IL324205A

IL324205A - Bicyclic heteroarylamides with GPR68 modulatory activity

Info

Publication number: IL324205A
Application number: IL324205A
Authority: IL
Inventors: Simon Richards; Michael Prime; Konstantinos Papachristos; Manisha Naik; Reid Hans Johnson Olsen
Original assignee: Recursion Pharmaceuticals Inc; Simon Richards; Michael Prime; Konstantinos Papachristos; Manisha Naik; Reid Hans Johnson Olsen
Priority date: 2023-06-01
Filing date: 2024-05-31
Publication date: 2025-12-01
Also published as: AU2024282839A1; CN121399126A; JP2026518315A; EP4720067A1; WO2024246559A1; CL2025003739A1; CO2025018379A2; MX2025014319A; KR20260019509A

Description

GPR68 MODULATORS TECHNICAL FIELD LO The present invention relates to novel GPR68 modulators , their pharmaceutically acceptable salts , and pharmaceutical compositions thereof . The present invention also relates to methods of using such compounds and compositions , including to treat various diseases and disorders ; particularly cancer and / or proliferative diseases or disorders .

BACKGROUND GPR68 ( also known as ovarian cancer G protein - coupled receptor 1 or OGR1 ) is a proton- sensing G - protein - coupled receptor ( GPCR ) that responds to extracellular acidity and regulates a variety of cellular functions . It has been found that GPR68 expression is highly upregulated in numerous types of cancer , such as colon cancer , medulloblastoma , head and neck cancer , pancreatic cancer and prostate cancer , and it has been suggested that GPRhas key roles in tumour biology . As such , GPR68 is an attractive target for anti - cancer drug development . Until now , however , few compounds have been identified as selective GPRligands / modulators .

An unmet medical need therefore exists for effective and safe GPR68 modulators .

The present invention has been devised to address at least one of the challenges described above .

SUMMARY OF THE INVENTION Generally , provided herein are compounds and pharmaceutical compositions capable of modulating GPR68 . Also provided are method of treatment and therapeutic / medical uses involving compounds or pharmaceutical compositions of this disclosure for for treating diseases , disorders or conditions associated with GPR68 .

In an aspect of this disclosure , there is provided a compound of formula ( 1 ) : 1 RL .N . R XA +X³R R( 1 ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein : Q is O or S ; 1✗ is selected from C and N ; ²X is selected from CR5 and N ; X3 is selected from CR and N ; X4 is selected from CR7 and N ; X5 is selected from C and N ; wherein X1 , X2 , X3 , X4 and X5 are selected so that the ring labelled A is aromatic ; X6 is selected from CR8R9 , O and N ; X7 is selected from CR10 , CR11 R12 , O and N ; q is 0 or 1 ; wherein when q is 0 , X7 is O or N ; and when X7 is O or N and q is 1 , X6 is CR8R9 ; ¹L is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S ; R1 is selected from C1 - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one 2 LO or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C1 - C4 haloalkoxy , ₁C - C4 alkyl - b¹Ra1RN , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; or R1 , R2 and L ' and the nitrogen atom to which R2 and L ' are attached form a 3- to 8- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , or 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , C1 - Calkoxy , C1 - C4 haloalkoxy and ₁C - C4 alkyl - NR1aR1b ; ³R is selected from H , OH , CN , b3R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , C1 - C4 alkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - C1 - C4 alkyl , C3 - C8 cycloalkyl - ₁C - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2- C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , C1- C4 alkyl , and d³Rc³RN ; a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³R³RN ; R3b , R3c , d³R , e³R and f³R are each independently selected from H and ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR4R4b and 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 ; R4a and R4b are each independently selected from H and C1 - C4 alkyl ; 3 LO R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - Chaloalkyl , C1 - C4 alkoxy , ₁C - C4 alkoxy - C1 - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , R8 , ⁹R , R10 , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 .

In embodiments , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , C1 - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - b1Rª¹RN , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; ³R is selected from H , OH , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C LO C4 alkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - ₁C - C4 alkoxy , C1 - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2- C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and NR3cR3d : ' a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³R³RN ; R3b , c³R , d³R , e³R and f³R are each independently selected from H and C1 - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) ª4RN R4 , C ( S ) NR 4 R4 and 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 ; R4a and R4b are each independently selected from H and ₁C - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , ³R , ⁹R , º¹R , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C3 - ɛC cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S ; R1 is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , C1 - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , halophenoxy , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , b³R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and d³Rc3RN ; a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Re³RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; 3e e³R and f³R are each independently selected from C1 - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) 4Rª4RN , C ( S ) ª4RN R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments , L ' is a bond , ₁C - C6 alkylene , ₁C - εC haloalkylene , or C3 - C6 cycloalkylene ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , C1 - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C6 LO alkyl - NR1aR1b , C3 - C8 cycloalkyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , and ₁C - C4 alkyl substituted by a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , b3R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , C1 - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC3RN ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR ª4 R4b , C ( S ) NR ª4 R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , R9 , º¹R , R11 , and R12 are each H.

In embodiments , L ' is a bond , ₁C - C6 alkylene , or ₁C - C6 haloalkylene ; R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- 7 NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC³RN ; a³R is selected from H and ₁C - C4 alkyl ; 3a R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; R4 is selected from the following groups : vir .OH .NHviv NH2 viv CH S ; and ; and wherein indicates the point of attachment to the rest of the compound ; R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments , L ' is a bond , ₁C - C6 alkylene , or C3 - C6 cycloalkylene ; O , R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each LO optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; ²R is H ; ³R is selected from H , CN , b3R³RN , ₁C - C4 alkyl optionally substituted by OH , C3 - Ccycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl - ₁C - C4 alkoxy , ₁C - C4 haloalkoxy- ₁C - C4 alkyl ,, ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : viv .OH ; S NH ; and viv .NH ; wherein indicates the point of attachment to the rest of the compound ; R5 is H ; R6 is selected from H and ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments , L ' is either a bond or ₁C - C6 alkylene ; R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; ²R is H ; ³R is selected from NR 3R 3b , ₁C - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR 3c d³R , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , C3 - C 9 LO cycloalkoxy - ₁C - C4 alkyl , ₁C - C4 alkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , ³C - Ccycloalkyl - C1 - C4 alkoxy , and alkyl - S - ₁C - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : .OH vir .NHviv NH indicates the S ; and point of attachment to the rest of the compound ; R5 , R7 , R8 , ⁹R , R10 , R11 , and R12 are each H ; and R6 is selected from H and ₁C - C4 alkyl .

In embodiments , Q is O.

In embodiments , L is either a bond or methylene .

In embodiments , R1 is selected from : ; wherein C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4 haloalkoxy ; C8 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl and C1 - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen and C1 - C4 alkyl ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , ○ and S , optionally substituted by one or more substituents independently selected from C1 - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl .

LO In embodiments , ²R is H.

In embodiments , ³R is selected from : NR3aR3b ₁C - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; wherein ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; and ₁C - C4 alkyl - S - ₁C - C4 alkyl ; R3a is H ; and R3b is selected from ₁C - C4 alkyl .

In embodiments , ³R is selected from ₁C - C4 alkoxy - ₁C - C4 alkyl .

In embodiments , R4 is selected from the following groups : OH viv NHviv CH viv viv NH ; N. ; ; and indicates the point of attachment to the rest of the S compound . wherein ' In embodiments , R5 is H.

In embodiments , R6 is H or methyl . 11 In embodiments , R7 , R8 , ºR , R10 , R11 , and R12 are each H.

In an aspect of this disclosure , there is provided a compound of formula ( 2a ) : R R R N.

RX ' N ' N R -R ( 2a ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein Q is O or S ; X1 is selected from C and N ; ²X is selected from CR5 and N ; X3 is selected from CR6 and N ; X4 is selected from CR7 and N ; X5 is selected from C and N ; wherein X1 , X2 , ³X , ªX and X5 are selected so that the ring labelled A is aromatic ; X6 is selected from CR8R9 , O and N ; X7 is selected from CR10 , CR11 R12 , O and N ; q is 0 or 1 ; wherein when q is 0 , X7 is O or N ; and when X7 is O or N and q is 1 , X6 is CR8R9 ; L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , C1 - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; R2 is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; or R1 , R2 and L1 and the nitrogen atom to which R2 and L1 are attached form a 3- to 8- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , or 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - Chaloalkoxy and ₁C - C4 alkyl - NR1aR1b ; ³R is selected from H , OH , CN , b³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C C4 alkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2- C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and NR3cR3d a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³R³RN ; ¸b³R c³R , d³R , e³R and f³R are each independently selected from H and C1 - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) b4Rª4RN , C ( S ) NR ª4 R4b and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a and R4b are each independently selected from H and ₁C - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , R8 , ⁹R , R10 , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , C1 - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - b1Rª¹RN , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; ³R is selected from H , OH , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C LO C4 alkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - ₁C - C4 alkoxy , C1 - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2- C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and NR3cR3d : ' a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³R³RN ; R3b , c³R , d³R , e³R and f³R are each independently selected from H and C1 - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) ª4RN R4 , C ( S ) NR 4 R4 and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a and R4b are each independently selected from H and ₁C - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , ³R , ⁹R , º¹R , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C3 - ɛC cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S ; R1 is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more S and SO2.selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ³¹Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - Calkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , halophenoxy , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is H ; ³R is selected from H , CN , b³R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and d³Rc3RN ; a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Re³RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; 3e e³R and f³R are each independently selected from C1 - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) 4Rª4RN , C ( S ) ª4RN R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments , L ' is a bond , ₁C - C6 alkylene , ₁C - εC haloalkylene , or C3 - C6 cycloalkylene ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , ₁O S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , LO ₁C - C4 haloalkoxy , ₁C - C4 alkyl - b1Rª¹RN , C3 - C8 cycloalkyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , and C1 - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC3RN ; a³R is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) b4Rª4RN , C ( S ) NR 4 R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments , L ' is a bond , ₁C - C6 alkylene , or ₁C - C6 haloalkylene ; R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC³RN ; a³R is selected from H and ₁C - C4 alkyl ; 3a R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; R4 is selected from the following groups : vir .OH .NHviv NH2 viv CH S ; and wherein ; and indicates the point of attachment to the rest of the compound ; R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments , L ' is either a bond or ₁C - C6 alkylene ; R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; ²R is H ; ³R is selected from NR 3R 3b , ₁C - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR 3c d³R , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , C3 - C 19 LO cycloalkoxy - ₁C - C4 alkyl , ₁C - C4 alkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , ³C - Ccycloalkyl - C1 - C4 alkoxy , and alkyl - S - ₁C - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : .OH vir .NHviv NH S ; and ; wherein indicates the point of attachment to the rest of the compound R5 , R7 , ºR , ºR , R10 , R11 , and R12 are each H ; and R6 is selected from H and ₁C - C4 alkyl .

In embodiments , Q is O.

In embodiments , L is either a bond or methylene .

In embodiments , R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4 haloalkoxy ; C8 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl and C1 - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen and C1 - C4 alkyl ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , ○ and S , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl .

LO In embodiments , ²R is H.

In embodiments , ³R is selected from ₁C - C4 alkoxy - ₁C - C4 alkyl .

In embodiments , R6 is H or methyl . 21 In embodiments , R7 , R8 , ºR , R10 , R11 , and R12 are each H.

In an aspect of this disclosure , there is provided a compound of formula ( 2aa ) : R R.N .

R.N R R -R ( 2aa ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein Q is O or S ; 1✗ is selected from C and N ; ²X is selected from CR5 and N ; ³X is selected from CR6 and N ; X4 is selected from CR7 and N ; X5 is selected from C and N ; wherein X1 , X2 , X3 , X4 and X5 are selected so that the ring labelled A is aromatic ; X6 is selected from CR8R9 , O and N ; X7 is selected from CR10 , CR11 R12 , O and N ; q is 0 or 1 ; wherein when q is 0 , X7 is O or N ; and when X7 is O or N and q is 1 , X6 is CR8R9 ; L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , C1 - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; R2 is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; or R1 , R2 and L1 and the nitrogen atom to which R2 and L1 are attached form a 3- to 8- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , or 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - Chaloalkoxy and ₁C - C4 alkyl - NR1aR1b ; ³R is selected from H , OH , CN , b³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C C4 alkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2- C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and NR3cR3d a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³R³RN ; ¸b³R c³R , d³R , e³R and f³R are each independently selected from H and C1 - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) b4Rª4RN , C ( S ) NR ª4 R4b and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a and R4b are each independently selected from H and ₁C - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , R8 , ⁹R , R10 , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments , L ' is a bond , ₁C - C6 alkylene , ₁C - εC haloalkylene , or C3 - C6 cycloalkylene ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , C1 - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C26 LO alkyl - NR1aR1b , C3 - C8 cycloalkyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , and ₁C - C4 alkyl substituted by a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , b3R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , C1 - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC3RN ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR ª4 R4b , C ( S ) NR ª4 R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , R9 , º¹R , R11 , and R12 are each H.

In embodiments , L ' is a bond , ₁C - C6 alkylene , or ₁C - C6 haloalkylene ; R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- 27 NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC³RN ; a³R is selected from H and ₁C - C4 alkyl ; 3a R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; R4 is selected from the following groups : vir .OH .NHviv NH2 viv CH S ; and ; and wherein indicates the point of attachment to the rest of the compound ; R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments , L ' is a bond , ₁C - C6 alkylene , or C3 - C6 cycloalkylene ; O , R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each LO optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; ²R is H ; ³R is selected from H , CN , b3R³RN , ₁C - C4 alkyl optionally substituted by OH , C3 - Ccycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl - ₁C - C4 alkoxy , ₁C - C4 haloalkoxy- ₁C - C4 alkyl ,, ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : viv .OH ; S NHviv ; and .NH ; wherein indicates the point of attachment to the rest of the compound ; R5 is H ; R6 is selected from H and ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments , L ' is either a bond or ₁C - C6 alkylene ; R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; ²R is H ; ³R is selected from NR 3R 3b , ₁C - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR 3c d³R , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , C3 - C 29 LO cycloalkoxy - ₁C - C4 alkyl , ₁C - C4 alkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , ³C - Ccycloalkyl - C1 - C4 alkoxy , and alkyl - S - ₁C - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : .OH vir .NHviv NH S ; and ; wherein indicates the point of attachment to the rest of the compound R5 , R7 , ºR , ºR , R10 , R11 , and R12 are each H ; and R6 is selected from H and ₁C - C4 alkyl .

In embodiments , Q is O.

In embodiments , L is either a bond or methylene .

LO In embodiments , ²R is H.

In embodiments , ³R is selected from ₁C - C4 alkoxy - ₁C - C4 alkyl .

In embodiments , R6 is H or methyl . 31 In embodiments , R7 , R8 , ºR , R10 , R11 , and R12 are each H.

In an aspect of this disclosure , there is provided a compound of formula ( 2ab ) : R RN R.N R' N ' R ³R- ( 2ab ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein Q is O or S ; 1✗ is selected from C and N ; ²X is selected from CR5 and N ; X3 is selected from CR6 and N ; X4 is selected from CR7 and N ; X5 is selected from C and N ; wherein X1 , X2 , X3 , X4 and X5 are selected so that the ring labelled A is aromatic ; X6 is selected from CR8R9 , O and N ; X7 is selected from CR10 , CR11 R12 , O and N ; q is 0 or 1 ; wherein when q is 0 , X7 is O or N ; and when X7 is O or N and q is 1 , X6 is ⁹R³RC ; L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S ; R1 is selected from C1 - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , C1 - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; R2 is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; or R1 , R2 and L1 and the nitrogen atom to which R2 and L1 are attached form a 3- to 8- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , or 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - Chaloalkoxy and ₁C - C4 alkyl - NR1aR1b ; ³R is selected from H , OH , CN , b³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C C4 alkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2- C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and NR3cR3d a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³R³RN ; ¸b³R c³R , d³R , e³R and f³R are each independently selected from H and C1 - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) b4Rª4RN , C ( S ) NR ª4 R4b and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a and R4b are each independently selected from H and ₁C - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , R8 , ⁹R , R10 , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments , L ' is a bond , ₁C - C6 alkylene , ₁C - εC haloalkylene , or C3 - C6 cycloalkylene ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , C1 - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C36 LO alkyl - NR1aR1b , C3 - C8 cycloalkyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , and ₁C - C4 alkyl substituted by a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , b3R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , C1 - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC3RN ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR ª4 R4b , C ( S ) NR ª4 R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , R9 , º¹R , R11 , and R12 are each H.

In embodiments , L ' is a bond , ₁C - C6 alkylene , or ₁C - C6 haloalkylene ; R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- 37 NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC³RN ; a³R is selected from H and ₁C - C4 alkyl ; 3a R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; R4 is selected from the following groups : vir .OH .NHviv NH2 viv CH S ; and ; and wherein indicates the point of attachment to the rest of the compound ; R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments , L ' is either a bond or ₁C - C6 alkylene ; R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; ²R is H ; ³R is selected from NR 3R 3b , ₁C - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR 3c d³R , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , C3 - C 39 LO cycloalkoxy - ₁C - C4 alkyl , ₁C - C4 alkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , ³C - Ccycloalkyl - C1 - C4 alkoxy , and alkyl - S - ₁C - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : .OH vir .NHviv NH S ; and ; wherein indicates the point of attachment to the rest of the compound R5 , R7 , ºR , ºR , R10 , R11 , and R12 are each H ; and R6 is selected from H and ₁C - C4 alkyl .

In embodiments , Q is O.

In embodiments , L is either a bond or methylene .

In embodiments , R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4 haloalkoxy ; C8 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl and C1 - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen and C1 - C4 alkyl ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , ○ and S , optionally substituted by one or more substituents independently selected from C1 - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl . 40 LO In embodiments , ²R is H.

In embodiments , ³R is selected from ₁C - C4 alkoxy - ₁C - C4 alkyl .

In embodiments , R6 is H or methyl . 41 In embodiments , R7 , R8 , ºR , R10 , R11 , and R12 are each H.

In an aspect of this disclosure , there is provided a compound of formula ( 2ad ) : R R RN ' N ' N ' N ' R R ( 2ad ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein Q is O or S ; X1 is selected from C and N ; X2 is selected from CR5 and N ; X3 is selected from CR and N ; X4 is selected from CR7 and N ; X5 is selected from C and N : wherein X1 , X2 , X3 , X4 and X5 are selected so that the ring labelled A is aromatic ; X6 is selected from CR8R9 , O and N ; X7 is selected from CR10 , CR11 R12 , O and N ; q is 0 or 1 ; wherein when q is 0 , X7 is O or N ; and when X7 is O or N and q is 1 , X6 is CR8R9 ; L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S ; R1 is selected from C1 - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- 42 LO membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - b¹Rª¹RN , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; or R1 , R2 and L ' and the nitrogen atom to which R2 and ₁L are attached form a 3- to 8- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , or 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1 R1b , ₁C - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - Chaloalkoxy and ₁C - C4 alkyl - b1Rª¹RN ; ³R is selected from H , OH , CN , b³R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C C4 alkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2- C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and d³Rc3RN a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³R³RN ; R3b , R3c , d³R , e³R and f³R are each independently selected from H and ₁C - C4 alkyl ; 43 LO R4 is selected from C ( O ) OH , C ( O ) b4Rª4RN , C ( S ) NR ª4 R4b and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a and R4b are each independently selected from H and ₁C - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , C1 - Chaloalkyl , ₁C - C4 alkoxy , C1 - C4 alkoxy - C1 - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , R8 , ºR , º1R , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; 44 LO ³R is selected from H , OH , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C C4 alkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - ₁C - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and C1 - C4 alkyl - SO2- C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and NR3CR3d . a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³R³RN ; R3b , R3c , d³R , e³R and f³R are each independently selected from H and C1 - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR 4R 4b and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a and R4b are each independently selected from H and ₁C - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - Chaloalkyl , ₁C - C4 alkoxy , C1 - C4 alkoxy - C1 - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , R8 , ⁹R , R10 , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments , L ' is a bond , C1 - C6 alkylene , C1 - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b¹Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1R1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or LO more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , halophenoxy , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , b³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , C1 - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - C1 - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and NR3CR3d : a³R is selected from H , ₁C - C4 alkyl , and C1 - C4 alkyl - f³R³RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; e³R and f³R are each independently selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR 4R 4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; Ra is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and LO phenoxy are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - Calkyl - NR1aR1b , C3 - C8 cycloalkyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , and ₁C - C4 alkyl substituted by a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , b3R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , зC - Ccycloalkyl - ₁C - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC3RN ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from C1 - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR4 R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ⁹R , º¹R , R11 , and R12 are each H.

In embodiments , L ' is a bond , ₁C - C6 alkylene , or ₁C - C6 haloalkylene ; R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from LO halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; R2 is H ; ³R is selected from H , CN , b3R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , C1 - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC3RN ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; R4 is selected from the following groups : .OH viv NHiv xxx ; S ; and NHCH ; and wherein indicates the point of attachment to the rest of the compound ; R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ⁹R , º¹R , R11 , and R12 are each H.

In embodiments , L ' is a bond , ₁C - C6 alkylene , or C3 - C6 cycloalkylene ; R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , C1 - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; ²R is H ; ³R is selected from H , CN , b³Rª³RN , ₁C - C4 alkyl optionally substituted by OH , C3 - Ccycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl - ₁C - C4 alkoxy , ₁C - C4 haloalkoxy- C1 - C4 alkyl ,, C1 - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2 - ₁C - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : .OH vir NHviv NH ; S ; and point of attachment to the rest of the compound ; R5 is H ; R6 is selected from H and ₁C - C4 alkyl ; and ; wherein indicates the R7 , R8 , R9 , R10 , R11 , and R12 are each H.

In embodiments , L ' is either a bond or ₁C - C6 alkylene ; R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; ²R is H ; ³R is selected from NR 3R 3b , ₁C - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR 3R3d , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- 49 membered heteroaryl having one or more heteroatoms selected from N , O and S , C3 - Ccycloalkoxy - ₁C - C4 alkyl , ₁C - C4 alkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , and alkyl - S - ₁C - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : LO viv .OH viv NHviv .NH S ; and ; wherein indicates the point of attachment to the rest of the compound R5 , R7 , ºR , ºR , R10 , R11 , and R12 are each H ; and R6 is selected from H and ₁C - C4 alkyl .

In embodiments , Q is O.

In embodiments , L is either a bond or methylene .

In embodiments , R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4 haloalkoxy ; C8 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl and C1 - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl .

LO In embodiments , ²R is H.

In embodiments , ³R is selected from : NR3aR3b . ' C1 - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; ₁C - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - C1 - C4 alkyl ; wherein ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; and ₁C - C4 alkyl - S - ₁C - C4 alkyl ; a³R is H ; and R3b is selected from ₁C - C4 alkyl .

In embodiments , ³R is selected from ₁C - C4 alkoxy - ₁C - C4 alkyl .

In embodiments , R4 is selected from the following groups : .OH viv NHviv .N . CH viv viv S NH wherein ' compound .

In embodiments , R5 is H.

; N ; ; and indicates the point of attachment to the rest of the In embodiments , R6 is H or methyl .

LO In embodiments , R7 , ³R , ºR , R10 , R11 , and R12 are each H.

In another aspect of this disclosure , there is provided a compound of formula ( 1 ) selected from Table 1. In another aspect there is provided a compound according to any one of compounds 1 to 242 , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof ; for example a compound selected from compounds 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , and 242 ; for example a compound selected from 1 , 2 , 4 , 5 , 6 , 7 , 8 , 9 , 11 , 14 , 15 , 18 , 19 , 20 , 21 , 22 , , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , and 242 ; for example a compound selected from 1 , 2 , 4 , 5 , 6 , 9 , 14 , 18 , 21 , 22 , 25 , 26 , 27 , 29 , 30 , 32 , , 34 , 35 , 36 , 37 , 39 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , , 86 , 87 , 88 , 91 , 92 , 93 , 94 , 95 , 97 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , LO 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , and 242 ; for example a compound selected from 1 , 2 , 4 , 6 , 21 , 26 , 27 , 33 , 34 , 37 , 42 , 43 , 44 , 46 , 48 , , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 78 , 79 , , 81 , 82 , 83 , 85 , 86 , 87 , 88 , 91 , 92 , 93 , 94 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 126 , 127 , 128 , 129 , 130 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , and 242 ; for example a compound selected from 27 , 33 , 34 , 37 , 46 , 54 , 56 , 57 , 58 , 59 , 60 , 61 , 64 , 66 , , 70 , 72 , 73 , 74 , 75 , 79 , 80 , 82 , 83 , 85 , 87 , 88 , 91 , 92 , 93 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 123 , 128 , 129 , 130 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 144 , 145 , 147 , 148 , 150 , 151 , 152 , 153 , 157 , 158 , 159 , 160 , 163 , 164 , 166 , 167 , 168 , 169 , 170 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 182 , 183 , 184 , 189 , 191 , 192 , 193 , 194 , 195 , 196 , 200 , 201 , 202 , 208 , 209 , 210 , 211 , 214 , 216 , 217 , 219 , 222 , 223 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , and 242 .

In another aspect of this disclosure , there is provided a compound of formula ( 1 ) as described above for use in medicine . In another aspect of this disclosure , there is provided a compound of formula ( 2aa ) as described above for use in medicine . In another aspect of this disclosure , there is provided a compound of formula ( 2ab ) as described above for use in medicine . In another aspect of this disclosure , there is provided a compound of formula ( 2ad ) as described above for use in medicine .

In embodiments , the compound of formula ( 1 ) , formula ( 2aa ) , ( 2ab ) , or ( 2ad ) is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder .

LO In embodiments , the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 1 ) , formula ( 2aa ) , formula ( 2ab ) or formula ( 2ad ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 1 ) , formula ( 2aa ) , formula ( 2ab ) , or formula ( 2ad ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier for use for use in medicine .

In embodiments , the pharmaceutical composition comprising a compound of formula ( 1 ) , formula ( 2aa ) , formula ( 2ab ) , or formula ( 2ad ) is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder .

LO In embodiments , the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , muscular myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) .

Within the scope of this disclosure it is expressly intended that the various aspects , embodiments , examples and alternatives set out in the preceding paragraphs , in the claims and / or in the following description and drawings , and in particular the individual features thereof , may be taken independently or in any combination . That is , all embodiments and / or features of any embodiment can be combined in any way and / or combination , unless such features are incompatible . More particularly , it is specifically intended that any embodiment of any aspect may form an embodiment of any other aspect , and all such combinations are encompassed within the scope of the invention . The applicant reserves the right to change any originally filed claim or file any new claim accordingly , including the right to amend any originally filed claim to depend from and / or incorporate any feature of any other claim although not originally claimed in that manner .

DETAILED DESCRIPTION Described herein are compounds and compositions ( e.g. organic molecules , research tools , pharmaceutical formulations and therapeutics ) ; uses for the compounds and compositions of the disclosure ( in vitro and in vivo ) ; as well as corresponding methods , whether diagnostic , LO therapeutic or for research applications . The chemical synthesis and biological testing of the compounds of the disclosure are also described . Beneficially , the compounds , compositions , uses and methods have utility in research towards and / or the treatment of diseases or disorders in animals , such as humans . Diseases or disorders which may benefit from GPRmodulation include , cancer and / or oncologic disease .

However , the compounds of the disclosure may also or alternatively be useful as lead molecules for the selection , screening and development of further derivatives that may have one or more improved beneficial drug property , as desired .

The disclosure also encompasses salts , solvates , tautomers , enantiomers and functional derivatives of the compounds described herein . These compounds may be useful in the treatment of various diseases or disorders ; particularly those which may benefit from modulation of GPR68 .

GPR68 modulators are useful in compositions and methods suitable for treating many disorders , and particularly cancer and / or proliferative diseases or disorders . In some embodiments , the disease is selected from the group consisting of adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In some embodiments , the disease is selected from the group consisting of colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma . 56 GPR68 modulators are also useful in compositions and methods suitable for treating fibrotic disease and inflammatory disease .

LO Definitions Unless defined otherwise , all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art ( e.g. in organic , physical or theoretical chemistry ; biochemistry and molecular biology ) .

Unless otherwise indicated , the practice of the present invention employs conventional techniques in chemistry and chemical methods , biochemistry , molecular biology , pharmaceutical formulation , and delivery and treatment regimens for patients , which are within the capabilities of a person of ordinary skill in the art . Such techniques are also described in the literature cited herein , each of which is herein incorporated by reference in its entirety .

Prior to setting forth the detailed description of the invention , a number of definitions are provided that will assist in the understanding of the invention .

In accordance with the invention , the terms ' molecule ' or ' molecules ' are used interchangeably with the terms ' compound ' or ' compounds ' , and sometimes the term ' chemical structure ' . The term ' drug ' is typically used in the context of a pharmaceutical , pharmaceutical composition , medicament or the like , which has a known or predicted physiological or in vitro activity of medical significance ; but such characteristics and qualities are not excluded in a molecule or compound of the invention . The term ' drug ' is therefore used interchangeably with the alternatives terms and phrases ' therapeutic ( agent ) ' , ‘ pharmaceutical ( agent ) ' , and ' active ( agent ) ' . Therapeutics of the invention also encompass compositions and pharmaceutical formulations comprising the compounds of the invention .

It will be appreciated that certain compounds provided herein may contain one or more centres of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture , or in an enantiomerically pure form .

A compound or molecule as disclosed herein is meant to include all stereoisomers , geometric isomers , tautomers , and isotopically enriched variants of the structures depicted . Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified . The term ' tautomer ' , as used herein refers to compounds whose structures differ markedly in arrangement of LO atoms , but which exist in easy and rapid equilibrium , and it is to be understood that compounds provided herein may be depicted as different tautomers , and when compounds have tautomeric forms , all tautomeric forms are intended to be within the scope of the disclosure , and the naming of the compounds does not exclude any tautomer .

The term ' substantially free of other stereoisomers ' as used herein means less than 10 % of other stereoisomers , preferably less than 5 % of other stereoisomers , more preferably less than 2 % of other stereoisomers and most preferably less than 1 % of other stereoisomers are present .

Prodrugs and solvates of the compounds of the invention are also encompassed within the scope of the invention . The term ' prodrug ' means a compound ( e.g. a drug precursor ) that is transformed in vivo to yield a compound of the invention or a pharmaceutically acceptable salt , solvate or ester of the compound . The transformation may occur by various mechanisms ( e.g. by metabolic or chemical processes ) , such as by hydrolysis of a hydrolysable bond , e.g. in blood ( see Higuchi & Stella ( 1987 ) , " Pro - drugs as Novel Delivery Systems " , vol . 14 of the A.C.S. Symposium Series ; ( 1987 ) , " Bioreversible Carriers in Drug Design " , Roche , ed . , American Pharmaceutical Association and Pergamon Press ) . The compositions and medicaments of the invention therefore may comprise prodrugs of the compounds of the invention . In some aspects and embodiments , the compounds of the disclosure are themselves prodrugs which may be metabolised in vivo to give the therapeutically effective compound . For example , a sulfoxide prodrug may be metabolized in vivo to the therapeutically active sulfone ( see Basarab G.S. et al . , ( 2008 ) , Bioorg Med . Chem Lett , 18 ( 16 ) , 4716-4722 ; Gibhard L. et al . , ( 2008 ) , Antimicrobial Agents and Chemotherapy , 62 ( 12 ) , 00261-18 ) .

The term ' pharmaceutically acceptable salt ' as used herein refers to a salt that is not biologically or otherwise undesirable ( e.g. , not toxic or otherwise harmful ) . Thus , a ' pharmaceutically acceptable ' compound is compatible chemically and / or toxicologically with the other ingredients comprising a formulation and / or the subject being treated therewith . A salt of a compound of the disclosure is formed between an acid and a basic group of the compound , or a base and an acidic group of the compound . For example , when the compounds of the disclosure contain at least one basic group ( i.e. , groups that can be protonated ) , the disclosure includes the compounds in the form of their acid addition salts . with organic or inorganic acids such as , for example , but not limited to salts with hydrogen chloride , hydrogen bromide , phosphoric acid , sulfuric acid , nitric acid , benzenesulfonic acid , acetic acid , citric acid , glutamic acid , lactic acid , and methanesulfonic acid . When LO compounds of the disclosure contain one or more acidic groups ( e.g. , a carboxylic acid ) , the disclosure includes the pharmaceutically acceptable salts of the compounds formed with but not limited to alkali metal salts , alkaline earth metal salts or ammonium salts . Examples of such salts include , but are not limited to , sodium salts , potassium salts , calcium salts , magnesium salts or salts with ammonia or organic amines such as , for example , ethylamine , ethanolamine , triethanolamine or amino acids . Additional examples of such salts can be , found in Stahl , P. H. et al . Pharmaceutical Salts : Properties , Selection , and Use , 2nd Revised Edition , Wiley , 2011 .

In the context of the present disclosure , the terms ' individual ' , ' subject ' , or ' patient ' are used interchangeably to indicate an animal that may be suffering from a medical ( pathological ) condition and may be responsive to a molecule , pharmaceutical drug , medical treatment or therapeutic treatment regimen of the disclosure . The animal is suitably a mammal , such as a human , cow , sheep , pig , dog , cat , bat , mouse or rat . In particular , the subject may be a human .

As used herein , the terms ' treat ' ' treating ' or ' treatment ' include their generally accepted meanings in relation to therapeutic or palliative measures . Beneficial or desired clinical results in relation to the management and care of a patient or potential patient include , but are not limited to , alleviation or relief , in whole or in part , of symptoms associated with a disease , disorder or condition , diminishment of the extent of the disease , disorder or condition , a stabilized ( i.e. , not worsening ) state of disease , delay or slowing of disease progression , amelioration or palliation of the disease state ( e.g. , one or more symptoms of the disease , disorder or condition ) , and remission ( whether partial or total ) , whether detectable or undetectable . ' Treatment ' can also mean prolonging survival as compared to expected survival if not receiving treatment .

The term ' preventing ' as used herein means the prevention of the onset , recurrence or spread , in whole or in part , of the disease or condition as described herein , or a symptom thereof .

The term ' therapeutically effective amount ' as used herein refers to that amount of compound of the disclosure that will elicit the biological or medical response of a tissue , system , animal , or human that is being sought by a researcher , veterinarian , medical doctor or other . As will be recognized by a person of ordinary skill in the art , a therapeutically effective amount of the compounds of the disclosure will vary and will depend on the disease treated , the severity of the disease , the route of administration , and the gender , age , and LO general health condition of the subject to whom the compound is being administered . The therapeutically effective amount may be administered as a single dose once a day , or as split doses administered multiple ( e.g. , two , three or four ) times a day . The therapeutically effective amount may also be administered through continuous dosing , such as through infusion or with an implant .

Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds . That is , an atom , in particular when mentioned in relation to a compound according to any of the formulas disclosed herein comprises all isotopes and isotopic mixtures of that atom , either naturally occurring or synthetically produced , either with natural abundance or in an isotopically enriched form . For example , when hydrogen is mentioned , it is understood to refer to H¹ , 2H , H³ or mixtures thereof ; when carbon is mentioned , it is understood to refer to 11C , 12C , 13C , 14C or mixtures thereof ; when nitrogen is mentioned , it is understood to refer to 13N , 14N , 15 N or mixtures thereof ; when oxygen is mentioned , it is understood to refer to 140 , 150 , 160 , 170 , 180 or mixtures thereof ; and when fluoro is mentioned , it is understood to refer to 18F , 19F or mixtures thereof ; unless expressly noted otherwise . For example , in deuteroalkyl and deuteroalkoxy groups , where one or more hydrogen atoms are specifically replaced with deuterium ( 2H ) . As some of the aforementioned isotopes are radioactive , the compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms , and mixtures thereof , including radioactive compounds , wherein one or more non - radioactive atoms has been replaced by one of its radioactive enriched isotopes . Radiolabelled compounds are useful as therapeutic agents , e.g. , cancer therapeutic agents , research reagents , e.g. , assay reagents , and diagnostic agents , e.g. , in vivo imaging agents . All isotopic variations of the compounds provided herein , whether radioactive or not , are intended to be encompassed within the scope of the present disclosure .

In this regard , the term ' deuterium ' as used herein refers to an isotope of hydrogen that has one proton and one neutron in its nucleus and that has twice the mass of ordinary hydrogen . Deuterium herein is represented by the symbol ' D ' . The term ' deuterated ' by itself or used to modify a compound or group as used herein refers to the presence of at least one deuterium atom attached to carbon . For example , the term ' deuterated compound ' refers to a compound which contains one or more carbon - bound deuterium ( s ) . In a deuterated compound of the present disclosure , when a particular position is designated as having deuterium , it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium , which is about 0.015 % . The term ' undeuterated ' or ' non - deuterated ' as used herein refers to the ratio of deuterium atoms of LO which is not more than the natural isotopic deuterium content , which is about 0.015 % ; in other words , all hydrogens are present at their natural isotopic percentages . Unless otherwise stated , when a position is designated specifically as ' H ' or ' hydrogen ' , the position is understood to have hydrogen at its natural abundance isotopic composition . However , it is explicitly intended that where H ( or hydrogen ) is mentioned as a substituent group in any of the aspects and embodiments of this disclosure , deuterium may also be a potential substituent at that position and can be considered implicitly recited as an optional substituent at each such position .

The term ' isotopic enrichment factor ' as used herein refers to the ratio between the isotope abundance and the natural abundance of a specified isotope .

The term ' isotopologue ' as used herein refers to a species in which the chemical structure differs from a specific compound of the disclosure only in the isotopic composition thereof .

The term ' ľykla ' refers to a monovalent , optionally substituted , saturated aliphatic hydrocarbon radical . Any number of carbon atoms may be present , but typically the number of carbon atoms in the alkyl group may be from 1 to about 20 , from 1 to about 12 , from 1 to about 6 or from 1 to about 4. Usefully , the number of carbon atoms is indicated , for example , a ₁C C4 alkyl refers to any alkyl group containing 1 to 4 carbon atoms in the chain . An alkyl group may be a straight chain ( i.e. linear ) , branched chain , or cyclic . ' Lower alkyl ' refers to an alkyl of 1 to 6 carbon atoms in the chain , and may have from 1 to 4 carbon atoms , or 1 to carbon atoms . Thus , representative examples of lower alkyl radicals include methyl , ethyl , n - propyl , n - butyl , n - pentyl , n - hexyl , isopropyl , isobutyl , isopentyl , amyl ( C5H11 ) , sec - butyl , tert - butyl , sec - amyl , tert - pentyl , 2 - ethylbutyl , 2,3 - dimethylbutyl , and the like . ' Higher alkyl ' refers to alkyls of 7 carbons and above , including n - heptyl , n - octyl , n - nonyl , n - decyl , n- dodecyl , n - tetradecyl , n - hexadecyl , n - octadecyl , n - eicosyl , and the like , along with branched variations thereof . A linear carbon chain of say 4 to 6 carbons would refer to the chain length not including any carbons residing on a branch , whereas in a branched chain it would refer to the total number . Optional substituents for alkyl and other groups are described below .

The term ' alkoxy ' refers to a monovalent radical of the formula RO- , where R is any alkyl , alkenyl or alkynyl as defined herein . Alkoxy groups may be optionally substituted by any of the optional substituents described herein . ' Lower alkoxy ' has the formula RO- , where the R group is a lower alkyl , alkenyl or alkynyl . Representative alkoxy radicals include methoxy , ethoxy , n - propoxy , n - butoxy , n - pentyloxy , n - hexyloxy , isopropoxy , isobutoxy , isopentyloxy , 61 LO amyloxy , sec - butoxy , tert - butoxy , tert - pentyloxy , and the like . Preferred alkoxy groups are methoxy and ethoxy The term ' ľyklaolcyc ' as used herein refers to a cyclized alkyl ring having the indicated number of carbon atoms in a specified range . Thus , for example , ' C3 - C6 ❜lyklaolcyc encompasses each of cyclopropyl , cyclobutyl , cyclopentyl , and cyclohexyl .

The term ' aryl ' as used herein refers to a substituted or unsubstituted aromatic carbocyclic radical containing from 5 to about 15 carbon atoms ( ' C6 - C15 aryl ' ) ; suitably 5 to 12 carbon atoms ( ' C5 - C12 aryl ' ) and more suitably 5 or 6 carbon atoms . An aryl group may have only one individual carbon ring , or may comprise one or more fused rings in which at least one ring is aromatic in nature . A ' phenyl ' is a radical formed by removal of a hydrogen atom from a benzene ring , and may be substituted or unsubstituted . A ' phenoxy ' group , therefore , is a radical of the formula RO- , wherein R is a phenyl radical . ' Benzyl ' is a radical of the formula R - CH2- , wherein R is phenyl , and ' benzyloxy ' is a radical of the formula RO- , wherein R is benzyl . The point of attachment to the base molecule on such fused aryl ring systems may be a C atom of the aromatic portion or a C or a N atom of the non - aromatic portion of the ring system . Non - limiting examples of aryl radicals include , phenyl , naphthyl , anthracenyl , benzyl , biphenyl , furanyl , pyridinyl , indanyl , anthraquinolyl , tetrahydronaphthyl , a benzoic acid radical , a furan - 2 - carboxylic acid radical , and the like .

A ' heteroaryl ' group is herein defined as a substituted or unsubstituted ‘ aryl ' group in which one or more carbon atoms in the ring structure has been replaced with a heteroatom , such as nitrogen , oxygen or sulphur . Generally , the heteroaryl group contains one , two or three heteroatoms ; particularly one or two heteroatoms . Particularly suitable heteroatoms are N and O ; and a preferred heteroatom is N. Exemplary heteroaryl groups include : furan , benzofuran , isobenzofuran , pyrrole , indole , isoindole , thiophene , benzothiophene , benzo [ c ] thiophene , imidazole , benzimidazole , purine , pyrazole , indazole , oxazole , benzoxazole , isoxazole , benzisoxazole , thiazole , benzothiazole , pyridine , quinoline , isoquinoline , pyrazine , quinoxaline , acridine , pyrimidine , quinazoline , pyridazine and cinnoline .

Heteroaryl groups include but are not limited to thienyl ( thiophenyl ) , benzo [ b ] thienyl , naphtho [ 2,3 - b ] thienyl , thianthrenyl , furyl ( furanyl ) , isobenzofuranyl , chromenyl , xanthenyl , phenoxanthiinyl , pyrrolyl , including without limitation 2H - pyrrolyl , imidazolyl , pyrazolyl , pyridyl ( pyridinyl ) , including without limitation 2 - pyridyl , 3 - pyridyl , and 4 - pyridyl , pyrazinyl , pyrimidinyl , pyridazinyl , indolizinyl , isoindolyl , 3H - indolyl , indolyl , indazolyl , purinyl , 4H- LO quinolizinyl , isoquinolyl , quinolyl , phthalzinyl , naphthyridinyl , quinozalinyl , cinnolinyl , pteridinyl , carbazolyl , b - carbolinyl , phenanthridinyl , acrindinyl , pyrimidinyl , phenanthrolinyl , phenazinyl , thiazolyl , isothiazolyl , phenothiazinyl , oxazolyl , isoxazolyl , furazanyl , phenoxazinyl , 1,4- dihydroquinoxaline - 2,3 - dione , 7 - aminoisocoumarin , 7 - aminoisocoumarin , pyrido [ 1,2- a ] pyrimidin - 4 - one , pyrazolo [ 1,5- a ] pyrimidinyl , including without limitation pyrazolo [ 1,5- a ] pyrimidin - 3 - yl , 1,2 - benzoisoxazol - 3- yl , benzimidazolyl , 2 - oxindolyl and 2- oxobenzimidazoly , oxadiazolyl , and thiadiazolyl . Where the heteroaryl group contains a nitrogen atom in a ring , such nitrogen atom may be in the form of an N - oxide , e.g. , a pyridyl N - oxide , pyrazinyl N - oxide and pyrimidinyl N - oxide .

The terms ' heterocycle ' or ' heterocyclic ' group as used herein refer to a monovalent radical of from about 4- to about 15- ring atoms / members , and preferably 4- , 5- or 6- ring members . Generally , the heterocyclic group contains one , two or three heteroatoms , selected independently from nitrogen , oxygen and sulphur . Particularly suitable heteroatoms are N and O ; and a preferred heteroatom is N. A heterocyclic group may have only one individual ring , or may comprise one or more fused rings in which at least one ring contains a heteroatom . It may be fully saturated or partially saturated , and may be substituted or unsubstituted as in the case or aryl and heteroaryl groups . Representative examples of unsaturated 5 - membered heterocycles with only one heteroatom include 2- or 3 - pyrrolyl , 2- or 3 - furanyl , and 2- or 3 - thiophenyl . Corresponding partially saturated or fully saturated radicals include 3 - pyrrolin - 2 - yl , 2- or 3 - pyrrolindinyl , 2- or 3 - tetrahydrofuranyl , and 2- or 3- tetrahydrothiophenyl . Representative unsaturated 5 - membered heterocyclic radicals having two heteroatoms include imidazolyl , oxazolyl , thiazolyl , pyrazolyl , and the like . The corresponding fully saturated and partially saturated radicals are also included . Representative examples of unsaturated 6 - membered heterocycles with only one heteroatom include 2- , 3- , or 4 - pyridinyl , 2H - pyranyl , and 4H - pryanyl . Corresponding partially saturated or fully saturated radicals include 2- , 3- , or 4 - piperidinyl , 2- , 3- , or 4- tetrahydropyranyl and the like . Representative unsaturated 6 - membered heterocyclic radicals having two heteroatoms include 3- or 4 - pyridazinyl , 2- , 4- , or 5 - pyrimidinyl , 2- pyrazinyl , morpholino , and the like . The corresponding fully saturated and partially saturated radicals are also included , e.g. 2 - piperazine . The heterocyclic radical is bonded through an available carbon atom or heteroatom in the heterocyclic ring directly to the entity or through a linker such as an alkylene such as methylene or ethylene .

The term ' cycloaryl ' refers to a polycyclic group wherein an aryl group is fused to a 5- or 6- membered aliphatic ring . For example , C6 - C12 cycloaryl means a C6 - C12 aryl fused to a 5- or - membered aliphatic ring .

LO The term ' heteroaryloxy ' or ‘ heteroaryloxyl ' as used herein refers to an -O- heteroaryl group .

The disclosure encompasses fused ring systems , for example , ' bicyclic ' or ' tricyclic ' ring systems . In the context of the present disclosure , it is specifically intended that a fused ring system may include more than one fused aromatic ring , more than one fused non - aromatic / aliphatic ring , or one or more aromatic ring fused to one or more non - aromatic / aliphatic ring , such as a fusion of an aryl group with a cycloalkyl ( or cycloalkenyl ) group . Furthermore , it is intended that a fused ring system termed a bicyclic ( or tricyclic ) aryl is attached to the associated molecule via an aryl group , whereas a bicyclic ( or tricyclic ) cycloalkyl / cycloalkenyl is attached to the associated molecule via the cycloalkyl / cycloalkenyl group .

Similarly , in the context of fused ring systems , it is specifically intended that a bicyclic ( or tricyclic ) heteroaryl or heterocycloalkyl / heterocycloalkenyl need not contain heteroatoms in each of the fused ring systems . Rather , a bicyclic of tricyclic heteroaryl group may have one or more heteroatoms in any ring of the fused ring system , and not necessarily in the aryl ring that is the point of attachment to the associated molecule . Likewise , a bicyclic of tricyclic heterocycloalkyl or heterocycloalkenyl group may have one or more heteroatoms in any ring of the fused ring system , and not necessarily in the heterocycloalkyl or heterocycloalkenyl ring that is the point of attachment to the associated molecule .

The term ' substituted ' means that one or more hydrogen atoms ( attached to a carbon or heteroatom ) is replaced with a selection from the indicated group of substituents , provided that the designated atom's normal valency under the existing circumstances is not exceeded . The group may be optionally substituted with particular substituents at positions that do not significantly interfere with the preparation of compounds falling within the scope of this invention and on the understanding that the substitution ( s ) does not significantly adversely affect the biological activity or structural stability of the compound . Combinations of substituents are permissible only if such combinations result in stable compounds . By ' stable compound ' or ' stable structure ' , it is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and / or formulation into an efficacious therapeutic agent . The term ' optionally substituted ' or ' optional substituents ' as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified . When the groups in question are substituted with more than one substituent , the substituents may be the same or different . By ' optionally substituted ' it is meant that the group concerned is either unsubstituted , or at least one hydrogen atom is replaced with one of the specified substituent groups , radicals or moieties .

LO When used herein , the term ' independently ' ( e.g. in the phrase ' independently selected from ' ) , in reference to the substitution of a parent moiety with one or more substituents , means that the parent moiety may be substituted with any of the listed substituents , either individually or in combination , and any number of chemically possible substituents may be used . In any of the embodiments , where a group is substituted , it may contain up to 5 , up to 4 , up to 3 , or 1 and 2 substituents . As a non - limiting example , useful substituents include : phenyl or pyridine , independently substituted with one or more lower alkyl , lower alkoxy or halo substituents , such as : chlorophenyl , dichlorophenyl , trichlorophenyl , tolyl , xylyl , 2- chloro - 3 - methylphenyl , 2,3 - dichloro- 4 - methylphenyl , etc.

As used herein , the term ' geminal ' refers to substituent atoms or groups attached to the same atom in a molecule . As used herein , the term ' vicinal ' refers to substituent atoms or groups attached to adjacent atoms in a molecule . The stereochemical relationship between the substituent atoms or groups can be cis , trans , undefined , or unresolved .

Any radical / group / moiety described herein that may be substituted ( or optionally substituted ) may be substituted with one or more ( e.g. one , two , three , four or five ) substituents , which are independently selected from the designated group of substituents . Thus , substituents may be selected from the group : halogen ( or ' halo ' , e.g. F , CI and Br ) , hydroxyl ( -OH ) , amino ( -NH2 ) , thiol ( -SH ) , cyano ( -CN ) , ( lower ) alkyl , ( lower ) alkoxy , ( lower ) alkenyl , ( lower ) alkynyl , aryl , heteroaryl , ( lower ) alkylthio , oxo , haloalkyl , hydroxyalkyl , nitro ( -NO2 ) , phosphate , azido ( -N3 ) , alkoxycarbonyl , carboxy , alkylcarboxy , alkylamino , dialkylamino , aminoalkyl , alkylaminoalkyl , dialkylaminoalkyl , thioalkyl , alkylsulfonyl , arylsulfinyl , alkylaminosulfonyl , arylaminosulfonyl , alkylsulfonylamino , arylsulfonylamino , carbamoyl , alkylcarbamoyl , dialkylcarbamoyl , arylcarbamoyl , alkylcarbonylamino , arylcarbonylamino , cycloalkyl , heterocycloalkyl , unless otherwise indicated . Alternatively , where the substituents are on an aryl or other cyclic ring system , two adjacent atoms may be substituted with a methylenedioxy or ethylenedioxy group . More suitably , the substituents are selected from : halogen , hydroxy , amino , thiol , cyano , ( ₁C - C6 ) alkyl , ( ₁C - C ) alkoxy , ( C1- C6 ) alkenyl , ( C1 - C6 ) alkynyl , aryl , aryl ( ₁C - C6 ) alkyl , aryl ( C1 - C6 ) alkoxy , heteroaryl , ( C1- C6 ) alkylthio , oxo , halo ( ₁C - C6 ) alkyl , hydroxy ( ₁C - C6 ) alkyl , nitro , phosphate , azido , ( C1- C6 ) alkoxycarbonyl , carboxy , ( ₁C - C6 ) alkylcarboxy , ( ₁C - C6 ) alkylamino , di ( ₁C - 6С ) alkylamino , amino ( ₁C - C6 ) alkyl , ( ₁C - C6 ) alkylamino ( ₁C - C6 ) alkyl , di ( ₁C - C ) alkylamino ( ₁C - C6 ) alkyl , thio ( -₁C 6С ) alkyl , ( ₁C - 6С ) alkylsulfonyl , arylsulfinyl , ( ₁C - C6 ) alkylaminosulfonyl , arylaminosulfonyl , ( -₁C C6 ) alkylsulfonylamino , arylsulfonylamino , carbamoyl , ( ₁C - C6 ) alkylcarbamoyl , di ( C1- C6 ) alkylcarbamoyl , arylcarbamoyl , ( ₁C - C6 ) alkylcarbonylamino , arylcarbonylamino , ( -₁C 65 LO C6 ) cycloalkyl , and heterocycloalkyl . Still more suitably , the substituents are selected from one or more of : fluoro , chloro , bromo , hydroxy , ( ₁C - C6 ) alkyl , ( ₁C - C6 ) haloalkyl , ( ₁C - 6С ) alkoxy , ( C5 - C6 ) aryl , a 5- or 6 - membered heteroaryl , ( C4 - C6 ) cycloalkyl , a 4- to 6 - membered heterocycloalkyl , cyano , ( ₁C - 6С ) alkylthio , amino , -NH ( alkyl ) , -NH ( ( ₁C - C6 ) cycloalkyl ) , -N ( ( -₁C C6 ) alkyl ) 2 , -OC ( O ) - ( ₁C - C6 ) alkyl , -OC ( O ) - ( C5 - C6 ) aryl , -OC ( O ) - ( ₁C - C6 ) cycloalkyl , carboxy and -C ( O ) O- ( ₁C - C6 ) alkyl . Most suitably , the substituents are selected from one or more of : fluoro , chloro , bromo , hydroxy , amino , ( ₁C - 6С ) alkyl and ( ₁C - C6 ) alkoxy , wherein alkyl and alkoxy are optionally substituted by one or more chloro . Particularly preferred substituents are : chloro , methyl , ethyl , methoxy and ethoxy .

As used herein , the term ' cyano ' refers to a -CN radical . As used herein , the term ' hydroxyl ' refers to an -OH radical . As used herein , the term ' amino ' refers to an -NH2 group . As used herein , the term " oxo " refers to an " O " group attached to a carbon atom .

The term ' halo ' is used interchangeably with the term ' halogen ' and refers to a monovalent halogen radical chosen from chloro , bromo , iodo , and fluoro . A ‘ halogenated ' compound is one substituted with one or more halo substituent . Particular halo groups are F , Cl and Br ; and most particularly are F or Cl . In some preferred embodiments the halo group is F.

The term ' ₁C - C6 haloalkyl ' refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence , for example fluorine , chlorine , bromine and iodine . The halogen atom may be present at any position on the hydrocarbon chain . Similarly , a C1 - C3 haloalkyl group is linear or branched hydrocarbon chain containing 1 , 2 , or 3 carbon atoms substituted with at least one halogen atom . For example , C1 - C3 haloalkyl may refer to chloromethyl , fluoromethyl , trifluoromethyl , chloroethyl e.g. 1 - chloroethyl and 2- chloroethyl , trichloroethyl e.g.1,2,2 - trichloroethyl , 2,2,2 - trichloroethyl , fluoroethyl e.g.1- fluoromethyl and 2- fluoroethyl , trifluoroethyl e.g. 1,2,2 - trifluoroethyl and 2,2,2 - trifluoroethyl , chloropropyl , trichloropropyl , fluoropropyl , trifluoropropyl .

' Alkylene ' or ' alkylenyl ' means a difunctional group obtained by removal of a hydrogen atom from an alkyl group as defined above . Non - limiting examples of alkylene include methylene , ethylene and propylene . ' Lower alkylene ' means an alkylene having from 1 to 6 carbon atoms in the chain , and may be straight or branched . Alkylene groups are optionally substituted . Preferred alkylene groups are - ( CR2 ) n- where n is from 1 to 6 , and R is independent selected from H , F , CI , NH2 or wherein R2 is = O . More preferably , n is 1 , 2 or and R is H. Most preferable alkylene groups are - ( CH2 ) 2- and -CH2 - CO- . 66 LO The term ' alkenyl ' refers to a monovalent , optionally substituted , unsaturated aliphatic hydrocarbon radical . Therefore , an alkenyl has at least one carbon - carbon double bond ( C = C ) . The number of carbon atoms in the alkenyl group may be indicated , such as from to about 20. For example , a C2-12 alkenyl ( or C2-12 alkenyl ) refers to an alkenyl group containing 2 to 12 carbon atoms in the structure . Alkenyl groups may be straight ( i.e. linear ) , branched chain , or cyclic . ' Lower alkenyl ' refers to an alkenyl of 1 to 6 carbon atoms , and may have from 1 to 4 carbon atoms , or 1 to 2 carbon atoms . Representative examples of lower alkenyl radicals include ethenyl , 1 - propenyl , 1 - butenyl , 1 - pentenyl , 1 - hexenyl , isopropenyl , isobutenyl , and the like . Higher alkenyl refers to alkenyls of seven carbons and above , such as 1 - heptenyl , 1 - octenyl , 1 - nonenyl , 1 - decenyl , 1 - dodecenyl , 1 - tetradecenyl , 1- hexadecenyl , 1 - octadecenyl , 1 - eicosenyl , and the like , along with branched variations thereof . Optional substituents include are described elsewhere .

' Alkenylene ' means a difunctional group obtained by removal of a hydrogen from an alkenyl group that is defined above . Non - limiting examples of alkenylene include -CH = CH- , - C ( CH3 ) = CH- , and -CH = CHCH2- .

' Alkynyl ' and ' lower alkynyl ' is defined similarly to the term ' alkenyl ' , except that it includes at least one carbon - carbon triple bond .

Unless defined otherwise , ' room temperature ' is intended to mean a temperature of from about 16 to 28 ° C , typically between about 18 and 25 ° C , and more typically between about and 22 ° C . As used herein , the phrase ' room temperature ' may be shortened to ' rt ' or ' RT ' .

Molecules and Compounds Disclosed herein is a compound according to the invention having the structural formula ( 1 ) : 67 RL .N . R XA +X³R R( 1 ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein : Q is O or S ; 1✗ is selected from C and N ; ²X is selected from CR5 and N ; X3 is selected from CR and N ; X4 is selected from CR7 and N ; X5 is selected from C and N ; wherein X1 , X2 , X3 , X4 and X5 are selected so that the ring labelled A is aromatic ; X6 is selected from CR8R9 , O and N ; X7 is selected from CR10 , CR11 R12 , O and N ; q is 0 or 1 ; wherein when q is 0 , X7 is O or N ; and when X7 is O or N and q is 1 , X6 is ⁹R³RC ; L ' is a bond , alkylene , haloalkylene , cycloalkylene , or heterocycloalkyl ; ¹R is selected from alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , aryl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , aryloxy , and heteroaryloxy , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , aryl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , aryloxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , alkyl , haloalkyl , alkoxy , haloalkoxy , alkyl - NR1aR1b , cycloalkyl , LO heterocycloakyl , aryl , heteroaryl , benzyl , aryloxy , haloaryloxy , heteroaryloxy , C4 alkyl substituted by a heterocycloalkyl ; R1a and R1b are each independently selected from H and alkyl ; ²R is selected from H , alkyl and cycloalkyl ; or R1 , R2 and L ' and the nitrogen atom to which R2 and L1 are attached form a heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl or bicyclic heteroaryl , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , alkyl , haloalkyl , alkoxy , haloalkoxy and alkyl - NR1aR1b ; ³R is selected from H , OH , CN , b³Rª³RN , alkyl , cycloalkyl , heterocycloalkyl , aryl , heteroaryl , alkoxyalkyl , haloalkoxyalkyl , cycloalkoxyalkyl , cycloalkylalkoxy , alkyl - S - alkyl , and alkyl - SO2- alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , aryl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , alkyl and NR3CR3d . a³R is selected from H , alkyl , alkyl - OH , and alkyl - f³Re3RN ; R3b , R3 , R3d , e³R and f³R are each independently selected from H and alkyl ; R4 is selected from C ( O ) OH , C ( O ) ª4RN R4b , C ( S ) NR ª4 R4b and heteroaryl ; R4a and R4b are each independently selected from H and alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , alkyl , haloalkyl , alkoxy , alkoxyalkyl , cycloalkyl , heterocycloalkyl , aryl and heteroaryl ; or R5 and R6 together with the carbon atoms to which they are attached form a heterocycle ; and R7 , R8 , ºR , º¹R , R11 and R12 are each independently selected from H , halogen , OH , CN , alkyl , haloalkyl , alkoxy , cycloalkyl , heterocycloalkyl , aryl and heteroaryl .

In embodiments of the compound of formula ( 1 ) , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally LO substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is selected from H , C1 - C4 alkyl and C3 - C8 cycloakyl ; or R1 , R2 and L ' and the nitrogen atom to which R2 and L1 are attached form a 3- to 8- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , or 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - Chaloalkoxy and ₁C - C4 alkyl - b1Rª¹RN ; ³R is selected from H , OH , CN , b3R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C C4 alkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2- C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and NR3cR3d a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and C1 - C4 alkyl - f³Rе³RN ; b³R , ³R , d³R , e³R and f³R are each independently selected from H and ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR 4 R4b and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a and R4b are each independently selected from H and ₁C - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , C1 - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; or 70 LO R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , R8 , ⁹R , R10 , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1 ) , L ' is a bond , ₁C - C6 alkylene , C1 - C haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , C1 - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - b1Rª¹RN , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; ³R is selected from H , OH , CN , b³R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C C4 alkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2- C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and NR3cR3d LO a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³R³RN ; R3b , R3c , d³R , e³R and f³R are each independently selected from H and ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR4 R4b and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; Ra and R4b are each independently selected from H and ₁C - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , ºR , ºR , º¹R , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1 ) , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1 is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , C1 - C4 alkoxy , C1 - C4 haloalkoxy , C1 - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , halophenoxy , and ₁C - C4 alkyl substituted by a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; 72 LO ³R is selected from H , OH , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - ₁C - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and C1 - C4 alkyl - SO2- C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl , and d³Rc³RN ; a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Re3RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; 3e e³R and f³R are each independently selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR ª4 R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; Ra is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , C1 - Chaloalkyl , C1 - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , ³R , ⁹R , º¹R , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1 ) , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and LO phenoxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , C1 - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , halophenoxy , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , b³R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and NR3cR3d . a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Re3RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R3e and f³R are each independently selected from C1 - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) 4Rª4RN , C ( S ) ª4RN R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is HR5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1 ) , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; ¹R selected from : ₁C - C4 haloalkyl ; 74 C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - Chaloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , halophenoxy , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - a¹RN R1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , optionally substituted by one or more substituents independently selected from C1 - C4 alkyl and ₁C - C4 haloalkyl ; 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substitutents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy optionally substituted by one or more ₁C - C4 alkyl ; R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is H ; R3 is selected from : - H ; CN ; NR3aR3b : C1 - C4 alkyl optionally substituted by one of more substituents selected from OH and NR3c R3d . C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , optionally substituted by one or more ₁C - C4 alkyl ; phenyl optionally substituted by one or more halogen ; 75 - or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; ₁C - C4 alkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C1 - C4 alkyl - S - ₁C - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Re3RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; e³R and f³R are each independently selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR ª4 R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1 ) , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1 selected from : ₁C - C4 haloalkyl ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1 R1b , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - Chaloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , halophenoxy , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or - membered heterocycloalkyl having one or more heteroatoms selected from N , and S ; 76 LO 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - ª1RN R1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , and S , substituted by one or more substituents independently selected from C1 - Calkyl and ₁C - C4 haloalkyl ; 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substitutents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy substituted by one or more C1 - C4 alkyl ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from : H ; CN ; NR3aR3b ₁C - C4 alkyl optionally substituted by one or more substituents selected from OH and NR3c R3d C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , optionally substituted by one or more ₁C - C4 alkyl ; phenyl optionally substituted by one or more halogen ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - C1 - C4 alkoxy ; ₁C - C4 alkyl - S - ₁C - C4 alkyl ; and C1 - C4 alkyl - SO2- C1 - C4 alkyl ; a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Re³RN ; R3b is selected from H and ₁C - C4 alkyl ; LO R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; e³R and f³R are each independently selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) 4RªªRN , C ( S ) ª4RN R4 and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and C1 - C4 alkoxy - C1 - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1 ) , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene ; ¹R is selected from C1 - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - Calkyl - NR1aR1b , C3 - C8 cycloalkyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , and ₁C - C4 alkyl substituted by a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is H ; ³R is selected from H , CN , b3R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - C1 - C4 alkyl , зC - Ccycloalkyl - C1 - C4 alkoxy , C1 - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC3RN ; a³R is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; LO R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR ª4 R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1 ) , L ' is a bond , ₁C - С alkylene , ₁C - C haloalkylene , or C3 - C6 cycloalkylene ; R1 is selected from : ₁C - C4 haloalkyl ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , C1 - C4 alkyl , C1 - C4 alkoxy , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , ○ and S , optionally substituted by one or more substituents independently selected from C1 - C4 alkyl and ₁C - C4 haloalkyl ; 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy optionally substituted by one or more ₁C - C4 alkyl ; R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is H ; ³R is selected from : H ; CN ; NR3aR3b ' ₁C - C4 alkyl optionally substituted by one or more substituents independently selected from OH and ³RN ¢ R3d . C3 - C8 cycloalkyl ; ' 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; phenyl substituted by one or more halogen ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; ₁C - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - C1 - C4 alkyl ; C1 - C4 haloalkoxy - ₁C - C4 alkyl ; C1 - C4 alkyl - S - ₁C - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; a³R is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) b4RªRN , C ( S ) NR4 R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; Ra is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 R9 R10 R11 , and R12 are each H.

In embodiments of the compound of formula ( 1 ) , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene ; R1 is selected from : ₁C - C4 haloalkyl ; 80 C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - ª¹RN R1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , substituted by one or more substituents independently selected from ₁C - Calkyl and C1 - C4 haloalkyl ; 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy substituted by one or more ₁C - C4 alkyl ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; R3 is selected from : - H ; CN ; NR3aR3b . ₁C - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR3cR3d . C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; ' phenyl substituted by one or more halogen ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; ₁C - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; ₁C - C4 alkyl - S - ₁C - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) b4Rª4RN , C ( S ) NR4R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , R9 , º¹R , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1 ) , ¹L is a bond , ₁C - С alkylene , ₁C - С haloalkylene , or C3 - C6 cycloalkylene ; R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , b3Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein LO said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³R³RN ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; R4 is selected from the following groups : NH 44; and CH ; and wherein indicates the point of attachment to the rest of the compound ; R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and C1 - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , R10 , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1 ) , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene ; R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , CN , ₁C - C4 alkyl , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , and ₁C - Calkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , C1 - C4 alkoxy , ₁C - C4 alkyl - NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 83 LO - or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , optionally substituted by one or more substituents independently selected from C1 - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is H ; ³R is selected from : H ; CN ; NR3aR3b ' C1 - C4 alkyl optionally substituted by one or more substituents independently selected from OH and d³Rc³RN ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; phenyl substituted by one or more halogen ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; ₁C - C4 alkyl - S - ₁C - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; a³R is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : 84 .OH NH S ; and viv NH ; and CH wherein indicates the point of attachment to the rest of the compound ; R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , R10 , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1 ) , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene ; R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , CN , ₁C - C4 alkyl , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , C1 - C4 haloalkyl , and ₁C - Calkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents .S independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , C1 - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - NR1 R1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , substituted by one or more substituents independently selected from ₁C - Calkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; R3 is selected from : H ; CN ; NR3aR3b . C1 - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR3cR3d : C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; phenyl substituted by one or more halogen ; 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; C1 - C4 alkyl - S - C1 - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; a³R is selected from H and ₁C - C4 alkyl ; 3a R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : .OH viv NH2 NH ggage S ; and CH ; and wherein indicates the point of attachment to the rest of the compound ; R5 is selected from H , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , R9 , R10 , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1 ) , L ' is a bond , ₁C - C6 alkylene , or C3 - C6 cycloalkylene ; 86 LO R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , hetercycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , C1 - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; R2 is H ; ³R is selected from H , CN , ³Rª³RN , ₁C - C4 alkyl optionally substituted by OH , ³C - Ccycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - C1 - C4 alkyl , C3 - C8 cycloalkyl- C1 - C4 alkoxy , ₁C - C4 haloalkoxy - C1 - C4 alkyl , C1 - C4 alkyl - S - C1 - C4 alkyl , and C1 - C4 alkyl - SO2- ₁C - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : viv .OH S .NH ; and viv NH ; wherein indicates the point of attachment to the rest of the compound ; R5 is H ; R6 is selected from H and ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1 ) , L ' is either a bond , ₁C - C6 alkylene , or C3 - C6 cycloalkylene ; R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and ₁C - C4 alkoxy ; 87 LO ²R is H ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; ³R is selected from : H ; CN ; NR3aR3b . ₁C - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - C1 - C4 alkoxy ; C3 - C8 cycloalkoxy - C1 - C4 alkyl ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; R3a is H ; ₁C - C4 alkyl - S - C1 - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; R3b is selected from ₁C - C4 alkyl . R4 is selected from the following groups : 88 .OH viv .NHviv S ; and point of attachment to the rest of the compound ; R5 is H ; R6 is selected from H and ₁C - C4 alkyl ; and R7 , R8 , R9 , R10 , R11 , and R12 are each H.

NH ; wherein indicates the In embodiments of the compound of formula ( 1 ) , L ' is either a bond , ₁C - C6 alkylene , or C3 - C6 cycloalkylene ; R1 is selected from : ²R is H ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and ₁C - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; ³R is selected from : - H ; CN ; NR3aR3b ; C1 - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; ' 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - C1 - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; R3a is H ; C1 - C4 alkyl - S - C1 - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; R3b is selected from ₁C - C4 alkyl . R4 is selected from the following groups : viv .OH viv NH2 NH S ; and point of attachment to the rest of the compound ; R5 is H ; R6 is selected from H and ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1 ) , L ' is either a bond or ₁C - C6 alkylene ; ; wherein indicates the R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; ²R is H ; ³R is selected from b³R³RN , ₁C - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR 3R3d , C3 - C8 cycloalkyl , 3- to 8 - membered LO heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , C3 - Ccycloalkoxy - ₁C - C4 alkyl , ₁C - C4 alkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , and alkyl - S - ₁C - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : .OH viv .NHviv NH S ; and point of attachment to the rest of the compound ; R5 , R7 , R8 , ⁹R , R10 , R11 , and R12 are each H ; and , R6 is selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , L ' is either a bond or C1 - C6 alkylene ; R1 is selected from : ²R is H ; ; wherein indicates the C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4 haloalkoxy ; C8 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl and C1 - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen and C1 - C4 alkyl ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from C1 - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; 91 ³R is selected from : NR3aR3b . C1 - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; and R3a is H ; ₁C - C4 alkyl - S - ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : .OH viv NH " S ; and viv point of attachment to the rest of the compound H ; R5 , R7 , ºR , ºR , R10 , R11 , and R12 are each H ; and NH ; wherein indicates the R6 is selected from H and C1 - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , L ' is either a bond or C1 - C6 alkylene ; R1 is selected from : C3 - C8 cycloalkyl substituted by one or more substituents independently selected from halogen and ₁C - C4 haloalkoxy ; C8 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl and ₁C - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; LO ²R is H ; phenyl substituted by one or more substituents independently selected from halogen and C1 - C4 alkyl ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; R3 is selected from : - NR3aR3b : C1 - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; C1 - C4 haloalkoxy - ₁C - C4 alkyl ; and R3a is H ; ₁C - C4 alkyl - S - ₁C - C4 alkyl ; R3b is selected from C1 - C4 alkyl ; R4 is selected from the following groups : viv .OH NH S ; and point of attachment to the rest of the compound ; R5 , R7 , R8 , ⁹R , R10 , R11 , and R12 are each H ; and R6 is selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , In embodiments of the compound of formula ( 1 ) , NH ; wherein indicates the LO L ' is a bond , ₁C - C6 alkylene , C1 - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1 ) , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene .

In embodiments of the compound of formula ( 1 ) , L ' is a bond , methylene , ethylidene , 2,2,2 - trifluoroethylidene , and cyclopropylidene .

In embodiments of the compound of formula ( 1 ) , L ' is a bond , ₁C - C6 alkylene or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1 ) , L ' is either a bond or ₁C - C6 alkylene .

In embodiments of the compound of formula ( 1 ) , L ' is either a bond or methylene .

In embodiments of the compound of formula ( 1 ) , L ' is C1 - C6 alkylene .

In embodiments of the compound of formula ( 1 ) , L ' is methylene .

In embodiments of the compound of formula ( 1 ) , L ' is a bond .

In embodiments of the compound of formula ( 1 ) , L ' is a 5- or 6 - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1 ) , ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , ₁O S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more ' LO ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , C1 - C4 haloalkoxy , ₁C - C4 alkyl - b1Rª¹RN , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and C1 - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , C9 - Cbicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , C1 - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - ¸b1Rª¹RN C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and ' R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , 95 LO ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ³¹Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - Calkoxy , C1 - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1 R1b , C1 - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , C1 - C4 alkyl- NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and C1 - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , 96 LO R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , -₁C C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1 R1b , ₁C - C4 alkyl , C1 - C4 haloalkyl , C1 - Calkoxy , C1 - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , halophenoxy , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- LO membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C1 - C4 haloalkoxy , -₁C C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , halophenoxy , and C1 - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , ○ and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , -₁C C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , halophenoxy , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , ○ and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring LO members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and C1 - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- b1R³¹RN , C3 - C8 cycloalkyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- NR1aR1b , C3 - C8 cycloalkyl , 5- or 6- membered heteroaryl having one or more heteroatoms 99 selected from N , O and S , benzyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and C1 - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and C1 - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring mambers selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected 100 from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , C1 - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy .

In embodiments of the compound of formula ( 1 ) , R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy .

In embodiments of the compound of formula ( 1 ) , R1 is selected from : ₁C - C4 haloalkyl ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1 R1b , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - Chaloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , halophenoxy , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or - membered heterocycloalkyl having one or more heteroatoms selected from N , ○ and S ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - ª¹RN R1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 101 LO - or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substitutents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy optionally substituted by one or more C1 - C4 alkyl ; wherein a¹R and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from : ₁C - C4 haloalkyl ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - Chaloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , halophenoxy , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or - membered heterocycloalkyl having one or more heteroatoms selected from N , ○ and S ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - ª1RN R1b , and 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 ( e.g. having one or more ring members selected from N , O and S ) ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and ₁C - C4 haloalkyl ; 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substitutents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy substituted by one or more ₁C - C4 alkyl ; 102 LO wherein a¹R and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from : ₁C - C4 haloalkyl ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , C1 - C4 alkyl , C1 - C4 alkoxy , and C1 - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - b¹Rª¹RN , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy optionally substituted by one or more C1 - C4 alkyl ; wherein a¹R and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from : ₁C - C4 haloalkyl ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 103 LO 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , C1 - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - NR1 R1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and ₁C - C4 haloalkyl ; 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy substituted by one or more ₁C - C4 alkyl ; wherein a¹R and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , CN , ₁C - C4 alkyl , and C1 - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , and ₁C - Calkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - NR1a R1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; and 104 LO 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; wherein a¹R and R1b are each independently selected from H and C1 - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , CN , ₁C - C4 alkyl , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , and ₁C - Calkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , C1 - C4 alkoxy , C1 - C4 alkyl - NR1 R1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from C1- C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and C1 - C4 alkyl ; wherein a¹R and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and ₁C - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 105 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and ₁C - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4 haloalkoxy ; 106 C8 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl and C1 - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 is selected from : C3 - C8 cycloalkyl substituted by one or more substituents independently selected from halogen and ₁C - C4 haloalkoxy ; C8 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl and ₁C - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl substituted by one or more substituents independently selected from halogen and C1 - C4 alkyl ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , 107 F.

R1 is selected from the following groups : ; IL F F ; ; F F F F + a F3C F H3C F F F3CO ; N 0582; ; ; ; CI CH H3C Z H3C H3C w m ﻊﺒﻳﺭ ﻊﺒﻳﺭ ﻊﺑﺭ . 8.

CH 6109 H3C H3C H3C H3C N. H3C NC .N .

; ' CF CH IN ﺱﺭ ; ; 00+ N. N H3C ; H3C H3C CH ; a H3C F3C viv ; H3C HO ' N ' viv ; CH ; ; viv H3C N CH F .CI N ; viv ; ; CF N ; F F ; ; N H3C F CH .CH 3 F- viv F CH; F F CFF ; F F CH3 viv ; of ; CI Br ; F F ; ; F N F 60,00,N CHF ; viv F F vi · F F ; ; ; F F F F ; viv ; ' N ' ; ; S.

; CI viv ; ; F xoç so of F ; viv F ; CH ﻢﻗﺪﻣﺓ F N F ; H3C Ja 20,00 C OH ; H3C F F CH; HO 1005.. 00,; F F ' N ' ; H3C CH; F ffo Ja S F F ; F F ; and indicates the point of attachment to the rest of the compound .

In embodiments of the compound of formula ( 1 ) , F ; wherein ¹R is selected from the following groups : F S M F ד . F F ; F F ∞ ta ; ; ; ' F a F H3C H3C ; F3C N 05; F F OC₂F viv ; F3CO .N . OCF ; ﺱﻯ m ; ; ; 0 CI N L ; ₂H Cl ... ﻊﺒﻳﺭ m CI CH H3C N ﻊﺒﻳﺭ IZ H3C F H3C H3C F3C N CI a CH FII- CH FI ; CH £ £ £ FI CH; ; H3C H3C .

AA H3C H3C ; H3C- N NC H3C ; H3C ' ﺎﺗ CF ; ; H3C ww N.

CH IN ww ; ; H3C .

H3C CH; ww fo or N IZ 00 , ; ; H3C ; ; H3C HO ...

CH E ; F3C H3C N N ; H3C ; HOIII- CH .CI ; C N ﺱﻯ ﺲﺗﺭ N ww ; H3C CH CF £ & q ; H3C ― N CHF aad F- F F 44+ ; -CH CH ; ; 123 CI LL F F F CF F F ; F a to to CH; F ﺖﻣ ﻩا F ﻱﺭ ; F F F F ; Br ; F ; F N F 60,00.

F ; N CH; M F F 0F F ; F F ; viv F F F ; ; Ja.Cl ; ; ww F F ; F 50 0 F CH' N ' IL F ; H3C Ja £ 0.OH ; F CHHO 1000 2F ; 00.F ; 1 LL F ; F ; 0050 N ; H3C CH F F the compound .

F ; wherein S.

F F ; and indicates the point of attachment to the rest of LO In embodiments of the compound of formula ( 1 ) , R1 is selected from the following groups : ; F F- H3C F F IL F F. m ; ; F ; F F ; ww F3CO ; F3C F ; viv ; N N ww CI .

; CH H3C N H3C 00,0,F H3C ; ∞ , za ; CI ; F3C N F CH3 CH; H3C- 100+ A H3C ; ; H3C H3C H3C H3C N. H3C NC .N .

; ' CF CH IN ﺱﺭ ; ; N 00+ N. N H3C ; H3C H3C CH HO ' N ' viv ; CH ; F3C ; F goa H3C F viv ; F F- F CH ; ; 1vi CH; LL F F F CF F F ; on to of CI CH F Br F ; 0700,F F ; N CH 133 F F F F v viv ; viv ; F F F ; ; F F .F viv ; S 00'00'N ; 134 ﻡﺓ ﻡﺓ ﻒﻳ ; ; CH ; ww F .F F viv F ; ; viv Ta OH F ; ; H3C CH H3C F ; HO 100 F F 00,; F F ; ' N ' ; H3C CH; F ffo Ja S F F ; F F ; and indicates the point of attachment to the rest of the compound .

In embodiments of the compound of formula ( 1 ) , F ; wherein ¹R is selected from the following groups : F S F F F ; F F ∞ ta ; ; ; ' F a F H3C H3C ; F3C F F OC₂F 05; F3CO .N .

W OCF ; ﺱﻯ ; m ww ; ; Cl N IZ CH H3C N Cl H3C M F a IZ H3C H3C M ﻊﺒﻳﺭ C m ; H3G ...

F3C a ﻊﺒﻳﺭ ; CI CH F CH Y LL F CH CH€ ...... m ; N H3C- N n H3C AA H3C .

H3C a C³H m H3C NG ||| ... ' ; ra H3C ; NC CF M ; ; H3C ww N.

CH IN ww ; ; H3C .

H3C CH; ww to a N IZ ; H3C m ; ; ; 141 H3C HO ...

CH ; H3C N N F3C ; F ; ; HOIII- F- CH F ; F- FL CH ; F viv CH; CF F- F F F ; CH to to to ; viv ; F ; CI ; Br F F F F F F F N 2000 , 0CH F F F F ; F F F F F ; ; viv ; 144 F F F F ; F por Ja ; F ; ; N S ' N ' CI S.

N ; ; ; ; ; ; S ; LO F F xoç so of ; ww F F ; 3050.F ; H3C CH Ja 10.· OH ; F CH; 1000 F ; 00,00 F F F ; N S H3C S CH S F F F ; and F ; wherein indicates the point of attachment to the rest F F of the compound .

In embodiments of the compound of formula ( 1 ) , R1 is selected from the following groups : ; F S F FL ﻊﺒﻳﺭ ; viv ; F F3C ; F3CO F F ; ﻊﺒﻳﺭ H3C F ; F F 148 F CH CH F3C CI H3C F H3C m CHH3C H3C H3C C LO H3C -N N H3C H3C H3C F N ' H3C N ; ; F F F ; N .CH NC .

F CF ww ﺱﻯ ; ; CHviv ; ; ; 150 F F CFF F F viv ; on to of CI CH F Br F ; O 0760,F F N CH 151 F F F viv ; F ; F F F ; F ; F ; ww ; 00.00.

' N ' 152 ﻡﺓ ﻡﺓ ﻒﻳ N F ; F to pox po ; F ; ; CH F ﺲﻳﺭ viv F ; OH ; ; 153 H3C H3C CH F ; ; HO 100x1 F F ; 00, ; F ; S.

; H3C CH3 F $ for fa S F ; and F F F ; wherein indicates the point of attachment to the rest of the compound .

In embodiments of the compound of formula ( 1 ) , R1 is selected from the following groups : F- S F F L ; F F ; ; F ; " F a F H3C H3C ; F F F3C F3CO / ﺱﻯ F3CO ; N OCF N ; ; ; H3C CHH3C Z 888 H3C m ﻊﻳﺩ m CH LL Z m Z. NC H3C LL w NG ... ww H3C ﻢﻣ viv N ; F aa F ; F F- F F F ; F- ; CF CH F ; F N vi ww ; ; CH; FL F F- F ox CH3 viv ; ww to of CI ; oa , oa F F Br F ; ; F F ; ; F ; LO F .N . 60 , 09.CH; 160 F F F F ; F F 0 of ; viv F F F ; ' N ' Ja.F ; N ; ; ; CI ; ' N ' ; to topo F ; 50 0 ; CH F F ; ; 162 FL w LL F F ; H3C Ja 20.OH ; H3C .F CH; 100 F F ; F F 00, 0030 ' N ' ; ; ; ; 163 H3C CH; F F F and F F of the compound . ; wherein indicates the point of attachment to the rest In embodiments of the compound of formula ( 1 ) , R1 is selected from the following groups : F 00.0 F n ; ' ; 164 F H3C F F F ; F F3C F F F3CO ; 05 $ 2,viv N CI 00000+ ; CHH3C ; H3C N 165 F F3C Z Z CH3 CH H3C CI Z F ﻊﺒﻳﺭ F LL F CH; FL F ; דו . F F CF viv ; CI F F CHviv ; ww Br , of F F ; ; 167 F .N .

F 60,00.N CH; F F F viv F F · F F ; viv ; viv ; F F S ; F 00 : 00.80 viv 168 ﺓ ﻡﺓ ﻒﻳ F ; F to pox po ; F ; F ; ; CH; F viv ; H3C FL ; CH; ; H3C 100.HO ; 100.00 , F ; F F F 100 to F S For Ja ; and F F the point of attachment to the rest of the compound .

In embodiments of the compound of formula ( 1 ) , R1 is selected from the following groups : F ; ; wherein indicates ; 170 ww F F H3C H3C F F. ﻊﺒﻳﺭ Z ﻢﺟھ F3C ﻊﺒﻳﺭ F3CO CI .

.N .

F. F viv ; 1OCF3 viv ; ; .N . ; ; ww CI- N.

; ; ; CH H3C H3C N n ﻊﺒﻳﺭ ∞ a ; H3C ﻼﻠﻫ اااﺭ H3C a ; F3C a CH D FI m ﻊﺒﻳﺭ ; CI ; FI ; M ; € ..... CH ; CH F F m F CF F ' N ' F CHviv ; ; F ﻡا viv ; on to to F to viv CH3 ; viv F ; w ; ; ; CI 00,Br F. F F F ; ; F F F F 60,00.N CH; F F · F F ; ; ; F F F F F ; ﺱﻯ F F F S ww 50.00 CI ; so do ; ; ; 176 F F ; ; F to a ; F CH ; F ; H3C CH; .HO ; F .00 , F ; F F 1.0070F .S .

F F ; and F F indicates the point of attachment to the rest of the compound .

In embodiments of the compound of formula ( 1 ) , R1 is selected from the following groups : F ; wherein ; ; ; F F F H3C S F ; F F ; viv ﻊﺒﻳﺭ F3CO FL F ﻊﺒﻳﺭ ; F F ; F3C viv ; .N . Cl N ; CH N H3C 02-; H3C F to of viv ; F ; ; CI Br ; F 0760,F F F F N CH F F viv viv ; viv ; F F viv F F ; 20F F viv ; ; 181 CI ﻢﻓﺮﻣﺓ F F ﻡﺓ ﻻﺮﻤﻳ F ; F viv H3C F ; F 100,0; 2000 , ; F ; ; ; ; S F S F F ; and F F of the compound .

F ; wherein In embodiments of the compound of formula ( 1 ) , R1 is selected from the following groups : indicates the point of attachment to the rest F 0000- F F.

; F ' ; ; ; F H3C F ; F3CO F LL FL H3C F.

F F3C ; N F OC₂F viv ; ; viv ﻊﺒﻳﺭ ; Z CI .N .

C Z Z w IN F ﻊﺒﻳﺭ w viv 185 F to to to F F ; F ; F ; 80 to F ; F F ; CI F F Br F F M ; F F ; ; ; 186 F .N .

F 60,00.N CH; F F F · F viv F LL F ; ; ww ; ; F ד . LL F ww F ; F ; 187 CI Ja 20F ; ; ' N ' ; F F S S F ás ' F ; 188 H3C .HO ; .F to to ; S F F F F of the compound . ; ; and ; ; wherein indicates the point of attachment to the rest In embodiments of the compound of formula ( 1 ) , R1 , R2 and L ' and the nitrogen atom to which R2 and L ' are attached form a heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl or bicyclic heteroaryl , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , alkyl , haloalkyl , alkoxy , haloalkoxy and alkyl - NR1aR1b ; and R1a and R1b are each independently selected from H and alkyl . 189 LO In embodiments of the compound of formula ( 1 ) , R1 , R2 and ¹L and the nitrogen atom to which R2 and ¹L are attached form a 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11- membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , or 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1R1b , ₁C - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - Chaloalkoxy and ₁C - C4 alkyl - NR1aR1b ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R1 , R2 and L ' and the nitrogen atom to which ²R and L ' are attached form a 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11- membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , or 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1 ) , R1 , R2 and L1 and the nitrogen atom to which R2 and L1 are attached form a 8- to 11- membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1 ) , R1 , R2 and ¹L and the nitrogen atom to which R2 and L1 are attached form the following bicyclic heterocycloalkyl group : N ; wherein indicates the point of attachment to the rest of the compound .

In embodiments of the compound of formula ( 1 ) , ²R is selected from H , ₁C - C4 alkyl and C3 - C8 cycloalkyl . 190 LO In embodiments of the compound of formula ( 1 ) , ²R is selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ²R is H.

In embodiments of the compound of formula ( 1 ) , ³R is selected from H , OH , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , зC - C8 cycloalkoxy - ₁C - C4 alkyl , ³C - Ccycloalkoxy - ₁C - C4 alkyl , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , C1 - C4 alkyl , C1- C4 alkoxy , and d³Rc³RN ; 3a a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and C1 - C4 alkyl - f³Re3RN ; R3b , R3c , d³R , e³R and f³R are each independently selected from H and C1 - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ³R is selected from H , CN , b3R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , C1- C4 alkyl , ₁C - C4 alkoxy , and d³Rc³RN ; a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³R³RN ; R3b , R3c , d³R , e³R and f³R are each independently selected from H and C1 - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ³R is selected from H , CN , b³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , зC - Ccycloalkyl - C1 - C4 alkoxy , C1 - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein 191 LO said alkyl , cycloalkyl , heterocycloalkyl , and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , C1 - Calkoxy , and NR3cR3d : a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³R³RN ; R3b , R3 , R3d , e³R and f³R are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ³R is selected from NR 3R3b , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , ³C - Ccycloalkyl - ₁C - C4 alkoxy , and ₁C - C4 alkyl - S - ₁C - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , C1 - C4 alkyl , C1 - C4 alkoxy , and ³RN ¢ d³R ; a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³Re³RN ; R3b , R3c , d³R , e³R and f³R are each independently selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ³R is selected from H , CN , b3Rа³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , C1 - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - C1 - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , C1 - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and NR3cR3d . a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³R³RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; and e³R and f³R are each independently selected from ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ³R is selected from H , CN , b3Rа³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , C1 - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - C192 cycloalkyl - ₁C - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and d³RC³RN ; a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Rе³RN ; LO R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; and R3e and f³R are each independently selected from ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ³R is selected from NR 3R 3b , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , and ₁C - C4 alkyl - S - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and d³Rc³RN ; a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Rе³RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; and R3e and f³R are each independently selected from C1 - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ³R is selected from H , CN , ³RN R3b , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC3RN ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; and R3d is selected from C1 - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , 193 wherein ³R is selected from H , CN , b3Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl - C1 - C4 alkoxy , C1 - Chaloalkoxy - C1 - C4 alkyl , ₁C - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , and heteroaryl are each optionally substituted by one . or more substituents independently selected from halogen , OH and d³RC³RN ; a³R is selected from H and ₁C - C4 alkyl ; R3b is selected from C1 - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; and R3d is selected from ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ³R is selected from b3R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - C4 alkoxy - C1 - C4 alkyl , C3 - Ccycloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl - ₁C - C4 alkoxy , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , and -₁C C4 alkyl - S - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³Rc³RN ; aзR is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; and R3d is selected from ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ³R is selected from H , CN , ³Rª³RN , ₁C - C4 alkyl optionally substituted by OH , ³C - Ccycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl- C1 - C4 alkoxy , C1 - C4 haloalkoxy - C1 - C4 alkyl , C1 - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2- ₁C - C4 alkyl ; a³R is H ; and R3b is selected from C1 - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , 194 LO ³R is selected from NR 3R 3b , ₁C - C4 alkyl substituted by one or more substituents independently selected from OH and NR30 R3d , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , C1 - Calkoxy - C1 - C4 alkyl , C3 - C8 cycloalkoxy - C1 - C4 alkyl , C3 - C8 cycloalkyl - C1 - C4 alkoxy , C1 - Chaloalkoxy - C1 - C4 alkyl , and ₁C - C4 alkyl - S - C1 - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R3 is selected from : H ; CN ; NR3aR3b : ₁C - C4 alkyl optionally substituted by one of more substituents selected from OH and NR3c R3d . C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , optionally substituted by one or more C1 - C4 alkyl ; phenyl optionally substituted by one or more halogen ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; wherein ₁C - C4 alkyl - S - ₁C - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Re³RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; and e³R and f³R are each independently selected from C1 - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ³R is selected from : 195 H ; CN ; NR3aR3b . C1 - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR3cR3d : C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; phenyl substituted by one or more halogen ; 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; wherein C1 - C4 alkyl - S - C1 - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; a³R is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; and R3d is selected from ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ³R is selected from : H ; CN ; NR3aR3b ; ₁C - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - C1 - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - C1 - C4 alkyl ; 196 wherein ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; C1 - C4 alkyl - S - C1 - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; R3a is H ; and R3b is selected from ₁C - C4 alkyl .

Clause 89. The compound of any preceding clause , wherein ³R is selected from : - wherein NR3aR3b : ₁C - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; and C1 - C4 alkyl - S - C1 - C4 alkyl ; R3a is H ; and R3b is selected from ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , ³R is selected from ₁C - C4 alkoxy - ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , wherein ³R is selected from methoxymethyl .

In embodiments of the compound of formula ( 1 ) , ³R is selected from the following groups : 197 viv .CH viv CH IZ .N . CHviv viv CHN viv .CN ; F vin viv ' N ' CH viv CH; IZ viv viv viv viv .CH ; viv .H viv viv ' N ' .CH CH CH N. CHviv ; -N . · CH3 ; viv CH ; -2H 2H H3C CH ; 2H ﺲﻧﻯ viv CH; ﻊﻴﻨﻳ ; viv ; viv CH ; ﻊﻧﻯ ; OH .CHCH CH3 CH; and ; wherein indicates the point of attachment to the rest of the compound .

In embodiments of the compound of formula ( 1 ) , ³R is selected from the following groups : viv vir CH .CN CH CH viv N viv CH N ' N ' CH F CH viv ; viv viv viv ' N ' ZI ; .CH viv CH ; H ; CH viv .N . viv ; 2H ; 2H · 2H CH CH ; LL F ; and OH viv .CH .CHviv CH viv CH; and indicates the point of attachment to the rest of the compound .

In embodiments of the compound of formula ( 1 ) , R3 is selected from the following groups : viv vin vir CH .CN CH viv viv .N CH CHN viv 2H 2H 2H ; viv viv H3C CH viv OH CH; wherein .CH F ; .CHﻮﺴﻜﺠﻣ viv ﻢﻌﻧﻯ ; and indicates the point of attachment to the rest of the compound .

In embodiments of the compound of formula ( 1 ) , ³R is selected from the following groups : vir H OH ; wherein viv viv .CH CH viv viv viv viv H N CH .CH CH CH LL F CH; viv viv viv and viv ; N.

OH S .CH viv 2H viv viv viv 2H 2H CH ; S CH; and viv compound .

CH; wherein indicates the point of attachment to the rest of the In embodiments of the compound of formula ( 1 ) , R4 is selected from C ( O ) OH , C ( O ) b4Rª¹RN , C ( S ) NR 4 R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; and R4a and R4b are each independently selected from H and alkyl .

In embodiments of the compound of formula ( 1 ) , R4 is selected from C ( O ) 4Rª4RN and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; and R4a and R4b are each independently selected from H and alkyl . 201 LO In embodiments of the compound of formula ( 1 ) , R4 is selected from C ( O ) OH , C ( O ) b4Rª4RN , C ( S ) NR ª4 R4 and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; and R4b is H.

In embodiments of the compound of formula ( 1 ) , R4 is selected from C ( O ) OH , C ( O ) ª4RN R4b , and C ( S ) b4Rª4RN ; R4a is selected from H and ₁C - C4 alkyl ; and R4b is H.

In embodiments of the compound of formula ( 1 ) , R4 is selected from C ( O ) OH , C ( O ) ª4RN R4b and C ( S ) ª4RN R4b ; and R4a and R4b are each H.

In embodiments of the compound of formula ( 1 ) , R4 is C ( O ) NR4aR4b ; and R4a and R4b are each H.

In embodiments of the compound of formula ( 1 ) , R4 is selected from the following groups : viv .OH viv .NH.N . IZ CH ; ; viv NH viv N ; ; and S wherein indicates the point of attachment to the rest of the compound .

In embodiments of the compound of formula ( 1 ) , R4 is selected from the following groups : 202 NHviv NHCH Ja Ja Ja Je viv OH S ; ; and wherein indicates the point of attachment to the rest of the compound .

In embodiments of the compound of formula ( 1 ) , R4 is selected from the following groups : viv .OH viv NH2 NH ; wherein indicates the S ; and point of attachment to the rest of the compound .

In embodiments of the compound of formula ( 1 ) , R4 is ﺎﺗ compound .

NH ; wherein indicates the point of attachment to the rest of the In embodiments of the compound of formula ( 1 ) , R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , C1 - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycle having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1 ) , R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , C1 - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered 203 LO heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycle having one or more heteroatoms selected from N and O.

In embodiments of the compound of formula ( 1 ) , R5 is selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - Calkoxy - C1 - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1 ) , R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1 ) , R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1 ) , R5 is selected from the following groups : N HN I H. H3C . ; and attachment to the rest of the compound .

In embodiments of the compound of formula ( 1 ) , R5 is selected from the following groups : HN N H ; and rest of the compound . ; wherein wherein ' indicates the point of indicates the point of attachment to the LO In embodiments of the compound of formula ( 1 ) , R5 is H.

In embodiments of the compound of formula ( 1 ) , 1- R6 is selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C1 - Calkoxy - C1 - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1 ) , R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R6 is selected from H and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1 ) , R6 is selected from the following groups : H. H3C H3C . ; and H3C indicates the point of attachment to the rest of the compound . In embodiments of the compound of formula ( 1 ) , R6 is H or methyl .

In embodiments of the compound of formula ( 1 ) , R6 is H. ; wherein In embodiments of the compound of formula ( 1 ) , R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycle having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1 ) , R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycle having one or more heteroatoms selected from N and O.

In embodiments of the compound of formula ( 1 ) , 205 R5 and R6 together with the carbon atoms to which they are attached form a 5 - membered heterocycle containing one O atom .

In embodiments of the compound of formula ( 1 ) , R7 , ³R , ºR , R10 , R11 , and R12 are each H.

Also disclosed herein is a compound according to the invention having the structural formula ( 2 ) : R RN XA N. ' X ' +³R ( 2 ) R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein : X1 , X2 , X3 , X4 , and X5 are as defined for compounds of formula ( 1 ) ; X7 is selected from CR10 , O , and N ; and q , ¹L , R1 , R2 , ³R , R4 , and R10 are as defined in any preceding clause ; wherein when q is 0 , X7 is O or N , and when q is 1 , X7 is CR10 .

Also disclosed herein is a compound according to the invention having the structural formula ( 2a ) : 206 R RN.

R RX ' N ' .N ³R- LO ( 2a ) R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein X1 , X5 , ¹L , ¹R , R2 , R3 , R4 , R5 and R6 are as defined for compounds of formula ( 1 ) ; wherein one of X1 and X5 is C and the other is N.

Also disclosed herein is a compound according to the invention having the structural formula ( 2aa ) : 207 R R2 .

R N R' N ' .N ' N ' -R LO ( 2aa ) R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein ¹L , R1 , ²R , ³R , R4 , R5 and R6 are as defined for compounds of formula ( 1 ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 2ab ) : R RN R RN N N R R3 LO ( 2ab ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein ¹L , R1 , ²R , ³R , R4 , R5 and R6 are as defined for compounds of formula ( 1 ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 2ac ) : R N R ' N ' .N .

.N R ³R ( 2ac ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein L1 , R1 , R2 , ³R and R4 are as defined for compounds of formula ( 1 ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 2ad ) : 209 R R R N ' L ' .N ' N ' N N R ( 2ad ) R Including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein ¹L , R1 , R2 , ³R , R4 , and R5 are as defined for compounds of formula ( 1 ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 2b ) : R L R R R' N ' .N . R R R210 ( 2b ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein q , ¹L , ¹R , ²R , ³R , R4 , R5 , R6 and R10 are as defined for compounds of formula ( 1 ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 3 ) : R N R N N. ³R- R( 3 ) R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein ¹L , R1 , ²R , ³R , R4 and R7 are as defined for compounds of formula ( 1 ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 4 ) : 211 R' L N.

+A XR R ( 4 ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein : X1 , X2 , X3 , X4 , and X5 are as defined in clause 1 ; X6 is selected from CR8 R9 and O ; X7 is selected from CR11 R12 and O ; and ¹L , q , R1 , R2 , ³R , R4 , ³R , ºR , ¹¹R , and R12 are as defined for compounds of formula ( 1 ) ; wherein when q is 0 , X7 is O ; and when X7 is O and q is 1 , X6 is CR8R9 .

Also disclosed herein is a compound according to the invention having the structural formula ( 4a ) : 212 R R R N RN ( 4a ) R -R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein : ¹L , q , R1 , R2 , R3 , R4 , and R6 are as defined for compounds of formula ( 1 ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 4b ) : R N. R R R' N ' R ³R R2 R12 ( 4b ) Including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein q , ¹L , ¹R , ²R , ³R , R4 , R5 , R6 , R11 and R12 are as defined for compounds of formula ( 1 ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 4c ) : R N. R R RN R8 R ³R R ( 4c ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein q , ¹L , R1 , ²R , ³R , R4 , R5 , R6 , R8 and R9 are as defined for compounds of formula ( 1 ) .

