes, the remaining PBS is flicked out of the plate, and 10ml of PARP7 assay buffer (20mM Hepes pH 7.4, 100mM NaCl, 0.1% BSA, 1mM DTT, 0.002% Tween-20) is added to each well of the 384-well MSD plate. Next, 10ml of 10nM PARP7 protein incubated for 1 hour at room temperature with a dose response curve of each test compound in a Greiner LDV polypropylene plate (#781201) is added to the MSD plate containing the immobilized probe. The interaction is allowed to reach equilibrium for 1.5 hours, and then 10ml of SULFO-TAG labeled anti-GST antibody (Cat# R32AA-1) is added to each well and allowed to incubate for an additional 1.5 hours at room temperature. Finally, 10ml of MSD read buffer T (4x, Cat. #R92C-1) is added to each well using a Bravo liquid handler to prevent air bubbles in the wells, and the plates are subsequently read in an MSD instrument. Light intensity is then measured to quantify the amount of PARP7 bound to the immobilized probe on the plate. Therefore, the ability of a compound to displace the PARP7/probe interaction results in decreased light emission. Control wells containing a DMSO (negative) and 10mM GS-11154611 (positive) were used to calculate the % inhibition, and the values were then plotted as a function of compound concentration and a 4-parameter fit was applied to derive the IC 50 values. Phospho-STAT1 (Tyr701 LANCE Ultra TR-FRET detection assay d. LANCE Ultra phospho-STAT1 (Tyr701) kits are designed for the detection of phosphorylated STAT1 in cell lysates using a simple, homogeneous LANCE Ultra sandwich assay (Cat. #TRF4028M). This assay is intended for assessing compound induction of endogenous levels of cellular STAT1 (phosphorylated at Tyr701) in NCI-H1373 cells. The NCI-H1373 cells are cultured in RPMI 1640 media containing 10% heat inactivated FBS, GlutaMAX, 1% Penicillin-Streptomycin. An Echo acoustic liquid handler is used to transfer 60 nanoliters of compound dilutions using the Echo Qualified, 384-well polypropylene microplate clear flat bottom source plates into a Greiner (#781080) cell culture microplate. NCI-H1373 cells are seeded into these compound-spotted culture plates at 30,000 cells/well in a 60uL volume in growth media. The plates are incubated in a 5% CO2 humidified incubator at 37 o C for 48 hours. The media is removed and the cells are processed according to the manufacturer’s suggested protocol. Briefly, 20mL of supplemented lysis buffer is added to each well and allowed to shake for 1 hour at 400rpm. Next, 5ul of remixed antibody solutions (vol/vol) prepared in detection buffer are added to each well and allowed to incubate at room temperature overnight. After spinning the plate down at 300rpm for 1min, the plate is read on an EnVision plate reader set up for Eu3+ Cryptate and fluorescence emission is measured at two different wavelengths (665nm and 620nm). The HTRF ratio is then calculated (665nM/620nM) for each well to determine the amount of pSTAT1 in the cell lysate, and the data is then normalized to 10uM GS-1154611 positive and DMSO negative controls. The values were then plotted as a function of compound concentration and a 4-parameter fit was applied to derive the EC50 values. VIII. Biological Data