Also disclosed herein is a compound of formula ( 1 ) which has the structural formula ( 1a ) : 214 R R + A +te R R( 1a ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein : Q is O or S ; X1 is selected from C and N ; X2 is selected from CR5 and N ; X3 is selected from CR and N ; X4 is selected from CR7 and N ; X5 is selected from C and N ; wherein X1 , X2 , X3 , X4 and X5 are selected so that the ring labelled A is aromatic ; X6 is selected from CR8R9 , O and N ; X7 is selected from CR10 , CR11 R12 , O and N ; q is 0 or 1 ; wherein when q is 0 , X7 is O or N ; and when X7 is O or N and q is 1 , X6 is CR8R9 ; L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , ³C - ɛC cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11- membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or 215 more heteroatoms selected from N , O and S , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - Calkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; or R1 , R2 and L1 and the nitrogen atom to which R2 and ¹L are attached form a 3- to 8- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , or 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - Chaloalkoxy and ₁C - C4 alkyl - NR1aR1b ; ³R is selected from H , OH , CN , b3R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C C4 alkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - C1 - C4 alkyl , and C3 - Ccycloalkyl - ₁C - C4 alkoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and d³RC³RN ; a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and C1 - C4 alkyl - f³R³RN ; R3b , R3 , R3d , e³R and f³R are each independently selected from H and ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR 4a R 4b and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a and R4b are each independently selected from H and C1 - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , C1 - C4 alkyl , C1 - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered 216 LO heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , R8 , ⁹R , º¹R , R11 , and R12 are each independently selected from H , halogen , OH , CN , C1- C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1a ) , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11- membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - Calkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; ³R is selected from H , OH , CN , b³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C C4 alkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , and C3 - Ccycloalkyl - C1 - C4 alkoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and d³RC3RN ; 217 LO a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³R³RN ; R3b , R3c , d³R , e³R and f³R are each independently selected from H and ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR4 R4b and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; Ra and R4b are each independently selected from H and ₁C - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , ºR , ºR , º¹R , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1a ) , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1 is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 8- to 11- membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , and phenoxy , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , C1 - C4 haloalkyl , C1 - C4 alkoxy , C1 - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , halophenoxy , and ₁C - C4 alkyl substituted by a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is H ; ³R is selected from H , CN , b3R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , C1 - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , and C3 - C8 cycloalkyl - ₁C - C4 alkoxy , wherein 218 LO said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and NR3cR3d a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Rе³RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; e³R and f³R are each independently selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) b4Rª4RN , C ( S ) NR ª4 R4 and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and C1 - C4 alkoxy - C1 - C4 alkyl ; and R7 R8 R9 R10 R11 , and R12 are each H. ' ' In embodiments of the compound of formula ( 1a ) , L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene ; R1 is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 8- to 11- membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , and phenoxy , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , -₁C C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - Ccycloalkyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , and C3 - C8 cycloalkyl - ₁C - C4 alkoxy , wherein 219 LO said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³R³RN ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) 4RªRN , C ( S ) NR 4 R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; Ra is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , R10 , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1a ) , L ' is a bond , ₁C - 6С alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene ; R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said cycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is H ; ³R is selected from H , CN , b3R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , C1 - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - C1 - C4 alkyl , and C3 - C8 cycloalkyl - ₁C - C4 alkoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC³RN ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from C1 - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; 220 d³R is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : viv .OH viv NH ; S ; and viv NH ; and viv CH ﻡا wherein indicates the point of attachment to the rest of the compound ; R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; ' R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , ºR , ºR , º¹R , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1a ) , L ' is a bond , ₁C - C6 alkylene , or ₁C - C6 haloalkylene ; R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said cycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , b³Ra³RN , ₁C - C4 alkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkoxy - ₁C - C4 alkyl , wherein said alkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen and d³Rc³RN ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is C ( O ) NR4R4b ; 221 R4a and R4b are each H ; R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , ³R , ºR , R10 , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1a ) , L ' is either a bond , ₁C - C6 alkylene , or C3 - C6 cycloalkylene ; ¹R is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said cycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - Chaloalkoxy ; ²R is H ; ³R is selected from H , CN , NR3R3b , ₁C - C4 alkyl optionally substituted by OH , C3 - Ccycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - C4 alkoxy - ₁C - C4 alkyl , зC - C8 cycloalkyl - ₁C - C4 alkoxy ; and ₁C - Chaloalkoxy - C1 - C4 alkyl ; a³R is H ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : OH NH2 NH YYY ; and point of attachment to the rest of the compound ; R5 is H ; R6 is selected from H and ₁C - C4 alkyl ; and ; wherein indicates the R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1a ) , L ' is either a bond or ₁C - C6 alkylene ; 222 LO R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said cycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , and C1 - Chaloalkoxy ; ²R is H ; ³R is selected from H , CN , b³Ra3RN , ₁C - C4 alkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is C ( O ) NR4R4b ; R4a and Rb are each H ; R5 is H ; R6 is selected from H and ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1a ) , L ' is either a bond or ₁C - C6 alkylene ; R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said cycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , and C1 - Chaloalkoxy ; ²R is H ; ³R is selected from NR 3R 3b , ₁C - C4 alkyl substituted by one or more substituents independently selected from OH and d³RC3RN , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , and ₁C - C4 haloalkoxy - C1 - C4 alkyl ; 3a aзR is H ; 223 R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : viv .OH m ₂HN viv NH S ; and point of attachment to the rest of the compound ; ; wherein indicates the R5 , R6 , R7 , R8 , R9 , R10 , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1a ) , L ' is either a bond or C1 - C6 alkylene ; R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , wherein said cycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , C1 - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; ²R is H ; ³R is selected from b³Rª³RN , ₁C - C4 alkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is C ( O ) NR4R4b ; R4a and R4b are each H ; R5 , R6 , R7 , ³R , ºR , R10 , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1a ) , Q is O.

In embodiments of the compound of formula ( 1a ) , ¹L is either a bond or ₁C - C6 alkylene ( e.g. methylene ) .

In embodiments of the compound of formula ( 1a ) , R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4 haloalkoxy ; 224 LO C8 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4 alkoxy ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen and C1 - C4 alkyl ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , ○ and S , optionally substituted by one or more substituents independently selected from C1 - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1a ) , ²R is H.

In embodiments of the compound of formula ( 1a ) , ³R is selected from : wherein NR3aR3b . ₁C - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; ' 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; ₁C - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; and ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; R3a is H ; and R3b is selected from ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1a ) , ³R is selected from ₁C - C4 alkoxy - ₁C - Calkyl .

In embodiments of the compound of formula ( 1a ) , 225 R4 is selected from the following groups : www .OH viv .NH viv NH ; ; S wherein compound . viv .N . CHN ; ; and indicates the point of attachment to the rest of the In embodiments of the compound of formula ( 1a ) , R4 is selected from C ( O ) OH , C ( O ) ª4RN R4b and C ( S ) ª4RN R4b ; and R4a and R4b are each H.

In embodiments of the compound of formula ( 1a ) , R5 is selected from the following groups : HN N H ; and ; wherein indicates the point of attachment to the rest of the compound .

In embodiments of the compound of formula ( 1a ) , R5 is H.

In embodiments of the compound of formula ( 1a ) , R6 is H or methyl .

In embodiments of the compound of formula ( 1a ) , R6 is H.

In embodiments of the compound of formula ( 1a ) , R7 , ³R , ºR , R10 , R11 , and R12 are each H.

Also disclosed herein is a compound according to the invention having the structural formula ( 2'a ) : 226 R RN.

R RX ' N ' .N ³R- LO ( 2'a ) R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein X1 , X5 , ¹L , ¹R , R2 , R3 , R4 , R5 and R6 are as defined for compounds of formula ( 1a ) ; wherein one of X1 and X5 is C and the other is N.

Also disclosed herein is a compound of formula ( 1a ) having the structural formula ( 2'aa ) : R RN R R' N ' ' N ' .N R ³R- LO ( 2'aa ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein L1 , R1 , R2 , ³R , R4 , R5 and R6 are as defined for compounds of formula ( 1a ) .

Also disclosed herein is a compound of formula ( 1a ) having the structural formula ( ba’2 ) : R R R N.

N R' N ' ( 2'ab ) N R ³R- including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein L ' , R1 , R2 , ³R , R4 , R5 and R6 are as defined for compounds of formula ( 1a ) .

Also disclosed herein is a compound of formula ( 1a ) having the structural formula ( 2'ad ) : 228 R R R N .N ' L ' ' N ' N N R ( 2'ad ) R Including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein ¹L , R1 , R2 , ³R , R4 , and R5 are as defined for compounds of formula ( 1a ) .

Also disclosed herein is a compound of formula ( 1 ) which has the structural formula ( 1b ) : R R.N .

X +A X R( 1b ) 2 6✗ R3 LO including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein : 1✗ is selected from C and N ; X2 is selected from CR5 and N ; X3 is selected from CR and N ; X4 is selected from CR7 and N ; X5 is selected from C and N ; wherein X1 , X2 , ³X , ªX and X5 are selected so that the ring labelled A is aromatic ; 6✗ is selected from CR8R9 , O and N ; X7 is selected from CR10 , CR11 R12 , O and N ; q is 0 or 1 ; wherein when q is 0 , X7 is O or N ; and when X7 is O or N and q is 1 , X6 is 9R³RC ; L ' is a bond , ₁C - C6 alkylene or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , ³C - ɛC cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11- membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - Calkyl , ₁C - C4haloalkyl , ₁C - Calkoxy , ₁C - C4haloalkoxy , ₁C - C4alkyl - b1Rª¹RN , C3 - C8cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4alkyl ; ²R is selected from H , C1 - C4 alkyl and C3 - C8 cycloakyl ; or R1 , R2 and L1 and the nitrogen atom to which R2 and L1 are attached form a 3- to 8- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , or 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected 230 from N , O and S , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1 R1b , ₁C - C4 alkyl , ₁C - C4haloalkyl , ₁C - C4alkoxy , C1- C4haloalkoxy and ₁C - C4alkyl - b1Rª¹RN ; ³R is selected from H , OH , CN , b³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C C4alkoxy - C1 - C4alkyl , ₁C - C4haloalkoxy - C1 - C4alkyl and C3 - C8cycloalkoxy - C1 - C4alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and NR3cR3d . 3a a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³Rе³RN ; R3b , R3 , R3d , e³R and f³R are each independently selected from H and C1 - C4 alkyl ; R4 is selected from C ( O ) NR4R4b and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a and R4b are each independently selected from H and ₁C - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , C1 - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4alkoxy - ₁C - C4alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , ³R , ⁹R , º¹R , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1b ) , L ' is a bond , ₁C - C6 alkylene or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1 is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11- membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , 231 LO bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - Calkyl , C1 - C4haloalkyl , ₁C - C4alkoxy , ₁C - C4haloalkoxy , ₁C - C4alkyl - NR1aR1b , C3 - C8cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , ○ and S , benzyl , phenoxy , halophenoxy and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4alkyl ; ²R is selected from H , C1 - C4 alkyl and C3 - C8 cycloakyl ; ³R is selected from H , OH , CN , b³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C C4alkoxy - C1 - C4alkyl , ₁C - C4haloalkoxy - ₁C - C4alkyl and C3 - C8cycloalkoxy - ₁C - C4alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and NR3cR3d . a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³Re3RN ; R3b , R3 , R3d , e³R and f³R are each independently selected from H and ₁C - C4 alkyl ; R4 is selected from C ( O ) NR4R4b and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a and R4b are each independently selected from H and C1 - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , C1 - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4alkoxy - ₁C - C4alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , R8 , ⁹R , R10 , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

In embodiments of the compound of formula ( 1b ) , L ' is a bond , ₁C - C6 alkylene or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 232 LO R1 is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 8- to 11- membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , and phenoxy , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , ₁C - C4haloalkyl , ₁C - Calkoxy , ₁C - C4haloalkoxy , ₁C - C4alkyl - b¹Rª¹RN , C3- lyklaolcycЯC , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , and halophenoxy ; R1a and R1b are each independently selected from H and ₁C - C4alkyl ; ²R is H ; ³R is selected from H , CN , ³Rª³RN , ₁C - C4 alkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4alkoxy - ₁C - C4alkyl , wherein said alkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl , and d³Rc³RN ; a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Re3RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; e³R and f³R are each independently selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) ª4RN R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4alkoxy - ₁C - C4alkyl ; and R7 , R8 , R9 , º¹R , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1b ) , L ' is either a bond or C1 - C6 alkylene ; R1 is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 8- to 11- membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , 233 LO O and S , 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , and phenoxy , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , -₁C C4 alkyl , C1 - C4haloalkyl , ₁C - C4alkoxy , ₁C - C4haloalkoxy , ₁C - C4alkyl - NR1R1b , C3- lyklaolcycɛC , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and benzyl ; R1a and R1b are each independently selected from H and ₁C - C4alkyl ; ²R is H ; ³R is selected from H , CN , b³R³RN , ₁C - C4 alkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4alkoxy - C1 - C4alkyl , wherein said alkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen and d³R³RN ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from C1 - C4 alkyl ; R3c is selected from H and C1 - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) NR 4R 4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a and R4b are each H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4alkoxy - ₁C - C4alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1b ) , L1 is either a bond or ₁C - C6 alkylene ; R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said cycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4haloalkyl , ₁C - C4alkoxy , -₁C C4haloalkoxy , ₁C - C4alkyl - b¹Rª¹RN , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 234 LO R1a and R1b are each independently selected from H and ₁C - C4alkyl ; ²R is H ; ³R is selected from H , CN , b³Ra3RN , ₁C - C4 alkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4alkoxy - C1 - C4alkyl , wherein said alkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen and d³RC3RN ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; R4 is C ( O ) NR4R4b ; R4a and R4b are each H ; R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4alkoxy - ₁C - C4alkyl ; and R7 , R8 , ⁹R , º¹R , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1b ) , L1 is either a bond or ₁C - C6 alkylene ; R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and 8- to - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said cycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl , ₁C - C4haloalkyl , ₁C - C4alkoxy , and -₁C C4haloalkoxy ; ²R is H ; ³R is selected from H , CN , b³Ra³RN , ₁C - C4 alkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4alkoxy - ₁C - C4alkyl ; a³R is H ; R3b is selected from ₁C - C4 alkyl ; R4 is C ( O ) NR4R4b ; R4a and R4b are each H ; R5 is H ; 235 LO R6 is selected from H and ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1b ) , L ' is either a bond or C1 - C6 alkylene ; R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , wherein said cycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , C1 - C4 alkyl , ₁C - Chaloalkyl , ₁C - C4alkoxy , and ₁C - C4haloalkoxy ; ²R is H ; ³R is selected from NR 3R 3b , ₁C - C4 alkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4alkoxy - C1 - C4alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is C ( O ) NR4R4b ; R4a and R4b are each H ; R5 , R6 , R7 , R8 , ºR , R10 , R11 , and R12 are each H.

In embodiments of the compound of formula ( 1b ) , L ' is either a bond or methylene .

In embodiments of the compound of formula ( 1b ) , R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4haloalkoxy ; C8 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogenand ₁C - C4alkoxy ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S ; phenyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , optionally substituted by one or more substituents independently selected from C1 - C4 alkyl and ₁C - C4 haloalkyl . 236 In embodiments of the compound of formula ( 1b ) , ²R is H.

LO In embodiments of the compound of formula ( 1b ) , R3 is selected from : - NR3aR3b . ' ₁C - C4 alkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; and wherein 3a C1 - C4alkoxy - C1 - C4alkyl ; a³R is H ; and R3b is selected from ₁C - C4 alkyl .

In embodiments of the compound of formula ( 1b ) , ³R is selected from ₁C - C4alkoxy - ₁C - C4alkyl .

In embodiments of the compound of formula ( 1b ) , R4 is selected from the following groups : viv NHviv IZ CHN. ; and indicates the point of attachment to the rest of the compound .

In embodiments of the compound of formula ( 1b ) , R5 is H.

In embodiments of the compound of formula ( 1b ) , R6 is H.

In embodiments of the compound of formula ( 1b ) , R7 , R8 , R9 , º¹R , R11 , and R12 are each H. wherein ' Also disclosed herein is a compound of formula ( 1b ) having the structural formula ( 2 " a ) : R R.N R RX ' N ' .N ³R ( 2 " a ) R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein X1 , X5 , L1 , ¹R , R2 , R3 , R4 , R5 and R6 are as defined for compounds of formula ( 1b ) wherein one of X1 and X5 is C and the other is N.

Also disclosed herein is a compound of formula ( 1b ) having the structural formula ( 2 " aa ) : 238 R R2 .

R N RN .N ' N ' -R LO ( 2 " aa ) R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein ¹L , R1 , ²R , ³R , R4 , R5 and R6 are as defined for compounds of formula ( 1b ) .

Also disclosed herein is a compound of formula ( 1b ) having the structural formula ( 2 " ab ) : ¹R R R N RN ' N N R( ba❞2 ) ³R- LO including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein L1 , ¹R , ²R , ³R , R4 , R5 and R6 are as defined for compounds of formula ( 1b ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 2 ' ) : R R.N .

A +X4 .

( N / R ( 2 ' ) R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein : X7 is selected from CR10 , O , and N ; and X1 , X2 , X3 , X4 , X5 , q , ¹L , ¹R , ²R , ³R , R4 , and R10 are as defined for compounds of formula ( 1a ) ; wherein when q is 0 , X7 is O or N , and when q is 1 , X7 is CR10 .

Also disclosed herein is a compound according to the invention having the structural formula ( 2'a ) : 240 R RN.

R RX ' N ' .N ³R- LO ( 2'a ) R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein X1 , X5 , ¹L , ¹R , R2 , R3 , R4 , R5 and R6 are as defined for compounds of formula ( 1a ) ; and wherein one of X1 and X5 is C and the other is N.

Also disclosed herein is a compound according to the invention having the structural formula ( 2'aa ) : 241 R R2 .

R N RN .N ' N ' -R LO ( 2'aa ) R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein ¹L , R1 , ²R , ³R , R4 , R5 and R6 are as defined for compounds of formula ( 1a ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 2'ab ) : R RN R RN N N R R3 LO ( 2'ab ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein L1 , R1 , R2 , ³R , R4 , R5 and R6 are as defined for compounds of formula ( 1a ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 2'ac ) : R N R ' N ' .N .

.N R ³R ( 2'ac ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein L1 , R1 , R2 , ³R and R4 are as defined for compounds of formula ( 1a ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 2'b ) : 243 R' L RN.

R.N . R R6 R R ( 2'b ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein q , L1 , ¹R , ²R , ³R , R4 , R5 , R6 and R10 are as defined for compounds of formula ( 1a ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 3 ' ) : 244 R R N N R -R R( 3 ' ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein L1 , R1 , R2 , ³R , R4 and R7 are as defined for compounds of formula ( 1a ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 4 ' ) : 245 R' L N.

+A XR R ( 4 ' ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein : X6 is selected from CR8R9 and O ; X7 is selected from CR11 R12 and O ; and ¹X , ²X , ³X , ªX , ³X , ¹L , q , ¹R , ²R , ³R , R4 , ³R , ⁹R , R11 , and R12 are as defined in any for compounds of formula ( 1a ) ; and wherein when q is 0 , X7 is O ; and when X7 is O and q is 1 , X6 is ⁹R8RC .

Also disclosed herein is a compound according to the invention having the structural formula ( 4'a ) : 246 R R R N RN ( 4'a ) R -R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein : ¹L , q , R1 , R2 , R3 , R4 , and R6 are as defined for compounds of formula ( 1a ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 4b ) : R N. R R R' N ' R R ³R R4 ( 4'b ) Including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein q , ¹L , ¹R , ²R , ³R , R4 , R5 , R6 , R11 and R12 are as defined ifor compounds of formula ( 1a ) .

Also disclosed herein is a compound according to the invention having the structural formula ( 4c ) : R N. R R RN R8 R ³R R ( 4 ° c ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein q , ¹L , R1 , ²R , ³R , R4 , R5 , R6 , R8 and R9 are as defined for compounds of formula ( 1a ) .

Also disclosed herein is a compound according to the invention as listed in Table 1 , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof . In embodiments , the compound is one of compounds 1 to 242 , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof . 248 LO In embodiments , the compound may be selected from the compounds listed in Table 1 .

Table 1 : Exemplary compounds of the present disclosure Compound Compound Number ﻞﻫ LO N7 - indan - 2 - ylpyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 4 - methylindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 5 - methoxyindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 4 - chloroindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 1,2,3,4 - tetrahydroquinolin - 3 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - chroman - 3 - ylpyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( trans - 3 - fluoro - 3 - methyl - cyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 00 N7- ( cis - 3 - hydroxy - 3 - methyl - cyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( cis - 3 - cyanocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,3 - diethylcyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( cis - 3 - methoxycyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 7 - oxaspiro [ 3.5 ] nonan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 5,6,7,8 - tetrahydroisoquinolin - 7 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- [ 4- ( 3,3,3 - trifluoropropyl ) indan - 2 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- [ 5- ( 2 - pyrrolidin - 1 - ylethyl ) indan - 2 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- [ 4- ( 4 - chlorophenoxy ) indan - 2 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- [ 4- ( 2 - pyridyl ) indan - 2 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 249 Compound Compound Number N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 6,7 - dihydro - 5H - pyrrolo [ 1,2 - a ] imidazol - 6 - yl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7- ( 1,2,3,4 - tetrahydro - 1,8 - naphthyridin - 3 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2 - cyano - N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ﻦﻫ ﻞﻫ ﺖﻫ ﻞﻠﻫ ﻞﻠﻫ ﻼﻠﻫ N7 - indan - 2 - yl - 2 - pyridazin - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 2- [ 2- ( dimethylamino ) ethylamino ] -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7 - indan - 2 - yl - 2- ( 1 - methylazetidin - 3 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2 - oxazol - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N8- ( 3,3 - difluorocyclobutyl ) -2 - methyl - imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide N7 - indan - 2 - yl - 2- ( isopropoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2- ( isopropoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 2 - [ ( dimethylamino ) methyl ] -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - indan - 2 - yl - 2- ( methylaminomethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N - indan - 2 - yl - 3 - oxazol - 2 - yl - pyrazolo [ 1,5 - a ] pyridine - 7 - carboxamide N7- ( 3,3 - difluorocyclobutyl ) -2 - methyl - 6- ( 1H - pyrazol - 4 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2 - oxazol - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2- ( methylamino ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 250 Compound Compound Number N7- ( 3,3 - difluorocyclobutyl ) -2- ( dimethylamino ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( 2 - fluorophenyl ) -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyridine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2,6 - dimethyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -5- ( methoxymethyl ) -2 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - N3 - methyl - 2 - phenyl - pyrazolo [ 1,5 - a ] pyridine - 3,7- dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -5 - methoxy - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2,5 - dimethyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2 - tetrahydrofuran - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2 - tetrahydrofuran - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7 - chroman - 3 - yl - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( cis - 3 - cyanocyclobutyl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 5 - benzylindan - 2 - yl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 251 Compound Compound Number N7- ( 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 6 - yl ) -2 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2 - methyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N8- ( 3,3 - difluorocyclobutyl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide ..... 2- ( methoxymethyl ) -N8- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide N8 - indan - 2 - yl - 2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide N7 - indan - 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7- [ 5- ( trifluoromethyl ) -2 - pyridyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- N7- [ 4 - [ ( dimethylamino ) methyl ] phenyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 1 - methylpyrazol - 4 - yl ) methyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 4,6 - dimethyl - 2 - pyridyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7-94- ( trifluoromethyl ) -2 - pyridyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,4 - difluorophenyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 2,3 - dihydrobenzofuran - 5 - ylmethyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 252 Compound Compound Number N7- ( 2,4 - difluorophenyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - benzyl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7 - [ ( 4 - fluorophenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7 - [ ( 3 - fluorophenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7- ( p - tolylmethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7- ( 7 - methoxytetralin - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 1R ) -tetralin - 1 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7 - cyclohexyl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - [ ( 2,2 - dimethylcyclopropyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7 - chroman - 3 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 2S ) -tetralin - 2 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7- ( cyclopropylmethyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 7 - fluorotetralin - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - [ ( 2,4 - difluorophenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 253 Compound Compound Number 2- ( methoxymethyl ) -N7- ( cis - 4 - methylcyclohexyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7- ( 5,6 - dihydro - 4H - cyclopenta [ c ] thiophen - 5 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7- ( trans - 3 - methylcyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7- ( 5 - chloroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -7- [ 4- [ 3- ( trifluoromethyl ) -2 - pyridyl ] piperazine - 1- carbonyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3 - carboxamide N7 - [ [ 1- ( dimethylamino ) cyclohexyl ] methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 4 - fluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ...

N7- ( 4,6 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7- ( 1,2,3,4 - tetrahydroquinolin - 3 - yl ) pyrazolo [ 1,5- N7- ( trans - 3 - fluoro - 3 - methyl - cyclobutyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide a ] pyrimidine - 3,7 - dicarboxamide 7- ( 2,3 - dihydro - 1H - isoindole - 2 - carbonyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3 - carboxamide N7- [ 2- ( 3 - methylphenoxy ) butyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- [ 2 - methyl - 5- ( pyridin - 4 - yl ) phenyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- [ 1- ( 5 - methoxy - 1H - 1,3 - benzodiazol - 2 - yl ) ethyl ] pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7- [ 1- ( 4 - tert - butylphenoxy ) propan - 2 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 254 Number Compound Compound N7- ( 3,3,3 - trifluoropropyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 1N7 - [ ( 4,4 - difluorocyclohexyl ) methyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 1N7- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 1N7- ( 4,4 - difluorocyclohexyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 1 N8- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide N8- ( 5,6 - dihydro - 4H - cyclopenta [ c ] thiophen - 5 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide 1N8- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2- ( methoxymethyl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide 1N8- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide 12- ( methoxymethyl ) -N8 - [ ( 4S ) -7 - fluorochroman - 4 - ylimidazo [ 1,2 - b ] pyridazine- 3,8 - dicarboxamide N8- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide N8 - [ ( 4 - fluorophenyl ) methyl ] -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine- 3,8 - dicarboxamide 12 - cyclopropyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 12 - cyclopropyl - N7- ( 3,3 - difluoroindan - 1 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 12 - cyclopropyl - N7 - [ ( 45 ) -7 - fluorochroman - 4 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 1N7- ( 6 - chlorochroman - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 12 - cyclopropyl - N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 4,4 - difluorotetralin - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 255 Compound Compound Number 1N7- ( 8 - fluoro - 3 - quinolyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 12- ( methoxymethyl ) -N7- ( 1 - methylindol - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 12- ( methoxymethyl ) -N7 - [ ( 3R ) -6,7 - difluoro - 2,3 - dihydrobenzofuran - 3- yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 1N7 - [ ( 3R ) -5 - fluoro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 12- ( methoxymethyl ) -N7- ( 2 - methylindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 1N7- [ 1- ( 4 - fluorophenyl ) ethyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 4S ) -7 - fluorochroman - 4 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 2,2 - difluoro - 6 - methyl - spiro [ 3.3 ] heptan - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 12- ( methoxymethyl ) -N7- ( 2,2,2 - trifluoro - 1- ( 4 - fluorophenyl ) ethyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 1N7- ( 2,2 - difluorospiro [ 3.3 ] heptan - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 . a ] pyrimidine - 3,7 - dicarboxamide 1N7- [ 1- ( 4 - fluorophenyl ) cyclopropyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 12- ( methoxymethyl ) -N7 - [ ( 3R ) -6 - fluoro - 2,3 - dihydrobenzofuran - 3- yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 1N7- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 2 - cyclopropyl - N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 2,2 - difluorospiro [ 3.3 ] heptan - 7 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7- [ cis - 4- ( trifluoromethoxy ) cyclohexyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 256 Compound Compound Number N7 - [ ( 4,4 - difluorocyclohexyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2 - cyclopropyl - N7- ( 5,6 - dihydro - 4H - cyclopenta [ c ] thiophen - 5 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2 - cyclopropyl - N7- ( 4,4 - difluorocyclohexyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 12 - cyclopropyl - N7- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3.7- dicarboxamide 12 - propyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 1N7- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2 - cyclopropyl - pyrazolo [ 1,5- alpyrimidine - 3,7 - dicarboxamide 1N7 - indan - 2 - yl - 2 - propyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 12 - cyclopropyl - N7 - [ ( 4 - fluorophenyl ) methyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( hydroxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pEyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( cyclopropylmethoxy ) -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 7- ( indan - 2 - ylcarbamoyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3- carboxylic acid N7- ( 6 - bromochroman - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 2- ( methylamino ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 7- ( indan - 2 - ylcarbamothioyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3- carboxamide 257 Compound Compound Number 13 - carbamothioyl - N - indan - 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- - carboxamide 2 - cyclopropyl - N8- ( 4,4 - difluorocyclohexyl ) imidazo [ 1,2 - b ] pyridazine - 3,8- 1dicarboxamide 12 - cyclopropyl - N8- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide 1N7- ( 1,1 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 1N7- ( 4,6 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 12- ( methoxymethyl ) -N7- ( 2,4,4 - trifluorocyclohexyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 12- ( methoxymethyl ) -N7- ( 1 - methylindan - 1 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 17 - cyclopropyl - N4- ( 4,4 - difluorocyclohexyl ) pyrazolo [ 5,1 - c ] [ 1,2,4 ] triazine - 4,8- dicarboxamide 12- ( trideuteriomethoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 12- ( fluoromethoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 1 N7 - Indan - 2 - yl - 2- ( methylamino ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 6,7 - dihydro - SH - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( trideuteriomethoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 12- ( methoxymethyl ) -N3 - methyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 12- ( cyclopropylmethoxy ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 1 2 - cyclopropyl - N8- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide N8- ( 4,6 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide 258 Compound Compound Number 1N7- ( 6,7 - dihydro - 5H - pyrrolo [ 1,2 - a ] imidazol - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 1N7 - [ ( 4R ) -7 - fluorochroman - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 1 N7 - [ ( 3S ) -6 - fluoro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 1N7 - [ ( 3R ) -7 - chloro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 1N7- ( 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 1N7- ( 3,4 - dihydro - 2H - pyrano [ 2,3 - b ] pyridin - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 1N7 - [ ( 4S ) -chroman - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 1N7- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 1N7- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 1N7 - [ - 4,4 - difluorotetralin - 1 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 1N7 - [ - 4,4 - difluorotetralin - 1 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 1N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 1N7 - [ ( 3R ) -7 - chloro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 1N7- ( 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 6 - yl ) -2- 1( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,4 - dihydro - 2H - pyrano [ 2,3 - b ] pyridin - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 259 Compound Compound Number N7 - [ ( 4S ) -chroman - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 6,7 - difluorochroman - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 1S ) -indan - 1 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 1N7- ( 2,3 - dihydrofuro [ 2,3 - b ] pyridin - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 1N7- ( 5,7 - difluorochroman - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 1N7- ( 4,4 - dimethyltetralin - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 12- ( methoxymethyl ) -N7- ( 5,6,7,8 - tetrahydroimidazo [ 1,2 - a ] pyridin - 6- 1yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7- ( 5,6,7,8 - tetrahydroimidazo [ 1,5 - a ] pyridin - 6- 1N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 12- ( methoxymethyl ) -N7- ( 4,5,6,7 - tetrahydro - 1,3 - benzothiazol - 6- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 1N7- ( 5,7 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- 1( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 7 - fluoro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 1S ) -tetralin - 1 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- 1dicarboxamide 1N7- ( 5 - fluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 1N7- ( 5,6 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 1N7- ( 6 - fluorochroman - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 260 Compound Compound Number N7 - [ ( 4 - hydroxyphenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 1S ) -3,3 - dimethylindan - 1 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7 - ( ( 2 - methoxyphenyl ) methyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( cis - 1 - hydroxyindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 22- ( methoxymethyl ) -N7 - cis - 1 - methylindan - 2 - yl ] pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 2- ( ethoxymethyl ) -N7 - Indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- 2dicarboxamide 2 - tetrahydrofuran - 2 - yl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( hydroxymethyl ) -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( ethoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -5 - methyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 2N7- ( 3,3 - difluorocyclobutyl ) -2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 22 - cyclopropyl - N8- ( 5,6 - dihydro - 4H - cyclopenta [ c ] thiophen - 5 - yl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide 2 - cyclopropyl - N8- ( 3,3 - difluoroindan - 1 - yl ) imidazo [ 1,2 - b ] pyridazine - 3,8- 2dicarboxamide N8- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2 - cyclopropyl - imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide 2 - cyclopropyl - N8 - [ ( 4S ) -7 - fluorochroman - 4 - ylimidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide N4- ( 4,4 - difluorocyclohexyl ) -6- ( methoxymethyl ) imidazo [ 2,1 - f ] [ 1,2,4 ] triazine- 4,7 - dicarboxamide 261 Compound Compound Number 2N7- ( 3,3 - difluorocyclobutyl ) -2- ( 1 - hydroxy - 1 - methyl - ethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2- ( methylsulfanylmethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- 2dicarboxamide N7 - indan - 2 - yl - 2- ( methylsulfonylmethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( cyclopropoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methylsulfanylmethyl ) -N7- [ cis - 3- ( trilluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N8- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) -6 - methyl - imidazo [ 1,2- 2b ] pyridazine - 3,8 - dicarboxamide 2 2- ( methoxymethyl ) -N8 - [ ( 4R ) -1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4- ylimidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide 2- ( methoxymethyl ) -N8 - [ ( 4S ) -1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4- yl ] imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide N8- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thlochromen - 4 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide 2 - cyclopropyl - N8- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide N8- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide 2- ( methoxymethyl ) -N7- [ trans - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 1,1 - dioxothietan - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7- ( 4,4 - difluorotetralin - 1 - yl ) -2- ( methoxymethyl ) -5 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2 N7 - indan - 2 - yl - 2- ( methoxymethyl ) -5 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2 - isopropyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 262 Compound Compound Number 22 - cyclopropyl - N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) pyrazolo [ 1,5- 2a ] pyrimidine - 3,7 - dicarboxamide N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2 - isopropyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 22 - cyclopropyl - N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2N7- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) -5 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2 N7 - [ ( 4R ) -1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7 - [ ( 4S ) -1,1 - dioxo - 3,4 - dihydro - 2H - thlochromen - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 2 - cyclopropyl - N7 - [ ( 4R ) -1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4- yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 2 - cyclopropyl - N7 - [ ( 4S ) -1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7- ( 3,3,6 - trifluoroindan - 1 - yl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7 - [ ( 35 ) -6,7 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7- ( 4,4,6 - trifluorotetralin - 1 - yl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) -5 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2- ( methoxymethyl ) -5- methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 2 - cyclopropyl - N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -5 - methyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 263 LO In embodiments , the compound may be selected from compounds 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , and 242 of Table 1. In embodiments , the compound may be selected from compounds 1 , 2 , 4 , 5 , 6 , 7 , 8 , 9 , 11 , 14 , 15 , 18 , 19 , 20 , , 22 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , and 242 of Table 1. In embodiments , the compound may be selected from compounds 1 , 2 , 4 , , 6 , 9 , 14 , 18 , 21 , 22 , 25 , 26 , 27 , 29 , 30 , 32 , 33 , 34 , 35 , 36 , 37 , 39 , 41 , 42 , 43 , 44 , 45 , 46 , , 48 , 49 , 50 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 91 , 92 , 93 , 94 , 95 , 97 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 264 LO 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , and 242 of Table 1. In embodiments , the compound may be selected from compounds 1 , 2 , 4 , 6 , 21 , 26 , 27 , 33 , , 37 , 42 , 43 , 44 , 46 , 48 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , , 73 , 74 , 75 , 76 , 78 , 79 , 80 , 81 , 82 , 83 , 85 , 86 , 87 , 88 , 91 , 92 , 93 , 94 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 126 , 127 , 128 , 129 , 130 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , and 242 of Table 1. In embodiments , the compound may be selected from compounds 27 , 33 , , 37 , 46 , 54 , 56 , 57 , 58 , 59 , 60 , 61 , 64 , 66 , 68 , 70 , 72 , 73 , 74 , 75 , 79 , 80 , 82 , 83 , 85 , 87 , , 91 , 92 , 93 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 123 , 128 , 129 , 130 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 144 , 145 , 147 , 148 , 150 , 151 , 152 , 153 , 157 , 158 , 159 , 160 , 163 , 164 , 166 , 167 , 168 , 169 , 170 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 182 , 183 , 184 , 189 , 191 , 192 , 193 , 194 , 195 , 196 , 200 , 201 , 202 , 208 , 209 , 210 , 211 , 214 , 216 , 217 , 219 , 222 , 223 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , and 242 of Table 1 .

In another aspect of this disclosure , there is provided a compound of formula ( 1 ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for use in medicine .

In embodiments , the compound of formula ( 1 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute 265 LO lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the compound of formula ( 1 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In embodiments , the compound of formula ( 1 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the compound of formula ( 1 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 1 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation . 266 LO In embodiments , the compound of formula ( 1 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 1 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the administering comprises administering the compound of formula ( 1 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the compound of formula ( 1 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 1 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a compound of formula ( 2 ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for use in medicine .

In embodiments , the compound of formula ( 2 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of a cancer or proliferative 267 LO disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the compound of formula ( 2 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In embodiments , the compound of formula ( 2 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the compound of formula ( 2 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or 268 combinations thereof , is for use in a method comprising administering the compound of formula ( 2 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation .

In embodiments , the compound of formula ( 2 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the administering comprises administering the compound of formula ( 2 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the compound of formula ( 2 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a compound of formula ( 2a ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and 269 LO enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for use in medicine .

In embodiments , the compound of formula ( 2a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the compound of formula ( 2a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In embodiments , the compound of formula ( 2a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite 270 thereof , or combinations thereof , is for use in a method comprising administering the compound orally , orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the compound of formula ( 2a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation .

In embodiments , the compound of formula ( 2a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYTinhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the administering comprises administering the compound of formula ( 2a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the compound of formula ( 2a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the 271 LO compound of formula ( 2a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a compound of formula ( 2aa ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for use in medicine .

In embodiments , the compound of formula ( 2aa ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma . 272 In embodiments , the compound of formula ( 2aa ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite . thereof , or combinations thereof , is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In embodiments , the compound of formula ( 2aa ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the compound of formula ( 2aa ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2aa ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation .

In embodiments , the compound of formula ( 2aa ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2aa ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYT35 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the administering comprises administering the compound of formula ( 2aa ) , or a stereoisomer or 273 LO mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the compound of formula ( 2aa ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2aa ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a compound of formula ( 2ab ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for use in medicine .

In embodiments , the compound of formula ( 2ab ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , 274 LO osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the compound of formula ( 2ab ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In embodiments , the compound of formula ( 2ab ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound orally , orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the compound of formula ( 2ab ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2ab ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation .

In embodiments , the compound of formula ( 2ab ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2ab ) , or a stereoisomer or mixture of stereoisomers including 275 LO diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYTinhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the administering comprises administering the compound of formula ( 2ab ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the compound of formula ( 2ab ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2ab ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a compound of formula ( 2ac ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for use in medicine .

In embodiments , the compound of formula ( 2ac ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal 276 LO cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the compound of formula ( 2ac ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In embodiments , the compound of formula ( 2ac ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound orally , orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the compound of formula ( 2ac ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2ac ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , as 277 LO a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation .

In embodiments , the compound of formula ( 2ac ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2ac ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYTinhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the administering comprises administering the compound of formula ( 2ac ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the compound of formula ( 2ac ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2ac ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a compound of formula ( 2ad ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for use in medicine . 278 LO In embodiments , the compound of formula ( 2ad ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the compound of formula ( 2ad ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In embodiments , the compound of formula ( 2ad ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound orally , topically , by inhalation , by intranasal administration , by 279 LO intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the compound of formula ( 2ad ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2ad ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation .

In embodiments , the compound of formula ( 2ad ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2ad ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYTinhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the administering comprises administering the compound of formula ( 2ad ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the compound of formula ( 2ad ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2ad ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , 280 solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a compound of formula ( 2b ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for use in medicine .

In embodiments , the compound of formula ( 2b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the compound of formula ( 2b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite 281 LO thereof , or combinations thereof , is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In embodiments , the compound of formula ( 2b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound orally , orally , topically , by inhalation , by by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the compound of formula ( 2b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation .

In embodiments , the compound of formula ( 2b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYTinhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the administering comprises administering the compound of formula ( 2b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite 282 LO thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the compound of formula ( 2b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 2b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a compound of formula ( 3 ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for use in medicine .

In embodiments , the compound of formula ( 3 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , 283 LO stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the compound of formula ( 3 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In embodiments , the compound of formula ( 3 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the compound of formula ( 3 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 3 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation .

In embodiments , the compound of formula ( 3 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 3 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional 284 LO therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the administering comprises administering the compound of formula ( 3 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the compound of formula ( 3 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 3 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a compound of formula ( 4 ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for use in medicine .

In embodiments , the compound of formula ( 4 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute 285 LO promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the compound of formula ( 4 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In embodiments , the compound of formula ( 4 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the compound of formula ( 4 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 4 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation . 286 LO In embodiments , the compound of formula ( 4 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 4 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the administering comprises administering the compound of formula ( 4 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the compound of formula ( 4 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 4 ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a compound of formula ( 4a ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for use in medicine .

In embodiments , the compound of formula ( 4a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of a cancer or 287 LO proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the compound of formula ( 4a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In embodiments , the compound of formula ( 4a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound orally , orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the compound of formula ( 4a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , 288 pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 4a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation .

In embodiments , the compound of formula ( 4a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 4a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYTinhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the administering comprises administering the compound of formula ( 4a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the compound of formula ( 4a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 4a ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy . 289 LO In another aspect of this disclosure , there is provided a compound of formula ( 4b ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for use in medicine .

In embodiments , the compound of formula ( 4b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the compound of formula ( 4b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease . 290 LO In embodiments , the compound of formula ( 4b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the compound of formula ( 4b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 4b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation .

In embodiments , the compound of formula ( 4b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 4b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYTinhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the administering comprises administering the compound of formula ( 4b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent . 291 LO In embodiments , the compound of formula ( 4b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 4b ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a compound of formula ( 4c ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for use in medicine .

In embodiments , the compound of formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected 292 LO from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the compound of formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In embodiments , the compound of formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound orally , orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the compound of formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation .

In embodiments , the compound of formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYT293 LO inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the administering comprises administering the compound of formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the compound of formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for use in a method comprising administering the compound of formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 1 ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 1 ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier , for use in medicine .

In embodiments , the pharmaceutical composition is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) 294 LO cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the pharmaceutical composition is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In embodiments , the pharmaceutical composition is for use in a method comprising administering the compound orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the pharmaceutical composition is for use in a method comprising administering the pharmaceutical composition as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation .

In embodiments , the pharmaceutical composition is for use in a method comprising administering the pharmaceutical composition in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , 295 LO CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti- angiogenesis inhibitor . In embodiments , the administering comprises administering the pharmaceutical composition simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the pharmaceutical composition is for use in a method comprising administering the pharmaceutical composition in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 2 ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 2 ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier , for use in medicine .

In embodiments , the pharmaceutical composition is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular 296 cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the pharmaceutical composition is for use in a method comprising administering the pharmaceutical composition in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti- angiogenesis inhibitor . In embodiments , the administering comprises administering the pharmaceutical composition simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the pharmaceutical composition is for use in a method comprising administering the pharmaceutical composition in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy . 297 LO In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 2a ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 2a ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier , for use in medicine .

In embodiments , the pharmaceutical composition is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma . 298 LO In embodiments , the pharmaceutical composition is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 2aa ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 2aa ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , 299 pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier , for use in medicine .

In embodiments , the pharmaceutical composition is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the pharmaceutical composition is for use in a method comprising administering the pharmaceutical composition as a monotherapy or in combination with a 300 secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation .

LO In embodiments , the pharmaceutical composition is for use in a method comprising administering the pharmaceutical composition in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti- angiogenesis inhibitor . In embodiments , the administering comprises administering the pharmaceutical composition simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 2ab ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 2ab ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier , for use in medicine .

In embodiments , the pharmaceutical composition is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of 301 LO connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the pharmaceutical composition is for use in a method comprising administering the pharmaceutical composition in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti- angiogenesis inhibitor . In embodiments , the administering comprises administering the 302 LO pharmaceutical composition simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 2ac ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 2ac ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier , for use in medicine .

In embodiments , the pharmaceutical composition is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal 303 cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 2b ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , 304 pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 2b ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier , for use in medicine .

In embodiments , the pharmaceutical composition is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease . 305 LO In embodiments , the pharmaceutical composition is for use in a method comprising administering the compound orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 3 ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 3 ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier , for use in medicine . 306 LO In embodiments , the pharmaceutical composition is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the pharmaceutical composition is for use in a method comprising administering the pharmaceutical composition as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation . 307 LO In embodiments , the pharmaceutical composition is for use in a method comprising administering the pharmaceutical composition in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti- angiogenesis inhibitor . In embodiments , the administering comprises administering the pharmaceutical composition simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 4 ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 4 ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier , for use in medicine .

In embodiments , the pharmaceutical composition is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute 308 LO myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the pharmaceutical composition is for use in a method comprising administering the pharmaceutical composition in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti- angiogenesis inhibitor . In embodiments , the administering comprises administering the pharmaceutical composition simultaneously , sequentially or separately from the one or more additional therapeutic agent . 309 In embodiments , the pharmaceutical composition is for use in a method comprising administering the pharmaceutical composition in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 4a ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 4a ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier , for use in medicine .

In embodiments , the pharmaceutical composition is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer 310 or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

LO In embodiments , the pharmaceutical composition is for use in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 4b ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier . 311 LO In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 4b ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier , for use in medicine .

In embodiments , the pharmaceutical composition is for use in a method comprising administering the compound orally , topically , by inhalation , by intranasal administration , by 312 LO intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 4c ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier .

In another aspect of this disclosure , there is provided a pharmaceutical composition comprising a compound of formula ( 4c ) as described above , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier , for use in medicine . 313 LO In embodiments , the pharmaceutical composition is for use in the treatment or prophylaxis of a cancer or proliferative disease or disorder , for example wherein the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the pharmaceutical composition is for use in a method comprising administering the pharmaceutical composition as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation . 314 LO In embodiments , the pharmaceutical composition is for use in a method comprising administering the pharmaceutical composition in combination with one or more additional therapeutic agent ( s ) . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti- angiogenesis inhibitor . In embodiments , the administering comprises administering the pharmaceutical composition simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In another aspect of this disclosure , there is provided a method of treatment comprising administration of a therapeutically effective amount of a compound of formula ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ac ) , formula ( 2ad ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , to a patient in need thereof .

In embodiments , the patient has a cancer or proliferative disease or disorder . In embodiments , the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , 315 prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma .

In embodiments , the patient has fibrotic disease or inflammatory disease .

In embodiments , the method comprises administering the compound orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the method comprises administering the compound of formula ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ac ) , formula ( 2ad ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation .

In embodiments , the method comprises administering the compound of formula ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ac ) , formula ( 2ad ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEEinhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embdoiments , the method comprises administering the compound of formula ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ac ) , formula ( 2ad ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite 316 LO thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the method comprising administering the compound of formula ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ac ) , formula ( 2ad ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided a method of treating a cancer or proliferative disease or disorder , comprising administering one or more compound ( s ) of formula ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ad ) , formula ( 2ac ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , to a subject in need thereof . In embodiments , the cancer or proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , 317 LO pancreatic cancer , prostate cancer and melanoma . In embodiments , the method comprises administering the compound ( s ) of formula ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ac ) , formula ( 2ad ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In another aspect of this disclosure , there is provided a method of treating fibrotic disease or inflammatory diseasea , comprising administering one or more compound ( s ) of formula . ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ad ) , formula ( 2ac ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , to a subject in need thereof . In embodiments , the method comprises administering the compound ( s ) of formula ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ac ) , formula ( 2ad ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the method comprises administering the compound ( s ) of formula ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ac ) , formula ( 2ad ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or 318 LO mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more additional therapeutic agent . In embodiments , the one or more additional therapeutic agent is selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEEinhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the method comprises administering the of formula ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ac ) , formula ( 2ad ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , simultaneously , sequentially or separately from the one or more additional therapeutic agent .

In embodiments , the method comprising administering the compound ( s ) of formula ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ac ) , formula ( 2ad ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

In another aspect of this disclosure , there is provided the use of a compound of formula ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ac ) , formula ( 2ad ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for the manufacture of a medicament .

In embodiments , the use of the compound of formula ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ac ) , formula ( 2ad ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for the manufacture of a medicament for the treatment or prophylaxis of a cancer or proliferative disease or disorder . In embodiments , the cancer or 319 LO proliferative disease or disorder is selected from : adrenal gland cancer , anal cancer , angiosarcoma , bladder cancer , blastic plasmacytoid dendritic cell neoplasm , bone cancer , brain cancer , breast cancer , bronchogenic carcinoma , central nervous system ( CNS ) cancer , cervical cancer , chondrosarcoma , colon cancer , colorectal cancer , cancer of connective tissue , esophageal cancer , embryonal carcinoma , fibrosarcoma , glioblastomas , medulloblastoma , head and neck cancer , hematological cancer , kidney cancer , leukemias ( e.g. , acute leukemia , acute lymphocytic leukemia , acute myelocytic leukemia , acute myeloblastic leukemia , acute promyelocytic leukemia , acute myelomonocytic leukemia , acute monocytic leukemia , acute erythroleukemia , chronic leukemia , chronic myelocytic leukemia , chronic lymphocytic leukemia ) , myelodysplastic syndrome , liposarcoma , liver cancer , lung cancer , lymphoid cancers ( e.g. , Hodgkin's and non - Hodgkin's lymphomas ) , mesothelioma , multiple myeloma , muscular cancer , myxosarcoma , neuroblastomas , ocular cancer , oral / digestive tract cancer , osteogenic sarcoma , ovarian cancer , papillary carcinoma , pancreatic cancer , polycythemia vera , prostate cancer , renal cancer , retinal cancer , skin cancer , small cell lung carcinoma , stomach cancer , testicular cancer , throat cancer , thyroid cancer , uterine cancer , vaginal cancer , vulvar cancer , gliomas , melanoma , non - small cell lung cancer and acute myeloid leukemia ( AML ) . In embodiments , the cancer or proliferative disease or disorder is selected from : colon cancer , medulloblastoma , head and neck cancer , myelodysplastic syndrome , pancreatic cancer , prostate cancer and melanoma . In embodiments , the treatment comprises administering the medicament orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the use of the compound of formula ( 1 ) , formula ( 2 ) , formula ( 2a ) , formula ( 2aa ) , formula ( 2ab ) , formula ( 2ac ) , formula ( 2ad ) , formula ( 2b ) , formula ( 3 ) , formula ( 4 ) , formula ( 4a ) , formula ( 4b ) , formula ( 4c ) , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , is for the manufacture of a medicament for the treatment or prophylaxis of fibrotic disease or inflammatory disease . In embodiments , the treatment comprises administering the medicament orally , topically , by inhalation , by intranasal administration , by intracerebroventricular ; or systemically by intravenous , intraperitoneal , subcutaneous , or intramuscular injection .

In embodiments , the treatment comprises administering the medicament as a monotherapy or in combination with a secondary agent such as immune checkpoint inhibitors , DNA damaging agents , or ionising radiation . 320 In embodiments , the treatment comprises administering the medicament in combination with one or more additional therapeutic agent ( s ) , for example one or more additional therapeutic agents selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEE1 inhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the treatment comprises administering the medicament , simultaneously , sequentially or separately from the one or more additional therapeutic agent . In embodiments , the medicament comprises one or more additional therapeutic agent ( s ) , for example one or more additional therapeutic agents selected from an EGFR inhibitor , CDK4 / 6 inhibitor , CDK2 inhibitor , USP1 inhibitor , ATR inhibitor , WEEinhibitor , Pole inhibitor , PKMYT1 inhibitor , ATM inhibitor , DNA - PK , inhibitor , CHK1 inhibitor , PRMT5 inhibitor , anti - androgen therapy ( in prostate cancer ) and anti - angiogenesis inhibitor . In embodiments , the treatment comprises administering the medicament in combination with one or more therapy selected from : radiation therapy , chemotherapy , immunotherapy and targeted therapy .

Dosage Forms , Medicaments and Pharmaceuticals The compounds , molecules or agents of the invention may be used to treat ( e.g. cure , alleviate or prevent ) one or more diseases , infections or disorders . Thus , in accordance with the invention , the compounds and molecules may be manufactured into medicaments or may be incorporated or formulated into pharmaceutical compositions .

The molecules , compounds and compositions of the invention may be administered by any convenient route , for example , methods of administration include intradermal , intramuscular , intraperitoneal , intravenous , subcutaneous , intranasal , epidural , oral , sublingual , intranasal , intravaginal , transdermal , rectally , by inhalation , or topically to the skin . Delivery systems are also known to include , for example , encapsulation in liposomes , microgels , microparticles , microcapsules , capsules , etc. Any other suitable delivery system known in the art is also envisioned in use of the present invention .

Administration can be systemic or local . The mode of administration may be left to the discretion of the practitioner .

The dosage administered will , of course , vary depending upon known factors , such as the pharmacodynamic properties of the particular active agent ; the chosen mode and route of administration ; the age , health and weight of the recipient ; the nature of the disease or 321 disorder to be treated ; the extent of the symptoms ; any simultaneous or concurrent treatments ; the frequency of treatment ; and the effect desired . In general , a daily dosage of active agent of between about 0.001 and about 1,000 mg / kg of body weight can be expected . For some applications , the dosage may suitably be within the range of about 0.01 to about 100 mg / kg , between about 0.1 to about 25 mg / kg , or between about 0.1 and 10 mg / kg .

Depending on known factors , such as those noted above , the required dosage of the active agent of the invention may be administered in a single daily dose , or the total daily dosage may be administered in divided doses of two , three , or four times daily .

Dosage forms of the pharmaceutical compositions of the invention suitable for administration may contain from about 1 mg to about 2,000 mg of the active ingredient per unit .

The effective amount ' or ' therapeutically effective amount ' is meant to describe an amount of compound or a composition of the disclosure that is effective in curing , inhibiting , alleviating , reducing or preventing the adverse effects of the diseases or disorders to be treated , or the amount necessary to achieve a physiological or biochemically - detectable effect . Thus , at the effective amount , the compound or agent is able to produce the desired therapeutic , ameliorative , inhibitory or preventative effect in relation to disease or disorder . Beneficially , an effective amount of the compound or composition of the disclosure may have the effect of inhibiting GPR68 . Diseases or disorders which may benefit from GPRinhibition include , for example , proliferative diseases or disorders and cancer .

When administered to a subject , a compound of the invention is suitably administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle . One or more additional pharmaceutical acceptable carrier ( such as diluents , adjuvants , excipients or vehicles ) may be combined with the compound of the invention in a pharmaceutical composition . Suitable pharmaceutical carriers are described in " Remingto's Pharmaceutical Science " by E. W. Martin . Pharmaceutical formulations and compositions of the invention are formulated to conform to regulatory standards and according to the chosen route of administration .

Acceptable pharmaceutical vehicles can be liquids , such as water and oils , including those of petroleum , animal , vegetable or synthetic origin , such as peanut oil , soybean oil , mineral oil , sesame oil and the like . The pharmaceutical vehicles can be saline , gum acacia , gelatin , starch paste , talc , keratin , colloidal silica , urea , and the like . In addition , auxiliary , stabilising , thickening , lubricating and colouring agents may be used . When administered to a subject , 322 the pharmaceutically acceptable vehicles are generally sterile . Water is a suitable vehicle when the compound of the invention is administered intravenously . Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles , particularly for injectable solutions . Suitable pharmaceutical vehicles also include excipients such as starch , glucose , lactose , sucrose , gelatin , malt , rice , flour , chalk , silica gel , sodium stearate , glycerol monostearate , talc , sodium chloride , dried skim milk , glycerol , propylene , glycol , water , ethanol and the like . The present compositions , if desired , can also contain minor amounts of wetting or emulsifying agents , or buffering agents .

The medicaments and pharmaceutical compositions of the invention can take the form of solutions , suspensions , emulsion , tablets , pills , pellets , powders , gels , capsules ( for example , capsules containing liquids or powders ) , modified - release formulations ( such as slow or sustained - release formulations ) , suppositories , emulsions , aerosols , sprays , suspensions , or any other form suitable for use . Other examples of suitable pharmaceutical vehicles are described in Remingto ; s Pharmaceutical Sciences , Alfonso R. Gennaro ed . , Mack Publishing Co. Easton , Pa . , 19th ed . , 1995 , see for example pages 1447-1676 .

Suitably , the therapeutic compositions or medicaments of the invention are formulated in accordance with routine procedures as a pharmaceutical composition adapted for oral administration ( more suitably for humans ) . Compositions for oral delivery may be in the form of tablets , lozenges , aqueous or oily suspensions , granules , powders , emulsions , capsules , syrups , or elixirs , for example . Thus , in one embodiment , the pharmaceutically acceptable vehicle is a capsule , tablet or pill .

Orally administered compositions may contain one or more agents , for example , sweetening agents such as fructose , aspartame or saccharin ; flavouring agents such as peppermint , oil of wintergreen , or cherry ; colouring agents ; and preserving agents , to provide a pharmaceutically palatable preparation . When the composition is in the form of a tablet or pill , the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract , so as to provide a sustained release of active agent over an extended period of time . Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions . In these dosage forms , fluid from the environment surrounding the capsule is imbibed by the driving compound , which swells to displace the agent or agent composition through an aperture . These dosage forms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations . A time delay material such as glycerol monostearate or glycerol stearate may also be used . Oral compositions can include standard vehicles such 323 LO as mannitol , lactose , starch , magnesium stearate , sodium saccharine , cellulose , magnesium carbonate , etc. Such vehicles are preferably of pharmaceutical grade . For oral formulations , the location of release may be the stomach , the small intestine ( the duodenum , the jejunem , or the ileum ) , or the large intestine . One skilled in the art is able to prepare formulations that will not dissolve in the stomach , yet will release the material in the duodenum or elsewhere in the intestine . Suitably , the release will avoid the deleterious effects of the stomach environment , either by protection of the peptide ( or derivative ) or by release of the peptide ( or derivative ) beyond the stomach environment , such as in the intestine . To ensure full gastric resistance a coating impermeable to at least pH 5.0 would be essential . Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate ( CAT ) , hydroxypropylmethylcellulose phthalate ( HPMCP ) , HPMCP 50 , HPMCP , polyvinyl acetate phthalate ( PVAP ) , Eudragit L30D , Aquateric , cellulose acetate phthalate ( CAP ) , Eudragit L , Eudragit S , and Shellac , which may be used as mixed films .

To aid dissolution of the therapeutic agent into the aqueous environment a surfactant might be added as a wetting agent . Surfactants may include anionic detergents such as sodium lauryl sulfate , dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate . Cationic detergents might be used and could include benzalkonium chloride or benzethomium chloride . Potential nonionic detergents that could be included in the formulation as surfactants include : lauromacrogol 400 , polyoxyl 40 stearate , polyoxyethylene hydrogenated castor oil 10 , 50 and 60 , glycerol monostearate , polysorbate 20 , 40 , 60 , 65 and 80 , sucrose fatty acid ester , methyl cellulose and carboxymethyl cellulose . These surfactants , when used , could be present in the formulation of the compound or derivative either alone or as a mixture in different ratios .

Typically , compositions for intravenous administration comprise sterile isotonic aqueous buffer . Where necessary , the compositions may also include a solubilising agent .

Another suitable route of administration for the therapeutic compositions of the invention is via pulmonary or nasal delivery .

Additives may be included to enhance cellular uptake of the therapeutic agent of the invention , such as the fatty acids oleic acid , linoleic acid and linolenic acid .

The therapeutic agents of the invention may also be formulated into compositions for topical application to the skin of a subject . 324 LO Where the invention provides more than one active agent for use in combination , generally , the agents may be formulated separately or in a single dosage form , depending on the prescribed most suitable administration regime for each of the agents concerned . When the therapeutic agents are formulated separately , the pharmaceutical compositions of the invention may be used in a treatment regime involving simultaneous , separate or sequential administration with the other one or more therapeutic agent . The other therapeutic agent ( s ) may comprise a compound of the invention or a therapeutic agent known in the art ) .

The molecules and pharmaceutical compositions of the invention may be formulated and suitable for administration to the central nervous system ( CNS ) and / or for crossing the blood- brain barrier ( BBB ) .

The invention will now be described by way of the following non - limiting examples .

EXAMPLES General experimental LCMS Methods Method Samples were analysed by reverse phase HPLC - MS using an Agilent 1200 Series HPLC system and a 6140 Single quadrupole Mass spectrometer equipped with a multi - mode ( APCI + ESI ) source . LCMS was carried out using a Phenomenex ⓇanuL C18 ( 2 ) -HST column ( 2.5 mμ , 50 x 2.mm ) at 254 nm and 220 nm . The column oven temperature was set to 45 ° C . The column flow rate was set to 1.0 mL / min and the solvents used were 0.1 % formic acid in water ( A ) and 0.1 % formic acid in acetonitrile ( B ) . The method timetable was 0.00 - 0.50 min ( 1 % B ) , 0.50 -2.00 min ( linear gradient from 1 % to 100 % B ) , and 2.00 – 3.25 min ( 100 % B ) . - Method Samples were analysed by reverse phase HPLC - MS using an Agilent 1200 Series HPLC system and a 6140 Single quadrupole Mass spectrometer equipped with a multi - mode ( APCI + ESI ) source . LCMS was carried out using a Phenomenex ⓇanuL C18 ( 2 ) -HST column ( 2.5 mμ , 50 x 2.mm ) at 254 nm and 220 nm . The column oven temperature was set to 45 ° C . The column flow rate was set to 1.0 mL / min and the solvents used were 0.1 % formic acid in water ( A ) 325 and 0.1 % formic acid in acetonitrile ( B ) . The method timetable was 0.00 - 0.50 min ( 1 % B ) , 0.50 – 3.50 min ( linear gradient from 1 % to 100 % B ) , and 3.50 – 4.25 min ( 100 % B ) . - - LO Method Samples were analysed by reverse phase HPLC - MS using an Agilent 1200 Series HPLC system and a 6140 Single quadrupole Mass spectrometer equipped with a multi - mode ( APCI + ESI ) source . LCMS was carried out using a Phenomenex ⓇanuL C18 ( 2 ) -HST column ( 2.5 mμ , 50 x 2.mm ) at 254 nm and 220 nm . The column oven temperature was set to 45 ° C . The column flow rate was set to 1.0 mL / min and the solvents used were 0.1 % formic acid in water ( A ) and 0.1 % formic acid in acetonitrile ( B ) . The method timetable was 0.00 – 1.50 min ( linear gradient from 1 % to 100 % B ) , and 1.50 – 1.90 min ( 100 % B ) . - - Method Samples were analysed by reverse phase HPLC - MS using an Agilent 1290 Series HPLC system and a 6140 Single quadrupole Mass spectrometer equipped with a multi - mode ( APCI + ESI ) source . LCMS was carried out using a Phenomenex ®xeteniK C18 Å001 ( 1.7 mµ , 50 x 2.1 mm ) at 254 nm and 220 nm . The column oven temperature was set to 40 ° C . The column flow rate was set to 0.8 mL / min and the solvents used were 0.1 % formic acid in water ( A ) and 0.1 % formic acid in acetonitrile ( B ) . The method timetable was 0.00 0.70 min ( 5 % B ) , 0.70 -3.min ( linear gradient from 5 % to 100 % B ) , and 3.70 -4.00 min ( 100 % B ) . - Method Samples were analysed by reverse phase HPLC - MS using an Agilent 1290 Series HPLC system and a 6140 Single quadrupole Mass spectrometer equipped with a multi - mode ( APCI + ESI ) source . LCMS was carried out using a Phenomenex ⓇanuL C18 ( 2 ) -HST column ( 2.5 mμ , 50 x 2.mm ) at 254 nm and 220 nm . The column oven temperature was set to 40 ° C . The column flow rate was set to 1.0 mL / min and the solvents used were 0.1 % formic acid in water ( A ) and 0.1 % formic acid in acetonitrile ( B ) . The method timetable was 0.00 – 1.50 min ( linear gradient from 5 % to 100 % B ) , and 1.50 -1.90 min ( 100 % B ) . - Method Samples were analysed by reverse phase HPLC - MS using an Agilent 1200 Series HPLC system and a 6140 Single quadrupole Mass spectrometer equipped with a multi - mode ( APCI + ESI ) source . 326 LCMS was carried out using a Phenomenex ⓇanuL C18 ( 2 ) -HST column ( 2.5 mμ , 50 x 2.mm ) at 254 nm and 220 nm . The column oven temperature was set to 45 ° C . The column flow rate was set to 1.0 mL / min and the solvents used were 0.1 % formic acid in water ( A ) and 0.1 % formic acid in acetonitrile ( B ) . The method timetable was 0.00 - 0.50 min ( 1 % B ) , 0.50 -2.50 min ( linear gradient from 1 % to 100 % B ) , and 2.50 -3.00 min ( 100 % B ) .

Method Samples were analysed by reverse phase HPLC - MS using an Agilent 1200 Series HPLC system and a 6140 Single quadrupole Mass spectrometer equipped with a multi - mode ( APCI + ESI ) source . LCMS was carried out using a Phenomenex ⓇanuL C18 ( 2 ) -HST column ( 2.5 mμ , 50 x 2.mm ) at 254 nm and 220 nm . The column oven temperature was set to 45 ° C . The column flow rate was set to 1.0 mL / min and the solvents used were 0.1 % formic acid in water ( A ) and 0.1 % formic acid in acetonitrile ( B ) . The method timetable was 0.00 – 0.50 min ( 1 % B ) , 0.50 -4.25 min ( linear gradient from 1 % to 100 % B ) , and 4.25 -5.00 min ( 100 % B ) .

Preparative HPLC Methods - Basic method - Preparative HPLC was carried out on a Teledyne ACCQPrep HP150 Prep HPLC System with 200 - 400 nm UV variable wavelength detector , ACCQPrep HP150 AS 2 × AutoSampler using a Waters xBridge BEH C18 OBD Prep column , 5 Mμ 19 mm x 50 mm i.d. column and a flow rate of 24 mL / minute . Compounds were eluted with a water : MeCN mixture containing 0.1 % NH4OH over 10 minutes using UV detection at 254 nm . Gradient information : 0.0 1.0 min , 10 % MeCN ; 1.0 - 9.0 min , ramped from 10 % MeCN to 100 % MeCN ; 9.0 – 10.0 min , held at 100 % MeCN . - - Acidic method Preparative HPLC was carried out on a Teledyne ACCQPrep HP150 Prep HPLC System with 200 - 400 nm UV variable wavelength detector , ACCQPrep HP150 AS 2 × 2 - AutoSampler using a Waters xBridge BEH C18 OBD Prep column , 5 Mμ 19 mm x 50 mm i.d. column and a flow rate of 24 mL / minute . Compounds were eluted with a water : MeCN mixture containing 0.1 % formic acid over 10 minutes using UV detection at 254 nm . Gradient information : 0.0 - 1.0 min , 10 % MeCN ; 1.0 - 9.0 min , ramped from 10 % MeCN to 100 % MeCN ; 9.0 10.0 min , held at 100 % MeCN . - Supercritical Fluid Chromatography 327 SFC separations were carried out using a Waters system comprising of a fluid delivery model , thermocube ( set to 4 ° C ) , autosampler , column oven ( set to 40 ° C ) , 2489 UV / visible detector ( 254 nm ) , fraction collection module , heat exchanger , and back pressure regulator . Semi - preparative separations were achieved using Chiralpak ( AS - H or AD - H ) or Chiralcel ( OD - H or OJ - H ) columns ( all 10 250 mm , 5 mμ ) . Liquid CO2 was used as the bulk mobile phase .

H - cube Hydrogenations were carried out using a THALESNano H - cube TM HC2-55 or a THALESNano H - cube Mini Plus ™ hydrogenation reactor with ⓇtraCtaC cartridges .

Flow reactor Reactions were carried out using a Uniqsis FlowSynTM 2011 continuous flow reactor .

Microwave reactor Reactions were carried out using a ®egatoiB Initiator Classic microwave reactor .

Column chromatography Column chromatography purifications were carried out on either a Biotage Isolera ™ or a Teledyne ISCO ®hsalFibmoC NextGen 300+ using ®egatoiB räfS or Teledyne ISCO ⓇpeSideR silica gel flash columns . Fraction collection was based on UV detection .

SCX Chromatography SCX purifications were carried out using Biotage ⓇetulosI SCX - 2 cartridges .

After loading the sample in an appropriate solvent , the cartridge was washed with MeOH before elution of the desired compounds with 2 M NH3 in MeOH .

Abbreviations AcOH Aq . BF3.OEtt - BuOH DABCO CUTC d DCC Acetic acid Aqueous Boron trifluoride etherate tertiary butanol Copper ( I ) thiophen - 2 - carboxylate 1,4 - Diazabicyclo [ 2.2.2 ] octane Days N , N ' - Dicyclohexylcarbodiimide 328 DCM DIAD DIPEA DMAP DME DMF DMSO LO DPPA dppf EDC / EDCI Et3N EtOAc ( EtO ) 3CH EtOH h HATU Dichloromethane Diisopropyl azodicarboxylate N , N - Diisopropylethylamine N , N - Dimethylpyridin - 4 - amine Dimethyl ether N , N - Dimethylformamide Dimethylsulfoxide Diphenyl phosphoryl azide 1,1 ' - Bis ( diphenylphosphino ) ferrocene - Ethyl - 3- ( 3 - dimethylaminopropyl ) carbodiimide Triethylamine Ethyl acetate triethylorthoformate Ethanol Hours O- ( 7 - Azabenzotriazol - 1 - yl ) -N , N , N ' , N ' - tetramethyluronium hexafluorophosphate HF - pyridine - Hydroxybenzotriazole High Performance Liquid Chromatography Isopropyl alcohol Liquid Chromatography Mass Spectrometry Lithium hexamethyldisilazide Acetonitrile HF.pyr HOBt HPLC IPA LCMS LiHMDS MeCN MeOH Methanol min Minutes NBS N - Bromosuccinimide NCS NMP NMR Pd ( OAc ) i - PrOH PS - PPhRaNi Raney nickel RT sat . SCX N - Chlorosuccinimide N - Methyl - 2 - pyrrolidone Nuclear Magnetic Resonance Palladium ( II ) acetate Isopropyl alcohol Polymer - supported triphenylphosphine Room temperature saturated Strong Cation Exchange 329 SFC STAB T3P TBDMSCI LO 5 TBME TFA THE Supercritical Fluid Chromatography Sodium triacetoxyborohydride - Propanephosphonic anhydride tert - Butyldimethylsilyl chloride tert - Butyl methyl ether Trifluoroacetic acid Tetrahydrofuran Example 1 - Compounds Synthesis of 4 - methylindan - 2 - amine ( General Method A ) ode | ₂HN- Synthesis of methyl 4 - methyl - 1 - oxo - indane - 2 - carboxylate MeO OMe NaH , THF , 66 ° ℃ OMe 00 % OH Dimethyl carbonate ( 430 Lμ , 5.13 mmol ) and NaH ( 273 mg , 6.84 mmol ) were added sequentially to a solution of 4 - methylindan - 1 - one ( 500 mg , 3.42 mmol ) in THF ( 10 mL ) at room temperature . The reaction was heated at 66 ° C for 30 min , then cooled to room temperature and acidified with 5 M aq . HCI . The reaction mixture was diluted with EtOAc and the layers were separated . The aqueous layer was extracted with EtOAc ( x 2 ) , and the combined organic layers were washed with water and brine , dried over Na2SO4 , and 330 concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 490 mg ) . - 1H NMR ( 400 MHz , CDCl3 ) б 7.66 - 7.58 ( m , 1H ) , 7.54 – 7.40 ( m , 1H ) , 7.32 ( t , J = 7.5 Hz , 1H ) , 3.80 ( s , 3H ) , 3.75 ( dd , J = 8.2 , 3.9 Hz , 1H ) , 3.49 – 3.40 ( m , 1H ) , 3.32 – 3.22 ( m , 1H ) , 2.38 ( s , 3H ) LCMS ( Method 2 ) : 1.61 min , 205.2 [ M + H ] * Synthesis of methyl 4 - methylindane - 2 - carboxylate - - ode HiS₂tE TFA , RT OMe 0OMe HiSзtE ( 1.66 mL , 10.40 mmol ) was added to a solution of methyl 4 - methyl - 1 - oxo - indane - 2- carboxylate ( 354 mg , 1.73 mmol ) in TFA ( 6 mL , 78.64 mmol ) and the reaction was stirred at room temperature for 96 h . The reaction mixture was concentrated in vacuo and the resulting residue was diluted with DCM and basified with sat . aq . NaHCO 3. The layers were separated , and the organic layer was washed with water , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 263 mg ) . - - H¹ NMR ( 400 MHz , ³lCDC ) ₫ 7.13 – 7.02 ( m , 2H ) , 7.01 – 6.94 ( m , 1H ) , 3.74 ( s , 3H ) , 3.41 – 3.30 ( m , 1H ) , 3.30 – 3.20 ( m , 2H ) , 3.20 – 3.09 ( m , 2H ) , 2.26 ( s , 3H ) - - LCMS ( Method 2 ) : 2.60 min ( product does not ionise ) Synthesis of 4 - methylindane - 2 - carboxylic acid O₂H.HOiL MeOH , O₂H , RT OMe % OH LiOH.H2O ( 299 mg , 7.12 mmol ) was added to a solution of methyl 4 - methylindane - 2- carboxylate ( 271 mg , 1.42 mmol ) in MeOH ( 2 mL ) and water ( 1 mL ) and the reaction was stirred at room temperature for 16 h . The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in DCM and acidified with 5 M aq . HCI . The layers were 331 LO separated , and the organic layer was washed with water and brine , dried over Na2SO4 , and concentrated in vacuo to provide the title compound ( 231 mg ) . г 1H NMR ( 400 MHz , CDCl3 ) Ŏ 7.14 - 7.07 ( m , 1H ) , 7.05 ( d , J = 7.2 Hz , 1H ) , 7.02 – 6.96 ( m , - 1H ) , 3.46 -3.33 ( m , 1H ) , 3.32 - 3.23 ( m , 2H ) , 3.20 ( d , J = 8.2 Hz , 2H ) , 2.26 ( s , 3H ) . Exchangeable proton not observed . LCMS ( Method 2 ) : 2.16 min ( product does not ionise ) Synthesis of 4 - methylindan - 2 - amine 1. DPPA , N₂tE par OH THF , 60 ° C 2. HCI , RT -NH NзtE ( 460 Lμ , 3.28 mmol ) and diphenylphosphoryl azide ( 338 Lµ , 1.57 mmol ) were added sequentially to a solution of 4 - methylindane - 2 - carboxylic acid ( 231 mg , 1.31 mmol ) in THF ( 4 mL ) . The reaction was heated at 60 ° C for 2 h , then cooled first to room temperature and then to 0 ° C in an ice bath . 5 M aq . HCI ( 1 mL ) was added and the reaction was allowed to warm to room temperature and stirred for 16 h . The reaction mixture was diluted with DCM and the layers were separated . The aqueous layer was extracted with DCM , then basified with 2 M aq . NaOH and further extracted with DCM ( × 3 ) . The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 56 mg ) . - - ' H NMR ( 400 MHz , ³lCDC ) г 7.15 – 6.99 ( m , 3H ) , 3.88 – 3.77 ( m , 1H ) , 3.24 – 3.19 ( m , 2H ) , - 3.18 3.07 ( m , 2H ) , 2.82 - 2.61 ( m , 2H ) , 2.23 ( s , 3H ) LCMS ( Method 2 ) : 1.13 min , 148.2 [ M + H ] * Synthesis of 4 - chloroindan - 2 - amine - CI -NH 4 - Chloroindan - 2 - amine ( 611 mg ) was synthesised following a similar procedure to that described in General Method A. 332 LO - - 1H NMR ( 400 MHz , ³lCDC ) б 7.17 – 7.11 ( m , 1H ) , 7.11 – 7.06 ( m , 2H ) , 3.87 ( tt , J = 6.8 , 4.Hz , 1H ) , 3.26 ( d , J = 6.8 Hz , 1H ) , 3.22 ( d , J = 6.8 Hz , 1H ) , 2.78 – 2.74 ( m , 1H ) , 2.74 – 2.( m , 1H ) , 1.46 ( br . s , 2H ) LCMS ( Method 1 ) : 1.07 min , 168.2 , 170.2 [ M + H ] * Synthesis of 4 - fluoroindan - 2 - amine -NHF 4 - Fluoroindan - 2 - amine ( 90 mg ) was synthesised following a similar procedure to that described in General Method A. - 1H NMR ( 400 MHz , ³lCDC ) б 7.18 – 7.07 ( m , 1H ) , 6.99 ( d , J = 7.4 Hz , 1H ) , 6.89 – 6.78 ( m , 1H ) , 3.95 – 3.85 ( m , 1H ) , 3.28 – 3.16 ( m , 2H ) , 2.73 ( dd , J = 16.1 , 5.0 Hz , 2H ) . Exchangeable protons not observed . - - Synthesis of 4,6 - difluoroindan - 2 - amine F. -NH 4,6 - Difluoroindan - 2 - amine ( 121 mg ) was synthesised following a similar procedure to that described in General Method A. г - 1H NMR ( 400 MHz , CDCl3 ) б 6.79 – 6.69 ( m , 1H ) , 6.60 ( td , J = 9.2 , 2.2 Hz , 1H ) , 3.97 – 3.( m , 1H ) , 3.23 – 3.08 ( m , 2H ) , 2.74 – 2.59 ( m , 2H ) . Exchangeable protons not observed . - Synthesis of compound 1 , N7 - indan - 2 - ylpyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( General Method B ) 333 .CI - ﻢﮨﺩ - ﺏﺩ EtO EtO ' N .N . ' N ' N NH Synthesis of ethyl ( E ) -4 - ethoxy - 2 - oxo - but - 3 - enoate OEt Eto EIOS CI N₂tE ° C to RT OEt EtO EtO ' N ' NH HO ' N ' N = ₂HN Ethyl 2 - chloro - 2 - oxo - acetate ( 8.2 mL , 73.20 mmol ) was added slowly over 10 min to a solution of ethyl vinyl ether ( 34.8 mL , 366.22 mmol ) and NзtE ( 12.25 mL , 87.89 mmol ) at ° C . The reaction was warmed to room temperature and stirred overnight . The reaction mixture was diluted with DCM and washed with sat . aq . NaHCO3 . The organic layer was washed with water , dried through a hydrophobic frit , and concentrated in vacuo to provide the title compound ( 12.48 g ) . ' H NMR ( 400 MHz , CDCl3 ) б 7.87 ( d , J = 12.7 Hz , 1H ) , 6.18 ( d , J = 12.7 Hz , 1H ) , 4.32 ( q , J - = 7.2 Hz , 2H ) , 4.06 ( q , J = 7.1 Hz , 2H ) , 1.47 – 1.28 ( m , 6H ) LCMS ( Method 1 ) : 1.59 min , 173.2 [ M + H ] + Synthesis of ethyl 3 - carbamoylpyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate 334 EtO OEt NHEtOH , 78 ° C EtO NHNHH A solution of 5 - amino - 1H - pyrazole - 4 - carboxamide ( 806 mg , 6.39 mmol ) and ethyl ( E ) -4- ethoxy - 2 - oxo - but - 3 - enoate ( 1.1 g , 6.39 mmol ) in EtOH ( 9 mL ) was heated at 78 ° C for 16 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The residue was suspended in EtOH and the resulting precipitate was collected by filtration , washed with EtOH , and dried to provide the title compound ( 895 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) 8 8.90 ( d , J = 4.3 Hz , 1H ) , 8.64 ( s , 1H ) , 7.62 ( d , J = 4.3 Hz , 1H ) , 7.56 ( s , 1H ) , 7.45 ( d , J = 17.6 Hz , 1H ) , 4.48 ( q , J = 7.1 Hz , 2H ) , 1.36 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 2 ) : 1.49 min , 235.2 [ M + H ] + Synthesis of 3 - carbamoylpyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid LiOH MeOH , THF , RT HO EtO . NH2 NHN = 4 M aq . LiOH ( 4.8 mL , 19.11 mmol ) was added to a solution of ethyl 3- carbamoylpyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 895 mg , 3.82 mmol ) in THF ( 10 mL ) and MeOH ( 3 mL ) and the reaction was stirred at room temperature for 16 h . The reaction mixture was concentrated in vacuo and the aqueous residue was acidified with 5 M aq . HCI . The resulting precipitate was collected by filtration , washed with water , and dried to provide the title compound ( 710 mg ) . § 1H NMR ( 400 MHz , DMSO - d6 ) 8 8.89 ( d , J = 4.3 Hz , 1H ) , 8.63 ( s , 1H ) , 7.56 ( d , J = 4.3 Hz , 2H ) , 7.49 ( s , 1H ) . Additional exchangeable proton not observed . LCMS ( Method 2 ) : 0.74 min , 207.1 [ M + H ] * Synthesis of compound 1 , N7 - indan - 2 - ylpyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 335 -NH2.HCI N HO ' N ' NH T3P , Et , N , DMF RT N asse NH 1 - Propanephosphonic anhydride ( 50 wt % in DMF ; 1.3 mL , 2.18 mmol ) and N³tE ( 304 Lµ , 2.18 mmol ) were added to a solution of indan - 2 - amine hydrochloride ( 136 mg , 0.80 mmol ) and 3 - carbamoylpyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 150 mg , 0.73 mmol ) in DMF ( 1.5 mL ) and the reaction was stirred at room temperature for 24 h then quenched with water . The resulting suspension was collected by filtration , washed with water and heptane , and dried to provide the title compound ( 199 mg ) . ☎ 1H NMR ( 400 MHz , DMSO - εd ) 5 9.92 ( d , J = 7.0 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 8.65 ( s , 1H ) , 7.64 ( d , J = 4.4 Hz , 1H ) , 7.58 ( s , 1H ) , 7.52 ( s , 1H ) , 7.28 ( dd , J = 5.4 , 3.3 Hz , 2H ) , 7.- 7.13 ( m , 2H ) , 4.85 – 4.72 ( m , 1H ) , 3.38 ( dd , J = 16.1 , 7.6 Hz , 2H ) , 2.99 ( dd , J = 16.1 , 5.Hz , 2H ) - LCMS ( Method 1 ) : 1.58 min , 322.0 [ M + H ] + Synthesis of compound 2 , N7- ( 4 - methylindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide cosse NH N7- ( 4 - methylindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 15 mg ) was synthesised following a similar procedure to that described in General Method B.

- - ' H NMR ( 400 MHz , DMSO - d ) ☎ 9.92 ( d , J = 7.0 Hz , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 8.66 ( s , 1H ) , 7.64 ( d , J = 4.4 Hz , 1H ) , 7.59 ( s , 1H ) , 7.52 ( s , 1H ) , 7.13 – 7.04 ( m , 2H ) , 7.04 – 6.95 ( m , 1H ) , 4.85 - 4.72 ( m , 1H ) , 3.43 - 3.33 ( m , 2H ) , 3.04 - 2.95 ( m , 1H ) , 2.95 - 2.85 ( m , 1H ) , 2.( s , 3H ) - LCMS ( Method 2 ) : 2.25 min , 336.2 [ M + H ] * 336 Synthesis of compound 3 , N7- ( 5 - methoxyindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide H Loosse MeO- NH N7- ( 5 - methoxyindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 30 mg ) was synthesised following a similar procedure to that described in General Method B. ' H NMR ( 400 MHz , DMSO - d6 ) ō 9.93 ( d , J = 7.0 Hz , 1H ) , 8.93 ( d , J = 4.3 Hz , 1H ) , 8.66 ( s , 1H ) , 7.65 ( d , J = 4.3 Hz , 1H ) , 7.60 ( s , 1H ) , 7.53 ( s , 1H ) , 7.17 ( d , J = 8.3 Hz , 1H ) , 6.87 ( d , J = - 2.5 Hz , 1H ) , 6.75 ( dd , J = 8.3 , 2.5 Hz , 1H ) , 4.84 – 4.71 ( m , 1H ) , 3.73 ( s , 3H ) , 3.40 - 3.( m , 2H ) , 3.00 – 2.85 ( m , 2H ) - LCMS ( Method 2 ) : 2.11 min , 352.2 [ M + H ] * Synthesis of compound 4 , N7- ( 4 - chloroindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide gosse CI ₂HN N7- ( 4 - chloroindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 45 mg ) was synthesised following a similar procedure to that described in General Method B. 1H NMR ( 400 MHz , DMSO - d ) § 9.93 ( d , J = 6.9 Hz , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 8.65 ( s , 1H ) , 7.63 ( d , J = 4.3 Hz , 1H ) , 7.59 ( br . s , 1H ) , 7.52 ( br . s , 1H ) , 7.32 – 7.18 ( m , 3H ) , 4.88 - 4.75 ( m , 1H ) , 3.47 ( dd , J = 19.8 , 7.7 Hz , 1H ) , 3.43 ( dd , J = 19.8 , 7.7 Hz , 1H ) , 3.09 ( dd , J = 16.6 , 5.2 Hz , 1H ) , 3.03 ( dd , J = 16.7 , 5.1 Hz , 1H ) LCMS ( Method 2 ) : 2.26 min , 356.1 , 358.2 [ M + H ] * Synthesis of compound 5 , a ] pyrimidine - 3,7 - dicarboxamide - = N7- ( 1,2,3,4 - tetrahydroquinolin - 3 - yl ) pyrazolo [ 1,5- 337 H .N . N cosse ' N ' ' N ' NH N7- ( 1,2,3,4 - tetrahydroquinolin - 3 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 18 mg ) was synthesised following a similar procedure to that described in General Method B. 1H NMR ( 400 MHz , DMSO - d6 ) à 10.02 ( d , J = 7.3 Hz , 1H ) , 8.94 ( d , J = 4.4 Hz , 1H ) , 8.56 ( s , 1H ) , 7.75 ( d , J = 4.4 Hz , 1H ) , 7.60 ( s , 1H ) , 7.54 ( s , 1H ) , 6.94 – 6.88 ( m , 2H ) , 6.56 ( dt , J = 7.5 , 1.1 Hz , 1H ) , 6.49 ( td , J = 7.3 , 1.2 Hz , 1H ) , 5.90 ( s , 1H ) , 4.48 – 4.38 ( m , 1H ) , 3.47 – 3.( m , 1H ) , 3.22 ( ddd , J = 11.6 , 6.1 , 1.4 Hz , 1H ) , 3.09 ( dd , J = 16.0 , 4.8 Hz , 1H ) , 2.84 ( dd , J : 16.2 , 6.1 Hz , 1H ) - = LCMS ( Method 2 ) 1.88 min , 337.2 [ M + H ] + Synthesis dicarboxamide of compound 6 , H .N . cosse NH N7 - chroman - 3 - ylpyrazolo [ 1,5 - a ] pyrimidine - 3,7- N7 - chroman - 3 - ylpyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 17.4 mg ) was synthesised following a similar procedure to that described in General Method B. 1H NMR ( 400 MHz , DMSO - d ) ☎ 10.03 ( d , J = 5.5 Hz , 1H ) , 8.93 ( d , J = 4.3 Hz , 1H ) , 8.59 ( s , 1H ) , 7.71 ( d , J = 4.4 Hz , 1H ) , 7.59 ( s , 1H ) , 7.52 ( s , 1H ) , 7.12 ( td , J = 7.4 , 1.5 Hz , 2H ) , 6.- - – 6.82 ( m , 2H ) , 4.54 ( s , 1H ) , 4.31 – 4.24 ( m , 1H ) , 4.18 ( ddd , J = 10.9 , 5.7 , 1.5 Hz , 1H ) , 3.( dd , J = 16.6 , 5.4 Hz , 1H ) , 2.92 ( dd , J = 16.6 , 5.6 Hz , 1H ) == LCMS ( Method 2 ) : 1.984 min , 338.15 [ M + H ] + Synthesis of compound 7 , N7- ( trans - 3 - fluoro - 3 - methyl - cyclobutyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 338 Fr H N ° ₂HN N = N7- ( trans - 3 - fluoro - 3 - methyl - cyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method B. 1H NMR ( 400 MHz , DMSO - d ) 5 9.92 ( d , J = 6.3 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 8.70 ( s , 1H ) , 7.64 ( d , J = 4.4 Hz , 1H ) , 7.61 ( s , 1H ) , 7.53 ( s , 1H ) , 4.62 – 4.50 ( m , 1H ) , 2.77 – 2.65 ( m , 2H ) , 2.38 – 2.26 ( m , 2H ) , 1.51 ( d , J = 22.3 Hz , 3H ) LCMS ( Method 2 ) : 1.77 min , 292.2 [ M + H ] * - Synthesis of compound 8 , N7- ( cis - 3 - hydroxy - 3 - methyl - cyclobutyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide NHHO N7- ( cis - 3 - hydroxy - 3 - methyl - cyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method B. ' H NMR ( 400 MHz , DMSO - d6 ) ō 9.92 ( d , J = 7.1 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 8.72 ( s , 1H ) , 7.67 ( d , J = 4.4 Hz , 1H ) , 7.61 ( br . s , 1H ) , 7.55 ( br . s , 1H ) , 5.14 ( s , 1H ) , 4.16 - 4.02 ( m , 1H ) , 2.47 – 2.39 ( m , 2H ) , 2.17 – 2.05 ( m , 2H ) , 1.28 ( s , 3H ) LCMS ( Method 2 ) : 1.45 min , 290.2 [ M + H ] * Synthesis of compound 9 , N7- ( cis - 3 - cyanocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N ' N ' NHN = 339 LO ( 33 mg ) was N7- ( cis - 3 - cyanocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide synthesised following a similar procedure to that described in General Method B. 1H NMR ( 400 MHz , DMSO - d ) ☎ 9.98 ( d , J = 7.5 Hz , 1H ) , 8.94 ( d , J = 4.3 Hz , 1H ) , 8.71 ( s , 1H ) , 7.64 ( d , J = 4.4 Hz , 1H ) , 7.62 ( s , 1H ) , 7.54 ( s , 1H ) , 4.52 ( q , J = 8.3 Hz , 1H ) , 3.25 – 3.( m , 1H ) , 2.82 - 2.70 ( m , 2H ) , 2.60 - 2.45 ( m , 2H ) LCMS ( Method 2 ) : 1.51 min , 285.2 [ M + H ] * - Synthesis of compound 10 , N7- ( 3,3 - diethylcyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide vise NH N7- ( 3,3 - diethylcyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 18 mg ) was synthesised following a similar procedure to that described in General Method B. 1H NMR ( 400 MHz , DMSO - d ) § 9.85 ( d , J = 7.2 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 8.70 ( s , 1H ) , 7.64 -7.57 ( m , 2H ) , 7.54 ( s , 1H ) , 4.45 - 4.35 ( m , 1H ) , 2.24 - 2.15 ( m , 2H ) , 1.82 - 1.( m , 2H ) , 1.46 ( dq , J = 24.6 , 7.4 Hz , 4H ) , 0.81 ( t , J = 7.4 Hz , 3H ) , 0.74 ( t , J = 7.4 Hz , 3H ) LCMS ( Method 4 ) : 2.28 min , 316.2 [ M + H ] * Synthesis of compound 11 , N7- ( cis - 3 - methoxycyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide Meo " NH N7- ( cis - 3 - methoxycyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 88 mg ) was synthesised following a similar procedure to that described in General Method B. § ' H NMR ( 400 MHz , DMSO - d6 ) ō 9.86 ( d , J = 7.3 Hz , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 8.71 ( s , 1H ) , 7.62 ( d , J = 4.3 Hz , 1H ) , 7.60 ( s , 1H ) , 7.53 ( s , 1H ) , 4.17 – 4.03 ( m , 1H ) , 3.75 – 3.63 ( m , 1H ) , 3.16 ( s , 3H ) , 2.78 - 2.66 ( m , 2H ) , 1.98 - 1.86 ( m , 2H ) - LCMS ( Method 2 ) : 1.55 min , 1.57 min , 290.2 [ M + H ] * 340 Synthesis of 2 - methyl - N- ( 7 - oxaspiro [ 3.5 ] nonan - 2 - yl ) propane - 2 - sulfinamide OUS N₂H 1. Ti ( OiPr ) 4 , THE reflux 2. NaBH4 , RT HN O = S g Ti ( OiPr ) 4 ( 796 Lµ , 2.68 mmol ) was added to a solution of tert - butylsulfinamide ( 259 mg , 2.mmol ) and 7 - oxaspiro [ 3.5 ] nonan - 2 - one ( 250 mg , 1.78 mmol ) in THF ( 10 mL ) and the reaction was heated to reflux overnight then cooled to room temperature . NaBH4 ( 135 mg , 3.57 mmol ) was added and the reaction was stirred at room temperature for 2 h then allowed to stand at room temperature for 5 days . The reaction was quenched with water , filtered , and washed with EtOAc . The filtrate was diluted with EtOAc and water , and the layers were separated . The organic layer was washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % ( 2 M NH3 in MeOH ) in DCM ) to provide the title compound ( 305 mg ) . - ' H NMR ( 400 MHz , CDCl3 ) г 3.97 - 3.84 ( m , 1H ) , 3.65 – 3.59 ( m , 2H ) , 3.58 – 3.52 ( m , 2H ) , 3.30 ( s , 1H ) , 2.41 – 2.26 ( m , 2H ) , 1.79 – 1.68 ( m , 2H ) , 1.60 ( dd , J = 10.0 , 4.8 Hz , 4H ) , 1.( s , 9H ) - - LCMS ( Method 2 ) : 1.87 min , 246.2 [ M + H ] + Synthesis of 7 - oxaspiro [ 3.5 ] nonan - 2 - amine hydrochloride HN HCI , 1,4 - Dioxane NH2.HCI RT 2 - Methyl - N- ( 7 - oxaspiro [ 3.5 ] nonan - 2 - yl ) propane - 2 - sulfinamide ( 305 mg , 1.24 mmol ) was suspended in HCI ( 4 M in 1,4 - dioxane ; 5 mL , 20.00 mmol ) and the reaction was stirred at 341 LO room temperature for 16 h then concentrated in vacuo . The residue was sonicated in Et2O , and the resulting precipitate was collected by filtration and dried to provide the title compound ( 172 mg ) . - - 1H NMR ( 400 MHz , DMSO - d ) § 8.24 ( s , 2H ) , 3.72 – 3.58 ( m , 1H ) , 3.53 – 3.42 ( m , 4H ) , 2.- 2.09 ( m , 2H ) , 1.96 – 1.87 ( m , 2H ) , 1.57 - 1.48 ( m , 4H ) . Additional exchangeable proton not observed .

Synthesis of compound 12 , N7- ( 7 - oxaspiro [ 3.5 ] nonan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide asse ` N NH N7- ( 7 - oxaspiro [ 3.5 ] nonan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 22 mg ) was synthesised following a similar procedure to that described in General Method B. 1H NMR ( 400 MHz , DMSO - d ) § 9.88 ( d , J = 7.1 Hz , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 8.70 ( s , 1H ) , 7.63 ( d , J = 4.4 Hz , 1H ) , 7.60 ( s , 1H ) , 7.54 ( s , 1H ) , 4.54 – 4.41 ( m , 1H ) , 3.59 – 3.49 ( m , - - - - - 2H ) , 3.49 – 3.41 ( m , 2H ) , 2.39 – 2.30 ( m , 2H ) , 1.92 – 1.82 ( m , 2H ) , 1.65 – 1.58 ( m , 2H ) , 1.- 1.50 ( m , 2H ) LCMS ( Method 2 ) : 1.73 min , 330.2 [ M + H ] * Synthesis of 5,6,7,8 - tetrahydroisoquinolin - 7 - amine NHPtO2 , TFA ₂H ( g ) , RT NH PtO2 ( 47 mg , 0.21 mmol ) and isoquinolin - 7 - amine ( 300 mg , 2.08 mmol ) were dissolved in TFA ( 5 mL , 65.34 mmol ) and the reaction was stirred under a hydrogen atmosphere ( balloon ) at room temperature for 20 h . The reaction mixture was filtered through a short pad of diatomaceous earth ( ®etilaciD ) , washed with EtOAc and MeOH , and concentrated in vacuo . The crude product was purified by SCX chromatography ( eluting with 2 M NH3 in MeOH ) and column chromatography ( eluting with 0 to 10 % ( 2 M NH3 in MeOH ) in DCM ) to provide the title compound ( 48 mg ) . 342 LO 1H NMR ( 400 MHz , DMSO - d ) ō 8.28 – 8.17 ( m , 2H ) , 7.05 ( d , J = 5.0 Hz , 1H ) , 3.07 - 2.- - - ( m , 2H ) , 2.93 – 2.64 ( m , 4H ) , 2.39 ( dd , J = 16.4 , 9.0 Hz , 1H ) , 1.91 – 1.79 ( m , 1H ) , 1.53 – 1.39 ( m , 1H ) Synthesis of compound 13 , N7- ( 5,6,7,8 - tetrahydroisoquinolin - 7 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide Dorse ' N ' N : NH N7- ( 5,6,7,8 - tetrahydroisoquinolin - 7 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 12 mg ) was synthesised following a similar procedure to that described in General Method B. ' H NMR ( 400 MHz , DMSO - d6 ) ☎ 9.82 ( d , J = 7.3 Hz , 1H ) , 8.94 ( d , J = 4.3 Hz , 1H ) , 8.65 ( s , 1H ) , 8.33 ( s , 1H ) , 8.27 ( d , J = 5.1 Hz , 1H ) , 7.67 ( d , J = 4.3 Hz , 1H ) , 7.60 ( s , 1H ) , 7.53 ( s , 1H ) , 7.14 ( d , J = 5.1 Hz , 1H ) , 4.35 ( d , J = 8.6 Hz , 1H ) , 3.19 ( dd , J = 16.7 , 5.1 Hz , 1H ) , 2.( t , J = 6.5 Hz , 2H ) , 2.84 ( dd , J = 16.5 , 8.5 Hz , 1H ) , 2.18 – 2.07 ( m , 1H ) , 1.92 ( s , 1H ) LCMS ( Method 2 ) : 1.17 min , 337.2 [ M + H ] * - Synthesis of N7- ( 4 - bromoindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide H Br N : NH N7- ( 4 - bromoindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 382 mg ) was synthesised following a similar procedure to that described in General Method B. = ' H NMR ( 400 MHz , DMSO - d ) г 9.93 ( d , J = 6.9 Hz , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 8.66 ( s , 1H ) , 7.63 ( d , J = 4.3 Hz , 1H ) , 7.58 ( br . s , 1H ) , 7.52 ( br . s , 1H ) , 7.40 ( d , J = 7.9 Hz , 1H ) , 7.( d , J = 7.4 Hz , 1H ) , 7.15 ( t , J = 7.7 Hz , 1H ) , 4.81 ( dtd , J = 12.8 , 7.5 , 5.2 Hz , 1H ) , 3.51 ( dd , J. = - 16.5 , 7.7 Hz , 1H ) , 3.40 ( dd , J = 16.7 , 7.7 Hz , 1H ) , 3.12 ( dd , J = 16.5 , 5.2 Hz , 1H ) , 3.00 ( dd , J = 16.7 , 5.1 Hz , 1H ) LCMS ( Method 1 ) : 1.68 min , 400.1 , 402.1 [ M + H ] * 343 Synthesis of compound 14 , N7- [ 4- ( 3,3,3 - trifluoropropyl ) indan - 2 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide Br bosse NHN : CFKF3B cataCXium A Pd GCS2CO1,4 - Dioxane , O₂H 100 ° C F3C -Bosse ` N` NHN N7- ( 4 - bromoindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 70 mg , 0.17 mmol ) , potassium trifluoro ( 3,3,3 - trifluoropropyl ) borate ( 152 mg , 0.74 mmol ) , cataCXium A Pd G( chloro [ ( di ( 1 - adamantyl ) -N - butylphosphine ) -2- ( 2 - aminobiphenyl ) ] palladium ( II ) ; 8.4 mg , 0.mmol ) , and Cs2CO3 ( 195 mg , 0.60 mmol ) were placed in a vial and the vial was sealed and purged with argon for 5 min . 1,4 - Dioxane ( 2 mL ) and water ( 200 Lµ ) were added , and the mixture was degassed by sparging with a stream of argon for 10 min . The reaction was heated at 100 ° C for 16 h then cooled to room temperature . Additional portions of potassium trifluoro ( 3,3,3 - trifluoropropyl ) borate ( 64 mg , 0.31 mmol ) , cataCXium A Pd G2 ( 8.4 mg , 0.mmol ) , and Cs2CO3 ( 81 mg , 0.25 mmol ) were added and the mixture was degassed by sparging with a stream of argon for 10 min . The reaction was heated at 100 ° C for a further h then cooled to room temperature . The reaction mixture was diluted with EtOAc and filtered through a short pad of ®etilaciD . The filtrate was concentrated in vacuo and the crude product was purified by column chromatography ( eluting with 0 to 5 % MeOH in DCM ) and preparative HPLC ( basic method ) to provide the title compound ( 45 mg ) . - - 1H NMR ( 400 MHz , DMSO - εd ) ☎ 9.91 ( d , J = 6.9 Hz , 1H ) , 8.93 ( d , J = 4.3 Hz , 1H ) , 8.63 ( s , 1H ) , 7.64 ( d , J = 4.3 Hz , 1H ) , 7.59 ( br . s , 1H ) , 7.52 ( br . s , 1H ) , 7.20 – 7.12 ( m , 2H ) , 7.12 - 7.07 ( m , 1H ) , 4.86 - 4.73 ( m , 1H ) , 3.39 ( ddd , J = 16.2 , 7.6 , 3.8 Hz , 2H ) , 2.99 ( ddd , J = 16.1 , 8.1 , 5.3 Hz , 2H ) , 2.84 – 2.74 ( m , 2H ) , 2.62 – 2.52 ( m , 2H ) - LCMS ( Method 2 ) : 2.44 min , 418.2 [ M + H ] + Synthesis of dicarboxamide - N7- [ 4- ( cyclopenten - 1 - yl ) indan - 2 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- 344 Br NHBpin SPhos Pd G3OC₂K 1,4 - Dioxane O₂H , 90 ° C Bosse NH N7- ( 4 - bromoindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 50 mg , 0.12 mmol ) , 2- ( cyclopenten - 1 - yl ) -4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolane ( 61 mg , 0.31 mmol ) , SPhos Pd G( chloro ( 2 - dicyclohexylphosphino - 2 ' , 6 ' - dimethoxy - 1,1 ' - biphenyl ) [ 2- ( 2 ' - amino - 1,1'- biphenyl ) ] palladium ( II ) ; 9 mg , 0.01 mmol ) , and K2CO3 ( 52 mg , 0.37 mmol ) were placed in a vial and the vial was sealed and purged with argon for 5 min . 1,4 - Dioxane ( 2 mL ) and water ( 200 Lµ ) were added and the mixture was sonicated and degassed by sparging with a stream of argon for 5 min . The reaction was heated at 90 ° C for 20 h then cooled to room temperature . The reaction mixture was filtered through a short pad of ⓇetilaciD and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 3 % MeOH in DCM ) to provide the title compound ( 45 mg ) . § ' H NMR ( 400 MHz , DMSO - d6 ) ō 9.91 ( d , J = 6.9 Hz , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 8.65 ( s , 1H ) , 7.64 ( d , J = 4.4 Hz , 1H ) , 7.58 ( br . s , 1H ) , 7.52 ( br . s , 1H ) , 7.26 – 7.06 ( m , 3H ) , 6.01 ( td , J = 2.6 , 1.3 Hz , 1H ) , 4.84 – 4.71 ( m , 1H ) , 3.54 – 3.44 ( m , 1H ) , 3.43 – 3.34 ( m , 1H ) , 3.04 . ( ddd , J = 21.8 , 16.3 , 5.2 Hz , 2H ) , 2.76 – 2.64 ( m , 2H ) , 2.56 – 2.52 ( m , 2H ) , 2.00 – 1.85 ( m , 2H ) - - LCMS ( Method 2 ) : 2.59 min , 388.2 [ M + H ] * - - - - Synthesis of compound 15 , N7- [ 5- ( 2 - pyrrolidin - 1 - ylethyl ) indan - 2 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide Bosse NH PtO2 , ₂H ( g ) EtOH , EtOAC RT NHN PtO2 ( 2.5 mg , 0.01 mmol ) was suspended in EtOH ( 6 mL ) and the reaction vessel was evacuated and backfilled with argon ( × 3 ) . A solution of N7- [ 4- ( cyclopenten - 1 - yl ) indan - 2- yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 62 mg , 0.16 mmol ) in EtOAc ( 6 mL ) was added and the reaction vessel was evacuated and backfilled with argon ( x3 ) then evacuated and backfilled with hydrogen ( x 3 ) . The reaction was stirred at room temperature under a 345 hydrogen atmosphere ( balloon ) for 20 h . The reaction mixture was filtered through a short pad of ⓇetilaciD and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 4 % MeOH in DCM ) and preparative HPLC ( basic and acidic methods ) to provide the title compound ( 5 mg ) . ☎ ' H NMR ( 400 MHz , DMSO - εd ) ō 9.91 ( d , J = 7.0 Hz , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 8.63 ( s , 1H ) , 7.63 ( d , J = 4.3 Hz , 1H ) , 7.58 ( br . s , 1H ) , 7.52 ( br . s , 1H ) , 7.18 – 7.05 ( m , 3H ) , 4.76 ( dt , - - J = 12.8 , 6.4 Hz , 1H ) , 3.45 – 3.35 ( m , 2H ) , 3.10 – 2.93 ( m , 3H ) , 2.11 – 1.89 ( m , 2H ) , 1.84 - - - 1.72 ( m , 2H ) , 1.72 – 1.61 ( m , 2H ) , 1.61 – 1.45 ( m , 2H ) - LCMS ( Method 2 ) : 2.64 min , 390.2 [ M + H ] + Synthesis of - compound 16 , N7- [ 4- ( 4 - chlorophenoxy ) indan - 2 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide Br NH 4 - chlorophenol N , N - dimethylglycine Cul , Cs2CO1,4 - Dioxane , 120 ° C CI NH N7- ( 4 - bromoindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 40 mg , 0.10 mmol ) , 4- chlorophenol ( 64 mg , 0.50 mmol ) , Cs2CO3 ( 65 mg , 0.20 mmol ) , Cul ( 9 mg , 0.05 mmol ) and N , N - dimethylglycine ( 15 mg , 0.15 mmol ) were placed in a vial and the vial was sealed and purged with argon for 5 min . 1,4 - Dioxane ( 2 mL ) was added and the reaction was heated at 120 ° C for 17 h then cooled to room temperature . The reaction mixture was diluted with EtOAc , filtered through a short pad of ®etilaciD , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 5 % MeOH in DCM ) and preparative HPLC ( basic method ) to provide the title compound ( 16 mg ) . ' H NMR ( 400 MHz , DMSO - d € ) ☎ 9.91 ( d , J = 5.9 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 8.65 ( s , 1H ) , 7.62 ( d , J = 4.3 Hz , 1H ) , 7.59 ( br . s , 1H ) , 7.52 ( br . s , 1H ) , 7.46 – 7.35 ( m , 2H ) , 7.26 ( t , J = 7.7 Hz , 1H ) , 7.16 ( dd , J = 7.4 , 1.0 Hz , 1H ) , 7.01 – 6.93 ( m , 2H ) , 6.84 ( dd , J = 8.0 , 1.0 Hz , - - 1H ) , 4.85 4.73 ( m , 1H ) , 3.43 ( dd , J = 16.4 , 7.6 Hz , 1H ) , 3.20 ( dd , J = 16.4 , 7.6 Hz , 1H ) , 3.05 ( dd , J = 16.4 , 5.4 Hz , 1H ) , 2.80 ( dd , J = 16.4 , 5.2 Hz , 1H ) LCMS ( Method 2 ) : 2.66 min , 448.1 , 450.1 [ M + H ] + Synthesis of compound 17 , N7- [ 4- ( 2 - pyridyl ) indan - 2 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 346 NH 1. ₂nip₂B , KOAC SPhos Pd G1,4 - Dioxane , DMF ° C Br N. bosse Br 2. SPhos Pd G3OC₂K 1,4 - Dioxane , O₂H ° C NH A mixture of N7- ( 4 - bromoindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 50 mg , 0.12 mmol ) , 2nip₂B ( bis ( pinacolato ) diboron ; 63 mg , 0.25 mmol ) , KOAc ( 37 mg , 0.37 mmol ) , and SPhos Pd G2 ( 9 mg , 0.01 mmol ) was purged with argon for 5 min . 1,4 - Dioxane ( 2.5 mL ) was added and the mixture was degassed by sparging with a stream of argon for 5 min . The reaction was heated at 90 ° C for 20 h then cooled to room temperature . DMF ( 1 mL ) and additional portions of 2nip₂B ( 63 mg , 0.25 mmol ) , KOAc ( 7 mg , 0.37 mmol ) , and SPhos Pd G2 ( 9 mg , 0.01 mmol ) were added and the mixture was degassed by sparging with a stream of argon for 5 min . The reaction was heated at 90 ° C for a further 20 h then cooled to room temperature . The reaction mixture was diluted with EtOAc and filtered through a short pad of ®etilaciD . The filtrate was concentrated in vacuo to give the crude intermediate boronate ester , N7- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) indan - 2 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide .

A mixture of the of the crude N7- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) indan - 2- yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide obtained as above , 2 - bromopyridine ( 40 mg , 0.25 mmol ) , SPhos Pd G2 ( 12 mg , 0.02 mmol ) , and K2CO3 ( 70 mg , 0.50 mmol ) was purged with argon for 5 min . 1,4 - Dioxane ( 3 mL ) and water ( 300 Lµ ) were added and the mixture was degassed by sparging with a stream of argon for 5 min . The reaction was heated at ° C for 20 h then cooled to room temperature . The reaction mixture was diluted with EtOAc and filtered through a short pad of ®etilaciD . The filtrate was concentrated in vacuo and the crude product was purified by column chromatography ( eluting with 0 to 6 % MeOH in DCM ) and preparative HPLC ( basic method ) to provide the title compound ( 9.2 mg ) . 1H NMR ( 400 MHz , DMSO - d ) ☎ 9.91 ( d , J = 6.7 Hz , 1H ) , 8.90 ( d , J = 4.3 Hz , 1H ) , 8.68 ( ddd , J = - 4.8 , 1.9 , 0.9 Hz , 1H ) , 8.63 ( s , 1H ) , 7.95 – 7.84 ( m , 1H ) , 7.72 ( dt , J = 8.0 , 1.1 Hz , 1H ) , 7.62 ( d , J = 4.4 Hz , 1H ) , 7.60 - 7.55 ( m , 2H ) , 7.51 ( br . s , 1H ) , 7.42 – 7.30 ( m , 3H ) , 4.85 – 347 LO 4.71 ( m , 1H ) , 3.64 ( dd , J = 16.8 , 7.5 Hz , 1H ) , 3.45 ( dd , J = 16.2 , 7.6 Hz , 1H ) , 3.30 – 3.19 ( m , 1H ) , 3.07 ( dd , J = 16.2 , 5.5 Hz , 1H ) LCMS ( Method 2 ) : 1.71 min , 399.2 [ M + H ] * Synthesis of tert - butyl N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] carbamate KF , 2 - fluoropyridine Selectfluor , AgOTf F F HO BOC N .F EtOAc , 0 ° C to RT BOC N Selectfluor dropwise ( 1- ( chloromethyl ) -4 - fluoro - 1,4 - diazabicyclo [ 2.2.2 ] octane - 1,4 - diium ditetrafluoroborate ; 2.17 g , 6.09 mmol ) , AgOTf ( silver trifluoromethanesulfonate ; 4.54 g , 17.67 mmol ) and KF ( 1.03 g , 17.67 mmol ) were added to a solution of tert - butyl N- ( cis - 3- hydroxycyclobutyl ) carbamate ( 827 mg , 4.42 mmol ) in EtOAc ( 30 mL ) , followed by the addition of 2 - fluoropyridine ( 1.52 mL , 17.67 mmol ) and trimethyl ( trifluoromethyl ) silane ( 1.63 mL , 11.04 mmol ) . The reaction was stirred at room temperature for 60 h , then the mixture was filtered through a short pad of ®etilaciD and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 567 mg ) . 1H NMR ( 400 MHz , CDCl3 ) б 4.65 ( s , 1H ) , 4.36 ( p , J = 7.2 Hz , 1H ) , 3.81 ( s , 1H ) , 2.83 ( d , J : 9.5 Hz , 2H ) , 2.14 – 2.02 ( m , 2H ) , 1.44 ( s , 9H ) Synthesis of 2,2,2 - trifluoroacetic acid ; cis - 3- ( trifluoromethoxy ) cyclobutanamine = F F F F TFA , DCM , RT BOC O > AFT.₂HN TFA ( 940 Lμ , 12.34 mmol ) was added dropwise to a solution of tert - butyl N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] carbamate ( 315 mg , 1.23 mmol ) in DCM ( 2 mL ) and the reaction was stirred at room temperature for 2 h . The reaction mixture was concentrated in vacuo and the residue was dissolved in Et2O ( 1 mL ) . Heptane ( ~ 4 mL ) was added and the mixture was cooled to 0 ° C and left to stand for 1 h . The resulting precipitate was collected by filtration , washed with heptane and dried to provide the title compound ( 260 mg ) . 348 LO 1H NMR ( 400 MHz , DMSO - d ) § 8.21 ( s , 3H ) , 4.71 – 4.59 ( m , 1H ) , 3.42 – 3.37 ( m , 1H ) , 2.- – 2.65 ( m , 2H ) , 2.41 – 2.27 ( m , 2H ) - Synthesis of compound 18 , N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N Losse F. NH N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 36 mg ) was synthesised following a similar procedure to that described in General Method B. ☎ ' H NMR ( 400 MHz , DMSO - d6 ) ō 9.92 ( d , J = 6.5 Hz , 1H ) , 8.94 ( d , J = 4.3 Hz , 1H ) , 8.71 ( s , 1H ) , 7.63 ( d , J = 4.3 Hz , 1H ) , 7.61 ( s , 1H ) , 7.54 ( s , 1H ) , 4.77 – 4.65 ( m , 1H ) , 4.26 – 4.16 ( m , 1H ) , 2.93 -2.82 ( m , 2H ) , 2.43 – 2.32 ( m , 2H ) - - - LCMS ( Method 2 ) : 2.04 min , 344.2 [ M + H ] + Synthesis of 4- [ tert - butyl ( dimethyl ) silyl ] oxypyrrolidin - 2 - one TBDMSCI imidazole HN OH DMF , RT HN OTBDMS Imidazole ( 0.94 g , 13.85 mmol ) and tert - butyldimethylsilyl chloride ( 1.57 g , 10.39 mmol ) were added to a solution of 4 - hydroxypyrrolidin - 2 - one ( 1 g , 9.89 mmol ) in DMF ( 6 mL ) and the reaction was stirred at room temperature for 16 h . The reaction mixture was poured into ice water ( ~ 200 mL ) and 0.2 M aq . HCI ( ~ 5 mL ) was added . The mixture was stirred for 10 mins then diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo to provide the title compound ( 2.21 g ) . - 1H NMR ( 400 MHz , ³ICDC ) г 6.02 ( s , 1H ) , 4.55 – 4.49 ( m , 1H ) , 3.59 ( ddd , J = 10.0 , 6.1 , 0.Hz , 1H ) , 3.23 ( ddd , J = 10.0 , 3.4 , 1.0 Hz , 1H ) , 2.54 ( dd , J = 16.9 , 6.8 Hz , 1H ) , 2.26 ( dd , 1H ) , 0.88 ( s , 9H ) , 0.07 ( d , J = 1.1 Hz , 6H ) Synthesis of tert - butyl - [ ( 5 - ethoxy - 3,4 - dihydro - 2H - pyrrol - 3 - yl ) oxy ] -dimethyl - silane 349 HN OTBDMS CS2CODCM RT BFﻢﺟھے OTBDMS CsCO3 ( 9.94 g , 30.51 mmol ) and triethyloxonium tetrafluoroborate ( 2.18 g , 11.49 mmol ) were added sequentially to a solution of 4- [ tert - butyl ( dimethyl ) silyl ] oxypyrrolidin - 2 - one ( 2.19 g , 10.17 mmol ) in DCM ( 66 mL ) and the reaction was stirred at room temperature for 23 h . The reaction mixture was diluted with water and stirred for 10 min . The layers were separated , and the organic layer was washed with water ( x 3 ) , dried over Na2SO4 , and concentrated in vacuo to provide the title compound ( 2.24 g ) .

- - - - H¹ NMR ( 400 MHz , ³lCDC ) § 4.55 – 4.49 ( m , 1H ) , 4.28 – 4.12 ( m , 2H ) , 3.85 – 3.76 ( m , 1H ) , 3.55 – 3.50 ( m , 1H ) , 2.72 – 2.63 ( m , 1H ) , 2.45 – 2.35 ( m , 1H ) , 1.30 ( t , J = 7.1 Hz , 3H ) , 0.( s , 9H ) , 0.05 ( s , 6H ) - Synthesis of 3- [ tert - butyl ( dimethyl ) silyl ] oxy - N- ( 2,2 - diethoxyethyl ) -3,4 - dihydro - 2H- pyrrol - 5 - amine OEt OTBDMS EtO HCI EtOH RT EtO OEt NH NHOEt N OTBDMS 2,2 - Diethoxyethanamine ( 1.34 mL , 9.20 mmol ) was added to a solution of tert - butyl - [ ( 5- ethoxy - 3,4 - dihydro - 2H - pyrrol - 3 - yl ) oxy ] -dimethyl - silane ( 2.24 g , 9.20 mmol ) in EtOH ( 35 mL ) . HCI ( 1.25 M in EtOH ; 7.36 mL , 9.20 mmol ) was added dropwise over 10 min and the reaction was stirred at room temperature for 16 h . The reaction mixture was concentrated in vacuo and the residue was suspended in boiling Et2O ( ~ 50 mL ) for 10 min . The mixture was cooled to room temperature and the precipitate was collected by filtration , washed with O₂tE , and dried to provide the title compound ( 2.68 g ) . - - - ' H NMR ( 400 MHz , CDCl3 ) г 10.27 - 10.05 ( m , 1H ) , 4.74 – 4.53 ( m , 2H ) , 3.89 – 3.47 ( m , 7H ) , 3.31 ( dd , J = 7.0 , 5.5 Hz , 1H ) , 3.23 – 2.74 ( m , 2H ) , 1.24 – 1.18 ( m , 6H ) , 0.87 ( d , J = 3.Hz , 9H ) , 0.11 – 0.04 ( m , 6H ) - 350 Synthesis of 6,7 - dihydro - 5H - pyrrolo [ 1,2 - a ] imidazol - 6 - ol Eto OEt NH HCI 1,4 - Dioxane 110 ° C .OH OTBDMS 0.625 M aq . HCI ( 8.08 mL , 5.05 mmol ) was added to a solution of 3- [ tert- butyl ( dimethyl ) silyl ] oxy - N- ( 2,2 - diethoxyethyl ) -3,4 - dihydro - 2H - pyrrol - 5 - amine ( 1.67 g , 5.mmol ) in 1,4 - dioxane ( 1.7 mL ) and the reaction was heated at 110 ° C for 2 h . The reaction mixture was cooled to room temperature and diluted with Et2O . The layers were separated , and the aqueous layer was basified with Na2CO3 and concentrated in vacuo . The residue was extracted with a 1 : 9 mixture of MeOH : DCM , and the combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The residue was dissolved in DCM and the solution was filtered through a short pad of ®etilaciD and concentrated in vacuo to provide the title compound ( 574 mg ) . ' H NMR ( 400 MHz , DMSO - d ) ō 7.05 ( d , J = 1.3 Hz , 1H ) , 6.87 ( d , J = 1.3 Hz , 1H ) , 5.51 ( s , 1H ) , 4.85 ( tt , J = 5.9 , 2.9 Hz , 1H ) , 4.12 ( dd , J = 11.3 , 5.8 Hz , 1H ) , 3.70 ( dd , J = 11.3 , 2.8 Hz , 1H ) , 3.01 ( dd , J = 16.2 , 6.5 Hz , 1H ) , 2.54 ( dd , J = 16.2 , 2.9 Hz , 1H ) Synthesis of 6 - azido - 6,7 - dihydro - 5H - pyrrolo [ 1,2 - a ] imidazole -OH DPPA , DIAD Ph3P , THF ° C to RT -N Diisopropyl azodicarboxylate ( 380 Lμ , 1.93 mmol ) was added dropwise over 10 min to a suspension of 6,7 - dihydro - 5H - pyrrolo [ 1,2 - a ] imidazol - 6 - ol ( 200 mg , 1.61 mmol ) and PзhP ( 507 mg , 1.93 mmol ) in THF ( 7.5 mL ) at 10 ° C . Diphenylphosphoryl azide ( 418 Lµ , 1.mmol ) was added dropwise over 10 min and the reaction was warmed to room temperature and stirred overnight . The reaction mixture was concentrated in vacuo , and the crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) to provide the title compound ( 226 mg ) . 351 - ' H NMR ( 400 MHz , ³lCDC ) ₫ 7.06 ( d , J = 1.4 Hz , 1H ) , 6.88 ( d , J = 1.4 Hz , 1H ) , 4.81 – 4.( m , 1H ) , 4.23 ( dd , J = 11.4 , 6.7 Hz , 1H ) , 3.91 ( dd , J = 11.4 , 3.8 Hz , 1H ) , 3.26 ( dd , J = 16.6 , 7.3 Hz , 1H ) , 2.97 ( dd , J = 16.6 , 4.0 Hz , 1H ) Synthesis of 6,7 - dihydro - 5H - pyrrolo [ 1,2 - a ] imidazol - 6 - amine ₂H ( g ) , Pd / C EtOH , RT -N3 -NH % Palladium on carbon ( 156 mg , 0.15 mmol ) was placed in a flask and the flask was purged with argon . A solution of 6 - azido - 6,7 - dihydro - 5H - pyrrolo [ 1,2 - a ] imidazole ( 219 mg , 1.47 mmol ) in EtOH ( 4 mL ) was added and the flask was evacuated and backfilled with argon ( x 3 ) , then evacuated and backfilled with hydrogen ( x 3 ) . The reaction was stirred under a hydrogen atmosphere ( balloon ) at room temperature for 1 h . The reaction mixture was filtered through a short pad of ®etilaciD , washed with EtOH , and concentrated in vacuo to provide the title compound ( 178 mg ) . ₫ ' H NMR ( 400 MHz , CDCl3 ) б 7.04 ( d , J = 1.3 Hz , 1H ) , 6.85 ( d , J = 1.3 Hz , 1H ) , 4.30 - 4.( m , 2H ) , 3.65 ( dd , J = 10.5 , 4.7 Hz , 1H ) , 3.21 ( dd , J = 16.1 , 7.3 Hz , 1H ) , 2.61 ( dd , J = 16.1 , 5.1 Hz , 1H ) . Exchangeable protons not observed .

Synthesis of compound 19 , N7- ( 6,7 - dihydro - 5H - pyrrolo [ 1,2 - a ] imidazol - 6- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ' N ' NH N7- ( 6,7 - dihydro - 5H - pyrrolo [ 1,2 - a ] imidazol - 6 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 18 mg ) was synthesised following a similar procedure to that described in General Method B. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.14 ( d , J = 7.1 Hz , 1H ) , 8.94 ( d , J = 4.4 Hz , 1H ) , 8.67 ( s , 1H ) , 7.65 ( d , J = 4.3 Hz , 1H ) , 7.60 ( s , 1H ) , 7.52 ( s , 1H ) , 7.12 ( d , J = 1.3 Hz , 1H ) , 6.92 ( d , J = - 1.3 Hz , 1H ) , 5.29 – 5.16 ( m , 1H ) , 4.41 ( dd , J = 11.2 , 7.5 Hz , 1H ) , 3.99 ( dd , J = 11.2 , 4.Hz , 1H ) , 3.27 ( dd , 1H ) , 2.86 ( dd , J = 16.3 , 4.6 Hz , 1H ) 352 LO LCMS ( Method 2 ) : 1.00 min , 312.2 [ M + H ] * Synthesis of methyl methyl 3- ( 2 - amino - 3 - pyridyl ) -2- ( tert - butoxycarbonylamino ) prop - 2- enoate NH Eto . THE -78 ° C to RT NHH Eto OMe HN OMe ﻞﻳﺓ BOC ﻞﻳ NHBOC 1,1,3,3 - Tetramethylguanidine ( 2.32 mL , 18.50 mmol ) was added to a solution of methyl 2- ( tert - butoxycarbonylamino ) -2 - dimethoxyphosphoryl - acetate ( 5 g , 16.82 mmol ) in THF ( mL ) at -78 ° C and the reaction was stirred for 15 min . A solution of 2 - aminopyridine - 3- carbaldehyde ( 2.05 g , 16.82 mmol ) in THF ( 20 mL ) was added , and the reaction was warmed to room temperature and stirred for 18 h . The reaction mixture was diluted with EtOAc and washed with water and brine . The organic layer was dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 2.43 g ) . - - ' H NMR ( 400 MHz , DMSO - d ) § 8.68 – 8.41 ( m , 1H ) , 7.93 ( dd , J = 4.8 , 1.8 Hz , 1H ) , 7.66 – 7.62 ( m , 1H ) , 7.02 ( s , 1H ) , 6.58 ( dd , J = 7.6 , 4.8 Hz , 1H ) , 6.09 ( s , 2H ) , 3.73 ( s , 3H ) , 1.40 ( s , 9H ) LCMS ( Method 1 ) : 0.68 min , 294.2 [ M + H ] * Synthesis of tert - butyl N- ( 2 - oxo - 3,4 - dihydro - 1H - 1,8 - naphthyridin - 3 - yl ) carbamate ₂HN Pd / C , ₂H ( g ) EtOH , RT OMe HN ' N ' BOC H N BOC % Pd / C ( palladium on carbon ; 689 mg , 0.65 mmol ) was added to a solution of methyl 3- ( 2 - amino - 3 - pyridyl ) -2- ( tert - butoxycarbonylamino ) prop - 2 - enoate ( 2 g , 6.48 mmol ) in EtOH ( 30 mL ) under an atmosphere of argon . A balloon of hydrogen was attached to the flask and the reaction was stirred at room temperature for 65 h . The reaction mixture was filtered 353 through a short pad of ⓇetilaciD , washed with EtOAc , and concentrated in vacuo . The crude product was purified twice by column chromatography ( eluting first with 0 to 100 % EtOAc in heptane and then with 10 % MeOH in DCM ) to provide the title compound ( 700 mg ) . - - ' H NMR ( 400 MHz , DMSO - d € ) ☎ 10.59 ( s , 1H ) , 8.14 – 8.08 ( m , 1H ) , 7.66 – 7.54 ( m , 1H ) , 7.03 ( d , J = 8.5 Hz , 1H ) , 6.96 ( dd , J = 7.4 , 5.0 Hz , 1H ) , 4.22 ( dt , J = 14.7 , 7.7 Hz , 1H ) , 3.- 2.86 ( m , 2H ) , 1.41 ( s , 9H ) LCMS ( Method 1 ) : 0.98 min , 264.2 [ M + H ] + Synthesis of 3 - amino - 3,4 - dihydro - 1H - 1,8 - naphthyridin - 2 - one hydrochloride N BOC HCI , DCM RT NH2.HCI ' N ' HCI ( 4 M in 1,4 - dioxane ; 3.32 mL , 13.29 mmol ) was added to a solution of tert - butyl N- ( 2- oxo - 3,4 - dihydro - 1H - 1,8 - naphthyridin - 3 - yl ) carbamate ( 700 mg , 2.66 mmol ) in DCM ( 5 mL ) and the reaction was stirred at room temperature for 1 h then concentrated in vacuo . The residue was diluted with Et2O and the resulting precipitate was collected by filtration , washed with Et2O , and dried to provide the title compound ( 530 mg ) . - ' H NMR ( 400 MHz , DMSO - ɓd ) § 11.14 ( s , 1H ) , 8.66 ( d , J = 5.7 Hz , 3H ) , 8.22 – 8.15 ( m , 1H ) , 7.73 ( dt , J = 7.6 , 1.4 Hz , 1H ) , 7.05 ( dd , J = 7.4 , 5.0 Hz , 1H ) , 4.32 ( dt , J = 14.4 , 6.2 Hz , 1H ) , 3.25 ( dd , J = 15.4 , 6.8 Hz , 1H ) , 3.16 – 3.01 ( m , 1H ) Synthesis of 1,2,3,4 - tetrahydro - 1,8 - naphthyridin - 3 - amine dihydrochloride NH2.HCI LiAlH , THE ° C ' N ' H HCI NH2.HCI LiAlH4 ( 2.4 M in THF ; 7 mL , 16.80 mmol ) was added dropwise to a suspension of 3 - amino- 3,4 - dihydro - 1H - 1,8 - naphthyridin - 2 - one hydrochloride ( 530 mg , 2.65 mmol ) in THF ( 10 mL ) and the reaction was heated at 60 ° C for 3 h . The reaction mixture was cooled to room temperature and then to 0 ° C and quenched with water ( 500 Lµ ) , 2 M aq . NaOH ( 500 Lµ ) and water ( 1.5 mL ) . The mixture was warmed to room temperature , MgSO4 was added , and the suspension was stirred rapidly for 30 min . The solids were removed by filtration and the 354 filtrate was concentrated in vacuo . The crude product was purified by SCX chromatography ( eluting with 2 M NH3 in MeOH ) . The basic fractions were concentrated in vacuo , and the residue was dissolved in DCM and treated with HCI ( 4 M in 1,4 - dioxane ) . The resulting precipitate was collected by filtration , washed with Et2O , and dried to provide the title compound ( 99 mg ) .

- ' H NMR ( 400 MHz , DMSO - d6 ) ō 8.25 ( s , 3H ) , 7.85 ( dd , J = 5.0 , 1.8 Hz , 1H ) , 7.32 ( dd , J = 7.2 , 1.7 Hz , 1H ) , 6.72 ( s , 1H ) , 6.55 ( dd , J = 7.2 , 5.0 Hz , 1H ) , 3.60 ( s , 1H ) , 3.52 – 3.44 ( m , 1H ) , 3.30 -3.26 ( m , 1H ) , 3.05 ( dd , J = 16.6 , 4.9 Hz , 1H ) , 2.80 ( dd , J = 16.6 , 6.6 Hz , 1H ) . Additional exchangeable proton not observed .

Synthesis of compound 20 , N7- ( 1,2,3,4 - tetrahydro - 1,8 - naphthyridin - 3 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ' N ' NH N7- ( 1,2,3,4 - tetrahydro - 1,8 - naphthyridin - 3 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 5 mg ) was synthesised following a similar procedure to that described in General Method B. ☎ ' H NMR ( 400 MHz , DMSO - d6 ) г 9.96 ( d , J = 7.1 Hz , 1H ) , 8.94 ( d , J = 4.3 Hz , 1H ) , 8.55 ( s , 1H ) , 7.83 ( dd , J = 5.0 , 1.8 Hz , 1H ) , 7.72 ( d , J = 4.3 Hz , 1H ) , 7.60 ( s , 1H ) , 7.53 ( s , 1H ) , 7.- 7.23 ( m , 1H ) , 6.57 ( d , J = 2.7 Hz , 1H ) , 6.50 ( dd , J = 7.2 , 4.9 Hz , 1H ) , 4.44 ( s , 1H ) , 3.54 ( d , - J = 11.9 Hz , 1H ) , 3.38 – 3.34 ( m , 1H ) , 3.09 ( dd , J = 16.1 , 4.6 Hz , 1H ) , 2.88 ( dd , J = 16.2 , 6.Hz , 1H ) LCMS ( Method 2 ) : 1.20 min , 338.2 [ M + H ] + Synthesis of compound 96 , N7- [ 2- ( 3 - methylphenoxy ) butyl ] pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ﻊﻧﺪﻫ N NHN 355 LO N7- [ 2- ( 3 - methylphenoxy ) butyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide synthesised following a similar procedure to that described in General Method B. - was ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.08 ( t , J = 5.8 Hz , 1H ) , 8.94 ( d , J = 4.3 Hz , 1H ) , 8.67 ( s , 1H ) , 7.70 ( d , J = 4.3 Hz , 1H ) , 7.61 ( s , 1H ) , 7.54 ( s , 1H ) , 7.14 ( t , J = 7.7 Hz , 1H ) , 6.89 - 6.- - - ( m , 2H ) , 6.75 – 6.68 ( m , 1H ) , 4.56 – 4.46 ( m , 1H ) , 3.78 – 3.62 ( m , 2H ) , 2.24 ( s , 3H ) , 1.77 - 1.63 ( m , 2H ) , 0.97 ( t , J = 7.4 Hz , 3H ) LCMS ( Method 7 ) : 2.64 min , 368.2 [ M + H ] * Synthesis of compound 97 , N7- [ 2 - methyl - 5- ( pyridin - 4 - yl ) phenyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide H .N . N = NH N7- [ 2 - methyl - 5- ( pyridin - 4 - yl ) phenyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide synthesised following a similar procedure to that described in General Method B. LCMS ( Method 7 ) : 1.64 min , 373.2 [ M + H ] + Synthesis of compound 98 , was N7- [ 1- ( 5 - methoxy - 1H - 1,3 - benzodiazol - 2- yl ) ethyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide HN N H NH.N . ' N ' N = N7- [ 1- ( 5 - methoxy - 1H - 1,3 - benzodiazol - 2 - yl ) ethyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide was synthesised following a similar procedure to that described in General Method B. LCMS ( Method 7 ) : 1.45 min , 380.2 [ M + H ] + Synthesis of compound 99 , N7- [ 1- ( 4 - tert - butylphenoxy ) propan - 2 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 356 to ₂HN N7- [ 1- ( 4 - tert - butylphenoxy ) propan - 2 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide synthesised following a similar procedure to that described in General Method B. LCMS ( Method 7 ) : 2.95 min , 396.2 [ M + H ] + was Synthesis of compound 100 , N7- ( 3,3,3 - trifluoropropyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide NH N7- ( 3,3,3 - trifluoropropyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide following a similar procedure to that described in General Method B. LCMS ( Method 7 ) : 1.91 min , 302.2 [ M + H ] + was synthesised Synthesis of compound 101 , N7 - [ ( 4,4 - difluorocyclohexyl ) methyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide NH N7 - [ ( 4,4 - difluorocyclohexyl ) methyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide was synthesised following a similar procedure to that described in General Method B. LCMS ( Method 7 ) : 2.21 min , 338.2 [ M + H ] * Synthesis of compound 102 , N7- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ₂HN 357 LO N7- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 106 mg ) was synthesised following a similar procedure to that described in General Method B. 1H NMR ( 400 MHz , MeOD ) 5 8.95 ( d , J = 4.3 Hz , 1H ) , 8.74 ( s , 1H ) , 7.86 ( d , J = 4.4 Hz , 1H ) , 4.40 ( m , 1H ) , 3.20 - 3.01 ( m , 2H ) , 2.91 – 2.76 ( m , 2H ) . Exchangeable protons not 4.observed . LCMS ( Method 2 ) : 1.74 min , 296.2 [ M + H ] + Synthesis of compound 103 , N7- ( 4,4 - difluorocyclohexyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide F D ₂HN N7- ( 4,4 - difluorocyclohexyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide was synthesised following a similar procedure to that described in General Method b . LCMS ( Method 7 ) : 2.09 min , 324.2 [ M + H ] * Synthesis of ethyl 2 - carbamoylpyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate N₂H HN- N Eto NHEIO DEt EtOH , 75 ° C EtO .

N₂H Ethyl ( E ) -4 - ethoxy - 2 - oxo - but - 3 - enoate ( 1.365 g , 7.93 mmol ) and 5 - amino - 1H - pyrazole - 3- carboxamide ( 1 g , 7.93 mmol ) were dissolved in EtOH ( 9.5 mL ) and the reaction was heated at 75 ° C for 2 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . MeOH was added to the residue , and the resulting precipitate was collected by filtration , washed with MeOH , and dried to provide the title compound ( 1.14 g ) . 1H NMR ( 400 MHz , DMSO - d € ) § 8.75 ( d , J = 4.1 Hz , 1H ) , 7.75 ( s , 1H ) , 7.70 ( s , 1H ) , 7.56 ( d , J = 4.1 Hz , 1H ) , 7.24 ( s , 1H ) , 4.50 ( q , J = 7.1 Hz , 2H ) , 1.39 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 2 ) : 1.52 min , 235.2 [ M + H ] * 358 Synthesis of ethyl 2 - cyanopyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate EtO T3P , N₂tE DMF , 60 ° C EtO ' N ' N₂H CN 1 - Propanephosphonic anhydride ( 50 wt % in DMF ; 12.2 mL , 20.49 mmol ) and NзtE ( 2.86 mL , 20.49 mmol ) were added to a solution of ethyl 2 - carbamoylpyrazolo [ 1,5 - a ] pyrimidine - 7- carboxylate ( 600 mg , 2.56 mmol ) in DMF ( 15 mL ) and the reaction was heated at 60 ° C for h . The reaction mixture was cooled to room temperature and diluted with water . The layers were separated , and the aqueous layer was extracted with DCM ( x 3 ) . The combined organic layers were concentrated in vacuo and the residue was dissolved in EtOAc . The solution was washed with sat . aq . LICI ( x 3 ) , dried through a hydrophobic frit , and concentrated in vacuo to provide the title compound ( 611 mg ) . The crude product was taken forward to the next step without purification . § ' H NMR ( 400 MHz , DMSO - d6 ) ō 8.90 ( d , J = 4.2 Hz , 1H ) , 7.76 ( d , J = 4.2 Hz , 1H ) , 7.74 ( s , 1H ) , 4.50 ( q , J = 7.1 Hz , 2H ) , 1.38 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 2 ) : 1.95 min , 217.2 [ M + H ] + Synthesis of ethyl 3 - bromo - 2 - cyano - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate EtO CN NBS , MeCN ° C EtO . N .Br ﻡﺮﻴﻜﻳﺓ CN NBS ( 553 mg , 3.11 mmol ) was added to a solution of ethyl 2 - cyanopyrazolo [ 1,5- a ] pyrimidine - 7 - carboxylate ( 611 mg , 2.83 mmol ) in MeCN ( 40 mL ) and the reaction was heated at 70 ° C for 24 h . The reaction mixture was cooled to room temperature , diluted with DCM , and washed with sat . aq . NaHCO3 ( × 3 ) . The organic layer was dried through a hydrophobic frit and concentrated in vacuo to provide the title compound ( 704 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) § 8.96 ( d , J = 4.2 Hz , 1H ) , 7.85 ( d , J = 4.2 Hz , 1H ) , 4.49 ( q , J. = 7.1 Hz , 2H ) , 1.38 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 2 ) : 2.25 min , 295.0 , 297.0 [ M + H ] * 359 Synthesis of 3 - bromo - 2 - cyano - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid Eto . Br O₂H.HOiL THF , O₂H RT HO .Br N : CN CN A solution of O₂H.HOiL ( 110 mg , 2.62 mmol ) in water ( 6 mL ) was added to a solution of ethyl - bromo - 2 - cyano - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 704 mg , 2.39 mmol ) in THF ( mL ) and the reaction was stirred at room temperature for 18 h . The reaction mixture was acidified to pH 2 with 1 M aq . HCI and extracted with EtOAc ( x 3 ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo to provide the title compound ( 525 mg ) . 1H NMR ( 400 MHz , DMSO - d € ) ō 8.93 ( d , J = 4.2 Hz , 1H ) , 7.75 ( d , J = 4.2 Hz , 1H ) . Exchangeable proton not observed . LCMS ( Method 2 ) : 1.40 min ( product does not ionise ) Synthesis of 3 - bromo - 2 - cyano - N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide N HO ' N ' .Br T3P , N₂tE DMF , RT ' N * .Br -NH2.HCI + N = N = CN CN 1 - Propanephosphonic anhydride ( 50 wt % in DMF ; 2.3 mL , 3.93 mmol ) and NзtE ( 1.37 mL , 9.83 mmol ) were added to a solution of 3 - bromo - 2 - cyano - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxylic acid ( 525 mg , 1.97 mmol ) and indan - 2 - amine hydrochloride ( 500 mg , 2.95 mmol ) in DMF ( 9.83 mL ) and the reaction was stirred at room temperature for 48 h . Additional portions of indan - 2 - amine hydrochloride ( 166 mg , 0.98 mmol ) , 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 0.72 mL , 1.23 mmol ) , and NзtE ( 0.46 mL , 3.30 mmol ) were added and the reaction mixture was stirred at room temperature for a further 4 h . The reaction mixture was diluted with water , and the resulting precipitate was collected by filtration , washed with water , and dried to provide the title compound ( 549 mg ) .

- ' H NMR ( 400 MHz , DMSO - d ) ☎ 9.46 ( d , J = 7.2 Hz , 1H ) , 8.94 ( d , J = 4.2 Hz , 1H ) , 7.68 ( d , J = 4.2 Hz , 1H ) , 7.30 – 7.25 ( m , 2H ) , 7.20 – 7.15 ( m , 2H ) , 4.77 ( d , J = 7.3 Hz , 1H ) , 3.40 – 3.( m , 2H ) , 2.97 ( dd , J = 16.1 , 5.3 Hz , 2H ) - - 360 LCMS ( Method 2 ) : 2.60 min , 382.0 , 384.0 [ M + H ] * Synthesis of ( 2,5 - dioxopyrrolidin - 1 - yl ) formate formic acid acetic anhydride OH ° C to RT H Acetic anhydride ( 72 mL , 764.62 mmol ) was added slowly over 10 min to formic acid ( mL , 955.77 mmol ) at 0 ° C . The reaction mixture was warmed to room temperature and stirred for 1.5 h . 1 - Hydroxypyrrolidine - 2,5 - dione ( 11 g , 95.58 mmol ) was added , and the reaction was stirred at room temperature overnight then concentrated in vacuo . The residue was suspended in heptane , collected by filtration , and dried to provide the title compound ( 13.g ) . ' H NMR ( 400 MHz , DMSO - d6 ) ō 8.78 ( s , 1H ) , 2.82 ( s , 4H ) Synthesis of compound 21 , 2 - cyano - N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ' N ' -Br 1 ) XantPhos Pd GN₂tE , NMP , 90 ° C ) HO₂HN , T3P N₂tE , DMF , RT CN ' N ' CN NH 3 - Bromo - 2 - cyano - N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 130 mg , 0.mmol ) and XantPhos Pd G3 ( [ ( 4,5 - bis ( diphenylphosphino ) -9,9 - dimethylxanthene ) -2- ( 2'- amino - 1,1 ' - biphenyl ) ] palladium ( II ) methanesulfonate ; 32.26 mg , 0.03 mmol ) were placed in a vial , which was then sealed and purged with argon for 5 min . NMP ( 3.4 mL ) and NзtE ( 1Lμ , 1.02 mmol ) were added and the mixture was degassed by sparging with a stream of 361 LO argon for 5 min . ( 2,5 - Dioxopyrrolidin - 1 - yl ) formate ( 243 mg , 1.70 mmol ) was added and the vial was sealed immediately . The reaction was heated at 90 ° C in a microwave reactor for h then cooled to room temperature . NзtE ( 140 Lμ , 1.02 mmol ) , 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 400 Lµ , 0.68 mmol ) , and NH4OH ( 240 Lµ , 3.40 mmol ) were added and the reaction was stirred at room temperature for 18 h . The reaction mixture was diluted with EtOAc and water and the layers were separated . The aqueous layer was extracted with EtOAc , and the combined organic layers were washed with sat . aq . LiCl , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by preparative HPLC ( acidic and basic methods ) to provide the title compound ( 34 mg ) .

- - ' H NMR ( 400 MHz , DMSO - d6 ) ō 9.49 ( d , J = 7.2 Hz , 1H ) , 9.06 ( d , J = 4.3 Hz , 1H ) , 8.00 ( s , 1H ) , 7.75 ( d , J = 4.3 Hz , 1H ) , 7.57 ( s , 1H ) , 7.31 – 7.25 ( m , 2H ) , 7.21 – 7.15 ( m , 2H ) , 4.84 – 4.74 ( m , 1H ) , 3.36 ( dd , J = 16.1 , 7.5 Hz , 2H ) , 2.98 ( dd , J = 16.1 , 5.3 Hz , 2H ) LCMS ( Method 4 ) 2.08 min , 347.2 [ M + H ] + Synthesis of ethyl 2 - bromopyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate OEt Eto NHEtOH , 78 ° C EtO HN Na Br Br 3 - Bromo - 1H - pyrazol - 5 - amine ( 10 g , 61.73 mmol ) and ethyl ( E ) -4 - ethoxy - 2 - oxo - but - 3 - enoate ( 15.94 g , 92.60 mmol ) were dissolved in EtOH ( 250 mL ) and the reaction was stirred at room temperature for 2 h then heated at 78 ° C overnight . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 20 % EtOAc in heptane ) to provide the title compound ( 11.82 g ) . ' H NMR ( 400 MHz , CDCl3 ) Ŏ 8.55 ( d , J = 4.2 Hz , 1H ) , 7.27 ( d , J = 4.2 Hz , 1H ) , 6.86 ( s , 1H ) , 4.54 ( q , J = 7.1 Hz , 2H ) , 1.44 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 1 ) : 1.61 min , 270.2 , 272.2 [ M + H ] * Synthesis of 2 - bromopyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid 362 O₂H.HOiL N THF , O₂H RT N EtO . HO Br Br Ethyl 2 - bromopyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 4 g , 14.81 mmol ) and LiOH.H2O ( 6mg , 14.81 mmol ) were dissolved in a mixture of THF ( 10 mL ) , and water ( 2.5 mL ) and the reaction was stirred at room temperature overnight . The reaction mixture was diluted with EtOAc and water and the layers were separated . The aqueous layer was acidified to pH with 1 M aq . HCI and extracted with EtOAc ( x 3 ) . The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 3.5 g ) . 1H NMR ( 400 MHz , DMSO - d ) ☎ 8.70 ( d , J = 4.2 Hz , 1H ) , 7.42 ( d , J = 4.2 Hz , 1H ) , 7.10 ( s , 1H ) . Exchangeable proton not observed .

Synthesis of 2 - bromo - N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide HO N : Br -NH2.HCI T3P , N₂tE DMF , RT Br 1 - Propanephosphonic anhydride ( 50 wt % in EtOAc ; 7.3 mL , 12.40 mmol ) was added to a solution of 2 - bromopyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 2 g , 8.26 mmol ) , indan - 2- amine hydrochloride ( 1.68 g , 9.92 mmol ) , and NзtE ( 3.46 mL , 24.79 mmol ) in DMF ( 25 mL ) and the reaction was stirred at room temperature overnight . The reaction mixture was diluted with water , and the resulting precipitate was collected by filtration and washed with water and heptane to provide the title compound ( 2.21 g ) . 1H NMR ( 400 MHz , DMSO - d6 ) 8 9.72 ( d , J = 7.1 Hz , 1H ) , 8.71 ( d , J = 4.3 Hz , 1H ) , 7.43 ( d , J = = 4.3 Hz , 1H ) , 7.28 ( dt , J = 7.3 , 3.7 Hz , 2H ) , 7.18 ( dd , J = 5.6 , 3.2 Hz , 2H ) , 7.11 ( s , 1H ) , 4.– 4.82 ( m , 1H ) , 3.37 ( dd , J = 16.2 , 7.6 Hz , 2H ) , 2.96 ( dd , J = 16.1 , 5.3 Hz , 2H ) - 363 Synthesis of N - indan - 2 - yl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide N cosa Br ₂nip₂B Pd ( dppf ) ₂lC , KOAC 1,4 - Dioxane , 100 ° C ﻡا 2 - Bromo - N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 500 mg , 1.40 mmol ) , 2nip₂B ( 427 mg , 1.68 mmol ) and KOAc ( 412 mg , 4.20 mmol ) were dissolved in 1,4 - dioxane ( 20 mL ) and the solution was degassed by sparging with a stream of argon . Pd ( dppf ) Cl2 ( 1mg , 0.14 mmol ) was added and the solution was degassed with argon for a further 10 min . The reaction was heated at 100 ° C for 16 h , then cooled to room temperature and diluted with EtOAc and water . The reaction mixture was filtered through a short pad of of ®etilaciD and washed with EtOAc . The layers were separated , and the organic layer was washed with brine , dried over Na2CO3 , and concentrated in vacuo to provide the title compound ( 1 g ) . The crude product was taken forward to the next step without further purification . LCMS ( Method 1 ) : 1.52 min , 323.2 [ M + H ] + ( boronic acid ) Synthesis of N - indan - 2 - yl - 2 - pyridazin - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide 00N = Bpin Br N - N Pd ( dppf ) ₂lC , Na2CO1,4 - Dioxane , O₂H , 100 ° C N = 3 - Bromopyridazine ( 288 mg , 1.81 mmol ) , Na2CO3 ( 393 mg , 3.71 mmol ) and water ( 2.7 mL ) were added to a solution of N - indan - 2 - yl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 500 mg , 1.24 mmol ) in 1,4 - dioxane ( 25 mL ) . The solution was degassed by sparging with a stream of argon for 10 min . Pd ( dppf ) Cl2 ( mg , 0.12 mmol ) was added and the solution was degassed with argon for a further 10 min . The reaction was heated at 100 ° C for 18 h then cooled to room temperature . The reaction mixture was diluted with EtOAc , filtered through a short pad of ®etilaciD , and washed with 3 Bpin EtOAc . The combined filtrate and washings were washed with water and brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 20 to 100 % EtOAc in heptane ) to provide the title compound ( 162 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) ☎ 10.29 ( d , J = 7.8 Hz , 1H ) , 9.29 ( dd , J = 4.9 , 1.7 Hz , 1H ) , 8.79 ( d , J = 4.2 Hz , 1H ) , 7.81 ( dd , J = 8.5 , 4.9 Hz , 1H ) , 7.67 - 7.63 ( m , 2H ) , 7.58 ( s , 1H ) , 7.36 ( dd , J = 5.4 , 3.3 Hz , 2H ) , 7.30 – 7.22 ( m , 2H ) , 4.94 – 4.82 ( m , 1H ) , 3.37 ( dd , J = 16.1 , 6.7 Hz , 2H ) , 3.05 ( dd , J = 16.0 , 3.7 Hz , 2H ) - LCMS ( Method 5 ) : 0.97 min , 357.2 [ M + H ] + Synthesis carboxamide of - 3 - bromo - N - indan - 2 - yl - 2 - pyridazin - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- cosa ' N ' NBS , THF RT ' N ' -Br N = N = NBS ( 25 mg , 0.14 mmol ) was added to a solution of N - indan - 2 - yl - 2 - pyridazin - 3 - yl- pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 50 mg , 0.14 mmol ) in THF ( 1.5 mL ) and the reaction was stirred at room temperature for 4 h . An additional portion of NBS ( 10 mg , 0.mmol ) was added and the reaction was stirred at room temperature for a further 1 h . The reaction mixture was diluted with EtOAc and washed with sat . aq . NaHCO3 . The aqueous layer was extracted with EtOAc ( x 2 ) , and the combined organic layers were washed with sat . aq . NaHCO3 , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 20 to 100 % EtOAc in heptane ) to provide the title compound ( 44 mg ) .

= ' H NMR ( 400 MHz , DMSO - d6 ) § 9.96 ( d , J = 7.6 Hz , 1H ) , 9.35 ( dd , J = 5.0 , 1.7 Hz , 1H ) , 8.( d , J = 4.2 Hz , 1H ) , 7.87 ( dd , J = 8.6 , 5.0 Hz , 1H ) , 7.78 ( dd , J = 8.6 , 1.7 Hz , 1H ) , 7.70 ( d , J = 4.2 Hz , 1H ) , 7.36 - 7.29 ( m , 2H ) , 7.28 - 7.20 ( m , 2H ) , 4.90 - 4.81 ( m , 1H ) , 3.36 ( dd , J = 16.2 , 6.9 Hz , 2H ) , 3.02 ( dd , J = 16.0 , 4.0 Hz , 2H ) LCMS ( Method 5 ) : 1.04 min , 435.0 , 437.0 [ M + H ] * Synthesis of compound 22 , N7 - indan - 2 - yl - 2 - pyridazin - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 365 ' N ' .Br H 1. XantPhos Pd GN₂tE , NMP , 100 ° C 2. NH OH , T3P , N₂tE DMF , RT NHcosqu N 3 - Bromo - N - indan - 2 - yl - 2 - pyridazin - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 50 mg , 0.11 mmol ) and NзtE ( 48 Lμ , 0.34 mmol ) were dissolved in NMP ( 1 mL ) and the solution was degassed by sparging with a stream of argon for 5 min . XantPhos Pd G3 ( 11 mg , 0.01 mmol ) was added , and the solution was degassed with argon for a further 5 min . ( 2,5- Dioxopyrrolidin - 1 - yl ) formate ( 82 mg , 0.57 mmol ) was added and the vial was sealed immediately . The reaction was heated at 100 ° C in a microwave reactor for 2 h then cooled to room temperature . NзtE ( 48 Lμ , 0.34 mmol ) , 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 137 Lμ , 0.23 mmol ) , and NH4OH ( 243 Lµ , 1.15 mmol ) were added sequentially and the reaction was stirred at room temperature for 2 h . The reaction mixture was diluted with EtOAc , filtered through a short pad of ®etilaciD , and washed with EtOAc and water . The layers were separated , and the organic layer was washed with brine , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by preparative HPLC ( acidic method ) to provide the title compound ( 19 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) u0000 10.00 ( d , J = 7.2 Hz , 1H ) , 9.32 ( dd , J = 5.0 , 1.7 Hz , 1H ) , 8.96 ( d , J = 4.3 Hz , 1H ) , 7.91 ( dd , J = 8.5 , 1.7 Hz , 1H ) , 7.85 ( s , 1H ) , 7.83 ( dd , J = 8.5 , 5.Hz , 1H ) , 7.70 ( d , J = 4.3 Hz , 1H ) , 7.61 ( s , 1H ) , 7.30 – 7.22 ( m , 2H ) , 7.21 – 7.12 ( m , 2H ) , 4.- 4.73 ( m , 1H ) , 3.41 - 3.33 ( m , 2H ) , 2.96 ( dd , J = 16.0 , 5.0 Hz , 2H ) LCMS ( Method 4 ) : 1.70 min , 400.0 [ M + H ] * Synthesis of - - 2- [ 2- ( dimethylamino ) ethylamino ] -N - indan - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide 366 H ` N ' N = Br -N₂H O₂uC Ethylene Glycol 140 ° C .N . N N- H 2 - Bromo - N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 200 mg , 0.56 mmol ) , O₂uC ( 8 mg , 0.06 mmol ) and N ' , N ' - dimethylethane - 1,2 - diamine ( 1.89 mL , 16.80 mmol ) were suspended in ethylene glycol ( 2.2 mL ) and the reaction was heated at 140 ° C in a microwave reactor for 5 h . The reaction mixture was cooled to room temperature and diluted with water and EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( x ) . The combined organic layers were dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 30 % MeOH in DCM ) , and the resulting material was dissolved in DCM and washed with sat . aq . NaHCO3 . The organic layer was dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 76 mg ) . == ' H NMR ( 400 MHz , ³lCDC ) ₫ 11.02 ( d , J = 7.9 Hz , 1H ) , 8.39 ( d , J = 4.5 Hz , 1H ) , 7.47 ( d , J 4.5 Hz , 1H ) , 7.30 – 7.16 ( m , 4H ) , 5.89 ( s , 1H ) , 5.08 – 4.96 ( m , 1H ) , 4.85 ( t , J = 5.1 Hz , 1H ) , 3.44 ( dd , J = 16.1 , 6.8 Hz , 2H ) , 3.02 ( dd , J = 16.0 , 4.0 Hz , 2H ) , 2.97 – 2.92 ( m , 2H ) , 2.50 – 2.41 ( m , 2H ) , 2.24 ( s , 6H ) LCMS ( Method 1 ) : 1.25 min , 365.2 [ M + H ] * - Synthesis of 3 - bromo - 2- [ 2- ( dimethylamino ) ethylamino ] -N - indan - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide ' N ' NBS THF , RT ' N ' Br N = NBS ( 40 mg , 0.23 mmol ) was added to a solution of 2- [ 2- ( dimethylamino ) ethylamino ] -N- indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 75 mg , 0.21 mmol ) in THF ( 4 mL ) and the reaction was stirred at room temperature for 1.5 h . The reaction mixture was diluted with 367 LO DCM and washed with water . The aqueous layer was extracted with DCM , and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 94 mg ) . ' H NMR ( 400 MHz , CDCl3 ) ₫ 10.81 ( s , 1H ) , 8.49 ( d , J = 4.4 Hz , 1H ) , 7.52 ( d , J = 4.4 Hz , 1H ) , 7.29 ( dd , J = 5.4 , 3.3 Hz , 2H ) , 7.22 – 7.20 ( m , 2H ) , 5.06 - 5.01 ( m , 1H ) , 3.46 – 3.40 ( m , 2H ) , 3.00 ( dd , J = 16.1 , 3.1 Hz , 2H ) , 2.91 ( s , 2H ) , 2.47 ( t , J = 5.7 Hz , 2H ) , 1.25 ( s , 6H ) . Exchangeable proton not observed . LCMS ( short acidic ) : 1.30 min , 443.2 , 445.2 [ M + H ] * Synthesis of compound 23 , 2- [ 2- ( dimethylamino ) ethylamino ] -N7 - indan - 2 - yl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide cos H ' N ' .Br 1. XantPhos Pd GN₂tE , NMP , 90 ° C 2. T3P , NH OH , RT ' N ' NHN H 3 - Bromo - 2- [ 2- ( dimethylamino ) ethylamino ] -N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide ( 91 mg , 0.21 mmol ) and XantPhos Pd G3 ( 10 mg , 0.01 mmol ) were placed in a vial and the vial was sealed and purged with argon for 5 min . NMP ( 2 mL ) and N³tE ( Lμ , 0.62 mmol ) were added and the solution was degassed by sparging with a stream of argon for 5 min . ( 2,5 - Dioxopyrrolidin - 1 - yl ) formate ( 147 mg , 1.03 mmol ) was added and the vial was sealed immediately . The reaction was heated at 90 ° C in a microwave reactor for h . Additional portions of XantPhos Pd G3 ( 10 mg , 0.01 mmol ) and NзtE ( 86 Lμ , 0.62 mmol ) were added and the mixture was purged with argon for 5 min . An additional portion of ( 2,5- dioxopyrrolidin - 1 - yl ) formate ( 147 mg , 1.03 mmol ) was added and the vial was sealed immediately . The reaction was heated at 90 ° C in a microwave reactor for a further 3 h . The reaction mixture was cooled to room temperature , and NH4OH ( 82 Lµ , 2.05 mmol ) and 1- propanephosphonic anhydride ( 50 wt % in EtOAc ; 240 Lμ , 0.41 mmol ) were added . The reaction was stirred at room temperature for 3 h , then quenched with water and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were washed with brine , dried through a hydrophobic frit , and 368 LO concentrated in vacuo . The crude product was purified by preparative HPLC ( acidic and basic methods ) to provide the title compound ( 12 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.56 ( d , J = 7.6 Hz , 1H ) , 8.64 ( d , J = 4.6 Hz , 1H ) , 7.50 ( d , J = 4.6 Hz , 1H ) , 7.39 - 7.27 ( m , 4H ) , 7.25 -7.16 ( m , 2H ) , 7.03 ( t , J = 5.4 Hz , 1H ) , 4.88 - 4.77 ( m , 1H ) , 3.37 ( dd , J = 16.2 , 6.6 Hz , 2H ) , 3.04 - 2.92 ( m , 4H ) , 2.40 ( t , J = 6.0 Hz , 2H ) , 2.16 ( s , 6H ) LCMS ( Method 2 ) : 1.64 min , 408.2 [ M + H ] + Synthesis of ethyl 2- ( 1 - tert - butoxycarbonylazetidin - 3 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxylate EtO N : BOC Br 1. Zn , THF , 40 ° C 2. Pd ( dppf ) ₂lC ' LiCl , Cul DMA , THF ° C Eto . N = BOC A solution of tert - butyl 3 - iodoazetidine - 1 - carboxylate ( 1.5 g , 5.30 mmol ) in THF ( 8 mL ) was pumped through a column packed with 12 g of zinc granules ( flow reactor , 0.5 mL / min , zinc previously activated with TMSCI and dibromoethane ) at 40 ° C . The resulting solution was collected to provide 10 mL of ( 1 - tert - butoxycarbonylazetidin - 3 - yl ) -iodo - zinc ( ~ 0.26 M in THF ) . Ethyl 2 - bromopyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 500 mg , 1.85 mmol ) , Pd ( dppf ) Cl2 ( 135 mg , 0.19 mmol ) , Cul ( 71 mg , 0.37 mmol ) , and LiCI ( 118 mg , 2.78 mmol ) were placed in a vial and the vial was purged with argon for 15 min . DMA ( 7 mL ) was added , followed by a solution of ( 1 - tert - butoxycarbonylazetidin - 3 - yl ) -iodo - zinc ( ~ 0.26 M in THF ; 7.mL , 1.85 mmol ) , and the reaction was heated at 80 ° C for 4 h . The reaction mixture was cooled to room temperature , diluted with EtOAc , and washed with sat . aq . NaHCO 3. The aqueous layer was extracted with EtOAc , and the combined organic layers were washed with brine ( x 6 ) , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 167 mg ) .

- - ' H NMR ( 400 MHz , CDCl3 ) ō 8.54 ( d , J = 4.2 Hz , 1H ) , 7.27 ( s , 1H ) , 6.84 ( s , 1H ) , 4.56 ( q , J = 7.2 Hz , 2H ) , 4.39 ( t , J = 8.5 Hz , 2H ) , 4.20 – 4.02 ( m , 3H ) , 1.49 – 1.44 ( m , 3H ) , 1.47 ( s , 9H ) LCMS ( Method 1 ) : 1.72 min , 247.2 [ M - Boc + H ] + 369 Synthesis of carboxylic acid 2- ( 1 - tert - butoxycarbonylazetidin - 3 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- Eto . ` N ' NaOH MeOH , RT HO . N = BOC BOC NaOH ( 20 mg , 0.51 mmol ) was added to a solution of ethyl 2- ( 1 - tert - butoxycarbonylazetidin- - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 167 mg , 0.46 mmol ) in MeOH ( 2 mL ) and the reaction was stirred at room temperature for 4 h . The reaction mixture was acidified with M aq . HCI and diluted with EtOAc and water . The layers were separated , and the aqueous layer was extracted with EtOAc . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo to provide the title compound ( 133 mg ) . 1H NMR ( 400 MHz , ³lCDC ) 5 8.75 ( d , J = 4.2 Hz , 1H ) , 7.75 ( d , J = 4.2 Hz , 1H ) , 6.89 ( s , 1H ) , 4.44 ( t , J = 8.7 Hz , 2H ) , 4.22 - 4.07 ( m , 2H ) , 4.07 – 4.00 ( m , 1H ) , 1.48 ( s , 9H ) . Exchangeable proton not observed . LCMS ( Method 1 ) : 1.57 min , 263.2 [ M - t - Bu + H ] + Synthesis of tert - butyl yl ] azetidine - 1 - carboxylate HO .

BOC 3- [ 7- ( indan - 2 - ylcarbamoyl ) pyrazolo [ 1,5 - a ] pyrimidin - 2- -NH2.HCI T3P , DIPEA DMF , RT N = BOC 1 - Propanephosphonic anhydride ( 50 wt % in EtOAc ; 360 Lµ , 0.60 mmol ) was added to a solution of 2- ( 1 - tert - butoxycarbonylazetidin - 3 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 133 mg , 0.40 mmol ) , indan - 2 - amine hydrochloride ( 82 mg , 0.48 mmol ) , and DIPEA ( 210 Lμ , 1.20 mmol ) in DMF ( 2 mL ) and the reaction was stirred at room temperature for 19 h . The 370 reaction mixture was diluted with EtOAc and washed with sat . aq . NaHCO3 . The aqueous layer was extracted with EtOAc , and the combined organic layers were washed with brine ( x 4 ) , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 119 mg ) . 1H NMR ( 400 MHz , ³lCDC ) ₫ 10.83 ( d , J = 7.1 Hz , 1H ) , 8.64 ( d , J = 4.3 Hz , 1H ) , 7.78 ( d , J = 4.3 Hz , 1H ) , 7.30 ( dd , J = 5.4 , 3.3 Hz , 2H ) , 7.24 - 7.20 ( m , 2H ) , 6.72 ( d , J = 0.5 Hz , 1H ) , - - 5.02 – 4.90 ( m , 1H ) , 4.31 ( t , J = 8.7 Hz , 2H ) , 4.04 ( dd , J = 8.5 , 6.0 Hz , 2H ) , 3.95 – 3.83 ( m , 1H ) , 3.47 ( dd , J = 16.0 , 6.9 Hz , 2H ) , 3.06 ( dd , J = 15.9 , 4.8 Hz , 2H ) , 1.47 ( s , 9H ) LCMS ( Method 1 ) : 1.94 min , 378.2 [ M − t - Bu + H ] * Synthesis of tert - butyl 3- [ 3 - bromo - 7- ( indan - 2 - ylcarbamoyl ) pyrazolo [ 1,5 - a ] pyrimidin - 2- yl ] azetidine - 1 - carboxylate N.

N BOC H NBS DCM , RT -Br BOC NBS ( 50 mg , 0.28 mmol ) was added to a solution of tert - butyl 3- [ 7- ( indan - 2- ylcarbamoyl ) pyrazolo [ 1,5 - a ] pyrimidin - 2 - yl ] azetidine - 1 - carboxylate ( 119 mg , 0.27 mmol ) in DCM ( 4 mL ) and the reaction was stirred at room temperature for 87 h . The reaction mixture was diluted with DCM and washed with sat . aq . NaHCO3 . The aqueous layer was extracted with DCM , and the combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo to provide the title compound ( 133 mg ) . - - = 1H NMR ( 400 MHz , CDCl3 ) б 10.55 ( d , J = 6.9 Hz , 1H ) , 8.73 ( d , J = 4.3 Hz , 1H ) , 7.85 ( d , J 4.3 Hz , 1H ) , 7.35 – 7.29 ( m , 2H ) , 7.27 – 7.19 ( m , 2H ) , 5.02 – 4.90 ( m , 1H ) , 4.33 ( t , J = 8.Hz , 2H ) , 4.16 – 4.09 ( m , 2H ) , 4.09 – 3.98 ( m , 1H ) , 3.48 ( dd , J = 16.0 , 6.7 Hz , 2H ) , 3.07 ( dd , J = 16.0 , 4.4 Hz , 2H ) , 1.49 ( s , 9H ) - - LCMS ( Method 1 ) : 2.03 min , 412.0 , 414.0 [ M - Boc + H ] + , 456.0 , 458.0 [ M - t - Bu + H ] * Synthesis of tert - butyl 3- [ 3 - carbamoyl - 7- ( indan - 2 - ylcarbamoyl ) pyrazolo [ 1,5- a ] pyrimidin - 2 - yl ] azetidine - 1 - carboxylate 371 H .Br 1. XantPhos Pd GEt N , NMP , 100 ° C 2. T3P , HO₂HN N₂tE , RT oose BOC ' N ' NH BOC XantPhos Pd G3 ( 24 mg , 0.02 mmol ) was placed in a vial and the vial was sealed and purged with argon for 10 min . A separate sealed flask containing tert - butyl 3- [ 3 - bromo - 7- ( indan - 2- ylcarbamoyl ) pyrazolo [ 1,5 - a ] pyrimidin - 2 - yl ] azetidine - 1 - carboxylate ( 133 mg , 0.25 mmol ) was purged with argon for 10 min . NMP ( 3 mL ) was added to the flask , and the solution was transferred to the vial containing XantPhos Pd G3 . NзtE ( 70 Lμ , 0.50 mmol ) was added , and the vial was purged with argon for a further 5 min . ( 2,5 - Dioxopyrrolidin - 1 - yl ) formate ( 1mg , 1.25 mmol ) was added , and the reaction was heated at 100 ° C in a microwave reactor for 6 h . Additional portions of XantPhos Pd G3 ( 62 mg , 0.04 mmol ) and ( 2,5 - dioxopyrrolidin- - yl ) formate ( 356 mg , 2.50 mmol ) were added , and the reaction was heated at 100 ° C in a microwave reactor for a further 6 h . 1 - Propanephosphonic anhydride ( 50 wt % in EtOAc ; 2Lμ , 0.37 mmol ) , N³tE ( 100 Lµ , 0.75 mmol ) , and NH4OH ( 170 Lµ , 2.49 mmol ) were added , and the reaction was stirred at room temperature for 3 h . The reaction mixture was diluted with EtOAc and washed with sat . aq . NaHCO3 . The aqueous layer was extracted with EtOAc , and the combined organic layers were washed with brine ( × 4 ) , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 46 mg ) . 1H NMR ( 400 MHz , CDCl3 ) 5 10.60 ( d , J = 6.8 Hz , 1H ) , 8.79 ( d , J = 4.4 Hz , 1H ) , 8.00 ( s , 1H ) , 7.95 ( d , J = 4.4 Hz , 1H ) , 7.32 ( dd , J = 5.4 , 3.3 Hz , 2H ) , 7.22 ( dd , J = 5.5 , 3.2 Hz , 2H ) , 5.( s , 1H ) , 5.00 – 4.89 ( m , 1H ) , 4.56 ( tt , J = 8.8 , 6.1 Hz , 1H ) , 4.36 ( t , J = 8.8 Hz , 2H ) , 4.06 ( dd , J = 8.8 , 6.1 Hz , 2H ) , 3.48 ( dd , J = 16.0 , 6.7 Hz , 2H ) , 3.08 ( dd , J = 16.0 , 4.3 Hz , 2H ) , 1.46 ( s , 9H ) LCMS ( Method 1 ) : 1.80 min , 421.2 [ M - t - Bu + H ] + Synthesis dicarboxamide of 2- ( azetidin - 3 - yl ) -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- 372 N TFA DCM , RT H .N . ' N ' NHNH N BOC TFA ( 140 Lμ , 1.83 mmol ) was added to a solution of tert - butyl 3- [ 3 - carbamoyl - 7- ( indan - 2- ylcarbamoyl ) pyrazolo [ 1,5 - a ] pyrimidin - 2 - yl ] azetidine - 1 - carboxylate ( 46 mg , 0.09 mmol ) in DCM ( 2 mL ) and the reaction was stirred at room temperature for 2 h then concentrated in vacuo . The crude product was purified by SCX chromatography ( eluting with 2 M NH3 in MeOH ) to provide the title compound ( 28 mg ) . - - 1H NMR ( 400 MHz , CDCl3 ) 5 10.74 ( d , J = 7.7 Hz , 1H ) , 8.77 ( d , J = 4.4 Hz , 1H ) , 8.04 ( s , 1H ) , 7.94 ( d , J = 4.4 Hz , 1H ) , 7.32 ( dd , J = 5.4 , 3.3 Hz , 2H ) , 7.25 – 7.22 ( m , 2H ) , 5.65 ( s , 1H ) , 5.10 4.99 ( m , 1H ) , 4.76 – 4.64 ( m , 1H ) , 4.00 ( t , J = 8.4 Hz , 2H ) , 3.77 – 3.65 ( m , 2H ) , 3.– 3.42 ( m , 2H ) , 3.07 ( dd , J = 16.1 , 3.5 Hz , 2H ) . Additional exchangeable proton not observed . LCMS ( Method 1 ) : 1.21 min , 377.2 [ M + H ] + Synthesis of compound 24 , N7 - indan - 2 - yl - 2- ( 1 - methylazetidin - 3 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide STAB formaldehyde formic acid O₂H , RT ` N N = NHNH Formaldehyde ( 37 wt % in water ; 40 Lμ , 0.53 mmol ) was added to a suspension of 2- ( azetidin - 3 - yl ) -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 44 mg , 0.mmol ) in water ( 2 mL ) and the reaction was stirred at room temperature for 5 min . Formic acid ( 20 Lμ , 0.53 mmol ) was added , and the reaction was stirred for a further 1 h . Sodium triacetoxyborohydride ( 112 mg , 0.53 mmol ) was added , and the reaction was stirred for a further 1 h , then diluted with EtOAc and sat . aq . NaHCO3 . The layers were separated , and the aqueous layer was extracted with EtOAc . The combined organic layers were washed 373 LO with brine ( x 2 ) , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by preparative HPLC ( basic method ) to provide the title compound ( 19 mg ) . - - 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.38 ( d , J = 7.4 Hz , 1H ) , 8.89 ( d , J = 4.4 Hz , 1H ) , 7.73 ( d , J = 4.4 Hz , 1H ) , 7.63 ( s , 1H ) , 7.47 ( s , 1H ) , 7.35 – 7.27 ( m , 2H ) , 7.24 – 7.16 ( m , 2H ) , 4.90 - 4.80 ( m , 1H ) , 4.28 – 4.16 ( m , 1H ) , 3.56 - 3.47 ( m , 2H ) , 3.45 - 3.37 ( m , 2H ) , 3.04 - 2.90 ( m , 4H ) , 2.16 ( s , 3H ) LCMS ( Method 2 ) : 1.49 min , 391.2 [ M + H ] + Synthesis carboxamide of - bromo - N- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- HO Br -NH2.HCI ﺲﻟﺎﻣ T3P , N₂tE DCM , RT N. F. Br 3 - Bromopyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 500 mg , 2.07 mmol ) , 3,3- difluorocyclobutanamine hydrochloride ( 326 mg , 2.27 mmol ) , NзtE ( 860 Lμ , 6.20 mmol ) , and - propanephosphonic anhydride ( 50 wt % in EtOAc ; 2.27 mL , 2.27 mmol ) were dissolved in DCM ( 10 mL ) and the reaction was stirred at room temperature overnight . The reaction mixture was concentrated in vacuo , and the crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 523 mg ) . LCMS ( Method 5 ) : 1.06 min , 331.0 , 333.0 [ M + H ] * Synthesis of N- ( 3,3 - difluorocyclobutyl ) -2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ‚ N. nip₂B , Pd ( dppf ) ₂lC KOAc , 1,4 - Dioxane 100 ° C Br ' N ' Bpin LO 2 - Bromo - N- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 523 mg , 1.mmol ) , 2nip₂B ( 481 mg , 1.90 mmol ) , and KOAc ( 465 mg , 4.74 mmol ) were suspended in 1,4- dioxane ( 10 mL ) and the mixture was degassed by sparging with a stream of argon for min . Pd ( dppf ) Cl2 ( 115 mg , 0.16 mmol ) was added , and the mixture was sparged with argon for a further 10 min . The reaction was heated at 100 ° C for 16 h then cooled to room temperature . The reaction mixture was filtered through a short pad of ®etilaciD , washed with EtOAc , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 427 mg ) .

- ' H NMR ( 400 MHz , DMSO - бd ) 5 10.33 ( d , J = 6.3 Hz , 1H ) , 8.73 ( d , J = 4.2 Hz , 1H ) , 7.49 ( d , J = 4.1 Hz , 1H ) , 7.13 ( s , 1H ) , 4.41 – 4.28 ( m , 1H ) , 3.20 – 3.05 ( m , 2H ) , 2.82 – 2.68 ( m , 2H ) , 1.16 ( s , 12H ) - - LCMS ( Method 5 ) : 0.69 min , 297.2 [ M + H ] + ( boronic acid ) Synthesis of N- ( 3,3 - difluorocyclobutyl ) -2 - oxazol - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide Bpin Br Pd ( dppf ) ₂lC , Na2CO1,4 - Dioxane , O₂H 100 ° C N N- ( 3,3 - difluorocyclobutyl ) -2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide ( 163 mg , 0.43 mmol ) , 2 - bromooxazole ( 67 mg , 0.45 mmol ) , and Na2CO3 ( 137 mg , 1.29 mmol ) , were suspended in 1,4 - dioxane ( 4 mL ) and water ( 1 mL ) and the mixture was degassed by sparging with a stream of argon for 5 min . Pd ( dppf ) ₂lC ( 32 mg , 0.04 mmol ) was added , and the reaction was heated at 100 ° C overnight . The reaction mixture was cooled to room temperature and diluted with EtOAc and water . The layers were separated , and the aqueous layer was extracted with EtOAc . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 76 mg ) . 375 LO ' H NMR ( 400 MHz , DMSO - d ) ₫ 10.07 ( d , J = 6.4 Hz , 1H ) , 8.80 ( d , J = 4.2 Hz , 1H ) , 8.37 ( d , J = 0.8 Hz , 1H ) , 7.55 ( d , J = 4.2 Hz , 1H ) , 7.52 ( d , J = 0.8 Hz , 1H ) , 7.41 ( s , 1H ) , 4.39 ( dd , J : - - 8.3 , 6.6 Hz , 1H ) , 3.21 – 3.07 ( m , 2H ) , 2.85 – 2.68 ( m , 2H ) LCMS ( Method 5 ) : 0.90 min , 320.2 [ M + H ] * = Synthesis of - bromo - N- ( 3,3 - difluorocyclobutyl ) -2 - oxazol - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide ' N ' NBS , THF RT -Br N = N N- ( 3,3 - difluorocyclobutyl ) -2 - oxazol - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 108 mg , 0.34 mmol ) and NBS ( 93 mg , 0.52 mmol ) were dissolved in THF ( 5 mL ) and the reaction was stirred at room temperature overnight . The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 91 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) ō 9.91 ( d , J = 6.4 Hz , 1H ) , 8.87 ( d , J = 4.2 Hz , 1H ) , 8.44 ( d , J = - = 0.8 Hz , 1H ) , 7.62 ( d , J = 4.2 Hz , 1H ) , 7.59 ( d , J = 0.8 Hz , 1H ) , 4.42 – 4.34 ( m , 1H ) , 3.20 - 3.05 ( m , 2H ) , 2.83 – 2.70 ( m , 2H ) LCMS ( Method 5 ) : 1.00 min , 398.0 , 400.0 [ M + H ] * Synthesis of compound 25 , N7- ( 3,3 - difluorocyclobutyl ) -2 - oxazol - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 376 ' N ° Br N = H 1. XantPhos Pd GEt N , NMP , 100 ° C 2. NH4OH , EtOAc , RT NHN = ﻡا 3 - Bromo - N- ( 3,3 - difluorocyclobutyl ) -2 - oxazol - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 91 mg , 0.23 mmol ) and NзtE ( 96 Lμ , 0.69 mmol ) were dissolved in NMP ( 4 mL ) and the solution was degassed by sparging with a stream of argon for 5 min . XantPhos Pd G3 ( mg , 0.02 mmol ) and ( 2,5 - dioxopyrrolidin - 1 - yl ) formate ( 164 mg , 1.14 mmol ) were added , and the vial was sealed immediately . The reaction was heated at 100 ° C in a microwave reactor for 2 h . Additional portions of XantPhos Pd G3 ( 11 mg , 0.01 mmol ) , N³tE ( 50 Lµ , 0.34 mmol ) , and ( 2,5 - dioxopyrrolidin - 1 - yl ) formate ( 82 mg , 0.57 mmol ) were added , and the solution was degassed by sparging with a stream of argon for 5 min . The reaction was heated at 100 ° C in a microwave reactor for a further 2 h then cooled to room temperature . The reaction mixture was diluted with EtOAc , NH4OH ( 320 Lμ , 2.29 mmol ) was added , and the reaction was stirred at room temperature for 2 h . The reaction mixture was diluted with EtOAc and water and the layers were separated . The aqueous layer was extracted with EtOAc , and the combined organic layers were dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) and preparative HPLC ( basic method ) to provide the title compound ( 20 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) 5 9.90 ( d , J = 6.4 Hz , 1H ) , 8.96 ( d , J = 4.3 Hz , 1H ) , 8.38 ( d , J. = 0.9 Hz , 1H ) , 7.98 ( s , 1H ) , 7.65 ( d , J = 4.3 Hz , 2H ) , 7.52 ( d , J = 0.8 Hz , 1H ) , 4.43 – 4.31 ( m , 1H ) , 3.18 -3.02 ( m , 2H ) , 2.83 - 2.70 ( m , 2H ) LCMS ( Method 4 ) : 1.55 min , 363.0 [ M + H ] * Synthesis of methyl 3 - aminopyridazine - 4 - carboxylate 4OS₂H , HOеM ° C HO NHMeO NH377 LO Concentrated H2SO4 ( 2 mL , 37.52 mmol ) was added to a solution of 3 - aminopyridazine - 4- carboxylic acid ( 2 g , 14.38 mmol ) in MeOH ( 40 mL ) and the reaction was stirred at 65 ° C for week . The reaction mixture was cooled to room temperature and concentrated in vacuo . The residue was diluted with water and the solution was basified to pH 8 with NaHCO3 . The aqueous layer was extracted with EtOAc ( x 3 ) , and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 1.85 g ) . § 1H NMR ( 400 MHz , DMSO - d6 ) 5 8.65 ( d , J = 4.9 Hz , 1H ) , 7.72 ( d , J = 4.9 Hz , 1H ) , 7.28 ( s , 2H ) , 3.87 ( s , 3H ) LCMS ( Method 1 ) : 0.84 min , 154.2 [ M + H ] * Synthesis of methyl 2 - methylimidazo [ 1,2 - b ] pyridazine - 8 - carboxylate ﺎﻤﺳﻻ CI 1. EtOAc ° C to 100 ° C 2. NaHCO3 , MeOH 100 ° C N MeO N NH MeO Methyl 3 - aminopyridazine - 4 - carboxylate ( 740 mg , 4.83 mmol ) was added to a solution of 1- chloropropan - 2 - one ( 3.85 mL , 48.32 mmol ) in EtOAc ( 9 mL ) and the reaction was heated at ° C for 16 h , and then at 100 ° C in a microwave reactor for 5 h . MeOH ( 3 mL ) and NaHCO( 812 mg , 9.66 mmol ) were added , and the reaction was heated at 100 ° C in a microwave reactor for 6 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 30 % MeOH in DCM ) to provide the title compound ( 355 mg ) . 1H NMR ( 400 MHz , MeOD ) ō 8.50 ( d , J = 4.7 Hz , 1H ) , 8.02 ( q , J = 0.9 Hz , 1H ) , 7.65 ( d , J = 4.7 Hz , 1H ) , 4.03 ( s , 3H ) , 2.51 ( d , J = 0.9 Hz , 3H ) LCMS ( Method 1 ) : 0.96 min , 192.2 [ M + H ] * Synthesis of 2 - methylimidazo [ 1,2 - b ] pyridazine - 8 - carboxylic acid 378 MeO O₂H.HOiL THF , MeOH , O₂H RT HO LO A solution of O₂H.HOiL ( 75 mg , 1.79 mmol ) in water ( 1 mL ) was added dropwise to a solution of methyl 2 - methylimidazo [ 1,2 - b ] pyridazine - 8 - carboxylate ( 345 mg , 1.62 mmol ) in THF ( mL ) and MeOH ( 1 mL ) and the reaction was stirred at room temperature for 1 h . The reaction mixture was concentrated in vacuo and diluted with water . The aqueous solution was acidified with 1 M aq . HCI and extracted with a 3 : 1 mixture of CHCI 3 : IPA . The aqueous layer was concentrated in vacuo to provide the title compound ( 361 mg ) . The crude product was taken forward to the next step without further purification . ' H NMR ( 400 MHz , MeOD ) à 8.96 ( d , J = 4.8 Hz , 1H ) , 8.32 ( s , 1H ) , 8.11 ( d , J = 4.9 Hz , 1H ) , 2.64 ( s , 3H ) . Exchangeable proton not observed .

Synthesis carboxamide of N- ( 3,3 - difluorocyclobutyl ) -2 - methyl - imidazo [ 1,2 - b ] pyridazine - 8- HO N F -NH2.HCI T3P , N₂tE DMF , RT N N 3,3 - Difluorocyclobutanamine hydrochloride ( 281 mg , 1.96 mmol ) was added to a solution of - methylimidazo [ 1,2 - b ] pyridazine - 8 - carboxylic acid ( 289 mg , 1.63 mmol ) , N³tE ( 1.14 mL , 8.16 mmol ) , and 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 1.94 mL , 3.26 mmol ) in DMF ( 6 mL ) and the reaction was stirred at room temperature for 20 h . The reaction mixture was diluted with EtOAc and brine and the layers were separated . The aqueous layer was extracted with EtOAc ( x 2 ) , and the combined organic layers were washed with 1 M aq . HCI . The aqueous layer was basified to pH 8 with NaHCO3 and extracted with EtOAc ( x 2 ) . The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 169 mg ) . 379 LO 1H NMR ( 400 MHz , CDCl3 ) б 10.54 ( s , 1H ) , 8.66 ( d , J = 4.8 Hz , 1H ) , 8.35 ( d , J = 4.8 Hz , 1H ) , - - 7.89 ( q , J = 0.8 Hz , 1H ) , 4.52 – 4.40 ( m , 1H ) , 3.16 – 2.86 ( m , 4H ) , 2.67 ( d , J = 0.9 Hz , 3H ) LCMS ( Method 1 ) : 1.59 min , 267.2 [ M + H ] * Synthesis of 3 - bromo - N- ( 3,3 - difluorocyclobutyl ) -2 - methyl - imidazo [ 1,2 - b ] pyridazine - 8- carboxamide NBS , MeOH RT .N . F.

' N .N . .Br F. F NBS ( 121 mg , 0.68 mmol ) was added to a solution of N- ( 3,3 - difluorocyclobutyl ) -2 - methyl- imidazo [ 1,2 - b ] pyridazine - 8 - carboxamide ( 165 mg , 0.62 mmol ) in MeOH ( 5 mL ) and the reaction was stirred at room temperature for 30 min then concentrated in vacuo . The residue was diluted with DCM and water , and the layers were separated . The aqueous layer was extracted with DCM , and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 182 mg ) . The crude product was taken forward to the next step without further purification . 1H NMR ( 400 MHz , CDCl3 ) б 10.13 ( s , 1H ) , 8.59 ( d , J = 4.7 Hz , 1H ) , 7.89 ( d , J = 4.7 Hz , 1H ) , 4.544.46 ( m , 1H ) , 3.17 – 3.09 ( m , 2H ) , 2.83 – 2.71 ( m , 2H ) , 2.56 ( s , 3H ) - - LCMS ( Method 1 ) : 1.82 min , 345.0 , 347.0 [ M + H ] * Synthesis of compound 26 , N8- ( 3,3 - difluorocyclobutyl ) -2 - methyl - imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide 380 F. F N. .Br H 1. XantPhos Pd GEt N , MeCN ° C 2. N₂tE , T3P , NHOH RT H F. F NH 3 - Bromo - N- ( 3,3 - difluorocyclobutyl ) -2 - methyl - imidazo [ 1,2 - b ] pyridazine - 8 - carboxamide ( 1mg , 0.52 mmol ) , XantPhos Pd G3 ( 50 mg , 0.05 mmol ) , and N³tE ( 220 Lµ , 1.56 mmol ) were dissolved in MeCN ( 5 mL ) and the solution was degassed by sparging with a stream of argon for 30 min . ( 2,5 - Dioxopyrrolidin - 1 - yl ) formate ( 373 mg , 2.61 mmol ) was added and the reaction vial was sealed immediately . The reaction was heated at 90 ° C for 3.5 h then cooled to room temperature . NзtE ( 220 Lµ , 1.56 mmol ) , 1 - propanephosphonic anhydride ( 50 wt % in EtOAc ; 620 Lμ , 1.04 mmol ) , and NH4OH ( 620 Lµ , 5.22 mmol ) were added and the reaction was stirred at room temperature for 16 h . The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography ( eluting with 0 to 8 % MeOH in DCM ) followed by preparative HPLC ( basic method ) to provide the title compound ( mg ) . 1H NMR ( 400 MHz , DMSO - d ) u0000 10.00 ( d , J = 6.5 Hz , 1H ) , 8.87 ( d , J = 4.8 Hz , 1H ) , 8.18 ( s , 1H ) , 7.97 ( s , 1H ) , 7.85 ( d , J = 4.8 Hz , 1H ) , 4.40 - 4.33 ( m , 1H ) , 3.16 - 3.03 ( m , 2H ) , 2.88 - 2.76 ( m , 2H ) , 2.75 ( s , 3H ) LCMS ( Method 2 ) : 1.90 min , 310.2 [ M + H ] * Synthesis of 2- ( 2 - isopropoxyacetyl ) propanedinitrile HO 1. ( COCI ) 2 , DMF DCM , RT 2. NaH , THF , propanedinitrile ° C to RT CN NC 381 DMF ( 105 Lμ , 1.35 mmol ) was added to a solution of 2 - isopropoxyacetic acid ( 1.6 g , 13.mmol ) in DCM ( 32 mL ) . Oxalyl chloride ( 1.39 mL , 16.25 mmol ) was added dropwise over h , and the reaction mixture was stirred at room temperature for 1 h then concentrated in vacuo to provide the crude acid chloride intermediate . A solution of propanedinitrile ( 895 mg , 13.55 mmol ) in THF ( 12 mL ) was added dropwise over 15 min to a suspension of NaH ( 1.g , 27.09 mmol ) in THF ( 12 mL ) at 0 ° C . The mixture was stirred at room temperature for min then cooled back to 0 ° C . A solution of the acid chloride in THF ( 12 mL ) was added . dropwise over 15 min , then the reaction was stirred at room temperature for 17 h . The reaction mixture was quenched with water , acidified with 1 M aq . HCI , and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 5 % MeOH in DCM ) to provide the title compound ( 1.43 g ) . 1H NMR ( 400 MHz , ³ICDC ) б 4.45 ( s , 2H ) , 3.86 ( hept , J = 6.1 Hz , 1H ) , 3.60 ( s , 1H ) , 1.28 ( d , J = 6.1 Hz , 6H ) LCMS ( Method 1 ) : 1.37 min ( product does not ionise ) Synthesis of 2- ( 2 - isopropoxy - 1 - methoxy - ethylidene ) propanedinitrile NC CN ( MeO ) , CH ° C CN NC eMŎ 2- ( 1 - Hydroxy - 2 - isopropoxy - ethylidene ) propanedinitrile ( 1.43 g , 8.61 mmol ) was dissolved in trimethoxymethane ( 15 mL , 137.11 mmol ) and the reaction mixture was heated at 70 ° C in a microwave reactor for 6 h , then cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 1.1 g ) . 1H NMR ( 400 MHz , ³lCDC ) ₫ 4.41 ( s , 2H ) , 4.23 ( s , 3H ) , 3.73 ( hept , J = 6.0 Hz , 1H ) , 1.23 ( d , J = 6.1 Hz , 6H ) LCMS ( Method 1 ) : 1.63 min ( product does not ionise ) Synthesis of 5 - amino - 3- ( isopropoxymethyl ) -1H - pyrazole - 4 - carbonitrile 382 NC CN eMŎ ﻞﻫ NHNH , NH , .H , O EtOH , RT CN HN Hydrazine monohydrate ( 500 Lµ , 10.26 mmol ) was added to a solution of 2- ( 2 - isopropoxy- - methoxy - ethylidene ) propanedinitrile ( 1.12 g , 6.22 mmol ) in EtOH ( 8.6 mL ) and the reaction was stirred at room temperature for 1.5 h then concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) to provide the title compound ( 921 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) § 11.81 ( s , 1H ) , 6.29 ( s , 2H ) , 4.26 ( s , 2H ) , 3.60 ( hept , J = 6.Hz , 1H ) , 1.10 ( d , J = 6.1 Hz , 6H ) LCMS ( Method 1 ) : 1.27 min , 181.2 [ M + H ] * Synthesis of ethyl carboxylate NH.CN HN N : 3 - cyano - 2- ( isopropoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- OEt ﻢﻫﺩ EtO EtOH , reflux EtO . ' N ' N = .CN - Amino - 3- ( isopropoxymethyl ) -1H - pyrazole - 4 - carbonitrile ( 921 mg , 5.11 mmol ) and ethyl ( E ) -4 - ethoxy - 2 - oxo - but - 3 - enoate ( 1.32 g , 7.67 mmol ) were dissolved in EtOH ( 7 mL ) and the reaction was heated at reflux for 2.5 h , then cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 1.25 g ) containing approximately 14 % of the regioisomeric product as an impurity . 1H NMR ( 400 MHz , CDCl3 ) б 8.79 ( d , J = 4.2 Hz , 1H ) , 7.47 ( d , J = 4.2 Hz , 1H ) , 4.85 ( s , 2H ) , 4.57 ( q , J = 7.1 Hz , 2H ) , 3.91 – 3.77 ( m , 1H ) , 1.47 ( t , J = 7.2 Hz , 3H ) , 1.29 ( d , J = 6.1 Hz , 6H ) . - LCMS ( Method 1 ) : 1.70 min , 289.2 [ M + H ] * 383 LO Synthesis of 3 - cyano - 2- ( isopropoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid EtO .CN LiOH MeOH , THF RT HO ' N ' .CN N = 4 M aq . LiOH ( 5.42 mL , 21.68 mmol ) was added to a solution of ethyl 3 - cyano - 2- ( isopropoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 1.25 g , 4.34 mmol ) in THF ( 12.mL ) and MeOH ( 4.2 mL ) and the reaction was stirred at room temperature for 1 h then concentrated in vacuo . The residue was dissolved in water and the solution was acidified with 5 M aq . HCI and diluted with DCM . The layers were separated , and the aqueous layer was extracted with DCM ( x 2 ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 5 % MeOH in DCM ) to provide the title compound ( 7mg ) . H¹ NMR ( 400 MHz , ³lCDC ) г 8.99 ( d , J = 6.1 Hz , 1H ) , 7.97 ( d , J = 4.3 Hz , 1H ) , 4.88 ( s , 2H ) , 3.86 ( hept , J = 6.1 Hz , 1H ) , 1.31 ( d , J = 6.1 Hz , 6H ) . Exchangeable proton not observed . LCMS ( Method 1 ) : 1.37 min , 261.2 [ M + H ] + Synthesis of 3 - cyano - N - indan - 2 - yl - 2- ( isopropoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide HO . ' N ' .CN -NH2.HCI T3P , N₂tE DMF , RT ' N ' .CN LO NзtE ( 241 Lμ , 1.73 mmol ) and 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 1.03 mL , 1.73 mmol ) were added to a solution of 3 - cyano - 2- ( isopropoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxylic acid ( 150 mg , 0.58 mmol ) and indan - 2 - amine hydrochloride ( 1mg , 0.63 mmol ) in DMF ( 1.9 mL ) and the reaction was stirred at room temperature for 20 h . The reaction was quenched with water and diluted with DCM . The layers were separated , and the aqueous layer was extracted with DCM ( x 2 ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 178 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) ō 9.75 ( d , J = 7.1 Hz , 1H ) , 8.94 ( d , J = 4.4 Hz , 1H ) , 7.67 ( d , J == - 4.4 Hz , 1H ) , 7.32 – 7.23 ( m , 2H ) , 7.22 – 7.13 ( m , 2H ) , 4.84 – 4.74 ( m , 1H ) , 4.73 ( s , 2H ) , 3.74 ( hept , J = 6.1 Hz , 1H ) , 3.37 ( dd , J = 16.2 Hz , 7.5 Hz 2H ) , 2.97 ( dd , J = 16.1 , 5.2 Hz , 2H ) , 1.16 ( d , J = 6.1 Hz , 6H ) Synthesis of compound 27 , N7 - indan - 2 - yl - 2- ( isopropoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide .CN HO H PS - ₂hPP , Pd ( OAc ) , EtOH , O₂H , 90 ° C NH 3 - Cyano - N - indan - 2 - yl - 2- ( isopropoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 1mg , 0.47 mmol ) , acetaldehyde oxime ( 116 Lμ , 1.9 mmol ) , Pd ( OAc ) 2 ( 16 mg , 0.07 mmol ) , and PS - PPh3 ( 1.4 - 2 mmol / g ; 49 mg , 0.07 – 0.1 mmol ) were suspended in EtOH ( 3.6 mL ) and water ( 900 Lμ ) and the reaction was heated at 90 ° C for 2 h . The reaction mixture was cooled to room temperature and diluted with DCM . The layers were separated , and the aqueous layer was extracted with DCM ( x 2 ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 8 % MeOH in DCM ) to provide the title compound . ( 141 mg ) . 1H NMR ( 400 MHz , DMSO - d € ) ₫ 10.24 ( d , J = 6.8 Hz , 1H ) , 8.90 ( d , J = 4.4 Hz , 1H ) , 7.69 ( d , J = 4.4 Hz , 1H ) , 7.68 ( br . s , 1H ) , 7.55 ( br . s , 1H ) , 7.27 ( dd , J = 5.4 , 3.3 Hz , 2H ) , 7.22 - 7.- 385 LO - ( m , 2H ) , 4.96 ( s , 2H ) , 4.85 – 4.73 ( m , 1H ) , 3.74 ( hept , J = 6.1 Hz , 1H ) , 3.41 ( dd , J = 7.5 Hz , 2H ) , 2.98 ( dd , J = 16.2 , 4.9 Hz , 2H ) , 1.12 ( d , J = 6.0 Hz , 6H ) LCMS ( Method 4 ) : 2.28 min , 394.2 [ M + H ] * Synthesis of 3 - cyano - N- ( 3,3 - difluorocyclobutyl ) -2- ( isopropoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide F -NH2.HCI HO . .CN T3P , N₂tE DMF , RT ' N ' CN NзtE ( 161 Lµ , 1.15 mmol ) and 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 690 Lμ , 1.15 mmol ) were added to a solution of 3 - cyano - 2- ( isopropoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxylic acid ( 100 mg , 0.38 mmol ) and 3,3 - difluorocyclobutanamine hydrochloride ( 61 mg , 0.42 mmol ) in DMF ( 1.3 mL ) and the reaction was stirred at room temperature for 24 h . The reaction was quenched with water and diluted with DCM . The layers were separated , and the aqueous layer was extracted with DCM ( x 2 ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 103 mg ) . - 1H NMR ( 400 MHz , CDCl3 ) Ŏ 10.38 ( d , J = 6.2 Hz , 1H ) , 8.90 ( d , J = 4.3 Hz , 1H ) , 7.97 ( d , J = 4.3 Hz , 1H ) , 4.88 ( s , 2H ) , 4.59 – 4.43 ( m , 1H ) , 3.88 ( hept , J = 6.0 Hz , 1H ) , 3.26 – 3.09 ( m , 2H ) , 2.81 – 2.64 ( m , 2H ) , 1.33 ( d , J = 6.1 Hz , 6H ) - - LCMS ( Method 1 ) : 1.75 min , 350.2 [ M + H ] * Synthesis of compound , N7- ( 3,3 - difluorocyclobutyl ) -2- ( isopropoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 386 N sosa .CN HO H PS - PPh3 , Pd ( OAc ) EtOH , O₂H , 90 ° C ' N ' NH 3 - Cyano - N- ( 3,3 - difluorocyclobutyl ) -2- ( isopropoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- - - carboxamide ( 102 mg , 0.29 mmol ) , acetaldehyde oxime ( 71 Lμ , 1.17 mmol ) , Pd ( OAc ) 2 ( mg , 0.04 mmol ) , and PS - ³hPP ( 1.4 – 2 mmol / g ; 30 mg , 0.04 – 0.06 mmol ) were suspended in EtOH ( 2.2 mL ) and water ( 550 Lµ ) and the reaction was heated at 90 ° C for 2 h . The reaction mixture was cooled to room temperature and diluted with DCM . The layers were separated , and the aqueous layer was extracted with DCM ( x 2 ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 5 % MeOH in DCM ) to provide the title compound ( 82 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.32 ( d , J = 6.4 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.68 ( s , 1H ) , 7.66 ( d , J = 4.4 Hz , 1H ) , 7.58 ( s , 1H ) , 5.04 ( s , 2H ) , 4.44 – 4.31 ( m , 1H ) , 3.82 ( hept , J : 6.1 Hz , 1H ) , 3.21 - 3.06 ( m , 2H ) , 2.82 – 2.66 ( m , 2H ) , 1.18 ( d , J = 6.1 Hz , 6H ) - LCMS ( Method 4 ) : 2.11 min , 368.2 [ M + H ] + Synthesis of ( 5 - amino - 1H - pyrazol - 3 - yl ) methanol - = ₂HN HN LiBH THF , 66 ° C NHHN NE N = -OEt -OH LiBH4 ( 2 M in THF ; 24.2 mL , 48.34 mmol ) was added slowly to a solution of ethyl 5 - amino- 1H - pyrazole - 3 - carboxylate ( 5 g , 32.23 mmol ) in THF ( 75 mL ) and the reaction was heated at 66 ° C overnight . The reaction mixture was cooled to room temperature , quenched with MeOH , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 20 % MeOH in DCM ) to provide the title compound ( 2.g ) . 387 LO ' H NMR ( 400 MHz , DMSO - εd ) ō 5.29 ( s , 1H ) , 4.94 ( s , 1H ) , 4.27 ( s , 2H ) . Additional exchangeable protons not observed .

Synthesis of ethyl 2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate Eto NHHN N -OH OEt N EtOH , 75 ° C Eto . N N : -OH Ethyl ( E ) -4 - ethoxy - 2 - oxo - but - 3 - enoate ( 4.11 g , 23.87 mmol ) and ( 5 - amino - 1H - pyrazol - 3- yl ) methanol ( 2.25 g , 19.89 mmol ) were dissolved in EtOH ( 75 mL ) and the reaction was heated at 75 ° C for 4 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 20 % MeOH in DCM ) to provide the title compound ( 3.51 g ) . 1H NMR ( 400 MHz , DMSO - d6 ) 8 8.64 ( d , J = 4.2 Hz , 1H ) , 7.38 ( d , J = 4.2 Hz , 1H ) , 6.82 ( s , 1H ) , 5.44 ( t , J = 5.8 Hz , 1H ) , 4.68 ( d , J = 4.9 Hz , 2H ) , 4.48 ( q , J = 7.1 Hz , 2H ) , 1.37 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 1 ) : 0.56 min , 222.2 [ M + H ] + Synthesis of ethyl carboxylate EtO . ' N ' -OH 3 - bromo - 2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- NBS MeCN , 60 ° C EtO . N .Br -OH NBS ( 454 mg , 2.55 mmol ) was added to a solution of ethyl 2- ( hydroxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxylate ( 470 mg , 2.13 mmol ) in MeCN ( 11 mL ) and the reaction was heated at 60 ° C for 18 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The residue was dissolved in DCM and washed with sat . aq . NaHCO( x 3 ) . The organic layer was dried through a hydrophobic frit and concentrated in vacuo to provide the title compound ( 699 mg ) . The crude product was taken forward to the next step without further purification . 388 LO 1H NMR ( 400 MHz , ³lCDC ) § 8.64 ( d , J = 4.1 Hz , 1H ) , 7.35 ( d , J = 4.1 Hz , 1H ) , 4.99 ( s , 2H ) , 4.56 ( q , J = 7.2 Hz , 2H ) , 1.47 ( t , J = 7.1 Hz , 3H ) . Exchangeable proton not observed .

Synthesis of 3 - bromo - 2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid O₂H.HOiL THF , O₂H , RT EtO HO ' N ' Br Br N = -OH -OH LiOH.H2O ( 147 mg , 3.49 mmol ) was added to a solution of ethyl 3 - bromo - 2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 699 mg , 2.33 mmol ) in THF ( 5.mL ) and water ( 5.8 mL ) and the reaction was stirred at room temperature for 18 h . The reaction mixture was diluted with EtOAc and water and acidified to pH 2 - 3 with 1 M aq . HCI . The layers were separated , and the aqueous layer was extracted with EtOAc ( x3 ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo to provide the title compound ( 394 mg ) . § 1H NMR ( 400 MHz , DMSO - d6 ) 8 8.71 ( d , J = 4.1 Hz , 1H ) , 7.44 ( d , J = 4.1 Hz , 1H ) , 4.66 ( s , 2H ) . Exchangeable protons not observed . LCMS ( Method 2 ) : 1.14 min , 272.0 , 274.0 [ M + H ] * Synthesis of 3 - bromo - 2- ( hydroxymethyl ) -N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide -NH2.HCI T3P , N₂tE N DMF , RT H .N . HO Br -Br Na -OH -OH Indan - 2 - amine hydrochloride ( 369 mg , 2.17 mmol ) , 1 - propanephosphonic anhydride ( wt % in DMF ; 1.69 mL , 2.9 mmol ) , and NзtE ( 1.01 mL , 7.24 mmol ) were added to a solution of 3 - bromo - 2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 394 mg , 1.mmol ) in DMF ( 10 mL ) and the reaction was stirred at room temperature for 72 h . The 389 LO reaction mixture was poured into water and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were washed with sat . aq . LICI ( x 2 ) , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 217 mg ) .

- ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.10 ( d , J = 7.1 Hz , 1H ) , 8.75 ( d , J = 4.2 Hz , 1H ) , 7.56 ( d , J = 4.2 Hz , 1H ) , 7.27 ( dd , J = 5.4 , 3.3 Hz , 2H ) , 7.22 – 7.14 ( m , 2H ) , 5.49 ( t , J = 5.9 Hz , 1H ) , 4.85 – 4.72 ( m , 1H ) , 4.65 ( d , J = 5.8 Hz , 2H ) , 3.45 – 3.28 ( m , 2H ) , 3.01 ( dd , J = 16.0 , 6.0 Hz , 2H ) LCMS ( Method 2 ) : 2.25 min , 387.0 , 389.0 [ M + H ] * Synthesis of [ 3 - bromo - 7- ( indan - 2 - ylcarbamoyl ) pyrazolo [ 1,5 - a ] pyrimidin - 2 - yl ] methyl methanesulfonate N MsCI , Et N DCM , RT N ' N ' Br ' N ' Br .OH -OMS NзtE ( 85 Lμ , 0.61 mmol ) and methanesulfonyl chloride ( 35 Lµ , 0.45 mmol ) were added to a solution of 3 - bromo - 2- ( hydroxymethyl ) -N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide ( 158 mg , 0.41 mmol ) in DCM ( 3 mL ) and the reaction was stirred at room temperature for 2 h . The reaction mixture was diluted with sat . aq . NaHCO3 and DCM and the layers were separated . The organic layer was washed with sat . aq . NaHCO3 ( x 2 ) , dried through a hydrophobic frit , and concentrated in vacuo to provide the title compound ( 1mg ) . - 7.1H NMR ( 400 MHz , CDCl3 ) б 10.29 ( d , J = 7.0 Hz , 1H ) , 8.79 ( d , J = 4.2 Hz , 1H ) , 7.94 ( d , J = 4.2 Hz , 1H ) , 7.33 – 7.15 ( m , 4H ) , 5.41 ( s , 2H ) , 5.03 – 4.91 ( m , 1H ) , 3.47 ( dd , J = 16.0 , Hz , 2H ) , 3.18 – 3.01 ( m , 2H ) , 2.97 ( s , 3H ) - LCMS ( Method 5 ) : 1.12 min , 465.0 , 467.0 [ M + H ] * - 3 - bromo - 2 - [ ( dimethylamino ) methyl ] -N - indan - 2 - yl - pyrazolo [ 1,5- Synthesis of a ] pyrimidine - 7 - carboxamide 390 ' N ' Br N : .OMs Nal , HN₂eM ₂OC₂K , Acetone ° C cost Br Sodium lodide ( 58 mg , 0.39 mmol ) was added to a solution of [ 3 - bromo - 7- ( indan - 2- ylcarbamoyl ) pyrazolo [ 1,5 - a ] pyrimidin - 2 - yl ] methyl methanesulfonate ( 180 mg , 0.39 mmol ) in acetone ( 2 mL ) and the reaction was heated at 60 ° C for 1 h . Me2NH ( 2 M in THF ; 290 Lμ , 0.58 mmol ) and K2CO3 ( 160 mg , 1.16 mmol ) were added and the reaction was heated at ° C for a further 1 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The residue was dissolved in DCM and washed with water . The aqueous layer was extracted with DCM , and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 151 mg ) . ' H NMR ( 400 MHz , CDCl3 ) ō 10.61 ( d , J = 7.1 Hz , 1H ) , 8.72 ( d , J = 4.3 Hz , 1H ) , 7.84 ( d , J = 4.3 Hz , 1H ) , 7.28 ( dd , J = 5.4 , 3.4 Hz , 2H ) , 7.23 – 7.19 ( m , 2H ) , 5.06 – 4.92 ( m , 1H ) , 3.72 ( s , 2H ) , 3.46 ( dd , J = 16.1 , 6.9 Hz , 2H ) , 3.04 ( dd , J = 16.0 , 4.6 Hz , 2H ) , 2.26 ( s , 6H ) - - Synthesis of compound 29 , 2 - [ ( dimethylamino ) methyl ] -N7 - indan - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide H .N . 1. XantPhos Pd GN¸tE , NMP , 120 ° C 2. T3P , N₂tE , NHOH RT to 50 ° C Br N ' N ' NH 3 - Bromo - 2 - [ ( dimethylamino ) methyl ] -N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 150 mg , 0.36 mmol ) , XantPhos Pd G3 ( 34 mg , 0.04 mmol ) , NзtE ( 150 Lμ , 1.09 mmol ) , and NMP ( 2 mL ) were placed in a vial and the vial was sealed and purged with argon for 15 min . ( 2,5 - Dioxopyrrolidin - 1 - yl ) formate ( 259 mg , 1.81 mmol ) was added and the vial was sealed 391 LO immediately . The reaction was heated at 120 ° C in a microwave reactor for 4 h , and then for a further 6 h , during which additional portions of XantPhos Pd G3 ( 69 mg , 0.08 mmol ) , Et3N ( 300 Lμ , 2.18 mmol ) , and ( 2,5 - dioxopyrrolidin - 1 - yl ) formate ( 518 mg , 3.62 mmol ) were added in total . The reaction mixture was cooled to room temperature and NзtE ( 150 Lμ , 1.09 mmol ) , - propanephosphonic anhydride ( 50 wt % in EtOAc ; 430 Lμ , 0.72 mmol ) and NH4OH ( 4Lμ , 3.62 mmol ) were added . The reaction was stirred at room temperature for 16 h , and then heated at 50 ° C for further 4 days , during which additional portions of NзtE ( 300 Lμ , 2.mmol ) , 1 - propanephosphonic anhydride ( 50 wt % in EtOAc ; 860 Lµ , 1.44 mmol ) and NH4OH ( 940 Lμ , 7.24 mmol ) were added in total . The reaction mixture was cooled to room temperature and diluted with water and EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were dried over Na2SOand concentrated in vacuo . The crude product was purified by preparative HPLC ( acidic method ) , SCX chromatography ( eluting with 2 M NH3 in MeOH ) , and column chromatography ( eluting with 0 to 10 % MeOH in DCM ) to provide the title compound ( 8.mg ) . ' H NMR ( 400 MHz , DMSO - d ) § 10.30 ( d , J = 7.1 Hz , 1H ) , 8.89 ( d , J = 4.4 Hz , 1H ) , 7.90 ( s , 1H ) , 7.70 ( d , J = 4.4 Hz , 1H ) , 7.48 ( s , 1H ) , 7.29 ( dd , J = 5.4 , 3.3 Hz , 2H ) , 7.23 - 7.14 ( m , 2H ) , 4.87 - 4.75 ( m , 1H ) , 3.96 ( s , 2H ) , 3.38 ( dd , J = 16.2 , 7.0 Hz , 2H ) , 2.96 ( dd , J = 16.2 , 4.Hz , 2H ) , 2.16 ( s , 6H ) - LCMS ( Method 2 ) : 1.27 min , 379.2 [ M + H ] * Synthesis carboxamide of - bromo - 2 - formyl - N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- Dess - Martin periodinane , DCM , RT .Br N : -OH N Br N = H Dess - Martin periodinane ( 263 mg , 0.62 mmol ) was added in one portion to a solution of 3- bromo - 2- ( hydroxymethyl ) -N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 200 mg , 0.52 mmol ) in DCM ( 12 mL ) and the reaction was stirred at room temperature for 4 h . An additional portion of Dess - Martin periodinane ( 263 mg , 0.62 mmol ) was added and the reaction was stirred at room temperature for a further 2 h . The reaction mixture was diluted with DCM and washed with sat . aq . NaHCO3 . The aqueous layer was extracted with DCM 392 ( x 2 ) , and the combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 141 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) § 10.12 ( s , 1H ) , 9.74 ( d , J = 7.1 Hz , 1H ) , 8.88 ( d , J = 4.2 Hz , - - 1H ) , 7.68 ( d , J = 4.3 Hz , 1H ) , 7.32 - 7.23 ( m , 2H ) , 7.22 – 7.14 ( m , 2H ) , 4.86 – 4.73 ( m , 1H ) , 3.37 ( dd , J = 16.1 , 7.6 Hz , 2H ) , 3.01 ( dd , J = 16.1 , 5.6 Hz , 2H ) LCMS ( Method 1 ) : 1.32 min , 385.0 , 387.0 [ M + H ] * Synthesis of 3 - bromo - N - indan - 2 - yl - 2- ( methylaminomethyl ) pyrazolo [ 1,5 - a ] pyrimidine- - carboxamide H ` N ' N cose N = H MeNH2 , AcOH STAB DCM , RT .Br cos N. ' N ' .Br N = MeNH2 ( 2 M in THF ; 930 Lµ , 1.86 mmol ) and acetic acid ( 36 Lµ , 0.62 mmol ) were added sequentially to a solution of 3 - bromo - 2 - formyl - N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide ( 143 mg , 0.37 mmol ) in DCM ( 7 mL ) and the reaction was stirred at room temperature for 1 h . Sodium triacetoxyborohydride ( 118 mg , 0.56 mmol ) was added in one portion , and the reaction was stirred at room temperature for 2 h . Additional sodium triacetoxyborohydride ( 50 mg , 0.24 mmol ) was added and the reaction was stirred at room temperature for a further 2 h . The reaction mixture was diluted with DCM and washed with sat . aq . NaHCO3 . The aqueous layer was extracted with DCM ( x 2 ) , and the combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 5 % ( 2 M NH3 in MeOH ) in DCM ) to provide the title compound ( 125 mg ) . ' H NMR ( 400 MHz , CDCl3 ) ō 10.61 ( d , J = 5.6 Hz , 1H ) , 8.71 ( d , J = 4.3 Hz , 1H ) , 7.82 ( d , J = 4.3 Hz , 1H ) , 7.33 – 7.28 ( m , 2H ) , 7.25 – 7.21 ( m , 2H ) , 5.08 – 4.96 ( m , 1H ) , 3.91 ( s , 2H ) , 3.( dd , J = 16.0 , 6.8 Hz , 2H ) , 3.04 ( dd , J = 16.0 , 4.2 Hz , 2H ) , 2.37 ( s , 3H ) . Exchangeable proton not observed . LCMS ( Method 1 ) : 0.66 min , 0.74 min , 400.0 , 402.0 [ M + H ] * Synthesis of - [ [ formyl ( methyl ) amino ] methyl ] -N7 - indan - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 393 H 1. XantPhos Pd GN₂tE , NMP , 100 ° C Br 2. N₂tE , T3P , HОHN , RT ' N ' NH 3 - Bromo - N - indan - 2 - yl - 2- ( methylaminomethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 125 mg , 0.31 mmol ) , NMP ( 3 mL ) , and NзtE ( 131 Lμ , 0.94 mmol ) were placed in a vial and the vial was sealed and purged with argon for 5 min . XantPhos Pd G3 ( 30 mg , 0.03 mmol ) was added and the vial was purged with argon for a further 5 min . ( 2,5 - Dioxopyrrolidin - 1 - yl ) formate ( 223 mg , 1.56 mmol ) was added and the vial was sealed immediately . The reaction was heated at 100 ° C in a microwave reactor for 2 h then cooled to room temperature . NзtE ( 131 Lμ , 0.94 mmol ) , 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 372 Lμ , 0.62 mmol ) , and NH4OH ( 405 Lµ , 3.12 mmol ) were added and the reaction was stirred at room temperature for 5 h . The reaction mixture was diluted with EtOAc , filtered through a short pad of ®etilaciD , and concentrated in vacuo to a small volume ( ~ 3 mL ) . The solution of crude product was taken forward to the next step without further purification and assuming 100 % conversion to the title compound . LCMS ( Method 3 ) : 1.05 min , 1.08 min , 393.2 [ M + H ] * Synthesis of compound 30 , N7 - indan - 2 - yl - 2- ( methylaminomethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide HCI , MeOH ° C NHN = cosal 1 M aq .

-H NH HCI ( 10 mL , 10.00 mmol ) was added to the solution of 2- [ [ formyl ( methyl ) amino ] methyl ] -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 3 -H generated in the previous step ( ~ 3 mL ) in MeOH ( 9.4 mL ) and the reaction was heated at ° C for 8 h . The reaction mixture was cooled to room temperature and the crude product was purified by SCX chromatography ( eluting with 2 M NH3 in MeOH ) and column chromatography ( eluting with 0 to 5 % ( 2 M NH3 in MeOH ) in DCM ) to provide the title compound ( 57 mg ) . ' H NMR ( 400 MHz , DMSO - ɓd ) ₫ 10.24 ( d , J = 7.2 Hz , 1H ) , 8.89 ( d , J = 4.4 Hz , 1H ) , 7.82 ( s , 1H ) , 7.68 ( dd , J = 4.4 , 0.8 Hz , 1H ) , 7.59 ( s , 1H ) , 7.34 – 7.25 ( m , 2H ) , 7.24 – 7.15 ( m , 2H ) , - - - 4.87 4.75 ( m , 1H ) , 3.98 ( s , 2H ) , 3.36 ( dd , J = 16.1 , 7.1 Hz , 2H ) , 3.00 ( dd , J = 16.0 , 4.8 Hz , 2H ) , 2.20 ( s , 3H ) . Additional exchangeable proton not observed . LCMS ( Method 2 ) : 1.48 min , 365.2 [ M + H ] * Synthesis of 2 - pyrazolo [ 1,5 - a ] pyridin - 3 - yloxazole Br n - Bu3Sn Pd ( PPh3 ) CSF , CUTC DMF , 100 ° C 3 - Bromopyrazolo [ 1,5 - a ] pyridine ( 500 mg , 2.54 mmol ) was dissolved in DMF ( 5 mL ) and the solution was degassed by sparging with a stream of argon . Tributyl ( oxazol - 2 - yl ) stannane ( mL , 3.30 mmol ) , Pd ( PPh3 ) 4 ( 150 mg , 0.13 mmol ) , thiophene - 2 - carbonyloxycopper ( 629 mg , 3.30 mmol ) , and CSF ( 501 mg , 3.30 mmol ) were added and the reaction was heated at 1° C for 3 h . The reaction mixture was cooled to room temperature , diluted with EtOAc , and filtered through a short pad of ®etilaciD . The filtrate was washed with 5 % aq . LiCl ( x 2 ) and sat . aq . NaHCO3 , and the organic layer was dried over Na2SO4 . A mixture of KF ( 10 wt % ) in silica gel was added , and the mixture was stirred at room temperature for 1 h then concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 243 mg ) . - - 1H NMR ( 400 MHz , CDCl3 ) § 8.57 – 8.50 ( m , 1H ) , 8.46 ( s , 1H ) , 8.30 – 8.23 ( m , 1H ) , 7.67 ( d , J = 0.9 Hz , 1H ) , 7.38 - 7.33 ( m , 1H ) , 7.22 ( d , J = 0.8 Hz , 1H ) , 6.96 – 6.88 ( m , 1H ) LCMS ( Method 1 ) : 1.48 min , 186.2 [ M + H ] * Synthesis of ethyl 2- ( 7 - bromopyrazolo [ 1,5 - a ] pyridin - 3 - yl ) oxazole 395 1. n - BuLi , THF , -78 ° C 2. гBC , -78 ° C to RT ' Br ﻢﻫ n - BuLi ( 2.5 M in hexanes ; 0.29 mL , 0.71 mmol ) was added to a solution of 2 - pyrazolo [ 1,5- a ] pyridin - 3 - yloxazole ( 110 mg , 0.59 mmol ) in THF ( 3 mL ) at 87− ° C and the mixture was stirred for 15 min . Carbon tetrabromide ( 256 mg , 0.77 mmol ) was added in one portion , and the reaction was stirred at 87− ° C for 45 min . The reaction mixture was warmed to room temperature , stirred for 1.5 h , then quenched with water and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 35 mg ) . 1H NMR ( 400 MHz , CDCl3 ) б 8.60 ( s , 1H ) , 8.39 – 8.30 ( m , 1H ) , 7.72 ( d , J = 0.9 Hz , 1H ) , 7.– 7.28 ( m , 1H ) , 7.28 – 7.26 ( m , 2H ) - - LCMS ( Method 1 ) : 1.65 min , 264.2 [ M + H ] + Synthesis of compound 31 , N - indan - 2 - yl - 3 - oxazol - 2 - yl - pyrazolo [ 1,5 - a ] pyridine - 7- carboxamide Br ' N ' N H 1. XantPhos Pd GEt3N , DMF , 70 ° C 2. N₂tE , T3P DMF , RT -NH2.HCI 2- ( 7 - Bromopyrazolo [ 1,5 - a ] pyridin - 3 - yl ) oxazole ( 35 mg , 0.13 mmol ) was dissolved in DMF ( mL ) and the solution was degassed by sparging with a stream of argon . ( 2,5 - Dioxopyrrolidin- - yl ) formate ( 38 mg , 0.27 mmol ) , XantPhos Pd G3 ( 13 mg , 0.01 mmol ) , and NзtE ( 40 Lμ , 396 LO 0.27 mmol ) were added , and the vial was sealed immediately . The reaction was heated at ° C for 2 h then cooled to room temperature . A solution of indan - 2 - amine hydrochloride ( 45 mg , 0.27 mmol ) and NзtE ( 40 Lμ , 0.27 mmol ) in DMF ( 500 Lµ ) was added dropwise and the reaction was stirred at room temperature for 1 h . 1 - Propanephosphonic anhydride ( wt % in DMF ; 160 Lμ , 0.27 mmol ) was added , and the reaction was stirred for a further 60 h . The reaction mixture was diluted with EtOAc and washed with 5 % aq . LiCl ( x 2 ) and brine . The organic layer was dried over Na2SO4 , filtered through a plug of silica gel , and concentrated in vacuo . The crude product was purified by preparative HPLC ( acidic method ) to provide the title compound ( 21 mg ) .

- - ' H NMR ( 400 MHz , 3№CDC ) г 10.85 ( d , J = 7.1 Hz , 1H ) , 8.52 ( dd , J = 8.9 , 1.5 Hz , 1H ) , 8.( s , 1H ) , 8.16 ( dd , J = 7.2 , 1.5 Hz , 1H ) , 7.73 ( d , J = 0.9 Hz , 1H ) , 7.55 ( dd , J = 8.8 , 7.2 Hz , 1H ) , 7.31 ( dd , J = 5.4 , 3.4 Hz , 2H ) , 7.27 ( d , J = 0.8 Hz , 1H ) , 7.26 – 7.21 ( m , 2H ) , 5.09 – 4.( m , 1H ) , 3.54 ( dd , J = 16.0 , 7.6 Hz , 2H ) , 3.13 ( dd , J = 16.0 , 6.1 Hz , 2H ) LCMS ( Method 2 ) : 2.71 min , 345.2 [ M + H ] * Synthesis of ethyl 3 - cyano - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate NHEtOH , 80 ° C OEt HN .CN EtO .CN EtO N = N : Ethyl ( E ) -4 - ethoxy - 2 - oxo - but - 3 - enoate ( 10.86 g , 63.05 mmol ) was added to a solution of 5- amino - 3 - methyl - 1H - pyrazole - 4 - carbonitrile ( 7 g , 57.32 mmol ) in EtOH ( 200 mL ) and the reaction was heated at 80 ° C for 1 h . The reaction mixture was cooled to room temperature and concentrated in vacuo to 50 % solvent volume . The solution was cooled to 0 ° C and left to stand for 1 h . The mixture was warmed to room temperature overnight , and the resulting precipitate was collected by filtration and dried to provide the title compound ( 6.05 g ) . § ' H NMR ( 400 MHz , DMSO - d6 ) Ŏ 8.90 ( d , J = 4.4 Hz , 1H ) , 7.67 ( d , J = 4.4 Hz , 1H ) , 4.47 ( q , J = 7.1 Hz , 2H ) , 2.56 ( s , 3H ) , 1.36 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 2 ) : 1.91 min , 231.2 [ M + H ] + Synthesis of 3 - cyano - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid 397 EtO .

NaOH THF , O₂H RT HO CN N CN N : N 2 M aq . NaOH ( 60.8 mL , 121.62 mmol ) was added to a solution of ethyl 3 - cyano - 2 - methyl- pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 5.6 g , 24.32 mmol ) in THF ( 45 mL ) and MeOH ( mL ) and the reaction was stirred at room temperature for 3 h . The reaction mixture was acidified with 1 M aq . HCI and cooled to 5 ° C . The resulting precipitate was collected by filtration and suspended in water . The aqueous suspension was extracted with EtOAc ( × 5 ) , and the combined organic layers were concentrated in vacuo to provide the title compound ( 4.51 g ) . ' H NMR ( 400 MHz , DMSO - d6 ) ō 8.88 ( d , J = 4.3 Hz , 1H ) , 7.60 ( d , J = 4.4 Hz , 1H ) , 2.57 ( s , 3H ) . Exchangeable proton not observed . LCMS ( Method 1 ) 0.72 min , 159.2 [ M - CO2H + H ] * Synthesis of 3 - cyano - N- ( 3,3 - difluorocyclobutyl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine- - carboxamide F -NH2.HCI N HO T3P , N₂tE DMF , RT N H .N . CN .CN N = N : 1 - Propanephosphonic anhydride ( 50 wt % in DMF ; 6.8 mL , 11.65 mmol ) was added dropwise to a solution of 3 - cyano - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 833 mg , 4.mmol ) , 3,3 - difluorocyclobutanamine hydrochloride ( 888 mg , 6.19 mmol ) and NзtE ( 3.1 mL , 22.24 mmol ) in DMF ( 5 mL ) and the reaction was stirred at room temperature for 16 h . The reaction mixture was acidified with 1 M aq . HCI and diluted with water . The resulting precipitate was collected by filtration , washed with water , and dried to provide the title compound ( 756 mg ) .

- - ' H NMR ( 400 MHz , DMSO - d6 ) ō 9.90 ( d , J = 6.5 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.65 ( d , J = 4.4 Hz , 1H ) , 4.42 – 4.26 ( m , 1H ) , 3.15 - 2.99 ( m , 2H ) , 2.87 – 2.74 ( m , 2H ) , 2.61 ( s , 3H ) LCMS ( Method 3 ) : 0.98 min , 292.2 [ M + H ] * 398 Synthesis of 6 - bromo - 3 - cyano - N- ( 3,3 - difluorocyclobutyl ) -2 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide Br Br Br Br . TFA , 70 ° C H ' N ' N = .CN CN N = 1,3,5 - Tribromo - 1,3,5 - triazinane - 2,4,6 - trione ( 754 mg , 206 mmol ) was added to a solution of - cyano - N- ( 3,3 - difluorocyclobutyl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 4mg , 1.37 mmol ) in TFA ( 6.8 mL , 88.86 mmol ) and the reaction was heated at 70 ° C for 4 h . The reaction mixture was cooled to room temperature and diluted with sat . aq . NaHCO3 and EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were washed with sat . aq . Na2SO3 ( x 2 ) , sat . aq . NaHCO3 ( x ) , and brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 60 % EtOAc in heptane ) to provide the title compound ( 306 mg ) . 1H NMR ( 400 MHz , CDCl3 ) г 8.71 ( s , 1H ) , 7.79 ( d , J = 6.6 Hz , 1H ) , 4.55 – 4.40 ( m , 1H ) , 3.- - 3.04 ( m , 2H ) , 2.72 – 2.58 ( m , 2H ) , 2.55 ( s , 3H ) LCMS ( Method 1 ) : 1.62 min , 370.0 , 372.0 [ M + H ] * - Synthesis of 3 - cyano - N- ( 3,3 - difluorocyclobutyl ) -2 - methyl - 6- ( 1 - tetrahydropyran - 2- ylpyrazol - 4 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide Br H .N .

Pd ( dppf ) ₂lC 3OC₂K 1,4 - Dioxane , O₂H ° C CN Bpin H ' N ' .CN F N = LO 1 - Tetrahydropyran - 2 - yl - 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) pyrazole ( 390 mg , 1.40 mmol ) , K2CO3 ( 280 mg , 2.03 mmol ) , and Pd ( dppf ) Cl2 ( 50 mg , 0.07 mmol ) were added to a solution of 6 - bromo - 3 - cyano - N- ( 3,3 - difluorocyclobutyl ) -2 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide ( 250 mg , 0.68 mmol ) in 1,4 - dioxane ( 2.3 mL ) and water ( 2Lμ ) and the reaction was heated at 90 ° C for 20 h . The reaction mixture was cooled to room temperature and diluted with EtOAc and water . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 133 mg ) . = - 1H NMR ( 400 MHz , ³lCDC ) ₫ 8.77 ( s , 1H ) , 7.95 ( d , J = 0.8 Hz , 1H ) , 7.77 ( d , J = 0.8 Hz , 1H ) , 7.10 ( d , J 6.8 Hz , 1H ) , 5.42 ( dd , J = 9.1 , 3.1 Hz , 1H ) , 4.56 - 4.42 ( m , 1H ) , 4.13 4.06 ( m , 1H ) , 3.78 – 3.68 ( m , 1H ) , 3.18 – 3.03 ( m , 2H ) , 2.66 – 2.49 ( m , 5H ) , 2.19 – 2.00 ( m , 3H ) , 1.- 1.62 ( m , 3H ) - - - - Synthesis of compound 32 , N7- ( 3,3 - difluorocyclobutyl ) -2 - methyl - 6- ( 1H - pyrazol - 4- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide H .N . ` N .CN N = 4OS₂H , O₂H RT H ' N ' NHN : 3 - Cyano - N- ( 3,3 - difluorocyclobutyl ) -2 - methyl - 6- ( 1 - tetrahydropyran - 2 - ylpyrazol - 4- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 133 mg , 0.30 mmol ) was dissolved in H2SO( 550 Lμ , 10.26 mmol ) and water ( 61 Lμ , 3.39 mmol ) and the reaction was stirred at room temperature for 4 h . The reaction mixture was neutralised with sat . aq . NaHCO3 and extracted with EtOAc ( x 3 ) . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by preparative HPLC ( basic and acidic methods ) to provide the title compound ( 33 mg ) . 400 LO - ' H NMR ( 400 MHz , DMSO - d ) § 13.28 ( s , 1H ) , 9.67 ( d , J = 6.2 Hz , 1H ) , 9.07 ( s , 1H ) , 8.( s , 1H ) , 7.84 ( s , 1H ) , 7.56 ( s , 1H ) , 7.47 ( s , 1H ) , 4.37 – 4.25 ( m , 1H ) , 3.16 – 3.01 ( m , 2H ) , 2.65 – 2.52 ( m , 5H ) LCMS ( Method 2 ) : 1.31 min , 376.0 [ M + H ] * - Synthesis of ethyl 2 - bromo - 3 - cyano - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate OEt EtO NHEtOH , 80 ° C .CN EtO . HN ' N ' .CN N : N = Br Br - Amino - 3 - bromo - 1H - pyrazole - 4 - carbonitrile ( 5 g , 26.74 mmol ) was added to a solution of ethyl ( E ) -4 - ethoxy - 2 - oxo - but - 3 - enoate ( 5.06 g , 29.41 mmol ) in EtOH ( 75 mL ) and the reaction was heated at 80 ° C for 4 h . An additional portion of ethyl ( E ) -4 - ethoxy - 2 - oxo - but- - enoate ( 3 g , 17.40 mmol ) was added and the reaction was heated at 80 ° C overnight . The reaction mixture was cooled to room temperature and concentrated in vacuo . Cold EtOH ( 10 ) mL ) was added to the residue , and the resulting suspension was cooled to 0 ° C and allowed to stand for 1 h . The precipitate was collected by filtration , washed with EtOH , and dried to provide the title compound ( 3.2 g ) . 1H NMR ( 400 MHz , DMSO - d6 ) ☎ 9.02 ( d , J = 4.4 Hz , 1H ) , 7.81 ( d , J = 4.4 Hz , 1H ) , 4.50 ( q , J. = 7.1 Hz , 2H ) , 1.38 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 1 ) : 0.98 min , 295.0 , 297.0 [ M + H ] * Synthesis of 2 - bromo - 3 - cyano - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid EtO .

LiOH THF , MeOH RT HO ' N ' .CN ' N ' .CN N : Br Br 2 M aq . LiOH ( 930 Lμ , 1.86 mmol ) was added dropwise to a solution of ethyl 2 - bromo - 3- cyano - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 500 mg , 1.69 mmol ) in THF ( 2 mL ) and 401 LO - EtOH ( 2 mL ) and the reaction was stirred at room temperature for 3 h . The reaction mixture was concentrated in vacuo and the residue was diluted with water and acidified to pH 1 with 5 M aq . HCI . The aqueous suspension was extracted with a 1:19 mixture of MeOH : EtOAc ( x 3 ) , and the combined organic layers were washed with brine , dried through a hydrophobic frit , and concentrated in vacuo to provide the title compound ( 435 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) ō 8.97 ( d , J = 4.4 Hz , 1H ) , 7.70 ( d , J = 4.4 Hz , 1H ) . Exchangeable proton not observed . ☎ LCMS ( Method 1 ) : 0.80 min , 0.96 min ( product does not ionise ) Synthesis of 2 - bromo - 3 - cyano - N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide -NH2.HCI HO T3P , DIPEA EtOAc , RT ' N ' .CN Br N ' N ' .CN N = Br 1 - Propanephosphonic anhydride ( 50 wt % in EtOAc ; 1.78 mL , 3.02 mmol ) was added to a suspension of 2 - bromo - 3 - cyano - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 403 mg , 1.mmol ) , indan - 2 - amine hydrochloride ( 307 mg , 1.81 mmol ) , and DIPEA ( 790 Lμ , 4.53 mmol ) in EtOAc ( 7 mL ) and the reaction was stirred at room temperature for 18 h . The reaction mixture was diluted with water and a 1:19 mixture of MeOH : EtOAc . The layers were separated , and the organic layer was washed with sat . aq . NH4Cl and sat . aq . NaHCO3 , dried over Na2CO3 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 60 % EtOAc in heptane ) to provide the title compound ( 4mg ) . – 1H NMR ( 400 MHz , CDCl3 ) б 9.86 ( d , J = 7.2 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 8.03 ( d , J = 4.4 Hz , 1H ) , 7.33 – 7.18 ( m , 4H ) , 5.04 - 4.91 ( m , 1H ) , 3.54 - 3.45 ( m , 2H ) , 3.05 ( dd , J = 15.9 , 5.7 Hz , 2H ) - LCMS ( Method 1 ) : 1.83 min , 382.0 , 384.0 [ M + H ] * Synthesis of - cyano - N - indan - 2 - yl - 2 - oxazol - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide 402 Pd ( PPh3 ) MeCN H Sn ( n - Bu ) 150 ° C ' N CN ₁N .CN Br Pd ( PPh3 ) 4 ( 29 mg , 0.04 mmol ) , tributyl ( oxazol - 2 - yl ) stannane ( 170 Lμ , 0.55 mmol ) , and 2- bromo - 3 - cyano - N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 150 mg , 0.39 mmol ) were dissolved in MeCN ( 5 mL ) and the solution was degassed by sparging with a stream of argon for 5 min . The reaction was heated at 150 ° C in a microwave reactor for 2 h then cooled to room temperature . The reaction mixture was filtered through a short pad of ⓇetilaciD , washed with EtOAc , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 10 mg ) . 1H NMR ( 400 MHz , DMSO - d ) § 9.70 ( d , J = 7.2 Hz , 1H ) , 9.04 ( d , J = 4.4 Hz , 1H ) , 8.49 ( d , J = : 0.8 Hz , 1H ) , 7.77 ( d , J = 4.4 Hz , 1H ) , 7.66 ( d , J = 0.8 Hz , 1H ) , 7.30 ( t , J = 4.4 Hz , 2H ) , 7.- – 7.16 ( m , 2H ) , 4.86 – 4.79 ( m , 1H ) , 3.43 ( d , J = 2.3 Hz , 2H ) , 2.98 ( dd , J = 16.1 , 5.0 Hz , 2H ) LCMS ( Method 1 ) : 1.74 min , 371.0 [ M + H ] * Synthesis of compound 33 , N7 - indan - 2 - yl - 2 - oxazol - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide HO .

H N ' N ' .CN Pd ( OAc ) 2 , PS - PPhEtOH , O₂H , 90 ° C H NHN = 3 - Cyano - N - indan - 2 - yl - 2 - oxazol - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 17 mg , 0.- mmol ) , acetaldehyde oxime ( 11 Lμ , 0.18 mmol ) , and PS - ³hPP ( 1.4 – 2 mmol / g ; 130 mg , 0.– 0.26 mmol ) were dissolved in EtOH ( 4 mL ) and water ( 1 mL ) , and the solution was degassed by sparging with a stream of argon for 5 min . Pd ( OAc ) 2 ( 1.6 mg , 0.01 mmol ) was added and the reaction was heated at 90 ° C for 3 days . The reaction mixture was cooled to 403 room temperature , filtered through a short pad of ®etilaciD , and washed with EtOAc , DCM , and MeOH . The filtrate was concentrated in vacuo , and the crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) and preparative HPLC ( basic method ) to provide the title compound ( 3.6 mg ) . ☎ ' H NMR ( 400 MHz , DMSO - d6 ) 5 9.88 ( d , J = 6.7 Hz , 1H ) , 8.95 ( d , J = 4.3 Hz , 1H ) , 8.36 ( d , J = 0.8 Hz , 1H ) , 8.01 ( s , 1H ) , 7.66 ( d , J = 4.3 Hz , 1H ) , 7.65 ( s , 1H ) , 7.52 ( d , J = 0.8 Hz , 1H ) , 7.28 ( dd , J = 5.4 , 3.3 Hz , 2H ) , 7.18 ( dd , J = 5.5 , 3.2 Hz , 2H ) , 4.83 – 4.74 ( m , 1H ) , 3.45 ( s , 2H ) , 2.97 ( dd , J = 16.1 , 5.3 Hz , 2H ) LCMS ( Method 2 ) : 2.07 min , 389.2 [ M + H ] + - Synthesis of 2 - bromo - 3 - cyano - N- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide F ✓ -NH2.HCI T3P , N₂tE , DMF RT H HO . N. .CN CN Na Br Br 1 - Propanephosphonic anhydride ( 50 wt % in DMF ; 2.9 mL , 4.89 mmol ) and N³tE ( 681 Lµ , 4.89 mmol ) were added to a solution of 2 - bromo - 3 - cyano - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxylic acid ( 435 mg , 1.63 mmol ) and 3,3 - difluorocyclobutanamine hydrochloride ( 3mg , 2.44 mmol ) in DMF ( 5 mL ) and the reaction was stirred at room temperature for 20 h . The reaction mixture was diluted with DCM and water and the layers were separated . The aqueous layer was extracted with DCM , and the combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 5mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) Ŏ 9.65 ( s , 1H ) , 9.01 ( d , J = 4.4 Hz , 1H ) , 7.67 ( d , J = 4.4 Hz , 1H ) , 4.39 – 4.27 ( m , 1H ) , 3.14 – 3.01 ( m , 2H ) , 2.83 – 2.68 ( m , 2H ) - - LCMS ( Method 1 ) : 1.21 min , 354.0 , 356.0 [ M − H ] ¯ Synthesis of dicarboxamide - 2 - bromo - N7- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- 404 .N . ąsx 4OS₂H , RT .N . -CN ` N NHN : Br N = Br 2 - Bromo - 3 - cyano - N- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 2mg , 0.78 mmol ) was dissolved in conc . H2SO4 ( 770 Lμ , 14.36 mmol ) and the reaction was stirred at room temperature for 1.5 h . The reaction mixture was cooled to 0 ° C and diluted with ice - cold water . The mixture was basified with NH3 ( 28 - 30 wt % in water ) and the resulting precipitate was collected by filtration , washed with water , and dried to provide the title compound ( 299 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) 8 9.74 ( s , 1H ) , 8.94 ( d , J = 4.4 Hz , 1H ) , 7.68 ( s , 2H ) , 7.58 ( d , J = 4.4 Hz , 1H ) , 4.44 – 4.27 ( m , 1H ) , 3.20 – 3.01 ( m , 2H ) , 2.85 – 2.67 ( m , 2H ) LCMS ( Method 1 ) : 0.99 min , 374.0 , 376.0 [ M + H ] * - - Synthesis of compound 34 , N7- ( 3,3 - difluorocyclobutyl ) -2- ( methylamino ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ' N ' Br NH O₂uC , MeNH2 , THE ethylene glycol 140 ° C NHN 2 - Bromo - N7- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 100 mg , 0.27 mmol ) , O₂uC ( 4 mg , 0.03 mmol ) , and MeNH2 ( 2 M in THF ; 4 mL , 8.02 mmol ) were suspended in ethylene glycol ( 1.1 mL ) and the reaction was heated at 140 ° C in a microwave reactor for 4 h . The reaction mixture was cooled to room temperature and diluted with MeOH . The mixture was filtered through a short pad of ®etilaciD and washed with MeOH and DCM . The filtrate was concentrated in vacuo and the crude product was purified by column chromatography ( eluting with 0 to 5 % MeOH in DCM ) to provide the title compound ( 12 mg ) . ' H NMR ( 400 MHz , ³lCDC ) ₫ 11.04 ( d , J = 6.6 Hz , 1H ) , 8.53 ( d , J = 4.6 Hz , 1H ) , 7.69 ( s , 1H ) , 7.65 ( d , J = 4.6 Hz , 1H ) , 6.92 ( s , 1H ) , 5.52 ( s , 1H ) , 4.62 – 4.47 ( m , 1H ) , 3.25 – 3.12 ( m , 2H ) , 3.10 ( s , 3H ) , 2.74 - 2.58 ( m , 2H ) LCMS ( Method 2 ) : 2.06 min , 325.2 [ M + H ] * - 405 Synthesis of 35 , N7- ( 3,3 - difluorocyclobutyl ) -2- compound ( dimethylamino ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide NH O₂uC , HN₂eM , THE ethylene glycol 140 ° C .N . ągos N NHBr N- 2 - Bromo - N7- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 50 mg , 0.13 mmol ) , O₂uC ( 1.9 mg , 0.01 mmol ) , and Me2NH ( 2 M in THF ; 2 mL , 4.01 mmol ) were suspended in ethylene glycol ( 530 Lμ ) and the reaction was heated at 140 ° C in a microwave reactor for 4 h . The reaction mixture was cooled to room temperature and diluted with MeOH . The mixture was filtered through a short pad of ⓇetilaciD and washed with MeOH and DCM . The filtrate was concentrated in vacuo and the crude product was purified twice by column chromatography ( eluting with 0 to 5 % MeOH in DCM and then with 0 to 3 % MeOH in DCM ) to provide the title compound ( 23 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) ō 10.39 ( d , J = 5.7 Hz , 1H ) , 8.70 ( d , J = 4.5 Hz , 1H ) , 7.91 ( s , 1H ) , 7.49 ( d , J = 4.5 Hz , 1H ) , 7.31 ( s , 1H ) , 4.45 - 4.32 ( m , 1H ) , 3.20 - 3.07 ( m , 8H ) , 2.79 - 2.63 ( m , 2H ) LCMS ( Method 2 ) : 2.04 min , 339.2 [ M + H ] + Synthesis of ethyl 3- ( 2 - fluorophenyl ) prop - 2 - ynoate LOE OEt n - BuLi , O₂tE -78 ° C to RT OEt fol n - BuLi ( 2.5 M in hexanes ; 7.33 mL , 18.32 mmol ) was added slowly to a solution of 1 - ethynyl- - fluoro - benzene ( 1.89 mL , 16.65 mmol ) in O₂tE ( 30 mL ) at -78 ° C and the reaction was stirred at -78 ° C for 30 min . Ethyl chloroformate ( 1.9 mL , 19.98 mmol ) was added , and the reaction was warmed to room temperature and stirred for 2 h . The reaction mixture was 406 cooled to 0 ° C and quenched with sat . aq . NH4Cl . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 40 % EtOAc in heptane ) to provide the title compound ( 2.07 g ) . - 1H NMR ( 400 MHz , ³lCDC ) б 7.61 – 7.51 ( m , 1H ) , 7.49 — 7.39 ( m , 1H ) , 7.20 – 7.05 ( m , 2H ) , 4.30 ( q , J = 7.1 Hz , 2H ) , 1.35 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 1 ) : 1.85 min ( product does not ionise ) Synthesis of ethyl 2- ( 2 - fluorophenyl ) pyrazolo [ 1,5 - a ] pyridine - 3 - carboxylate NHן OEt 3OC₂K DMF , RT OEt Na F Pyridin - 1 - ium - 1 - amine iodide ( 1.73 g , 7.80 mmol ) , ethyl 3- ( 2 - fluorophenyl ) prop - 2 - ynoate ( 1.g , 7.80 mmol ) , and K2CO3 ( 1.62 g , 11.71 mmol ) were dissolved in DMF ( 7 mL ) and the reaction was stirred at room temperature overnight . The reaction mixture was poured into water and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 30 % EtOAc in heptane ) to provide the title compound ( 584 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) г 8.90 ( dt , J = 6.9 , 1.1 Hz , 1H ) , 8.13 ( dt , J = 8.9 , 1.2 Hz , 1H ) , 7.65 ( ddd , J = 8.9 , 6.9 , 1.1 Hz , 1H ) , 7.60 – 7.49 ( m , 2H ) , 7.36 - 7.26 ( m , 2H ) , 7.21 ( td , J = - - 6.9 , 1.4 Hz , 1H ) , 4.16 ( q , J = 7.1 Hz , 2H ) , 1.14 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 1 ) : 1.84 min , 285.2 [ M + H ] * Synthesis of ethyl 7 - bromo - 2- ( 2 - fluorophenyl ) pyrazolo [ 1,5 - a ] pyridine - 3 - carboxylate 407 F LiHMDS , CBr O₂tE -78 ° C to RT Br OEt F OEt LiHMDS ( 1 M in THF ; 2.56 mL , 2.56 mmol ) was added to a solution of ethyl 2- ( 2- fluorophenyl ) pyrazolo [ 1,5 - a ] pyridine - 3 - carboxylate ( 560 mg , 1.97 mmol ) in Et2O ( 20 mL ) at -78 ° C and the mixture was stirred at -78 ° C for 30 min . Carbon tetrabromide ( 979 mg , 2.mmol ) was added in one portion , and the reaction was warmed to room temperature and stirred for 1.5 h . The reaction mixture was cooled to 0 ° C and quenched by the slow addition of sat . aq . NH4Cl . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 40 % EtOAc in heptane ) to provide the title compound ( 439 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) ō 8.19 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 7.65 ( dd , J = 7.4 , 1.3 Hz , 1H ) , 7.60 -7.54 ( m , 3H ) , 7.39 – 7.29 ( m , 2H ) , 4.18 ( q , J = 7.1 Hz , 2H ) , 1.15 ( t , J = 7.1 Hz , 3H ) - LCMS ( Method 1 ) : 1.98 min , 363.0 , 365.2 [ M + H ] * Synthesis of ethyl 2- ( 2 - fluorophenyl ) -7- ( indan - 2 - ylcarbamoyl ) pyrazolo [ 1,5 - a ] pyridine- - carboxylate H 1. XantPhos Pd GEt3N , DMF , 90 ° C H ' N OEt N = Br ` N` N = OEt 2. N₂tE , T3P , 50 ° ℃ -NH2.HCI 408 LO Ethyl 7 - bromo - 2- ( 2 - fluorophenyl ) pyrazolo [ 1,5 - a ] pyridine - 3 - carboxylate ( 400 mg , 1.10 mmol ) was dissolved in DMF ( 4 mL ) and the solution was degassed by sparging with a stream of argon . NзtE ( 307 Lμ , 2.20 mmol ) , XantPhos Pd G3 ( 52 mg , 0.06 mmol ) , and ( 2,5- dioxopyrrolidin - 1 - yl ) formate ( 472 mg , 3.30 mmol ) were added , and the vial was sealed immediately . The reaction was heated at 90 ° C for 4 h then cooled to room temperature . Indan - 2 - amine hydrochloride ( 186 mg , 1.10 mmol ) , NзtE ( 307 Lµ , 2.20 mmol ) , and 1- propylphosphonic anhydride ( 50 wt % in EtOAc ; 1.31 mL , 2.20 mmol ) were added , and the reaction was heated at 50 ° C for 18 h . The reaction mixture was cooled to room temperature and diluted with EtOAc and water . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were washed with 5 % aq . LiCl ( x ) , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 60 % EtOAc in heptane ) to provide the title compound ( 2mg ) . 1H NMR ( 400 MHz , ³ICDC ) ₫ 10.92 ( d , J = 7.2 Hz , 1H ) , 8.42 ( dd , J = 8.9 , 1.5 Hz , 1H ) , 8.( dd , J = 7.3 , 1.5 Hz , 1H ) , 7.65 - 7.54 ( m , 1H ) , 7.53 - 7.39 ( m , 1H ) , 7.41 - 7.35 ( m , 1H ) , 7.– 7.09 ( m , 5H ) , 4.95 – 4.87 ( m , 1H ) , 4.28 ( q , J = 7.1 Hz , 2H ) , 3.43 ( dd , J = 15.9 , 7.0 Hz , 2H ) , 2.99 ( dd , J = 15.9 , 5.3 Hz , 2H ) , 1.23 ( t , J = 7.1 Hz , 4H ) LCMS ( Method 1 ) : 2.10 min , 444.2 [ M + H ] + Synthesis of 2- ( 2 - fluorophenyl ) -7 - indan - 2 - ylcarbamoyl ) pyrazolo [ 1,5 - a ] pyridine - 3- carboxylic acid H .N . LiOH MeOH , THF reflux OEt N F- cosge F OH 2 M aq . LiOH ( 230 Lµ , 0.45 mmol ) was added to a solution of ethyl 2- ( 2 - fluorophenyl ) -7- ( indan - 2 - ylcarbamoyl ) pyrazolo [ 1,5 - a ] pyridine - 3 - carboxylate ( 200 mg , 0.45 mmol ) in THF ( mL ) and MeOH ( 3 mL ) , and the reaction was heated at reflux overnight . The reaction mixture was cooled to room temperature and concentrated in vacuo . The residue was dissolved in water and TBME , and the layers were separated . The aqueous layer was acidified to pH with 5 M aq . HCI and extracted with a 1 : 9 mixture of MeOH : DCM ( x3 ) . The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 1mg ) . 409 ' H NMR ( 400 MHz , DMSO - d ) § 10.26 ( d , J = 7.2 Hz , 1H ) , 8.32 ( dd , J = 8.8 , 1.5 Hz , 1H ) , 7.81 ( dd , J = 7.2 , 1.5 Hz , 1H ) , 7.72 ( dd , J = 8.8 , 7.2 Hz , 1H ) , 7.58 – 7.49 ( m , 1H ) , 7.41 ( td , J - - = 7.4 , 1.8 Hz , 1H ) , 7.35 – 7.26 ( m , 2H ) , 7.23 ( dd , J = 5.4 , 3.4 Hz , 2H ) , 7.19 – 7.11 ( m , 2H ) , - - 4.85 – 4.68 ( m , 1H ) , 2.91 ( dd , J = 16.0 , 4.8 Hz , 2H ) . Exchangeable proton not observed , 2H obscured by solvent peak . LCMS ( Method 1 ) : 1.84 min , 416.2 [ M + H ] + Synthesis of compound 36 , 2- ( 2 - fluorophenyl ) -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyridine- 3,7 - dicarboxamide N. ' N ' NHCI , HATU DIPEA DMF , RT OH F F 2- ( 2 - Fluorophenyl ) -7- ( indan - 2 - ylcarbamoyl ) pyrazolo [ 1,5 - a ] pyridine - 3 - carboxylic acid ( 1mg , 0.24 mmol ) , HATU ( 138 mg , 0.36 mmol ) , DIPEA ( 130 Lµ , 0.72 mmol ) , and NH4Cl ( mg , 0.72 mmol ) were dissolved in DMF ( 2 mL ) and the reaction was stirred at room temperature overnight . The reaction mixture was poured into water and stirred for 30 min , and the resulting precipitate was collected by filtration and dried . The crude product was purified by preparative HPLC ( basic method ) to provide the title compound ( 35 mg ) .

- ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.54 ( d , J = 7.2 Hz , 1H ) , 8.11 ( dd , J = 8.9 , 1.5 Hz , 1H ) , 7.83 ( dd , J = 7.2 , 1.5 Hz , 1H ) , 7.64 – 7.48 ( m , 2H ) , 7.40 ( td , J = 7.5 , 1.7 Hz , 1H ) , 7.36 – 7.( m , 5H ) , 7.227.15 ( m , 2H ) , 4.85 - 4.77 ( m , 1H ) , 2.94 ( dd , J = 16.0 , 4.4 Hz , 2H ) . Additional exchangeable proton not observed , 2H obscured by solvent peak . LCMS ( Method 2 ) : 2.43 min , 415.2 [ M + H ] * Synthesis of 2- ( tetrahydrofuran - 3 - carbonyl ) propanedinitrile NH2 HO 1. ( COCI ) 2 , DMF DCM , RT 2. NaH , THF ° C to RT NC CN CN NC OH DMF ( 167 Lμ , 2.15 mmol ) was added to a solution of tetrahydrofuran - 3 - carboxylic acid ( 2.mL , 21.53 mmol ) in DCM ( 50 mL ) , followed by the dropwise addition of oxalyl chloride ( 2.mL , 25.84 mmol ) over 1 h . The reaction was stirred at room temperature for 1 h then concentrated in vacuo . NaH ( 1.66 g , 41.62 mmol ) was suspended in THF ( 10 mL ) and the mixture was cooled to 0 ° C . A solution of propanedinitrile ( 1.37 g , 20.81 mmol ) in THF ( mL ) was added dropwise over 15 min and the reaction was stirred at room temperature for a further 15 min . The reaction mixture was cooled back to 0 ° C and a solution of tetrahydrofuran - 3 - carbonyl chloride ( formed as above , 2.8 g , 20.81 mmol ) in THF ( 10 mL ) was added dropwise over 15 min . The reaction was stirred at room temperature for 24 h then quenched with water . The mixture was acidified with 1 M aq . HCI and diluted with EtOAc . The layers were separated , and the organic layer was washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) to provide the title compound ( 4mg ) . - - - 1H NMR ( 400 MHz , MeOD ) 5 3.98 – 3.90 ( m , 1H ) , 3.89 – 3.82 ( m , 1H ) , 3.80 – 3.69 ( m , 2H ) , 3.65 3.56 ( m , 1H ) , 2.13 – 2.02 ( m , 2H ) . Exchangeable proton not observed . LCMS ( Method 2 ) : 1.36 min , 163.2 [ M − H ] ¯ - Synthesis of 2- [ methoxy ( tetrahydrofuran - 3 - yl ) methylene ] propanedinitrile NC CN OH co ( MeO ) , CH ° C CN NC OMe 2- [ Hydroxy ( tetrahydrofuran - 3 - yl ) methylene ] propanedinitrile ( 735 mg , 4.48 mmol ) was dissolved in trimethoxymethane ( 8 mL , 73.12 mmol ) and the reaction was heated at 70 ° C for 15 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . 411 The crude product was purified by column chromatography ( eluting with 0 to 40 % EtOAc in heptane ) to provide the title compound ( 492 mg ) . - - ' H NMR ( 400 MHz , CDCl3 ) г 4.40 ( s , 3H ) , 3.97 – 3.87 ( m , 2H ) , 3.87 – 3.76 ( m , 2H ) , 3.72 – 3.63 ( m , 1H ) , 2.30 – 2.20 ( m , 1H ) , 2.10 – 1.99 ( m , 1H ) - - LCMS ( Method 2 ) : 1.66 min , 177.0 [ M − H ] ¯ Synthesis of 5 - amino - 3 - tetrahydrofuran - 3 - yl - 1H - pyrazole - 4 - carbonitrile ﺢﻴﻣ CN NC eMŎ NHNH , NH , H , O EtOH , RT .CN HN N Hydrazine monohydrate ( 230 Lμ , 4.72 mmol ) was added to a solution of 2- [ methoxy ( tetrahydrofuran - 3 - yl ) methylene ] propanedinitrile ( 488 mg , 2.74 mmol ) in EtOH ( mL ) and the reaction was stirred at room temperature for 1.5 h then concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in DCM ) to provide the title compound ( 302 mg ) . - ' H NMR ( 400 MHz , DMSO - d ) § 11.80 ( s , 1H ) , 6.15 ( s , 2H ) , 3.96 ( t , J = 7.9 Hz , 1H ) , 3.86 – 3.69 ( m , 2H ) , 3.69 – 3.61 ( m , 1H ) , 3.29 ( d , J = 7.6 Hz , 1H ) , 2.29 – 2.11 ( m , 1H ) , 2.09 – 1.( m , 1H ) - LCMS ( Method 2 ) : 1.28 min , 179.0 [ M + H ] * Synthesis of - - ethyl 3 - cyano - 2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxylate NHHN N = .CN Etos Eto EtOH , 80 ° C OEt Eto .CN of q - Amino - 3 - tetrahydrofuran - 3 - yl - 1H - pyrazole - 4 - carbonitrile ( 302 mg , 1.69 mmol ) and ethyl ( E ) -4 - ethoxy - 2 - oxo - but - 3 - enoate ( 195 mg , 1.13 mmol ) were dissolved in EtOH ( 7 mL ) and 412 LO the reaction was heated at 80 ° C for 5 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 5 % MeOH in DCM ) to provide the title compound ( 2mg ) . ' H NMR ( 400 MHz , ³ICDC ) г 8.78 ( d , J = 4.3 Hz , 1H ) , 7.45 ( d , J = 4.2 Hz , 1H ) , 4.57 ( q , J = 7.1 Hz , 2H ) , 4.32 – 4.24 ( m , 1H ) , 4.18 – 3.96 ( m , 3H ) , 3.95 – 3.84 ( m , 1H ) , 2.58 – 2.36 ( m , 2H ) , 1.48 ( t , J = 7.1 Hz , 3H ) - LCMS ( Method 2 ) : 2.05 min , 287.2 [ M + H ] * Synthesis of 3 - cyano - 2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid EtO .CN O₂H.HOiL THF , O₂H , RT HO . CN N = A solution of O₂H.HOiL ( 36 mg , 0.86 mmol ) in water ( 2 mL ) was added to a solution of ethyl - cyano - 2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 225 mg , 0.mmol ) in THF ( 2 mL ) and the reaction was stirred at room temperature for 2 h then concentrated in vacuo . The residue was dissolved in EtOAc and water , and the layers were separated . The aqueous layer was acidified to pH 2 with 1 M aq . HCI and extracted with EtOAc . The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 279 mg ) . ₫ 1H NMR ( 400 MHz , CDCl3 ) б 8.98 ( d , J = 4.3 Hz , 1H ) , 7.96 ( d , J = 4.3 Hz , 1H ) , 4.34 - 4.24 . - - ( m , 1H ) , 4.21 – 4.10 ( m , 1H ) , 4.09 – 3.85 ( m , 4H ) , 2.66 – 2.51 ( m , 1H ) . Exchangeable proton not observed . LCMS ( Method 2 ) : 1.50 min , 259.2 [ M + H ] * Synthesis of 3 - cyano - N - indan - 2 - yl - 2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine- - carboxamide 413 -NH2.HCI HO ' N ' CN T3P , DIPEA EtOAc , RT CN N = ﻡا 1 - Propanephosphonic anhydride ( 50 wt % in EtOAc ; 650 Lμ , 1.08 mmol ) was added to a suspension of 3 - cyano - 2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 186 mg , 0.72 mmol ) , indan - 2 - amine hydrochloride ( 147 mg , 0.87 mmol ) , and DIPEA ( 3Lμ , 2.17 mmol ) in EtOAc ( 7 mL ) and the reaction was stirred at room temperature for 3 days . The reaction mixture was diluted with EtOAc and washed with brine . The organic layer was dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 431 mg ) . The crude product was taken forward to the next step without further purification . ₫ - ' H NMR ( 400 MHz , CDCl3 ) ō 8.86 ( d , J = 4.4 Hz , 1H ) , 7.99 ( d , J = 4.4 Hz , 1H ) , 7.33 – 7.( m , 4H ) , 5.11 – 4.90 ( m , 1H ) , 4.20 – 4.07 ( m , 1H ) , 3.88 – 3.70 ( m , 4H ) , 3.48 – 3.42 ( m , 2H ) , - - - - 3.04 2.99 ( m , 2H ) , 2.40 -2.25 ( m , 1H ) , 2.12 – 1.91 ( m , 1H ) . Exchangeable proton not observed . LCMS ( Method 2 ) : 2.43 min , 374.2 [ M + H ] + Synthesis of compound 37 , N7 - indan - 2 - yl - 2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ' N ' N = CN HO N PS - PPh3 , Pd ( OAc ) EtOH , O₂H , 90 ° C ₂HN 3 - Cyano - N - indan - 2 - yl - 2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 2mg , 0.74 mmol ) , acetaldehyde oxime ( 180 Lμ , 2.96 mmol ) , Pd ( OAc ) 2 ( 25 mg , 0.11 mmol ) , and PS - PPh3 ( 1.4 - 2 mmol / g ; 130 mg , 0.18 – 0.26 mmol ) were suspended in EtOH ( 6 mL ) and water ( 1.5 mL ) and the mixture was degassed by sparging with a stream of argon for - 414 LO min . The reaction was heated at 90 ° C for 18 h , then cooled to room temperature , filtered through a short pad of ®etilaciD , and concentrated in vacuo . The crude product was purified by preparative HPLC ( basic method ) to provide the title compound ( 16 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) г 10.28 ( d , J = 7.3 Hz , 1H ) , 8.90 ( d , J = 4.4 Hz , 1H ) , 7.72 ( d , J = 4.4 Hz , 2H ) , 7.54 ( s , 1H ) , 7.35 – 7.26 ( m , 2H ) , 7.24 – 7.15 ( m , 2H ) , 4.88 – 4.77 ( m , 1H ) , 4.34 4.23 ( m , 1H ) , 4.07 ( dd , J = 8.3 , 7.5 Hz , 1H ) , 3.79 – 3.65 ( m , 2H ) , 3.56 ( dd , J = 8.3 , - - 6.2 Hz , 1H ) , 3.38 ( dd , J = 16.2 , 6.7 Hz , 2H ) , 2.96 ( dd , J = 16.0 , 3.4 Hz , 2H ) , 2.17 – 2.05 ( m , 1H ) , 2.03 – 1.92 ( m , 1H ) - LCMS ( Method 2 ) : 2.18 min , 392.2 [ M + H ] * Synthesis of ethyl ( E ) -4 - ethoxy - 3 - methyl - 2 - oxo - but - 3 - enoate N₂tE 1,4 - Dioxane ° C to RT CI Eto . OEt EtO Eto ( E ) -1 - Ethoxyprop - 1 - ene ( 8.1 mL , 73.24 mmol ) was added to a solution of NзtE ( 2.45 mL , 17.58 mmol ) in 1,4 - dioxane ( 4 mL ) and the solution was cooled to 0 ° C . Ethyl 2 - chloro - 2- oxo - acetate ( 1.64 mL , 14.65 mmol ) was added dropwise and the reaction was warmed to room temperature and stirred overnight . The reaction mixture was diluted with DCM and washed with sat . aq . NaHCO3 and water . The organic layer was dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 2.097 g ) . - 1H NMR ( 400 MHz , DMSO - d6 ) ō 7.58 ( q , J = 1.1 Hz , 1H ) , 4.30 – 4.24 ( m , 4H ) , 1.61 ( d , J = 1.1 Hz , 3H ) , 1.30 – 1.25 ( m , 6H ) - LCMS ( Method 2 ) : 2.23 min , 187.2 [ M + H ] * Synthesis of ethyl 3 - cyano - 2,6 - dimethyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate EtO DE OEt NHEtOH RT to 80 ° C .CN EtO ' N ' .CN N N 415 LO Ethyl ( E ) -4 - ethoxy - 3 - methyl - 2 - oxo - but - 3 - enoate ( 2.01 g , 10.81 mmol ) and 5 - amino - 3- methyl - 1H - pyrazole - 4 - carbonitrile ( 1.1 g , 9.01 mmol ) were dissolved in EtOH ( 20 mL ) and the reaction was stirred at room temperature for 2 h and then heated at 80 ° C for 18 h . The reaction mixture was cooled to room temperature , and the resulting precipitate was collected by filtration , washed sparingly with EtOH and dried . The filtrate was concentrated in vacuo and purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) . The purified product was combined with that of the solid precipitate to provide the title compound ( 1.414 g ) . ' H NMR ( 400 MHz , CDCl3 ) Ŏ 8.58 ( s , 1H ) , 4.61 ( q , J = 7.1 Hz , 2H ) , 2.61 ( s , 3H ) , 2.42 ( s , 3H ) , 1.47 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 2 ) : 2.20 min , 245.0 [ M + H ] + Synthesis of 3 - cyano - 2,6 - dimethyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid LiOH MeOH , THF RT EtO HO .CN CN N = N = 4 M aq . LiOH ( 614 Lµ , 2.46 mmol ) was added to a solution of ethyl 3 - cyano - 2,6 - dimethyl- pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 500 mg , 2.05 mmol ) in THF ( 10 mL ) and MeOH ( mL ) and the reaction was stirred at room temperature for 16 h . The reaction mixture was concentrated in vacuo , and the residue was acidified with 5 M aq . HCI . The resulting precipitate was collected by filtration , washed with water , and dried to provide the title compound ( 352 mg ) . ' H NMR ( 400 MHz , DMSO - d ) б 8.80 ( s , 1H ) , 2.52 ( s , 3H ) , 2.35 ( s , 3H ) . Exchangeable proton not observed . LCMS ( Method 2 ) : 1.27 min , 215.2 [ M − H ] ¯ Synthesis of - cyano - N- ( 3,3 - difluorocyclobutyl ) -2,6 - dimethyl - pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide 416 F -NH2.HCI T3P , N₂tE DMF , RT HO ' N ' .CN ' N ' _CN N : 1 - Propanephosphonic anhydride ( 50 wt % in DMF ; 2.89 mL , 4.86 mmol ) was added to a suspension of 3 - cyano - 2,6 - dimethyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 350 mg , 1.62 mmol ) , 3,3 - difluorocyclobutanamine hydrochloride ( 279 mg , 1.94 mmol ) , and N³tE ( 6Lμ , 4.86 mmol ) in DMF ( 2.5 mL ) and the reaction was stirred at room temperature for 16 h . The reaction mixture was diluted with 0.5 M aq . HCI , and the resulting precipitate was collected by filtration , washed with water and Et2O , and dried to provide the title compound ( 101 mg ) . - 1H NMR ( 400 MHz , DMSO - d ) § 9.64 ( d , J = 6.2 Hz , 1H ) , 8.82 ( s , 1H ) , 4.37 – 4.25 ( m , 1H ) , 3.15 3.06 ( m , 2H ) , 2.74 – 2.57 ( m , 2H ) , 2.53 ( s , 3H ) , 2.32 ( d , J = 3.5 Hz , 3H ) Synthesis of compound 38 , N7- ( 3,3 - difluorocyclobutyl ) -2,6 - dimethyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide HO H Pd ( OAc ) 2 , PS - PPhEtOH , O₂H , 90 ° C ' N ' ` N N = CN NH 3 - Cyano - N- ( 3,3 - difluorocyclobutyl ) -2,6 - dimethyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide - ( 100 mg , 0.33 mmol ) , acetaldehyde oxime ( 80 Lμ , 1.31 mmol ) , Pd ( OAc ) 2 ( 11 mg , 0.mmol ) , and PS - PPh3 ( 1.4- 2 mmol / g ; 20 mg , 0.03 0.04 mmol ) were suspended in EtOH ( 4 mL ) and water ( 1 mL ) , and the reaction was heated at 90 ° C for 3 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The residue was dissolved in DCM and washed with brine . The aqueous layer was extracted with DCM , and the combined organic layers were dried over Na2SO4 and concentrated in vacuo . The crude product was purified by preparative HPLC ( basic method ) to provide the title compound ( 23 mg ) . 417 ' H NMR ( 400 MHz , DMSO - d € ) ☎ 9.63 ( s , 1H ) , 8.75 ( s , 1H ) , 7.56 ( s , 1H ) , 7.42 ( s , 1H ) , 4.- ( s , 1H ) , 3.16 – 3.06 ( m , 2H ) , 2.70 – 2.64 ( m , 2H ) , 2.61 ( s , 3H ) , 2.31 ( s , 3H ) - LCMS ( Method 2 ) : 1.73 min , 324.2 [ M + H ] + Synthesis of 5 - methoxy - 2,4 - dioxo - pentanoate Etoji Deti Me + OEt NaOEt , EtOH RT EtO Egil OMG 1 - Methoxypropan - 2 - one ( 5 mL , 54.31 mmol ) was added to a solution of NaOEt ( 21 % in EtOH ; 24.3 mL , 65.17 mmol ) in EtOH ( 50 mL ) and the mixture was stirred at room temperature for 15 min . Diethyl oxalate ( 8.11 mL , 59.74 mmol ) was added dropwise and the reaction was stirred at room temperature for 5 days . The reaction mixture was acidified with M aq . HCI and diluted with DCM . The layers were separated , and the aqueous layer was extracted with DCM . The combined organic layers were dried over Na2SO4 and concentrated in vacuo . The crude product was purified by vacuum distillation ( 17 mbar ) to provide the title compound ( 3.6 g ) . - ' H NMR ( 400 MHz , ³lCDC ) г 6.62 ( s , 1H ) , 4.38 – 4.33 ( m , 2H ) , 4.11 ( s , 2H ) , 3.46 ( s , 3H ) , 1.37 ( s , 3H ) . Exchangeable proton of enol tautomer not observed . LCMS ( Method 1 ) : 0.97 min , 189.2 [ M + H ] * Synthesis of ethyl ( E / Z ) -4 - ethoxy - 5 - methoxy - 2 - oxo - pent - 3 - enoate ( EtO ) , CH NHCI , EtOH RT OMe Eto glLo OEt OMe EtO alla Ethyl 5 - methoxy - 2,4 - dioxo - pentanoate ( 3.6 g , 19.13 mmol ) , triethylorthoformate ( 3.82 mL , 22.96 mmol ) , and NH4CI ( 307 mg , 5.74 mmol ) were suspended in EtOH ( 20 mL ) and the reaction was stirred at room temperature for 60 h then concentrated in vacuo . The residue was dissolved in Et2O and the solution was filtered and concentrated in vacuo to provide the title compound ( 3.6 g ) as a 1 : 1 mixture of E : Z isomers . The crude product was taken forward to the next step without purification . 418 LO LCMS ( Method 1 ) : 1.08 min , 217.2 [ M + H ] + Synthesis of ethyl 3 - cyano - 5- ( methoxymethyl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxylate MeO NHOEt EtOH RT to 80 ° C N Eto OMe + HN Na .CN EtO ' N ' .CN NE Ethyl ( E / Z ) -4 - ethoxy - 5 - methoxy - 2 - oxo - pent - 3 - enoate ( 3.6 g , 11.65 mmol ) and 5 - amino - 3- methyl - 1H - pyrazole - 4 - carbonitrile ( 1.85 g , 15.15 mmol ) were suspended in EtOH ( 10 mL ) and the reaction was stirred at room temperature for 2 h then heated at 80 ° C for 5 h . The reaction mixture was cooled to room temperature and then to 4 ° C and left to settle . The resulting suspension was filtered and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 2.6 g ) . ' H NMR ( 400 MHz , ³lCDC ) ₫ 7.62 ( s , 1H ) , 4.67 ( s , 2H ) , 4.57 ( q , J = 7.1 Hz , 2H ) , 3.53 ( s , 3H ) , 2.66 ( s , 3H ) , 1.47 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 1 ) : 1.15 min , 275.2 [ M + H ] + Synthesis of carboxylic acid - cyano - 5- ( methoxymethyl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7- MeO N EtO ' N ' .CN N NaOH MeOH , THF RT MeO N HO . ' N ' .CN Na 2 M aq . NaOH ( 16 mL , 32 mmol ) was added to a solution of ethyl 3 - cyano - 5- ( methoxymethyl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 2.6 g , 6.64 mmol ) in MeOH ( 2 mL ) and THF ( 18 mL ) and the reaction was stirred at room temperature for 1 h then concentrated in vacuo . The residue was suspended in water and acidified to pH 2 with 419 LO M aq . HCI . The resulting precipitate was collected by filtration , washed with water , and dried to provide the title compound ( 617 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) 5 6.92 ( s , 1H ) , 4.56 ( s , 2H ) , 3.39 ( s , 3H ) , 2.49 ( s , 3H ) . Exchangeable proton not observed . LCMS ( Method 1 ) : 0.86 min , 203.2 [ M - CO2H + H ] * Synthesis of 3 - cyano - N- ( 3,3 - difluorocyclobutyl ) -5- ( methoxymethyl ) -2 - methyl- pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide MeO HO ' N ' .CN N = F 2HN✗ -NH2.HCI MeO EDCI , HOBt , N₂tE DMF , RT N ' N ' CN N = NзtE ( 540 Lμ , 3.90 mmol ) was added to a suspension of 3 - cyano - 5- ( methoxymethyl ) -2- methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid acid ( 160 mg , 0.65 mmol ) , 3,3- difluorocyclobutanamine hydrochloride ( 187 mg , 1.30 mmol ) , HOBt ( 299 mg , 1.95 mmol ) , and EDCI ( 374 mg , 1.95 mmol ) in DMF ( 2 mL ) and the reaction was stirred at room temperature for 72 h . The reaction mixture was diluted with EtOAc and washed with 5 % aq . LICI ( x2 ) , 1 Maq . HCI , and brine . The organic layer was dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 65 mg ) . ' H NMR ( 400 MHz , 3№CDC ) б 10.44 ( s , 1H ) , 8.13 ( s , 1H ) , 4.70 ( s , 2H ) , 4.54 - 4.46 ( m , 1H ) , 3.53 ( s , 3H ) , 3.21 - 3.11 ( m , 2H ) , 2.78 - 2.70 ( m , 2H ) , 2.70 ( s , 3H ) - LCMS ( Method 1 ) 1.24 min , 336.2 [ M + H ] * Synthesis of compound 39 , N7- ( 3,3 - difluorocyclobutyl ) -5- ( methoxymethyl ) -2 - methyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 420 MeO N ' N ' .CN HO " H N Pd ( OAc ) 2 , PS - PPhEtOH , O₂H , 80 ° C F MeO NH 3 - Cyano - N- ( 3,3 - difluorocyclobutyl ) -5- ( methoxymethyl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine- - - - carboxamide ( 65 mg , 0.19 mmol ) , Pd ( OAc ) 2 ( 8.7 mg , 0.04 mmol ) , PS - ³hPP ( 1 – 1.mmol / g ; 30 mg , 0.03 0.05 mmol ) , and acetaldehyde oxime ( 59 Lμ , 0.97 mmol ) were suspended in EtOH ( 2.5 mL ) and water ( 500 Lµ ) and the reaction was heated at 80 ° C for h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % ( 2 M NH3 in MeOH ) in DCM ) to provide the title compound ( 38 mg ) . - 1H NMR ( 400 MHz , DMSO - d ) ð 10.17 ( d , J = 6.5 Hz , 1H ) , 7.67 ( s , 1H ) , 7.57 ( s , 1H ) , 7.( s , 1H ) , 4.70 ( s , 2H ) , 4.40 – 4.32 ( m , 1H ) , 3.44 ( s , 3H ) , 3.16 – 3.01 ( m , 2H ) , 2.91 – 2.74 ( m , 2H ) , 2.70 ( s , 3H ) - LCMS ( Method 2 ) : 2.06 min , 354.2 [ M + H ] + - Synthesis of ethyl 2 - phenylpyrazolo [ 1,5 - a ] pyridine - 3 - carboxylate NHן OEt 3OC₂K DMF , RT ' N ' OEt Pyridin - 1 - ium - 1 - amine iodide ( 1 g , 4.5 mmol ) , ethyl 3 - phenylprop - 2 - ynoate ( 1.49 mL , 9.mmol ) , and K2CO3 ( 870 mg , 6.31 mmol ) were dissolved in DMF ( 9 mL ) and the reaction was stirred at room temperature overnight . The reaction mixture was poured into water and diluted with EtOAc . The layers were separated , and the organic layer was washed with water and brine ( x 2 ) , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 30 % EtOAc in heptane ) to provide the title compound ( 696 mg ) . 421 1H NMR ( 400 MHz , CDC 3 ) б 8.52 ( dt , J = 6.9 , 1.1 Hz , 1H ) , 8.21 ( ddd , J = 9.0 , 1.1 Hz , 1H ) , - 7.857.76 ( m , 2H ) , 7.49 – 7.43 ( m , 3H ) , 7.40 ( ddd , J = 9.0 , 6.9 , 1.2 Hz , 1H ) , 6.95 ( td , J = 6.9 , 1.4 Hz , 1H ) , 4.32 ( q , J = 7.1 Hz , 2H ) , 1.31 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 1 ) : 1.87 min , 267.2 [ M + H ] + Synthesis of ethyl 7 - bromo - 2 - phenyl - pyrazolo [ 1,5 - a ] pyridine - 3 - carboxylate LiHMDS , ₁rBC THF -78 ° C to RT Br OEt OEt N = LIHMDS ( 1 M in THF ; 3.42 mL , 3.42 mmol ) was added to a solution of ethyl 2- phenylpyrazolo [ 1,5 - a ] pyridine - 3 - carboxylate ( 700 mg , 2.63 mmol ) in THF ( 13 mL ) at -78 ° C and the mixture was stirred at 87− ° C for 30 min . Carbon tetrabromide ( 1.133 g , 3.42 mmol ) was added in one portion , and the reaction was warmed to room temperature and stirred for 1.5 h . The reaction mixture was quenched by the slow addition of sat . aq . NH4Cl and diluted with water and EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 30 % EtOAc in heptane ) to provide the title compound ( 719 mg ) . - - ' H NMR ( 400 MHz , ³lCDC ) б 8.25 ( dd , J = 7.8 , 2.3 Hz , 1H ) , 7.83 – 7.77 ( m , 2H ) , 7.50 – 7.( m , 3H ) , 7.32 - 7.26 ( m , 2H ) , 4.31 ( q , J = 7.1 Hz , 2H ) , 1.29 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 1 ) : 1.99 min , 345.1 , 347.1 [ M + H ] * Synthesis of ethyl 7- ( indan - 2 - ylcarbamoyl ) -2 - phenyl - pyrazolo [ 1,5 - a ] pyridine - 3- carboxylate 422 Br ' N OEt H 1. Xantphos Pd GN₂tE , DMF , 90 ° C 2. N₂tE , T3P , 50 ° C -NH2.HCI cosqu OEt N = Ethyl 7 - bromo - 2 - phenyl - pyrazolo [ 1,5 - a ] pyridine - 3 - carboxylate ( 200 mg , 0.55 mmol ) and Xantphos Pd G3 ( 26 mg , 0.03 mmol ) were placed in a vial , and the vial was sealed and purged with argon for 5 min . DMF ( 2 mL ) and NзtE ( 0.15 mL , 1.1 mmol ) were added , and the mixture was degassed by sparging with argon for 5 min . ( 2,5 - Dioxopyrrolidin - 1 - yl ) formate ( 393 mg , 2.75 mmol ) was added and the vial was sealed immediately . The reaction was heated at 90 ° C in a microwave reactor for 1 h then cooled to room temperature . Indan- - amine hydrochloride ( 140 mg , 0.83 mmol ) , NзtE ( 0.15 mL , 1.1 mmol ) , and 1- propanephosphonic anhydride ( 50 wt % in DMF ; 0.66 mL , 1.1 mmol ) were added and the reaction was heated at 50 ° C for 18 h . The reaction mixture was cooled to room temperature and diluted with 0.5 M aq . HCI and EtOAc . The layers were separated , and the organic layer was washed with sat . aq . NaHCO3 and brine ( x 2 ) , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 60 % EtOAc in heptane ) to provide the title compound ( 147 mg ) .

- ' H NMR ( 400 MHz , CDCl3 ) ō 11.05 ( d , J = 7.2 Hz , 1H ) , 8.41 ( dd , J = 8.9 , 1.5 Hz , 1H ) , 8.( dd , J = 7.3 , 1.5 Hz , 1H ) , 7.62 – 7.59 ( m , 2H ) , 7.57 ( dd , J = 8.9 , 7.2 Hz , 1H ) , 7.48 — 7.37 ( m , 3H ) , 7.29 - 7.24 ( m , 2H ) , 7.24 – 7.19 ( m , 2H ) , 5.00 ( s , 1H ) , 4.34 ( q , J = 7.1 Hz , 2H ) , 3.( dd , J = 16.0 , 6.9 Hz , 2H ) , 3.02 ( dd , J = 16.0 , 4.6 Hz , 2H ) , 1.32 ( t , J = 7.1 Hz , 3H ) - LCMS ( Method 1 ) : 2.10 min , 426.2 [ M + H ] * Synthesis of 7- ( indan - 2 - ylcarbamoyl ) -2 - phenyl - pyrazolo [ 1,5 - a ] pyridine - 3 - carboxylic acid 423 LiOH MeOH , THF ° C corge #corge cosqu ` N OEt N : OH 2 M aq . LiOH ( 290 Lμ , 0.59 mmol ) was added to a solution of ethyl 7- ( indan - 2 - ylcarbamoyl ) - - phenyl - pyrazolo [ 1,5 - a ] pyridine - 3 - carboxylate ( 50 mg , 0.12 mmol ) in THF ( 4 mL ) and MeOH ( 2 mL ) and the reaction was heated at 70 ° C for 22 h . The reaction mixture was cooled to room temperature , and an additional portion of 2 M aq . LiOH ( 150 Lμ , 0.29 mmol ) was added . The reaction was heated at 70 ° C for 8 h , then cooled to room temperature and concentrated in vacuo . The residue was dissolved in water and TBME , and the layers were separated . The aqueous layer was acidified to pH 1 - 2 with 5 M aq . HCI and extracted with a 1 : 9 mixture of MeOH : DCM ( x 3 ) . The combined organic layers were concentrated in vacuo to provide the title compound ( 42 mg ) . § ' H NMR ( 400 MHz , DMSO - d6 ) ō 12.74 ( s , 1H ) , 10.48 ( d , J = 7.2 Hz , 1H ) , 8.36 ( dd , J = 8.9 , 1.5 Hz , 1H ) , 7.86 ( dd , J = 7.2 , 1.5 Hz , 1H ) , 7.70 ( dd , J = 8.9 , 7.3 Hz , 1H ) , 7.66 – 7.60 ( m , 2H ) , 7.50 -7.40 ( m , 3H ) , 7.33 – 7.25 ( m , 2H ) , 7.24 – 7.17 ( m , 2H ) , 4.88 – 4.76 ( m , 1H ) , 3.- 3.33 ( m , 2H ) , 2.95 ( dd , J = 16.1 , 4.0 Hz , 2H ) LCMS ( Method 1 ) : 1.83 min , 398.2 [ M + H ] + Synthesis of compound 40 . N7 - indan - 2 - yl - N3 - methyl - 2 - phenyl - pyrazolo [ 1,5- a ] pyridine - 3,7 - dicarboxamide eM₂HN , HATU ' N ' N₂tE DMF , RT OH Bosge N = N- H HATU ( 58 mg , 0.15 mmol ) was added to a solution of 7- ( indan - 2 - ylcarbamoyl ) -2 - phenyl- pyrazolo [ 1,5 - a ] pyridine - 3 - carboxylic acid ( 40 mg , 0.10 mmol ) , eM₂HN ( 2 M in THF ; 250 Lµ , 0.50 mmol ) and NзtE ( 30 Lµ , 0.22 mmol ) in DMF ( 2 mL ) and the reaction was stirred at room temperature for 16 h . Additional portions of HATU ( 12 mg , 0.03 mmol ) and NH2Me ( 2 M in THF ; 130 Lµ , 0.25 mmol ) were added and the reaction was stirred at room temperature for a further 6 h . The reaction mixture was diluted with EtOAc and washed with 0.5 M aq . HCI , 424 LO sat . aq . NaHCO3 , and brine ( x 2 ) . The organic layer was dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by preparative HPLC ( basic method ) to provide the title compound ( 30 mg ) . - - 1H NMR ( 400 MHz , DMSO - d ) г 10.76 ( d , J = 7.5 Hz , 1H ) , 8.12 ( q , J = 4.5 Hz , 1H ) , 7.97 ( dd , J = 8.9 , 1.4 Hz , 1H ) , 7.85 ( dd , J = 7.2 , 1.4 Hz , 1H ) , 7.58 – 7.50 ( m , 3H ) , 7.47 – 7.40 ( m , 3H ) , 7.35 ( dd , J = 5.4 , 3.3 Hz , 2H ) , 7.29 – 7.22 ( m , 2H ) , 4.92 – 4.81 ( m , 1H ) , 3.44 – 3.34 ( m , 2H ) , 2.99 ( dd , J = 16.1 , 3.2 Hz , 2H ) , 2.78 ( d , J = 4.6 Hz , 3H ) LCMS ( Method 2 ) : 2.53 min , 411.2 [ M + H ] + Synthesis of 5,7 - dihydroxy - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3 - carbonitrile C₂OtE tE₂OC OH NHNaOEt , EtOH ° C .CN HN § HO ' N ' .CN N : NaOEt ( 21 wt % in EtOH ; 30.6 mL , 81.88 mmol ) was added dropwise to a solution of 5- amino - 3 - methyl - 1H - pyrazole - 4 - carbonitrile ( 5 g , 40.94 mmol ) and diethyl malonate ( 6.87 mL , 45.03 mmol ) in EtOH ( 125 mL ) and the reaction was heated at 80 ° C overnight . The reaction mixture was cooled to room temperature and the resulting precipitate was collected by filtration . The solid was suspended in water and the mixture was acidified to pH 3 with conc . HCI . The suspension was stirred at room temperature for 20 min then the solids were collected by filtration , azeotroped with MeCN , and dried to provide the title compound ( 6.g ) . ' H NMR ( 400 MHz , DMSO - d6 ) ō 5.13 ( s , 1H ) , 2.31 ( s , 3H ) . Exchangeable protons not observed . LCMS ( Method 1 ) : 1.07 min , 191.2 [ M + H ] * Synthesis of 5,7 - dichloro - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3 - carbonitrile OH N HO ' N ' .CN N , N - dimethylaniline POCI 3 , 110 ° C CI CI CN N : LO N , N - dimethylaniline ( 1.74 mL , 10.96 mmol ) was added to a mixture of 5,7 - dihydroxy - 2- methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3 - carbonitrile ( 1.39 g , 7.31 mmol ) and POCl3 ( 4.1 mL , 43.86 mmol ) and the reaction was heated at 110 ° C in a microwave reactor for 15 min . The reaction mixture was cooled to room temperature and diluted with DCM ( 10 mL ) . The mixture was added slowly to warm water ( 50 mL ) with vigorous stirring , then cooled to room temperature and diluted with DCM . The biphasic mixture was dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 5 to 40 % EtOAc in heptane ) to provide the title compound ( 980 mg ) . 1H NMR ( 400 MHz , CDCl3 ) г 7.15 ( s , 1H ) , 2.66 ( s , 3H ) LCMS ( Method 1 ) : 1.64 min , 227.2 , 229.2 [ M + H ] * Synthesis of 5 - chloro - 2 - methyl - 7 - [ ( E ) -styryl ] pyrazolo [ 1,5 - a ] pyrimidine - 3 - carbonitrile Ph CI Bpin ģ N ° .CN Pd ( PPh3 ) NaHCO1,4 - Dioxane , O₂H 100 ° C CI N .CN Na Ph NaHCO3 ( 721 mg , 8.58 mmol ) and Pd ( PPh3 ) 4 ( 248 mg , 0.21 mmol ) were added to a solution of 4,4,5,5 - tetramethyl - 2 - [ ( E ) -styryl ] -1,3,2 - dioxaborolane ( 1.18 g , 5.15 mmol ) in 1,4 - dioxane ( 5 mL ) and the mixture was purged with argon for 10 min then heated to 100 ° C . A solution of 5,7 - dichloro - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3 - carbonitrile ( 980 mg , 4.29 mmol ) in 1,4- dioxane ( 4 mL ) was added , followed by water ( 1 mL ) , and the reaction was heated at 1° C for 2 h then cooled to room temperature . The reaction mixture was diluted with DCM and washed with water . The organic layer was dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 916 mg ) . - 1H NMR ( 400 MHz , ³lCDC ) § 7.94 ( d , J = 16.5 Hz , 1H ) , 7.77 – 7.63 ( m , 3H ) , 7.58 – 7.41 ( m , 3H ) , 7.20 ( s , 1H ) , 2.65 ( s , 3H ) LCMS ( Method 1 ) : 2.01 min , 295.2 , 297.2 [ M + H ] * Synthesis of 5 - chloro - 7 - formyl - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3 - carbonitrile 426 CI ﭖھﺭ Ph .CN OsO 4 , NalO2,6 - lutidine 1,4 - Dioxane , O₂H RT to 35 ° C CI H. ' N ' CN 2,6 - Lutidine ( 440 Lμ , 3.80 mmol ) , followed by a solution of NalO4 ( 1.63 g , 7.60 mmol ) in water ( 10 mL ) , and OsO4 ( 4 wt % in water ; 121 Lμ , 0.02 mmol ) were added sequentially to a solution of 5 - chloro - 2 - methyl - 7 - [ ( E ) -styryl ] pyrazolo [ 1,5 - a ] pyrimidine - 3 - carbonitrile ( 560 mg , 1.90 mmol ) in 1,4 - dioxane ( 30 mL ) and the reaction was stirred at room temperature for h , then heated at 35 ° C for a further 16 h . The reaction mixture was cooled to room temperature and diluted with EtOAc and brine . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 3 ) . The combined organic layers were dried over Na2SOand concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 70 % EtOAc in heptane ) to provide the title compound ( 397 mg ) as an impure gum . This crude product was taken forward to the next step without further purification . LCMS ( Method 1 ) : 1.36 min , 221.2 , 223.2 [ M + H ] * Synthesis of 5 - chloro - 3 - cyano - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid NaClO2 , NaH2PO2 - methylbut - 2 - ene CI t - BuOH , O₂H , RT N H. HO . _CN ' N ' CN Water ( 7.5 mL ) , NaH2PO4 ( 216 mg , 1.80 mmol ) , 2 - methylbut - 2 - ene ( 1.53 mL , 14.40 mmol ) , and NaClO2 ( 325 mg , 3.60 mmol ) were added sequentially to a solution of the crude 5- chloro - 7 - formyl - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3 - carbonitrile ( 397 mg ) in t - BuOH ( 15 ) mL ) and the reaction was stirred at room temperature for 1 h . The reaction mixture was acidified to pH 3 with 1 M aq . HCI then diluted with brine . The aqueous solution was extracted with a 1 : 9 mixture of i - PrOH : EtOAc ( x 3 ) , and the combined organic layers were dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column 427 chromatography ( eluting with 0 to 30 % MeOH in DCM ) to provide the title compound ( mg ) . 1H NMR ( 400 MHz , MeOD ) 5 7.34 ( s , 1H ) , 2.61 ( s , 3H ) . Exchangeable proton not observed . LCMS ( Method 2 ) : 1.51 min , 237.2 , 239.2 [ M + H ] * LO Synthesis of - chloro - 3 - cyano - N- ( 3,3 - difluorocyclobutyl ) -2 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide CI CI N T3P , N₂tE DMF , RT N -NH2.HCI HO N. N .CN ' N ' .CN N = NзtE ( 650 Lμ , 4.65 mmol ) , 3,3 - difluorocyclobutanamine hydrochloride ( 160 mg , 1.12 mmol ) and 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 1.78 mL , 2.79 mmol ) were added to a solution of 5 - chloro - 3 - cyano - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 2mg , 0.93 mmol ) in DMF ( 5 mL ) and the reaction was stirred at room temperature for 16 h . The reaction mixture was diluted with EtOAc and washed with water ( x 3 ) . The combined aqueous layers were extracted with EtOAc ( x 3 ) , and the combined organic layers were dried over MgSO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 40 % EtOAc in heptane ) to provide the title compound ( mg ) . ' H NMR ( 400 MHz , CDCl3 ) г 10.30 ( br . s , 1H ) , 7.89 ( s , 1H ) , 4.55 - 4.44 ( m , 1H ) , 3.25 -3.( m , 2H ) , 2.80 - 2.64 ( m , 2H ) , 2.61 ( s , 3H ) LCMS ( Method 2 ) : 1.79 min , 324.0 , 326.0 [ M - H ] - Synthesis of 3 - cyano - N- ( 3,3 - difluorocyclobutyl ) -5 - methoxy - 2 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide CI N ' N ' CN N = OMe N₂tE , MeOH 100 ° C ' N ° .CN F 428 LO NзtE ( 80 Lμ , 0.57 mmol ) was added to a solution of 5 - chloro - 3 - cyano - N- ( 3,3- difluorocyclobutyl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 62 mg , 0.19 mmol ) in MeOH ( 2 mL , 49.49 mmol ) and the reaction was heated at 100 ° C in a microwave reactor for 20 min . The reaction mixture was cooled to room temperature and dry loaded onto silica gel . The crude product was purified by column chromatography ( eluting with 50 to 100 % DCM in heptane ) to provide the title compound ( 19 mg ) . 1H NMR ( 400 MHz , CDCl3 ) б 10.44 ( d , J = 6.0 Hz , 1H ) , 7.37 ( s , 1H ) , 4.54 – 4.39 ( m , 1H ) , 4.12 ( s , 3H ) , 3.22 - 3.07 ( m , 2H ) , 2.79 – 2.63 ( m , 2H ) , 2.61 ( s , 3H ) - LCMS ( Method 1 ) : 1.80 min , 322.2 [ M + H ] + Synthesis of compound 41 , N7- ( 3,3 - difluorocyclobutyl ) -5 - methoxy - 2 - methyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide HO . " H OMe Pd ( OAc ) 2 , PS - PPhEtOH , O₂H 100 ° C OMe .CN se ₂HN N : Pd ( OAc ) 2 ( 4 mg , 0.02 mmol ) , acetaldehyde oxime ( 14 mg , 0.24 mmol ) and PS - ³hPP ( 1.4 - mmol / g ; 9.3 mg , 0.01 - 0.02 mmol ) were added to a solution of 3 - cyano - N- ( 3,3- difluorocyclobutyl ) -5 - methoxy - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 22 mg , 0.06 mmol ) , in EtOH ( 2 mL ) and water ( 500 Lµ ) and the mixture was purged with argon for min . The reaction was heated at 100 ° C in a microwave reactor for 40 min . The reaction mixture was cooled to room temperature , filtered through a short pad of ®etilaciD , and washed with MeOH . The filtrate was concentrated in vacuo , and the resulting solid was recrystallised from DMSO in EtOAc . The solid was collected by filtration , washed with EtOAc , and dried to provide the title compound ( 4.1 mg ) . ' H NMR ( 400 MHz , DMSO - d ) § 10.09 ( d , J = 6.5 Hz , 1H ) , 7.42 ( s , 1H ) , 7.38 ( s , 1H ) , 7.( s , 1H ) , 4.40 4.23 ( m , 1H ) , 4.06 ( s , 3H ) , 3.17 – 2.96 ( m , 2H ) , 2.90 – 2.70 ( m , 2H ) , 2.61 ( s , 3H ) - LCMS ( Method 2 ) : 2.13 min , 340.0 [ M + H ] * Synthesis of ethyl ( Z ) -4 - ethoxy - 2 - oxo - pent - 3 - enoate 429 ( EtO ) , CH CẠHN OEt EtOH , RT Eto Eto .

Ethyl 2,4 - dioxopentanoate ( 5.02 g , 31.7 mmol ) , triethylorthoformate ( 6.34 mL , 38.10 mmol ) and NH4CI ( 509 mg , 9.52 mmol ) were suspended in EtOH ( 60 mL ) and the reaction was stirred at room temperature for 60 h . The reaction mixture was concentrated in vacuo and Et2O was added to the residue . The suspension was filtered and the filtrate was concentrated in vacuo . The crude product was purified by vacuum distillation ( 5 mBar ) to provide the title compound ( 4.3 g ) . ' H NMR ( 400 MHz , ³lCDC ) г 6.21 ( s , 1H ) , 4.30 ( q , J = 7.2 Hz , 2H ) , 4.00 ( q , J = 7.0 Hz , 2H ) , 2.38 ( s , 3H ) , 1.38 ( t , J = 7.0 Hz , 3H ) , 1.36 ( t , J = 7.2 Hz 3H ) Synthesis of ethyl 3 - cyano - 2,5 - dimethyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate HN N : OEt EtO NHEtOH RT to 80 ° C .CN EtO . ' N ' .CN N = Ethyl ( Z ) -4 - ethoxy - 2 - oxo - pent - 3 - enoate ( 4.3 g , 23.09 mmol ) was added to a solution of 5- amino - 3 - methyl - 1H - pyrazole - 4 - carbonitrile ( 2.80 g , 22.93 mmol ) in EtOH ( 25 mL ) and the reaction was stirred at room temperature for 1 h then heated at 80 ° C for 16 h . The reaction mixture was cooled to room temperature and the resulting precipitate was collected by filtration and dried to provide the title compound ( 4.57 g ) . ' H NMR ( 400 MHz , CDCl3 ) Ŏ 7.31 ( s , 1H ) , 4.59 ( q , J = 7.1 Hz , 2H ) , 2.76 ( s , 3H ) , 2.68 ( s , 3H ) , 1.49 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 1 ) : 1.08 min , 245.2 [ M + H ] * Synthesis of ethyl 3 - carbamoyl - 2,5 - dimethyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate 430 Eto ' N ' .CN HO H Pd ( OAc ) 2 , PS - PPhEtOH , O₂H , 80 ° C EtO ' N ' NH Ethyl 3 - cyano - 2,5 - dimethyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 1.38 g , 5.65 mmol ) was suspended in EtOH ( 10 mL ) and water ( 2 mL ) and the mixture was degassed by sparging with a stream of argon . Acetaldehyde oxime ( 2.75 mL , 45.20 mmol ) , Pd ( OAc ) 2 ( 190 mg , 0.mmol ) , and PS - PPh3 ( 2–4.1 mmol / g ; 1.11 g , 1.55 - 2.22 mmol ) were added and the reaction was heated at 80 ° C for 2 h . The reaction mixture was cooled to room temperature , filtered through a short pad of ®etilaciD , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) to provide the title compound ( 962 mg ) . 1H NMR ( 400 MHz , CDCl3 ) Ŏ 8.11 ( s , 1H ) , 7.21 ( s , 1H ) , 5.60 ( s , 1H ) , 4.57 ( q , J = 7.2 Hz , 2H ) , 2.83 ( s , 3H ) , 2.71 ( s , 3H ) , 1.47 ( t , J = 7.1 Hz , 3H ) Synthesis of 3 - carbamoyl - 2,5 - dimethyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid O₂H.HOiL THF , O₂H , RT EtO HO . NH2 NHN = A solution of O₂H.HOiL ( 167 mg , 4.00 mmol ) in water ( 5 mL ) was added dropwise to a solution of ethyl 3 - carbamoyl - 2,5 - dimethyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 962 mg , 3.63 mmol ) in THF ( 15 mL ) and the reaction was stirred at room temperature for 2 h . The reaction mixture was concentrated in vacuo , diluted with water , and acidified with 5 M aq . HCI . The resulting precipitate was collected by filtration and dried to provide the title compound ( 826 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) ō 7.71 ( s , 1H ) , 7.42 ( s , 1H ) , 7.40 ( s , 1H ) , 2.66 ( s , 3H ) , 2.( s , 3H ) . Exchangeable proton not observed . 431 Synthesis of compound 42 , N7- ( 3,3 - difluorocyclobutyl ) -2,5 - dimethyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide F -NH2.HCI T3P , N₂tE DMF , RT HO ' N ' N NH2 NH NзtE ( 327 Lμ , 2.35 mmol ) , 3,3 - difluorocyclobutanamine hydrochloride ( 135 mg , 0.94 mmol ) , and 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 560 Lμ , 0.94 mmol ) were added to a suspension of 3 - carbamoyl - 2,5 - dimethyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 1mg , 0.47 mmol ) in DMF ( 1 mL ) and the reaction was stirred at room temperature for 16 h . The reaction mixture was quenched with 0.5 M aq . HCI , and the resulting precipitate was collected by filtration , washed with 0.5 M aq . HCI and water , and dried . The solid was dissolved in hot DMSO , and the solution was cooled to room temperature . The resulting precipitate was collected by filtration , washed with water , and dried to provide the title compound ( 88 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.16 ( d , J = 6.5 Hz , 1H ) , 7.74 ( s , 1H ) , 7.51 ( s , 1H ) , 7.( d , J = 2.7 Hz , 1H ) , 3.16 – 3.01 ( m , 2H ) , 2.89 – 2.71 ( m , 2H ) , 2.69 ( s , 3H ) , 2.67 ( s , 3H ) . - Additional exchangeable proton not observed . LCMS ( Method 2 ) : 1.84 min , 324.2 [ M + H ] * - Synthesis of tetrahydrofuran - 2 - carbonyl chloride HO ( COCI ) 2 , DMF DCM , RT , CI .

DMF ( 121 Lμ , 1.57 mmol ) was added to a solution of tetrahydrofuran - 2 - carboxylic acid ( 1.mL , 15.68 mmol ) in DCM ( 30 mL ) , followed by the dropwise addition of oxalyl chloride ( 1.mL , 18.82 mmol ) over 30 min . The reaction was stirred at room temperature for 1 h then the 432 LO mixture was concentrated in vacuo to provide the title compound ( 2.11 g ) . The crude product was taken forward to the next step without purification . 1H NMR ( 400 MHz , CDCl3 ) б 4.75 ( dd , J = 8.7 , 5.1 Hz , 1H ) , 4.12 – 3.99 ( m , 2H ) , 2.47 – 2.( m , 1H ) , 2.32 – 2.20 ( m , 1H ) , 2.10 – 1.91 ( m , 2H ) - - Synthesis of 2- [ hydroxy ( tetrahydrofuran - 2 - yl ) methylene ] propanedinitrile NC CN NaH , THF ° C to RT CN CI . NC OH A solution of propanedinitrile ( 1.04 g , 15.68 mmol ) in THF ( 15 mL ) was added dropwise over min to a suspension of NaH ( 1.25 g , 31.36 mmol ) in THF ( 15 mL ) at 0 ° C . The mixture was stirred at room temperature for 15 min then cooled to 0 ° C . A solution of tetrahydrofuran- - carbonyl chloride ( prepared as previous step , 2.11 g , 15.68 mmol ) in THF ( 15 mL ) was added dropwise over 20 min , then the reaction was warmed to room temperature and stirred for 18 h . The reaction was quenched with water , acidified with 1 M aq . HCI , and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 20 % MeOH in DCM ) to provide the title compound ( 1.732 g ) . 1H NMR ( 400 MHz , MeOD ) 5 4.75 ( dd , J = 7.9 , 7.0 Hz , 1H ) , 4.09 ( dt , J = 8.0 , 6.5 Hz , 1H ) , 3.91 3.84 ( m , 1H ) , 2.49 – 2.36 ( m , 1H ) , 2.11 - 1.82 ( m , 4H ) - - LCMS ( Method 2 ) : 1.19 min , 163.2 [ M - H ] - Synthesis of 2- [ methoxy ( tetrahydrofuran - 2 - yl ) methylene ] propanedinitrile ﻡﺓ NC CN OH 1. POCI RT to 80 ° C 2. MeOH CN ° C to RT NC OMe 433 A mixture of 2- [ hydroxy ( tetrahydrofuran - 2 - yl ) methylene ] propanedinitrile ( 1.73 g , 10.mmol ) and ³ICOP ( 8.84 mL , 94.85 mmol ) was stirred at room temperature for 30 min then heated at 80 ° C for 1 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The residue was cooled to 0 ° C and MeOH ( 40 mL , 900 mmol ) was added dropwise . The reaction was stirred at room temperature for 30 min then concentrated in vacuo . The residue was diluted with EtOAc and water and the layers were separated . The aqueous layer was extracted with EtOAc ( x 2 ) , and the combined organic layers were washed with sat . aq . NaHCO3 and brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 628 mg ) . - - 1H NMR ( 400 MHz , CDCl3 ) б 4.89 – 4.83 ( m , 1H ) , 4.29 ( s , 3H ) , 4.14 – 4.04 ( m , 1H ) , 3.96 – 3.89 ( m , 1H ) , 2.46 – 2.27 ( m , 1H ) , 2.09 – 1.90 ( m , 3H ) - - LCMS ( Method 2 ) : 1.71 min , 177.2 [ M - H ] - Synthesis of 5 - amino - 3 - tetrahydrofuran - 2 - yl - 1H - pyrazole - 4 - carbonitrile CN NC OMe NH , NH , H , O EtOH , RT NH.CN HN N = Hydrazine monohydrate ( 305 Lμ , 6.26 mmol ) was added to a solution of 2- [ methoxy ( tetrahydrofuran - 2 - yl ) methylene ] propanedinitrile ( 620 mg , 3.48 mmol ) in EtOH ( mL ) and the reaction was stirred at room temperature for 16 h then concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) to provide the title compound ( 355 mg ) . - ' H NMR ( 400 MHz , DMSO - α ) § 11.78 ( s , 1H ) , 6.25 ( s , 2H ) , 4.69 ( s , 1H ) , 3.91 – 3.79 ( m , 1H ) , 3.75 ( td , J = 7.9 , 5.5 Hz , 1H ) , 2.30 – 1.80 ( m , 4H ) - LCMS ( Method 2 ) : 1.29 min , 179.3 [ M + H ] * Synthesis of ethyl 3 - cyano - 2 - tetrahydrofuran - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxylate 434 HN N : NH-CN OEt Eto EtO EtOH , 80 ° C CN N = ﻡا A solution of 5 - amino - 3 - tetrahydrofuran - 2 - yl - 1H - pyrazole - 4 - carbonitrile ( 475 mg , 2.67 mmol ) in EtOH ( 10 mL ) was heated to 80 ° C . A solution of ethyl ( E ) -4 - ethoxy - 2 - oxo - but - 3 - enoate ( 597 mg , 3.47 mmol ) in EtOH ( 5 mL ) was added , and the reaction was heated at 80 ° C for h . An additional portion of ethyl ( E ) -4 - ethoxy - 2 - oxo - but - 3 - enoate ( 300 mg , 1.74 mmol ) was added , and the reaction was heated at 80 ° C for a further 2 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified twice by column chromatography ( eluting first with 0 to 20 % EtOAc in DCM and then with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 430 mg ) . 1H NMR ( 400 MHz , CDCl3 ) б 8.78 ( d , J = 4.2 Hz , 1H ) , 7.46 ( d , J = 4.2 Hz , 1H ) , 5.38 - 5.28 . ( m , 1H ) , 4.57 ( q , J = 7.1 Hz , 2H ) , 4.27 ( dt , J = 8.0 , 6.6 Hz , 1H ) , 4.08 – 3.98 ( m , 1H ) , 2.54 – 2.41 ( m , 1H ) , 2.29 - 2.00 ( m , 3H ) , 1.47 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 2 ) : 2.06 min , 287.2 [ M + H ] * - - Synthesis of 3 - cyano - 2 - tetrahydrofuran - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid N Eto . ' N ' .CN LiOH . O₂H THF , O₂H , RT HO .CN N : N = A solution of LiOH.H2O ( 69 mg , 1.63 mmol ) in water ( 3 mL ) was added to a solution of ethyl - cyano - 2 - tetrahydrofuran - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 425 mg , 1.mmol ) in THF ( 3 mL ) and the reaction was stirred at room temperature for 2 h then concentrated in vacuo . The residue was dissolved in DCM and water and the layers were separated . The aqueous layer was acidified to pH 2 with 1 M aq . HCI and extracted with EtOAc ( x 2 ) , DCM ( x 2 ) , and a 1 : 9 mixture of MeOH : EtOAc ( x 5 ) . The combined organic 435 layers were dried through a hydrophobic frit and concentrated in vacuo to provide the title compound ( 286 mg ) . - - 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 8.91 ( d , J = 4.3 Hz , 1H ) , 7.62 ( d , J = 4.3 Hz , 1H ) , 5.22 - 5.13 ( m , 1H ) , 4.03 ( dt , J = 9.8 , 6.8 Hz , 1H ) , 3.94 – 3.86 ( m , 1H ) , 2.45 – 2.33 ( m , 1H ) , 2.14 - 1.94 ( m , 3H ) . Exchangeable proton not observed . LCMS ( Method 2 ) : 1.35 min , 259.2 [ M + H ] * Synthesis of 3 - cyano - N- ( 3,3 - difluorocyclobutyl ) -2 - tetrahydrofuran - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide F -NH2.HCI N HO . CN T3P , N₂tE DMF , RT N = F N .CN 3,3 - Difluorocyclobutanamine hydrochloride ( 156 mg , 1.08 mmol ) , 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 790 Lµ , 1.36 mmol ) , and NзtE ( 380 Lµ , 2.71 mmol ) were added to a solution of 3 - cyano - 2 - tetrahydrofuran - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 140 mg , 0.54 mmol ) in DMF ( 3 mL ) and the reaction was stirred at room temperature for h . The reaction was quenched with sat . aq . NaHCO3 and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 109 mg ) . 1H NMR ( 400 MHz , CDCl3 ) б 10.42 ( d , J = 6.5 Hz , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 7.99 ( d , J = 4.3 Hz , 1H ) , 5.41 – 5.30 ( m , 1H ) , 4.61 – 4.47 ( m , 1H ) , 4.32 – 4.23 ( m , 1H ) , 4.15 – 4.05 ( m , - - - - - - - 1H ) , 3.28 3.13 ( m , 2H ) , 2.80 – 2.64 ( m , 2H ) , 2.63 – 2.49 ( m , 1H ) , 2.34 – 2.07 ( m , 3H ) - LCMS ( Method 2 ) : 2.25 min , 348.2 [ M + H ] + Synthesis of compound 43 , N7- ( 3,3 - difluorocyclobutyl ) -2 - tetrahydrofuran - 2 - yl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 436 F xsla N .CN N : HO H PS - PPh3 , Pd ( OAc ) EtOH , O₂H , 90 ° C ' N ' NH 3 - Cyano - N- ( 3,3 - difluorocyclobutyl ) -2 - tetrahydrofuran - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide ( 105 mg , 0.30 mmol ) , acetaldehyde oxime ( 74 Lµ , 1.21 mmol ) , Pd ( OAc ) 2 ( mg , 0.05 mmol ) , and PS - ³hPP ( 1.4 - 2 mmol / g ; 54 mg , 0.08 -0.11 mmol ) were suspended in EtOH ( 4 mL ) and water ( 1 mL ) and the reaction was heated at 90 ° C for 2 h . An additional portion of Pd ( OAc ) 2 ( 10 mg , 0.05 mmol ) was added and the reaction was heated at 90 ° C for a further 2 h . The reaction mixture was cooled to room temperature , filtered through a short pad of ®etilaciD , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 7 % MeOH in DCM ) to provide the title compound ( 44 mg ) . ' H NMR ( 400 MHz , DMSO - d ) § 10.32 ( d , J = 6.2 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.73 ( s , 1H ) , 7.67 ( d , J = 4.4 Hz , 1H ) , 7.59 ( s , 1H ) , 5.91 ( dd , J = 7.7 , 4.3 Hz , 1H ) , 4.39 ( s , 1H ) , 4.– 4.00 ( m , 1H ) , 3.96 – 3.86 ( m , 1H ) , 3.17 ( s , 2H ) , 2.77 – 2.61 ( m , 2H ) , 2.43 – 2.31 ( m , 1H ) , 2.11 1.92 ( m , 3H ) - LCMS ( Method 2 ) : 1.98 min , 366.2 [ M + H ] * - Synthesis of 3 - cyano - N - indan - 2 - yl - 2 - tetrahydrofuran - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine- - carboxamide -NH2.HCI HO .CN T3P , N₂tE DMF , RT N CN Indan - 2 - amine hydrochloride ( 138 mg , 0.81 mmol ) , 1 - propanephosphonic anhydride ( wt % in DMF ) ( 630 Lμ , 1.08 mmol ) , and NзtE ( 300 Lµ , 2.17 mmol ) were added to a solution of 3 - cyano - 2 - tetrahydrofuran - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 140 mg , 0.437 LO mmol ) in DMF ( 3 mL ) and the reaction was stirred at room temperature for 18 h . The reaction was quenched with sat . aq . NaHCO3 and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 126 mg ) . - - - = 1H NMR ( 400 MHz , ³lCDC ) б 10.31 ( d , J = 7.6 Hz , 1H ) , 8.87 ( d , J = 4.3 Hz , 1H ) , 7.99 ( d , J 4.3 Hz , 1H ) , 7.32 – 7.26 ( m , 2H ) , 7.24 – 7.20 ( m , 2H ) , 5.19 – 5.13 ( m , 1H ) , 5.06 – 4.95 ( m , 1H ) , 4.07 - 3.91 ( m , 2H ) , 3.47 ( dd , J = 16.1 , 6.8 Hz , 2H ) , 3.02 ( dd , J = 16.0 , 4.2 Hz , 2H ) , 2.38 2.23 ( m , 1H ) , 2.05 - 1.93 ( m , 3H ) LCMS ( Method 2 ) : 2.56 min , 374.2 [ M + H ] + Synthesis of compound 44 , N7 - indan - 2 - yl - 2 - tetrahydrofuran - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide HO H ' N ' N = .CN PS - PPh3 , Pd ( OAc ) EtOH , O₂H , 90 ° C ' N ' NHN = 3 - Cyano - N - indan - 2 - yl - 2 - tetrahydrofuran - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 1 - mg , 0.32 mmol ) , acetaldehyde oxime ( 78 Lμ , 1.29 mmol ) , Pd ( OAc ) 2 ( 11 mg , 0.05 mmol ) , and PS - PPh3 ( 1.4 - 2 mmol / g ; 57 mg , 0.08 – 0.11 mmol ) were suspended in EtOH ( 4 mL ) and water ( 1 mL ) and the reaction was heated at 90 ° C for 2 h . An additional portion of Pd ( OAc ) 2 ( 11 mg , 0.05 mmol ) was added and the reaction was heated at 90 ° C for a further h . The reaction mixture was cooled to room temperature , filtered through a short pad of ®etilaciD , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 7 % MeOH in DCM ) to provide the title compound ( 29 mg ) . 1H NMR ( 400 MHz , DMSO- d6 ) ō 10.28 ( d , J = 7.2 Hz , 1H ) , 8.90 ( d , J = 4.4 Hz , 1H ) , 7.78 - 7.70 ( m , 2H ) , 7.56 ( s , 1H ) , 7.34 - 7.27 ( m , 2H ) , 7.22 - 7.16 ( m , 2H ) , 5.87 ( dd , J = 7.6 , 4.Hz , 1H ) , 4.86 – 4.78 ( m , 1H ) , 3.79 – 3.67 ( m , 2H ) , 3.45 – 3.36 ( m , 2H ) , 3.00 – 2.92 ( m , 2H ) , - - 2.29 — 2.19 ( m , 1H ) , 1.89 – 1.79 ( m , 3H ) - LCMS ( Method 2 ) : 2.25 min , 392.2 [ M + H ] * 438 Synthesis carboxylate NHCN HN N = of ethyl 3 - cyano - 2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- EtO OEt EtOH , 80 ° C Eto ' N ' .CN Ethyl ( E ) -4 - ethoxy - 2 - oxo - but - 3 - enoate ( 563 mg , 3.27 mmol ) and 5 - amino - 3 - tetrahydrofuran- - yl - 1H - pyrazole - 4 - carbonitrile ( 583 mg , 3.27 mmol ) were dissolved in EtOH ( 20 mL ) and the reaction was heated at 80 ° C for 2 h . An additional portion of ethyl ( E ) -4 - ethoxy - 2 - oxo- but - 3 - enoate ( 563 mg , 3.27 mmol ) was added and the reaction was heated at 80 ° C for a further 2 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 2 % MeOH in DCM ) to provide the title compound ( 366 mg ) . = ' H NMR ( 400 MHz , ³lCDC ) г 8.78 ( d , J = 4.2 Hz , 1H ) , 7.45 ( d , J = 4.2 Hz , 1H ) , 4.57 ( q , J 7.1 Hz , 2H ) , 4.31 - 4.26 ( m , 1H ) , 4.16 – 3.97 ( m , 3H ) , 3.95 – 3.83 ( m , 1H ) , 2.58 – 2.35 ( m , 2H ) , 1.48 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 2 ) : 2.02 min , 287.2 [ M + H ] + Synthesis of 3 - cyano - 2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid EtO CN O₂H.HOiL THF , O₂H , RT HO CN N : N : A solution of O₂H.HOiL ( 59 mg , 1.41 mmol ) in water ( 3.2 mL ) was added to a solution of ethyl 3 - cyano - 2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 366 mg , 1.mmol ) in THF ( 3.2 mL ) and the reaction was stirred at room temperature for 2 h then concentrated in vacuo . The residue was dissolved in EtOAc and water and the layers were 439 LO separated . The aqueous layer was acidified to pH 2 with 1 M aq . HCI and extracted with EtOAc ( x 2 ) and DCM ( x 2 ) . The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 308 mg ) . г 1H NMR ( 400 MHz , CDCl3 ) б 8.98 ( d , J = 4.3 Hz , 1H ) , 7.97 ( d , J = 4.3 Hz , 1H ) , 4.32 - 4.25 . - ( m , 1H ) , 4.20 4.10 ( m , 1H ) , 4.08 – 3.89 ( m , 3H ) , 2.65 – 2.51 ( m , 1H ) , 2.44 - 2.30 ( m , 1H ) . Exchangeable proton not observed . LCMS ( Method 2 ) : 1.46 min , 259.2 [ M + H ] + Synthesis of 3 - cyano - N- ( 3,3 - difluorocyclobutyl ) -2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide F -NH2.HCI T3P , N₂tE HO N. .CN DMF , RT N : xsq N N ° .CN N = 3,3 - Difluorocyclobutanamine hydrochloride ( 257 mg , 1.79 mmol ) , 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 840 Lµ , 1.43 mmol ) , and NзtE ( 830 Lμ , 5.96 mmol ) were added sequentially to a solution of 3 - cyano - 2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxylic acid ( 308 mg , 1.19 mmol ) in DMF ( 12 mL ) and the reaction was stirred at room temperature for 3 h . Additional portions of 3,3 - difluorocyclobutanamine hydrochloride ( 5mg , 3.58 mmol ) , 1 - propanephosphonic anhydride ( 50 wt % in DMF ) ( 840 Lµ , 1.43 mmol ) , and NзtE ( 830 Lµ , 5.96 mmol ) were added in total over the course of a further 21 h . The reaction mixture was diluted with EtOAc and washed with sat . aq . LICI ( x 3 ) . The organic layer was dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 2 % MeOH in DCM ) to provide the title compound ( 171 mg ) . - - - 1H NMR ( 400 MHz , CDCl3 ) Ŏ 8.89 ( d , J = 4.3 Hz , 1H ) , 7.97 ( d , J = 4.3 Hz , 1H ) , 4.56 - 4.45 . ( m , 1H ) , 4.31 – 4.21 ( m , 1H ) , 4.19 – 3.99 ( m , 4H ) , 3.99 – 3.87 ( m , 1H ) , 3.26 – 3.10 ( m , 2H ) , 2.73 – 2.53 ( m , 2H ) , 2.40 – 2.28 ( m , 1H ) . Exchangeable proton not observed . LCMS ( Method 2 ) : 2.17 min , 346.2 [ M − H ] ¯ Synthesis of compound 45 , N7- ( 3,3 - difluorocyclobutyl ) -2 - tetrahydrofuran - 3 - yl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 440 F. F H N. .CN N : HO H PS - PPh3 , Pd ( OAc ) EtOH , O₂H , 90 ° C H N. N N = NH 3 - Cyano - N- ( 3,3 - difluorocyclobutyl ) -2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- - carboxamide ( 91 mg , 0.26 mmol ) , acetaldehyde oxime ( 64 Lµ , 1.05 mmol ) , Pd ( OAc ) 2 ( 9 mg , 0.04 mmol ) , and PS - ³hPP ( 1.4 - 2 mmol / g ; 47 mg , 0.07 – 0.09 mmol ) were suspended in EtOH ( 2 mL ) and water ( 500 Lµ ) and the mixture was degassed by sparging with a stream of argon for 5 min . The reaction was heated at 90 ° C for 3 h . The reaction mixture was cooled to room temperature , filtered through a short pad of ®etilaciD , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 7 % MeOH in DCM ) to provide the title compound ( 39 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) 8 10.24 ( d , J = 6.6 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.76 ( d , J = 2.6 Hz , 1H ) , 7.66 ( d , J = 4.4 Hz , 1H ) , 7.57 ( s , 1H ) , 4.49 – 4.31 ( m , 2H ) , 4.14 ( dd , J = 8.2 , 7.4 Hz , 1H ) , 3.99 – 3.91 ( m , 1H ) , 3.90 – 3.79 ( m , 2H ) , 3.22 – 3.06 ( m , 2H ) , 2.80 - 2.63 ( m , 2H ) , 2.39 — 2.26 ( m , 2H ) - LCMS ( Method 2 ) : 1.95 min , 366.2 [ M + H ] + Synthesis of compound 203 , 2 - tetrahydrofuran - 2 - yl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ﻝا eorge ' N ' NH 2 - Tetrahydrofuran - 2 - yl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ( 31 mg ) was synthesised following a similar procedure to that described in General Method F. 441 ' H NMR ( 400 MHz , DMSO - ɓd ) § 10.21 ( d , J = 7.4 Hz , 1H ) , 8.90 ( d , J = 4.4 Hz , 1H ) , 7.72 ( s , 1H ) , 7.65 ( d , J = 4.4 Hz , 1H ) , 7.58 ( s , 1H ) , 5.95 – 5.88 ( m , 1H ) , 4.79 – 4.67 ( m , 1H ) , 4.29 – - - - - 4.14 ( m , 1H ) , 4.11 – 4.02 ( m , 1H ) , 3.97 – 3.87 ( m , 1H ) , 3.00 – 2.90 ( m , 2H ) , 2.42 – 2.34 ( m , 1H ) , 2.26 ( d , J = 9.9 Hz , 2H ) , 2.09 – 1.94 ( m , 3H ) - LCMS ( Method 7 ) : 2.50 min , 414.2 [ M + H ] * Synthesis of compound 46 , N7 - indan - 2 - yl - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( General Method C ) NH NHHN HO OH .OEt ﻢﺤﻟ EtO EtO NH | HO N ₂HN N = NH Synthesis of ethyl 3 - carbamoyl - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate OEt EtO NHEtOH , 80 ° C Eto . NH2 HO OH NH2 N- H A solution of 5 - amino - 3 - methyl - 1H - pyrazole - 4 - carboxamide sulfuric acid salt ( 1 g , 4.mmol ) and ethyl ( E ) -4 - ethoxy - 2 - oxo - but - 3 - enoate ( 1.08 g , 6.30 mmol ) in EtOH ( 10 mL ) was heated at 80 ° C for 3 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 20 % MeCN in DCM ) to provide the title compound ( 420 mg ) . 442 LO ' H NMR ( 400 MHz , DMSO - d ) § 8.85 ( d , J = 4.3 Hz , 1H ) , 7.63 ( br . s , 1H ) , 7.56 ( d , J = 4.Hz , 1H ) , 7.49 ( br . s , 1H ) , 4.49 ( q , J = 7.1 Hz , 2H ) , 2.66 ( s , 3H ) , 1.37 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 1 ) : 1.34 min , 249.2 [ M + H ] + Synthesis of 3 - carbamoyl - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid EtO NHN = LiOH THF , EtOH RT HO NHN = A solution of LiOH.H2O ( 27 mg , 14.05 mmol ) in water ( 500 Lµ ) was added to a solution of ethyl 3 - carbamoyl - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 146 mg , 12.77 mmol ) in THF ( 30 mL ) and EtOH ( 500 Lµ ) and the reaction was stirred at room temperature for h . The reaction mixture was concentrated in vacuo . Water was added to the residue and the mixture was acidified with 5 M aq . HCI . The resulting precipitate was collected by filtration , washed with water , and dried to provide the title compound ( 129 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) ō 8.81 ( d , J = 4.3 Hz , 1H ) , 7.65 ( s , 1H ) , 7.49 - 7.41 ( m , 2H ) , 2.66 ( s , 3H ) . Exchangeable proton not observed . LCMS ( Method 1 ) : 1.04 min , 221.2 [ M + H ] * Synthesis of compound 46 , N7 - indan - 2 - yl - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide -NH2.HCI T3P , N₂tE DMF , RT HO NHNH NзtE ( 240 Lμ , 1.76 mmol ) and 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 1.05 mL , 1.76 mmol ) were added to a solution of 3 - carbamoyl - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxylic acid ( 129 mg , 0.59 mmol ) and indan - 2 - amine hydrochloride ( 109 mg , 0.64 mmol ) in DMF ( 2.2 mL ) and the reaction was stirred at room temperature for 64 h . The reaction 443 LO mixture was diluted with water and the resulting precipitate was collected by filtration , washed with water , and dried . The crude product was purified by column chromatography ( eluting with 0 to 3 % MeOH in DCM ) to provide the title compound ( 119 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) 8 10.15 ( d , J = 7.1 Hz , 1H ) , 8.86 ( d , J = 4.4 Hz , 1H ) , 7.66 ( s , 1H ) , 7.61 ( d , J = 4.4 Hz , 1H ) , 7.49 ( s , 1H ) , 7.29 ( dd , J = 5.4 , 3.3 Hz , 2H ) , 7.24 - 7.14 ( m , - 2H ) , 4.83 – 4.75 ( m , 1H ) , 3.40 – 3.35 ( m , 2H ) , 2.99 ( dd , J = 16.0 , 5.3 Hz , 2H ) , 2.61 ( s , 3H ) LCMS ( Method 2 ) : 2.27 min , 336.2 [ M + H ] + Synthesis of compound 47 , N7 - chroman - 3 - yl - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide orqu ' N ' NH N7 - chroman - 3 - yl - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 34 mg ) was synthesised following a similar procedure to that described in General Method C. 1H NMR ( 400 MHz , DMSO - d ) u0000 10.50 ( d , J = 7.9 Hz , 1H ) , 8.88 ( d , J = 4.4 Hz , 1H ) , 7.72 ( d , - J = 4.4 Hz , 1H ) , 7.65 ( br . s , 1H ) , 7.49 ( br . s , 1H ) , 7.19 - 7.13 ( m , 2H ) , 6.93 – 6.87 ( m , 2H ) , - 4.66 4.60 ( m , 1H ) , 4.29 - 4.21 ( m , 2H ) , 3.26 ( dd , J = 16.5 , 5.0 Hz , 1H ) , 2.87 ( dd , J = 16.5 , 4.0 Hz , 1H ) , 2.47 ( s , 3H ) LCMS ( Method 2 ) : 2.15 min , 352.2 [ M + H ] * Synthesis of compound 48 , N7- ( 3,3 - difluorocyclobutyl ) -2 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ' N ' NH N7- ( 3,3 - difluorocyclobutyl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 20 mg ) was synthesised following a similar procedure to that described in General Method C. 444 LO 1H NMR ( 400 MHz , DMSO - d6 ) § 10.16 ( d , J = 6.5 Hz , 1H ) , 8.88 ( d , J = 4.4 Hz , 1H ) , 7.68 ( br . - s , 1H ) , 7.59 ( d , J = 4.4 Hz , 1H ) , 7.51 ( br . s , 1H ) , 4.42 - 4.30 ( m , 1H ) , 3.15 – 3.03 ( m , 2H ) , 2.88 2.75 ( m , 2H ) , 2.71 ( s , 3H ) - LCMS ( Method 2 ) : 1.94 min , 310.2 [ M + H ] * Synthesis of compound 49 , N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2 - methyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide NH N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 12 mg ) was synthesised following a similar procedure to that described in General Method C. § ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.14 ( d , J = 7.1 Hz , 1H ) , 8.86 ( d , J = 4.4 Hz , 1H ) , 8.38 - 8.32 ( m , 1H ) , 7.70 - 7.64 ( m , 2H ) , 7.60 ( d , J = 4.4 Hz , 1H ) , 7.50 ( s , 1H ) , 7.19 ( dd , J = 7.6 , 5.0 Hz , 1H ) , 4.86 – 4.80 ( m , 1H ) , 3.47 - 3.39 ( m , 2H ) , 3.07 ( t , J = 5.4 Hz , 1H ) , 3.03 ( t , J = 5.2 Hz , 1H ) , 2.63 ( s , 3H ) - LCMS ( Method 4 ) : 1.27 min , 337.2 [ M + H ] + Synthesis of compound 50 , N7- ( cis - 3 - cyanocyclobutyl ) -2 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ' N ' Na NH N7- ( cis - 3 - cyanocyclobutyl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 21 mg ) was synthesised following a similar procedure to that described in General Method C. ' H NMR ( 400 MHz , DMSO - d ) § 10.07 ( d , J = 7.5 Hz , 1H ) , 8.87 ( d , J = 4.4 Hz , 1H ) , 7.68 ( br . s , 1H ) , 7.58 ( d , J = 4.4 Hz , 1H ) , 7.51 ( br . s , 1H ) , 4.56 - 4.44 ( m , 1H ) , 3.25 -3.11 ( m , 1H ) , 2.80 - 2.73 ( m , 2H ) , 2.72 ( s , 3H ) , 2.55 – 2.49 ( m , 2H ) . Peak at 6 2.55 – 2.49 overlaps with solvent peak . - - 445 LO LCMS ( Method 2 ) : 1.67 min , 299.2 [ M + H ] * Synthesis of compound 51 , a ] pyrimidine - 3,7 - dicarboxamide N7- ( 5 - benzylindan - 2 - yl ) -2 - methyl - pyrazolo [ 1,5- goosqu ' N ' N = NH N7- ( 5 - benzylindan - 2 - yl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 38 mg ) was synthesised following a similar procedure to that described in General Method C. 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.12 ( d , J = 7.2 Hz , 1H ) , 8.85 ( d , J = 4.4 Hz , 1H ) , 7.66 ( s , 1H ) , 7.59 ( d , J = 4.4 Hz , 1H ) , 7.49 ( s , 1H ) , 7.31 – 7.12 ( m , 7H ) , 7.07 ( d , J = 7.9 Hz , 1H ) , 4.- - – 4.71 ( m , 1H ) , 3.91 ( s , 2H ) , 3.28 ( s , 2H ) , 2.93 ( dt , J = 16.0 , 4.5 Hz , 2H ) , 2.58 ( s , 3H ) LCMS ( Method 2 ) : 2.68 min , 426.2 [ M + H ] * Synthesis of compound 52 , N7- ( 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 6 - yl ) -2 - methyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ' N ' N = NH N7- ( 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 6 - yl ) -2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 21 mg ) was synthesised following a similar procedure to that described in General Method C. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.11 ( d , J = 7.1 Hz , 1H ) , 8.86 ( d , J = 4.4 Hz , 1H ) , 8.50 ( d , J = 1.0 Hz , 1H ) , 8.38 ( d , J = 4.9 Hz , 1H ) , 7.66 ( br . s , 1H ) , 7.59 ( d , J = 4.4 Hz , 1H ) , 7.50 ( br . - s , 1H ) , 7.35 ( dd , J = 4.9 , 1.0 Hz , 1H ) , 4.86 - 4.79 ( m , 1H ) , 3.43 ( dd , J = 7.4 , 3.3 Hz , 1H ) , 3.39 ( dd , J = 7.3 , 3.9 Hz , 1H ) , 3.06 ( d , J = 5.1 Hz , 1H ) , 3.02 ( d , J = 5.0 Hz , 1H ) , 2.62 ( s , 3H ) LCMS ( Method 2 ) : 0.91 min , 337.2 [ M + H ] * 446 LO Synthesis of compound 53 , 2 - methyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide xosqe NH 2 - methyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 27 mg ) was synthesised following a similar procedure to that described in General Method C. 1H NMR ( 400 MHz , DMSO - εd ) ☎ 10.01 ( d , J = 7.3 Hz , 1H ) , 8.86 ( d , J = 4.4 Hz , 1H ) , 7.67 ( s , 1H ) , 7.57 ( d , J = 4.4 Hz , 1H ) , 7.51 ( s , 1H ) , 4.76 - 4.65 ( m , 1H ) , 4.27 - 4.12 ( m , 1H ) , 2.93 - 2.81 ( m , 2H ) , 2.71 ( s , 3H ) , 2.44 – 2.32 ( m , 2H ) - LCMS ( Method 2 ) : 2.20 min , 358.2 [ M + H ] * Synthesis of compound 54 , N8- ( 3,3 - difluorocyclobutyl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide ( General Method D ) F MeO MeO Br ----- MeO NH-CI ! -CI H .N . Br OMe H .N . ₂HN OMe HO MeO .Br -Br OMe Synthesis of methyl 2- ( chloromethyl ) imidazo [ 1,2 - b ] pyridazine - 8 - carboxylate 4 eMOu0000 MeO NH CliCI 1. Acetone , 90 ° C 2. MeOH , NaHCO3 , 70 ° C MeO .Cl ﻡا Methyl 3 - aminopyridazine - 4 - carboxylate ( 1.35 g , 8.82 mmol ) and 1,3 - dichloropropan - 2 - one ( 4.82 mL , 44.08 mmol ) were dissolved in acetone ( 15 mL ) and the reaction was heated at ° C in a microwave reactor for 4 h . The reaction mixture was cooled to room temperature and NaHCO3 ( 1.48 g , 17.63 mmol ) and MeOH ( 2 mL ) were added . The reaction was heated at 70 ° C for 16 h then cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 20 % MeOH in DCM ) to provide the title compound ( 794 mg ) . ' H NMR ( 400 MHz , CDCl3 ) б 8.45 ( d , J = 4.6 Hz , 1H ) , 8.14 ( d , J = 0.7 Hz , 1H ) , 7.64 ( d , J = 4.6 Hz , 1H ) , 4.87 ( d , J = 0.7 Hz , 2H ) , 4.08 ( s , 3H ) LCMS ( Method 1 ) : 1.38 min , 226.2 , 228.2 [ M + H ] * Synthesis of methyl 3 - bromo - 2- ( chloromethyl ) imidazo [ 1,2 - b ] pyridazine - 8 - carboxylate N N MeO NBS , MeOH , RT MeO .Br N N CI .CI NBS ( 619 mg , 3.48 mmol ) was added to a solution of methyl 2- ( chloromethyl ) imidazo [ 1,2- b ] pyridazine - 8 - carboxylate ( 785 mg , 3.48 mmol ) in MeOH ( 20 mL ) and the reaction was stirred at room temperature for 2 h then concentrated in vacuo . The residue was dissolved in DCM and water and the layers were separated . The aqueous layer was extracted with DCM ( x 2 ) , and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 977 mg ) . 1H NMR ( 400 MHz , CDCl3 ) б 8.60 ( d , J = 4.6 Hz , 1H ) , 7.71 ( d , J = 4.6 Hz , 1H ) , 4.89 ( s , 2H ) , 4.09 ( s , 3H ) LCMS ( Method 1 ) : 1.57 min , 304.0 , 306.0 [ M + H ] * 448 Synthesis of methyl 3 - bromo - 2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 8 - carboxylate N MeO 1. NaBr , Acetone , 60 ° C 2. AgOTf , MeOH , 50 ° C N MeO .Br .Br CI -OMe NaBr ( 342 mg , 3.32 mmol ) was added to a solution of methyl 3 - bromo - 2- ( chloromethyl ) imidazo [ 1,2 - b ] pyridazine - 8 - carboxylate ( 920 mg , 3.02 mmol ) in acetone ( 15 ) mL ) and the reaction was heated at 60 ° C for 5 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The residue was dissolved in DCM and water and the layers were separated . The aqueous layer was extracted with DCM ( x 3 ) , and the combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude methyl 3 - bromo - 2- ( bromomethyl ) imidazo [ 1,2 - b ] pyridazine - 8 - carboxylate ( 8mg , 2.44 mmol ) thus obtained was dissolved in MeOH ( 12 mL ) and AgOTf ( 939 mg , 3.mmol ) was added . The reaction was heated at 50 ° C for 2 h , then cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) to provide the title compound ( 1.g ) as the impure product . LCMS ( Method 1 ) : 1.46 min , 300.0 , 302.0 [ M + H ] * Synthesis of 3 - bromo - 2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 8 - carboxylic acid O₂H.HOiL THF , RT MeO HO . .Br .Br -OMe -OMe LiOH.H2O ( 112 mg , 2.68 mmol ) was added to a solution of the crude methyl 3 - bromo - 2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 8 - carboxylate ( 1.15 g ; generated in the previous step ) in THF ( 15 mL ) and the reaction was stirred at room temperature for 2 h then concentrated in vacuo . The residue was diluted with water and acidified to pH 2 with 1 M aq . HCI . The aqueous solution was diluted with EtOAc and the layers were separated . The aqueous layer was extracted with a 3 : 1 mixture of CHCI 3 : IPA ( x 3 ) , and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 6mg ) . 449 1H NMR ( 400 MHz , DMSO - d6 ) § 8.79 ( d , J = 4.6 Hz , 1H ) , 7.69 ( d , J = 4.6 Hz , 1H ) , 4.58 ( s , 2H ) , 3.32 ( s , 3H ) . Exchangeable proton not observed . LCMS ( Method 1 ) : 1.30 min , 286.0 , 288.0 [ M + H ] * LO Synthesis of - bromo - N- ( 3,3 - difluorocyclobutyl ) -2- ( methoxymethyl ) imidazo [ 1,2- b ] pyridazine - 8 - carboxamide 1. ₂ICOS , 50 ° C 2. N₂tE , DCM , RT ✓ HO -Br -NH2.HCI .Br -OMe -OMe 3 - Bromo - 2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 8 - carboxylic acid ( 200 mg , 0.63 mmol ) was dissolved in thionyl chloride ( 2 mL , 0.63 mmol ) and the reaction was heated at 50 ° C for 1 h then cooled to room temperature . The reaction mixture was concentrated in vacuo and the residue was dissolved in DCM ( 5 mL ) . 3,3 - Difluorocyclobutanamine hydrochloride ( 99 mg , 0.69 mmol ) and NзtE ( 263 Lμ , 1.89 mmol ) were added , and the reaction was stirred at room temperature for 16 h . The reaction mixture was diluted with DCM and washed with water and sat . aq . NH4Cl . The organic layer was dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) to provide the title compound ( 210 mg ) . = 1H NMR ( 400 MHz , CDCl3 ) б 10.01 ( d , J = 6.3 Hz , 1H ) , 8.63 ( d , J = 4.6 Hz , 1H ) , 7.92 ( d , J 4.6 Hz , 1H ) , 4.71 ( s , 2H ) , 4.53 - 4.43 ( m , 1H ) , 3.52 ( s , 3H ) , 3.19 – 3.08 ( m , 2H ) , 2.83 – 2.( m , 2H ) LCMS ( Method 1 ) : 1.74 min , 375.0 , 377.0 [ M + H ] * Synthesis of compound 54 , N8- ( 3,3 - difluorocyclobutyl ) -2- ( methoxymethyl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide 450 .Br -OMe OH 1. XantPhos Pd G3 , CO ( g ) Et N , MeCN , 86 ° C 2. T3P , HO₂HN RT to 50 ° C NHOMe 3 - Bromo - N- ( 3,3 - difluorocyclobutyl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 8- carboxamide ( 210 mg , 0.56 mmol ) , N - hydroxysuccinimide ( 97 mg , 0.84 mmol ) , XantPhos Pd G3 ( 53 mg , 0.06 mmol ) , and NзtE ( 234 Lµ , 1.68 mmol ) were dissolved in MeCN ( 3 mL ) and the solution was degassed by sparging with a stream of argon for 30 min . The reaction vial was evacuated and backfilled with argon ( x 3 ) , then evacuated and backfilled with carbon monoxide ( x3 ) . The reaction was heated at 86 ° C for 20 h , then cooled to room temperature and degassed with argon . NH4OH ( 33 wt % in water ) ( 661 Lμ , 5.6 mmol ) and 1- propanephosphonic anhydride ( 50 wt % in EtOAc ) ( 1 mL , 1.68 mmol ) were added , and the reaction was stirred at room temperature for 24 h then heated at 50 ° C for a further 24 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) to provide the title compound ( 87 mg ) .

- ' H NMR ( 400 MHz , ³ICDC ) г 10.25 ( d , J = 6.1 Hz , 1H ) , 8.68 ( d , J = 4.7 Hz , 1H ) , 8.44 ( s , 1H ) , 8.05 ( d , J = 4.7 Hz , 1H ) , 5.92 ( s , 1H ) , 5.13 ( s , 2H ) , 4.56 – 4.41 ( m , 1H ) , 3.60 ( s , 3H ) , 3.23 – 3.06 ( m , 2H ) , 2.88 – 2.69 ( m , 2H ) - LCMS ( Method 2 ) : 1.84 min , 340.2 [ M + H ] + Synthesis of compound 55 , 2- ( methoxymethyl ) -N8- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide ﻻﺄﻣ Losge NH-OMe 451 2- ( Methoxymethyl ) -N8- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide ( 66 mg ) was synthesised following a similar procedure to that described in General Method D. ' H NMR ( 400 MHz , ³ICDC ) б 10.13 ( d , J = 7.1 Hz , 1H ) , 8.67 ( d , J = 4.7 Hz , 1H ) , 8.45 ( s , 1H ) , 8.05 ( d , J = 4.7 Hz , 1H ) , 5.91 ( s , 1H ) , 5.13 ( s , 2H ) , 4.58 – 4.46 ( m , 1H ) , 4.36 - 4.22 ( m , 1H ) , 3.61 ( s , 3H ) , 3.08 – 2.95 ( m , 2H ) , 2.50 – 2.38 ( m , 2H ) LCMS ( Method 2 ) : 2.14 min , 388.2 [ M + H ] + Synthesis of compound b ] pyridazine - 3,8 - dicarboxamide , N8 - indan - 2 - yl - 2- ( methoxymethyl ) imidazo [ 1,2- N. cored NH-OMe N8 - indan - 2 - yl - 2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide ( 4 mg ) was synthesised following a similar procedure to that described in General Method D. - - 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.07 ( d , J = 7.1 Hz , 1H ) , 8.90 ( d , J = 4.8 Hz , 1H ) , 8.17 ( s , 1H ) , 8.04 ( s , 1H ) , 7.93 ( d , J = 4.8 Hz , 1H ) , 7.32 – 7.25 ( m , 2H ) , 7.23 – 7.14 ( m , 2H ) , 4.86 ( s , 2H ) , 4.84 - 4.74 ( m , 1H ) , 3.40 ( dd , J = 16.2 , 7.2 Hz , 2H ) , 3.28 ( s , 3H ) , 2.96 ( dd , J = 16.1 , 4.Hz , 2H ) LCMS ( Method 2 ) : 2.15 min , 366.2 [ M + H ] + Synthesis of ethyl 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate Eto . ' N -OH NaH , Mel DMF ° C to RT EtO ' N N : OMe NaH ( 83 mg , 2.08 mmol ) and Mel ( 162 Lμ , 2.06 mmol ) were added sequentially to a solution of ethyl 2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 383 mg , 1.73 mmol ) in DMF ( 6 mL ) at 0 ° C . The reaction mixture was warmed to room temperature and stirred overnight . The reaction was quenched with water , acidified with 1 M aq . HCI , and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 452 2 ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 150 mg ) . ' H NMR ( 400 MHz , CDCl3 ) б 8.54 ( dd , J = 4.1 , 0.4 Hz , 1H ) , 7.27 ( dd , J = 4.1 , 0.5 Hz , 1H ) , 6.87 ( s , 1H ) , 4.77 ( s , 2H ) , 4.59 – 4.51 ( m , 2H ) , 3.47 ( d , J = 0.5 Hz , 3H ) , 1.48 – 1.43 ( m , 3H ) LCMS ( Method 2 ) : 1.74 min , 236.2 [ M + H ] * Synthesis of ethyl carboxylate Eto .

OMe 3 - bromo - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- NBS MeCN , 70 ° C EtO . ' N ' .Br -OMe NBS ( 136 mg , 0.77 mmol ) was added to a solution of ethyl 2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxylate ( 150 mg , 0.64 mmol ) in MeCN ( 5 mL ) and the reaction was heated at 70 ° C for 24 h . The reaction mixture was cooled to room temperature , diluted with DCM , and washed with sat . aq . ³OCHaN ( × 3 ) . The organic layer was dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 186 mg ) . 1H NMR ( 400 MHz , ³ICDC ) ₫ 8.63 ( d , J = 4.1 Hz , 1H ) , 7.34 ( d , J = 4.1 Hz , 1H ) , 4.77 ( s , 2H ) , 4.56 ( d , J = 7.1 Hz , 2H ) , 3.48 ( s , 3H ) , 1.46 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 2 ) : 2.06 min , 314.0 , 316.0 [ M + H ] * Synthesis of 3 - bromo - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid EtO -Br -OMe O₂H.HOiL THF , O₂H RT N HO .Br OMe LiOH.H2O ( 37 mg , 0.89 mmol ) was added to a solution of ethyl 3 - bromo - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 186 mg , 0.59 mmol ) in THF ( 1.mL ) and water ( 1.5 mL ) and the reaction was stirred at room temperature for 4 h . The 453 reaction mixture was diluted with EtOAc and water and acidified to pH 2 - 3 with 1 M aq . HCI . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 3 ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo to provide the title compound ( 147 mg ) . § ' H NMR ( 400 MHz , DMSO - d6 ) ō 8.73 ( d , J = 4.2 Hz , 1H ) , 7.46 ( d , J = 4.2 Hz , 1H ) , 4.61 ( s , 2H ) , 3.33 ( s , 3H ) . Exchangeable proton not observed . LCMS ( Method 2 ) : 1.29 min , 286.0 , 288.0 [ M + H ] * Synthesis of 3 - bromo - N - indan - 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide -NH2.HCI T3P , N₂tE DMF , RT H HO .N . .Br ' N ' Br N : N = -OMe -OMe 1 - Propanephosphonic anhydride ( 50 wt % in DMF ; 300 Lµ , 0.51 mmol ) and NзtE ( 360 Lµ , 2.57 mmol ) were added sequentially to a solution of 3 - bromo - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 147 mg , 0.51 mmol ) and indan - 2 - amine hydrochloride ( 131 mg , 0.77 mmol ) in DMF ( 2.6 mL ) and the reaction was stirred at room temperature for 18 h . The reaction mixture was diluted with EtOAc and water , and the layers were separated . The aqueous layer was extracted with EtOAc ( x 2 ) , and the combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 95 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.01 ( d , J = 7.1 Hz , 1H ) , 8.77 ( d , J = 4.2 Hz , 1H ) , 7.57 ( d , J = 4.3 Hz , 1H ) , 7.31 – 7.25 ( m , 2H ) , 7.21 – 7.16 ( m , 2H ) , 4.84 – 4.74 ( m , 1H ) , 4.56 ( s , 2H ) , 3.34 ( s , 2H ) , 3.27 ( s , 3H ) , 2.97 ( dd , J = 16.1 , 5.0 Hz , 2H ) - LCMS ( Method 2 ) : 2.61 min , 401.0 , 403.0 [ M + H ] * Synthesis of compound 57 , a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5- 454 H .N . ' N ' Br N = -OMe H 1. XantPhos Pd GN₂tE , NMP , 90 ° C 2. HO₂HN , T3P N₂tE , RT H .N . N NHN = -OMe 3 - Bromo - N - indan - 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 93 mg , 0.23 mmol ) and XantPhos Pd G3 ( 22 mg , 0.02 mmol ) were placed in a vial and the vial was sealed and purged with argon for 5 min . NMP ( 2.3 mL ) and NзtE ( 100 Lµ , 0.70 mmol ) were added and the mixture was degassed by sparging with a stream of argon for 5 min . ( 2,5- Dioxopyrrolidin - 1 - yl ) formate ( 166 mg , 1.16 mmol ) was added and the vial was sealed immediately . The reaction was heated at 90 ° C in a microwave reactor for 1 h . Additional portions of XantPhos Pd G3 ( 44 mg , 0.04 mmol ) , NзtE ( 200 Lµ , 1.40 mmol ) , and ( 2,5- dioxopyrrolidin - 1 - yl ) formate ( 332 mg , 2.32 mmol ) were added in total and the reaction was heated at 90 ° C in a microwave reactor for a further 5 h . The reaction mixture was cooled to room temperature , and NзtE ( 100 Lµ , 0.70 mmol ) , 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 280 Lμ , 0.46 mmol ) , and NH4OH ( 240 Lµ , 2.32 mmol ) were added . The reaction was stirred at room temperature for 18 h , then the mixture was diluted with EtOAc and water and the layers were separated . The aqueous layer was extracted with EtOAc ( x 2 ) , and the combined organic layers were washed with sat . aq . LiCl , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by preparative HPLC ( acidic method ) to provide the title compound ( 5 mg ) . - - 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.20 ( d , J = 7.0 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.71 – 7.63 ( m , 2H ) , 7.58 ( s , 1H ) , 7.29 ( dd , J = 5.4 , 3.3 Hz , 2H ) , 7.21 – 7.16 ( m , 2H ) , 4.91 ( s , 2H ) , 4.85 – 4.75 ( m , 1H ) , 3.39 ( dd , J = 16.2 , 7.3 Hz , 2H ) , 3.30 ( s , 3H ) , 2.97 ( dd , J = 16.2 , 4.6 Hz , 2H ) - LCMS ( Method 2 ) 2.14 min . , 366.2 [ M + H ] + Synthesis of 3 - bromo - N- ( 3,3 - difluorocyclobutyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide 455 ﻝا F. -NH2.HCI T3P , N₂tE DMF , RT HO .N . ' N ' .Br Br N = -OMe -OMe 3,3 - Difluorocyclobutanamine hydrochloride ( 298 mg , 2.08 mmol ) , 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 890 Lµ , 1.52 mmol ) , and NзtE ( 960 Lµ , 6.92 mmol ) were added to a solution of 3 - bromo - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 3mg , 1.38 mmol ) in DMF ( 6.9 mL ) and the reaction was stirred at room temperature for 72 h . Additional portions of 3,3 - difluorocyclobutanamine hydrochloride ( 298 mg , 2.08 mmol ) , 1- propanephosphonic anhydride ( 50 wt % in DMF ; 890 Lμ , 1.52 mmol ) , and NзtE ( 960 Lμ , 6.mmol ) were added and the reaction was stirred at room temperature for a further 4 h . The reaction mixture was diluted with EtOAc and water and the layers were separated . The aqueous layer was extracted with EtOAc ( x 2 ) , and the combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 252 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) Ō 10.00 ( s , 1H ) , 8.79 ( d , J = 4.2 Hz , 1H ) , 7.54 ( d , J = 4.2 Hz , 1H ) , 4.66 ( s , 2H ) , 4.35 ( br . s , 1H ) , 3.36 ( s , 3H ) , 3.19 – 3.01 ( m , 2H ) , 2.85 – 2.70 ( m , 2H ) Synthesis of compound 58 , N7- ( 3,3 - difluorocyclobutyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide H ' N ' -Br 1. XantPhos Pd GEt3N , NMP , 100 ° C 2. HO₂HN , T3P N₂tE , DMF , RT -OMe H ' N ' NH-OMe 3 - Bromo - N- ( 3,3 - difluorocyclobutyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide ( 180 mg , 0.48 mmol ) and XantPhos Pd G3 ( 46 mg , 0.05 mmol ) were placed in a vial and the vial was sealed and purged with argon for 5 min . NMP ( 4.8 mL ) and NзtE ( 2Lμ , 1.44 mmol ) were added and the mixture was degassed by sparging with a stream of argon for 5 min . ( 2,5 - Dioxopyrrolidin - 1 - yl ) formate ( 343 mg , 2.40 mmol ) was added and the vial was sealed immediately . The reaction was heated at 90 ° C in a microwave reactor for h . The reaction was heated at 100 ° C for a further 8 h , during which additional portions of XantPhos Pd G3 ( 69 mg , 0.07 mmol ) , NзtE ( 305 Lμ , 2.20 mmol ) , and ( 2,5 - dioxopyrrolidin - 1- yl ) formate ( 523 mg , 3.66 mmol ) were added in total . The reaction mixture was cooled to room temperature , and NзtE ( 201 Lµ , 1.44 mmol ) , 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 571 Lµ , 0.96 mmol ) , and NH4OH ( 243 Lµ , 4.80 mmol ) were added . The reaction was stirred at room temperature for 18 h , then additional portions of Et3N ( 201 Lμ , 1.mmol ) , 1 - propanephosphonic anhydride ( 50 wt % in DMF ; 571 Lμ , 0.96 mmol ) , and NH4OH ( 243 Lμ , 4.80 mmol ) were added . The reaction was stirred at room temperature for a further h , then the reaction mixture was diluted with EtOAc and water . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 3 ) . The combined organic layers were washed with sat . aq . LiCI ( x 2 ) , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by preparative HPLC ( acidic method ) to provide the title compound ( 31 mg ) . § 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.18 ( d , J = 6.0 Hz , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 7.68 ( s , 1H ) , 7.64 ( d , J = 4.4 Hz , 1H ) , 7.60 ( s , 1H ) , 4.99 ( s , 2H ) , 4.43 - 4.31 ( m , 1H ) , 3.42 ( s , 3H ) , - 3.19 3.06 ( m , 2H ) , 2.81 – 2.66 ( m , 2H ) LCMS ( Method 4 ) 1.63 min , 340.2 [ M + H ] * Synthesis of compound 104 , N8- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide H corg NH-OMe N8- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine- 3,8 - dicarboxamide ( 52 mg ) was synthesised following a similar procedure to that described in General Method D. 457 1H NMR ( 400 MHz , DMSO - d ) ō 10.08 ( d , J = 7.0 Hz , 1H ) , 8.90 ( d , J = 4.8 Hz , 1H ) , 8.38 – 8.31 ( m , 1H ) , 8.17 ( s , 1H ) , 8.04 ( s , 1H ) , 7.92 ( d , J = 4.7 Hz , 1H ) , 7.72 – 7.65 ( m , 1H ) , 7.( dd , J = 7.6 , 4.9 Hz , 1H ) , 4.89 - 4.77 ( m , 3H ) , 3.46 ( dd , J = 16.6 , 7.5 Hz , 2H ) , 3.29 ( s , 3H ) , 3.01 ( dd , J = 16.7 , 4.7 Hz , 2H ) LCMS ( Method 7 ) : 1.21 min , 367.2 [ M + H ] + Synthesis of compound 105 , N8- ( 5,6 - dihydro - 4 - cyclopenta [ c ] thiophen - 5 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide ₂HN -OMe N8- ( 5,6 - dihydro - 4H - cyclopenta [ c ] thiophen - 5 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide ( 80 mg ) was synthesised following a similar procedure to that described in General Method D. 1H NMR ( 400 MHz , DMSO - d6 ) ō 10.11 ( d , J = 7.3 Hz , 1H ) , 8.90 ( d , J = 4.7 Hz , 1H ) , 8.18 ( s , 1H ) , 8.05 ( s , 1H ) , 7.92 ( d , J = 4.7 Hz , 1H ) , 7.14-7.10 ( m , 2H ) , 5.07 - 4.94 ( m , 1H ) , 4.89 ( s , 2H ) , 3.19 ( dd , J = 16.0 , 7.3 Hz , 2H ) , 2.72 ( dd , J = 15.8 , 5.9 Hz , 2H ) . 3H obscured by residual H2O peak at Ŏ 3.35 . LCMS ( Method 7 ) : 2.24 min , 372.2 [ M + H ] + Synthesis of compound 106. N8- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide asse ₂HN N8- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide ( 33 mg ) was synthesised following a similar procedure to that described in General Method D. 458 ' H NMR ( 400 MHz , DMSO - d6 ) § 10.32 ( d , J = 7.0 Hz , 1H ) , 8.92 ( d , J = 4.7 Hz , 1H ) , 8.19 ( s , 1H ) , 8.06 ( s , 1H ) , 7.96 ( d , J = 4.8 Hz , 1H ) , 7.38 – 7.21 ( m , 4H ) , 5.61 – 5.53 ( m , 1H ) , 4.89 ( d , J = 1.4 Hz , 2H ) , 3.78 ( dd , J = 14.2 , 4.9 Hz , 1H ) , 3.30 ( s , 3H ) , 3.16 ( dd , J = 14.3 , 2.3 Hz , 1H ) LCMS ( Method 7 ) : 2.24 min , 352.2 [ M + H ] * Synthesis of compound 107 , N8- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide -OMe NB- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide ( 81 mg ) was synthesised following a similar procedure to that described in General Method . D. 1H NMR ( 400 MHz , DMSO - d ) § 10.23 ( d , J = 7.5 Hz , 1H ) , 8.93 ( d , J = 4.8 Hz , 1H ) , 8.18 ( s , 1H ) , 8.06 ( s , 1H ) , 7.96 ( d , J = 4.7 Hz , 1H ) , 7.71 - 7.53 ( m , 4H ) , 5.77 - 5.65 ( m , 1H ) , 4.93 - 4.80 ( m , 2H ) , 3.30 – 3.15 ( m , 1H ) , 3.27 ( s , 3H ) , 2.66 ( qd , J = 14.8 , 5.2 Hz , 1H ) LCMS ( Method 7 ) : 2.39 min , 402.2 [ M + H ] + Synthesis of of compound 108 , 2- ( methoxymethyl ) -N8 - [ ( 4S ) -7 - fluorochroman - 4- yl ] imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide Brid ₂HN 2- ( Methoxymethyl ) -N8 - [ ( 4S ) -7 - fluorochroman - 4 - yl ] imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide ( 56 mg ) was synthesised following a similar procedure to that described in General Method D. ' H NMR ( 400 MHz , DMSO - бd ) Ō 10.18 ( d , J = 7.8 Hz , 1H ) , 8.93 ( d , J = 4.8 Hz , 1H ) , 8.17 ( s , 1H ) , 8.06 ( s , 1H ) , 7.97 ( d , J = 4.8 Hz , 1H ) , 7.44 — 7.35 ( m , 1H ) , 6.80 – 6.68 ( m , 2H ) , 5.35 - 5.26 ( m , 1H ) , 4.88 ( d , J = 0.9 Hz , 2H ) , 4.45 – 4.35 ( m , 1H ) , 4.31 -4.21 ( m , 1H ) , 3.27 ( s , 3H ) , 2.33 – 2.23 ( m , 1H ) , 2.17 – 2.05 ( m , 1H ) 459 LCMS ( Method 7 ) : 1.74 min , 400.2 [ M + H ] * Synthesis of compound 109 , N8- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide ₂HN N8- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide ( 68 mg ) was synthesised following a similar procedure to that described in General Method D. 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 9.99 ( d , J = 7.6 Hz , 1H ) , 8.91 ( d , J = 4.7 Hz , 1H ) , 8.18 ( s , 1H ) , 8.07 ( s , 1H ) , 7.92 ( d , J = 4.7 Hz , 1H ) , 4.95 ( s , 2H ) , 4.22 – 4.09 ( m , 1H ) , 3.40 ( s , 3H ) , 2.16 - 1.96 ( m , 6H ) , 1.78 – 1.65 ( m , 2H ) LCMS ( Method 7 ) : 2.24 min , 368.2 [ M + H ] * Synthesis of compound 110 , NS - [ ( 4 - fluorophenyl ) methyl ] -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide ' ₂HN OMe NB - [ ( 4 - fluorophenyl ) methyl ] -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide ( 61 mg ) was synthesised following a similar procedure to that described in General Method D. 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.09 ( t , J = 5.8 Hz , 1H ) , 8.92 ( d , J = 4.7 Hz , 1H ) , 8.20 ( s , 1H ) , 8.06 ( s , 1H ) , 7.94 ( d , J = 4.7 Hz , 1H ) , 7.46 ( dd , J = 8.4 , 5.5 Hz , 2H ) , 7.19 ( t , J = 8.8 Hz , 2H ) , 4.92 ( s , 2H ) , 4.69 ( d , J = 5.9 Hz , 2H ) , 3.33 ( s , 3H ) LCMS ( Method 7 ) : 2.26 min , 358.2 [ M + H ] + Synthesis of compound 163 , 2 - cyclopropyl - N8- ( 6,7 - dihydro - SH - cyclopenta [ b ] pyridin- - yl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide 460 sorge NH 2 - Cyclopropyl - N8- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide ( 8.3 mg ) was synthesised following a similar procedure to that described in General Method D.

- ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.04 ( d , J = 7.3 Hz , 1H ) , 8.82 ( d , J = 4.8 Hz , 1H ) , 8.( d , J = 4.9 Hz , 1H ) , 8.19 ( s , 1H ) , 7.96 ( s , 1H ) , 7.87 ( d , J = 4.8 Hz , 1H ) , 7.78 ( d , J = 7.5 Hz , 1H ) , 7.27 ( dd , J = 7.6 , 5.2 Hz , 1H ) , 4.85 – 4.79 ( m , 1H ) , 3.49 – 3.43 ( m , 2H ) , 3.14 – 3.08 ( m , 1H ) , 2.98 ( dt , J = 16.7 , 3.8 Hz , 2H ) , 1.03 – 0.96 ( m , 2H ) , 0.79 – 0.71 ( m , 2H ) LCMS ( Method 7 ) : 1.49 min , 363.2 [ M + H ] * - - Synthesis of compound 164 , N8- ( 4,6 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide sosed .N .

F- NH-OMe N8- ( 4,6 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide ( 65 mg ) was synthesised following a similar procedure to that described in General Method D.

- ' H NMR ( 400 MHz , DMSO - бd ) ō 10.08 ( d , J = 7.1 Hz , 1H ) , 8.90 ( d , J = 4.8 Hz , 1H ) , 8.16 ( s , 1H ) , 8.04 ( s , 1H ) , 7.91 ( d , J = 4.7 Hz , 1H ) , 7.10 – 6.99 ( m , 2H ) , 4.93 – 4.81 ( m , 3H ) , 3.49 - 3.37 ( m , 2H ) , 3.30 ( s , 3H ) , 3.07 – 2.91 ( m , 2H ) LCMS ( Method 7 ) : 2.52 min , 402.2 [ M + H ] + Synthesis of ethyl 3 - [ ( 4 - methoxyphenyl ) methylamino ] -6 - methyl - pyridazine - 4 - carboxylate 461 EtO CI N₂H DIPEA OMe 1,4 - Dioxane , 140 ° C HN OMe ﻢﺤﻣﺩ Ethyl 3 - chloro - 6 - methyl - pyridazine - 4 - carboxylate ( 2 g , 9.mmol ) , ( 4- methoxyphenyl ) methanamine ( 2.6 mL , 19.94 mmol ) , and DIPEA ( 5.2 mL , 29.91 mmol ) were dissolved in 1,4 - dioxane ( 10 mL ) and the reaction was heated at 140 ° C in a microwave reactor for 2 h . The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc and water . The layers were separated , and the organic layer was washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 70 % EtOAc in heptane ) to provide the title compound ( 2.46 g ) .

- - ' H NMR ( 400 MHz , ³lCDC ) ₫ 7.63 ( s , 1H ) , 7.58 ( s , 1H ) , 7.39 — 7.31 ( m , 2H ) , 6.91 – 6.83 ( m , 2H ) , 4.79 ( d , J = 5.4 Hz , 2H ) , 4.35 ( q , J = 7.1 Hz , 2H ) , 3.79 ( s , 3H ) , 2.60 ( s , 3H ) , 1.38 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 6 ) : 2.31 mins , 302.2 [ M + H ] * Synthesis of ethyl 3 - amino - 6 - methyl - pyridazine - 4 - carboxylate TFA , 72 ° C OMe EtO EtO HN ﻢﺟﺩ ₂HN ﻱﺩ Ethyl 3 - [ ( 4 - methoxyphenyl ) methylamino ] -6 - methyl - pyridazine - 4 - carboxylate ( 3.26 g , 10.mmol ) was suspended in TFA ( 24.8 mL , 324.54 mmol ) and the reaction was heated at ° C for 2 h . The reaction mixture was cooled to room temperature , basified to pH 8 with sat . aq . NaHCO3 , and diluted with EtOAc . The layers were separated , and the organic layer was washed with water and brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 5 % MeOH in DCM ) to provide the title compound ( 1.48 g ) . 462 LO ' H NMR ( 400 MHz , ³lCDC ) г 7.61 ( s , 1H ) , 6.27 ( s , 2H ) , 4.39 ( q , J = 7.1 Hz , 2H ) , 2.62 ( s , 3H ) , 1.41 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 6 ) : 0.90 mins , 182.2 [ M + H ] * Synthesis of compound 218 , N8- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) -6- methyl - imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide sosge F NH-OMe N8- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) -6 - methyl - imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide ( 25 mg ) was synthesised following a similar procedure to that described in General Method D.

- ' H NMR ( 400 MHz , DMSO - d ) ☎ 9.98 ( d , J = 7.6 Hz , 1H ) , 8.28 ( s , 1H ) , 8.03 ( s , 1H ) , 7.85 ( s , 1H ) , 4.93 ( s , 2H ) , 4.20 – 4.10 ( m , 1H ) , 3.39 ( s , 3H ) , 2.72 ( s , 3H ) , 2.13 – 1.97 ( m , 6H ) , 1.– 1.64 ( m , 2H ) LCMS ( Method 7 ) : 2.26 mins , 382.2 [ M + H ] + Synthesis of compound 219 , 2- ( methoxymethyl ) -N8 - [ ( 4R ) -1,1 - dioxo - 3,4 - dihydro - 2H- thiochromen - 4 - yl ] imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide NHOMe 2- ( Methoxymethyl ) -N8 - [ ( 4R ) -1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ] imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide ( 34 mg ) was synthesised following a similar procedure to that described in General Method D. 1H NMR ( 400 MHz , DMSO - d6 ) à 10.22 ( d , J = 8.2 Hz , 1H ) , 8.93 ( d , J = 4.7 Hz , 1H ) , 8.18 ( s , 1H ) , 8.07 ( s , 1H ) , 7.94 ( d , J = 4.7 Hz , 1H ) , 7.90 - 7.84 ( m , 1H ) , 7.69 – 7.64 ( m , 2H ) , 7.64 - 7.57 ( m , 1H ) , 5.66 – 5.56 ( m , 1H ) , 4.88 ( d , J = 2.8 Hz , 2H ) , 3.91 – 3.80 ( m , 1H ) , 3.73 – 3.( m , 1H ) , 3.28 ( s , 3H ) , 2.70 ( s , 1H ) , 2.64 – 2.53 ( m , 1H ) - 463 LO LCMS ( Method 7 ) : 1.83 min , 430.2 [ M + H ] + Synthesis of compound 220 , 2- ( methoxymethyl ) -N8 - [ ( 4S ) -1,1 - dioxo - 3,4 - dihydro - 2H- thiochromen - 4 - yl ] imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide N grou NH-OMe 2- ( Methoxymethyl ) -N8 - [ ( 4S ) -1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ] imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide ( 44 mg ) was synthesised following a similar procedure to that described in General Method D. - - 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.22 ( d , J = 8.3 Hz , 1H ) , 8.93 ( d , J = 4.7 Hz , 1H ) , 8.18 ( s , 1H ) , 8.07 ( s , 1H ) , 7.94 ( d , J = 4.7 Hz , 1H ) , 7.90 – 7.84 ( m , 1H ) , 7.70 – 7.57 ( m , 3H ) , 5.69 – 5.56 ( m , 1H ) , 4.88 ( d , J = 2.8 Hz , 2H ) , 3.91 - 3.80 ( m , 1H ) , 3.73 - 3.62 ( m , 1H ) , 3.28 ( s , 3H ) , 2.76 – 2.65 ( m , 1H ) , 2.65 – 2.53 ( m , 1H ) - - - LCMS ( Method 7 ) : 1.86 min , 430.1 [ M + H ] * Synthesis of compound 221 , N8- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide Brid NH-OMe N8- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide ( 26 mg ) was synthesised following a similar procedure to that described in General Method D. - - 1H NMR ( 400 MHz , DMSO - d ) § 10.22 ( d , J = 8.2 Hz , 1H ) , 8.93 ( d , J = 4.7 Hz , 1H ) , 8.18 ( s , 1H ) , 8.07 ( s , 1H ) , 7.94 ( d , J = 4.8 Hz , 1H ) , 7.90 – 7.84 ( m , 1H ) , 7.71 – 7.55 ( m , 3H ) , 5.66 – 5.56 ( m , 1H ) , 4.88 ( d , J = 2.9 Hz , 2H ) , 3.91 – 3.80 ( m , 1H ) , 3.73 – 3.63 ( m , 1H ) , 3.28 ( s , 3H ) , 2.76 – 2.64 ( m , 1H ) , 2.64 – 2.55 ( m , 1H ) - - LCMS ( Method 7 ) : 1.82 min , 430.1 [ M + H ] * 464 Synthesis of compound 222 , 2 - cyclopropyl - N8- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen- - yl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide H gige NH 2 - Cyclopropyl - N8- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide ( 58 mg ) was synthesised following a similar procedure to that described in General Method D.

- - ' H NMR ( 400 MHz , DMSO - d ) § 10.28 ( d , J = 7.7 Hz , 1H ) , ð 8.85 ( d , J = 4.8 Hz , 1H ) , 8.27 – 8.13 ( m , 1H ) , 7.98 ( s , 1H ) , 7.94 - 7.87 ( m , 2H ) , 7.84 - 7.68 ( m , 3H ) , 6.02 – 5.84 ( m , 1H ) , 4.13 ( dd , J = 13.7 , 7.3 Hz , 1H ) , 3.74 ( dd , J = 13.7 , 4.1 Hz , 1H ) , 3.17 – 3.06 ( m , 1H ) , 1.01 - 0.89 ( m , 3H ) , 0.88 0.79 ( m , 1H ) - LCMS ( Method 7 ) : 2.16 min , 412.1 [ M + H ] * Synthesis of compound 223 , N8- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide H 85Q = S . SUO NH-OMe N8- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine- 3,8 - dicarboxamide ( 99 mg ) was synthesised following a similar procedure to that described in General Method D.

- ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.34 ( d , J = 7.5 Hz , 1H ) , 8.94 ( d , J = 4.7 Hz , 1H ) , 8.17 ( s , 1H ) , 8.07 ( s , 1H ) , 7.96 ( d , J = 4.8 Hz , 1H ) , 7.90 – 7.87 ( m , 1H ) , 7.82 – 7.74 ( m , 2H ) , 7.73 – 7.67 ( m , 1H ) , 6.02 - 5.92 ( m , 1H ) , 4.90 ( d , J = 13.1 Hz , 1H ) , 4.83 ( d , J = 13.1 Hz , 1H ) , 4.( dd , J = 13.6 , 7.5 Hz , 1H ) , 3.78 ( dd , J = 13.6 , 5.5 Hz , 1H ) , 3.26 ( s , 3H ) - LCMS ( Method 7 ) : 1.82 min , 416.1 [ M + H ] * Synthesis of compound 59 , 2- ( methoxymethyl ) -N7- [ 5- ( trifluoromethyl ) -2- pyridyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( General Method E ) 465 CN CN MeO Moomal MeO CN MeO CN OH OMe EtO N ₂HN .CN HN -CN NHOMe EtO -- N -OMe H Longe F3C N NH-OMe Synthesis of 2- ( 1 - hydroxy - 2 - methoxy - ethylidene ) propanedinitrile CI CN NaH , THF ° C to RT CN MeO MeO CN CN OH -OMe A solution of propanedinitrile ( 12.3 g , 186.19 mmol ) in THF ( 100 mL ) was added dropwise over 1 h to a suspension of NaH ( 14.9 g , 372.50 mmol ) in THF ( 200 mL ) at 0 ° C and the reaction was stirred at 0 ° C for 1 h . A solution of 2 - methoxyacetyl chloride ( 17 mL , 185.mmol ) in THF ( 100 mL ) was added dropwise over 1 h and the reaction was warmed to room temperature and stirred for 3 h . The reaction was quenched with 5 M aq . HCI and diluted with EtOAc and water . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 3 ) . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo . The residue was dissolved in DCM and the solution was dried through a hydrophobic frit and concentrated in vacuo to provide the title compound ( 30.2 g ) . The crude product was taken forward to the next step without purification . 1H NMR ( 400 MHz , 3№CDC ) Ŏ 4.45 ( s , 1H ) , 4.08 ( s , 1H ) , 3.60 ( d , J = 1.0 Hz , 3H ) . Exchangeable proton of enol tautomer not observed . 466 Synthesis of 2- ( 1,2 - dimethoxyethylidene ) propanedinitrile CN ( MeO ) 3CH 100 ° C CN MeO CN MeO CN OH OMe The crude 2- ( 1 - hydroxy - 2 - methoxy - ethylidene ) propanedinitrile ( 30.2 g , 218.63 mmol ) was dissolved in trimethoxymethane ( 144 mL , 1.32 mol ) and the reaction was heated at 100 ° C for 2 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 19.44 g ) . ' H NMR ( 400 MHz , ³lCDC ) ₫ 4.40 ( s , 2H ) , 4.22 ( s , 3H ) , 3.46 ( s , 3H ) Synthesis of 5 - amino - 3- ( methoxymethyl ) -1H - pyrazole - 4 - carbonitrile CN O₂H.4H₂N EtOH , RT NH.CN HN MeO CN N = OMe -OMe Hydrazine monohydrate ( 4.9 mL , 100.82 mmol ) was added to a solution of 2- ( 1,2- dimethoxyethylidene ) propanedinitrile ( 15.3 g , 100.36 mmol ) in EtOH ( 220 mL ) and the reaction was stirred at room temperature for 16 h . The reaction mixture was concentrated in vacuo and the residue was azeotroped with EtOAc ( x 2 ) . The crude product was recrystallised from hot EtOAc , and the resulting precipitate was collected by filtration and dried to provide the title compound ( 5.89 g ) . ' H NMR ( 400 MHz , DMSO - d6 ) ō 11.91 ( s , 1H ) , 6.21 ( s , 2H ) , 4.22 ( s , 2H ) , 3.22 ( s , 3H ) LCMS ( Method 1 ) : 0.70 min , 153.2 [ M + H ] * Synthesis of ethyl 3 - cyano - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate 467 O₂H.4H₂N ﻢﻫﺪﻳ NHCN HN N = -OMe EtOH RT to 78 ° C EtO . OEt ' N ' -CN Eto N = -OMe - amino - 3- ( methoxymethyl ) -1H - pyrazole - 4 - carbonitrile ( 5 g , 32.9 mmol ) was added to a solution of ethyl ( E ) -4 - ethoxy - 2 - oxo - but - 3 - enoate ( 6.8 g , 39.50 mmol ) in EtOH ( 70 mL ) and the reaction was stirred briefly at room temperature then heated at 78 ° C for 16 h . The reaction mixture was concentrated in vacuo and the residue was sonicated in O₂tE for min . The supernatant was decanted and the process was repeated a further three times . A suspension of the product in Et2O was cooled to 5 ° C overnight , and the resulting precipitate was collected by filtration and dried to provide the title compound ( 4.3 g ) . 1H NMR ( 400 MHz , CDC 3 ) б 8.81 ( d , J = 4.2 Hz , 1H ) , 7.50 ( d , J = 4.2 Hz , 1H ) , 4.83 ( s , 2H ) , 4.58 ( q , J = 7.2 Hz , 2H ) , 3.54 ( s , 3H ) , 1.47 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 1 ) : 1.53 min , 261.2 [ M + H ] * Synthesis of 3 - carbamoyl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid 1. 4OS₂H , RT 2. NaOH , 0 ° C to RT EtO HO ' N .CN ' N ' NH-OMe -OMe Ethyl 3 - cyano - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 878 mg , 3.mmol ) was dissolved in conc . H2SO4 ( 1.9 mL , 35.45 mmol ) and the reaction was stirred at room temperature for 3 h . The reaction mixture was carefully added to ice - cooled 2 M aq . NaOH ( 53 mL , 106.00 mmol ) at 0 ° C and the reaction was stirred at 0 ° C to room temperature over 16 h . The reaction mixture was cooled back to 0 ° C and acidified with 5 M aq . HCI . The resulting precipitate was collected by filtration , washed with Et2O , and dried to provide the title compound ( 730 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) § 8.86 ( d , J = 4.3 Hz , 1H ) , 7.65 ( s , 1H ) , 7.53 ( d , J = 4.3 Hz , 2H ) , 4.93 ( s , 2H ) , 3.36 ( s , 3H ) . Additional exchangeable proton not observed . LCMS ( Method 1 ) : 1.04 min , 251.2 [ M + H ] + 468 Synthesis of compound 59 , 2- ( methoxymethyl ) -N7- [ 5- ( trifluoromethyl ) -2- pyridyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide HO F3C- -NH TBTU , DIPEA DMF , 50 ° C N NHLorge NHOMe OMe TBTU ( 90 mg , ( 90 mg , 0.28 mmol ) was added to a solution of 3 - carbamoyl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 50 mg , 0.20 mmol ) , 5- ( trifluoromethyl ) pyridin - 2 - amine ( 60 mL , 0.40 mmol ) , and DIPEA ( 70 mL , 0.40 mmol ) in DMF ( 285 Lµ ) and the reaction was heated at 50 ° C for 16 h . The reaction mixture was cooled to room temperature and diluted with water . The resulting precipitate was collected by filtration , washed with 0.5 M aq . HCI , water , and Et2O , and dried to provide the title compound ( mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) ō 12.67 ( s , 1H ) , 8.99 ( d , J = 4.4 Hz , 1H ) , 8.87 ( s , 1H ) , 8.( d , J = 8.8 Hz , 1H ) , 8.37 ( d , J = 9.2 Hz , 1H ) , 7.87 ( d , J = 4.4 Hz , 1H ) , 7.72 ( s , 1H ) , 7.65 ( s , 1H ) , 5.03 ( s , 2H ) , 3.45 ( s , 3H ) LCMS ( Method 2 ) : 2.32 min , 395.2 [ M + H ] * Synthesis of compound 60 , N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide H ' N ' NH-OMe N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ( 13 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) б 10.21 ( d , J = 7.0 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 8.35 ( dd , J = 5.0 , 1.5 Hz , 1H ) , 7.72 – 7.67 ( m , 2H ) , 7.66 ( s , 1H ) , 7.58 ( s , 1H ) , 7.19 ( dd , J = 7.6 , 5. 469 Hz , 1H ) , 4.92 ( s , 2H ) , 4.90 – 4.78 ( m , 1H ) , 3.51 – 3.40 ( m , 2H ) , 3.31 ( s , 3H ) , 3.06 – 2.96 ( m , 2H ) LCMS ( Method 2 ) : 1.32 min , 367.2 [ M + H ] + Synthesis of compounds 146 and 147 , N7- ( 6,7 - dihydro - SH - cyclopenta [ b ] pyridin - 6 - yl ) - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ₂HW * ₂HN -OMe Racemic N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 67 mg ) was separated using preparative SFC ( eluting with % MeOH in CO2 ) to provide enantiomer 1 ( 25 mg ) and enantiomer 2 ( 26 mg ) with unknown absolute configurations . 1H NMR ( 400 MHz , DMSO - d6 ) 8 10.21 ( d , J = 7.0 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 8.( dd , J = 5.0 , 1.5 Hz , 1H ) , 7.72 – 7.64 ( m , 3H ) , 7.58 ( s , 1H ) , 7.22 – 7.15 ( m , 1H ) , 4.92 ( s , 2H ) , 4.88 – 4.79 ( m , 1H ) , 3.50 – 3.45 ( m , 1H ) , 3.45 – 3.40 ( m , 1H ) , 3.31 ( s , 3H ) , 3.03 ( d , J = 4.Hz , 1H ) , 2.99 ( d , J = 4.5 Hz , 1H ) - - LCMS ( Method 7 ) : 1.38 min , 367.2 [ M + H ] + - Synthesis of compound , 2- ( methoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide F. NH -OMe 2- ( Methoxymethyl ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 22 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.05 ( d , J = 7.2 Hz , 1H ) , 8.91 ( d , J = 4.3 Hz , 1H ) , 7.68 ( s , 1H ) , 7.62 ( d , J = 4.3 Hz , 1H ) , 7.59 ( s , 1H ) , 4.99 ( s , 2H ) , 4.75 -4.68 ( m , 1H ) , 4.25 -4.16 ( m , 1H ) , 3.43 ( s , 3H ) , 2.95 – 2.87 ( m , 2H ) , 2.35 – 2.27 ( m , 2H ) - 470 LO LCMS ( Method 2 ) : 2.13 min , 388.2 [ M + H ] * Synthesis of compound 62 , N7- [ 4 - [ ( dimethylamino ) methyl ] phenyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ' N ' NH-OMe N7- [ 4 - [ ( dimethylamino ) methyl ] phenyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 73 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 11.85 ( s , 1H ) , 8.97 ( d , J = 4.4 Hz , 1H ) , 7.75 ( d , J = 4.4 Hz , 1H ) , 7.73 - 7.66 ( m , 3H ) , 7.62 ( s , 1H ) , 7.40 — 7.33 ( m , 2H ) , 5.02 ( s , 2H ) , 3.44 ( s , 3H ) , 3.( s , 2H ) , 2.16 ( s , 6H ) LCMS ( Method 2 ) : 1.31 min , 383.2 [ M + H ] + Synthesis of compound 63. 2- ( methoxymethyl ) -N7 - [ ( 1 - methylpyrazol - 4- yl ) methyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N― NH-OMe 2- ( methoxymethyl ) -N7 - [ ( 1 - methylpyrazol - 4 - yl ) methyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 11 mg ) was synthesised following a similar procedure to that described in General Method E. – ' H NMR ( 400 MHz , DMSO - d ) Ŏ 10.12 ( t , J = 5.4 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.76 - 7.66 ( m , 3H ) , 7.60 ( s , 1H ) , 7.47 ( d , J = 0.8 Hz , 1H ) , 4.98 ( s , 2H ) , 4.49 ( d , J = 5.4 Hz , 2H ) , 3.81 ( s , 3H ) , 3.37 ( s , 3H ) LCMS ( Method 2 ) : 1.55 min . 344.2 [ M + H ] * Synthesis of compound 64 , N7- ( 4,6 - dimethyl - 2 - pyridyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 471 ora NH.OMe N7- ( 4,6 - dimethyl - 2 - pyridyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 85 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 12.25 ( s , 1H ) , 8.97 ( d , J = 4.4 Hz , 1H ) , 7.95 ( s , 1H ) , 7.( d , J = 4.4 Hz , 1H ) , 7.71 ( s , 1H ) , 7.63 ( s , 1H ) , 6.98 ( s , 1H ) , 5.03 ( s , 2H ) , 3.50 ( s , 3H ) , 2.( s , 3H ) , 2.35 ( s , 3H ) LCMS ( Method 2 ) : 2.12 min , 355.2 [ M + H ] + Synthesis of compound 65 , 2- ( methoxymethyl ) -N7-94- ( trifluoromethyl ) -2- pyridyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ' N ' N : NHOMe 2- ( Methoxymethyl ) -N7- [ 4- ( trifluoromethyl ) -2 - pyridyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 50 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) ō 12.70 ( s , 1H ) , 9.00 ( d , J = 4.4 Hz , 1H ) , 8.75 ( d , J = 5.1 Hz , 1H ) , 8.58 ( s , 1H ) , 7.87 ( d , J = 4.4 Hz , 1H ) , 7.72 ( s , 1H ) , 7.67 ( dd , J = 8.7 , 4.1 Hz , 2H ) , 5.( s , 2H ) , 3.45 ( s , 3H ) LCMS ( Method 2 ) : 2.32 min , 395.2 [ M + H ] * Synthesis of compound 66 , N7- ( 3,4 - difluorophenyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 472 F ' N ' ose NH-OMe N7- ( 3,4 - difluorophenyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d ) § 11.93 ( s , 1H ) , 8.97 ( d , J = 4.4 Hz , 1H ) , 7.94 ( ddd , J = 12.6 , 7.3 , 2.5 Hz , 1H ) , 7.73 ( d , J = 4.4 Hz , 1H ) , 7.69 ( s , 1H ) , 7.62 ( s , 1H ) , 7.55 ( dt , J = 10.5 , 9.Hz , 1H ) , 7.48 - 7.40 ( m , 1H ) , 5.00 ( s , 2H ) , 3.42 ( s , 3H ) LCMS ( Method 2 ) : 2.27 min , 362.2 [ M + H ] * Synthesis of compound , N7- ( 2,3 - dihydrobenzofuran - 5 - ylmethyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N NH-OMe N7- ( 2,3 - dihydrobenzofuran - 5 - ylmethyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 28 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d € ) § 10.20 ( t , J = 5.6 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.75 – 7.68 ( m , 2H ) , 7.59 ( s , 1H ) , 7.34 – 7.29 ( m , 1H ) , 7.16 ( d , J = 8.1 Hz , 1H ) , 6.73 ( d , J = 8.1 Hz , 1H ) , 4.97 ( s , 2H ) , 4.58 ( d , J = 5.7 Hz , 2H ) , 4.51 ( t , J = 8.7 Hz , 2H ) , 3.35 ( s , 3H ) , 3.16 ( t , J = 8.7 Hz , 2H ) LCMS ( Method 2 ) : 2.02 min , 382.2 [ M + H ] * = Synthesis of compound 68 , N7- ( 2,4 - difluorophenyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 473 F orge ' N ' NH-OMe N7- ( 2,4 - difluorophenyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide - ( mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d ) § 12.35 ( s , 1H ) , 9.00 ( d , J = 4.4 Hz , 1H ) , 8.47 – 8.37 ( m , 1H ) , 7.91 ( d , J = 4.4 Hz , 1H ) , 7.72 ( s , 1H ) , 7.66 ( s , 1H ) , 7.57 – 7.47 ( m , 1H ) , 7.27 – 7.17 ( m , 1H ) , 5.03 ( s , 2H ) , 3.43 ( s , 3H ) LCMS ( Method 2 ) : 2.215 min , 362.17 [ M + H ] + - Synthesis of compound 69 , N7 - benzyl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide NH-OMe N7 - benzyl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 52 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.27 ( t , J = 5.8 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.72 - 7.67 ( m , 2H ) , 7.60 ( s , 1H ) , 7.50 – 7.43 ( m , 2H ) , 7.41 - 7.35 ( m , 2H ) , 7.33 - 7.25 ( m , 1H ) , 4.98 ( s , 2H ) , 4.68 ( d , J = 5.8 Hz , 2H ) , 3.36 ( s , 3H ) - LCMS ( Method 2 ) : 2.02 min , 340.2 [ M + H ] * Synthesis of compound 70 , " N7 - [ ( 4 - fluorophenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide F.

N : NH-OMe 474 LO N7 - [ ( 4 - fluorophenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 53 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d ) ☎ 10.25 ( t , J = 5.9 Hz , 1H ) , 8.94 ( d , J = 4.4 Hz , 1H ) , 7.71 ( d , J = 4.4 Hz , 2H ) , 7.61 ( s , 1H ) , 7.57 - 7.48 ( m , 2H ) , 7.26 – 7.16 ( m , 2H ) , 4.99 ( s , 2H ) , 4.68 ( d , J = 5.8 Hz , 2H ) , 3.37 ( s , 3H ) LCMS ( Method 2 ) : 2.04 min , 358.2 [ M + H ] + compound , N7 - [ ( 3 - fluorophenyl ) methyl ] -2- Synthesis of ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide Ligh NHOMe N7 - [ ( 3 - fluorophenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 63 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) § 10.27 ( t , J = 5.8 Hz , 1H ) , 8.94 ( d , J = 4.4 Hz , 1H ) , 7.71 ( d , J = 4.4 Hz , 2H ) , 7.61 ( s , 1H ) , 7.48 - 7.38 ( m , 1H ) , 7.37 – 7.29 ( m , 2H ) , 7.16 – 7.09 ( m , 1H ) , 4.99 ( s , 2H ) , 4.71 ( d , J = 5.9 Hz , 2H ) , 3.38 ( s , 3H ) LCMS ( Method 2 ) : 2.07 min , 358.2 [ M + H ] + Synthesis of compound 72 , 2- ( methoxymethyl ) -N7- ( p - tolylmethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ' N ' NH-OMe 2- ( Methoxymethyl ) -N7- ( p - tolylmethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 18 mg ) was synthesised following a similar procedure to that described in General Method E. 475 LO 1H NMR ( 400 MHz , DMSO - d ) § 10.24 ( s , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.78 – 7.65 ( m , 2H ) , 7.60 ( s , 1H ) , 7.34 ( d , J = 8.0 Hz , 2H ) , 7.18 ( d , J = 7.8 Hz , 2H ) , 4.98 ( s , 2H ) , 4.63 ( s , 2H ) , 3.35 ( s , 3H ) , 2.30 ( s , 3H ) LCMS ( Method 2 ) : 2.17 min , 354.2 [ M + H ] + Synthesis of compound 73 , 2- ( methoxymethyl ) -N7- ( 7 - methoxytetralin - 2- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide OMe H .N . ` ´N N = ₂HN OMe 2- ( Methoxymethyl ) -N7- ( 7 - methoxytetralin - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 23 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d ) § 10.17 ( d , J = 7.4 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.73 ( d , J = 4.4 Hz , 1H ) , 7.67 ( d , J = 2.7 Hz , 1H ) , 7.58 ( d , J = 2.5 Hz , 1H ) , 7.04 ( d , J = 8.4 Hz , 1H ) , 6.72 ( dd , J = 8.4 , 2.7 Hz , 1H ) , 6.68 ( d , J = 2.7 Hz , 1H ) , 4.89 ( d , J = 0.7 Hz , 2H ) , 4.48 – 4.( m , 1H ) , 3.70 ( s , 3H ) , 3.33 ( s , 3H ) , 3.15 ( dd , J = 16.7 , 5.0 Hz , 1H ) , 2.99 – 2.88 ( m , 1H ) , 2.- - – 2.76 ( m , 2H ) , 2.14 – 2.01 ( m , 1H ) , 1.99 – 1.86 ( m , 1H ) LCMS ( Method 2 ) : 2.25 min , 410.2 [ M + H ] * - Synthesis of compound 74 , 2- ( methoxymethyl ) -N7 - [ ( 1R ) -tetralin - 1 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N = NH-OMe 2- ( Methoxymethyl ) -N7 - [ ( 1 R ) -tetralin - 1 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method E. 476 ' H NMR ( 400 MHz , DMSO - d ) ₫ 10.30 ( d , J = 8.3 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.73 ( d , - J = 4.4 Hz , 1H ) , 7.67 ( s , 1H ) , 7.58 ( s , 1H ) , 7.25 – 7.10 ( m , 4H ) , 5.34 – 5.26 ( m , 1H ) , 4.93 ( s , - - - 2H ) , 3.28 ( s , 3H ) , 2.93 – 2.72 ( m , 2H ) , 2.20 - 2.03 ( m , 1H ) , 1.96 – 1.86 ( m , 3H ) LCMS ( Method 2 ) : 2.32 min , 380.2 [ M + H ] * LO Synthesis of compound 75 , N7- ( 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N NH-OMe N7- ( 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 115 mg ) was synthesised following a similar procedure to that described in General Method E.

- - - ' H NMR ( 400 MHz , DMSO - d6 ) г 10.38 ( d , J = 6.7 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.71 ( d , J = 4.4 Hz , 1H ) , 7.66 ( s , 1H ) , 7.59 ( s , 1H ) , 7.52 – 7.46 ( m , 1H ) , 7.33 – 7.25 ( m , 1H ) , 7.01 - 6.94 ( m , 1H ) , 6.92 ( dd , J = 8.2 , 0.9 Hz , 1H ) , 5.82 - 5.72 ( m , 1H ) , 4.97 - 4.87 ( m , 2H ) , 4.( dd , J = 9.9 , 8.2 Hz , 1H ) , 4.47 ( dd , J = 9.9 , 4.4 Hz , 1H ) , 3.26 ( s , 3H ) LCMS ( Method 2 ) : 2.05 min , 368.2 [ M + H ] + Synthesis of compound 76 , a ] pyrimidine - 3,7 - dicarboxamide N7 - cyclohexyl - 2- ( methoxymethyl ) pyrazolo [ 1,5- ' N ' NHOMe N7 - cyclohexyl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 29 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.10 ( d , J = 7.7 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.71 ( d , J = 4.4 Hz , 1H ) , 7.69 ( s , 1H ) , 7.60 ( s , 1H ) , 5.01 ( s , 2H ) , 4.07 – 3.89 ( m , 1H ) , 3.44 ( s , 3H ) , - 1.98 1.82 ( m , 2H ) , 1.81 – 1.66 ( m , 2H ) , 1.60 – 1.49 ( m , 1H ) , 1.50 – 1.26 ( m , 5H ) LCMS ( Method 2 ) : 2.21 min , 332.2 [ M + H ] * 477 Synthesis of compound 77 , N7 - [ ( 2,2 - dimethylcyclopropyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide A NH-OMe N7 - [ ( 2,2 - dimethylcyclopropyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 23 mg ) was synthesised following a similar procedure to that described in General Method E. - 1H NMR ( 400 MHz , DMSO - d6 ) ō 10.08 ( t , J = 5.4 Hz , 1H ) , 8.94 ( d , J = 4.4 Hz , 1H ) , 7.75 ( d , J = 4.4 Hz , 1H ) , 7.72 ( s , 1H ) , 7.62 ( s , 1H ) , 5.01 ( s , 2H ) , 3.77 – 3.68 ( m , 1H ) , 3.42 ( s , 3H ) , 3.25 -3.16 ( m , 1H ) , 1.19 ( s , 3H ) , 1.09 ( s , 3H ) , 0.97 – 0.87 ( m , 1H ) , 0.52 ( dd , J = 8.6 , 4.3 Hz , 1H ) , 0.27 ( t , J = 4.8 Hz , 1H ) LCMS ( Method 2 ) : 2.19 min , 332.2 [ M + H ] + Synthesis of compound 78 , N7 - chroman - 3 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide H NH-OMe N7 - chroman - 3 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 122 mg ) was synthesised following a similar procedure to that described in General Method E. - 1H NMR ( 400 MHz , DMSO - d6 ) ₫ 10.32 ( d , J = 7.5 Hz , 1H ) , 8.95 – 8.90 ( m , 1H ) , 7.77 ( d , J = 4.4 Hz , 1H ) , 7.67 ( s , 1H ) , 7.57 ( s , 1H ) , 7.17 - 7.09 ( m , 2H ) , 6.93 – 6.82 ( m , 2H ) , 4.84 - 4.- ( m , 2H ) , 4.65 – 4.56 ( m , 1H ) , 4.29 – 4.18 ( m , 2H ) , 3.33 – 3.27 ( m , 1H ) , 3.24 ( s , 3H ) , 2.94 – 2.78 ( m , 1H ) - LCMS ( Method 2 ) : 2.09 min , 382.2 [ M + H ] * Synthesis of compound 79 , 2- ( methoxymethyl ) -N7 - [ ( 2S ) -tetralin - 2 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 478 oral NHOMe 2- ( Methoxymethyl ) -N7 - [ ( 2S ) -tetralin - 2 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( - mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.17 ( d , J = 7.4 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.73 ( d , J = 4.4 Hz , 1H ) , 7.67 ( d , J = 2.5 Hz , 1H ) , 7.58 ( s , 1H ) , 7.19 – 7.07 ( m , 4H ) , 4.89 ( s , 2H ) , 4.- 4.37 ( m , 1H ) , 3.32 ( s , 3H ) , 3.19 ( dd , J = 16.6 , 5.1 Hz , 1H ) , 3.07 – 2.96 ( m , 1H ) , 2.96 – 2.( m , 1H ) , 2.84 ( dd , J = 16.9 , 6.9 Hz , 1H ) , 2.17 - 2.05 ( m , 1H ) , 2.02 – 1.89 ( m , 1H ) LCMS ( Method 2 ) : 2.28 min , 380.2 [ M + H ] + - Synthesis of compound 80 , N7- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide .N . NH-OMe N7- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 30 mg ) was synthesised following a similar procedure to that described in General Method E. - ' H NMR ( 400 MHz , DMSO - d6 ) б 10.11 ( d , J = 7.5 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.71 – 7.66 ( m , 2H ) , 7.61 ( s , 1H ) , 5.00 ( s , 2H ) , 4.25 – 4.09 ( m , 1H ) , 3.42 ( s , 3H ) , 2.17 - 1.93 ( m , 6H ) , 1.82 – 1.65 ( m , 2H ) - LCMS ( Method 2 ) : 2.02 min , 368.2 [ M + H ] + - Synthesis of compound 81 , N7- ( cyclopropylmethyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 479 NH-OMe N7- ( cyclopropylmethyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d ) ☎ 10.04 ( t , J = 5.5 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.72 – 7.69 ( m , 2H ) , 7.60 ( d , J = 2.5 Hz , 1H ) , 5.01 ( s , 2H ) , 3.44 ( s , 3H ) , 3.39 – 3.33 ( m , 2H ) , 1.16 - 1.03 ( m , 1H ) , 0.58 – 0.48 ( m , 2H ) , 0.38 – 0.28 ( m , 2H ) LCMS ( Method 2 ) : 1.82 min , 304.2 [ M + H ] + Synthesis of compound 82 , N7- ( 7 - fluorotetralin - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide - N NH-OMe N7- ( 7 - fluorotetralin - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 27 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - éd ) § 10.16 ( d , J = 7.4 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.72 ( d , - - J = 4.4 Hz , 1H ) , 7.67 ( d , J = 2.6 Hz , 1H ) , 7.59 ( s , 1H ) , 7.22 – 7.13 ( m , 1H ) , 7.02 – 6.92 ( m , 2H ) , 4.89 ( s , 2H ) , 4.52 - 4.31 ( m , 1H ) , 3.33 ( s , 3H ) , 3.19 ( dd , J = 17.0 , 5.1 Hz , 1H ) , 3.05 - 2.93 ( m , 1H ) , 2.93 - 2.81 ( m , 2H ) , 2.16 – 2.03 ( m , 1H ) , 2.02 – 1.88 ( m , 1H ) LCMS ( Method 2 ) : 2.27 min , 398.2 [ M + H ] * Synthesis of compound 83 , N7 - [ ( 2,4 - difluorophenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 480 F.

' N ' N = NH-OMe N7 - [ ( 2,4 - difluorophenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 25 mg ) was synthesised following a similar procedure to that described in General Method E. - ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.31 – 10.27 ( m , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.73 – 7.( m , 2H ) , 7.69 – 7.62 ( m , 1H ) , 7.61 ( s , 1H ) , 7.30 ( ddd , J = 10.5 , 9.3 , 2.6 Hz , 1H ) , 7.11 ( ddd , J = 8.5 , 2.6 , 1.1 Hz , 1H ) , 4.99 ( s , 2H ) , 4.69 ( d , J = 5.0 Hz , 2H ) , 3.38 ( s , 3H ) LCMS ( Method 2 ) : 2.11 min , 376.2 [ M + H ] + Synthesis of compound 84 . 2- ( methoxymethyl ) -N7- ( cis - 4- methylcyclohexyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide H N orgy NH-OMe 2- ( Methoxymethyl ) -N7- ( cis - 4 - methylcyclohexyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 47 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - éd ) § 10.15 ( d , J = 7.9 Hz , 1H ) , 8.64 ( d , J = 4.4 Hz , 1H ) , 7.49 ( d , J = 4.4 Hz , 1H ) , 7.42 ( s , 1H ) , 7.32 ( s , 1H ) , 4.73 ( s , 2H ) , 4.00 – 3.93 ( m , 1H ) , 3.12 ( s , 3H ) , - - - 1.52 – 1.44 ( m , 2H ) , 1.40 – 1.25 ( m , 4H ) , 1.23 – 1.15 ( m , 1H ) , 1.06 – 0.94 ( m , 2H ) , 0.65 ( d , - J = 6.4 Hz , 3H ) LCMS ( Method 2 ) : 2.33 min , 346.2 [ M + H ] + Synthesis of compound 85 , N7- ( 5,6 - dihydro - 4H - cyclopenta [ c ] thiophen - 5 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 481 cosqu N = NH-OMe N7- ( 5,6 - dihydro - 4H - cyclopenta [ c ] thiophen - 5 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 33 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.25 ( d , J = 7.3 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.70 - 7.65 ( m , 2H ) , 7.58 ( s , 1H ) , 7.12 ( d , J = 0.9 Hz , 2H ) , 5.05 – 4.96 ( m , 1H ) , 4.94 ( s , 2H ) , 3.( s , 3H ) , 3.24 3.13 ( m , 2H ) , 2.77 - 2.67 ( m , 2H ) - LCMS ( Method 2 ) : 2.19 min , 372.1 [ M + H ] + Synthesis of compound , 2- ( methoxymethyl ) -N7- ( trans - 3- methylcyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide H ssge ' N ' N = NH-OMe 2- ( Methoxymethyl ) -N7- ( trans - 3 - methylcyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 10 mg ) was synthesised following a similar procedure to that described in General Method E.

- ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.15 ( d , J = 7.1 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.71 - 7.62 ( m , 2H ) , 7.60 ( s , 1H ) , 5.01 ( s , 2H ) , 4.64 – 4.50 ( m , 1H ) , 3.44 ( s , 3H ) , 2.42 ( s , 1H ) , 2.– 2.15 ( m , 2H ) , 2.12 – 2.00 ( m , 2H ) , 1.16 ( s , 3H ) - - LCMS ( Method 2 ) : 2.04 min , 318.2 [ M + H ] + Synthesis of compound 87 , N7- ( 5 - chloroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 482 ` N N posse Cl N : NH-OMe N7- ( 5 - chloroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.19 ( d , J = 7.1 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.71 - - - 7.65 ( m , 2H ) , 7.60 – 7.55 ( m , 1H ) , 7.37 ( d , J = 2.0 Hz , 1H ) , 7.31 ( d , J = 8.1 Hz , 1H ) , 7.27 - 7.20 ( m , 1H ) , 4.92 ( s , 2H ) , 4.86 – 4.76 ( m , 1H ) , 3.45 – 3.34 ( m , 2H ) , 3.31 ( s , 3H ) , 3.03 – 2.( m , 2H ) - LCMS ( Method 2 ) : 2.32 min , 400.14 [ M + H ] * - Synthesis of compound 88 , N7- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide .N . ' N ' oral NH-OMe N7- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 23 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.52 ( d , J = 6.0 Hz , 1H ) , 8.94 ( d , J = 4.4 Hz , 1H ) , 7.72 ( d , - J = 4.4 Hz , 1H ) , 7.68 ( s , 1H ) , 7.60 ( s , 1H ) , 7.40 – 7.21 ( m , 4H ) , 5.56 ( s , 1H ) , 4.96 ( d , J = 1.Hz , 2H ) , 3.83 - 3.73 ( m , 1H ) , 3.34 ( s , 3H ) , 3.23 - 3.15 ( m , 1H ) LCMS ( Method 2 ) : 2.34 , 352.2 [ M + H ] + Synthesis of compound 89 . 2- ( methoxymethyl ) -7- [ 4- [ 3- ( trifluoromethyl ) -2- pyridyl ] piperazine - 1 - carbonyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3 - carboxamide 483 ' N ' Zagy CFN : NH-OMe 2- ( Methoxymethyl ) -7- [ 4- [ 3- ( trifluoromethyl ) -2 - pyridyl ] piperazine - 1 - carbonyl ] pyrazolo [ 1,5- a ] pyrimidine - 3 - carboxamide ( 53 mg ) was synthesised following a similar procedure to that described in General Method E.

- ' H NMR ( 400 MHz , DMSO - d6 ) ō 8.87 ( d , J = 4.3 Hz , 1H ) , 8.60 – 8.53 ( m , 1H ) , 8.11 ( dd , J = 7.8 , 1.8 Hz , 1H ) , 7.67 ( s , 1H ) , 7.55 ( s , 1H ) , 7.43 ( d , J = 4.3 Hz , 1H ) , 7.30 – 7.22 ( m , 1H ) , 4.94 ( d , J = 9.4 Hz , 2H ) , 3.88 ( d , J = 16.4 Hz , 2H ) , 3.41 – 3.33 ( m , 7H ) , 3.16 ( d , J = 5.2 Hz , 2H ) LCMS ( Method 2 ) : 2.11 , 464.2 [ M + H ] * Synthesis of compound 90 , N7 - [ [ 1- ( dimethylamino ) cyclohexyl ] methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide H NH-OMe N7 - [ [ 1- ( dimethylamino ) cyclohexyl ] methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 11 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.22 ( t , J = 5.4 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.77 ( d , J = 4.4 Hz , 1H ) , 7.72 ( s , 1H ) , 7.61 ( s , 1H ) , 4.98 ( s , 2H ) , 3.56 ( d , J = 5.5 Hz , 2H ) , 3.39 ( s , 3H ) , 2.29 ( s , 6H ) , 1.72 – 1.31 ( m , 10H ) . LCMS ( Method 2 ) : 1.32 min , 389.2 [ M + H ] * Synthesis of compound 91 , N7- ( 4 - fluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 484 H ' N ' cosas N = NH-OMe N7- ( 4 - fluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 10 ) mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.21 ( d , J = 7.1 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.73 - - 7.61 ( m , 2H ) , 7.58 ( s , 1H ) , 7.29 – 7.20 ( m , 1H ) , 7.15 ( d , J = 7.4 Hz , 1H ) , 7.06 – 6.98 ( m , 1H ) , 4.91 ( s , 2H ) , 4.91 – 4.82 ( m , 1H ) , 3.49 – 3.37 ( m , 2H ) , 3.31 ( s , 3H ) , 3.02 ( dt , 2H ) LCMS ( Method 7 ) : 2.45 min , 384.2 [ M + H ] * - Synthesis of compound 92 , N7- ( 4,6 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide F N : NHOMe N7- ( 4,6 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 10 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d ) § 10.21 ( d , J = 7.1 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.67 ( t , - - - J = 4.3 Hz , 2H ) , 7.58 ( s , 1H ) , 7.11 – 7.00 ( m , 2H ) , 4.92 ( s , 2H ) , 4.91 – 4.82 ( m , 1H ) , 3.48 – 3.32 ( m , 5H ) , 3.07 – 2.92 ( m , 2H ) . - LCMS ( Method 7 ) : 2.52 min , 402.2 [ M + H ] * Synthesis of tert - butyl 3 - [ [ 3 - carbamoyl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- - carbonyl ] amino ] -3,4 - dihydro - 2H - quinoline - 1 - carboxylate 485 H N.

Borge BOC N NH-OMe Tert - butyl 3 - [ [ 3 - carbamoyl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carbonyl ] amino ] - 3,4 - dihydro - 2H - quinoline - 1 - carboxylate ( 197 mg ) was synthesised following a similar procedure to that described in General Method E. - - - - - 1H NMR ( 400 MHz , CDCl3 ) б 10.55 ( d , J = 7.4 Hz , 1H ) , 8.79 ( d , J = 4.4 Hz , 1H ) , 8.04 - 7.( m , 2H ) , 7.78 – 7.71 ( m , 1H ) , 7.25 – 7.15 ( m , 2H ) , 7.11 – 7.03 ( m , 1H ) , 5.64 ( s , 1H ) , 5.02 ( d , J = 13.7 Hz , 1H ) , 4.86 ( d , J = 13.6 Hz , 1H ) , 4.79 – 4.69 ( m , 1H ) , 4.15 – 4.05 ( m , 1H ) , 3.( dd , J = 13.0 , 3.6 Hz , 1H ) , 3.36 – 3.26 ( m , 4H ) , 2.98 ( dd , J = 16.5 , 5.2 Hz , 1H ) , 1.36 ( s , 9H ) LCMS ( Method 2 ) : 2.43 min , 481.2 [ M + H ] * Synthesis of compound 93 , 2- ( methoxymethyl ) -N7- ( 1,2,3,4 - tetrahydroquinolin - 3- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide TFA , DCM RT NH-OMe .N . ﻲﻨﻳﺓ ' N ' BOC ' N ' NH` N -OMe TFA ( 250 Lμ , 3.26 mmol ) was added to a solution of tert - butyl 3 - [ [ 3 - carbamoyl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carbonyl ] amino ] -3,4 - dihydro - 2H - quinoline - 1- carboxylate ( 100 mg , 0.21 mmol ) in DCM ( 2 mL ) and the reaction was stirred at room temperature for 5 h . The reaction mixture was concentrated in vacuo and the residue was azeotroped with DCM ( x 3 ) . 2 M NH3 in MeOH ( 20 mL ) was added and the mixture was concentrated in vacuo ( x 2 ) . The crude product was purified by column chromatography ( eluting with 0 to 80 % MeOH in DCM ) to provide the title compound ( 71 mg ) . - - 1H NMR ( 400 MHz , DMSO - d6 ) 8 10.31 ( d , J = 7.6 Hz , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 7.78 ( d , J = 4.4 Hz , 1H ) , 7.71 – 7.63 ( m , 1H ) , 7.56 ( s , 1H ) , 6.95 – 6.87 ( m , 2H ) , 6.55 ( dd , J = 8.0 , 1.Hz , 1H ) , 6.53 – 6.46 ( m , 1H ) , 5.88 ( s , 1H ) , 4.84 – 4.72 ( m , 2H ) , 4.50 ( s , 1H ) , 3.41 ( d , J = 11.6 Hz , 1H ) , 3.27 ( s , 4H ) , 3.12 ( dd , J = 16.4 , 4.9 Hz , 1H ) , 2.84 – 2.74 ( m , 1H ) LCMS ( Method 2 ) : 2.00 min , 381.2 [ M + H ] * - - 486 LO Synthesis of compound 95 . 7- ( isoindoline - 2 - carbonyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3 - carboxamide WH 7- ( Isoindoline - 2 - carbonyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3 - carboxamide ( mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) ☎ 8.92 ( d , J = 4.3 Hz , 1H ) , 7.68 ( s , 1H ) , 7.58 ( s , 1H ) , 7.( d , J = 4.3 Hz , 1H ) , 7.45 ( d , J = 7.5 Hz , 1H ) , 7.37 – 7.26 ( m , 2H ) , 7.19 ( d , J = 7.4 Hz , 1H ) , 4.98 ( s , 2H ) , 4.91 ( s , 2H ) , 4.62 ( s , 2H ) , 3.30 ( s , 3H ) LCMS ( Method 7 ) : 2.00 min , 352.2 [ M + H ] * Synthesis of 111 , - cyclopropyl - N7- [ cis - 3- compound ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide assge ₂HN 2 - Cyclopropyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 23 mg ) was synthesised following a similar procedure to that described in General Method E. ... ' H NMR ( 400 MHz , DMSO - d6 } ☎ 9.91 ( d , J = 7.4 Hz , 1H ) , 8.84 ( d , J = 4.4 Hz , 1H ) , 7.80 - 7.72 ( m , 1H ) , 7.59 - 7.50 ( m , 2H ) , 4.71 ( p , J = 7.1 Hz , 1H ) , 4.25 -4.11 ( m , 1H ) , 3.26 - 3.( m , 1H ) , 2.96 – 2.85 ( m , 2H ) , 2.33 – 2.22 ( m , 2H ) , 1.20 – 1.03 ( m , 4H ) LCMS ( Method 4 ) : 2.41 min , 384.0 [ M + H ] * - Synthesis of compound 112 , 2 - cyclopropyl - N7- ( 3,3 - difluoroindan - 1 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 487 Bizi NH 2 - Cyclopropyl - N7- ( 3,3 - difluoroindan - 1 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - бd ) ō 10.25 ( d , J = 7.5 Hz , 1H ) , 8.86 ( d , J = 4.4 Hz , 1H ) , 7.75 ( s , 1H ) , 7.72 – 7.62 ( m , 4H ) , 7.62 – 7.56 ( m , 1H ) , 7.54 ( s , 1H ) , 5.74 – 5.64 ( m , 1H ) , 3.30 – 3.( m , 2H ) , 2.70 – 2.56 ( m , 1H ) , 1.10 – 0.98 ( m , 2H ) , 0.89 – 0.79 ( m , 2H ) - - LCMS ( Method 7 ) : 2.67 min , 398.2 [ M + H ] * 2 - cyclopropyl - N7 - [ ( 4S ) -7 - fluorochroman - 4- 10 Synthesis of compound 113 , yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide Brau NN 2 - Cyclopropyl - N7 - [ ( 4S ) -7 - fluorochroman - 4 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 56 mg ) was synthesised following a similar procedure to that described in General Method . E.

- ' H NMR ( 400 MHz , DMSO - d6 ) O 10.11 ( d , J = 7.5 Hz , 1H ) , 8.85 ( d , J = 4.4 Hz , 1H ) , 7.75 ( d , J = 2.7 Hz , 1H ) , 7.63 ( d , J = 4.4 Hz , 1H ) , 7.53 ( s , 1H ) , 7.47 – 7.39 ( m , 1H ) , 6.86 – 6.66 ( m , 2H ) , 5.28 – 5.19 ( m , 1H ) , 4.41 – 4.31 ( m , 1H ) , 4.26 – 4.16 ( m , 1H ) , 3.21 – 3.09 ( m , 1H ) , 2.- 2.19 ( m , 1H ) , 2.16 - 2.04 ( m , 1H ) , 1.09 1.00 ( m , 2H ) , 0.83 - 0.73 ( m , 2H ) - - LCMS ( Method 7 ) : 2.67 min , 396.2 [ M + H ] * - Synthesis of N - chroman - 3 - yl - 2,2,2 - trifluoro - acetamide - 488 BC CF ICH₂HN DIPEA DCM , RT DIPEA ( 840 Lμ , 4.85 mmol ) and trifluoroacetic anhydride ( 270 Lµ , 1.94 mmol ) were added to a suspension of chroman - 3 - amine hydrochloride ( 300 mg , 1.62 mmol ) in DCM ( 16 mL ) , and the reaction was stirred at room temperature for 2 h . The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography ( eluting with 0 to 1 % MeOH in DCM ) to provide the title compound ( 210 mg ) . ' H NMR ( 400 MHz , ³lCDC ) ₫ 7.22 – 7.12 ( m , 1H ) , 7.07 ( d , J = 7.5 Hz , 1H ) , 6.95 ( td , J = 7.4 , 1.2 Hz , 1H ) , 6.89 ( dd , J = 8.3 , 1.2 Hz , 1H ) , 6.60 ( s , 1H ) , 4.61 - 4.49 ( m , 1H ) , 4.29 - 4.20 ( m , 1H ) , 4.194.08 ( m , 1H ) , 3.22 ( dd , J = 17.1 , 5.4 Hz , 1H ) , 2.90 – 2.77 ( m , 1H ) LCMS ( Method 7 ) : 2.52 min , 244.1 [ M − H ] ¯ Synthesis of N- ( 6 - chlorochroman - 3 - yl ) -2,2,2 - trifluoro - acetamide NCS MeCN , 70 ° C NCS ( 137 mg , 1.03 mmol ) was added to a solution of N - chroman - 3 - yl - 2,2,2 - trifluoro- acetamide ( 210 mg , 0.86 mmol ) in MeCN ( 5 mL ) , and the reaction was heated at 70 ° C for h . The reaction mixture was cooled to room temperature , diluted with EtOAc , and washed with sat . aq . NaHCO3 . The organic layer was dried over Na2S04 and concentrated in vacuo to provide the title compound ( 249 mg ) . 1H NMR ( 400 MHz , ³lCDC ) б 7.15 – 7.09 ( m , 1H ) , 7.06 ( dd , J = 2.4 , 1.1 Hz , 1H ) , 6.83 ( d , J == - - - ± 8.7 Hz , 1H ) , 6.58 ( s , 1H ) , 4.57 – 4.48 ( m , 1H ) , 4.28 – 4.21 ( m , 1H ) , 4.14 – 4.10 ( m , 1H ) , 3.233.13 ( m , 1H ) , 2.86 – 2.79 ( m , 1H ) - LCMS ( Method 7 ) : 2.82 min , 278.1 [ M - H ] - Synthesis of 6 - chlorochroman - 3 - amine 489 LO ﻼﻤﻤﻣ NaOH DCM , RT ₂HN 4 M aq . NaOH ( 2.23 mL , 8.9 mmol ) was added to a solution of N- ( 6 - chlorochroman - 3 - yl ) - 2,2,2 - trifluoro - acetamide ( 249 mg , 0.89 mmol ) in DCM ( 2.2 mL ) and the reaction was stirred at room temperature for 17 h . The reaction mixture was diluted with DCM and water , and the layers were separated . The organic layer was dried over Na2S04 and concentrated in vacuo to provide the title compound ( 128 mg ) . - - m 1H NMR ( 400 MHz , CDCl3 ) Ŏ 7.09 - 7.01 ( m , 2H ) , 6.76 ( d , J = 8.5 Hz , 1H ) , 4.19 - 4.07 ( m , 1H ) , 3.90 – 3.77 ( m , 1H ) , 3.38 ( dt , J = 9.8 , 7.1 Hz , 1H ) , 3.09 – 2.94 ( m , 1H ) , 2.57 ( dd , J. 16.3 , 7.0 Hz , 1H ) . Exchangeable protons not observed . LCMS ( Method 7 ) : 1.05 min , 184.3 [ M + H ] + Synthesis of compound ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 114 , N7- ( 6 - chlorochroman - 3 - yl ) -2- ₂HN N7- ( 6 - chlorochroman - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 83 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.30 ( d , J = 7.3 Hz , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 7.76 ( d , J = 4.4 Hz , 1H ) , 7.67 ( s , 1H ) , 7.58 ( s , 1H ) , 7.24 ( d , J = 2.6 Hz , 1H ) , 7.17 ( dd , J = 8.7 , 2.7 Hz , 1H ) , 6.88 ( d , J = 8.7 Hz , 1H ) , 4.87 – 4.73 ( m , 2H ) , 4.65 – 4.55 ( m , 1H ) , 4.30 – 4.22 ( m , 2H ) , 3.30 3.28 ( m , 1H ) , 3.26 ( s , 3H ) , 2.88 ( dd , J = 17.1 , 3.9 Hz , 1H ) - LCMS ( Method 7 ) : 2.45 min , 416.1 [ M + H ] + Synthesis of 115 , 2 - cyclopropyl - N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 490 2 - Cyclopropyl - N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 28 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) ☎ 10.18 ( d , J = 7.3 Hz , 1H ) , 8.85 ( d , J = 4.4 Hz , 1H ) , 8.- 8.35 ( m , 1H ) , 7.77 - 7.68 ( m , 2H ) , 7.65 ( d , J = 4.4 Hz , 1H ) , 7.53 ( s , 1H ) , 7.21 ( dd , J = 7.6 , - 5.0 Hz , 1H ) , 4.88 – 4.76 ( m , 1H ) , 3.49 – 3.38 ( m , 2H ) , 3.20 – 3.07 ( m , 1H ) , 2.97 ( ddd , J - - 16.7 , 8.6 , 3.7 Hz , 2H ) , 1.07 – 0.98 ( m , 2H ) , 0.78 – 0.67 ( m , 2H ) LCMS ( Method 4 ) : 1.33 min , 363.2 [ M + H ] * == Synthesis of compound 116 , N7- ( 4,4 - difluorotetralin - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide Bre ₂HN OMe N7- ( 4,4 - difluorotetralin - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 168 mg ) was synthesised following a similar procedure to that described in General Method E. § ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.26 ( d , J = 8.3 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.72 - 7.63 ( m , 4H ) , 7.62 – 7.46 ( m , 3H ) , 5.50 – 5.35 ( m , 1H ) , 4.95 ( s , 2H ) , 3.31 ( s , 3H ) , 2.59 – 2.( m , 1H ) , 2.46 ( s , 1H ) , 2.37 – 2.27 ( m , 1H ) , 2.14 – 2.01 ( m , 1H ) - LCMS ( Method 7 ) : 2.50 min , 416.2 [ M + H ] + - Synthesis of compounds 175 and 176 , N7 - [ - 4,4 - difluorotetralin - 1 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide NH ﻲﻴﻴﻴﻴﻳ OMe F F ₂HN OMe F. N : F Racemic N7 - [ - 4,4 - difluorotetralin - 1 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 40 mg ) was separated by preparative SFC ( eluting with 35 % MeOH in CO2 ) 491 to provide enantiomer 1 ( 16 mg ) and enantiomer 2 ( 14 mg ) with unknown absolute configurations . Enantiomer 1 has a retention time of 2.46 min and enantiomer 2 has a retention time of 3.88 min . 1H NMR ( 400 MHz , MeOD ) 5 8.93 ( d , J = 4.4 Hz , 1H ) , 7.90 ( d , J = 4.4 Hz , 1H ) , 7.75 -7.( m , 1H ) , 7.62 7.55 ( m , 1H ) , 7.54 - 7.42 ( m , 2H ) , 5.50 ( s , 1H ) , 5.08 - 4.93 ( m , 2H ) , 3.34 ( s , 3H ) , 2.69 – 2.33 ( m , 3H ) , 2.31 – 2.18 ( m , 1H ) . Exchangeable protons not observed . - LCMS ( Method 7 ) 2.53 min ; 416.2 [ M + H ] + Synthesis of compound 117 , N7- ( 8 - fluoro - 3 - quinolyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide corse ' ₂NN N7- ( 8 - fluoro - 3 - quinolyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) б 12.31 ( s , 1H ) , 9.07 – 8.98 ( m , 3H ) , 7.92 ( d , J = 8.2 Hz , 1H ) , - - 7.81 ( d , J = 4.4 Hz , 1H ) , 7.71 ( s , 1H ) , 7.69 - 7.61 ( m , 2H ) , 7.61 - 7.51 ( m , 1H ) , 5.04 ( s , 2H ) , 3.45 ( s , 3H ) LCMS ( Method 7 ) : 2.32 min , 395.2 [ M + H ] * Synthesis of compound 118 , 2- ( methoxymethyl ) -N7- ( 1 - methylindol - 2 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ₂HN OMe 2- ( Methoxymethyl ) -N7- ( 1 - methylindol - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method E. 492 ' H NMR ( 400 MHz , DMSO - d6 ) ō 12.95 ( s , 1H ) , 9.02 ( d , J = 4.4 Hz , 1H ) , 7.96 ( d , J = 4.4 Hz , 1H ) , 7.71 ( d , J = 11.8 Hz , 2H ) , 7.54 ( d , J = 7.8 Hz , 1H ) , 7.48 ( d , J = 8.1 Hz , 1H ) , 7.20 – 7.( m , 1H ) , 7.05 ( t , J = 7.4 Hz , 1H ) , 6.94 ( s , 1H ) , 5.12 ( s , 2H ) , 3.93 ( s , 3H ) , 3.49 ( s , 3H ) LCMS ( Method 7 ) : 2.73 min , 379.2 [ M + H ] + Synthesis of compound 119 , 2- ( methoxymethyl ) -N7 - [ ( 3R ) -6,7 - difluoro - 2,3- dihydrobenzofuran - 3 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide " ₂HN 2- ( Methoxymethyl ) -N7 - [ ( 3R ) -6,7 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 51 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.41 ( d , J = 6.8 Hz , 1H ) , 8.93 ( d , J = 4.3 Hz , 1H ) , 7.( d , J = 4.3 Hz , 1H ) , 7.65 ( s , 1H ) , 7.60 ( s , 1H ) , 7.35 – 7.27 ( m , 1H ) , 7.07 – 6.96 ( m , 1H ) , 5.- – 5.78 ( m , 1H ) , 5.03 ( dd , J = 10.0 , 8.2 Hz , 1H ) , 4.99 – 4.87 ( m , 2H ) , 4.69 ( dd , J = 10.0 , 4.Hz , 1H ) , 3.30 ( s , 3H ) LCMS ( Method 7 ) : 2.34 min , 404.2 [ M + H ] + Synthesis of compound 120 , N7 - [ ( 3R ) -5 - fluoro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ₂HN N7 - [ ( 3R ) -5 - fluoro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ( 34 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) u0000 10.40 ( d , J = 6.7 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.( d , J = 4.4 Hz , 1H ) , 7.65 ( s , 1H ) , 7.60 ( s , 1H ) , 7.36 – 7.29 ( m , 1H ) , 7.12 ( td , J = 9.0 , 2.9 Hz , 4 - 1H ) , 6.92 ( dd , J = 8.8 , 4.1 Hz , 1H ) , 5.83 – 5.74 ( m , 1H ) , 4.99 – 4.90 ( m , 2H ) , 4.90 – 4.84 ( m , 1H ) , 4.50 ( dd , J = 9.9 , 4.6 Hz , 1H ) , 3.29 ( s , 3H ) LCMS ( Method 7 ) : 2.35 min , 386.2 [ M + H ] + Synthesis of compound 121 , 2- ( methoxymethyl ) -N7- ( 2 - methylindan - 2 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide gray ₂HN OMe 2- ( Methoxymethyl ) -N7- ( 2 - methylindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 31 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.32 ( s , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.70 ( d , J = 4.4 Hz , 1H ) , 7.67 ( s , 1H ) , 7.59 ( s , 1H ) , 7.28 - 7.22 ( m , 2H ) , 7.18 - 7.12 ( m , 2H ) , 4.98 ( s , 2H ) , 3.( d , J = 16.0 Hz , 2H ) , 3.42 ( s , 3H ) , 3.11 ( d , J = 16.0 Hz , 2H ) , 1.62 ( s , 3H ) LCMS ( Method 7 ) : 2.66 min , 380.2 [ M + H ] + Synthesis of compound 122 , N7- [ 1- ( 4 - fluorophenyl ) ethyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide F ₂HN N7- [ 1- ( 4 - fluorophenyl ) ethyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 30 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , CDCl3 ) ₫ 10.97 ( d , J = 7.4 Hz , 1H ) , 8.79 ( d , J = 4.4 Hz , 1H ) , 8.02 ( s , 1H ) , 7.92 ( d , J = 4.4 Hz , 1H ) , 7.49 – 7.40 ( m , 2H ) , 7.11 – 7.01 ( m , 2H ) , 5.60 ( s , 1H ) , 5.38 – 5.( m , 1H ) , 5.18 ( d , J = 2.7 Hz , 2H ) , 3.56 ( s , 3H ) , 1.67 ( d , J = 6.9 Hz , 3H ) LCMS ( Method 7 ) : 2.48 min , 372.2 [ M + H ] + 494 LO Synthesis of compound 123 , 2- ( methoxymethyl ) -N7 - [ ( 4S ) -7 - fluorochroman - 4- yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ₂HN 2- ( Methoxymethyl ) -N7 - [ ( 4S ) -7 - fluorochroman - 4 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 54 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - de ) 8 10.26 ( d , J = 7.3 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.( d , J = 4.4 Hz , 1H ) , 7.66 ( s , 1H ) , 7.59 ( s , 1H ) , 7.52 – 7.44 ( m , 1H ) , 6.76 ( td , J = 8.5 , 2.7 Hz , 1H ) , 6.71 ( dd , J = 10.5 , 2.6 Hz , 1H ) , 5.29 ( d , J = 6.5 Hz , 1H ) , 4.95 ( s , 2H ) , 4.43 - 4.33 ( m , 1H ) , 4.27 ( ddd , J = 11.5 , 8.7 , 2.9 Hz , 1H ) , 3.30 ( s , 3H ) , 2.31 —- 2.21 ( m , 1H ) , 2.16 – 2.06 ( m , 1H ) LCMS ( Method 7 ) : 2.47 min , 400.2 [ M + H ] + - Synthesis of compound 124 , N7- ( 2,2 - difluoro - 6 - methyl - spiro [ 3.3 ] heptan - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ₂HN N7- ( 2,2 - difluoro - 6 - methyl - spiro [ 3.3 ] heptan - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 31 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.12 ( s , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.69 ( s , 1H ) 7.( dd , J = 4.4 Hz , 1H ) , 7.60 ( s , 1H ) , 5.00 ( s , 2H ) , 3.44 ( s , 3H ) , 2.76 – 2.63 ( m , 4H ) , 2.62 – 2.( m , 2H ) , 2.33 ( d , J = 12.6 Hz , 2H ) , 1.52 ( s , 3H ) LCMS ( Method 7 ) : 2.55 min , 394.2 [ M + H ] + 495 LO Synthesis of compound 125 , 2- ( methoxymethyl ) -N- [ 2,2,2 - trifluoro - 1- ( 4- fluorophenyl ) ethyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide F ₂HN 2- ( Methoxymethyl ) -N7- [ 2,2,2 - trifluoro - 1- ( 4 - fluorophenyl ) ethyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 27 mg ) was synthesised following a similar procedure to that described in General Method E. ... ' H NMR ( 400 MHz , DMSO - d6 ) § 11.25 ( d , J = 9.2 Hz , 1H ) , 8.94 ( d , J = 4.4 Hz , 1H ) , 7.80 - 7.71 ( m , 3H ) , 7.65 ( d , J = 11.4 Hz , 2H ) , 7.38 - 7.28 ( m , 2H ) , 6.25 ( p , J = 8.2 Hz , 1H ) , 5.04 ( s , 2H ) , 3.46 ( s , 3H ) LCMS ( Method 7 ) : 2.75 min , 426.2 [ M + H ] + Synthesis of compound 126 , N7- ( 2,2 - difluorospiro [ 3.3 ] heptan - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ₂HN F N7- ( 2,2 - difluorospiro [ 3.3 ] heptan - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 57 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.10 ( d , J = 7.1 Hz , 1H ) , 8.91 ( d , J = 4.3 Hz , 1H ) , 7.68 ( s , 1H ) , 7.64 ( d , J = 4.3 Hz , 1H ) , 7.60 ( s , 1H ) , 5.00 ( s , 2H ) , 4.48 – 4.34 ( m , 1H ) , 3.44 ( s , 3H ) , - 2.78 2.53 ( m , 6H ) , 2.26 - 2.14 ( m , 2H ) - LCMS ( Method 7 ) : 2.39 min , 380.2 [ M + H ] + Synthesis of compound ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 127 , N7- [ 1- ( 4 - fluorophenyl ) cyclopropyl ] -2- 496 " ₂MN -OMe N7- [ 1- ( 4 - fluorophenyl ) cyclopropyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 61 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.28 ( s , 1H ) , 8.91 ( d , J = 4.3 Hz , 1H ) , 7.63 ( d , J = 35.3 Hz , 2H ) , 7.59 ( d , J = 4.4 Hz , 1H ) , 7.50 – 7.40 ( m , 2H ) , 7.18 – 7.07 ( m , 2H ) , 5.02 ( s , 2H ) , 3.45 ( s , 3H ) , 1.36 ( s , 4H ) LCMS ( Method 7 ) : 2.44 min , 384.2 [ M + H ] * Synthesis of compound 128 , 2- ( methoxymethyl ) -N7 - [ ( 3R ) -6 - fluoro - 2,3- dihydrobenzofuran - 3 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ₂HN 2- ( Methoxymethyl ) -N7 - [ ( 3R ) -6 - fluoro - 2,3 - dihydrobenzofuran - 3 - yl ] pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ( 27 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.37 ( d , J = 6.7 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.( dd , J = 4.3 , 0.8 Hz , 1H ) , 7.65 ( s , 1H ) , 7.59 ( s , 1H ) , 7.53 – 7.45 ( m , 1H ) , 6.88 – 6.75 ( m , 2H ) , 5.78 – 5.69 ( m , 1H ) , 4.99 – 4.86 ( m , 3H ) , 4.56 ( dd , J = 10.0 , 4.1 Hz , 1H ) , 3.28 ( s , 3H ) LCMS ( Method 7 ) : 2.39 min , 386.2 [ M + H ] + N7- ( 3,3 - difluoroindan - 1 - yl ) -2- Synthesis of compound 129 , ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 497 gree ₂HN N7- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 27 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , CDCl3 ) б 10.98 ( d , J = 6.9 Hz , 1H ) , 8.83 ( d , J = 4.4 Hz , 1H ) , 8.06 - 7.( m , 2H ) , 7.65 ( d , J = 7.5 Hz , 1H ) , 7.61 – 7.56 ( m , 2H ) , 7.56 – 7.49 ( m , 1H ) , 5.82 – 5.75 ( m , 1H ) , 5.59 ( s , 1H ) , 5.14 – 5.00 ( m , 2H ) , 3.40 ( s , 3H ) , 3.37 – 3.23 ( m , 1H ) , 2.72 – 2.56 ( m , 1H ) LCMS ( Method 7 ) : 2.51 min , 402.2 [ M + H ] + Synthesis of compounds 173 and 174 , N7- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide gige NHOMe NH.OMe Racemic N7- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 39 mg ) was separated by preparative SFC ( eluting with 20 % MeOH in CO2 ) to provide enantiomer 1 ( 14 mg ) and enantiomer 2 ( 15 mg ) with unknown absolute configurations . Enantiomer 1 has a retention time of 4.14 minutes and enantiomer 2 has a retention time of 5.73 minutes . 1H NMR ( 400 MHz , CDCl3 ) ō 10.99 ( d , J = 7.2 Hz , 1H ) , 8.84 ( d , J = 4.4 Hz , 1H ) , 8.04 - 7.( m , 2H ) , 7.66 ( d , J = 7.5 Hz , 1H ) , 7.63 – 7.48 ( m , 3H ) , 5.84 – 5.74 ( m , 1H ) , 5.61 ( br . s , 1H ) , 5.15 5.01 ( m , 2H ) , 3.41 ( s , 3H ) , 3.37 - 3.23 ( m , 1H ) , 2.73 - 2.57 ( m , 1H ) LCMS ( Method 7 ) : 2.42 min , 402.2 [ M + H ] * Synthesis of compound 130 , 2 - cyclopropyl - N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 498 LO cosqu ₂HN 2 - Cyclopropyl - N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 33 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - do ) ☎ 10.19 ( d , J = 7.4 Hz , 1H ) , 8.84 ( d , J = 4.5 Hz , 1H ) , 7.( d , J = 2.8 Hz , 1H ) , 7.66 ( d , J = 4.4 Hz , 1H ) , 7.52 ( s , 1H ) , 7.36 - 7.28 ( m , 2H ) , 7.24 - 7.( m , 2H ) , 4.84 – 4.73 ( m , 1H ) , 3.36 ( dd , J = 16.1 , 6.7 Hz , 2H ) , 3.15 – 3.06 ( m , 1H ) , 2.( dd , J = 16.1 , 3.5 Hz , 2H ) , 1.05 - 0.96 ( m , 2H ) , 0.73 - 0.65 ( m , 2H ) LCMS ( Method 7 ) : 2.76 min , 362.2 [ M + H ] + Synthesis of compound 131 , N7- ( 2,2 - difluorospiro [ 3.3 ] heptan - 7 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide NH N7- ( 2,2 - difluorospiro [ 3.3 ] heptan - 7 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 32 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d € ) 8 10.10 ( d , J = 7.3 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.68 ( s , 1H ) , 7.65 ( d , J = 4.3 Hz , 1H ) , 7.60 ( s , 1H ) , 5.00 ( s , 2H ) , 4.58 - 4.48 ( m , 1H ) , 3.42 ( s , 3H ) , - - -- 3.13 2.97 ( m , 1H ) , 2.84 – 2.69 ( m , 1H ) , 2.62 - 2.51 ( m , 2H ) , 2.33 – 2.22 ( m , 1H ) , 2.08 - 1.93 ( m , 2H ) , 1.93- 1.80 ( m , 1H ) LCMS ( Method 7 ) : 2.40 min , 380.2 [ M + H ] * Synthesis of compound 132 , 2- ( methoxymethyl ) -N7- [ cis - 4- ( trifluoromethoxy ) cyclohexyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 499 ₂HN -OMe 2- ( Methoxymethyl ) -N7- [ cis - 4- ( trifluoromethoxy ) cyclohexyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 102 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.23 ( d , J = 7.6 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.74 - 7.65 ( m , 2H ) , 7.61 ( s , 1H ) , 5.02 ( s , 2H ) , 4.62 – 4.52 ( m , 1H ) , 4.15 – 4.05 ( m , 1H ) , 3.43 ( s , 3H ) , 2.00 1.69 ( m , 8H ) - LCMS ( Method 7 ) : 2.61 min , 416.2 [ M + H ] + Synthesis of compound - - 133 , N7 - [ ( 4,4 - difluorocyclohexyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide F F ' ₂HN N7 - [ ( 4,4 - difluorocyclohexyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 109 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) ☎ 9.95 ( t , J = 5.8 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.72 – 7.( m , 2H ) , 7.60 ( s , 1H ) , 4.99 ( s , 2H ) , 3.43 - 3.35 ( m , 5H ) , 2.11 - 1.96 ( m , 2H ) , 1.95 - 1.71 ( m , 5H ) , 1.38 - 1.25 ( m , 2H ) LCMS ( Method 7 ) : 2.31 min , 382.2 [ M + H ] + Synthesis of 2- ( methoxymethyl ) -N7- ( 1 - oxoindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 500 N. N orge NH-OMe 2- ( Methoxymethyl ) -N7- ( 1 - oxoindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 2mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , ³ICDC ) г 11.01 ( d , J = 6.4 Hz , 1H ) , 8.81 ( d , J = 4.3 Hz , 1H ) , 8.05 ( s , 1H ) , 7.93 ( d , J = 4.4 Hz , 1H ) , 7.87 ( d , J = 7.7 Hz , 1H ) , 7.68 ( td , J = 7.5 , 1.3 Hz , 1H ) , 7.52 ( d , J = 7.8 , 0.9 Hz , 1H ) , 7.46 ( t , J = 7.5 Hz , 1H ) , 5.62 ( s , 1H ) , 5.19 ( s , 2H ) , 4.85 – 4.69 ( m , 1H ) , 3.( dd , J = 16.7 , 8.2 Hz , 1H ) , 3.60 ( s , 3H ) , 3.29 ( dd , J = 16.7 , 5.6 Hz , 1H ) LCMS ( Method 7 ) : 1.99 min , 380.2 [ M + H ] + Synthesis of 2- ( methoxymethyl ) -N7 - spiro [ 1,3 - dithiolane - 2,1 ' - indane ] -2 ' - yl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide SH HS BF ₂tEO.DCM ° C to RT SH ' N ' N = NH-OMe NH-OMe BF3.OEt2 ( 380 Lμ , 3.06 mmol ) was added to a solution of 2- ( methoxymethyl ) -N7- ( 1- oxoindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 290 mg , 0.76 mmol ) and ethane - 1,2 - dithiol ( 96 Lμ , 1.15 mmol ) in DCM ( 3.8 mL ) at 0 ° C . The reaction was warmed to room temperature and stirred overnight . The reaction mixture was quenched with sat . aq . NaHCO3 and diluted with EtOAc . The layers were separated , and the organic layer was dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 241 mg ) . ' H NMR ( 400 MHz , ³lCDC ) § 11.07 ( d , J = 8.9 Hz , 1H ) , 8.76 ( d , J = 4.4 Hz , 1H ) , 8.01 ( s , 1H ) , 7.95 ( d , J = 4.3 Hz , 1H ) , 7.54 ( d , J = 7.8 Hz , 1H ) , 7.26 ( t , J = 7.4 Hz , 1H ) , 7.21 ( dd , J = 7.4 , 1.4 Hz , 1H ) , 7.13 ( d , J = 7.4 Hz , 1H ) , 5.58 ( s , 1H ) , 5.12 ( td , J = 8.7 , 7.1 Hz , 1H ) , 5.03 ( d , J - == 1.7 Hz , 2H ) , 3.55 - 3.44 ( m , 1H ) , 3.45 – 3.40 ( m , 3H ) , 3.39 ( s , 3H ) , 3.37 ( td , J = 5.1 , 2.1 Hz , 1H ) , 2.94 – 2.85 ( m , 1H ) LCMS ( Method 7 ) : 2.63 min , 456.1 [ M + H ] + 501 Synthesis of compound 152 , N7- ( 1,1 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide SH Br - N ` N- -Br HF.pyridine DCM -78 ° C to RT NH-OMe H N orge N : NH-OMe HF.pyridine ( 339 Lμ , 2.63 mmol ) was added dropwise to a solution of 1,3 - dibromo - 5,5- dimethyl - imidazolidine - 2,4 - dione ( 188 mg , 0.66 mmol ) in DCM ( 6.6 mL ) at -78 ° C and the mixture was stirred at 87− ° C for 30 min . A solution of 2- ( methoxymethyl ) -N7 - spiro [ 1,3- dithiolane - 2,1 ' - indane ] -2 ' - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 200 mg , 0.44 . mmol ) in DCM ( 2.2 mL ) was added dropwise , and the reaction was warmed to room temperature and stirred for 18 h . The reaction mixture was added dropwise into sat . aq . NaHCO3 and extracted with EtOAc . The organic layer was dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 2 % MeOH in DCM ) and preparative HPLC ( basic method ) to provide the title compound ( 20 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.58 ( d , J = 8.2 Hz , 1H ) , 8.96 ( d , J = 4.4 Hz , 1H ) , 7.78 ( d , J = 4.4 Hz , 1H ) , 7.72 – 7.56 ( m , 4H ) , 7.51 – 7.44 ( m , 2H ) , 5.26 – 5.10 ( m , 1H ) , 4.97 ( d , J - - - - 1.0 Hz , 2H ) , 3.67 – 3.57 ( m , 1H ) , 3.36 ( s , 3H ) , 3.08 – 2.96 ( m , 1H ) LCMS ( Method 7 ) : 2.43 min , 402.2 [ M + H ] + Synthesis of ethyl 4,6 - difluorobenzofuran - 3 - carboxylate = St. H Eto i ₂N O₂tE.H4FB DCM , 0 ° C to RT F tE₂OC F OH BF4H.Et2O ( 200 Lμ , 1.46 mmol ) and ethyl diazoacetate ( 2.14 mL , 17.30 mmol ) were added sequentially to a solution of 2,4 - difluoro - 6 - hydroxy - benzaldehyde ( 2.1 g , 13.30 mmol ) DCM ( 20 mL ) at 0 ° C . The reaction was warmed to room temperature , stirred for 30 min , then quenched with NaHCO3 . The mixture was diluted with DCM and water , and the layers 502 were separated . The aqueous layer was extracted with DCM , and the combined organic layers were washed with sat . aq . K2CO3 and brine , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 901 mg ) . - ' H NMR ( 400 MHz , CDCl3 ) ō 8.21 ( s , 1H ) , 7.12 - 7.05 ( m , 1H ) , 6.91 – 6.81 ( m , 1H ) , 4.39 ( q , J = 7.1 Hz , 2H ) , 1.40 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 3 ) : 1.35 min , 227.2 [ M + H ] + Synthesis of ethyl 4,6 - difluoro - 2,3 - dihydrobenzofuran - 3 - carboxylate F tE₂OC Pd / C , ₂H ( g ) AcOH , EtOH RT F tE₂OC ﺖﻣﺎﻣ % Pd / C ( 42 mg , 0.40 mmol ) was added to a solution of ethyl 4,6 - difluorobenzofuran - 3- carboxylate ( 1.8 g , 3.98 mmol ) in EtOH ( 9 mL ) and AcOH ( 1 mL ) under argon . A balloon of hydrogen was attached , and the reaction was stirred at room temperature for 20 h . The reaction mixture was filtered through a short pad of ®etilaciD and concentrated in vacuo . The residue was dissolved in DCM and washed with sat . aq . K2CO3 . The organic layer was dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 680 mg ) . - 1H NMR ( 400 MHz , CDCl3 ) б 6.43 – 6.35 ( m , 2H ) , 4.91 ( dd , J = 9.3 , 5.4 Hz , 1H ) , 4.80 - 4.( m , 1H ) , 4.37 – 4.32 ( m , 1H ) , 4.25 – 4.20 ( m , 2H ) , 1.30 – 1.26 ( m , 3H ) - - - Synthesis of 4,6 - difluoro - 2,3 - dihydrobenzofuran - 3 - carboxylic acid tE₂OC O₂H.HOiL THF , O₂H , RT F H₂OC F A solution of O₂H.HOiL ( 139 mg , 3.31 mmol ) in water ( 7.5 mL ) was added to a solution of ethyl 4,6 - difluoro - 2,3 - dihydrobenzofuran - 3 - carboxylate ( 680 mg , 3.01 mmol ) in THF ( 7.5 mL ) and the reaction was stirred at room temperature for 2 h then concentrated in vacuo . The 503 residue was dissolved in EtOAc and water , and the layers were separated . The aqueous layer was acidified to pH 2 with 1 M aq . HCI and extracted with EtOAc . The combined organic layers were dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 4 % MeOH in DCM ) to provide the title compound ( 133 mg ) . - - 4.1H NMR ( 400 MHz , CDCl3 ) б 6.42 – 6.40 ( m , 1H ) , 6.40 – 6.37 ( m , 1H ) , 4.95 ( dd , J = 9.4 , Hz , 1H ) , 4.78 ( dd , J = 9.5 , 9.5 Hz , 1H ) , 4.47 - 4.34 ( m , 1H ) . Exchangeable proton not observed . LCMS ( Method 7 ) : 2.10 min , 199.1 [ M − H ] ¯ Synthesis of benzyl N- ( 4,6 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ) carbamate H₂OC DPPA BnOH , N₂tE Toluene , 100 ° C N H_Cbz N³tE ( 176 Lμ , 1.26 mmol ) , was added to a solution of 4,6 - difluoro - 2,3 - dihydrobenzofuran - 3- carboxylic acid ( 133 mg , 0.46 mmol ) , benzyl alcohol ( 78 Lµ , 0.75 mmol ) , and diphenylphosphoryl azide ( 163 Lµ , 0.76 mmol ) in toluene ( 9 mL ) , and the reaction was heated at 100 ° C for 1 h . The reaction mixture was cooled to room temperature and quenched with water . The layers were separated , and the organic layer was dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 60 % EtOAc in heptane ) to provide the title compound ( 1mg ) . ' H NMR ( 400 MHz , CDCl3 ) Ŏ 7.36 - 7.20 ( m , 5H ) , 6.38 – 6.24 ( m , 2H ) , 5.44 ( s , 1H ) , 5.07 ( s , 2H ) , 4.74 – 4.61 ( m , 1H ) , 4.44 ( d , J = 7.8 Hz , 1H ) . Exchangeable proton not observed . LCMS ( Method 7 ) : 2.94 min ( product does not ionise ) Synthesis of 4,6 - difluoro - 2,3 - dihydrobenzofuran - 3 - amine N- ₂H , Pd / C MeOH , 60 ° C NH 504 Benzyl N- ( 4,6 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ) carbamate ( 119 mg , 0.39 mmol ) was dissolved in MeOH ( 2.6 mL ) and the solution was hydrogenated over 10 % Pd / C at 60 ° C and 1 bar ( H - cube , 1 mL / min ) . The resultant solution was concentrated in vacuo to provide the title compound ( 15 mg ) . ' H NMR ( 400 MHz , CDCl3 ) ō 6.41 – 6.31 ( m , 2H ) , 4.81 ( dd , J = 8.1 , 4.0 Hz , 1H ) , 4.71 ( dd , J = 9.7 , 8.1 Hz , 1H ) , 4.32 ( dd , J = 9.8 , 4.0 Hz , 1H ) . Exchangeable protons not observed .

Synthesis of compound 153 , N7- ( 4,6 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ' NH OMe N7- ( 4,6 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ( 11 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.44 ( d , J = 6.6 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.68 ( d , - J = 4.4 Hz , 1H ) , 7.65 ( s , 1H ) , 7.59 ( s , 1H ) , 6.88 – 6.75 ( m , 2H ) , 5.95 – 5.84 ( m , 1H ) , 4.98 – 4.89 ( m , 3H ) , 4.66 ( dd , J = 10.0 , 3.5 Hz , 1H ) , 3.29 ( s , 3H ) LCMS ( Method 7 ) : 2.34 min , 404.1 [ M + H ] * Synthesis of 2 - methyl - N- ( 2,4,4 - trifluorocyclohexyl ) propane - 2 - sulfinamide F.

N₂H 1. Ti ( Oi - Pr ) F THF , 66 ° C 2. NaBH4 , RT Titanium isopropoxide ( 290 Lμ , 0.99 mmol ) was added to a solution of t - butylsulfinamide ( mg , 0.79 mmol ) and 2,4,4 - trifluorocyclohexanone ( 100 mg , 0.66 mmol ) in THF ( 5 mL ) and 505 LO the reaction was heated at 66 ° C for 17 h then cooled to room temperature . NaBH4 ( 50 mg , 1.31 mmol ) was added , and the reaction was stirred at room temperature for 2 h then quenched with water . The mixture was diluted with EtOAc and the layers were separated . The organic layer was washed with water and brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 3 % MeOH in DCM ) to provide the title compound ( 67 mg ) . LCMS ( Method 6 ) : 2.20 min , 258.2 [ M + H ] * NMR data not reported due to a complex mixture of diastereoisomers plus fluorine splitting .

Synthesis of 2,4,4 - trifluorocyclohexanamine hydrochloride HN S = HCI 1,4 - Dioxane RT F NH2.HCI 2 - Methyl - N- ( 2,4,4 - trifluorocyclohexyl ) propane - 2 - sulfinamide ( 67 mg , 0.26 mmol ) was dissolved in HCI ( 4 M in 1,4 - dioxane ) ( 2 mL , 8 mmol ) and the reaction was stirred at room temperature for 16 h . The reaction mixture was concentrated in vacuo to provide the title compound ( 49 mg ) . LCMS ( Method 6 ) : 0.16 min , 154.3 [ M + H ] + NMR data not reported due to a complex mixture of diastereoisomers plus fluorine splitting . Synthesis of 154 . 2- ( methoxymethyl ) -N7- ( 2,4,4- compound trifluorocyclohexyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ' N ' NHN = .OMe 2- ( Methoxymethyl ) -N7- ( 2,4,4 - trifluorocyclohexyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 21 mg , 2 : 1 mixture of diastereoisomers ) was synthesised following a similar procedure to that described in General Method E. 506 1H NMR ( 400 MHz , DMSO - d6 ) § 10.37 ( d , J = 8.1 Hz , 1H ) , 8.94 ( d , J = 4.5 Hz , 1H ) , 7.76 ( d , - - J = 4.3 Hz , 1H ) , 7.69 – 7.59 ( m , 2H ) , 4.99 ( d , J = 1.3 Hz , 4H ) , 4.58 – 4.29 ( m , 2H ) , 3.42 ( s , - 3H ) , 2.15 2.09 ( m , 2H ) , 1.97 – 1.87 ( m , 2H ) . Major diastereoisomer is reported . LCMS ( Method 7 ) : 2.23 min , 386.2 [ M + H ] + Synthesis of 1 - methylindane - 1 - carboxylic acid H₂OC Mel , LDA THF , hexanes ° C to RT H₂OC LDA ( 1 M in THF / hexanes ) ( 25 mL , 24.66 mmol ) was added to a solution of indane - 1- carboxylic acid ( 2 g , 12.33 mmol ) in THF ( 20 mL ) at 0 ° C and the reaction was stirred at 0 ° C for 1 h then at room temperature for 1 h . Mel ( 2.3 mL , 36.99 mmol ) was added , and the reaction was stirred at room temperature overnight . The reaction mixture was acidified with M aq . HCI and diluted with DCM . The layers were separated , and the aqueous layer was extracted with DCM . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo to provide the title compound ( 2.27 g ) . - - ' H NMR ( 400 MHz , DMSO - d6 ) ð 12.29 ( s , 1H ) , 7.29 – 7.14 ( m , 4H ) , 3.02 – 2.82 ( m , 2H ) , 2.58 ( ddd , J = 12.7 , 8.4 , 5.1 Hz , 1H ) , 18.1–39.1 ( m , 1H ) , 1.43 ( s , 3H ) LCMS ( Method 6 ) : 1.80 min , 175.2 [ M − H ] ¯ Synthesis of 1 - methylindan - 1 - amine H₂OC DPPA , N₂tE THF , 60 ° C NH NзtE ( 1.98 mL , 14.19 mmol ) and diphenylphosphoryl azide ( 1.46 mL , 6.81 mmol ) were added to a solution of 1 - methylindane - 1 - carboxylic acid ( 1 g , 5.68 mmol ) in THF ( 20 mL ) , and the reaction was heated at 60 ° C overnight . The reaction mixture was cooled to room temperature , and then to 0 ° C . The mixture was acidified with 5 M aq . HCI , warmed to room temperature , and stirred overnight . The mixture was diluted with DCM , and the layers were separated . The aqueous layer was extracted with DCM , then basified with 2 M aq . NaOH . and further extracted with DCM ( × 3 ) . The combined organic layers were dried over Na2SO507 and concentrated in vacuo . The crude product was purified by SCX chromatography ( eluting with 2 M NH3 in MeOH ) to provide the title compound ( 110 mg ) . - 1H NMR ( 400 MHz , DMSO - d6 ) 5 7.33 – 7.26 ( m , 1H ) , 7.21 - 7.07 ( m , 3H ) , 2.85 ( ddd , J = - 15.8 , 8.4 , 4.2 Hz , 1H ) , 2.80 – 2.70 ( m , 1H ) , 1.99 ( ddd , J = 12.1 , 7.7 , 4.2 Hz , 1H ) , 1.89 ( dt , J 12.4 , 8.2 Hz , 1H ) , 1.26 ( s , 3H ) . Exchangeable protons not observed . = Synthesis of compound 155 , 2- ( methoxymethyl ) -N7- ( 1 - methylindan - 1 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide odhou NH-OMe 2- ( methoxymethyl ) -N7- ( 1 - methylindan - 1 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 51 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , ³lCDC ) ₫ 11.00 ( s , 1H ) , 8.77 ( d , J = 4.4 Hz , 1H ) , 8.04 ( s , 1H ) , 7.90 ( d , J = 4.4 Hz , 1H ) , 7.60 - 7.53 ( m , 1H ) , 7.33 - 7.27 ( m , 3H ) , 5.60 ( s , 1H ) , 5.22 - 4.95 ( m , 2H ) , 3.51 ( s , 3H ) , 3.12 ( ddd , J = 15.9 , 8.7 , 4.9 Hz , 1H ) , 3.06 – 2.94 ( m , 1H ) , 2.75 – 2.63 ( m , 1H ) , 2.50 ( ddd , J = 13.1 , 8.1 , 4.9 Hz , 1H ) , 1.83 ( s , 3H ) . LCMS ( Method 7 ) : 2.58 min , 380.2 [ M + H ] * - - Synthesis of compound 165 , N7- ( 6,7 - dihydro - 5H - pyrrolo [ 1,2 - a ] imidazol - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ' N ' NH-OMe N7- ( 6,7 - dihydro - 5H - pyrrolo [ 1,2 - a ] imidazol - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 25 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - бd ) ō 10.30 ( d , J = 7.1 Hz , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 7.66 ( d , J = 4.4 Hz , 2H ) , 7.56 ( s , 1H ) , 7.12 ( d , J = 1.3 Hz , 1H ) , 6.92 ( d , J = 1.3 Hz , 1H ) , 5.23 ( tt , J = 508 7.4 , 4.1 Hz , 1H ) , 4.96 ( s , 2H ) , 4.42 ( dd , J = 11.3 , 7.2 Hz , 1H ) , 3.98 ( dd , J = 11.3 , 4.1 Hz , 1H ) , - 3.37 ( s , 3H ) , 3.34 – 3.27 ( m , 1H ) , 2.83 ( dd , J = 16.2 , 4.3 Hz , 1H ) LCMS ( Method 7 ) : 0.87 min , 356.2 [ M + H ] + LO Synthesis of compound 166 , N7 - [ ( 4R ) -7 - fluorochroman - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide F NH.OMe N7 - [ ( 4R ) -7 - fluorochroman - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 98 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d € ) ₫ 10.27 ( d , J = 7.8 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.70 ( d , J = 4.4 Hz , 1H ) , 7.66 ( s , 1H ) , 7.59 ( s , 1H ) , 7.48 ( ddd , J = 8.6 , 6.7 , 0.9 Hz , 1H ) , 6.81 – 6.- - - ( m , 2H ) , 5.34 – 5.25 ( m , 1H ) , 4.95 ( s , 2H ) , 4.38 ( ddd , J = 10.0 , 6.3 , 3.3 Hz , 1H ) , 4.27 ( ddd , J = 11.5 , 8.7 , 2.9 Hz , 1H ) , 3.30 ( s , 3H ) , 2.31 – 2.20 ( m , 1H ) , 2.17 2.05 ( m , 1H ) LCMS ( Method 7 ) 2.37 min , 400.2 [ M + H ] * Synthesis of compound 167 , N7 - [ ( 3S ) -6 - fluoro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide F- ' N ' N = NH-OMe N7 - [ ( 3S ) -6 - fluoro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ( 77 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.37 ( d , J = 6.7 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.( d , J = 4.4 Hz , 1H ) , 7.65 ( s , 1H ) , 7.59 ( s , 1H ) , 7.49 ( ddd , J = 8.3 , 5.9 , 0.9 Hz , 1H ) , 6.88 - 6.75 ( m , 2H ) , 5.74 ( td , J = 7.4 , 4.1 Hz , 1H ) , 4.99 - 4.86 ( m , 3H ) , 4.56 ( dd , J = 10.0 , 4.2 Hz , 1H ) , 3.28 ( s , 3H ) 509 LO LCMS ( Method 7 ) 2.28 min , 386.2 [ M + H ] * Synthesis of compound 168 , N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide H NHOMe N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 40 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.53 ( s , 1H ) , 8.95 ( d , J = 4.4 Hz , 1H ) , 7.90 – 7.84 ( m , 2H ) , 7.83 – 7.78 ( m , 1H ) , 7.74 – 7.68 ( m , 2H ) , 7.66 ( br . s , 1H ) , 7.57 ( br . s , 1H ) , 6.03 – 5.94 ( m , - - 1H ) , 5.02 – 4.86 ( m , 2H ) , 4.19 ( dd , J = 13.6 , 7.6 Hz , 1H ) , 3.72 ( dd , J = 13.6 , 5.6 Hz , 1H ) , 3.30 ( s , 3H ) LCMS ( Method 7 ) : 1.87 min , 416.2 [ M + H ] + Synthesis of compound 169 , N7 - [ ( 3R ) -7 - chloro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide CI NH-OMe N7 - [ ( 3R ) -7 - chloro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 20 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.40 ( s , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 7.70 ( d , J = 4.4 Hz , 1H ) , 7.65 ( s , 1H ) , 7.59 ( s , 1H ) , 7.45 ( dt , J = 7.5 , 1.0 Hz , 1H ) , 7.39 ( dd , J = 7.9 , 1.5 Hz , 1H ) , 6.99 ( dd , J = 8.0 , 7.4 Hz , 1H ) , 5.90 – 5.83 ( m , 1H ) , 4.99 – 4.87 ( m , 3H ) , 4.59 ( dd , J = 10.0 , 4.5 Hz , 1H ) , 3.28 ( s , 3H ) - LCMS ( Method 7 ) 2.40 min ; 402.2 [ M + H ] * - 510 Synthesis of compound 170 , N7- ( 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide H .N . ` N coral NH-OMe N7- ( 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ( 11 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d ) § 10.18 ( s , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 8.50 ( d , J = 1.0 Hz , 1H ) , 8.38 ( d , J = 4.9 Hz , 1H ) , 7.70 - 7.63 ( m , 2H ) , 7.60 - 7.55 ( m , 1H ) , 7.35 ( dd , J = 5.0 , 1.Hz , 1H ) , 4.91 ( s , 2H ) , 4.88 – 4.79 ( m , 1H ) , 3.47 – 3.39 ( m , 2H ) , 3.30 ( s , 3H ) , 3.06 – 2.96 ( m , 2H ) - LCMS ( Method 7 ) : 1.10 min , 367.2 [ M + H ] + Synthesis of compound 171 , N7- ( 3,4 - dihydro - 2H - pyrano [ 2,3 - b ] pyridin - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide H N. ' N ' NH-OMe N7- ( 3,4 - dihydro - 2H - pyrano [ 2,3 - b ] pyridin - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ( 20 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.23 ( d , J = 7.8 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 8.( ddd , J = 4.8 , 2.0 , 0.6 Hz , 1H ) , 7.91 ( ddd , J = 7.5 , 2.0 , 0.9 Hz , 1H ) , 7.69 ( d , J = 4.4 Hz , 1H ) , 7.66 ( s , 1H ) , 7.59 ( s , 1H ) , 7.01 ( dd , J = 7.5 , 4.8 Hz , 1H ) , 5.43 – 5.34 ( m , 1H ) , 4.95 ( s , 2H ) , 4.52 4.35 ( m , 2H ) , 3.32 ( s , 3H ) , 2.34 – 2.24 ( m , 1H ) , 2.14 - 2.05 ( m , 1H ) - - LCMS ( Method 7 ) : 1.57 min , 383.2 [ M + H ] * - 511 LO Synthesis of compound 172 , N7 - [ ( 4S ) -chroman - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N = NH-OMe N7 - [ ( 4S ) -chroman - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) ō 10.29 ( d , J = 7.8 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.( d , J = 4.4 Hz , 1H ) , 7.66 ( br . s , J = 2.7 Hz , 1H ) , 7.59 ( br . s , 1H ) , 7.45 - 7.40 ( m , 1H ) , 7.23 - 7.17 ( m , 1H ) , 6.91 ( td , J = 7.5 , 1.2 Hz , 1H ) , 6.83 ( dd , J = 8.2 , 1.2 Hz , 1H ) , 5.36 – 5.27 ( m , 1H ) , 4.94 ( s , 2H ) , 4.38 – 4.31 ( m , 1H ) , 4.29 – 4.20 ( m , 1H ) , 3.28 ( s , 3H ) , 2.34 – 2.22 ( m , 1H ) , 2.15 2.06 ( m , 1H ) LCMS ( Method 7 ) : 2.29 min , 382.2 [ M + H ] * - Synthesis of compound 177 , N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide NH-OMe N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 40 mg ) was synthesised following a similar procedure to that described in General Method E. - 1H NMR ( 400 MHz , DMSO - d € ) ₫ 10.53 ( s , 1H ) , 8.95 ( d , J = 4.4 Hz , 1H ) , 7.90 – 7.84 ( m , 2H ) , 7.83 7.78 ( m , 1H ) , 7.74 – 7.68 ( m , 2H ) , 7.66 ( br . s , 1H ) , 7.57 ( br . s , 1H ) , 6.03 - 5.94 ( m , - 1H ) , 5.024.86 ( m , 2H ) , 4.19 ( dd , J = 13.6 , 7.6 Hz , 1H ) , 3.72 ( dd , J = 13.6 , 5.6 Hz , 1H ) , 3.30 ( s , 3H ) LCMS ( Method 7 ) : 1.87 min , 416.2 [ M + H ] + Synthesis of compound 178 , N7 - [ ( 3R ) -7 - chloro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 512 N gray NH-OMe N7 - [ ( 3R ) -7 - chloro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 20 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.40 ( s , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 7.70 ( d , J = 4.4 Hz , 1H ) , 7.65 ( s , 1H ) , 7.59 ( s , 1H ) , 7.45 ( dt , J = 7.5 , 1.0 Hz , 1H ) , 7.39 ( dd , J = 7.9 , 1.5 Hz , 1H ) , 6.99 ( dd , J = 8.0 , 7.4 Hz , 1H ) , 5.90 – 5.83 ( m , 1H ) , 4.99 – 4.87 ( m , 3H ) , 4.59 ( dd , J = 10.0 , 4.5 Hz , 1H ) , 3.28 ( s , 3H ) LCMS ( Method 7 ) 2.40 min ; 402.2 [ M + H ] + Synthesis of compound 179 , N7- ( 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide Dorge NH-OMe N7- ( 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ( 11 mg ) was synthesised following a similar procedure to that described in General Method E. - - 1H NMR ( 400 MHz , DMSO - ɓd ) ₫ 10.18 ( s , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 8.50 ( d , J = 1.0 Hz , 1H ) , 8.38 ( d , J = 4.9 Hz , 1H ) , 7.70 – 7.63 ( m , 2H ) , 7.60 – 7.55 ( m , 1H ) , 7.35 ( dd , J = 5.0 , 1.Hz , 1H ) , 4.91 ( s , 2H ) , 4.88 – 4.79 ( m , 1H ) , 3.47 – 3.39 ( m , 2H ) , 3.30 ( s , 3H ) , 3.06 – 2.96 ( m , 2H ) - LCMS ( Method 7 ) : 1.10 min , 367.2 [ M + H ] + Synthesis of compound 180 , N7- ( 3,4 - dihydro - 2H - pyrano [ 2,3 - b ] pyridin - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 513 N. N. N BIBL NH.OMe N7- ( 3,4 - dihydro - 2H - pyrano [ 2,3 - b ] pyridin - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ( 20 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.23 ( d , J = 7.8 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 8.( ddd , J = 4.8 , 2.0 , 0.6 Hz , 1H ) , 7.91 ( ddd , J = 7.5 , 2.0 , 0.9 Hz , 1H ) , 7.69 ( d , J = 4.4 Hz , 1H ) , 7.66 ( s , 1H ) , 7.59 ( s , 1H ) , 7.01 ( dd , J = 7.5 , 4.8 Hz , 1H ) , 5.43 – 5.34 ( m , 1H ) , 4.95 ( s , 2H ) , - 4.52 4.35 ( m , 2H ) , 3.32 ( s , 3H ) , 2.34 - 2.24 ( m , 1H ) , 2.14 - 2.05 ( m , 1H ) - LCMS ( Method 7 ) : 1.57 min , 383.2 [ M + H ] * Synthesis of compound 181 , N7 - [ ( 4S ) -chroman - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N = NH-OMe N7 - [ ( 4S ) -chroman - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 31 ) mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.29 ( d , J = 7.8 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.( d , J = 4.4 Hz , 1H ) , 7.66 ( br . s , J = 2.7 Hz , 1H ) , 7.59 ( br . s , 1H ) , 7.45 – 7.40 ( m , 1H ) , 7.23 - 7.17 ( m , 1H ) , 6.91 ( td , J = 7.5 , 1.2 Hz , 1H ) , 6.83 ( dd , J = 8.2 , 1.2 Hz , 1H ) , 5.36 – 5.27 ( m , - - 1H ) , 4.94 ( s , 2H ) , 4.38 – 4.31 ( m , 1H ) , 4.29 – 4.20 ( m , 1H ) , 3.28 ( s , 3H ) , 2.34 - 2.22 ( m , 1H ) , 2.15 2.06 ( m , 1H ) - LCMS ( Method 7 ) : 2.29 min , 382.2 [ M + H ] * Synthesis of 6,7 - difluorochroman - 4 - one oxime 514 ICH.HO₂HN Pyridine , RT OH N- F ICH.HO₂HN ( 377 mg , 5.43 mmol ) was added to a solution of 6,7 - difluorochroman - 4 - one ( 5mg , 2.72 mmol ) in pyridine ( 5 mL ) and the reaction was stirred at room temperature for h . The reaction mixture was concentrated in vacuo , and the residue was dissolved in EtOAc and water . The layers were separated , and the aqueous layer was extracted with EtOAc ( x ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo to provide the title compound ( 532 mg ) . ' H NMR ( 400 MHz , ³lCDC ) ₫ 7.61 ( dd , J = 11.1 , 9.0 Hz , 1H ) , 7.56 ( s , 1H ) , 6.71 ( dd , J = 11.1 , 6.9 Hz , 1H ) , 4.23 ( dd , J = 6.5 , 5.9 Hz , 2H ) , 2.95 ( t , J = 6.3 Hz , 2H ) LCMS ( Method 6 ) : 1.84 min , 200.2 [ M + H ] * Synthesis of 6,7 - difluorochroman - 4 - amine OH RaNi , ₂H EtOH , 25 ° C F F.

F NH ﻕﺭ 6,7 - Difluorochroman - 4 - one oxime ( 532 mg , 2.67 mmol ) was dissolved in EtOH ( 55 mL ) and the solution was hydrogenated over RaNi at 25 ° C and 10 bar ( H - cube , 1 mL / min ) . The resultant solution was concentrated in vacuo to provide the title compound ( 356 mg ) . ' H NMR ( 400 MHz , DMSO - бd ) Ŏ 7.42 ( ddd , J = 11.7 , 9.4 , 0.8 Hz , 1H ) , 6.79 ( dd , J = 12.2 , 7.- Hz , 1H ) , 4.29 4.18 ( m , 1H ) , 4.17 - 4.07 ( m , 1H ) , 3.82 ( t , J = 5.9 Hz , 1H ) , 2.04 ( s , 2H ) , 2.– 1.93 ( m , 1H ) , 1.76 – 1.64 ( m , 1H ) - Synthesis - of compound 182 . N7- ( 6,7 - difluorochroman - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide F. F Brou NH-OMe 515 LO N7- ( 6,7 - difluorochroman - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 72 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d ) § 10.25 ( d , J = 7.8 Hz , 1H ) , 8.93 ( d , J = 4.3 Hz , 1H ) , 7.70 ( d , J = 4.4 Hz , 1H ) , 7.66 ( s , 1H ) , 7.59 ( s , 1H ) , 7.51 ( dd , J = 11.3 , 9.1 Hz , 1H ) , 6.97 ( dd , J = 12.0 , - - - - 7.1 Hz , 1H ) , 5.34 – 5.24 ( m , 1H ) , 5.00 – 4.89 ( m , 2H ) , 4.40 – 4.31 ( m , 1H ) , 4.31 – 4.20 ( m , - 1H ) , 3.31 ( s , 3H ) , 2.31 – 2.20 ( m , 1H ) , 2.14 - 2.04 ( m , 1H ) LCMS ( Method 7 ) : 2.45 min , 418.2 [ M + H ] + Synthesis of compound 183 , 2- ( methoxymethyl ) -N7 - [ ( 1S ) -indan - 1 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide H N. orge NH-OMe 2- ( Methoxymethyl ) -N7 - [ ( 1S ) -indan - 1 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d ) § 10.23 ( d , J = 7.7 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.72 ( d , J = 4.4 Hz , 1H ) , 7.70 - 7.64 ( m , 1H ) , 7.59 ( s , 1H ) , 7.48 ( d , J = 7.1 Hz , 1H ) , 7.35 - 7.20 ( m , - 3H ) , 5.61 – 5.51 ( m , 1H ) , 4.95 ( d , J = 1.6 Hz , 2H ) , 3.32 ( s , 3H ) , 3.08 – 2.86 ( m , 2H ) , 2.68 – 2.56 ( m , 1H ) , 2.03 – 1.89 ( m , 1H ) - LCMS ( Method 7 ) : 2.41 min , 366.2 [ M + H ] * Synthesis of methyl 3 - hydroxyfuro [ 2,3 - b ] pyridine - 2 - carboxylate NaH , DME HO ✓ oft -5 ° C to 40 ° C OEt + ﻞﻠﻳ OMe OMe NaH ( 1.87 g , 46.63 mmol ) was added to a solution of ethyl 2 - hydroxyacetate ( 2.65 mL , 27.mmol ) in DME ( 50 mL ) at 5− ° C . The mixture was warmed to room temperature and stirred for 30 mins . A solution of methyl 2 - chloropyridine - 3 - carboxylate ( 4 g , 23.31 mmol ) in DME ( 15 mL ) was added slowly and the reaction was heated at 40 ° C overnight . The resulting 516 solid was dissolved in sat . aq . NaHCO3 and the mixture was diluted with EtOAc . The layers were separated , and the aqueous layer was acidified to pH 4 with AcOH and extracted with DCM . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The residue was triturated with heptane , and the resulting precipitate was collected by filtration and dried to provide the title compound ( 1.99 g ) . ' H NMR ( 400 MHz , DMSO - d € ) ☎ 8.50 ( dd , J = 4.8 , 1.7 Hz , 1H ) , 8.37 ( m , 1H ) , 7.42 ( m , 1H ) , 3.84 ( s , 3H ) . Exchangeable proton not observed . LCMS ( Method 6 ) : 1.38 min , 194.2 [ M + H ] * Synthesis of furo [ 2,3 - b ] pyridin - 3 - one OH 1. NaOH , O₂H EtOH , 100 ° C 2. HCI , 100 ° C OMe A solution of NaOH ( 1.25 g , 31.17 mmol ) in water ( 4 mL ) was added to a solution of methyl - hydroxyfuro [ 2,3 - b ] pyridine - 2 - carboxylate ( 1.5 g , 7.77 mmol ) in EtOH ( 25 mL ) and the reaction was heated at 100 ° C for 1 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The residue was dissolved in water and the solution was acidifed to pH 2-3 with concentrated HCI . The reaction was heated at 100 ° C for 2 h then cooled to room temperature . The mixture was neutralised with NaHCO3 and diluted with DCM . The layers were separated , and the organic layer was dried through a hydrophobic frit and concentrated in vacuo to provide the title compound ( 960 mg ) . ' H NMR ( 400 MHz , DMSO - d ) u0000 8.60 ( dd , J = 4.9 , 1.9 Hz , 1H ) , 8.15 ( dd , J = 7.5 , 1.9 Hz , 1H ) , 7.26 ( dd , J = 7.5 , 4.9 Hz , 1H ) , 4.89 ( s , 2H ) - LCMS ( Method 6 ) : 0.69 min , 136.2 [ M + H ] + Synthesis of furo [ 2,3 - b ] pyridin - 3 - one oxime ICH.HO₂HN MeOH , RT N - OH 08 " 517 LO Hydroxylamine hydrochloride ( 551 mg , 7.93 mmol ) was added to a solution of furo [ 2,3- b ] pyridin - 3 - one ( 357 mg , 2.64 mmol ) in MeOH ( 5 mL ) and the reaction was stirred at room temperature overnight . The reaction mixture was concentrated in vacuo and diluted with EtOAc and water . The resulting precipitate was collected by filtration and dried to provide the title compound ( 128 mg ) . ' H NMR ( 400 MHz , DMSO - d ) ☎ 11.60 ( s , 1H ) , 8.20 ( dd , J = 5.1 , 1.8 Hz , 1H ) , 7.96 ( dd , J : 7.4 , 1.8 Hz , 1H ) , 7.07 ( dd , J = 7.4 , 5.0 Hz , 1H ) , 5.18 ( s , 2H ) LCMS ( Method 6 ) : 1.00 min , 151.2 [ M + H ] + Synthesis of 2,3 - dihydrofuro [ 2,3 - b ] pyridin - 3 - amine = N - OH ₂H , RaNi EtOH , 80 ° C NH Furo [ 2,3 - b ] pyridin - 3 - one oxime ( 150 mg , 1.00 mmol ) was dissolved in EtOH ( 50 mL ) and the solution was hydrogenated over RaNi at 80 ° C and 70 bar ( H - cube , 1 mL / min ) . The resultant solution was concentrated in vacuo to provide the title compound ( 141 mg ) . The crude product was taken forward to the next step without purification .

Synthesis of compound 184 , N7- ( 2,3 - dihydrofuro [ 2,3 - b ] pyridin - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide H ' N ' NH-OMe N7- ( 2,3 - dihydrofuro [ 2,3 - b ] pyridin - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 49 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d € ) § 10.40 ( s , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 8.12 ( ddd , J = 5.1 , 1.8 , 0.7 Hz , 1H ) , 7.90 ( ddd , J = 7.3 , 1.8 , 1.0 Hz , 1H ) , 7.71 – 7.56 ( m , 3H ) , 7.01 ( dd , J = 7.3 , - - 5.1 Hz , 1H ) , 5.83 ( dd , J = 8.6 , 4.5 Hz , 1H ) , 4.96 – 4.86 ( m , 3H ) , 4.50 ( dd , J = 10.0 , 4.5 Hz , 1H ) , 3.30 ( s , 3H ) 518 LCMS ( Method 7 ) : 1.63 min , 369.2 [ M + H ] * Synthesis of 5,7 - difluoro - 2H - chromene - 3 - carbonitrile CN F DABCO , 80 ° C H " CN OH DABCO ( 1.7 g , 15.81 mmol ) was added to a solution of 2,4 - difluoro - 6 - hydroxy - benzaldehyde ( 2.5 g , 15.81 mmol ) in prop - 2 - enenitrile ( 17 mL , 253.00 mmol ) and the reaction was heated at 80 ° C for 18 h . The reaction mixture was cooled to room temperature , quenched with 1 M aq . HCI , and diluted with EtOAc . The layers were separated , and the organic layer was washed with water and brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 40 % EtOAc in heptane ) to provide the title compound ( 1.46 g ) . ' H NMR ( 400 MHz , ³lCDC ) ₫ 7.37 – 7.30 ( m , 1H ) , 6.52 – 6.41 ( m , 2H ) , 4.84 ( d , J = 0.8 Hz , 2H ) LCMS ( Method 7 ) : 2.71 min ( product does not ionise ) Synthesis of 5,7 - difluoro - 2H - chromene - 3 - carboxylic acid CN NaOH EtOH , 100 ° C OH 2 M aq . NaOH ( 24 mL , 59.26 mmol ) was added to a solution of 5,7 - difluoro - 2H - chromene- - carbonitrile ( 1.46 g , 7.41 mmol ) in EtOH ( 9 mL ) and the reaction was heated at 100 ° C for h . The reaction mixture was cooled to room temperature and acidified to pH 4 with 1 M aq . HCI . The resulting precipitate was collected by filtration , washed with water , and dried to provide the title compound ( 1.06 g ) . ₫ 1H NMR ( 400 MHz , DMSO - d6 ) 7.41 - 7.34 ( m , 1H ) , 6.90 ( td , J = 9.8 , 2.4 Hz , 1H ) , 6.75 - 6.67 ( m , 1H ) , 4.98 ( d , J = 1.5 Hz , 2H ) . Exchangeable proton not observed . LCMS ( Method 7 ) : 2.44 min , 211.1 [ M − H ] ¯ 519 Synthesis of 5,7 - difluorochromane - 3 - carboxylic acid Pd / C , ₂H MeOH , 50 ° C OH OH ,7 - difluoro - 2H - chromene - 3 - carboxylic acid ( 1.06 g , 4.71 mmol ) was dissolved in MeOH ( 157 mL ) and the solution was hydrogenated over 10 % Pd / C at 50 ° C ( H - cube , 1 mL / min , bar ) . The resultant solution was concentrated in vacuo to provide the title compound ( 797 mg ) . - - ' H NMR ( 400 MHz , MeOD ) d 6.51 – 6.43 ( m , 1H ) , 6.42 – 6.35 ( m , 1H ) , 4.49 – 4.30 ( m , 1H ) , 4.24 ( dd , J = 10.9 , 7.5 Hz , 1H ) , 3.12 – 2.97 ( m , 2H ) , 2.99 – 2.82 ( m , 2H ) LCMS ( Method 7 ) : 2.35 min , 213.2 [ M - H ] - Synthesis of 5,7 - difluorochroman - 3 - amine sol DPPA , ELN THF , 60 ° C NHOH NзtE ( 651 Lμ , 4.67 mmol ) and diphenylphosphoryl azide ( 482 Lμ , 2.24 mmol ) were added sequentially to a solution of 5,7 - difluorochromane - 3 - carboxylic acid ( 400 mg , 1.87 mmol ) in THF ( 4.7 mL ) , and the reaction was heated at 60 ° C for 2 h . The reaction mixture was cooled to room temperature and then to 0 ° C . The solution was acidified with 5 M aq . HCI , then warmed to room temperature and stirred for 2 h . The mixture was diluted with DCM and the layers were separated . The aqueous layer was basified with 2 M aq . NaOH and extracted with DCM . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 7 % MeOH in DCM ) to provide the title compound as the impure product ( 29 mg ) . LCMS ( Method 6 ) : 2.09 min , 186.2 [ M + H ] * Synthesis of compound 185 , N7- ( 5,7 - difluorochroman - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 520 Sorge NH-OMe N7- ( 5,7 - difluorochroman - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 3.1 mg ) was synthesised following a similar procedure to that described in General Method E.

- ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.29 ( d , J = 7.3 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.75 ( d , J = 4.4 Hz , 1H ) , 7.67 ( s , 1H ) , 7.58 ( s , 1H ) , 6.87 – 6.77 ( m , 1H ) , 6.71 – 6.61 ( m , 1H ) , 4.89 – 4.77 ( m , 2H ) , 4.70 – 4.58 ( m , 1H ) , 4.37 – 4.24 ( m , 2H ) , 3.28 ( s , 3H ) , 3.15 – 3.06 ( m , 1H ) , 2.91 2.77 ( m , 1H ) - - - LCMS ( Method 7 ) : 2.36 min , 418.2 [ M + H ] + - Synthesis of compound 186 , N7- ( 4,4 - dimethyltetralin - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide NHN = OMe N7- ( 4,4 - dimethyltetralin - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 16 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.33 ( d , J = 8.3 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.( d , J = 4.4 Hz , 1H ) , 7.67 ( s , 1H ) , 7.58 ( s , 1H ) , 7.47 – 7.37 ( m , 2H ) , 7.26 ( td , J = 7.6 , 1.5 Hz , 1H ) , 7.15 ( td , J = 7.5 , 1.3 Hz , 1H ) , 5.32 – 5.23 ( m , 1H ) , 4.99 – 4.87 ( m , 2H ) , 3.25 ( s , 3H ) , - 2.19 2.08 ( m , 1H ) , 1.98 – 1.83 ( m , 2H ) , 1.78 - 1.67 ( m , 1H ) , 1.34 ( s , 3H ) , 1.28 ( s , 3H ) - LCMS ( Method 7 ) 2.81 min ; 408.2 [ M + H ] * Synthesis of compound 187 , 2- ( methoxymethyl ) -N7- ( 5,6,7,8 - tetrahydroimidazo [ 1,2- a ] pyridin - 6 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 521 N se NH-OMe 2- ( Methoxymethyl ) -N7- ( 5,6,7,8 - tetrahydroimidazo [ 1,2 - a ] pyridin - 6 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 30 mg ) was synthesised following a similar procedure to that described in General Method E.

- ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.31 ( d , J = 7.2 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.( d , J = 4.4 Hz , 1H ) , 7.69 – 7.63 ( m , 1H ) , 7.63 – 7.56 ( m , 1H ) , 7.02 ( d , J = 1.3 Hz , 1H ) , 6.( d , J = 1.2 Hz , 1H ) , 4.92 ( s , 2H ) , 4.66 – 4.57 ( m , 1H ) , 4.29 ( dd , J = 12.8 , 4.4 Hz , 1H ) , 4.( dd , J = 12.9 , 4.5 Hz , 1H ) , 3.35 ( s , 3H ) , 3.06 - 2.88 ( m , 2H ) , 2.21 - 2.13 ( m , 2H ) == - LCMS ( Method 7 ) : 0.94 min , 370.2 [ M + H ] + Synthesis of compound 188 , 2- ( methoxymethyl ) -N7- ( 5,6,7,8 - tetrahydroimidazo [ 1,5- a ] pyridin - 6 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide IN ' N ' N : NH-OMe 2- ( Methoxymethyl ) -N7- ( 5,6,7,8 - tetrahydroimidazo [ 1,5 - a ] pyridin - 6 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 22 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , MeOD ) 5 8.91 ( d , J = 4.4 Hz , 1H ) , 7.89 ( d , J = 4.4 Hz , 1H ) , 7.57 ( d , J = 1.1 Hz , 1H ) , 6.81 – 6.76 ( m , 1H ) , 4.98 ( s , 2H ) , 4.79 – 4.72 ( m , 1H ) , 4.40 – 4.27 ( m , 2H ) , 3.- - ( s , 3H ) , 3.22 – 2.98 ( m , 2H ) , 2.33 – 2.16 ( m , 2H ) . Exchangeable protons not observed . LCMS ( Method 7 ) : 1.12 min ; 370.2 [ M + H ] + Synthesis of compound 189 , N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 522 H N arge ' N ' NH-OMe N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 34 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.28 ( d , J = 8.2 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.86 ( dd , J = 7.8 , 1.5 Hz , 1H ) , 7.80 – 7.75 ( m , 1H ) , 7.71 – 7.57 ( m , 5H ) , 5.67 – 5.55 ( m , 1H ) , 4.95 ( s , 2H ) , 3.90 – 3.77 ( m , 1H ) , 3.75 – 3.64 ( m , 1H ) , 3.33 ( s , 3H ) , 2.74 – 2.63 ( m , 1H ) , 2.62 – 2.( m , 1H ) - LCMS ( Method 7 ) : 1.88 min , 430.2 [ M + H ] + - Synthesis of compound 190 , 2- ( methoxymethyl ) -N7- ( 4,5,6,7 - tetrahydro - 1,3- benzothiazol - 6 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N. ' N ' N = NH-OMe 2- ( Methoxymethyl ) -N7- ( 4,5,6,7 - tetrahydro - 1,3 - benzothiazol - 6 - yl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 36 mg ) was synthesised following a similar procedure to that described in General Method E.

- ' H NMR ( 400 MHz , CDCl3 ) Ŏ 10.81 ( d , J = 7.4 Hz , 1H ) , 8.80 ( d , J = 4.4 Hz , 1H ) , 8.71 ( s , 1H ) , 8.01 ( s , 1H ) , 7.95 ( d , J = 4.4 Hz , 1H ) , 5.59 ( s , 1H ) , 5.06 ( s , 2H ) , 4.79 – 4.67 ( m , 1H ) , 3.( s , 3H ) , 3.33 ( dd , J = 16.6 , 5.0 Hz , 1H ) , 3.24 – 3.01 ( m , 3H ) , 2.30 – 2.20 ( m , 2H ) LCMS ( Method 7 ) : 1.80 min , 387.2 [ M + H ] + - - Synthesis of 2 - bromo - 1- ( 3,5 - difluoro - 2 - hydroxy - phenyl ) ethenone F Sc ₂rB , AcOH OH ° C F OH Br A solution of bromine ( 279 Lµ , 5.44 mmol ) in AcOH ( 1.2 mL ) was added dropwise to a suspension of 1- ( 3,5 - difluoro - 2 - hydroxy - phenyl ) ethanone ( 780 mg , 4.53 mmol ) in AcOH ( 5.mL ) , and the reaction was heated at 70 ° C in a microwave reactor for 2 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 30 % EtOAc in heptane ) to provide the title compound ( 1.23 g ) as the impure product . 1H NMR ( 400 MHz , CDCl3 ) б 11.44 ( s , 1H ) , 7.30 – 7.24 ( m , 1H ) , 7.20 – 7.13 ( m , 1H ) , 4.( s , 2H ) Synthesis of 5,7 - difluorobenzofuran - 3 - one ON QC₂K MeCN , 0 ° C K2CO3 ( 336 mg , 2.43 mmol ) was added to a solution of 2 - bromo - 1- ( 3,5 - difluoro - 2 - hydroxy- phenyl ) ethanone ( 407 mg , 1.62 mmol ) in MeCN ( 10.2 mL ) at 0 ° C and the reaction was stirred at 0 ° C for 1 h . The reaction mixture was acidified with 1 M aq . HCI and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were washed with brine , dried through a hydrophobic frit , and concentrated in vacuo to provide the title compound ( 203 mg ) . The crude product was taken forward to the next step without further purification . ' H NMR ( 400 MHz , CDCl3 ) Ŏ 7.23 - 7.15 ( m , 2H ) , 4.75 ( s , 2H ) Synthesis of 5,7 - difluorobenzofuran - 3 - one oxime ICH.HO₂HN Pyridine , RT N - OH Hydroxylamine hydrochloride ( 257 mg , 3.70 mmol ) was added to a solution of 5,7- difluorobenzofuran - 3 - one ( 315 mg , 1.85 mmol ) in pyridine ( 5.1 mL ) and the reaction was stirred at room temperature overnight . The reaction mixture was concentrated in vacuo , and the residue was diluted with EtOAc and water . The layers were separated , and the aqueous 524 LO layer was extracted with EtOAc ( × 3 ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 25 % EtOAc in heptane ) to provide the title compound ( 1mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) ō 11.71 ( s , 1H ) , 7.41 ( ddd , J = 11.0 , 9.5 , 2.5 Hz , 1H ) , 7.( ddd , J = 7.5 , 2.5 , 1.1 Hz , 1H ) , 5.28 ( s , 2H ) Synthesis of 5,7 - difluoro - 2,3 - dihydrobenzofuran - 3 - amine F F N - OH ₂H , RaNi EtOH , 80 ° C F NH ,7 - difluorobenzofuran - 3 - one oxime ( 116 mg , 0.63 mmol ) was dissolved in EtOH ( 60 mL ) and the solution was hydrogenated over RaNi at 80 ° C and 70 bar ( H - cube , 1 mL / min ) . The resultant solution was concentrated in vacuo , and the crude product was purified by SCX chromatography ( eluting with 2 M NH3 in MeOH ) to provide the title compound ( 44 mg ) . ' H NMR ( 400 MHz , ³lCDC ) § 6.87 – 6.81 ( m , 1H ) , 6.78 – 6.70 ( m , 1H ) , 4.75 ( dd , J = 9.4 , 8.Hz , 1H ) , 4.66 ( dd , J = 8.1 , 5.0 Hz , 1H ) , 4.27 ( dd , J = 9.4 , 5.0 Hz , 1H ) , 1.95 ( s , 2H ) - Synthesis of compound 191 , - N7- ( 5,7 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide F N. ' N ' NH-OMe N7- ( 5,7 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ( 44 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) § 10.42 ( d , J = 6.9 Hz , 1H ) , 8.93 ( d , J = 4.3 Hz , 1H ) , 7.69 ( d , - J = 4.4 Hz , 1H ) , 7.65 ( s , 1H ) , 7.60 ( s , 1H ) , 7.38 – 7.28 ( m , 1H ) , 7.23 ( dd , J = 7.4 , 2.6 Hz , 1H ) , 5.90 - 5.82 ( m , 1H ) , 5.03 - 4.88 ( m , 3H ) , 4.61 ( dd , J = 9.9 , 4.7 Hz , 1H ) . CH3 signal obscured by O₂H peak at 5 3.32 . LCMS ( Method 7 ) : 2.34 min , 404.2 [ M + H ] + 525 Synthesis of 7 - fluorobenzofuran - 3 - one oxime ICH.HO₂HN Pyridine , RT N - ON Hydroxylamine hydrochloride ( 91 mg , 1.31 mmol ) was added to a solution of 7- fluorobenzofuran - 3 - one ( 200 mg , 1.31 mmol ) in pyridine ( 3.6 mL ) and the reaction was stirred at room temperature for 19 h . The reaction mixture was concentrated in vacuo , and the residue was diluted with EtOAc and water . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo to provide the title compound ( 197 mg ) . 1H NMR ( 400 MHz , CDCl3 ) Ŏ 7.36 ( dd , J = 7.7 , 1.1 Hz , 1H ) , 7.13 ( ddd , J = 10.6 , 8.2 , 1.1 Hz , 1H ) , 6.94 ( ddd , J = 8.2 , 7.7 , 4.1 Hz , 1H ) , 5.27 ( s , 2H ) . Exchangeable proton not observed . LCMS ( Method 6 ) : 1.62 min , 168.2 [ M + H ] * Synthesis of 7 - fluoro - 2,3 - dihydrobenzofuran - 3 - amine N - ON ₂H ( g ) , Pd / C EICH , RT ₂HN 7 - Fluorobenzofuran - 3 - one oxime ( 100 mg , 0.60 mmol ) was added to a suspension of 10 % Pd / C in EtOH ( 10 mL ) and the reaction was stirred at room temperature under a hydrogen atmosphere ( balloon ) for 18 h . The reaction mixture was filtered through a short pad of ®etilaCiD and concentrated in vacuo to provide the title compound ( 78 mg ) . 1H NMR ( 400 MHz , CDCl3 ) ₫ 7.09 ( d , J = 7.4 Hz , 1H ) , 6.97 ( dd , J = 10.6 , 8.1 Hz , 1H ) , 6.- 6.80 ( m , 1H ) , 4.77 – 4.62 ( m , 2H ) , 4.35 - 4.23 ( m , 1H ) , 3.02 ( s , 2H ) Synthesis of compound 192 , N7- ( 7 - fluoro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 526 .N . N esge NH-OMe N7- ( 7 - fluoro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 19 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) Ō 10.41 ( s , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.70 ( d , J = 4.4 Hz , 1H ) , 7.65 ( s , 1H ) , 7.59 ( s , 1H ) , 7.32 ( dt , J = 7.5 , 1.0 Hz , 1H ) , 7.27 - 7.20 ( m , 1H ) , 7.01 - 6.94 ( m , 1H ) , 5.91 – 5.81 ( m , 1H ) , 4.98 – 4.88 ( m , 3H ) , 4.60 ( dd , J = 9.9 , 4.5 Hz , 1H ) , 3.( s , 3H ) - - LCMS ( Method 7 ) : 2.26 min , 386.2 [ M + H ] * Synthesis of compound 193 , 2- ( methoxymethyl ) -N7 - [ ( 1S ) -tetralin - 1 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N. N = NH-OMe 2- ( Methoxymethyl ) -N7 - [ ( 1S ) -tetralin - 1 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide - ( mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.30 ( d , J = 8.3 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.73 ( d , J = 4.4 Hz , 1H ) , 7.67 ( s , 1H ) , 7.58 ( s , 1H ) , 7.48 – 7.42 ( m , 1H ) , 7.23 – 7.13 ( m , 3H ) , 5.33 – 5.26 ( m , 1H ) , 4.93 ( s , 2H ) , 3.28 ( s , 3H ) , 2.90 – 2.71 ( m , 2H ) , 2.17 – 2.08 ( m , 1H ) , 1.99 – 1.( m , 3H ) - - - - LCMS ( Method 7 ) : 2.54 min , 380.2 [ M + H ] * Synthesis of compound 194 , N7- ( 5 - fluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 527 H coral F N NH-OMe N7- ( 5 - fluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method E. - - - 1H NMR ( 400 MHz , DMSO - d6 ) г 10.21 ( d , J = 7.1 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.72 – 7.63 ( m , 2H ) , 7.58 ( s , 1H ) , 7.34 - 7.25 ( m , 1H ) , 7.13 ( dd , J = 9.3 , 2.5 Hz , 1H ) , 7.04 - 6.( m , 1H ) , 4.92 ( s , 2H ) , 4.87 - 4.78 ( m , 1H ) , 3.44 - 3.32 ( m , 5H ) , 3.03 – 2.88 ( m , 2H ) LCMS ( Method 7 ) : 2.45 min , 384.2 [ M + H ] * - Synthesis of compound 195 , N7- ( 5,6 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ' N ' N = F- NH-OMe N7- ( 5,6 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 20 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) г 10.20 ( d , J = 7.2 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.73 - 7.63 ( m , 2H ) , 7.58 ( s , 1H ) , 7.37 ( t , J = 9.2 Hz , 2H ) , 4.92 ( s , 2H ) , 4.87 – 4.78 ( m , 1H ) , 3.42 – - - 3.32 ( m , 5H ) , 2.94 ( dd , J = 16.4 , 4.3 Hz , 2H ) LCMS ( Method 7 ) : 2.50 min , 402.2 [ M + H ] + Synthesis of t - butyl - 6 - fluoro - 2H - chromene - 3 - carboxylate 528 F OH Ot - Bu 3OC₂K DMF , 100 ° C F. ool ... Ot - Bu t - Butyl acrylate ( 13.6 mL , 93.09 mmol ) was added to a suspension of 5 - fluoro - 2 - hydroxy- benzaldehyde ( 5 g , 35.69 mmol ) and K2CO3 ( 14.8 g , 107.06 mmol ) in DMF ( 75 mL ) and the reaction was heated at 100 ° C for 18 h . The reaction mixture was cooled to room temperature and diluted with EtOAc . The organic layer was washed with 5 % aq . LiCI ( x3 ) and brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 2.09 g ) . 1H NMR ( 400 MHz , DMSO - d6 ) § 7.39 ( s , 1H ) , 7.26 ( dd , J = 8.7 , 3.1 Hz , 1H ) , 7.10 ( td , J = 8.7 , 3.1 Hz , 1H ) , 6.87 ( ddd , J = 8.9 , 4.6 , 0.7 Hz , 1H ) , 4.87 ( d , J = 1.5 Hz , 2H ) , 1.49 ( s , 9H ) LCMS ( Method 7 ) : 3.41 min , 193.2 [ M - t - Bu ] ¯ Synthesis of t - butyl 6 - fluorochromane - 3 - carboxylate F.

₂H , 10 % Pd / C EtOH , MeOH ° C F Ot - Bu Ot - Bu t - Butyl 6 - fluoro - 2H - chromene - 3 - carboxylate ( 2.09 g , 8.33 mmol ) was dissolved in EtOH ( mL ) and MeOH ( 8 mL ) , and the solution was hydrogenated over 10 % Pd / C at 35 ° C and bar ( H - cube , 1 mL / min ) . The resultant solution was concentrated in vacuo to provide the title compound ( 838 mg ) . - - - ' H NMR ( 400 MHz , DMSO - d € ) ₫ 7.02 – 6.94 ( m , 1H ) , 6.94 – 6.84 ( m , 1H ) , 6.76 ( dd , J = 8.9 , 5.0 Hz , 1H ) , 4.30 – 4.21 ( m , 1H ) , 4.12 – 4.06 ( m , 1H ) , 2.99 – 2.89 ( m , 3H ) , 1.39 ( s , 9H ) LCMS ( Method 7 ) : 3.25 min , 195.2 [ M - t - Bu ] ¯ - Synthesis of 6 - fluorochromane - 3 - carboxylic acid 529 100 % TFA DCM , RT Ot - Bu OH TFA ( 1.18 mL , 15.47 mmol ) was added to a solution of t - butyl 6 - fluorochromane - 3- carboxylate ( 838 mg , 3.16 mmol ) in DCM ( 5 mL ) , and the reaction was stirred at room temperature for 2 h . The reaction mixture was concentrated in vacuo , and the residue was dissolved in DCM and filtered . The filtrate was left to stand overnight , and the resulting precipitate was collected by filtration , washed with heptane , and dried to provide the title . compound ( 390 mg ) . - 1H NMR ( 400 MHz , DMSO - d ) § 12.67 ( s , 1H ) , 6.98 ( dd , J = 9.2 , 3.1 Hz , 1H ) , 6.93 – 6.( m , 1H ) , 6.76 ( dd , J = 8.9 , 5.0 Hz , 1H ) , 4.32 – 4.23 ( m , 1H ) , 4.15 – 4.09 ( m , 1H ) , 3.01 – 2.( m , 3H ) LCMS ( Method 7 ) : 2.15 min , 195.2 [ M − H ] ¯ Synthesis of 6 - fluorochroman - 3 - amine DPPA , N₂tE THF , 60 ° C NHOH Diphenylphosphoryl azide ( 513 Lµ , 2.39 mmol ) and NзtE ( 690 Lµ , 4.98 mmol ) were added to a solution of 6 - fluorochromane - 3 - carboxylic acid ( 390 mg , 1.99 mmol ) in THF ( 2.5 mL ) , and the reaction was heated at 60 ° C for 2 h . The reaction mixture was cooled to 0 ° C and acidified with 5 M aq . HCI . The mixture was warmed to room temperature , stirred for h , then diluted with DCM . The layers were separated , and the aqueous layer was extracted with DCM ( x 2 ) . The aqueous layer was basified with 2 M aq . NaOH and extracted with DCM ( x 3 ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo to provide the title compound ( 49 mg ) . - ' H NMR ( 400 MHz , DMSO - d ) ☎ 6.93 – 6.84 ( m , 2H ) , 6.73 ( dd , J = 8.7 , 5.0 Hz , 1H ) , 4.( ddd , J = 10.4 , 3.5 , 1.9 Hz , 1H ) , 3.57 ( dd , J = 10.3 , 8.5 Hz , 1H ) , 3.14 - 3.06 ( m , 1H ) , 2.92 - - 2.85 ( m , 1H ) , 2.48 – 2.39 ( m , 1H ) , 1.65 ( s , 2H ) LCMS ( Method 7 ) : 0.14 min , 168.2 [ M + H ] * 530 Synthesis of compound 196 , N7- ( 6 - fluorochroman - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ' N ' N = NH-OMe N7- ( 6 - fluorochroman - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 15 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) ō 10.32 ( d , J = 7.4 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.- ( d , J = 4.4 Hz , 1H ) , 7.67 ( s , 1H ) , 7.58 ( s , 1H ) , 7.05 – 6.94 ( m , 2H ) , 6.87 ( dd , J = 8.9 , 4.9 Hz , 1H ) , 4.87 - 4.74 ( m , 2H ) , 4.64 – 4.56 ( m , 1H ) , 4.27 – 4.19 ( m , 2H ) , 3.26 ( s , 4H ) , 2.88 ( dd , J = 17.1 , 3.9 Hz , 1H ) LCMS ( Method 7 ) : 2.30 min , 400.2 [ M + H ] * Synthesis of compound 197 , N7 - [ ( 4 - hydroxyphenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide HO N ₂HN -OMe N7 - [ ( 4 - hydroxyphenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 20 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d ) г 10.18 ( t , J = 5.6 Hz , 1H ) , 9.37 ( s , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.73 – 7.67 ( m , 2H ) , 7.59 ( s , 1H ) , 7.29 – 7.21 ( m , 2H ) , 6.79 – 6.71 ( m , 2H ) , 4.97 ( s , 2H ) , 4.55 ( d , J = 5.6 Hz , 2H ) , 3.35 ( s , 3H ) LCMS ( Method 7 ) : 1.87 min , 356.2 [ M + H ] + Synthesis of compound 198 , 2- ( methoxymethyl ) -N7 - [ ( 1S ) -3,3 - dimethylindan - 1- yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 531 N. ' N ' gree NH-OMe 2- ( Methoxymethyl ) -N7 - [ ( 1S ) -3,3 - dimethylindan - 1 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 61 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) г 10.26 ( d , J = 7.7 Hz , 1H ) , 8.94 ( d , J = 4.4 Hz , 1H ) , 7.74 ( d , J = 4.4 Hz , 1H ) , 7.71 – 7.66 ( m , 1H ) , 7.59 ( s , 1H ) , 7.45 ( d , J = 7.5 , 1.1 Hz , 1H ) , 7.36 – 7.- - - ( m , 2H ) , 7.27 – 7.20 ( m , 1H ) , 5.67 – 5.56 ( m , 1H ) , 4.94 ( s , 2H ) , 3.30 ( s , 3H ) , 2.49 – 2.47 ( m , - 1H ) , 1.93 – 1.83 ( m , 1H ) , 1.40 ( s , 3H ) , 1.26 ( s , 3H ) LCMS ( Method 7 ) : 2.72 min , 394.2 [ M + H ] + Synthesis of 199 . 2- ( methoxymethyl ) -N7 - [ ( 2- compound methoxyphenyl ) methyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide OMe N = NH-OMe 2- ( methoxymethyl ) -N7 - [ ( 2 - methoxyphenyl ) methyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 25 mg ) was synthesised following a similar procedure to that described in General Method E.

= ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.35 ( t , J = 5.8 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.75 ( d , J = 4.4 Hz , 1H ) , 7.72 ( s , 1H ) , 7.60 ( s , 1H ) , 7.43 ( dd , J = 7.4 , 1.7 Hz , 1H ) , 7.31 ( ddd , J 8.2 , 7.4 , 1.7 Hz , 1H ) , 7.05 ( dd , J = 8.3 , 1.1 Hz , 1H ) , 6.94 ( td , J = 7.4 , 1.1 Hz , 1H ) , 5.00 ( s , 2H ) , 4.62 ( d , J = 5.7 Hz , 2H ) , 3.88 ( s , 3H ) , 3.37 ( s , 3H ) LCMS ( Method 7 ) : 2.33 min , 370.2 [ M + H ] + Synthesis of compound 200 , N7- ( cis - 1 - hydroxyindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 532 N. NHOH -OMe N7- ( cis - 1 - hydroxyindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 20 mg ) was synthesised following a similar procedure to that described in General Method E.

- ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.54 ( d , J = 7.2 Hz , 1H ) , 8.95 ( d , J = 4.4 Hz , 1H ) , 7.84 ( d , J = 4.4 Hz , 1H ) , 7.72 ( s , 1H ) , 7.59 ( s , 1H ) , 7.45 – 7.38 ( m , 1H ) , 7.31 – 7.21 ( m , 3H ) , 5.73 ( d , J = 5.6 Hz , 1H ) , 5.10 ( t , J = 5.6 Hz , 1H ) , 4.91 ( d , J = 0.6 Hz , 2H ) , 4.75 -4.64 ( m , 1H ) , 3.( s , 3H ) , 3.28 ( d , J = 7.3 Hz , 1H ) , 3.04 – 2.94 ( m , 1H ) - LCMS ( Method 7 ) : 2.06 min , 382.2 [ M + H ] * 2- ( methoxymethyl ) -N7 - cis - 1 - methylindan - 2- Synthesis of compound 201 , yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N N NH-OMe 2- ( Methoxymethyl ) -N7 - cis - 1 - methylindan - 2 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 41 mg ) was synthesised following a similar procedure to that described in General Method E. - - - ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.15 ( d , J = 8.0 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.73 ( d , J = 4.4 Hz , 1H ) , 7.67 ( s , 1H ) , 7.58 ( s , 1H ) , 7.32 – 7.25 ( m , 2H ) , 7.24 – 7.14 ( m , 2H ) , 4.93 – 4.81 ( m , 3H ) , 3.55 - 3.43 ( m , 1H ) , 3.28 ( d , J = 6.9 Hz , 1H ) , 3.23 ( s , 3H ) , 2.94 ( dd , J = 16.1 , 4.6 Hz , 1H ) , 1.31 ( d , J = 7.3 Hz , 3H ) LCMS ( Method 7 ) : 2.53 min , 380.1 [ M + H ] * Synthesis of tert - butyl N- [ trans - 3- ( trifluoromethoxy ) cyclobutyl ] carbamate 533 KF , 2 - fluoropyridine Selectfluor , AgOTf BOC EtOAc , 0 ° C to RT HO N F H F F BOC O N Selectfluor ™ ( 1- ( Chloromethyl ) -4 - fluoro - 1,4 - diazabicyclo [ 2.2.2 ] octane - 1,4 - diium ditetrafluoroborate ; 6.75 g , 18.94 mmol ) , AgOTf ( 14.11 g , 54.90 mmol ) , and KF ( 3.19 g , 54.90 mmol ) were added to a solution of tert - butyl N- ( trans - 3 - hydroxycyclobutyl ) carbamate ( 2.57 g , 13.73 mmol ) in EtOAc ( 51 mL ) , followed by the dropwise addition of 2 - fluoropyridine ( 3.6 mL , 41.80 mmol ) and trimethyl ( trifluoromethyl ) silane ( 5.1 mL , 34.31 mmol ) . The reaction was stirred at room temperature for 72 h , then the mixture was filtered through a short pad of ®etilaciD and concentrated in vacuo . The residue was dissolved in EtOAc and the solution was washed with 10 % aq . CuSO4 , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 2.57 g ) . - 1H NMR ( 400 MHz , ³lCDC ) ₫ 4.88 – 4.79 ( m , 1H ) , 4.70 ( br s , 1H ) , 4.24 ( br s , 1H ) , 2.68 – 2.57 ( m , 2H ) , 2.43 - 2.32 ( m , 2H ) , 1.46 ( s , 9H ) Synthesis of trans - 3- ( trifluoromethoxy ) cyclobutanamine ; hydrochloride F F F- BOC HCI 1,4 - Dioxane , RT F F F- O II ■ NH2.HCI HCI ( 4 M in 1,4 - dioxane ) ( 6.4 mL , 25.47 mmol ) was added to a solution of tert - butyl N- [ trans- 3- ( trifluoromethoxy ) cyclobutyl ] carbamate ( 1.30 g , 5.09 mmol ) in DCM ( 39 mL ) and the reaction was stirred at room temperature for 18 h then concentrated in vacuo . The residue was redissolved in DCM and concentrated in vacuo . The process was repeated three times to provide the title compound ( 952 mg ) . ' H NMR ( 400 MHz , DMSO - ɓd ) § 8.49 ( s , 3H ) , 5.27 – 5.15 ( m , 1H ) , 3.86 – 3.72 ( m , 1H ) , 2.- 2.53 ( m , 4H ) Synthesis of compound 224 , 2- ( methoxymethyl ) -N7- [ trans - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 534 F. essay N = NH-OMe 2- ( Methoxymethyl ) -N7- [ trans - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 63 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.12 ( d , J = 6.5 Hz , 1H ) , 8.92 ( d , J = 4.3 Hz , 1H ) , 7.72 - 7.56 ( m , 3H ) , 5.11 – 5.03 ( m , 1H ) , 5.00 ( s , 2H ) , 4.60 – 4.50 ( m , 1H ) , 3.43 ( s , 3H ) , 2.76 – 2.( m , 2H ) , 2.61 – 2.47 ( m , 2H ) - LCMS ( Method 7 ) : 2.36 min , 388.2 [ M + H ] + Synthesis of compound 225 , N7- ( 1,1 - dioxothietan - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide H squ NH-OMe N7- ( 1,1 - dioxothietan - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 41 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.48 ( d , J = 4.7 Hz , 1H ) , 8.95 ( d , J = 4.3 Hz , 1H ) , 7.72 - 7.65 ( m , 2H ) , 7.61 ( s , 1H ) , 4.98 ( s , 2H ) , 4.80 – 4.69 ( m , 3H ) , 4.30 – 4.21 ( m , 2H ) , 3.42 ( s , 3H ) LCMS ( Method 7 ) : 1.43 min , 354.14 [ M + H ] + - - Synthesis of compound 226 , N7- ( 4,4 - difluorotetralin - 1 - yl ) -2- ( methoxymethyl ) -5- methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 535 Bra F. NHOMe N7- ( 4,4 - difluorotetralin - 1 - yl ) -2- ( methoxymethyl ) -5 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 32 mg ) was synthesised following a similar procedure to that described in General Method E.

- - - ' H NMR ( 400 MHz , DMSO - d ) ō 10.26 ( d , J = 8.3 Hz , 1H ) , 7.76 – 7.70 ( m , 1H ) , 7.69 – 7.( m , 2H ) , 7.61 ( s , 1H ) , 7.58 - 7.47 ( m , 3H ) , 5.47 - 5.38 ( m , 1H ) , 4.91 ( s , 2H ) , 3.30 ( s , 3H ) , 2.72 ( s , 3H ) , 2.59 – 2.51 ( m , 2H ) , 2.37 – 2.25 ( m , 1H ) , 2.13 – 2.00 ( m , 1H ) - - LCMS ( Method 7 ) : 2.61 min , 430.2 [ M + H ] * Synthesis of compound 227 , N7 - indan - 2 - yl - 2- ( methoxymethyl ) -5 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide corge N : NH-OMe N7 - indan - 2 - yl - 2- ( methoxymethyl ) -5 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 90 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d ) § 10.21 ( d , J = 7.0 Hz , 1H ) , 7.75 – 7.71 ( m , 1H ) , 7.61 ( s , 1H ) , - - - 7.55 7.48 ( m , 1H ) , 7.32 - 7.24 ( m , 2H ) , 7.22 – 7.14 ( m , 2H ) , 4.88 ( s , 2H ) , 4.84 – 4.74 ( m , - 1H ) , 3.38 ( dd , J = 16.2 , 7.2 Hz , 2H ) , 3.29 ( s , 3H ) , 2.96 ( dd , J = 16.2 , 4.6 Hz , 2H ) , 2.70 ( s , 3H ) LCMS ( Method 7 ) : 2.48 min , 380.2 [ M + H ] * Synthesis of compound 228 , N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2- isopropyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 536 gigi ' N ' NH N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2 - isopropyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 143 mg ) was synthesised following a similar procedure to that described in General Method E. - - - = 1H NMR ( 400 MHz , DMSO - d6 ) г 10.73 ( d , J = 7.7 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.92 - 7.88 ( m , 1H ) , 7.86 – 7.69 ( m , 5H ) , 7.56 – 7.45 ( m , 1H ) , 6.03 – 5.95 ( m , 1H ) , 4.18 ( dd , J 13.7 , 7.4 Hz , 1H ) , 3.99 – 3.88 ( m , 1H ) , 3.74 ( dd , J = 13.7 , 4.4 Hz , 1H ) , 1.19 ( d , J = 6.9 Hz , 3H ) , 1.17 ( d , J = 6.9 Hz , 3H ) LCMS ( Method 7 ) : 2.23 min , 414.2 [ M + H ] + Synthesis of compound 229 , 2 - cyclopropyl - N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H- thiochromen - 4 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N.

Bige NH 2 - Cyclopropyl - N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ( 210 mg ) was synthesised following a similar procedure to that described in General Method E. 1H ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.08 ( d , J = 8.1 Hz , 1H ) , 8.85 ( d , J = 4.4 Hz , 1H ) , 7.90 – 7.86 ( m , 1H ) , 7.74 ( s , 1H ) , 7.72 – 7.62 ( m , 3H ) , 7.57 ( d , J = 4.4 Hz , 1H ) , 7.53 ( s , 1H ) , 5.59 – 5.52 ( m , 1H ) , 3.85 – 3.75 ( m , 1H ) , 3.72 – 3.62 ( m , 1H ) , 3.20 – 3.12 ( m , 1H ) , 2.71 – 2.54 ( m , - - - 2H ) , 1.10 1.00 ( m , 2H ) , 0.90 - 0.79 ( m , 2H ) LCMS ( Method 7 ) : 2.10 min , 426.0 [ M + H ] * - - - Synthesis of compound 230 , N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2- isopropyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 537 N Brai N NH N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2 - isopropyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 130 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.33 ( d , J = 8.0 Hz , 1H ) , 8.89 ( d , J = 4.4 Hz , 1H ) , 7.89 - 7.85 ( m , 1H ) , 7.81 – 7.73 ( m , 2H ) , 7.70 – 7.60 ( m , 3H ) , 7.53 – 7.43 ( m , 1H ) , 5.63 – 5.54 ( m , - - - 1H ) , 4.00 -3.89 ( m , 1H ) , 3.87 – 3.76 ( m , 1H ) , 3.73 – 3.62 ( m , 1H ) , 2.75 – 2.52 ( m , 2H ) , 1.( dd , J = 6.9 , 1.4 Hz , 6H ) LCMS ( Method 7 ) : 2.22 min , 428.2 [ M + H ] * Synthesis of compound 231 , 2 - cyclopropyl - N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen- - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide .N . N ₂HN 2 - Cyclopropyl - N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 185 mg ) was synthesised following a similar procedure to that described in General Method E. § 1H NMR ( 400 MHz , DMSO - d6 ) 8 10.47 ( d , J = 7.8 Hz , 1H ) , 8.89 ( d , J = 4.4 Hz , 1H ) , 7.( d , J = 7.7 Hz , 1H ) , 7.87 – 7.67 ( m , 5H ) , 7.56 ( s , 1H ) , 6.02 – 5.92 ( m , 1H ) , 4.16 ( dd , J = 13.7 , 7.4 Hz , 1H ) , 3.73 ( dd , J = 13.7 , 4.5 Hz , 1H ) , 3.20 – 3.11 ( m , 1H ) , 1.07 – 0.97 ( m , 2H ) , 0.-0.87 ( m , 1H ) , 0.88 – 0.80 ( m , 1H ) - LCMS ( Method 7 ) : 2.12 min , 412.1 [ M + H ] * Synthesis of compound 232 , N7- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) -5 - methyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 538 gras NH-OMe N7- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) -5 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 45 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) 8 10.35 ( d , J = 7.6 Hz , 1H ) , 7.75 -7.71 ( m , 1H ) , 7.70 - 7.( m , 3H ) , 7.63 ( s , 1H ) , 7.60 - 7.52 ( m , 2H ) , 5.76 – 5.66 ( m , 1H ) , 4.91 ( d , J = 2.8 Hz , 2H ) , 3.- ( s , 3H ) , 3.28 – 3.19 ( m , 1H ) , 2.72 ( s , 3H ) , 2.69 – 2.56 ( m , 1H ) - LCMS ( Method 7 ) : 2.54 min , 416.2 [ M + H ] + Synthesis of compounds 233 and 234 , N7- [ 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4- yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N. ' N ' ' N ' NH2 NHOMe -OMe Racemic N- [ 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 50 mg ) was separated by preparative SFC ( eluting with % MeOH in CO2 ) to provide N7 - [ ( 4R ) -1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamidfe ( 13 mg , early eluting enantiomer , 3.51 min ) and N7 - [ ( 4S ) -1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 14 mg , late eluting enantiomer , 5.16 min ) . 1H NMR ( 400 MHz , MeOD ) ð 8.93 ( d , J = 4.4 Hz , 1H ) , 7.93 ( dd , J = 7.7 , 1.6 Hz , 1H ) , 7.( d , J = 4.4 Hz , 1H ) , 7.75 – 7.69 ( m , 1H ) , 7.69 – 7.56 ( m , 2H ) , 5.68 ( dd , J = 7.3 , 4.8 Hz , 1H ) , 5.03 ( d , J = 0.7 Hz , 2H ) , 3.74 ( ddd , J = 14.3 , 9.0 , 3.5 Hz , 1H ) , 3.64 ( ddd , J = 14.3 , 8.8 , 3.- - Hz , 1H ) , 3.40 ( s , 3H ) , 2.94 – 2.73 ( m , 2H ) . Exchangeable protons not observed . LCMS ( Method 7 ) 1.60 min , 430.2 [ M + H ] * Synthesis of compound 235 , 2 - cyclopropyl - N7 - [ ( 4R ) -1,1 - dioxo - 3,4 - dihydro - 2H- thiochromen - 4 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 539 ' N ' esge ₂HN 2 - Cyclopropyl - N7 - [ ( 4R ) -1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 21 mg ) was synthesised following a similar procedure to that described in General Method E. - - - - 1H NMR ( 400 MHz , DMSO - d6 ) ☎ 10.08 ( d , J = 8.1 Hz , 1H ) , 8.85 ( d , J = 4.4 Hz , 1H ) , 7.( d , J = 7.8 Hz , 1H ) , 7.82 – 7.45 ( m , 6H ) , 5.72 – 5.38 ( m , 1H ) , 3.85 – 3.75 ( m , 1H ) , 3.71 - 3.61 ( m , 1H ) , 3.22 – 3.11 ( m , 1H ) , 2.77 – 2.57 ( m , 2H ) , 1.15 – 1.00 ( m , 2H ) , 0.94 – 0.76 ( m , 2H ) - LCMS ( Method 7 ) : 2.11 min ; 426.2 [ M + H ] * - Synthesis of compound 236 , 2 - cyclopropyl - N7 - [ ( 4S ) -1,1 - dioxo - 3,4 - dihydro - 2H- thiochromen - 4 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N esge N ° N = NH 2 - Cyclopropyl - N7 - [ ( 4S ) -1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 14 mg ) was synthesised following a similar procedure to that described in General Method E.

- ' H NMR ( 400 MHz , DMSO - d6 ) г 10.08 ( d , J = 8.0 Hz , 1H ) , 8.85 ( d , J = 4.5 Hz , 1H ) , 7.88 . ☎ ( d , J = 7.7 Hz , 1H ) , 7.82 - 7.47 ( m , 6H ) , 5.67 - 5.45 ( m , 1H ) , 3.87 – 3.74 ( m , 1H ) , 3.73 - 3.61 ( m , 1H ) , 3.21 – 3.10 ( m , 1H ) , 2.69 – 2.55 ( m , 2H ) , 1.12 – 0.99 ( m , 2H ) , 0.93 – 0.77 ( m , 2H ) LCMS ( Method 7 ) : 2.11 min , 426.1 [ M + H ] * Synthesis of 6 - fluoroindan - 1 - one oxime 540 ICH.HO₂HN , Pyridine , RT F. N - OH 05 " Hydroxylamine hydrochloride ( 1.02 g , 14.65 mmol ) was added to a solution of 6 - fluoroindan- - one ( 2 g , 13.32 mmol ) in pyridine ( 15 mL ) and the reaction was stirred at room temperature for 3 h . The reaction mixture was diluted with EtOAc and acidified to pH 2 with M aq . HCI . The layers were separated , and the organic layer was washed successively with 1 M aq . HCI , 10 % aq . CuSO4 , and brine , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 1.94 g ) . - ' H NMR ( 400 MHz , MeOD ) ð 7.36 – 7.25 ( m , 2H ) , 7.07 ( ddd , J = 9.1 , 8.4 , 2.6 Hz , 1H ) , 3.- 2.98 ( m , 2H ) , 2.96 - 2.91 ( m , 2H ) . Exchangeable proton not observed . LCMS ( Method 6 ) : 1.64 mins , 166.3 [ M + H ] * Synthesis of 6 - fluoroindan - 1 - amine N - OH Pd / C , ₂H ( g ) AcOH , EtOH NHRT F.

% Pd / C ( 166 mg , 0.16 mmol ) was added to a solution of 6 - fluoroindan - 1 - one oxime ( 1.g , 10.05 mmol ) in EtOH ( 100 mL ) under an atmosphere of argon . A balloon of hydrogen was attached to the flask and the reaction was stirred at room temperature for 20 h . An additional portion of 10 % Pd / C ( 166 mg , 0.16 mmol ) was added and the flask was recharged with hydrogen . The reaction was stirred at room temperature for a further 3 d . The reaction mixture was filtered through a short pad of ®etilaciD and concentrated in vacuo . The residue was dissolved in EtOH ( 100 mL ) and AcOH ( 10 mL ) and 10 % Pd / C ( 166 mg , 0.16 mmol ) was added to the solution under an atmosphere of argon . A balloon of hydrogen was attached to the flask and the reaction was stirred at room temperature for 20 h . The reaction mixture was filtered through a short pad of ®etilaciD and concentrated to approximately mL in vacuo . The solution was basified to pH 8 with sat . aq . NaHCO3 and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) and a 1 : mixture of MeOH : EtOAc . The combined organic layers were dried through a hydrophobic frit 541 and concentrated in vacuo to provide the title compound ( 1.47 g ) . The crude product was taken forward to the next step without purification . - 1H NMR ( 400 MHz , CDCl3 ) г 7.18 -7.11 ( m , 1H ) , 7.07 – 6.96 ( m , 1H ) , 6.93 – 6.83 ( m , 1H ) , 4.- 4.26 ( m , 1H ) , 2.98 - 2.69 ( m , 2H ) , 2.60 - 2.46 ( m , 1H ) , 1.79 - 1.66 ( m , 1H ) . Exchangeable protons not observed .

Synthesis of 2,2,2 - trifluoro - N- ( 6 - fluoroindan - 1 - yl ) acetamide NHF tE₂OCC3F N₂tE , MeOH , RT F. F F Ethyl trifluoroacetate ( 1.38 mL , 11.63 mmol ) was added to a solution of 6 - fluoroindan - 1- amine ( 1.47 g , 9.69 mmol ) and NзtE ( 2.01 mL , 14.54 mmol ) in MeOH ( 20 mL ) at 0 ° C . The reaction was stirred at room temperature for 18 h then concentrated in vacuo . The residue was dissolved in EtOAc and washed with water . The organic layer was dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 1.63 g ) .

- - - ' H NMR ( 400 MHz , ³lCDC ) ₫ 7.25 – 7.19 ( m , 1H ) , 7.02 – 6.95 ( m , 2H ) , 6.41 ( s , 1H ) , 5.( q , J = 7.7 Hz , 1H ) , 3.08 – 2.96 ( m , 1H ) , 2.95 - 2.83 ( m , 1H ) , 2.76 – 2.63 ( m , 1H ) , 2.03 – 1.89 ( m , 1H ) LCMS ( Method 6 ) : 1.97 min , 246.0 [ M - H ] - - Synthesis of 2,2,2 - trifluoro - N- ( 6 - fluoro - 3 - oxo - indan - 1 - yl ) acetamide F F KMnO4 , O₂H7.4OSgM Acetone , O₂H ° C to RT N- both A solution of MgSO4.7H2O ( 3.24 g , 13.15 mmol ) in water ( 10 mL ) was added to a solution of 2,2,2 - trifluoro - N- ( 6 - fluoroindan - 1 - yl ) acetamide ( 1.63 g , 6.57 mmol ) in acetone ( 20 mL ) and the mixture was cooled to 0 ° C . KMnO4 ( 3.12 g , 19.72 mmol ) was added , and the reaction 542 LO was warmed to room temperature and stirred for 23 h . An additional portion of KMnO4 ( 1.g , 6.57 mmol ) was added , and the reaction was stirred at room temperature for a further h . A solution of Na2S2O3.5H2O ( 3.26 g , 13.15 mmol ) in water ( 10 mL ) was added , and the mixture was stirred for 10 min . The reaction mixture was filtered through a short pad of ⓇetilaciD and washed with EtOAc and water . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 2 ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 8mg ) . ' H NMR ( 400 MHz , MeOD ) ō 7.80 ( dd , J = 8.3 , 5.1 Hz , 1H ) , 7.35 - 7.26 ( m , 2H ) , 5.66 ( dd , J = 8.0 , 3.6 Hz , 1H ) , 3.21 ( dd , J = 18.9 , 7.9 Hz , 1H ) , 2.66 ( dd , J = 18.9 , 3.6 Hz , 1H ) . Exchangeable proton not observed . LCMS ( Method 6 ) : 1.69 min , 260.2 [ M - H ] - Synthesis of 2,2,2 - trifluoro - N- ( 6 ' - fluorospiro [ 1,3 - dithiolane - 2,3 ' - indane ] -1 ' - yl ) acetamide HS SH H N- F. BF 3.OEt2 , DCM , 0 ° C to RT F. F F S BF3.OEt2 ( 900 Lµ , 7.27 mmol ) was added dropwise to a suspension of ethane - 1,2 - dithiol ( 230 Lμ , 2.73 mmol ) and 2,2,2 - trifluoro - N- ( 6 - fluoro - 3 - oxo - indan - 1 - yl ) acetamide ( 475 mg , 1.82 mmol ) in DCM ( 10 mL ) at 0 ° C , then the reaction was warmed to room temperature and stirred for 19 h . The reaction was quenched with sat . aq . NaHCO3 and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo to provide the title compound ( 596 mg ) . - - - - 1H NMR ( 400 MHz , ³lCDC ) ₫ 7.62 – 7.55 ( m , 1H ) , 7.14 – 7.05 ( m , 1H ) , 7.05 – 6.98 ( m , 1H ) , 6.76 ( s , 1H ) , 5.55 – 5.46 ( m , 1H ) , 3.62 – 3.54 ( m , 2H ) , 3.53 – 3.44 ( m , 2H ) , 3.16 ( dd , J 13.9 , 7.1 Hz , 1H ) , 2.64 ( dd , J = 14.0 , 4.6 Hz , 1H ) - = LCMS ( Method 6 ) : 2.13 min , 336.0 [ M − H ] ¯ Synthesis of 2,2,2 - trifluoro - N- ( 3,3,6 - trifluoroindan - 1 - yl ) acetamide 543 F.

S N- ' N ' -N Br Br HF.pyr DCM -70 ° C to RT F F HF.pyr ( 2.03 mL , 15.74 mmol ) was added dropwise to a suspension of 1,3 - dibromo - 5,5- dimethyl - imidazolidine - 2,4 - dione ( 2 g , 7.00 mmol ) in DCM ( 6 mL ) at -70 ° C , and the reaction was stirred at -70 ° C for 1.5 h . A solution of 2,2,2 - trifluoro - N- ( 6 ' - fluorospiro [ 1,3 - dithiolane- 2,3 ' - indane ] -1 ' - yl ) acetamide ( 590 mg , 1.75 mmol ) in DCM ( 4 mL ) was added dropwise , and the reaction was stirred at -70 ° C for 3 h then at room temperature for a further 1 h . The reaction mixture was quenched with 2 M aq . NaOH at 0 ° C and diluted with DCM . The layers were separated , and the organic layer was washed with brine , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified twice by column chromatography ( eluting first with 0 to 80 % EtOAc in heptane and then with 0 to 80 % DCM in heptane ) to provide the title compound ( 145 mg ) as the impure product . - - - - 1H NMR ( 400 MHz , ³ICDC ) г 7.64 – 7.57 ( m , 1H ) , 7.21 ( td , J = 8.6 , 2.3 Hz , 1H ) , 7.15 – 7.( m , 1H ) , 6.54 ( s , 1H ) , 5.65 – 5.55 ( m , 1H ) , 3.27 - 3.11 ( m , 1H ) , 2.59 – 2.44 ( m , 1H ) LCMS ( Method 6 ) : 2.00 min , 282.0 [ M - H ] - Synthesis of 3,3,6 - trifluoroindan - 1 - amine H N NaOH , DCM RT NHF. 4 M aq . NaOH ( 1.24 mL , 4.94 mmol ) was added to a solution of 2,2,2 - trifluoro - N- ( 3,3,6- trifluoroindan - 1 - yl ) acetamide ( 140 mg , 0.49 mmol ) in DCM ( 3 mL ) and the reaction was stirred at room temperature for 24 h . The reaction mixture was diluted with DCM and water and the layers were separated . The aqueous layer was extracted with DCM ( x 2 ) , and the 544 combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) to provide the title compound ( 62 mg ) . - - 1H NMR ( 400 MHz , ³lCDC ) ₫ 7.55 – 7.47 ( m , 1H ) , 7.19 – 7.04 ( m , 2H ) , 4.51 – 4.41 ( m , 1H ) , - 3.13 2.98 ( m , 1H ) , 2.36 - 2.18 ( m , 1H ) . Exchangeable protons not observed . - Synthesis of compound 237 , 2- ( methoxymethyl ) -N7- ( 3,3,6 - trifluoroindan - 1 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide F gige ' N ' N : NH-OMe 2- ( Methoxymethyl ) -N7- ( 3,3,6 - trifluoroindan - 1 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 51 mg ) was synthesised following a similar procedure to that described in General Method E. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.35 ( d , J = 7.6 Hz , 1H ) , 8.94 ( d , J = 4.4 Hz , 1H ) , 7.88 – 7.54 ( m , 4H ) , 7.56 – 7.47 ( m , 1H ) , 7.46 — 7.36 ( m , 1H ) , 5.80 – 5.61 ( m , 1H ) , 5.05 – 4.84 ( m , - - 2H ) , 3.37 - 3.22 ( m , 4H ) , 2.77 – 2.60 ( m , 1H ) - LCMS ( Method 7 ) : 2.47 min , 420.1 [ M + H ] + - Synthesis of compound 238 , N7 - [ ( 3S ) -6,7 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide F ' N ' N = NH-OMe N7 - [ ( 3S ) -6,7 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 97 mg ) was synthesised following a similar procedure to that described in General Method E. 1H NMR ( 400 MHz , DMSO - d6 ) ō 10.41 ( d , J = 6.8 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.69 . ( d , J = 4.4 Hz , 1H ) , 7.63 ( s , 1H ) , 7.58 ( s , 1H ) , 7.35 – 7.27 ( m , 1H ) , 7.07 – 6.96 ( m , 1H ) , 5. 545 LO – 5.77 ( m , 1H ) , 5.07 – 4.96 ( m , 1H ) , 4.94 ( d , J = 2.8 Hz , 2H ) , 4.69 ( dd , J = 10.0 , 4.3 Hz , 1H ) , 3.30 ( s , 3H ) LCMS ( Method 7 ) : 2.36 min , 404.1 [ M + H ] + Synthesis of 7 ' - fluorospiro [ 1,3 - dithiolane - 2,1 ' - tetralin ] HS . SH BF3.OEt2 , DCM , 0 ° C to RT BF3.OEt2 ( 6 mL , 48.73 mmol ) was added to a solution of ethane - 1,2 - dithiol ( 1.54 mL , 18.mmol ) and 7 - fluorotetralin - 1 - one ( 2 g , 12.18 mmol ) in DCM ( 50 mL ) at 0 ° C , then the reaction was warmed to room temperature and stirred for 16 h . The reaction mixture was quenched with sat . aq . NaHCO3 and diluted with DCM . The layers were separated , and the aqueous layer was extracted with DCM . The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound ( 3.08 g ) . - - 1H NMR ( 400 MHz , 3№CDC ) б 7.62 ( dd , J = 10.8 , 2.7 Hz , 1H ) , 6.98 – 6.90 ( m , 1H ) , 6.87 – 6.77 ( m , 1H ) , 3.64 – 3.52 ( m , 2H ) , 3.52 – 3.40 ( m , 2H ) , 2.76 – 2.73 ( m , 2H ) , 2.42 – 2.33 ( m , 2H ) , 2.04 1.94 ( m , 2H ) - - LCMS ( Method 7 ) : 3.41 mins , 241.2 [ M + H ] * - - Synthesis of 1,1,7 - trifluorotetralin Br -N F Br HF.pyr DCM -70 ° C to RT 546 LO HF.pyr ( 4.82 mL , 37.45 mmol ) was added dropwise to a solution of 1,3 - dibromo - 5,5- dimethyl - imidazolidine - 2,4 - dione ( 4.76 g , 16.64 mmol ) in DCM ( 7 mL ) at -70 ° C , and the reaction was stirred at -70 ° C for 30 min . A solution of 7 ' - fluorospiro [ 1,3 - dithiolane - 2,1'- tetralin ] ( 1 g , 4.16 mmol ) in DCM ( 2 mL ) was added dropwise , and the reaction was stirred at -70 ° C for 3 h then at room temperature for a further 1 h . The reaction mixture was quenched with 2 M aq . NaOH at 0 ° C and diluted with DCM . The layers were separated , and the organic layer was washed with sat . aq . NaHSO3 , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % EtOAc in heptane ) to provide the title compound ( 263 mg ) . ' H NMR ( 400 MHz , CDCl3 ) Ŏ 7.35 ( dd , J = 9.2 , 2.7 Hz , 1H ) , 7.18 - 7.00 ( m , 2H ) , 2.84 – 2.( m , 2H ) , 2.34 – 2.18 ( m , 2H ) , 2.05 - 1.94 ( m , 2H ) - LCMS ( Method 7 ) : 3.04 min ( product does not ionise ) Synthesis of 4,4,6 - trifluorotetralin - 1 - one F F F KMnO4 , MgSO Acetone , water RT MgSO4 ( 336 mg , 2.79 mmol ) and KMnO4 ( 660 mg , 4.19 mmol ) were added sequentially to a solution of 1,1,7 - trifluorotetralin ( 260 mg , 1.4 mmol ) in acetone ( 3 mL ) and water ( 3 mL ) , and the reaction was stirred at room temperature for 3 h . EtOH ( 10 mL ) was added , and the reaction mixture was stirred for a further 1 h , then filtered and concentrated in vacuo . The residue was diluted with DCM and water , and the layers were separated . The organic layer was dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % EtOAc in heptane ) to provide the title compound ( 131 mg ) . - - - 1H NMR ( 400 MHz , ³ICDC ) г 8.14 – 8.06 ( m , 1H ) , 7.49 – 7.41 ( m , 1H ) , 7.33 – 7.23 ( m , 1H ) , 2.90 ( dd , J = 7.3 , 6.2 Hz , 2H ) , 2.73 – 2.59 ( m , 2H ) - LCMS ( Method 7 ) : 3.04 min ( product does not ionise ) Synthesis of 4,4,6 - trifluorotetralin - 1 - one oxime 547 ICH.HO₂HN , Pyridine , RT F OH Hydroxylamine hydrochloride ( 48 mg , 0.70 mmol ) was added to a solution of 4,4,6- trifluorotetralin - 1 - one ( 127 mg , 0.63 mmol ) in pyridine ( 1 mL ) and the reaction was stirred at room temperature for 5 h . The reaction mixture was diluted with EtOAc and acidified to pH with 5 M aq . HCI . The layers were separated , and the organic layer was washed successively with 1 M aq . HCI , 10 % aq . CuSO4 , water , and brine , dried over Na2SO4 , and concentrated in vacuo to provide the title compound ( 122 mg ) . - - ' H NMR ( 400 MHz , DMSO - d ) § 11.67 ( s , 1H ) , 8.07 – 7.98 ( m , 1H ) , 7.50 – 7.37 ( m , 2H ) , 2.85 ( t , J = 7.0 Hz , 2H ) , 2.48 - 2.33 ( m , 2H ) LCMS ( Method 7 ) : 2.51 min ( product does not ionise ) Synthesis of 4,4,6 - trifluorotetralin - 1 - amine OH Pd / C , H2 ( g ) EtOH , RT NH % Pd / C ( 25 mg , 0.23 mmol ) was added to a solution of 4,4,6 - trifluorotetralin - 1 - one oxime ( 122 mg , 0.57 mmol ) in EtOH ( 5 mL ) under an atmosphere of argon . A balloon of hydrogen was attached to the flask and the reaction was stirred at room temperature for 18 h . The reaction mixture was filtered through a short pad of ®etilaciD and concentrated in vacuo . The crude product was purified by SCX chromatography ( eluting with 2 M NH3 in MeOH ) and then by column chromatography ( eluting with 0 to 3 % ( 2 M NH3 in MeOH ) in DCM ) to provide the title compound ( 36 mg ) . - - H¹ NMR ( 400 MHz , ³lCDC ) ₫ 7.56 – 7.47 ( m , 1H ) , 7.37 – 7.29 ( m , 1H ) , 7.19 – 7.09 ( m , 1H ) , 4.04 3.95 ( m , 1H ) , 2.60 - 2.43 ( m , 1H ) , 2.31 -2.12 ( m , 2H ) , 1.91 – 1.77 ( m , 1H ) , 1.54 ( s , 2H ) - Synthesis of compound 239 , 2- ( methoxymethyl ) -N7- ( 4,4,6 - trifluorotetralin - 1- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 548 F.

BIBL NH-OMe 2- ( Methoxymethyl ) -N7- ( 4,4,6 - trifluorotetralin - 1 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 29 mg ) was synthesised following a similar procedure to that described in General Method E. - - 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.24 ( d , J = 8.3 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.75 ( dd , J = 8.7 , 5.4 Hz , 1H ) , 7.71 – 7.54 ( m , 3H ) , 7.52 — 7.37 ( m , 2H ) , 5.45 – 5.39 ( m , 1H ) , 4.95 ( s , 2H ) , 3.32 ( s , 3H ) , 2.59 – 2.51 ( m , 2H ) , 2.34 - 2.26 ( m , 1H ) , 2.15 – 2.01 ( m , 1H ) LCMS ( Method 7 ) : 2.57 min , 434.2 [ M + H ] + Synthesis of compound 94 , N7- ( trans - 3 - fluoro - 3 - methyl - cyclobutyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( General Method F ) Synthesis of 3 - cyano - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid O₂H.HOIL THF , O₂H , RT HO A solution of LiOH.H2O ( 35 mg , 0.85 mmol ) in water ( 1 mL ) was added to a solution of ethyl - cyano - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 200 mg , 0.77 mmol ) in THF ( 1 mL ) and the reaction was stirred at room temperature for 3 h . The reaction mixture was concentrated in vacuo and the aqueous residue was acidified with 5 M aq . HCI . The suspension was diluted with water , and the precipitate was collected by filtration , washed with water , and dried to provide the title compound ( 146 mg ) . ☎ 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 8.94 ( d , J = 4.3 Hz , 1H ) , 7.66 ( d , J = 4.3 Hz , 1H ) , 4.74 ( s , 2H ) , 3.38 ( s , 3H ) . Exchangeable proton not observed . LCMS ( Method 1 ) : 1.23 min , 233.2 [ M + H ] * Synthesis of - cyano - N- ( trans - 3 - fluoro - 3 - methyl - cyclobutyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide 549 NO .

RA NH_HCI T3P , N₂tE , DMF RT to 50 ° C LO NзtE ( 108 Lμ , 0.78 mmol ) was added to a solution of trans - 3 - fluoro - 3 - methyl- cyclobutanamine hydrochloride ( 30 mg , 0.21 mmol ) and 3 - cyano - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 45 mg , 0.19 mmol ) in DMF ( 500 Lµ ) and the mixture was stirred at room temperature for 5 min . 1 - Propanephosphonic anhydride ( 50 wt % in DMF ) ( 173 Lµ , 0.29 mmol ) was added and the reaction was stirred at room temperature for 18 h . Additional portions of N³tE ( 108 Lμ , 0.78 mmol ) and 1- propanephosphonic anhydride ( 50 wt % in DMF ) ( 173 Lµ , 0.29 mmol ) were added and the reaction was stirred at room temperature for 6 h and then heated at 50 ° C for 2 h . The reaction mixture was cooled to room temperature and diluted with 1 M aq . HCI and EtOAc . The layers were separated , and the organic layer was washed with brine , dried over Na2S04 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 70 % EtOAc in heptane ) to provide the title compound ( 19 mg ) . ' H NMR ( 400 MHz , ³lCDC ) г 10.20 ( s , 1H ) , 8.91 ( d , J = 4.3 Hz , 1H ) , 8.00 ( d , J = 4.3 Hz , 1H ) , 4.84 ( s , 2H ) , 4.75 -4.65 ( m , 1H ) , 3.58 ( s , 3H ) , 2.98 - 2.86 ( m , 2H ) , 2.34 – 2.24 ( m , 2H ) , 1.( d , J = 22.0 Hz , 3H ) LCMS ( Method 1 ) : 1.65 min , 318.2 [ M + H ] * - Synthesis of compound 94 , N7- ( trans - 3 - fluoro - 3 - methyl - cyclobutyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide F sosa HO PS - PPh ,, Pd ( OAc ) , EtOH , O₂H , 80 ° C ₂HN 3 - Cyano - N- ( trans - 3 - fluoro - 3 - methyl - cyclobutyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide ( 19 mg , 0.06 mmol ) , acetaldehyde oxime ( 14 Lµ , 0.23 mmol ) , and PS - PPh3 ( 1.4- 2 mmol / g ; 15 mg , 0.02 -0.03 mmol ) were suspended in EtOH ( 440 Lµ ) and water ( 110 Lµ ) and the reaction was heated at 80 ° C for 3 hours . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 4 % MeOH in DCM ) and preparative HPLC ( basic method ) to provide the title compound ( 6.9 mg ) . - 1H NMR ( 400 MHz , DMSO - d6 ) ō 10.15 ( d , J = 6.1 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.68 ( br . s , 1H ) , 7.65 ( d , J = 4.3 Hz , 1H ) , 7.60 ( br . s , 1H ) , 5.00 ( s , 2H ) , 4.57 – 4.48 ( m , 1H ) , 3.43 ( s , 3H ) , 2.84-2.71 ( m , 2H ) , 2.33 - 2.20 ( m , 2H ) , 1.55 ( d , J = 22.4 Hz , 3H ) LCMS ( Method 2 ) : 1.91 min , 336.2 [ M + H ] * Synthesis of compound 134 , - cyclopropyl - N7- ( 5,6 - dihydro - 4H- cyclopenta [ c ] thiophen - 5 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide sosau ﻞﻛ ₂HN 2 - Cyclopropyl - N7- ( 5,6 - dihydro - 4H - cyclopenta [ c ] thiophen - 5 - yl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ( 8.1 mg ) was synthesised following a similar procedure to that described in General Method F. ' H NMR ( 400 MHz , CDCl3 ) Ŏ 10.70 ( d , J = 7.6 Hz , 1H ) , 8.70 ( d , J = 4.4 Hz , 1H ) , 8.15 ( s , 1H ) , 7.86 ( d , J = 4.4 Hz , 1H ) , 6.96 ( s , 2H ) , 5.61 ( s , 1H ) , 5.17 ( s , 1H ) , 3.31 – 3.20 ( m , 3H ) , 2.- ( dd , J = 15.9 , 4.2 Hz , 2H ) , 1.19 – 1.11 ( m , 2H ) , 0.87 – 0.79 ( m , 2H ) LCMS ( Method 6 ) : 1.88 min , 368.2 [ M + H ] * Synthesis of compound 135 , 2 - cyclopropyl - N7- ( 4,4 - difluorocyclohexyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 551 F osqu ₂HN LO 2 - Cyclopropyl - N7- ( 4,4 - difluorocyclohexyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method F. 1H NMR ( 400 MHz , CDCl3 ) б 10.40 ( d , J = 7.3 Hz , 1H ) , 8.73 ( d , J = 4.4 Hz , 1H ) , 8.18 ( s , 1H ) , 7.86 ( d , J = 4.4 Hz , 1H ) , 5.66 ( s , 1H ) , 4.22 - 4.18 ( m , 1H ) , 3.43 - 3.33 ( m , 1H ) , 2.23 - 2.10 . ( m , 4H ) , 2.09 1.95 ( m , 2H ) , 1.85 - 1.74 ( m , 2H ) , 1.33 – 1.24 ( m , 2H ) , 1.12 - 1.04 ( m , 2H ) LCMS ( Method 7 ) : 2.46 min , 364.2 [ M + H ] * Synthesis of compound 136 , 2 - cyclopropyl - N7- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide sosqu ₂HN 2 - Cyclopropyl - N7- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method F. 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.10 ( s , 1H ) , 8.85 ( d , J = 4.5 Hz , 1H ) , 7.77 ( s , 1H ) , 7.( d , J = 4.4 Hz , 1H ) , 7.55 ( s , 1H ) , 4.37 ( s , 1H ) , 3.26 – 3.07 ( m , 3H ) , 2.76 – 2.61 ( m , 2H ) , 1.- 1.11 ( m , 2H ) , 1.11 – 1.05 ( m , 2H ) LCMS ( Method 7 ) : 2.40 min , 336.2 [ M + H ] * Synthesis of compound 137 , 2 - propyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 552 NH ₂ 2 - Propyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 84 mg ) was synthesised following a similar procedure to that described in General Method F. 1H NMR ( 400 MHz , DMSO - d6 ) ō 10.10 ( d , J = 7.4 Hz , 1H ) , 8.87 ( d , J = 4.3 Hz , 1H ) , 7.73 ( d , J = 2.7 Hz , 1H ) , 7.59 ( d , J = 4.4 Hz , 1H ) , 7.49 ( d , J = 2.5 Hz , 1H ) , 4.77 – 4.66 ( m , 1H ) , 4.- – 4.13 ( m , 1H ) , 3.20 – 3.11 ( m , 2H ) , 2.96 – 2.85 ( m , 2H ) , 2.38 – 2.26 ( m , 2H ) , 1.85 – 1.( m , 2H ) , 0.99 ( t , J = 7.4 Hz , 3H ) LCMS ( Method 7 ) 2.83 min , 386.2 [ M + H ] * Synthesis of compound 138 , N7- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2 - cyclopropyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide coral ₂HN N7- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2 - cyclopropyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 24 mg ) was synthesised following a similar procedure to that described in General Method F. 1H NMR ( 400 MHz , DMSO - d6 ) ō 10.40 ( d , J = 6.8 Hz , 1H ) , 8.86 ( d , J = 4.4 Hz , 1H ) , 7.( d , J = 2.8 Hz , 1H ) , 7.65 ( d , J = 4.4 Hz , 1H ) , 7.57 – 7.50 ( m , 1H ) , 7.40 – 7.25 ( m , 3H ) , 7.28 - 7.21 ( m , 1H ) , 5.55 – 5.47 ( m , 1H ) , 3.77 ( dd , J = 14.3 , 5.0 Hz , 1H ) , 3.21 - 3.10 ( m , 2H ) , 1.... – 0.99 ( m , 2H ) , 0.97 – 0.81 ( m , 2H ) LCMS ( Method 7 ) : 2.70 min , 348.2 [ M + H ] * Synthesis of compound 139 , N7 - indan - 2 - yl - 2 - propyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 553 cosqu ' ₂HN N7 - indan - 2 - yl - 2 - propyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 67 mg ) was synthesised following a similar procedure to that described in General Method F. - 1H NMR ( 400 MHz , DMSO - d6 ) ō 10.37 ( d , J = 7.4 Hz , 1H ) , 8.87 ( d , J = 4.4 Hz , 1H ) , 7.71 ( s , 1H ) , 7.68 ( d , J = 4.4 Hz , 1H ) , 7.47 ( s , 1H ) , 7.35 – 7.26 ( m , 2H ) , 7.22 – 7.18 ( m , 2H ) , 4.85 – 4.77 ( m , 1H ) , 3.37 ( dd , J = 16.1 , 6.9 Hz , 2H ) , 3.07 – 2.93 ( m , 4H ) , 1.61 – 1.52 ( m , 2H ) , 0.( t , J = 7.4 Hz , 3H ) LCMS ( Method 7 ) : 2.88 min , 364.2 [ M + H ] + Synthesis of compound 140 , 2 - cyclopropyl - N7 - [ ( 4 - fluorophenyl ) methyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide NH ; 2 - Cyclopropyl - N7 - [ ( 4 - fluorophenyl ) methyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method F. 1H NMR ( 400 MHz , DMSO - d6 ) : ō 10.05 ( t , J = 5.7 Hz , 1H ) , 8.85 ( d , J = 4.4 Hz , 1H ) , 7.77 ( br . s , 1H ) , 7.62 ( d , J = 4.4 Hz , 1H ) , 7.54 ( br . s , 1H ) , 7.52 – 7.47 ( m , 2H ) , 7.26 – 7.16 ( m , 2H ) , ... 4.66 – 4.60 ( m , 2H ) , 3.23 – 3.15 ( m , 1H ) , 1.12 – 1.06 ( m , 2H ) , 1.01 – 0.94 ( m , 2H ) LCMS ( Method 7 ) : 2.48 min , 354.2 [ M + H ] + Synthesis of sodium 1,1 - dicyano - 3 - ethoxy - 3 - oxo - prop - 1 - en - 2 - olate 554 NC ON NaQEt EtOH , RT CN QEt N NaOEt ( 21 wt % in EtOH ) ( 9.4 mL , 25.19 mmol ) was added dropwise to a solution of propanedinitrile ( 1.64 g , 24.84 mmol ) and diethyl oxalate ( 3.37 mL , 24.84 mmol ) in EtOH ( mL ) and the reaction was stirred at room temperature for 1 h then concentrated in vacuo . The residue was dissolved in EtOAc ( 75 mL ) and the solution was stirred at room temperature for 1 h . The solvent was decanted , filtered through a short pad of ®etilaciD , and concentrated in vacuo . The residue was suspended in EtOH and O₂tE , and the mixture was sonicated for 5 min . The solvent was decanted , and the residual gum was washed with Et2O and dried to provide the title compound ( 2.27 g ) . The crude product was taken forward to the next step without purification .

Synthesis of ethyl 3,3 - dicyano - 2 - methoxy - prop - 2 - enoate 1. ĄICOP ° C to 105 ° C 2. MeOH ° C to RT E Sodium 1,1 - dicyano - 3 - ethoxy - 3 - oxo - prop - 1 - en - 2 - olate ( 10 g , 53.16 mmol ) was added to POCI3 ( 30 mL , 321.85 mmol ) at 0 ° C . The mixture was warmed to room temperature and stirred until the solid was in solution . The reaction was heated at 105 ° C for 45 min then cooled to room temperature . The reaction mixture was concentrated in vacuo and the residue was cooled to 0 ° C . MeOH ( 200 mL ) was added slowly and the reaction was stirred at room temperature for 15 min . The reaction mixture was concentrated in vacuo and the residue was dissolved in a 1 : 2.5 mixture of EtOAc : heptane . The solution was filtered through a plug of silica gel and concentrated in vacuo to provide the title compound ( 4.g ) . The crude product was taken forward to the next step without further purification .

Synthesis of ethyl 5 - amino - 4 - cyano - 1H - pyrazole - 3 - carboxylate 555 NHANH , HO CN EIOH , RT $ ₂HN CN E ﻼﻌﻠﻣ LO A solution of ethyl 3,3 - dicyano - 2 - methoxy - prop - 2 - enoate ( 4.47 g , 24.81 mmol ) in EtOH ( mL ) was added to a solution of hydrazine monohydrate ( 1.2 mL , 24.81 mmol ) in EtOH ( 150 ) mL ) and the reaction was stirred at room temperature for 1.25 h . The resulting precipitate was collected by filtration , washed with cold EtOH , and dried to provide the crude product . The filtrate was concentrated in vacuo , and the residue was suspended in EtOAc and sonicated for 5 min . The resulting precipitate was collected by filtration , washed with EtOAc , and dried to provide a second batch of the crude product . The batches were combined to provide the title compound ( 2.38 g ) . 1H NMR ( 400 MHz , DMSO - ¸d } ₫ 12.68 ( s , 1H ) , 6.60 ( s , 2H ) , 4.27 ( q , J = 7.1 Hz , 2H ) , 1.28 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 6 ) : 1.21 min , 181.2 [ M + H ] + Synthesis of 5 - amino - 3- ( hydroxymethyl ) -1H - pyrazole - 4 - carbonitrile ₂HN LIBH , THE ₂HN CN RT to 60 ° C EON LIBH4 ( 2 M in THF ) ( 10.3 mL , 20.65 mmol ) was added slowly to a solution of ethyl 5 - amino- - cyano - 1H - pyrazole - 3 - carboxylate ( 1.5 g , 8.33 mmol ) in THF ( 21 mL ) and the reaction was heated at 60 ° C for 18 h . The reaction mixture was cooled to room temperature and diluted with MeOH . The mixture was stirred at room temperature for 1 h then concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 20 % MeOH in DCM ) to provide the title compound ( 863 mg ) . LCMS ( Method 6 ) : 0.16 min , 139.3 [ M + H ] + Synthesis of ethyl carboxylate - cyano - 2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- 556 HN ₂HN CN OH Eto Et EtOH , 75 ° C ON - Amino - 3- ( hydroxymethyl ) -1H - pylole - 4 - carbonitrile ( 863 mg , 6.25 mmol ) and ethyl ( E ) -4- ethoxy - 2 - oxo - but - 3 - enoate ( 1.61 g , 9.37 mmol ) were dissolved in EtOH ( 14.7 mL ) and the reaction was heated at 75 ° C in a microwave reactor for 2 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 736 mg ) .

' H NMR ( 400 MHz , CDCl3 ) Ō 8.82 ( d , J = 4.2 Hz , 1H ) , 7.51 ( d , J = 4.2 Hz , 1H ) , 5.09 ( s , 2H ) , 4.58 ( q , J = 7.2 Hz , 2H ) , 1.48 ( t , J = 7.1 Hz , 3H ) . Exchangeable proton not observed . LCMS ( Method 6 ) : 1.42 min ( split peak ) , 247.2 [ M + H ] + Synthesis of 3 - cyano - 2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid O₂H.HOiL THF , O₂H RT NO OH OH LiOH.H2O ( 51 mg , 1.22 mmol ) was added to a solution of ethyl 3 - cyano - 2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 251 mg , 1.02 mmol ) in THF ( 3.mL ) and water ( 860 Lµ ) and the reaction was stirred at room temperature for 18 h . The reaction mixture was acidified to pH 1 with 1 M aq . HCI and the resulting suspension was concentrated in vacuo to provide the title compound ( 260 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) § 8.73 ( d , J = 4.4 Hz , 1H ) , 7.17 ( d , J = 4.4 Hz , 1H ) , 5.74 ( s , 1H ) , 4.70 ( s , 2H ) . Additional exchangeable proton not observed . LCMS ( Method 6 ) : 1.02 min , 219.2 [ M + H ] + Synthesis of - cyano - 2- ( hydroxymethyl ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide HO OH ICH₂HN- EDC , HOBT EGN , DMF , RT ﻢﻠﻛﺓ ﻼﺤﻳاﺓ LO Cis - 3- ( trifluoromethoxy ) cyclobutanamine hydrochloride ( 226 mg , 1.18 mmol ) , HOBt ( 2mg , 1.97 mmol ) , EDC ( 377 mg , 1.97 mmol ) , and NзtE ( 549 Lμ , 3.94 mmol ) were added to a suspension of 3 - cyano - 2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 1mg , 0.66 mmol ) in DMF ( 2.6 mL ) and the reaction was stirred at room temperature for h . The reaction mixture was diluted with water and DCM and the layers were separated . The aqueous layer was extracted with DCM ( ´ 2 ) , and the combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 80 % EtOAc in heptane ) to provide the title compound ( 193 mg ) . ' H NMR ( 400 MHz , DMSO- d6 ) ō 9.77 ( d , J = 5.8 Hz , 1H ) , 8.95 ( d , J = 4.4 Hz , 1H ) , 7.66 ( d , J = 4.4 Hz , 1H ) , 5.85 ( t , J = 5.7 Hz , 1H ) , 4.82 ( d , J = 5.1 Hz , 2H ) , 4.77 - 4.63 ( m , 1H ) , 4.- - – 4.12 ( m , 1H ) , 2.91 – 2.80 ( m , 2H ) , 2.41 – 2.30 ( m , 2H ) LCMS ( Method 6 ) 1.79 min , 356.2 [ M + H ] + - Synthesis of compound 141 , 2- ( hydroxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ON HO .

Pd ( OAc ) 2 , PS - PPhEtOH , O₂H ° C amum ₂HN ON LO - mmol / g ) ( 114 mg , 0.- 3 - Cyano - 2- ( hydroxymethyl ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine- - carboxamide ( 188 mg , 0.53 mmol ) , acetaldehyde oxime ( 129 Lµ , 2.12 mmol ) , and PS- PPh 3 ( 1.4 0.23 mmol ) were suspended in EtOH ( 4 ) mL ) and water ( 880 Lµ ) and the mixture was degassed by sparging with a stream of argon for 10 min . Pd ( OAc ) 2 ( 18 mg , 0.08 mmol ) was added and the mixture was sparged with argon for a further 10 min . The reaction was heated at 90 ° C for 3.5 h . The reaction mixture was cooled to room temperature , diluted with DCM , and filtered through a short pad of ®etilaciD . The filtrate was concentrated in vacuo , and the crude product was purified by column chromatography ( eluting with 0 to 5 % MeOH in DCM ) to provide the title compound ( 145 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) г 10.11 ( d , J = 7.1 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.83 ( s , 2H ) , 7.66 ( d , J = 4.4 Hz , 1H ) , 5.88 ( t , J = 6.4 Hz , 1H ) , 4.95 ( d , J = 5.4 Hz , 2H ) , 4.70 ( p , J : 7.3 Hz , 1H ) , 4.28 - 4.14 ( m , 1H ) , 2.92 - 2.81 ( m , 2H ) , 2.47 - 2.35 ( m , 2H ) - LCMS ( Method 7 ) : 2.26 min , 374.2 [ M + H ] + = Synthesis of compound 202 , a ] pyrimidine - 3,7 - dicarboxamide N N = NH.OEt 2- ( ethoxymethyl ) -N7 - indan - 2 - yl - pyrazolo [ 1,5- 2- ( Ethoxymethyl ) -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 40 mg ) was synthesised following a similar procedure to that described in General Method F. 1H NMR ( 400 MHz , DMSO - d € ) ₫ 10.22 ( d , J = 6.9 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.69 ( d , J = 4.4 Hz , 1H ) , 7.68 ( s , 1H ) , 7.57 ( s , 1H ) , 7.29 – 7.26 ( m , 2H ) , 7.22 – 7.15 ( m , 2H ) , 4.96 ( s , - - 2H ) , 4.84 – 4.76 ( m , 1H ) , 3.55 ( q , J = 7.0 Hz , 2H ) , 3.41 ( dd , J = 16.2 , 7.4 Hz , 2H ) , 2.97 ( dd , J = 16.2 , 4.8 Hz , 2H ) , 1.11 ( t , J = 7.0 Hz , 3H ) LCMS ( Method 7 ) : 2.54 min , 380.0 [ M + H ] * Synthesis of compound 204 , a ] pyrimidine - 3,7 - dicarboxamide 2- ( hydroxymethyl ) -N7 - indan - 2 - yl - pyrazolo [ 1,5- 559 corge .OH NH 2- ( Hydroxymethyl ) -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 14 mg ) was synthesised following a similar procedure to that described in General Method F.

- ' H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.16 ( d , J = 7.1 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.84 ( s , 2H ) , 7.68 ( d , J = 4.4 Hz , 1H ) , 7.31 - 7.25 ( m , 2H ) , 7.21 – 7.16 ( m , 2H ) , 5.84 ( s , 1H ) , 4.85 ( s , 2H ) , 4.83 -4.75 ( m , 1H ) , 3.37 ( dd , J = 16.0 , 7.6 Hz , 2H ) , 3.02 ( dd , J = 16.0 , 5.8 Hz , 2H ) LCMS ( Method 7 ) : 2.27 min , 352.2 [ M + H ] * Synthesis of compound 205 , 2- ( ethoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N. F N : NH-OEt 2- ( Ethoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 75 mg ) was synthesised following a similar procedure to that described in General Method F. § 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.21 ( d , J = 7.4 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.78 - 7.55 ( m , 3H ) , 5.05 ( s , 2H ) , 4.77 – 4.68 ( m , 1H ) , 4.28 – 4.17 ( m , 1H ) , 3.67 ( q , J = 7.0 Hz , 2H ) , 2.97 – 2.87 ( m , 2H ) , 2.35 – 2.24 ( m , 2H ) , 1.19 ( t , J = 7.0 Hz , 3H ) LCMS ( Method 7 ) : 2.53 min , 402.2 [ M + H ] + Synthesis of ethyl - 4 - ethoxy - 2 - oxo - pent - 3 - enoate Eto . Erzie ( EtO3 ) CH , IC₁HN EtOH , RT OEt Eto .

Ethyl 2,4 - dioxopentanoate ( 2 g , 12.65 mmol ) , triethylorthoformate ( 2.52 mL , 15.18 mmol ) , and NH4Cl ( 203 mg , 3.79 mmol ) were suspended in EtOH ( 24 mL ) , and the reaction was 560 LO stirred at room temperature for 21 h then concentrated in vacuo . The residue was dissolved in TBME , and the resulting suspension was filtered and concentrated in vacuo . The crude product was purified by vacuum distillation at 17 mbar to provide the title compound ( 1.g ) . ' H NMR ( 400 MHz , CDCl3 ) г 6.21 ( s , 1H ) , 4.30 ( q , J = 7.1 Hz , 2H ) , 4.00 ( q , J = 7.0 Hz , 2H ) , 2.38 ( s , 3H ) , 1.39 ( t , J = 6.9 Hz , 3H ) , 1.35 ( t , J = 7.2 Hz , 3H ) LCMS ( Method 6 ) : 1.83 min , 187.2 [ M + H ] * Synthesis of compound 206 , 2- ( methoxymethyl ) -5 - methyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide easte ﻡاﺪﻣ N. N NH-OMe 2- ( Methoxymethyl ) -5 - methyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 68 mg ) was synthesised following a similar procedure to that described in General Method F. 1H NMR ( 400 MHz , DMSO - d6 ) 8 10.04 ( d , J = 7.3 Hz , 1H ) , 7.74 ( s , 1H ) , 7.54 ( s , 2H ) , 4.( s , 2H ) , 4.71 ( p , J = 7.2 Hz , 1H ) , 4.26 - 4.12 ( m , 1H ) , 3.42 ( s , 3H ) , 2.96 – 2.84 ( m , 2H ) , 2.( s , 3H ) , 2.34 – 2.24 ( m , 2H ) - LCMS ( Method 7 ) : 2.44 min , 402.2 [ M + H ] + Synthesis of compound 207 , N7- ( 3,3 - difluorocyclobutyl ) -2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide H .N . ' N ' N = NH.OH N7- ( 3,3 - difluorocyclobutyl ) -2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 73 mg ) was synthesised following a similar procedure to that described in General Method F. 561 LO - 1H NMR ( 400 MHz , DMSO - d ) § 10.22 ( d , J = 5.3 Hz , 1H ) , 8.94 ( d , J = 4.4 Hz , 1H ) , 7.84 ( s , 2H ) , 7.68 ( d , J = 4.4 Hz , 1H ) , 5.87 ( t , J = 6.6 Hz , 1H ) , 4.95 ( d , J = 6.6 Hz , 2H ) , 4.43 – 4.( m , 1H ) , 3.16 – 3.01 ( m , 2H ) , 2.93 – 2.75 ( m , 2H ) - LCMS ( Method 7 ) : 1.85 min , 326.2 [ M + H ] * Synthesis of compound 240 , N7- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) -5- methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide NHN = -OMe N7- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) -5 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 43 mg ) was synthesised following a similar procedure to that described in General Method F. - - 1H NMR ( 400 MHz , DMSO - d6 ) § 10.12 ( d , J = 7.5 Hz , 1H ) , 7.79 – 7.71 ( m , 1H ) , 7.61 ( s , 1H ) , 7.59 – 7.52 ( m , 1H ) , 4.97 ( s , 2H ) , 4.20 – 4.10 ( m , 1H ) , 3.41 ( s , 3H ) , 2.71 ( s , 3H ) , 2.14 – 1.( m , 6H ) , 1.80 – 1.65 ( m , 2H ) - LCMS ( Method 7 ) : 2.32 min , 382.2 [ M + H ] + Synthesis of compound 241 , N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2- ( methoxymethyl ) -5 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide Brai O = NHOMe N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2- ( methoxymethyl ) -5 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 51 mg ) was synthesised following a similar procedure to that described in General Method F. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.28 ( d , J = 8.3 Hz , 1H ) , 7.85 ( dd , J = 7.8 , 1.5 Hz , 1H ) , 7.76 ( dt , J = 7.8 , 1.0 Hz , 1H ) , 7.74 – 7.70 ( m , 1H ) , 7.68 ( td , J = 7.6 , 1.5 Hz , 1H ) , 7.61 ( td , J 562 = 7.7 , 1.3 Hz , 1H ) , 7.58 ( s , 1H ) , 7.56 – 7.50 ( m , 1H ) , 5.65 – 5.55 ( m , 1H ) , 4.92 ( s , 2H ) , 3.- - - - – 3.77 ( m , 1H ) , 3.75 – 3.64 ( m , 1H ) , 3.33 ( s , 3H ) , 2.71 ( s , 3H ) , 2.69 – 2.62 ( m , 1H ) , 2.61 – 2.52 ( m , 1H ) LCMS ( Method 7 ) : 1.99 min , 444.2 [ M + H ] * LO Synthesis of compound 242 , 2 - cyclopropyl - N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H- thiochromen - 4 - yl ) -5 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide NH 2 - Cyclopropyl - N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -5 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 119 mg ) was synthesised following a similar procedure to that described in General Method F. - 1H NMR ( 400 MHz , DMSO - d6 ) 8 10.08 ( d , J = 8.0 Hz , 1H ) , 7.87 ( dt , J = 7.7 , 1.0 Hz , 1H ) , 7.82 ( d , J = 3.0 Hz , 1H ) , 7.73 - 7.61 ( m , 3H ) , 7.49 ( s , 1H ) , 7.47 ( d , J = 2.9 Hz , 1H ) , 5.59 - 5.50 ( m , 1H ) , 3.85 – 3.74 ( m , 1H ) , 3.71 – 3.60 ( m , 1H ) , 3.19 – 3.08 ( m , 1H ) , 2.68 ( s , 3H ) , - - 2.67 - 2.52 ( m , 2H ) , 1.09 -0.95 ( m , 2H ) , 0.89 - 0.77 ( m , 2H ) LCMS ( Method 7 ) : 2.22 min , 440.2 [ M + H ] * - Synthesis of compound 142 , 2- ( cyclopropylmethoxy ) -N7 - indan - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( General Method G ) 563 IN .N . N cost ' N ' N Br IZ N N N .N . N. N ' N ' Br N NHN = Synthesis of 2- ( cyclopropylmethoxy ) -N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ąso N¸ . N : Br OH Pd2 ( dba ) , t - BuBrett Phos , KOH , 1,4 - Dioxane , 100 ° C N = Cyclopropylmethanol ( 8.40 mL , 103.66 mmol ) and KOH ( 94 mg , 1.68 mmol ) were added to a solution of 2 - bromo - N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 300 mg , 0.mmol ) in 1,4 - dioxane ( 8.4 mL ) and the solution was degassed by sparging with a stream of argon for 5 min . Pd2 ( dba ) 3 ( 39 mg , 0.04 mmol ) and t - BuBrettPhos ( 41 mg , 0.08 mmol ) were added , and the solution was degassed with argon for a further 5 min . The reaction was heated at 100 ° C for 16 h then cooled to room temperature , filtered through a short pad of silica , and concentrated in vacuo . The residue was azeotroped with toluene ( × 3 ) and the crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 191 mg ) . = 1H NMR ( 400 MHz , CDCl3 ) г 10.58 ( d , J = 7.6 Hz , 1H ) , 8.51 ( d , J = 4.4 Hz , 1H ) , 7.62 ( d , J 4.4 Hz , 1H ) , 7.31 – 7.24 ( m , 2H ) , 7.24 – 7.17 ( m , 2H ) , 6.10 ( s , 1H ) , 5.04 – 4.95 ( m , 1H ) , 3.( d , J = 7.2 Hz , 2H ) , 3.44 ( dd , J = 16.1 , 6.7 Hz , 2H ) , 3.01 ( dd , J = 16.1 , 3.8 Hz , 2H ) , 1.31 – 1.16 ( m , 1H ) , 0.71 – 0.58 ( m , 2H ) , 0.34 ( dt , J = 6.1 , 4.7 Hz , 2H ) - - 564 LO LCMS ( Method 7 ) : 3.25 min , 349.2 [ M + H ] * Synthesis of 3 - bromo - 2- ( cyclopropylmethoxy ) -N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide N NBS EtOH N ' N ' ° C to RT .Br N : N = NBS ( 117 mg , 0.65 mmol ) was added to a suspension of 2- ( cyclopropylmethoxy ) -N - indan- - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 190 mg , 0.55 mmol ) in EtOH ( 5.5 mL ) at 0 ° C and the reaction was stirred for 5 min . Additional EtOH ( 5.5 mL ) was added , and the reaction was warmed to room temperature and stirred for a further 10 min . The reaction was quenched with sat . aq . Na2S2O3 and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( × 4 ) . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 213 mg ) .

- - ' H NMR ( 400 MHz , CDCl3 ) б 10.32 ( d , J = 7.8 Hz , 1H ) , 8.61 ( d , J = 4.4 Hz , 1H ) , 7.68 ( d , J = 4.4 Hz , 1H ) , 7.31 – 7.27 ( m , 2H ) , 7.25 – 7.19 ( m , 2H ) , 5.05 – 4.97 ( m , 1H ) , 3.79 ( d , J = 7.Hz , 2H ) , 3.44 ( dd , J = 16.2 , 6.5 Hz , 2H ) , 2.99 ( dd , J = 16.2 , 3.0 Hz , 2H ) , 1.32 – 1.17 ( m , 1H ) , 0.70 0.59 ( m , 2H ) , 0.43 -0.31 ( m , 2H ) LCMS ( Method 7 ) : 3.48 min , 427.0 , 429.0 [ M + H ] * - Synthesis of compound 142 , 2- ( cyclopropylmethoxy ) -N7 - indan - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 565 ` N .Br N = H 1. XantPhos Pd GEt3N , NMP , 120 ° C 2. T3P , HO₂HN N₂tE , RT ' N ' NH N³tE ( 200 Lμ , 1.40 mmol ) was added to a vial containing a solution of 3 - bromo - 2- ( cyclopropylmethoxy ) -N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 200 mg , 0.mmol ) in NMP ( 4.7 mL ) . The vial was sealed , and the solution was degassed by sparging with a stream of argon for 5 min . XantPhos Pd G3 ( 45 mg , 0.05 mmol ) was added , and the solution was degassed with argon for a further 5 min . ( 2,5 - Dioxopyrrolidin - 1 - yl ) formate ( 3mg , 2.34 mmol ) was added and the vial was sealed immediately . The reaction was heated at 120 ° C in a microwave reactor for 2 h . Additional portions of XantPhos Pd G3 ( 45 mg , 0.05 mmol ) and NзtE ( 200 Lμ , 1.40 mmol ) were added , and the mixture was purged with argon for 5 min . An additional portion of ( 2,5 - dioxopyrrolidin - 1 - yl ) formate ( 335 mg , 2.mmol ) was added and the vial was sealed immediately . The reaction was heated at 120 ° C in a microwave reactor for a further 2 h . The reaction mixture was cooled to room temperature , and NзtE ( 200 Lμ , 1.40 mmol ) , NH4OH ( 610 Lμµ , 4.68 mmol ) and 1- propanephosphonic anhydride ( 50 wt % in DMF ) ( 560 Lμ , 0.94 mmol ) were added . The reaction was stirred at room temperature for 16 h then quenched with water . The resulting precipitate was collected by filtration , washed with water , and dried . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) and preparative HPLC ( basic method ) to provide the title compound ( 70 mg ) .

- - - ' H NMR ( 400 MHz , DMSO - d6 ) ō 9.87 ( d , J = 7.3 Hz , 1H ) , 8.78 ( d , J = 4.5 Hz , 1H ) , 7.( d , J = 4.5 Hz , 1H ) , 7.39 ( br . s , 1H ) , 7.32 – 7.24 ( m , 3H ) , 7.23 – 7.15 ( m , 2H ) , 4.84 . 4.( m , 1H ) , 3.96 ( d , J = 7.2 Hz , 2H ) , 3.35 ( dd , J = 16.1 , 6.8 Hz , 2H ) , 2.96 ( dd , J = 16.2 , 3.8 Hz , 2H ) , 1.35 – 1.20 ( m , 1H ) , 0.64 – 0.53 ( m , 2H ) , 0.40 – 0.32 ( m , 2H ) LCMS ( Method 7 ) : 2.61 min , 392.2 [ M + H ] + 566 Synthesis of compound 143 , 7- ( indan - 2 - ylcarbamoyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3 - carboxylic acid ( General Method H ) H .N . ' N ' .Br -OMe H XantPhos Pd G3 , Et N , MeOH 100 ° C ' N ' OH N = -OMe 3 - Bromo - N - indan - 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 1mg , 0.43 mmol ) , NзtE ( 180 Lµ , 1.29 mmol ) , and MeOH ( 3.5 mL ) were placed in a vial and the vial was sealed and purged with argon for 5 min . XantPhos Pd G3 ( 41 mg , 0.04 mmol ) was added and the mixture was purged with argon for a further 5 min . ( 2,5 - Dioxopyrrolidin- - yl ) formate ( 307 mg , 2.14 mmol ) was added and the reaction was heated at 100 ° C in a microwave reactor for 2 h . An additional portion of ( 2,5 - dioxopyrrolidin - 1 - yl ) formate ( 307 ) mg , 2.14 mmol ) was added and the reaction was heated at 100 ° C in a microwave reactor for a further 2 h . The reaction mixture was cooled to room temperature , diluted with water , and stirred for 2 h . The mixture was diluted with a 1 : 9 mixture of MeOH : DCM , filtered through a short pad of ®etilaciD , and washed with a 1 : 9 mixture of MeOH : DCM and water . The layers were separated , and the combined organic layers were washed with brine , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by preparative HPLC ( acidic method ) to provide the title compound ( 23 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) : 5 12.72 ( s , 1H ) , 10.20 ( d , J = 7.2 Hz , 1H ) , 8.89 ( d , J = 4.Hz , 1H ) , 7.65 ( d , J = 4.3 Hz , 1H ) , 7.29 ( dd , J = 5.4 , 3.2 Hz , 2H ) , 7.23 - 7.15 ( m , 2H ) , 4.( s , 2H ) , 4.82 – 4.75 ( m , 1H ) , 3.38 ( dd , J = 16.2 , 7.3 Hz , 2H ) , 3.29 ( s , 3H ) , 2.97 ( dd , J = 16.1 , 4.6 Hz , 2H ) - LCMS ( Method 7 ) : 2.41 min , 367.2 [ M + H ] + Synthesis of compound 144 , N7- ( 6 - bromochroman - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( General Method I ) 567 NBS DMF , 50 ° C auuuuuuuuuuuuuuuuuuu ₂HN Br oorge ₂HN LO NBS ( 19 mg , 0.14 mmol ) mmol ) was added to a solution solution of N7 - chroman - 3 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 50 mg , 0.13 mmol ) in DMF ( 700 Lµ ) and the reaction was heated at 50 ° C for 4 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by preparative HPLC ( basic method ) to provide the title compound ( 21 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) § 10.30 ( d , J = 7.4 Hz , 1H ) , 8.92 ( d , J = 4.4 Hz , 1H ) , 7.76 ( d , J = 4.4 Hz , 1H ) , 7.67 ( s , 1H ) , 7.58 ( s , 1H ) , 7.36 ( d , J = 2.5 Hz , 1H ) , 7.29 ( dd , J = 8.7 , 2.5 Hz , 1H ) , 6.83 ( d , J = 8.7 Hz , 1H ) , 4.87 - 4.74 ( m , 2H ) , 4.65 - 4.57 ( m , 1H ) , 4.26 ( d , J = 2.9 Hz , 2H ) , 3.29 3.24 ( m , 4H ) , 2.89 ( dd , J = 17.0 , 3.9 Hz , 1H ) - LCMS ( Method 7 ) : 2.48 min , 460.1 , 462.1 [ M + H ] * Synthesis of compound 145 , 2- ( methylamino ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( General Method J ) HO . -CN -CN N : F3C - N Br Br ' N ' ' N ' F3C- NHN : F3C - NHN : Br HN- Synthesis of - bromo - 3 - cyano - N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide 568 F F FX ■ NH2.HCI T3P , N₂tE DMF , RT HO .CN Br N ' N ' .CN N : Br 1 - Propanephosphonic anhydride ( 50 wt % in DMF ) ( 1.34 mL , 2.25 mmol ) was added to a solution of 2 - bromo - 3 - cyano - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 200 mg , 0.mmol ) , cis - 3- ( trifluoromethoxy ) cyclobutanamine hydrochloride ( 215 mg , 1.12 mmol ) , and NзtE ( 310 Lμ , 2.25 mmol ) in DMF ( 2.5 mL ) and the reaction was stirred at room temperature for 22 h . The reaction mixture was diluted with EtOAc and water , and the layers were separated . The aqueous layer was extracted with EtOAc ( × 3 ) , and the combined organic layers were washed with brine , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 80 % EtOAc in heptane ) to provide the title compound ( 225 mg ) .

- ' H NMR ( 400 MHz , CDCl3 ) б 9.82 ( d , J = 6.8 Hz , 1H ) , 8.95 ( d , J = 4.4 Hz , 1H ) , 8.03 ( d , J = 4.4 Hz , 1H ) , 4.63 – 4.50 ( m , 1H ) , 4.39 – 4.25 ( m , 1H ) , 3.12 – 2.96 ( m , 2H ) , 2.50 – 2.37 ( m , 2H ) - - LCMS ( Method 6 ) : 2.08 min , 402.0 , 404.0 [ M - H ] - Synthesis of 2 - bromo - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide H2SORT ' N ' .CN Br NHBr 2 - Bromo - 3 - cyano - N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide ( 118 mg , 0.29 mmol ) was dissolved in conc . H2SO4 ( 580 Lµ , 10.74 mmol ) and the reaction was stirred at room temperature for 2 h . The reaction mixture was cooled to ° C and ice - cold water was added . The mixture was basified with NH3 ( 28 – 30 wt % in water ) and the resulting precipitate was collected by filtration , washed with water and MeOH , and dried to provide the title compound ( 82 mg ) . 5 - 1H NMR ( 400 MHz , DMSO - d ) ☎ 9.60 ( d , J = 7.3 Hz , 1H ) , 8.93 ( d , J = 4.4 Hz , 1H ) , 7.68 ( s , 2H ) , 7.56 ( d , J = 4.4 Hz , 1H ) , 4.70 ( p , J = 7.1 Hz , 1H ) , 4.26 - 4.12 ( m , 1H ) , 2.96 - 2.80 ( m , 2H ) , 2.38 – 2.26 ( m , 2H ) LCMS ( Method 6 ) : 1.86 min , 422.0 , 424.0 [ M + H ] * LO Synthesis of compound 145 , 2- ( methylamino ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide MeNH2 , O₂uC ﻢﻟاء ' N ' Ethylene glycol Br NHTHF , 140 ° C ﺄﺣﺩ ' N ' NH 2 - Bromo - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide ( 110 mg , 0.26 mmol ) , O₂uC ( 4 mg , 0.03 mmol ) , and MeNH2 ( 2 M in THF ) ( 3.mL , 7.82 mmol ) were suspended in ethylene glycol ( 1 mL ) and the reaction was heated at 140 ° C in a microwave reactor for 1 h . The reaction mixture was cooled to room temperature , diluted with MeOH , and filtered through a short pad of ®etilaciD . The filtrate was concentrated in vacuo , and the crude product was purified by column chromatography ( eluting with 0 to 5 % MeOH in DCM ) to provide the title compound ( 22 mg ) . ' H NMR ( 400 MHz , CDCl3 ) ō 10.88 ( d , J = 7.0 Hz , 1H ) , 8.52 ( d , J = 4.6 Hz , 1H ) , 7.68 ( s , 1H ) , 7.63 ( d , J = 4.6 Hz , 1H ) , 6.93 ( s , 1H ) , 5.50 ( s , 1H ) , 4.54 ( p , J = 7.2 Hz , 1H ) , 4.37 – 4.22 ( m , 1H ) , 3.12 ( d , J = 2.9 Hz , 3H ) , 3.10 – 3.00 ( m , 2H ) , 2.38 – 2.26 ( m , 2H ) LCMS ( Method 7 ) : 2.64 min , 373.2 [ M + H ] * - Synthesis of compound 148 , 7- ( indan - 2 - ylcarbamothioyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3 - carboxamide ( General Method K ) N. ' N ' CN -CN -OMe Synthesis of carbothioamide -OMe ' N ' N = NH-OMe 3 - cyano - N - indan - 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- 570 1. O₂fT , pyridine DCM , 0 ° C to RT 2. ( NH4 ) 2S , RT H ' N CN N : -OMe .CN N = -OMe LO O₂fT ( 340 Lμ , 2.03 mmol ) was added to a solution of 3 - cyano - N - indan - 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 3mg , 0.mmol ) and pyridine ( 410 Lμ , 5.08 mmol ) in DCM ( 4 mL ) at 0 ° C . The reaction was stirred at ° C for 2 h then warmed to room temperature and stirred for 3.5 days . ( NH4 ) 2S ( 20 wt % in water ) ( 870 Lμ , 2.54 mmol ) was added , and the reaction was stirred for 1 h . The reaction mixture was diluted with DCM and water , and the layers were separated . The aqueous layer was extracted with DCM , and the combined organic layers were washed with water and brine , dried over Na2SO4 , and concentrated in vacuo to provide the title compound ( 329 mg ) . ' H NMR ( 400 MHz , CDCl3 ) г 12.45 ( s , 1H ) , 8.85 ( d , J = 4.6 Hz , 1H ) , 8.53 ( d , J = 4.6 Hz , 1H ) , 7.347.29 ( m , 2H ) , 7.27 – 7.22 ( m , 2H ) , 5.49 – 5.37 ( m , 1H ) , 4.61 ( s , 2H ) , 3.59 ( dd , J = 16.3 , 6.9 Hz , 2H ) , 3.42 ( s , 3H ) , 3.16 ( dd , J = 16.3 , 4.0 Hz , 2H ) LCMS ( Method 6 ) : 2.22 min , 364.2 [ M + H ] * Synthesis of compound 148 , 7- ( indan - 2 - ylcarbamothioyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3 - carboxamide N HON₂tE ° C N .CN ' N ° ₂HN N = N : -OMe OMe 3 - cyano - N - indan - 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carbothioamide ( 3mg , 0.70 mmol ) was dissolved in N , N - diethylhydroxylamine ( 6 mL , 58.36 mmol ) and the reaction was stirred at 35 ° C for 3 days . The reaction mixture was cooled to room temperature and diluted with water and EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc . The combined organic layers were washed with water ( × ) and brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was triturated with MeCN and dried to provide the title compound ( 82 mg ) . 571 LO - - ' H NMR ( 400 MHz , ³lCDC ) ₫ 13.12 ( s , 1H ) , 8.75 ( d , J = 4.6 Hz , 1H ) , 8.50 ( d , J = 4.6 Hz , 1H ) , 8.04 ( s , 1H ) , 7.30 ( dd , J = 5.4 , 3.3 Hz , 2H ) , 7.24 – 7.21 ( m , 2H ) , 5.59 ( s , 1H ) , 5.45 – 5.( m , 1H ) , 5.03 ( s , 2H ) , 3.62 ( dd , J = 16.3 , 7.2 Hz , 2H ) , 3.41 ( s , 3H ) , 3.21 ( dd , J = 16.3 , 4.Hz , 2H ) LCMS ( Method 7 ) : 2.77 min , 382.2 [ M + H ] * Synthesis of compound 149 , 3 - carbamothioyl - N - indan - 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( General Method L ) N HO . ' N ' -CN Synthesis carboxamide -OMe of ﻯ - ' N ' -CN -OMe corre N N = NH-OMe 3 - cyano - N - indan - 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- HO . CN N : -OMe -NH2.HCI T3P , DIPEA DMF , RT .CN .OMe 1 - Propanephosphonic anhydride ( 50 wt % in EtOAc ) ( 2.37 mL , 3.99 mmol ) was added to a solution of 3 - cyano - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 630 mg , 2.66 mmol ) , indan - 2 - amine hydrochloride ( 541 mg , 3.19 mmol ) , and DIPEA ( 930 Lµ , 5.mmol ) in DMF ( 5 mL ) , and the reaction was stirred at room temperature overnight . The reaction mixture was diluted with water , and the resulting precipitate was collected by filtration , washed with water , and dried to provide the title compound ( 890 mg ) . 1H NMR ( 400 MHz , CDCl3 ) б 10.28 ( d , J = 7.3 Hz , 1H ) , 8.91 ( d , J = 4.3 Hz , 1H ) , 8.04 ( d , J = 4.3 Hz , 1H ) , 7.33 – 7.20 ( m , 4H ) , 5.08 – 4.95 ( m , 1H ) , 4.69 ( s , 2H ) , 3.55 – 3.45 ( m , 5H ) , 3.( dd , J = 16.0 , 5.0 Hz , 2H ) LCMS ( Method 6 ) : 2.04 min , 348.2 [ M + H ] * 572 Synthesis of compound 149 , 3 - carbamothioyl - N - indan - 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide .N . ( NH4 ) 2S DMSO , RT H .N . .CN NHN = N : -OMe OMe ( NH4 ) 2S ( 20 wt % in water ) ( 490 Lμ , 1.44 mmol ) was added to a solution of 3 - cyano - N - indan- ( 100 mg , 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide 0.mmol ) in DMSO ( 3 mL ) and the reaction was stirred at room temperature for 24 h . An additional portion of ( NH4 ) 2S ( 20 wt % in water ) ( 490 Lµ , 1.44 mmol ) was added , and the reaction was stirred for a further 48 h . A third portion of ( NH4 ) 2S ( 20 wt % in water ) ( 490 Lµ , 1.44 mmol ) was added , followed by additional DMSO ( 1 mL ) , and the reaction was stirred for a further 5 h . The resulting precipitate was collected by filtration , washed with water and EtOAc , and dried to provide the title compound ( 27 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) ₫ 10.22 ( d , J = 7.0 Hz , 1H ) , 9.71 ( s , 1H ) , 9.57 ( s , 1H ) , 8.( d , J = 4.4 Hz , 1H ) , 7.72 ( d , J = 4.4 Hz , 1H ) , 7.33 – 7.24 ( m , 2H ) , 7.22 – 7.14 ( m , 2H ) , 5.- - - ( s , 2H ) , 4.86 – 4.75 ( m , 1H ) , 3.40 ( dd , J = 16.2 , 7.3 Hz , 2H ) , 3.33 ( s , 3H ) , 2.97 ( dd , J = 16.2 , 4.5 Hz , 2H ) LCMS ( Method 6 ) : 2.06 min , 382.2 [ M + H ] * Synthesis of compound 150 , 2 - cyclopropyl - N8- ( 4,4 - difluorocyclohexyl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide ( General Method M ) F F .NH.HH2CI F F N + HO N NHF NHN- F .N .

.N . NH OEt N- OEt OEt Br Synthesis of 3 - amino - N- ( 4,4 - difluorocyclohexyl ) pyridazine - 4 - carboxamide NH2.HCI EDC , HOBt N₂tE , DMF , RT HO N NHNH EDC ( 4.13 g , 21.57 mmol ) was added to a solution of 3 - aminopyridazine - 4 - carboxylic acid ( 1 g , 7.19 mmol ) , 4,4 - difluorocyclohexanamine hydrochloride ( 1.48 g , 8.63 mmol ) , N³tE ( 5.01 mL , 35.94 mmol ) , and HOBt ( 3.3 g , 21.57 mmol ) in DMF ( 9.5 mL ) , and the reaction was stirred at room temperature for 20 h . The reaction mixture was concentrated in vacuo , and the crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) and SCX chromatography ( eluting with 2 M NH3 in MeOH ) to provide the title compound ( 1.19 g ) . § 1H NMR ( 400 MHz , DMSO - d6 ) ō 8.64 ( d , J = 7.6 Hz , 1H ) , 8.60 ( d , J = 4.9 Hz , 1H ) , 7.( d , J = 4.9 Hz , 1H ) , 7.04 ( s , 2H ) , 4.02 – 3.90 ( m , 1H ) , 2.12 – 1.82 ( m , 6H ) , 1.67 – 1.55 ( m , 2H ) - LCMS ( Method 6 ) : 1.13 min , 257.2 [ M + H ] * Synthesis of ethyl 2 - bromo - 3 - cyclopropyl - 3 - oxo - propanoate - - NBS , p - O₂H.HOsT DCM , 0 ° C to RT OEt OEt Br NBS ( 2.39 g , 13.45 mmol ) and p - TsOH.H2O were added to a solution of ethyl 3 - cyclopropyl- - oxo - propanoate ( 1.89 mL , 12.81 mmol ) in DCM ( 50 mL ) at 0 ° C , and the reaction was stirred at 0 ° C for 10 min then warmed to room temperature and stirred for 18 h . The reaction mixture was diluted with DCM and washed with brine ( × 2 ) , and the organic layer was dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column . chromatography ( eluting with 0 to 10 % EtOAc in heptane ) to provide the title compound ( 2.84 g ) . - H¹ NMR ( 400 MHz , CDCl3 ) г 4.90 ( s , 1H ) , 4.30 ( q , J = 7.1 Hz , 2H ) , 2.34 – 2.27 ( m , 1H ) , 1.( t , J = 7.1 Hz , 3H ) , 1.20 – 1.16 ( m , 2H ) , 1.09 – 1.04 ( m , 2H ) - - 574 Synthesis of ethyl b ] pyridazine - 3 - carboxylate - cyclopropyl - 8 - [ ( 4,4 - difluorocyclohexyl ) carbamoyl ] imidazo [ 1,2- OEt Br Na2CO1,4 - Dioxane , 100 ° C N F. F. NHorge OEt 3 - Amino - N- ( 4,4 - difluorocyclohexyl ) pyridazine - 4 - carboxamide ( 600 mg , 2.34 mmol ) , ethyl 2- bromo - 3 - cyclopropyl - 3 - oxo - propanoate ( 826 mg , 3.51 mmol ) , and Na2CO3 ( 744 mg , 7.mmol ) were dissolved in 1,4 - dioxane ( 9.5 mL ) , and the reaction was heated at 100 ° C for h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 40 % EtOAc in heptane ) to provide the title compound ( 117 mg ) . - - - 1H NMR ( 400 MHz , 3№CDC ) б 9.97 ( d , J = 7.6 Hz , 1H ) , 8.67 ( d , J = 4.7 Hz , 1H ) , 7.97 ( d , J = 4.7 Hz , 1H ) , 4.53 ( q , J = 7.1 Hz , 2H ) , 4.24 – 4.18 ( m , 1H ) , 2.95 – 2.87 ( m , 1H ) , 2.15 – 1.( m , 6H ) , 1.84 1.76 ( m , 2H ) , 1.47 ( t , J = 7.1 Hz , 3H ) , 1.24 – 1.17 ( m , 2H ) , 1.17 – 1.11 ( m , 2H ) - LCMS ( Method 6 ) : 2.21 min , 393.2 [ M + H ] * - - Synthesis of compound 150 , 2 - cyclopropyl - N8- ( 4,4 - difluorocyclohexyl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide sosge NH3 , MeOH RT OEt xorge NH Ethyl - cyclopropyl - 8 - [ ( 4,4 - difluorocyclohexyl ) carbamoyl ] imidazo [ 1,2 - b ] pyridazine - 3- carboxylate ( 117 mg , 0.27 mmol ) was dissolved in NH3 ( 7 M in MeOH ) ( 3.83 mL , 26.mmol ) and the reaction was stirred at room temperature for 64 h . The reaction mixture was concentrated in vacuo , and the crude product was purified by column chromatography 575 ( eluting with 0 to 4 % MeOH in DCM ) and preparative HPLC ( basic method ) to provide the title compound ( 39 mg ) . - - 1H NMR ( 400 MHz , DMSO - d6 ) ō 9.76 ( d , J = 7.5 Hz , 1H ) , 8.83 ( d , J = 4.8 Hz , 1H ) , 8.23 ( s , 1H ) , 8.00 ( s , 1H ) , 7.87 ( d , J = 4.8 Hz , 1H ) , 4.17 – 4.08 ( m , 1H ) , 3.26 – 3.15 ( m , 1H ) , 2.10 - 1.94 ( m , 6H ) , 1.74 – 1.64 ( m , 2H ) , 1.19 - 1.11 ( m , 2H ) , 1.07 -0.99 ( m , 2H ) LCMS ( Method 7 ) : 2.51 min , 364.2 [ M + H ] + Synthesis of compound 151 , - cyclopropyl - N8- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide sorge ₂HN 2 - Cyclopropyl - N8- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide ( 24 mg ) was synthesised following a similar procedure to that described in General Method M. ' H NMR ( 400 MHz , DMSO - d ) ☎ 9.81 ( d , J = 7.5 Hz , 1H ) , 8.82 ( d , J = 4.8 Hz , 1H ) , 8.22 ( s , 1H ) , 7.99 ( s , 1H ) , 7.82 ( d , J = 4.8 Hz , 1H ) , 4.72 ( p , J = 7.1 Hz , 1H ) , 4.24 – 4.13 ( m , 1H ) , 3.- - - - - – 3.17 ( m , 1H ) , 2.96 – 2.86 ( m , 2H ) , 2.31 – 2.19 ( m , 2H ) , 1.19 – 1.08 ( m , 4H ) LCMS ( Method 4 ) : 2.41 min , 384.0 [ M + H ] * Synthesis of compound 208 , - cyclopropyl - N8- ( 5,6 - dihydro - 4H- cyclopenta [ c ] thiophen - 5 - yl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide sorge NH 2 - Cyclopropyl - N8- ( 5,6 - dihydro - 4H - cyclopenta [ c ] thiophen - 5 - yl ) imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide ( 25 mg ) was synthesised following a similar procedure to that described in General Method M. 576 LO ' H NMR ( 400 MHz , DMSO - d6 ) г 10.06 ( d , J = 7.5 Hz , 1H ) , 8.82 ( d , J = 4.8 Hz , 1H ) , 8.20 ( s , - - 1H ) , 7.95 ( s , 1H ) , 7.87 ( d , J = 4.8 Hz , 1H ) , 7.14 ( s , 2H ) , 5.02 – 4.93 ( m , 1H ) , 3.20 – 3.09 ( m , 3H ) , 2.68 ( dd , J = 15.7 , 4.6 Hz , 2H ) , 1.09 – 1.00 ( m , 2H ) , 0.91 – 0.82 ( m , 2H ) LCMS ( Method 7 ) : 2.54 min , 368.2 [ M + H ] * Synthesis of compound 209 , 2 - cyclopropyl - N8- ( 3,3 - difluoroindan - 1 - yl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide N.

Esqu NH 2 - Cyclopropyl - N8- ( 3,3 - difluoroindan - 1 - yl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide ( mg ) was synthesised following a similar procedure to that described in General Method M. ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.15 ( d , J = 7.3 Hz , 1H ) , 8.85 ( d , J = 4.8 Hz , 1H ) , 8.21 ( s , 1H ) , 7.97 ( s , 1H ) , 7.91 ( d , J = 4.8 Hz , 1H ) , 7.73 – 7.54 ( m , 4H ) , 5.71 – 5.62 ( m , 1H ) , 3.28 – 3.07 ( m , 2H ) , 2.67 – 2.54 ( m , 1H ) , 1.04 – 0.95 ( m , 2H ) , 0.86 – 0.79 ( m , 2H ) - - LCMS ( Method 7 ) : 2.65 min , 398.2 [ M + H ] * - Synthesis of compound 210 , N8- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2 - cyclopropyl- imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide - arge NH N8- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2 - cyclopropyl - imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide ( 10 mg ) was synthesised following a similar procedure to that described in General Method M. - 1H NMR ( 400 MHz , DMSO - d6 ) à 10.28 ( d , J = 6.5 Hz , 1H ) , 8.85 ( d , J = 4.8 Hz , 1H ) , 8.22 ( s , 1H ) , 7.97 ( s , 1H ) , 7.90 ( d , J = 4.8 Hz , 1H ) , 7.41 – 7.21 ( m , 4H ) , 5.52 – 5.46 ( m , 1H ) , 3.( dd , J = 14.3 , 4.9 Hz , 1H ) , 3.19 – 3.08 ( m , 2H ) , 1.09 – 0.97 ( m , 2H ) , 0.96 – 0.81 ( m , 2H ) LCMS ( Method 7 ) : 2.63 min , 348.2 [ M + H ] + 577 2 - cyclopropyl - N8 - [ ( 4S ) -7 - fluorochroman - 4- Synthesis of compound 211 , yl ] imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide Brze NH 2 - Cyclopropyl - N8 - [ ( 4S ) -7 - fluorochroman - 4 - yl ] imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide ( 35 mg ) was synthesised following a similar procedure to that described in General Method M. 1H NMR ( 400 MHz , DMSO - d ) б 10.06 ( d , J = 7.4 Hz , 1H ) , 8.85 ( d , J = 4.8 Hz , 1H ) , 8.21 ( s , 1H ) , 7.98 ( s , 1H ) , 7.90 ( d , J = 4.8 Hz , 1H ) , 7.39 ( dd , J = 8.5 , 6.7 Hz , 1H ) , 6.84 – 6.69 ( m , 2H ) , 5.27 – 5.18 ( m , 1H ) , 4.45 – 4.34 ( m , 1H ) , 4.24 – 4.14 ( m , 1H ) , 3.16 – 3.08 ( m , 1H ) , 2.- - – 2.24 ( m , 1H ) , 2.13 – 2.05 ( m , 1H ) , 1.09 – 0.95 ( m , 2H ) , 0.86 – 0.70 ( m , 2H ) LCMS ( Method 7 ) : 2.68 min , 396.2 [ M + H ] * Synthesis of compound 156 , 7 - cyclopropyl - N4- ( 4,4 - difluorocyclohexyl ) pyrazolo [ 5,1- c ] [ 1,2,4 ] triazine - 4,8 - dicarboxamide ( General Method N ) .NH.HH2CI OEt H N. OEt N N ' N ' NHN = F F Synthesis of ethyl 2 - [ ( 4,4 - difluorocyclohexyl ) amino ] -2 - oxo - acetate PPh NHHN N -CN N H ' N ' -CN N = ICH.₂HN N₂tE , DCM ° C to RT F OEt CI H N. OEt Dila N³tE ( 6.6 mL , 47.6 mmol ) and ethyl 2 - chloro - 2 - oxo - acetate ( 2.7 mL , 23.8 mmol ) were added sequentially to a suspension of 4,4 - difluorocyclohexanamine hydrochloride ( 3.4 g , 19.mmol ) in DCM ( 30 mL ) at 0 ° C and the reaction was warmed to room temperature and stirred for 20 h . The reaction was quenched with sat . aq . NH4Cl and diluted with DCM . The layers were separated , and the aqueous layer was extracted with DCM . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 3.65 g ) . 1H NMR ( 400 MHz , CDCl3 ) г 7.02 ( s , 1H ) , 4.35 ( q , J = 7.1 Hz , 2H ) , 3.99 – 3.84 ( m , 1H ) , 2.- - - 1.77 ( m , 6H ) , 1.70 – 1.59 ( m , 2H ) , 1.39 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 6 ) : 0.98 min , 236.2 [ M + H ] * Synthesis of phosphanylidene ) propenamide OEt N- ( 4,4 - difluorocyclohexyl ) -2 - oxo - 3- ( triphenyl - A5- n - BuLi , rB₂HCP₂hP PPh3 THF , -78 ° C F. n - BuLi ( 2.5 M in hexanes ) ( 6.8 mL , 16.90 mmol ) was added dropwise to a suspension of methyl ( triphenyl ) phosphonium bromide ( 6 g , 16.90 mmol ) in THF ( 15 mL ) at -78 ° C and the mixture was stirred at -78 ° C for 30 min . A solution of ethyl 2 - [ ( 4,4- difluorocyclohexyl ) amino ] -2 - oxo - acetate ( 1.6 g , 6.80 mmol ) in THF ( 15 mL ) was added dropwise , and the reaction was stirred at 87− ° C for a further 45 min . The reaction was quenched with water and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc . The combined organic layers were dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 907 mg ) . 579 LO ' H NMR ( 400 MHz , DMSO - d ) § 8.05 ( d , J = 8.3 Hz , 1H ) , 7.71 – 7.56 ( m , 15H ) , 4.74 ( d , - - - - == J 25.0 Hz , 1H ) , 3.77 – 3.65 ( m , 1H ) , 2.01 – 1.94 ( m , 2H ) , 1.95 – 1.81 ( m , 2H ) , 1.79 – 1.72 ( m , 2H ) , 1.63 – 1.50 ( m , 2H ) - LCMS ( Method 6 ) : 1.20 min , 466.2 [ M + H ] * Synthesis of 8 - cyano - 7 - cyclopropyl - N- ( 4,4 - difluorocyclohexyl ) pyrazolo [ 5,1 - c ] [ 1,2,4 ] triazine- - carboxamide NHisoamyl nitrite PPh.CN HN AcOH , MeCN RT ' N ' .CN N = N = Isoamyl nitrite ( 350 Lµ , 2.61 mmol ) was added to a suspension of N- ( 4,4 - difluorocyclohexyl ) - - oxo - 3- ( triphenyl - 5 - phosphanylidene ) propanamide ( 1.3 g , 2.70 mmol ) and 5 - amino - 3- cyclopropyl - 1H - pyrazole - 4 - carbonitrile ( 200 mg , 1.40 mmol ) in MeCN ( 10 mL ) and AcOH ( 230 Lμ , 4.1 mmol ) , and the reaction was stirred at room temperature for 2 h . The reaction mixture was concentrated in vacuo , and the crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 80 mg ) . - 1H NMR ( 400 MHz , CDCl3 ) § 9.71 ( s , 1H ) , 9.56 ( d , J = 7.7 Hz , 1H ) , 4.28 – 4.17 ( m , 1H ) , 2.( tt , J = 8.3 , 4.9 Hz , 1H ) , 2.22 - 2.12 ( m , 4H ) , 2.02 – 1.94 ( m , 2H ) , 1.81 – 1.72 ( m , 2H ) , 1.– 1.41 ( m , 2H ) , 1.33 – 1.26 ( m , 2H ) LCMS ( Method 6 ) : 1.26 min , 347.2 [ M + H ] + Synthesis of compound 156 , 7 - cyclopropyl - N4- ( 4,4 - difluorocyclohexyl ) pyrazolo [ 5,1- c ] [ 1,2,4 ] triazine - 4,8 - dicarboxamide HO .

H Pd ( OAc ) 2 , PS - PPhEtOH , O₂H , 80 ° C .N . ' N ' -CN NH 8 - Cyano - 7 - cyclopropyl - N- ( 4,4 - difluorocyclohexyl ) pyrazolo [ 5,1 - c ] [ 1,2,4 ] triazine - 4- carboxamide ( 80 mg , 0.22 mmol ) , acetaldehyde oxime ( 70 Lμ , 1.10 mmol ) , Pd ( OAc ) 2 ( 9.580 mg , 0.04 mmol ) , and PS - PPh3 ( 3 mmol / g ) ( 20 mg , 0.06 mmol ) were suspended in EtOH ( 8Lμ ) and water ( 200 Lµ ) , and the reaction was heated at 80 ° C for 2 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) and triturated with a 1 : mixture of DMSO : water to provide the title compound ( 13 mg ) . ' H NMR ( 400 MHz , DMSO - d ) § 9.41 ( d , J = 7.3 Hz , 1H ) , 9.37 ( s , 1H ) , 7.89 ( s , 1H ) , 7.85 ( s , - - - - 1H ) , 4.17 – 4.10 ( m , 1H ) , 3.30 – 3.25 ( m , 1H ) , 2.13 – 1.94 ( m , 6H ) , 1.78 – 1.65 ( m , 2H ) , 1.- 1.22 ( m , 2H ) , 1.15 – 1.05 ( m , 2H ) - LCMS ( Method 7 ) : 2.38 min , 365.2 [ M + H ] + Synthesis of compound 157 , 2- ( trideuteriomethoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( General Method O ) EtO .

-OH EtO . ' N ' CD HO . EtO -Br ' N ' -Br N = CD NHF3CO OC₂F CD CD N -Br Synthesis of ethyl 2- ( trideuteriomethoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate NaH , CD3l Eto . ' N ' .OH DMF ° C to RT EtO .

D D CD NaH ( 109 mg , 2.71 mmol ) and trideuterio ( iodo ) methane ( 675 Lµ , 10.85 mmol ) were added to a solution of ethyl 2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 400 mg , 1.81 mmol ) in DMF ( 18 mL ) at 0 ° C . The reaction was warmed to room temperature and stirred for 18 h . The reaction mixture was diluted with EtOAc and water , and the layers were 581 separated . The aqueous layer was acidified with 1 M aq . HCI and extracted with EtOAc . The combined organic layers were washed with sat . aq . LiCl , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) to provide the title compound ( 183 mg ) . ' H NMR ( 400 MHz , CDCl3 ) б 8.57 – 8.49 ( m , 1H ) , 7.30 – 7.22 ( m , 1H ) , 6.89 – 6.84 ( m , 1H ) , 4.75 ( s , 2H ) , 4.53 ( q , J = 7.2 Hz , 2H ) , 1.44 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 6 ) : 1.55 min , 239.2 [ M + H ] * Synthesis of ethyl 3 - bromo - 2- ( trideuteriomethoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxylate EtO ' N ' DD NBS MeCN , RT Eto . Br -D D D Ethyl 2- ( trideuteriomethoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 180 mg , 0.15 mmol ) and NBS ( 135 mg , 0.76 mmol ) were dissolved in MeCN ( 4 mL ) and the reaction was stirred at room temperature for 16 h . The reaction mixture was concentrated in vacuo and dissolved in DCM . The solution was washed with water , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 5 % MeOH in DCM ) to provide the title compound ( 247 mg ) .

' H NMR ( 400 MHz , ³lCDC ) б 8.63 ( d , J = 4.1 Hz , 1H ) , 7.33 ( d , J = 4.1 Hz , 1H ) , 4.76 ( d , J : 0.7 Hz , 2H ) , 4.55 ( q , J = 7.1 Hz , 2H ) , 1.45 ( t , J = 7.1 Hz , 3H ) LCMS ( Method 6 ) : 1.77 min , 317.2 , 319.2 [ M + H ] * = Synthesis of 3 - bromo - 2- ( trideuteriomethoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid Eto ' N ' Br O₂H.HOiL THF , O₂H , RT HO Br D D D D LO A solution of O₂H.HOiL ( 39 mg , 0.93 mmol ) in water ( 1 mL ) was added dropwise to a solution of ethyl 3 - bromo - 2- ( trideuteriomethoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 2mg , 0.77 mmol ) in THF ( 2 mL ) and the reaction was stirred at room temperature for 2 h . The reaction mixture was concentrated in vacuo , diluted with EtOAc , and acidified to pH 4 with Maq . HCI . The layers were separated , and the organic layer was washed with brine , dried over Na2SO4 , and concentrated in vacuo to provide the title compound ( 200 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 8.74 ( d , J = 4.2 Hz , 1H ) , 7.48 ( d , J = 4.2 Hz , 1H ) , 4.61 ( s , 2H ) . Exchangeable proton not observed . LCMS ( Method 6 ) : 1.34 min , 289.2 , 291.2 [ M + H ] * Synthesis of - bromo - 2- ( trideuteriomethoxymethyl ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide F F ■ NH2.HCI HO . ' N ' Br EDC , HOBt N₂tE , DMF , RT .Br -D D D Cis - 3- ( trifluoromethoxy ) cyclobutanamine hydrochloride ( 133 mg , 0.69 mmol ) , HOBt ( 1mg , 1.04 mmol ) , EDC ( 199 mg , 1.04 mmol ) , and NзtE ( 290 Lµ , 2.08 mmol ) were added to a solution of 3 - bromo - 2- ( trideuteriomethoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 100 mg , 0.35 mmol ) in DMF ( 2 mL ) , and the reaction was stirred at room temperature for 16 h then diluted with EtOAc . The reaction mixture was washed with brine , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) to provide the title compound ( 1mg ) . = 1H NMR ( 400 MHz , CDCl3 ) б 10.47 ( d , J = 6.9 Hz , 1H ) , 8.74 ( d , J = 4.2 Hz , 1H ) , 7.83 ( d , J 4.2 Hz , 1H ) , 4.77 ( s , 2H ) , 4.59 – 4.47 ( m , 1H ) , 4.33 - 4.24 ( m , 1H ) , 3.07 - 2.99 ( m , 2H ) , 2.– 2.36 ( m , 2H ) - LCMS ( Method 6 ) : 2.12 min , 426.0 , 428.0 [ M + H ] * Synthesis of compound ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 157 , 2- ( trideuteriomethoxymethyl ) -N7- [ cis - 3- 583 .Br 1. XantPhos Pd GCO ( g ) , Et , N NMP , 120 ° C 2. T3P , NH4OH , RT D D NH DD 3 - Bromo - 2- ( trideuteriomethoxymethyl ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide ( 120 mg , 0.28 mmol ) , XantPhos Pd G3 ( 27 mg , 0.03 mmol ) , N- hydroxysuccinimide ( 49 mg , 0.42 mmol ) , and NзtE ( 118 Lμ , 0.84 mmol ) were dissolved in NMP ( 2 mL ) and the solution was degassed by sparging with a stream of argon for 30 min . The reaction vial was sealed , evacuated , and backfilled with argon ( × 3 ) , then evacuated and backfilled with carbon monoxide ( × 3 ) . The reaction was heated at 120 ° C in a microwave reactor for 4 h then cooled to room temperature . The reaction mixture was degassed with argon , then 1 - propanephosphonic anhydride ( 50 wt % in EtOAc ) ( 503 Lµ , 0.mmol ) and NH4OH ( 332 Lμ , 2.82 mmol ) were added . The reaction was stirred at room temperature for 24 h , then diluted with EtOAc and washed with brine . The organic layer was dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) and preparative HPLC ( acidic method ) to provide the title compound ( 15 mg ) .

- - ' H NMR ( 400 MHz , DMSO - d6 ) ō 10.05 ( d , J = 7.4 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.68 ( s , 1H ) , 7.62 ( d , J = 4.4 Hz , 1H ) , 7.59 ( s , 1H ) , 4.99 ( s , 2H ) , 4.77 – 4.66 ( m , 1H ) , 4.28 – 4.13 ( m , 1H ) , 2.96 – 2.85 ( m , 2H ) , 2.36 – 2.25 ( m , 2H ) LCMS ( Method 7 ) : 2.39 min , 391.2 [ M + H ] * Synthesis of compound 160 , N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( trideuteriomethoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide .N . N cosse ₂HN 584 N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( trideuteriomethoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( 7mg ) was synthesised following a similar procedure to that described in General Method O. ' H NMR ( 400 MHz , DMSO - бd ) Ō 10.21 ( d , J = 7.0 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 8.35 ( dd , J = 5.0 , 1.6 Hz , 1H ) , 7.73 – 7.65 ( m , 3H ) , 7.60 – 7.55 ( m , 1H ) , 7.19 ( dd , J = 7.6 , 4.9 Hz , 1H ) , 4.92 ( s , 2H ) , 4.90 – 4.78 ( m , 1H ) , 3.45 ( dd , J = 16.8 , 7.6 Hz , 2H ) , 3.01 ( dd , J = 16.7 , 4.5 Hz , 2H ) - LCMS ( Method 7 ) : 1.37 min , 370.2 [ M + H ] + Synthesis of compound 158 , 2- ( fluoromethoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( General Method P ) ﮦﺩ - ﻢﺤﻣﺩ ﺱﺩ OMe Meori OMe MeO OMe F .S .

N N Br N ' -Br N = F3CO NE F3CO -OH Synthesis of fluoromethylsulfanylbenzene CSF , PEG - 2CI MeCN , 80 ° C 585 Chloromethylsulfanylbenzene ( 5 mL , 38.80 mmol ) and CSF ( 11.78 g , 77.50 mmol ) were suspended in MeCN ( 15 mL ) and PEG - 200 ( 5 mL , 38.80 mmol ) and the reaction was heated at 80 ° C for 3 h . The reaction mixture was cooled to room temperature and diluted with O₂tE and water . The layers were separated , and the organic layer was washed with water ( × 4 ) and brine , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % DCM in heptane ) to provide the title compound ( 2.9 g ) . ' H NMR ( 400 MHz , CDCl3 ) ō 7.51 - 7.48 ( m , 2H ) , 7.36 – 7.30 ( m , 3H ) , 5.73 ( d , J = 52.8 Hz , 2H ) Synthesis of dimethyl 2 - diazopropanedioate wollow lok N₂tE , MeCN ° C to RT MeO OMe to a solution of N- ( 4- Dimethyl malonate ( 2 mL , 17.56 mmol ) was added to azidosulfonylphenyl ) acetamide ( 5 g , 20.81 mmol ) and NзtE ( 4.9 mL , 35.12 mmol ) in MeCN ( 50 mL ) at 0 ° C . The reaction was warmed to room temperature and stirred for 18 h . The reaction mixture was diluted with Et2O , filtered , and concentrated in vacuo . The crude product was triturated with heptane to provide the title compound ( 2.3 g ) . 1H NMR ( 400 MHz , CDCl3 ) O 3.84 ( s , 6H ) Synthesis of dimethyl 2- [ fluoromethyl ( phenyl ) -4 - sulfanylidene ] propanedioate MeO ₂N OMe ₂hR ( esp ) 2 , DCM , 40 ° C MeO OMe F 586 LO A solution of dimethyl 2 - diazopropanedioate ( 2.35 g , 14.86 mmol ) in DCM ( 30 mL ) was added to a solution of fluoromethylsulfanylbenzene ( 2.11 ₁g 14.86 mmol ) and bis [ rhodium ( a , a , a ' , a ' - tetramethyl - 1,3 - benzenedipropionic acid ) ] ( 15 mg , 0.02 mmol ) in DCM ( 50 mL ) . The reaction was heated at 40 ° C for 23 h , then cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 2.9 g ) . 1H NMR ( 400 MHz , CDCl3 ) б 7.68 – 7.60 ( m , 2H ) , 7.60 – 7.42 ( m , 3H ) , 6.41 ( dd , J = 50.5 , 7.Hz , 1H ) , 5.86 ( dd , J = 45.3 , 7.6 Hz , 1H ) , 3.71 ( s , 6H ) LCMS ( Method 3 ) 0.93 min , 273.2 [ M + H ] + Synthesis of - bromo - 2- ( fluoromethoxymethyl ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide OMe MeO ﻞﻠﻫ N H N. NaH , DMF , RT ' N ' Br ' N Br F. N = -OH NaH ( 60 wt % in mineral oil ) ( 87 mg , 2.18 mmol ) was added to a solution of 3 - bromo - 2- ( hydroxymethyl ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide ( 445 mg , 1.09 mmol ) in DMF ( 10 mL ) and the mixture was stirred at room temperature for 30 min . Dimethyl 2- [ fluoromethyl ( phenyl ) -4 - sulfanylidene ] propanedioate ( 296 mg , 1.09 mmol ) was added and the reaction was stirred at room temperature for 18 h . The reaction mixture was diluted with EtOAc and water , and the layers were separated . The organic layer was washed with water ( × 3 ) and brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 200 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) 0 10.41 ( d , J = 6.9 Hz , 1H ) , 8.76 ( d , J = 4.2 Hz , 1H ) , 7.86 ( d , J = 4.2 Hz , 1H ) , 5.54 ( s , 1H ) , 5.42 ( d , J = 14.2 Hz , 1H ) , 5.10 ( d , J = 1.7 Hz , 2H ) , 4.59 – 4.- - ( m , 1H ) , 4.38 – 4.23 ( m , 1H ) , 3.09 — 2.97 ( m , 2H ) , 2.46 – 2.34 ( m , 2H ) - LCMS ( Method 7 ) : 3.03 min , 441.0 , 443.0 [ M + H ] + 587 Synthesis of compound 158 , 2- ( fluoromethoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide F ﻡا ﺄﻣ rosa -Br N = H 1. XantPhos Pd GEt , N , NMP , 90 ° C 2. T3P , NH OH , RT ﻡا ﺃﺭ ' N ' NHN = 3 - Bromo - 2- ( fluoromethoxymethyl ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide ( 100 mg , 0.23 mmol ) and XantPhos Pd G3 ( 22 mg , 0.02 mmol ) were placed in a vial and the vial was sealed and purged with argon for 5 min . NMP ( mL ) and NзtE ( 95 Lµ , 0.68 mmol ) were added and the solution was degassed by sparging with a stream of argon for 5 min . ( 2,5 - Dioxopyrrolidin - 1 - yl ) formate ( 162 mg , 1.13 mmol ) was added and the vial was sealed immediately . The reaction was heated at 90 ° C in a microwave reactor for 2 h . Additional portions of XantPhos Pd G3 ( 22 mg , 0.01 mmol ) and NзtE ( 95 Lμ , 0.68 mmol ) were added and the mixture was purged with argon for 5 min . An additional portion of ( 2,5 - dioxopyrrolidin - 1 - yl ) formate ( 162 mg , 1.13 mmol ) was added and the vial was sealed immediately . The reaction was heated at 90 ° C in a microwave reactor for a further 2 h . The reaction mixture was cooled to room temperature , and NH4OH ( 2Lμ , 2.97 mmol ) and 1 - propanephosphonic anhydride ( 50 wt % in DMF ) ( 240 Lμ , 0.mmol ) were added . The reaction was stirred at room temperature for 18 h then quenched with water . The resulting precipitate was collected by filtration , washed with water , and dried . The crude product was purified by column chromatography ( eluting with 0 to 3 % MeOH in DCM ) to provide the title compound ( 29 mg ) . - - 1H NMR ( 400 MHz , DMSO - d € ) ☎ 9.98 ( d , J = 7.4 Hz , 1H ) , 8.94 ( d , J = 4.3 Hz , 1H ) , 7.70 - 7.62 ( m , 3H ) , 5.52 ( d , J = 56.5 Hz , 2H ) , 5.33 ( d , J = 1.9 Hz , 2H ) , 4.77 – 4.65 ( m , 1H ) , 4.28 – 4.13 ( m , 1H ) , 2.95 – 2.83 ( m , 2H ) , 2.38 – 2.28 ( m , 2H ) - - LCMS ( Method 7 ) : 2.53 min , 406.1 [ M + H ] * Synthesis of compound 159 , N7 - indan - 2 - yl - 2- ( methylamino ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( General Method Q ) 588 N -CN N N = NHN = NHBr Br —NH Synthesis of 2 - bromo - N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide HO .

N cosg N = Br .CN H Pd ( OAc ) 2 , PS - PPhEtOH , O₂H , 90 ° C ' N ' NHBr 2 - Bromo - 3 - cyano - N - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 200 mg , 0.mmol ) , acetaldehyde oxime ( 128 Lμ , 2.09 mmol ) , and PS - ³hPP ( 1.4 - 2 mmol / g ) ( 113 mg , 0.16 0.23 mmol ) were suspended in EtOH ( 4.1 mL ) and water ( 870 Lµ ) , and the mixture was sparged with argon for 10 min . Pd ( OAc ) 2 ( 18 mg , 0.08 mmol ) was added , and the suspension was sparged with argon for a further 10 min . The reaction was heated at 90 ° C in a microwave reactor for 3 h , then cooled to room temperature , diluted with DCM , and filtered through a short pad of ®etilaciD . The filtrate was concentrated in vacuo , and the crude product was purified by column chromatography ( eluting with 0 to 5 % MeOH in DCM ) to provide the title compound ( 86 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) ☎ 9.62 ( d , J = 7.1 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 7.67 ( d , J = 5.9 Hz , 2H ) , 7.57 ( d , J = 4.4 Hz , 1H ) , 7.32 – 7.25 ( m , 2H ) , 7.22 – 7.15 ( m , 2H ) , 4.82 – 4.= - - ( m , 1H ) , 3.38 ( dd , J = 16.0 , 7.7 Hz , 2H ) , 2.96 ( dd , J = 16.1 , 5.1 Hz , 2H ) LCMS ( Method 6 ) : 1.88 min , 400.0 , 402.0 [ M + H ] * - Synthesis of compound 159 , N7 - indan - 2 - yl - 2- ( methylamino ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide MeNH2 , O₂uC THF , ethylene glycol 140 ° C ' N ' NHBr corge N ° NHN- 2 - Bromo - N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 83 mg , 0.mmol ) , Cu2O ( 3 mg , 0.02 mmol ) , and MeNH2 ( 2 M in THF ) ( 3.1 mL , 6.22 mmol ) were suspended in ethylene glycol ( 830 Lµ ) and the reaction was heated at 140 ° C in a microwave reactor for 1 h . The reaction mixture was cooled to room temperature , filtered through a short pad of ®etilaciD and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 5 % MeOH in DCM ) then triturated with Et2O to provide the title compound ( 17 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) 5 10.64 ( d , J = 7.6 Hz , 1H ) , 8.63 ( d , J = 4.7 Hz , 1H ) , 7.49 ( d , J = 4.7 Hz , 1H ) , 7.37 ( s , 1H ) , 7.33 – 7.26 ( m , 3H ) , 7.21 – 7.15 ( m , 2H ) , 6.92 ( q , J = 5.0 Hz , - - 1H ) , 4.87 - 4.76 ( m , 1H ) , 3.36 ( dd , J = 16.1 , 6.5 Hz , 2H ) , 2.95 ( dd , J = 16.1 , 3.3 Hz , 2H ) , 2.58 ( d , J 5.0 Hz , 3H ) = LCMS ( Method 7 ) : 2.64 min , 351.2 [ M + H ] + Synthesis of compound 161 , 2- ( methoxymethyl ) -N3 - methyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( General Method R ) ﻡ ﻻﺄﻣ F DH -OMe 1. XantPhos Pd GCO ( g ) , Et , N NMP , 120 ° C 2. T3P , eM₂HN , RT ' N ' N : Br 3 - Bromo - 2- ( methoxymethyl ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide ( 120 mg , 0.28 mmol ) , XantPhos Pd G3 ( 22 mg , 0.03 mmol ) , N- hydroxysuccinimide ( 41 mg , 0.35 mmol ) , and NзtE ( 99 Lµ , 0.71 mmol ) were dissolved in NMP ( 2 mL ) , and the solution was degassed by sparging with a stream of argon for 30 min . The reaction vial was sealed , evacuated and backfilled with argon ( × 3 ) , then evacuated and backfilled with carbon monoxide ( × 3 ) . The reaction was heated at 120 ° C in a microwave reactor for 4 h then cooled to room temperature . The reaction mixture was degassed with argon , then 1 - propanephosphonic anhydride ( 50 wt % in EtOAc ) ( 422 Lµ , 0.71 mmol ) and NH2Me ( 2 M in THF ) ( 1.18 mL , 2.36 mmol ) were added . The reaction was stirred at room temperature for 24 h , then diluted with EtOAc and washed with brine . The organic layer was H -OMe dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) and preparative HPLC ( acidic method ) to provide the title compound ( 29 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.04 ( d , J = 7.4 Hz , 1H ) , 8.91 ( d , J = 4.4 Hz , 1H ) , 8.12 - 8.06 ( m , 1H ) , 7.62 ( d , J = 4.3 Hz , 1H ) , 4.99 ( s , 2H ) , 4.77 – 4.66 ( m , 1H ) , 4.27 – 4.13 ( m , 1H ) , 3.42 ( s , 3H ) , 2.96 – 2.85 ( m , 5H ) , 2.36 – 2.25 ( m , 2H ) - LCMS ( Method 7 ) : 2.53 min , 402.2 [ M + H ] * Synthesis of compound 162 , 2- ( cyclopropylmethoxy ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( General Method S ) N. ' N ' HO N N = F3CO - F3CO Br Br N ' N ' ' N ' Br NHF3CO F3CO Synthesis of 2 - bromo - N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide HO ' N ' N = Br ■ ICH.₂HN EDC , HOBt , N₂tE DMF , 0 ° C to RT 20Br NзtE ( 3.46 mL , 24.79 mmol ) was added to a solution of 2 - bromopyrazolo [ 1,5 - a ] pyrimidine- - carboxylic acid ( 1 g , 4.13 mmol ) , cis - 3- ( trifluoromethoxy ) cyclobutanamine hydrochloride ( 950 mg , 4.96 mmol ) , HOBt ( 2.37 g , 12.4 mmol ) , and EDC ( 2.38 g , 12.4 mmol ) in DMF ( mL ) at 0 ° C and the reaction was stirred at 0 ° C for 5 min then warmed to room temperature 591 and stirred for 16 h . The reaction mixture was diluted with EtOAc and washed with 5 % aq . LICI ( 3 ) and brine . The organic layer was dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 40 % EtOAc in heptane ) to provide the title compound ( 1.44 g ) . ' H NMR ( 400 MHz , CDCl3 ) Ŏ 10.30 ( br . d , J = 6.5 Hz , 1H ) , 8.68 ( d , J = 4.3 Hz , 1H ) , 7.- - ( d , J = 4.3 Hz , 1H ) , 6.93 ( s , 1H ) , 4.53 ( p , J = 7.2 Hz , 1H ) , 4.37 – 4.23 ( m , 1H ) , 3.10 – 2.( m , 2H ) , 2.48 2.36 ( m , 2H ) - LCMS ( Method 7 ) : 3.07 min , 379.0 , 381.0 [ M + H ] * Synthesis of 2- ( cyclopropylmethoxy ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide 20N = Br OH Pd2 ( dba ) 3 , t - BuBrettPhos KOH , 1,4 - Dioxane 100 ° C H ' N ' Cyclopropylmethanol ( 26.4 mL , 325.53 mmol ) and KOH ( 296 mg , 5.28 mmol ) were added to a solution of 2 - bromo - N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide ( 1 g , 2.64 mmol ) in 1,4 - dioxane ( 26.4 mL ) and the solution was degassed by sparging with a stream of argon for 10 min . Pd2 ( dba ) 3 ( 121 mg , 0.13 mmol ) and t- BuBrett Phos ( 128 mg , 0.26 mmol ) were added , and the solution was degassed with argon for a further 10 min . The reaction was heated at 100 ° C for 16 h then cooled to room temperature , filtered through a pad of silica gel , and concentrated in vacuo . The residue was azeotroped with toluene ( × 3 ) , and the crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 4mg ) . 1H NMR ( 400 MHz , CDCl3 ) : 5 10.58 ( br . d , J = 7.1 Hz , 1H ) , 8.55 ( d , J = 4.4 Hz , 1H ) , 7.( d , J = 4.4 Hz , 1H ) , 6.20 ( s , 1H ) , 4.53 ( p , J = 7.2 Hz , 1H ) , 4.40 - 4.26 ( m , 1H ) , 4.15 ( d , J = - - - - 7.2 Hz , 2H ) , 3.11 – 2.99 ( m , 2H ) , 2.42 – 2.30 ( m , 2H ) , 1.49 – 1.35 ( m , 1H ) , 0.78 – 0.65 ( m , 2H ) , 0.52 – 0.43 ( m , 2H ) LCMS ( Method 7 ) : 3.19 min , 371.2 [ M + H ] + 592 Synthesis of - bromo - 2- ( cyclopropylmethoxy ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide N H N. NBS N. EtOH , RT ' N ' Br N : NBS ( 277 mg , 1.56 mmol ) was added to a suspension of 2- ( cyclopropylmethoxy ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 480 mg , 1.30 mmol ) in EtOH ( 26 mL ) at 0 ° C and the reaction was stirred for 5 min then warmed to room temperature and stirred for a further 10 min . The reaction was quenched with sat . aq . Na2S2O3 and diluted with EtOAc . The layers were separated , and the aqueous layer was extracted with EtOAc ( × 4 ) . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 40 % EtOAc in heptane ) to provide the title compound ( 5mg ) . - - 1H NMR ( 400 MHz , CDCI ) : 5 10.32 ( d , J = 7.2 Hz , 1H ) , 8.63 ( d , J = 4.4 Hz , 1H ) , 7.65 ( d , J = 4.4 Hz , 1H ) , 4.55 ( p , J = 7.1 Hz , 1H ) , 4.40 - 4.26 ( m , 3H ) , 3.12 – 3.00 ( m , 2H ) , 2.34 – 2.( m , 2H ) , 1.54 - 1.39 ( m , 1H ) , 0.80 – 0.67 ( m , 2H ) , 0.52 – 0.44 ( m , 2H ) LCMS ( Method 7 ) : 3.40 min , 449.0 , 451.0 [ M + H ] * - Synthesis of compound 162 . 2- ( cyclopropylmethoxy ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 593 N N. ` N Br N = H 1. XantPhos Pd GN¸tE , NMP , 120 ° C 2. T3P , Et3N N. HO₂HN , RT F. ' N ' N = NH NзtE ( 470 Lμ , 3.34 mmol ) was added to a vial containing a solution of 3 - bromo - 2- ( cyclopropylmethoxy ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide ( 500 mg , 1.11 mmol ) in NMP ( 11 mL ) . The vial was sealed , and the solution was degassed by sparging with a stream of argon for 10 min . XantPhos Pd G3 ( 106 mg , 0.11 mmol ) was added , and the solution was degassed with argon for a further 10 min . ( 2,5- Dioxopyrrolidin - 1 - yl ) formate ( 796 mg , 5.57 mmol ) was added , and the vial was sealed immediately . The reaction was heated at 120 ° C in a microwave reactor for 2 h . Additional portions of XantPhos Pd G3 ( 106 mg , 0.11 mmol ) and NзtE ( 470 Lμ , 3.34 mmol ) were added , and the mixture was purged with argon for 5 min . An additional portion of ( 2,5- dioxopyrrolidin - 1 - yl ) formate ( 398 mg , 2.78 mmol ) was added and the vial was sealed immediately . The reaction was heated at 120 ° C in a microwave reactor for a further 1 h . The reaction mixture was cooled to room temperature , and NзtE ( 470 Lµ , 3.34 mmol ) , NH4OH ( 1.44 mL , 11.1 mmol ) and 1 - propanephosphonic anhydride ( 50 wt % in DMF ) ( 1.mL , 2.23 mmol ) were added . The reaction was stirred at room temperature for 72 h , then quenched with water . The resulting precipitate was collected by filtration , washed with water , and purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) to provide the title compound ( 280 mg ) . 1H NMR ( 400 MHz , DMSO - d6 ) : 59.74 ( br . s , 1H ) , 8.78 ( d , J = 4.5 Hz , 1H ) , 7.47 ( d , J = 4.Hz , 1H ) , 7.42 ( br . s , 1H ) , 7.32 ( br . s , 1H ) , 4.70 ( p , J = 7.1 Hz , 1H ) , 4.30 ( d , J = 7.2 Hz , 2H ) , - - - - - 4.25 4.14 ( m , 1H ) , 2.95 – 2.84 ( m , 2H ) , 2.37 – 2.25 ( m , 2H ) , 1.50 – 1.36 ( m , 1H ) , 0.65 – 0.55 ( m , 2H ) , 0.45-0.37 ( m , 2H ) LCMS ( Method 7 ) : 2.61 min , 414.2 [ M + H ] + Synthesis of compound 212 , N4- ( 4,4 - difluorocyclohexyl ) -6- ( methoxymethyl ) imidazo [ 2,1 - f ] [ 1,2,4 ] triazine - 4,7 - dicarboxamide ( General Method S ) 594 Synthesis of 4 - chloro - 6 - hydrazino - pyrimidin - 5 - amine N CI NHNH , NH , H , O THF , RT CI NHNHCI Hydrazine monohydrate ( 8.13 mL , 167.69 mmol ) was added to a solution of 4,6- dichloropyrimidin - 5 - amine ( 5 g , 30.49 mmol ) in THF ( 20 mL ) and the reaction was stirred at room temperature for 20 h . The resulting precipitate was collected by filtration , washed with i - PrOH , and dried to provide the title compound ( 4.33 g ) . ' H NMR ( 400 MHz , DMSO - d ) § 8.06 ( s , 1H ) , 7.79 ( s , 1H ) , 5.04 ( s , 2H ) , 4.42 ( s , 2H ) Synthesis of 5 - chloro - 1,2 - dihydropyrimido [ 5,4 - e ] [ 1,2,4 ] triazine N HCI , ( EtO ) , CH CI CI RT NHNH' N ' NH ` N H Concentrated HCI ( 500 Lµ , 16.46 mmol ) was added slowly to a suspension of 4 - chloro - 6- hydrazino - pyrimidin - 5 - amine ( 1 g , 6.27 mmol ) in triethylorthoformate ( 11 mL , 66.06 mmol ) and the reaction was stirred at room temperature for 1 h . The resulting precipitate was collected by filtration , washed with acetone , and dried to provide the title compound ( 8mg ) . 1H NMR ( 400 MHz , DMSO - d ) § 9.11 ( s , 1H ) , 8.01 ( s , 1H ) , 7.40 ( s , 1H ) , 6.21 ( s , 1H ) LCMS ( Method 6 ) : 0.77 min , 170.2 [ M + H ] * Synthesis of 5 - methoxypyrimido [ 5,4 - e ] [ 1,2,4 ] triazine CI O₂gA , MeOH RT OMe NH NH N = N 595 LO Silver oxide ( 2.73 g , 11.79 mmol ) and 5 - chloro - 1,2 - dihydropyrimido [ 5,4 - e ] [ 1,2,4 ] triazine ( g , 5.90 mmol ) were suspended in MeOH ( 160 mL ) and the reaction was stirred at room temperature for 66 h . The reaction mixture was filtered through a short pad of ⓇetilaciD layered with silica gel and washed with EtOAc . The filtrate was concentrated in vacuo , and the crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 296 mg ) . 1H NMR ( 400 MHz , MeOD ) 5 10.20 ( s , 1H ) , 9.13 ( s , 1H ) , 4.34 ( s , 3H ) LCMS ( Method 6 ) : 0.63 min , 164.2 [ M + H ] * Synthesis of methyl 6 - amino - 1,2,4 - triazine - 5 - carboxylate OMe HCI , MeOH RT N = N MeO . N NH 1 M aq . HCI ( 2.5 mL , 69.04 mmol ) was added to a solution of 5 - methoxypyrimido [ 5,4 - e ] [ 1,2,4 ] triazine ( 292 mg , 1.79 mmol ) in MeOH ( 10 mL ) . The reaction was stirred at room temperature for 20 h then concentrated in vacuo . Water was added to the residue , and the mixture was basified to pH 8 with sat . aq . NaHCO3 and diluted with DCM . The layers were separated , and the aqueous layer was extracted with DCM ( × 3 ) . The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo to provide the title compound ( 250 mg ) .

' H NMR ( 400 MHz , DMSO - d ) § 9.17 ( s , 1H ) , 7.55 ( s , 2H ) , 3.91 ( s , 3H ) LCMS ( Method 6 ) : 0.57 min , 155.3 [ M + H ] * Synthesis of 6 - amino - N- ( 4,4 - difluorocyclohexyl ) -1,2,4 - triazine - 5 - carboxamide N₂tE , lA₂eM NH2.HCI Toluene , THF RT MeO N NH HN N NH2 LO NзtE ( 830 Lμ , 5.98 mmol ) and lAзeM ( trimethylaluminium ; 2 M in toluene ) ( 4.98 mL , 9.mmol ) were added sequentially to a suspension of 4,4 - difluorocyclohexanamine hydrochloride ( 941 mg , 5.48 mmol ) in THF ( 10 mL ) , and the reaction was stirred at room temperature for 30 min . A solution of methyl 6 - amino - 1,2,4 - triazine - 5 - carboxylate ( 768 mg , 4.98 mmol ) in THF ( 15 mL ) was added dropwise and the reaction was stirred at room temperature for 5.5 h . The reaction mixture was poured into 10 % aq . Rochelle salt and the mixture was stirred for 10 min then diluted with DCM . The layers were separated , and the aqueous layer was extracted with DCM . The combined organic layers were washed with brine , dried through a hydrophobic frit , and filtered through a short pad of silica gel . The filtrate was concentrated in vacuo to provide the title compound ( 972 mg ) . ' H NMR ( 400 MHz , DMSO - d ) Ŏ 9.20 – 8.98 ( m , 2H ) , 7.70 ( s , 2H ) , 4.05 – 3.89 ( m , 1H ) , 2.– 1.65 ( m , 8H ) - LCMS ( Method 6 ) : 1.57 min , 258.2 [ M + H ] * Synthesis of methyl 2 - chloro - 4 - methoxy - 3 - oxo - butanoate MelloMe ₂lC₂OS , DCM RT MeO OMe CI Sulfuryl chloride ( 1.2 mL , 14.80 mmol ) was added slowly to a solution of methyl 4 - methoxy- - oxo - butanoate ( 1.77 mL , 13.69 mmol ) in DCM ( 20 mL ) and the reaction was stirred at room temperature for 21 h . The reaction mixture was concentrated in vacuo , and the crude product was purified by column chromatography ( eluting with 0 to 50 % EtOAc in heptane ) to provide the title compound ( 1.75 g ) . 1H NMR ( 400 MHz , ³ICDC ) б 5.06 ( s , 1H ) , 4.28 ( d , J = 1.5 Hz , 2H ) , 3.84 ( s , 3H ) , 3.43 ( s , 3H ) Synthesis of methyl 4 - [ ( 4,4 - difluorocyclohexyl ) carbamoyl ] -6- ( methoxymethyl ) imidazo [ 2,1- f ] [ 1,2,4 ] triazine - 7 - carboxylate F. .N . N NHMeO wallow CI OMe NaBr , H , O DMF , 100 ° C OMe -OMe NaBr ( 132 mg , 1.28 mmol ) and water ( 130 Lμ , 7.34 mmol ) were added to a solution of 6- amino - N- ( 4,4 - difluorocyclohexyl ) -1,2,4 - triazine - 5 - carboxamide ( 472 mg , 1.83 mmol ) and methyl 2 - chloro - 4 - methoxy - 3 - oxo - butanoate ( 663 mg , 3.67 mmol ) in DMF ( 6 mL ) , and the reaction was heated at 100 ° C for 4 h . An additional portion of methyl 2 - chloro - 4- methoxy - 3 - oxo - butanoate ( 331 mg , 1.83 mmol ) was added , and the reaction was heated at 100 ° C for a further 1 h . The reaction mixture was cooled to room temperature , quenched with water , and extracted with EtOAc ( x 3 ) . The combined organic layers were washed with brine , dried through a hydrophobic frit , and concentrated in vacuo . The crude product was purified twice by column chromatography ( eluting first with 20 to 100 % EtOAc in DCM and then with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 43 mg ) as the impure product . The product was taken forward to the next step without further purification . 1H NMR ( 400 MHz , CDCl3 ) б 9.60 ( d , J = 7.6 Hz , 1H ) , 9.22 ( s , 1H ) , 4.99 ( s , 2H ) , 4.36 – 4.( m , 1H ) , 4.08 ( s , 3H ) , 3.55 ( s , 3H ) , 2.23 – 1.80 ( m , 8H ) LCMS ( Method 6 ) : 1.66 min , 384.2 [ M + H ] + - Synthesis of compound 212 , N4- ( 4,4 - difluorocyclohexyl ) -6- ( methoxymethyl ) imidazo [ 2,1- f ] [ 1,2,4 ] triazine - 4,7 - dicarboxamide orac OMe -OMe NH3 , MeOH RT NH-OMe Methyl 4 - [ ( 4,4 - difluorocyclohexyl ) carbamoyl ] -6- ( methoxymethyl ) imidazo [ 2,1- f ] [ 1,2,4 ] triazine - 7 - carboxylate ( 42 mg , 0.11 mmol ) was dissolved in NH3 ( 7 M in MeOH ) ( 1.mL , 10.96 mmol ) , and the reaction was stirred at room temperature for 22 h then concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 10 % MeOH in DCM ) then triturated with heptane to provide the title compound ( 10 mg ) . ' H NMR ( 400 MHz , DMSO - d6 ) ō 9.26 ( d , J = 6.2 Hz , 2H ) , 8.25 ( s , 1H ) , 8.09 ( s , 1H ) , 4.92 ( s , 2H ) , 4.17 - 4.05 ( m , 1H ) , 3.38 ( s , 3H ) , 2.14 – 1.90 ( m , 6H ) , 1.76 – 1.64 ( m , 2H ) - - LCMS ( Method 7 ) : 1.83 min , 369.2 [ M + H ] * Synthesis of compound 213 , N7- ( 3,3 - difluorocyclobutyl ) -2- ( 1 - hydroxy - 1 - methyl- ethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( General Method T ) 598 Synthesis of 3 - amino - 5- ( 1 - hydroxy - 1 - methyl - ethyl ) -1H - pyrazole - 4 - carbonitrile MeMgBr O₂tE , THF NH2 NH.CN ° C to RT CN HN * + HN N : EtO N = .OH MeMgBr ( methyl magnesium bromide ; 3 M in O₂tE ) ( 15 mL , 45 mmol ) was added dropwise to a solution of ethyl 3 - amino - 4 - cyano - 1H - pyrazole - 5 - carboxylate ( 1.5 g , 8.33 mmol ) in THF ( 25 mL ) at 0 ° C . The reaction was warmed to room temperature and stirred for 17 h , then the mixture was poured into sat . aq . NH4Cl . The layers were separated , and the aqueous layer was extracted with EtOAc ( x 3 ) . The combined organic layers were washed with brine ( x 2 ) and the resulting emulsion was filtered through a short pad of ®etilaciD . The layers were separated , and the organic layer was dried through a hydrophobic frit and concentrated in vacuo to provide the title compound ( 733 mg ) . The crude product was taken forward to the next step without purification . LCMS ( Method 7 ) : 1.08 min , 165.2 [ M - H ] - Synthesis of ethyl 3 - cyano - 2- ( 1 - hydroxy - 1 - methyl - ethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxylate OEt Eto NHCN HN EtOH , 80 ° C Eto . NE .OH ' N ' _CN -OH 3 - Amino - 5- ( 1 - hydroxy - 1 - methyl - ethyl ) -1H - pyrazole - 4 - carbonitrile ( 733 mg , 4.41 mmol ) was added to a solution of ethyl ( E ) -4 - ethoxy - 2 - oxo - but - 3 - enoate ( 1.5 g , 8.71 mmol ) in EtOH ( mL ) and the reaction was heated at 80 ° C for 4 h . The reaction mixture was cooled to room temperature and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 35 % EtOAc in DCM ) to provide the title compound ( 4mg ) . 599 LO 1H NMR ( 400 MHz , DMSO - d6 ) § 8.92 ( d , J = 4.3 Hz , 1H ) , 7.70 ( d , J = 4.3 Hz , 1H ) , 4.49 ( q , J = 7.1 Hz , 2H ) , 1.58 ( s , 6H ) , 1.37 ( t , J = 7.1 Hz , 3H ) . Exchangeable proton not observed . LCMS ( Method 7 ) : 2.04 min , 275.2 [ M + H ] * Synthesis of 3 - cyano - 2- ( 1 - hydroxy - 1 - methyl - ethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid Eto ` N ' .CN O₂H.HOiL THF , O₂H RT HO N === .OH + N ` ´N .CN N : .OH LiOH.H2O ( 92 mg , 2.20 mmol ) was added to a solution of ethyl 3 - cyano - 2- ( 1 - hydroxy - 1- methyl - ethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylate ( 498 mg , 1.81 mmol ) in THF ( 4 mL ) and water ( 1 mL ) , and the reaction was stirred at room temperature for 3 h . The reaction mixture was acidified with 1 M aq . HCI , and the layers were separated . The aqueous layer was extracted with DCM ( x 2 ) , and the combined organic layers were concentrated in vacuo to provide the title compound ( 280 mg ) . The crude product was taken forward to the next step without purification . 1H NMR ( 400 MHz , DMSO - d6 ) : 5 8.88 ( d , J = 4.3 Hz , 1H ) , 7.59 ( d , J = 4.3 Hz , 1H ) , 1.58 ( s , 6H ) . Exchangeable protons not observed . LCMS ( Method 7 ) : 1.26 min , 247.2 [ M + H ] + Synthesis of 3 - cyano - N- ( 3,3 - difluorocyclobutyl ) -2- ( 1 - hydroxy - 1 - methyl - ethyl ) pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide HO . ' N ' .CN OH ☑ -NH2.HCI EDC , HOBt , N₂tE DMF , RT sosa ' N ' N : .CN OH 600 LO 3,3 - Difluorocyclobutanamine hydrochloride ( 294 mg , 2.05 mmol ) , HOBt ( 461 mg , 3.mmol ) , EDC ( 654 mg , 3.41 mmol ) , and NзtE ( 950 Lµ , 6.82 mmol ) were added to a solution of 3 - cyano - 2- ( 1 - hydroxy - 1 - methyl - ethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 2mg , 1.14 mmol ) in DMF ( 3.5 mL ) , and the reaction was stirred at room temperature for 3 h . The reaction mixture was diluted with water and EtOAc and the layers were separated . The aqueous layer was extracted with EtOAc ( x 2 ) , and the combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title . compound ( 287 mg ) .

- - ' H NMR ( 400 MHz , DMSO - d6 ) : 5 9.97 ( d , J = 6.6 Hz , 1H ) , 8.95 ( d , J = 4.3 Hz , 1H ) , 7.73 - 7.68 ( m , 1H ) , 4.43 – 4.31 ( m , 1H ) , 3.29 ( s , 1H ) , 3.20 – 3.04 ( m , 2H ) , 2.79 – 2.65 ( m , 2H ) , 1.62 ( s , 6H ) . LCMS ( Method 7 ) : 2.23 min , 336.2 [ M + H ] + Synthesis of compound 213 . N7- ( 3,3 - difluorocyclobutyl ) -2- ( 1 - hydroxy - 1 - methyl- ethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N .N . ' N ' .CN F N = OH HO Pd ( OAc ) 2 , PS - PPhEtOH , O₂H , 90 ° C H .N . N : NH.OH 3 - Cyano - N- ( 3,3 - difluorocyclobutyl ) -2- ( 1 - hydroxy - 1 - methyl - ethyl ) pyrazolo [ 1,5 - a ] pyrimidine- - carboxamide ( 287 mg , 0.86 mmol ) , acetaldehyde oxime ( 200 mg , 3.39 mmol ) , Pd ( OAc ) ( 20 mg , 0.09 mmol ) , and PS - ³hPP ( 1.4 - 2 mmol / g ) ( 175 mg , 0.25 - 0.35 mmol ) were suspended in EtOH ( 2 mL ) and water ( 400 Lµ ) and the reaction was heated at 90 ° C for h . The reaction mixture was cooled to room temperature and filtered through a short pad of ®etilaciD . The ⓇetilaciD was slurried with a 1 : 1 mixture of MeOH : DCM , filtered , and washed with a further 1 : 1 mixture of MeOH : DCM . The filtrate was concentrated in vacuo , and the crude product was purified by preparative HPLC ( acidic method ) to provide the title compound ( 66 mg ) . 601 LO 1H NMR ( 400 MHz , DMSO - éd ) § 10.16 ( d , J = 6.6 Hz , 1H ) , 8.96 ( d , J = 4.4 Hz , 1H ) , 8.31 ( d , J = 2.7 Hz , 1H ) , 8.14 ( d , J = 2.4 Hz , 1H ) , 7.71 ( d , J = 4.4 Hz , 1H ) , 7.56 ( s , 1H ) , 4.45 - 4.- ( m , 1H ) , 3.22 – 3.07 ( m , 2H ) , 2.80 – 2.62 ( m , 2H ) , 1.60 ( s , 6H ) - LCMS ( Method 7 ) : 2.23 min , 354.2 [ M + H ] + Synthesis of compound 214 , N7 - indan - 2 - yl - 2- ( methylsulfanylmethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ( General Method U ) Synthesis of methanesulfonate [ 3 - carbamoyl - 7- ( indan - 2 - ylcarbamoyl ) pyrazolo [ 1,5 - a ] pyrimidin - 2 - yl ] methyl .N . MsCI , N₂tE DCM , 0 ° C to RT ' N ' N : NH-OH NH-OMs MSCI ( methanesulfonyl chloride ; 10 Lμ , 0.13 mmol ) was added dropwise to a solution of 2- ( hydroxymethyl ) -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 41 mg , 0.mmol ) and NзtE ( 24 Lμ , 0.17 mmol ) in DCM ( 3 mL ) at 0 ° C . The reaction was stirred at 0 ° C for 10 min , then warmed to room temperature and stirred for 18 h . The reaction mixture was cooled to 0 ° C and additional portions of Et3N ( 48 Lµ , 0.34 mmol ) and MsCI ( 20 Lμ , 0.mmol ) were added . The reaction was stirred at 0 ° C for 10 min , then warmed to room temperature and stirred for a further 4 h . The reaction mixture was diluted with DCM and washed with sat . aq . Na2CO3 . The aqueous layer was extracted with DCM , and the combined organic layers were washed with brine , dried over Na2SO4 , and concentrated in vacuo to provide the title compound ( 49 mg ) . The crude product was taken forward to the next step without purification . = 1H NMR ( 400 MHz , ³lCDC ) г 10.42 ( d , J = 7.0 Hz , 1H ) , 8.84 ( d , J = 4.4 Hz , 1H ) , 8.02 ( d , J 4.4 Hz , 1H ) , 7.99 ( s , 1H ) , 7.30 – 7.27 ( m , 2H ) , 7.22 - 7.16 ( m , 2H ) , 5.85 ( s , 2H ) , 5.64 ( s , 1H ) , - - 5.00 – 4.94 ( m , 1H ) , 3.48 ( d , J = 7.4 Hz , 1H ) , 3.44 ( d , J = 7.4 Hz , 1H ) , 3.18 ( d , J = 6.2 Hz , 1H ) , 3.14 ( d , J = 6.1 Hz , 1H ) , 3.08 ( s , 3H ) LCMS ( Method 6 ) : 1.12 min , 430.2 [ M + H ] * Synthesis of compound 214 , a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2- ( methylsulfanylmethyl ) pyrazolo [ 1,5- 602 cosse NH.OMs NaSMe THF , RT Dorge NH-SMe of NaSMe ( sodium methanthiolate ; 21 wt % in water ; 57 Lµ , 0.17 mmol ) was added to a solution [ 3 - carbamoyl - 7- ( indan - 2 - ylcarbamoyl ) pyrazolo [ 1,5 - a ] pyrimidin - 2 - yl ] methyl methanesulfonate ( 49 mg , 0.11 mmol ) in THF ( 1 mL ) and the reaction was stirred at room temperature for 1 h . An additional portion of NaSMe ( 21 wt % in water ; 19 Lμ , 0.06 mmol ) was added , and the reaction was stirred for a further 18 h . The reaction mixture was diluted with EtOAc and washed with brine . The aqueous layer was extracted with EtOAc and DCM , and the combined organic layers were dried over Na2SO4 and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 2 % MeOH in DCM ) to provide the title compound ( 16 mg ) . - - 1H NMR ( 400 MHz , DMSO - d6 ) 8 10.17 ( d , J = 7.2 Hz , 1H ) , 8.90 ( d , J = 4.4 Hz , 1H ) , 7.( d , J = 4.3 Hz , 2H ) , 7.57 ( s , 1H ) , 7.31 – 7.27 ( m , 2H ) , 7.20 – 7.16 ( m , 2H ) , 4.83 – 4.77 ( m , 1H ) , 4.13 ( s , 2H ) , 3.40 ( d , J = 7.2 Hz , 1H ) , 3.36 ( d , J = 7.2 Hz , 1H ) , 2.99 ( d , J = 4.6 Hz , 1H ) , 2.95 ( d , J = 4.5 Hz , 1H ) , 1.97 ( s , 3H ) LCMS ( Method 7 ) : 2.61 min , 382.2 [ M + H ] * Synthesis of compound 217 , 2- ( methylsulfanylmethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide NaSMe THF , RT N. F. F. Na NH-OMS ﻡا ﺄﻣ H NHN -SMe 2- ( Methylsulfanylmethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide ( 14 mg ) , was synthesised following a similar procedure to that described in General Method U. ' H NMR ( 400 MHz , ³lCDC ) ₫ 10.69 ( d , J = 7.0 Hz , 1H ) , 8.79 ( d , J = 4.4 Hz , 1H ) , 8.06 ( br . s , 1H ) , 7.91 ( d , J = 4.4 Hz , 1H ) , 5.62 ( br . s , 1H ) , 4.57 - 4.50 ( m , 1H ) , 4.44 ( s , 2H ) , 4.34 - 4.- - ( m , 1H ) , 3.08 – 3.00 ( m , 2H ) , 2.44 – 2.35 ( m , 2H ) , 2.27 ( s , 3H ) LCMS ( Method 7 ) : 2.68 min , 404.1 [ M + H ] * 603 Synthesis of compound 215 , N7 - indan - 2 - yl - 2- ( methylsulfonylmethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide ‚ N. ⓇenoxO MeOH , O₂H MeCN , RT H NH-SMe NHeM₂OS- N7 - indan - 2 - yl - 2- ( methylsulfanylmethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( 8 mg , 0.02 mmol ) and ®enoxO ( 19 mg , 0.03 mmol ) were dissolved in MeOH ( 2 mL ) , and the reaction was stirred at room temperature for 19 h . An additional portion of ⓇenoxO ( 19 mg , 0.03 mmol ) was added , and the reaction was stirred at room temperature for a further 20 h . A third portion of ®enoxO ( 60 mg , 0.10 mmol ) was added , and the reaction was stirred at room temperature for 4 days . The reaction mixture was concentrated in vacuo , and the residue was suspended in MeCN ( 3 mL ) and water ( 3 mL ) . A final portion of ⓇenoxO ( mg , 0.03 mmol ) was added , and the reaction was stirred at room temperature for 16 h . The reaction mixture was concentrated in vacuo , and the residue was dissolved in EtOAc and water . The layers were separated , and the organic layer was dried through a hydrophobic frit and concentrated in vacuo . The residue was dissolved in DCM and water , and the layers were separated . The organic layer was dried through a hydrophobic frit and concentrated in vacuo . The crude product was dissolved in a 2 : 1 mixture of EtOAc : DCM and filtered through a short plug of silica ( eluting with EtOAc ) . The filtrate was concentrated in vacuo , and the resulting solid was washed with heptane and dried to provide the title compound ( 3.8 mg ) . ' H NMR ( 400 MHz , ³lCDC ) ₫ 10.46 ( d , J = 7.1 Hz , 1H ) , 8.86 ( d , J = 4.4 Hz , 1H ) , 8.08 ( s , 1H ) , 8.05 ( d , J = 4.4 Hz , 1H ) , 7.32 – 7.27 ( m , 2H ) , 7.25 – 7.19 ( m , 2H ) , 5.66 ( s , 1H ) , 5.05 ( s , 2H ) , 5.01 – 4.89 ( m , 1H ) , 3.48 ( dd , J = 16.0 , 7.1 Hz , 2H ) , 3.15 – 3.05 ( m , 2H ) , 2.88 ( s , 3H ) LCMS ( Method 4 ) : 1.99 min , 414.0 [ M + H ] * - - - - Synthesis of compound 216 , 2- ( cyclopropoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide ( General Method V ) Synthesis of 3 - bromo - 2- ( hydroxymethyl ) -N- [ 3- ( cis - trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide 604 HO . ' N ' Br -OH F F F- ■ NH2.HCI EDC , HOBt , Et N DMF , RT ' N ' Br -OH LO 3- ( Cis - trifluoromethoxy ) cyclobutanamine hydrochloride ( 634 mg , 3.31 mmol ) , HOBt ( 3mg , 2.40 mmol ) , EDC ( 1.27 g , 6.62 mmol ) , and NзtE ( 1.84 mL , 13.23 mmol ) were added to a suspension of 3 - bromo - 2- ( hydroxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxylic acid ( 6mg , 2.21 mmol ) in DMF ( 6.5 mL ) and the reaction was stirred at room temperature for 18 h . The reaction mixture was diluted with DCM and water and the layers were separated . The organic layer was washed with water ( x 3 ) and brine , dried over Na2SO4 , and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 553 mg ) . - : 1H NMR ( 400 MHz , CDCl3 ) б 10.34 ( d , J = 6.7 Hz , 1H ) , 8.68 ( d , J = 4.2 Hz , 1H ) , 7.77 ( d , J = 4.2 Hz , 1H ) , 4.98 – 4.92 ( m , 2H ) , 4.53 – 4.41 ( m , 1H ) , 4.31 – 4.17 ( m , 1H ) , 3.02 – 2.91 ( m , 2H ) , 2.37 – 2.28 ( m , 2H ) , 2.02 ( s , 1H ) LCMS ( Method 7 ) : 2.58 min , 409.0 , 411.0 [ M + H ] * Synthesis of 3 - bromo - 2- ( bromomethyl ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide CBrP₂hP , DCM F insa RT Br essa .Br N OH -Br CBr4 ( 665 mg , 2 mmol ) and PзhP ( 526 mg , 2 mmol ) were added to a solution of 3 - bromo - 2- ( hydroxymethyl ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 7- carboxamide ( 410 mg , 1 mmol ) in DCM ( 13 mL ) , and the reaction was stirred at room temperature for 18 h . The reaction mixture was concentrated in vacuo , and the crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 476 mg ) . 605 LO - = 1H NMR ( 400 MHz , ³lCDC ) ₫ 10.31 ( d , J = 7.0 Hz , 1H ) , 8.76 ( d , J = 4.2 Hz , 1H ) , 7.86 ( d , J 4.2 Hz , 1H ) , 4.72 ( s , 2H ) , 4.54 ( p , J = 7.3 Hz , 1H ) , 4.38 – 4.24 ( m , 1H ) , 3.10 – 2.98 ( m , 2H ) , 2.47 2.35 ( m , 2H ) LCMS ( Method 7 ) : 3.27 min , 471.0 , 473.0 , 475.0 [ M + H ] + - Synthesis of - bromo - 2- ( cyclopropoxymethyl ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide -OH AgOTf H ° C ' N ' -Br .Br N : -Br AgOTf ( 131 mg , 0.51 mmol ) was added to a suspension of 3 - bromo - 2- ( bromomethyl ) -N- [ cis- 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide ( 160 mg , 0.mmol ) in cyclopropanol ( 1.7 mL ) and the reaction was heated at 50 ° C for 2 h . The reaction mixture was cooled to room temperature and diluted with EtOAc and water . The layers were separated , and the organic layer was dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by column chromatography ( eluting with 0 to 100 % EtOAc in heptane ) to provide the title compound ( 79 mg ) . = 1H NMR ( 400 MHz , CDCl3 ) г 10.51 ( d , J = 7.1 Hz , 1H ) , 8.74 ( d , J = 4.2 Hz , 1H ) , 7.82 ( d , J 4.2 Hz , 1H ) , 4.86 ( s , 2H ) , 4.60 – 4.49 ( m , 1H ) , 4.36 - 4.24 ( m , 1H ) , 3.59 – 3.52 ( m , 1H ) , 3.- - – 2.97 ( m , 2H ) , 2.46 – 2.33 ( m , 2H ) , 0.79 – 0.73 ( m , 2H ) , 0.62 – 0.55 ( m , 2H ) LCMS ( Method 7 ) : 3.28 min , 449.0 , 451.0 [ M + H ] * Synthesis of compound 216 , 2- ( cyclopropoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 606 H 1. XantPhos Pd GN₂tE , NMP ' N ' .Br 100 ° C Na N NH 2. HO₂HN , T3P N₂tE , RT 3 - Bromo - 2- ( cyclopropoxymethyl ) -N- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 7 - carboxamide ( 79 mg , 0.18 mmol ) , NзtE ( 74 Lµ , 0.53 mmol ) , and NMP ( 1.mL ) were placed in a vial , and the vial was sealed and purged with argon for 5 min . XantPhos Pd G3 ( 17 mg , 0.02 mmol ) was added , and the vial was purged with argon for a further min . ( 2,5 - Dioxopyrrolidin - 1 - yl ) formate ( 126 mg , 0.88 mmol ) was added and the vial was sealed immediately . The reaction was heated at 100 ° C in a microwave reactor for 2 h . Additional portions of N³tE ( 74 Lµ , 0.53 mmol ) and XantPhos Pd G3 ( 17 mg , 0.mmol ) were added , and the reaction mixture was degassed with argon for 5 min . Additional ( 2,5 - dioxopyrrolidin - 1 - yl ) formate ( 126 mg , 0.88 mmol ) was added , and the reaction was heated at 100 ° C in a microwave reactor for a further 2 h . The reaction mixture was cooled to room temperature , and NзtE ( 74 Lµ , 0.53 mmol ) , 1 - propanephosphonic anhydride ( wt % in DMF ) ( 209 Lµ , 0.35 mmol ) , and NH4OH ( 230 Lµ , 1.76 mmol ) were added . The reaction was stirred at room temperature for 18 h . The reaction mixture was diluted with EtOAc and water , and the layers were separated . The aqueous layer was extracted with EtOAc ( x 3 ) , and the combined organic layers were dried through a hydrophobic frit and concentrated in vacuo . The crude product was purified by preparative HPLC ( acidic method ) to provide the title compound ( 14 mg ) .

- - ' H NMR ( 400 MHz , DMSO - d6 ) Ŏ 10.17 ( d , J = 7.5 Hz , 1H ) , 8.91 ( d , J = 4.3 Hz , 1H ) , 7.75 - 7.56 ( m , 3H ) , 5.08 ( s , 2H ) , 4.72 ( p , J = 7.2 Hz , 1H ) , 4.29 – 4.14 ( m , 1H ) , 3.67 – 3.58 ( m , 1H ) , 2.97 – 2.86 ( m , 2H ) , 2.33 – 2.23 ( m , 2H ) , 0.66 – 0.57 ( m , 2H ) , 0.53 – 0.43 ( m , 2H ) LCMS ( Method 7 ) : 2.65 min , 414.2 [ M + H ] * Example 2 - GPR68 Biochemical Assay GPR68 antagonism was determined using the Promega GloSensor TM CAMP assay ( F.I. Wang et al . , Methods 2021 , S1046-2023 ( 21 ) 00249-8 ) . HEK293T cells ( obtained from 607 ECACC , Cat 12022001 , Lot no . 17E044 ) were cultured in T175 flasks ( Greiner , Cat 660175 ) in DMEM ( Gibco , Cat 11995-065 ) supplemented with 10 % Fetal Bovine Serum ( Gibco Cat 16000-044 ) , and 100 u / mL Pen - Strep ( Gibco , Cat 15140 ) at 37 ° C and 5 % CO2 . GPRexpression was achieved by transient transfection with a mammalian expression plasmid encoding full - length human GPR68 ( uniprot ID : Q15743 ) under control of a CMV promoter . The day before transfection , cell media was aspirated and HEK293T cells were incubated with accutase ( Sigma , Cat A6964 ) for 3-4 minutes 37 ° C and 5 % CO2 before being manually detached with excess DMEM and trituration . Cell density was determined by automated cell counting ( Countess , Invitrogen ) and adjusted to 6x106 cells / 20 mL and transferred to 15 cm dishes ( Thermo Fisher , Cat 130183 ) for overnight incubation at 37 ° C and 5 % CO2 . The next day separate mammalian expression plasmids encoding hGPR68 ( 4 gµ ) and Promega GloSensor ( 8 gµ ) were diluted to 1 mL in Opti - MEM ( Thermo Fisher Scientific , Cat 31985070 ) and incubated with 30 Lµ of lipofectamine 3000 ( also diluted to 1 mL in Opti- MEM ) for 15 minutes at room temperature and subsequently added dropwise to the plated cells . Post transfection cells were then incubated at 37 ° C and 5 % CO2 for at least 16 hours before transfer to assay plates the following day . Transfer was conducted by washing cells with PBS and incubating with accutase for 3-4 minutes 37 ° C and 5 % CO2 before being manually detached with excess DMEM and mild trituration . The suspension was then centrifuged at 192 RCF for 4 minutes in a 50 mL centrifuge tube ( Greiner , Cat 227261 ) . Supernatant was removed by aspiration and the cell pellet was resuspended in DMEM + 1 % dialysed FBS ( Gibco , Cat 26400-044 ) and 100 u / mL Pen - Strep to a cell density of 5cells / Lμ . Cells were plated into poly - L - Lysine coated 384 - well white assay plates ( Corning , Cat 3570 ) at a final volume of 40 Lμ and a density of 20,000 cells / well before overnight incubation at 37 ° C and 5 % CO2 . The following day media was manually ejected from the 384 - well assay plate and replaced with 10 Lμ GloSensor substrate ( Promega , Cat E1291 ) prepared in pH 8.0 assay buffer ( 1x HBSS , 10 mM HEPES , 10 mM MOPS ) . Cells were incubated with this solution for 60 minutes at room temperature in the dark . Test compounds or an equivalent volume of DMSO ( vehicle ) were added to compounds plates to create a 9- point , half - log concentration series for each compound with a maximum final assay concentration of 50 Mµ and a consistent final DMSO concentration of 0.5 % . Assay buffer with 0.1 % BSA and 0.01 % ascorbic acid was prepared at three pHs : pH 8.0 , pH 5.5 and pH 4.5 . pH 8.0 and 4.5 were added to the compound plate as maximum and minimum effect controls whilst pH 5.5 was added to all compound wells to stimulate GPR68 to a level corresponding to 90 % of maximal stimulation after addition to the cells already in pH 8.0 . ( assay acceptance criteria range 70-90 % ) . DMSO / Compound and buffer was added to the plated cells containing the GloSensor substrate and incubated for 15 minutes at room temperature before being read on a microplate reader ( BMG PHERAstar , optic module LUM 608 LO Plus with Gain 3600 ) . Data was exported and analysed in excel and Graphpad prism ( version ) . Assay QC acceptance criteria required the maximum and minimum controls to return a ≥'Z 0.5 , the EC 80 to be 80 % ± 10 % of expected and the reference ligand pIC 50 to be within one - half - log unit of its historical IC50 . Percent inhibition was calculated using the mean EC( pH 5.5 ) and mean minimum effect control ( pH 8.0 ) . Data were plotted as percentage inhibition , average ± SEM . IC50 , Emax , Emin , Actual max , actual min , ²R and fit confidence were calculated using Graphpad Prism's sigmoidal dose - response function .

Table 2. hGPR68 biochemical IC50 data hGPR68 IC50 : A = 50 Mμ to 100 Mµ ; B = 5 Mμ to 50 Mμ ; C = 500 nM to 5 Mμ ; D = 50 nM to 500 nM ; E = < 50 nM Compound hGPRStructure name number IC1 D D N7 - indan - 2 - ylpyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 4 - methylindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide A N7- ( 5 - methoxyindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- D N7- ( 4 - chloroindan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- LO 5 C N7- ( 1,2,3,4 - tetrahydroquinolin - 3 - yl ) pyrazolo [ 1,5- D N7 - chroman - 3 - ylpyrazolo [ 1,5 - a ] pyrimidine - 3,7- B 8 00 B 9 C A 11 B 12 A 13 A 14 C B dicarboxamide dicarboxamide a ] pyrimidine - 3,7 - dicarboxamide dicarboxamide N7- ( trans - 3 - fluoro - 3 - methyl - cyclobutyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( cis - 3 - hydroxy - 3 - methyl - cyclobutyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( cis - 3 - cyanocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 3,3 - diethylcyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( cis - 3 - methoxycyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 7 - oxaspiro [ 3.5 ] nonan - 2 - yl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7- ( 5,6,7,8 - tetrahydroisoquinolin - 7 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- [ 4- ( 3,3,3 - trifluoropropyl ) indan - 2 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- [ 5- ( 2 - pyrrolidin - 1 - ylethyl ) indan - 2 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 609 N7- [ 4- ( 4 - chlorophenoxy ) indan - 2 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- [ 4- ( 2 - pyridyl ) indan - 2 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 6,7 - dihydro - 5H - pyrrolo [ 1,2 - a ] imidazol - 6- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 1,2,3,4 - tetrahydro - 1,8 - naphthyridin - 3 - yl ) pyrazolo [ 1,5- Compound hGPRStructure name number IC16 A 17 A 18 C 19 B B 21 D 22 23 A 24 A 26 D 27 ﻞﻟا E 28 B C B ﻞﻟا a ] pyrimidine - 3,7 - dicarboxamide - cyano - N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - indan - 2 - yl - 2 - pyridazin - 3 - yl - pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 2- [ 2- ( dimethylamino ) ethylamino ] -N7 - indan - 2 - yl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2- ( 1 - methylazetidin - 3 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2 - oxazol - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N8- ( 3,3 - difluorocyclobutyl ) -2 - methyl - imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide N7 - indan - 2 - yl - 2- ( isopropoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2- ( isopropoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide - [ ( dimethylamino ) methyl ] -N7 - indan - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2- ( methylaminomethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N - indan - 2 - yl - 3 - oxazol - 2 - yl - pyrazolo [ 1,5 - a ] pyridine - 7- carboxamide N7- ( 3,3 - difluorocyclobutyl ) -2 - methyl - 6- ( 1H - pyrazol - 4- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2 - oxazol - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- E 34 E 36 C 37 E 38 B dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2- ( methylamino ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2- ( dimethylamino ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( 2 - fluorophenyl ) -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyridine- 3,7 - dicarboxamide N7 - indan - 2 - yl - 2 - tetrahydrofuran - 3 - yl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2,6 - dimethyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 610 N7- ( 3,3 - difluorocyclobutyl ) -5- ( methoxymethyl ) -2 - methyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - N3 - methyl - 2 - phenyl - pyrazolo [ 1,5 - a ] pyridine- 3,7 - dicarboxamide Compound number hGPRStructure name IC39 C 40 A 41 C 42 D 43 D D 45 46 E 47 C 48 D 49 C 50 C 51 B 52 B 53 D 54 E 55 D 56 E 57 E 58 E 59 E 60 E N7- ( 3,3 - difluorocyclobutyl ) -5 - methoxy - 2 - methyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2,5 - dimethyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2 - tetrahydrofuran - 2 - yl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2 - tetrahydrofuran - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2 - tetrahydrofuran - 3 - yl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - chroman - 3 - yl - 2 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2 - methyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( cis - 3 - cyanocyclobutyl ) -2 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 5 - benzylindan - 2 - yl ) -2 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 6 - yl ) -2 - methyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide - methyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N8- ( 3,3 - difluorocyclobutyl ) -2- ( methoxymethyl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide 2- ( methoxymethyl ) -N8- [ cis - 3- ( trifluoromethoxy ) cyclobutylimidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide N8 - indan - 2 - yl - 2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine- 3,8 - dicarboxamide N7 - indan - 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7- [ 5- ( trifluoromethyl ) -2- pyridyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 611 Compound number hGPRStructure name ICE 62 C 64 E 65 D 66 E 67 D 68 E 69 D 70 E 71 D ﻞﻳا ﻞﻟا E E 2- ( methoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- [ 4 - [ ( dimethylamino ) methyl ] phenyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 1 - methylpyrazol - 4- yl ) methyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 4,6 - dimethyl - 2 - pyridyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7-94- ( trifluoromethyl ) -2- pyridyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,4 - difluorophenyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 2,3 - dihydrobenzofuran - 5 - ylmethyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 2,4 - difluorophenyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7 - benzyl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7 - [ ( 4 - fluorophenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - [ ( 3 - fluorophenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7- ( p - tolylmethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7- ( 7 - methoxytetralin - 2- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 1 R ) -tetralin - 1 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - cyclohexyl - 2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7 - [ ( 2,2 - dimethylcyclopropyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - chroman - 3 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 2S ) -tetralin - 2 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 72 E 73 E 274 E 75 E 76 D 78 D 80 N7- ( cyclopropylmethyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- Compound hGPRStructure name number IC81 D 82 E 83 E 84 C 85 E 86 D 87 E 88 E 89 A 90 A 91 LUI E 92 ﻞﻳا E 93 E 94 D 95 C 96 B 97 98 B 99 B 100 B a ] pyrimidine - 3,7 - dicarboxamide N7- ( 7 - fluorotetralin - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7 - [ ( 2,4 - difluorophenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7- ( cis - 4- methylcyclohexyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 5,6 - dihydro - 4H - cyclopenta [ c ] thiophen - 5 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7- ( trans - 3- methylcyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 5 - chloroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -7- [ 4- [ 3- ( trifluoromethyl ) -2- pyridyl ] piperazine - 1 - carbonyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3- carboxamide N7 - [ [ 1- ( dimethylamino ) cyclohexyl ] methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 4 - fluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 4,6 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7- ( 1,2,3,4 - tetrahydroquinolin - 3- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( trans - 3 - fluoro - 3 - methyl - cyclobutyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 7- ( 2,3 - dihydro - 1H - isoindole - 2 - carbonyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3 - carboxamide N7- [ 2- ( 3 - methylphenoxy ) butyl ] pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide N7- [ 2 - methyl - 5- ( pyridin - 4 - yl ) phenyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- [ 1- ( 5 - methoxy - 1H - 1,3 - benzodiazol - 2- yl ) ethyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- [ 1- ( 4 - tert - butylphenoxy ) propan - 2 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,3,3 - trifluoropropyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 613 N7 - [ ( 4,4 - difluorocyclohexyl ) methyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide Compound hGPRStructure name number IC101 C 102 C 103 C 104 D 105 E 106 E 107 E 108 E 109 E 110 E 111 E 112 E 113 E 114 E 115 E 116 E 117 ﻞﻳا E 118 E 119 E 120 E N7- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 4,4 - difluorocyclohexyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N8- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide N8- ( 5,6 - dihydro - 4H - cyclopenta [ c ] thiophen - 5 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide N8- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide N8- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide 2- ( methoxymethyl ) -N8 - [ ( 4S ) -7 - fluorochroman - 4- yl ] imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide N8- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide N8 - [ ( 4 - fluorophenyl ) methyl ] -2- ( methoxymethyl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide - cyclopropyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide - cyclopropyl - N7- ( 3,3 - difluoroindan - 1 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide - cyclopropyl - N7 - [ ( 4S ) -7 - fluorochroman - 4 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 6 - chlorochroman - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide - cyclopropyl - N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 4,4 - difluorotetralin - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 8 - fluoro - 3 - quinolyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7- ( 1 - methylindol - 2 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 3R ) -6,7 - difluoro - 2,3- dihydrobenzofuran - 3 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - [ ( 3R ) -5 - fluoro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 614 Compound hGPRStructure name number IC121 D 122 D 2- ( methoxymethyl ) -N7- ( 2 - methylindan - 2 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- [ 1- ( 4 - fluorophenyl ) ethyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 123 E 124 C 125 C 126 D 127 D 128 ﻞﻳا E 129 E 130 E 131 132 D 2- ( methoxymethyl ) -N7 - [ ( 4S ) -7 - fluorochroman - 4- yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 2,2 - difluoro - 6 - methyl - spiro [ 3.3 ] heptan - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7- [ 2,2,2 - trifluoro - 1- ( 4- fluorophenyl ) ethyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 2,2 - difluorospiro [ 3.3 ] heptan - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- [ 1- ( 4 - fluorophenyl ) cyclopropyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 3R ) -6 - fluoro - 2,3- dihydrobenzofuran - 3 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide - cyclopropyl - N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 2,2 - difluorospiro [ 3.3 ] heptan - 7 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7- [ cis - 4- ( trifluoromethoxy ) cyclohexyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - [ ( 4,4 - difluorocyclohexyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- 2 - cyclopropyl - N7- ( 5,6 - dihydro - 4H - cyclopenta [ c ] thiophen - 5- 133 E dicarboxamide 1 E ﻞﻟا E ﻞﻳا E 137 E ﻞﻳا E ﻞﻳا E yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide - cyclopropyl - N7- ( 4,4 - difluorocyclohexyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide - cyclopropyl - N7- ( 3,3 - difluorocyclobutyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide - propyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2 - cyclopropyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2 - propyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 615 Compound hGPRStructure name number IC140 E 141 E 142 E 143 D 144 E 145 E 2 - cyclopropyl - N7 - [ ( 4 - fluorophenyl ) methyl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( hydroxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( cyclopropylmethoxy ) -N7 - indan - 2 - yl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 7- ( indan - 2 - ylcarbamoyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3 - carboxylic acid N7- ( 6 - bromochroman - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( methylamino ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- 146 D dicarboxamide 147 E 148 E 149 D 150 ﻞﻳا E 151 E 152 ﻞﻳا E 153 E N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 7- ( indan - 2 - ylcarbamothioyl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3 - carboxamide - carbamothioyl - N - indan - 2 - yl - 2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 7 - carboxamide - cyclopropyl - N8- ( 4,4 - difluorocyclohexyl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide - cyclopropyl - N8- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide N7- ( 1,1 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 4,6 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- 154 D 155 D 156 D 157 E ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- ﻞﻳا E E dicarboxamide 2- ( methoxymethyl ) -N7- ( 2,4,4- trifluorocyclohexyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7- ( 1 - methylindan - 1 - yl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide - cyclopropyl - N4- ( 4,4 - difluorocyclohexyl ) pyrazolo [ 5,1- c ] [ 1,2,4 ] triazine - 4,8 - dicarboxamide 2- ( trideuteriomethoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( fluoromethoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - indan - 2 - yl - 2- ( methylamino ) pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 616 Compound number 1 hGPRStructure name ICE 161 C N7- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6 - yl ) -2- ( trideuteriomethoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N3 - methyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( cyclopropylmethoxy ) -N7- [ cis - 3- 162 D dicarboxamide 163 E 164 E 165 D 166 E 167 E ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- 2 - cyclopropyl - N8- ( 6,7 - dihydro - 5H - cyclopenta [ b ] pyridin - 6- yl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide N8- ( 4,6 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide N7- ( 6,7 - dihydro - 5H - pyrrolo [ 1,2 - a ] imidazol - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - [ ( 4R ) -7 - fluorochroman - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - [ ( 3S ) -6 - fluoro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- 168 E 169 ﻞﻳا E 170 E 171 D 172 D 173 ﻞﻧا E 174 E 175 E 176 E 177 E ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - [ ( 3R ) -7 - chloro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 3,4 - dihydro - 2H - pyrano [ 2,3 - b ] pyridin - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - [ ( 4S ) -chroman - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7 - [ - 4,4 - difluorotetralin - 1 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - [ - 4,4 - difluorotetralin - 1 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 617 Compound number 1 hGPRStructure name ICE N7 - [ ( 3R ) -7 - chloro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 6 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- 179 E 180 D 181 D 182 E 183 ﻞﻟا E 184 E 185 D 186 C 187 C 1 189 E 190 D 191 E 192 E dicarboxamide N7- ( 3,4 - dihydro - 2H - pyrano [ 2,3 - b ] pyridin - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - [ ( 4S ) -chroman - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 6,7 - difluorochroman - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 1S ) -indan - 1 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 2,3 - dihydrofuro [ 2,3 - b ] pyridin - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 5,7 - difluorochroman - 3 - yl ) -2- dicarboxamide ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- N7- ( 4,4 - dimethyltetralin - 1 - yl ) -2- dicarboxamide 2- ( methoxymethyl ) -N7- ( 5,6,7,8 - tetrahydroimidazo [ 1,2- a ] pyridin - 6 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7- ( 5,6,7,8 - tetrahydroimidazo [ 1,5- a ] pyridin - 6 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7- ( 4,5,6,7 - tetrahydro - 1,3- benzothiazol - 6 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 5,7 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 7 - fluoro - 2,3 - dihydrobenzofuran - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- E ﻞﻟا ןש E E dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 1S ) -tetralin - 1 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 5 - fluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 5,6 - difluoroindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 6 - fluorochroman - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 618 Compound number hGPRStructure name ICC 1 198 D 199 D 200 E 201 LUI E 202 E 203 D 204 D 205 D 206 D 207 N7 - [ ( 4 - hydroxyphenyl ) methyl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 1S ) -3,3 - dimethylindan - 1- yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide 2- ( methoxymethyl ) -N7 - [ ( 2- methoxyphenyl ) methyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( cis - 1 - hydroxyindan - 2 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7 - cis - 1 - methylindan - 2 - yl ] pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( ethoxymethyl ) -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide - tetrahydrofuran - 2 - yl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( hydroxymethyl ) -N7 - indan - 2 - yl - pyrazolo [ 1,5 - a ] pyrimidine- 3,7 - dicarboxamide 2- ( ethoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -5 - methyl - N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 3,3 - difluorocyclobutyl ) -2- ( hydroxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide - cyclopropyl - N8- ( 5,6 - dihydro - 4H - cyclopenta [ c ] thiophen - 5- yl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide - cyclopropyl - N8- ( 3,3 - difluoroindan - 1 - yl ) imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide N8- ( 7 - bicyclo [ 4.2.0 ] octa - 1,3,5 - trienyl ) -2 - cyclopropyl- imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide - cyclopropyl - N8 - [ ( 4S ) -7 - fluorochroman - 4 - yl ] imidazo [ 1,2- b ] pyridazine - 3,8 - dicarboxamide 208 E 209 ﻞﻧا E 210 E 211 ﻞﻳا E 212 D N4- ( 4,4 - difluorocyclohexyl ) -6- ( methoxymethyl ) imidazo [ 2,1- f ] [ 1,2,4 ] triazine - 4,7 - dicarboxamide 213 D N7- ( 3,3 - difluorocyclobutyl ) -2- ( 1 - hydroxy - 1 - methyl- 214 E ethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2- ( methylsulfanylmethyl ) pyrazolo [ 1,5- 215 D 216 E a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2- ( methylsulfonylmethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide 2- ( cyclopropoxymethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 619 Compound number 2 hGPRStructure name ICE 2- ( methylsulfanylmethyl ) -N7- [ cis - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N8- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) -6 - methyl- imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide 2- ( methoxymethyl ) -N8 - [ ( 4R ) -1,1 - dioxo - 3,4 - dihydro - 2H- 218 D 219 ﻝا E dicarboxamide 220 D thiochromen - 4 - yl ] imidazo [ 1,2 - b ] pyridazine - 3,8- 2- ( methoxymethyl ) -N8 - [ ( 4S ) -1,1 - dioxo - 3,4 - dihydro - 2H- thiochromen - 4 - yl ] imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide N8- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8- 221 D dicarboxamide 222 ﻞﻳا E - cyclopropyl - N8- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3- 223 E 224 D 225 E 226 ﻞﻳا E 227 E 228 E 229 E 230 E 231 ﻞﻳا E 232 E 233 ﻝا E 234 E 235 E yl ) imidazo [ 1,2 - b ] pyridazine - 3,8 - dicarboxamide N8- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2- ( methoxymethyl ) imidazo [ 1,2 - b ] pyridazine - 3,8- dicarboxamide 2- ( methoxymethyl ) -N7- [ trans - 3- ( trifluoromethoxy ) cyclobutyl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7- ( 1,1 - dioxothietan - 3 - yl ) -2- ( methoxymethyl ) pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 4,4 - difluorotetralin - 1 - yl ) -2- ( methoxymethyl ) -5 - methyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7 - indan - 2 - yl - 2- ( methoxymethyl ) -5 - methyl - pyrazolo [ 1,5- a ] pyrimidine - 3,7 - dicarboxamide N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3 - yl ) -2 - isopropyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide - cyclopropyl - N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen- - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2- isopropyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide - cyclopropyl - N7- ( 1,1 - dioxo - 2,3 - dihydrobenzothiophen - 3- yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 3,3 - difluoroindan - 1 - yl ) -2- ( methoxymethyl ) -5 - methyl- pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7 - [ ( 4R ) -1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide N7 - [ ( 4S ) -1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide - cyclopropyl - N7 - [ ( 4R ) -1,1 - dioxo - 3,4 - dihydro - 2H- thiochromen - 4 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 620 Compound number 2 hGPRStructure name ICE 237 E 238 E 239 ﻞﻟا E 2 - cyclopropyl - N7 - [ ( 4S ) -1,1 - dioxo - 3,4 - dihydro - 2H- thiochromen - 4 - yl ] pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7- ( 3,3,6 - trifluoroindan - 1 - yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7 - [ ( 3S ) -6,7 - difluoro - 2,3 - dihydrobenzofuran - 3 - yl ] -2- ( methoxymethyl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 2- ( methoxymethyl ) -N7- ( 4,4,6 - trifluorotetralin - 1- 240 ןש E yl ) pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 4,4 - difluorocyclohexyl ) -2- ( methoxymethyl ) -5 - methyl- 241 D pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen - 4 - yl ) -2- ( methoxymethyl ) -5 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7- dicarboxamide 242 E - cyclopropyl - N7- ( 1,1 - dioxo - 3,4 - dihydro - 2H - thiochromen- - yl ) -5 - methyl - pyrazolo [ 1,5 - a ] pyrimidine - 3,7 - dicarboxamide CLAUSES AND PARAGRAPHS : Alternative expressions of the inventive concept are set out in each of the following numbered clauses : Clause 1. A compound of formula ( 1 ) : R' L ' .N .

+A R R3 LO ( 1 ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein : Q is O or S ; 1✗ is selected from C and N ; X2 is selected from CR5 and N ; X3 is selected from CR and N ; X4 is selected from CR7 and N ; X5 is selected from C and N ; wherein X1 , X2 , X3 , X4 and X5 are selected so that the ring labelled A is aromatic ; X6 is selected from CR8R9 , O and N ; X7 is selected from CR10 , CR11 R12 , O and N ; q is 0 or 1 ; wherein when q is 0 , X7 is O or N ; and when X7 is O or N and q is 1 , X6 is CR8R9 ; L ' is a bond , alkylene , haloalkylene , cycloalkylene , or heterocycloalkyl ; R1 is selected from alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , aryl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , aryloxy , and heteroaryloxy , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , aryl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , aryloxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1 R1b , alkyl , haloalkyl , alkoxy , haloalkoxy , alkyl - NR1aR1b , cycloalkyl , heterocycloakyl , aryl , heteroaryl , benzyl , aryloxy , haloaryloxy , heteroaryloxy , C4 alkyl substituted by a heterocycloalkyl ; R1a and R1b are each independently selected from H and alkyl ; R2 is selected from H , alkyl and cycloalkyl ; or R1 , R2 and L1 and the nitrogen atom to which R2 and L ' are attached form a heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl or bicyclic heteroaryl , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1 R1b , alkyl , haloalkyl , alkoxy , haloalkoxy and alkyl - NR1aR1b ; ³R is selected from H , OH , CN , b³Ra3³RN , alkyl , cycloalkyl , heterocycloalkyl , aryl , heteroaryl , alkoxyalkyl , haloalkoxyalkyl , cycloalkoxyalkyl , cycloalkylalkoxy , alkyl - S - alkyl , and alkyl - SO2- alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , aryl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , alkyl and NR3CR3d . 3a a³R is selected from H , alkyl , alkyl - OH , and alkyl - ³RN f³ ; 622 LO b³R , c³R , d³R , e³R and f³R are each independently selected from H and alkyl ; R4 is selected from C ( O ) OH , C ( O ) b4Rª4RN , C ( S ) ª4RN R4b and heteroaryl ; R4a and R4b are each independently selected from H and alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , alkyl , haloalkyl , alkoxy , alkoxyalkyl , cycloalkyl , heterocycloalkyl , aryl and heteroaryl ; or R5 and R6 together with the carbon atoms to which they are attached form a heterocycle ; and R7 , R8 , ⁹R , R10 , R11 and R12 are each independently selected from H , halogen , OH , CN , alkyl , haloalkyl , alkoxy , cycloalkyl , heterocycloalkyl , aryl and heteroaryl .

Clause 2. The compound of clause 1 , wherein L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , ³C - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and C1 - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; or R1 , R2 and L ' and the nitrogen atom to which R2 and L1 are attached form a 3- to 8- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11 - membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , or 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected 623 LO from N , O and S , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C1 - Chaloalkoxy and ₁C - C4 alkyl - b1Rª¹RN ; ³R is selected from H , OH , CN , b³R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C C4 alkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2- C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and NR3CR3d a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³Rе³RN ; R3b , R3 , R3d , e³R and f³R are each independently selected from H and ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR ª4 R4b and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a and R4b are each independently selected from H and C1 - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , C1 - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - 1₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , R8 , ⁹R , R10 , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

Clause 3 . The compound of clause 1 or clause 2 , wherein L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6 - membered 624 LO heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , C1 - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and C1 - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; R2 is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; ³R is selected from H , OH , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , -₁C C4 alkoxy - C1 - C4 alkyl , C1 - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - C1 - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2- C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , and NR3cR3d . a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and C1 - C4 alkyl - f³Re³RN ; R3b , R3 , R3d , e³R and f³R are each independently selected from H and ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR4R4b and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a and R4b are each independently selected from H and ₁C - C4 alkyl ; R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , ³R , ⁹R , º¹R , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S. 625 LO Clause 4. The compound of any preceding clause , wherein L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1 is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6 - membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - b1Rª¹RN , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , halophenoxy , and ₁C - C4 alkyl substituted by a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; R2 is selected from H , ₁C - C4 alkyl and C3 - C8 cycloakyl ; ³R is selected from H , OH , CN , b³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , C1 - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2- C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , C1 - C4 alkyl , and d³RC3RN ; a³R is selected from H , ₁C - C4 alkyl , and C1 - C4 alkyl - f³Re³RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R3e and f³R are each independently selected from C1 - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) 4Rª4RN , C ( S ) ª4RN R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; 626 LO R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R7 , ºR , ºR , º¹R , R11 , and R12 are each independently selected from H , halogen , OH , CN , -₁C C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

Clause 5. The compound of any preceding clause , wherein ¹L is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents . independently selected from halogen , OH , CN , ³¹Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - Calkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - b1Rª¹RN , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , halophenoxy , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N. O and S : ' R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is H ; ³R is selected from H , CN , NR3R3b , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - ₁C - C4 alkoxy , C1 - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted 627 LO by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and d³Rc3RN . a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Re3RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; 3e e³R and f³R are each independently selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR ª4 R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is HR5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , R10 , R11 , and R12 are each H.

Clause 6. The compound of any preceding clause , wherein L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1 selected from : ₁C - C4 haloalkyl ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1 R1b , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - Chaloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , halophenoxy , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and C1 - C4 alkyl substituted by a 5- or - membered heterocycloalkyl having one or more heteroatoms selected from N , ○ and S ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 628 LO - or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substitutents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy optionally substituted by one or more ₁C - C4 alkyl ; R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is H ; R3 is selected from : H ; CN ; a³RN R3b ' ₁C - C4 alkyl optionally substituted by one of more substituents selected from OH and NR3c d³R . C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , optionally substituted by one or more C1 - C4 alkyl ; phenyl optionally substituted by one or more halogen ; 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - C1 - C4 alkyl ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; ₁C - C4 alkyl - S - ₁C - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Re³RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R3e and f³R are each independently selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR ª4 R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; 629 LO R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , R10 , R11 , and R12 are each H.

Clause 7. The compound of any preceding clause , wherein L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1 selected from : ₁C - C4 haloalkyl ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1 R1b , C1 - C4 alkyl , C1 - C4 alkoxy , and ₁C - Chaloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , C1 - C4 haloalkyl , C1 - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , halophenoxy , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or - membered heterocycloalkyl having one or more heteroatoms selected from N , ○ and S ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and ₁C - C4 haloalkyl ; 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substitutents independently selected from halogen , C1 - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy substituted by one or more ₁C - C4 alkyl ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; R3 is selected from : 630 H ; 3a - CN : NR3aR3b . ₁C - C4 alkyl optionally substituted by one or more substituents selected from OH and NR3cR3d . C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , optionally substituted by one or more ₁C - C4 alkyl ; phenyl optionally substituted by one or more halogen ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; ₁C - C4 alkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; ₁C - C4 alkyl - S - C1 - C4 alkyl ; and C1 - C4 alkyl - SO2- ₁C - C4 alkyl ; a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Rе³RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; e³R and f³R are each independently selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) b4Rª4RN , C ( S ) NR4 R4 and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

Clause 8. The compound of any one of clauses 1 to 5 , wherein L ' is a bond , ₁C - 6С alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene ; R1 is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected 631 LO from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C1 - C4 haloalkoxy , ₁C - C4 alkyl - b1Rª¹RN , C3 - C8 cycloalkyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - ₁C - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC³RN ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) 4Rª4RN , C ( S ) ª4RN R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , C1 - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , R9 , R10 , R11 , and R12 are each H.

Clause 9. The compound of any one of clauses 1 to 6 or 8 , wherein L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene ; R1 is selected from : ₁C - C4 haloalkyl ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , C1 - C4 alkyl , C1 - C4 alkoxy , and C1 - C4 haloalkoxy ; 632 C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , C1 - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - b1Rª¹RN , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy optionally substituted by one or more ₁C - C4 alkyl ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; R3 is selected from : Hi - CN ; NR3aR3b ' ₁C - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR3cR3d . C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; phenyl substituted by one or more halogen ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; C1 - C4 haloalkoxy - C1 - C4 alkyl ; 633 ₁C - C4 alkyl - S - C1 - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR 4a R 4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; R4b is H ; R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

Clause 10. The compound of preceding clause , wherein L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene ; R1 is selected from : ₁C - C4 haloalkyl ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and C1 - C4 haloalkyl ; 634 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy substituted by one or more ₁C - C4 alkyl ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from : H ; CN ; NR3aR3b . C1 - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR3CR3d . C3 - C8 cycloalkyl ; ' 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; phenyl substituted by one or more halogen ; 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - C1 - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; C1 - C4 alkyl - S - C1 - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; a³R is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; c³R is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from C ( O ) OH , C ( O ) 4Rª4RN , C ( S ) ª4RN R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and C1 - C4 alkyl ; R4b is H : R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - C1 - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H. 635 LO Clause 11. The compound of any one of clauses 1 to 5 or 8 , wherein L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene ; R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; ³R is selected from H , CN , b3Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC³RN ; a³R is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : .OH viv ₂HN viv NHCH ۲-۲S ; and ; and wherein indicates the point of attachment to the rest of the compound ; R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and 636 R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

Clause 12. The compound of any one of clauses 1 to 5 , 8 , 9 or 11 , wherein L ' is a bond , ₁C - 6С alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene ; ¹R is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , CN , ₁C - C4 alkyl , and C1 - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , and ₁C - Calkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and C1 - C4 alkyl ; R1a and R1b are each independently selected from H and ₁C - C4 alkyl ; ²R is H ; R3 is selected from : Hi CN ; NR3aR3b ' C1 - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR3cR3d . C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; phenyl substituted by one or more halogen ; 637 - - or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; ₁C - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - C1 - C4 alkyl ; C1 - C4 alkyl - S - ₁C - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; aзR is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : .OH viv .NH2 NH2 viv S ; and ; and CH wherein indicates the point of attachment to the rest of the compound ; R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; ' R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - C1 - C4 alkyl ; and R7 , R8 , R9 , R10 , R11 , and R12 are each H. , Clause 13. The compound of any preceding clause , wherein L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene ; R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , CN , ₁C - C4 alkyl , and C1 - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , and ₁C - Calkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 638 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , C1 - C4 alkyl - NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; R1a and R1b are each independently selected from H and C1 - C4 alkyl ; ²R is H ; ³R is selected from : Hi CN ; NR3aR3b : ₁C - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR3CR3d . C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; phenyl substituted by one or more halogen ; 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - C1 - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; ₁C - C4 alkyl - S - ₁C - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; aзR is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : 639 .OH NH S ; and viv NH ; and CH wherein indicates the point of attachment to the rest of the compound ; R5 is selected from H , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - C4 alkoxy - ₁C - C4 alkyl ; and R7 , R8 , ºR , R10 , R11 , and R12 are each H.

Clause 14. The compound of any one of clauses 1 to 5 , 8 or 11 , wherein L ' is a bond , ₁C - C6 alkylene , or C3 - C6 cycloalkylene ; R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , hetercycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , C1 - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy ; ²R is H ; ³R is selected from H , CN , ³Rª³RN , ₁C - C4 alkyl optionally substituted by OH , ³C - Ccycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl- ₁C - C4 alkoxy , ₁C - C4 haloalkoxy - C1 - C4 alkyl , C1 - C4 alkyl - S - C1 - C4 alkyl , and C1 - C4 alkyl - SO2- ₁C - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : 640 .OH viv .NHviv S ; and point of attachment to the rest of the compound ; R5 is H ; R6 is selected from H and ₁C - C4 alkyl ; and R7 , R8 R9 R10 R11 , and R12 are each H. , ' NH ; wherein indicates the Clause 15 . The compound of any one of clauses 1 to 5 , 8 , 9 , 11 , 12 or 14 , wherein L ' is either a bond , ₁C - C6 alkylene , or C3 - C6 cycloalkylene ; R1 is selected from : ²R is H ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and ₁C - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; ³R is selected from : - H ; CN ; NR3aR3b ; ₁C - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 641 ﻡا 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; ' 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - C1 - C4 alkyl ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; R3a is H ; C1 - C4 alkyl - S - C1 - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; R3b is selected from ₁C - C4 alkyl . R4 is selected from the following groups : .OH viv NH2 NH YYY ; and point of attachment to the rest of the compound ; R5 is H ; R6 is selected from H and ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H. ; wherein Clause 16 . The compound of any preceding clause , wherein indicates the L ' is either a bond , ₁C - C6 alkylene , or C3 - C6 cycloalkylene ; R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and ₁C - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; 642 LO ²R is H ; - or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; R3 is selected from : H ; CN ; NR3aR3b . ₁C - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - C1 - C4 alkyl ; R3a is H ; ₁C - C4 alkyl - S - C1 - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; R3b is selected from ₁C - C4 alkyl . R4 is selected from the following groups : .OH viv S .NH ; and viv point of attachment to the rest of the compound ; R5 is H ; R6 is selected from H and ₁C - C4 alkyl ; and R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

NH ; wherein indicates the Clause 17. The compound of any one of clauses 1 to 5 , 8 , 11 or 14 , wherein 643 LO L ' is either a bond or C1 - C6 alkylene ; R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , C1 - C4 haloalkyl , C1 - C4 alkoxy , and ₁C - C4 haloalkoxy ; ²R is H ; ³R is selected from b³R³RN , ₁C - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR30 R3d , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , C3 - Ccycloalkoxy - C1 - C4 alkyl , ₁C - C4 alkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , and alkyl - S - ₁C - C4 alkyl ; R3a is H ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : .OH .NH2 NH S ; and point of attachment to the rest of the compound ; R5 , R7 , R8 , ºR , R10 , R11 , and R12 are each H ; and R6 is selected from H and ₁C - C4 alkyl . ; wherein indicates the Clause 18. The compound of any one of clauses 1 to 5 , 8 , 9 , 11 , 12 , 14 , 15 or 17 , wherein L ' is either a bond or ₁C - C6 alkylene ; R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4 haloalkoxy ; C8 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl and ₁C - C4 alkoxy ; 644 LO ²R is H ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen and C1 - C4 alkyl ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; ³R is selected from : a³RN R3b - ₁C - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; and a³R is H ; ₁C - C4 alkyl - S - ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : viv OH NH2 NH S ; and point of attachment to the rest of the compound H ; R5 , R7 , R8 , ºR , R10 , R11 , and R12 are each H ; and 6 ; wherein indicates the R6 is selected from H and ₁C - C4 alkyl .

Clause 19 . The compound of any preceding clause , wherein L ' is either a bond or ₁C - C6 alkylene ; ¹R is selected from : ²R is H ; C3 - C8 cycloalkyl substituted by one or more substituents independently selected from halogen and C1 - C4 haloalkoxy ; C8 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl and ₁C - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl substituted by one or more substituents independently selected from halogen and C1 - C4 alkyl ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; ³R is selected from : - NR3aR3b . ' R3a is H ; C1 - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - C1 - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; and C1 - C4 alkyl - S - ₁C - C4 alkyl ; 646 R3b is selected from ₁C - C4 alkyl ; R4 is selected from the following groups : .OH viv NHviv ₂HN S ; and point of attachment to the rest of the compound ; ; wherein indicates the R5 , R7 , R8 , ⁹R , R10 , R11 , and R12 are each H ; and , R6 is selected from H and ₁C - C4 alkyl .

Clause 20 .

Clause 21 .

The compound of any one of clauses 1 to 19 , wherein Q is O.

The compound of any one of clauses 1 to 7 and 20 , wherein L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , C3 - C6 cycloalkylene , or a 5- or 6 - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S.

Clause 22. The compound of any one of clauses 1 to 7 , 20 and 21 , wherein L ' is a bond , ₁C - C6 alkylene , ₁C - C6 haloalkylene , or C3 - C6 cycloalkylene .

Clause 23 . The compound of any one of clauses 1 to 7 , and 20 to 22 , wherein L1 is a bond , methylene , ethylidene , 2,2,2 - trifluoroethylidene , and cyclopropylidene .

Clause 24. The compound of any one of clauses 1 to 7 , 20 and 21 , wherein L ' is a bond , ₁C - C6 alkylene or a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S.

Clause 25. The compound of any one of clauses 1 to 22 and 24 , wherein L ' is either a bond or C1 - C6 alkylene .

Clause 26. The compound of any preceding clause , wherein L1 is either a bond or methylene .

Clause 27 . The compound of any one of clauses 1 to 22 , 24 and 25 , wherein ¹L is -₁C C6 alkylene .

Clause 28 . The compound of any preceding clause , wherein ₁L is methylene . 647 Clause 29 . The compound of any one of clauses 1 to 26 , wherein L ' is a bond .

LO Clause 30. The compound of any one of clauses 1 to 7 , 20 and 21 , wherein ¹L is a 5- or - membered heterocycloalkylene having one or more heteroatoms selected from N , O and S.

Clause 31. The compound of any one of clauses 1 to 3 and 20 to 30 , wherein . ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6 - membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , bicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and C1 - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and C1 - C4 alkyl .

Clause 32. The compound of any one of clauses 1 to 3 , or 20 to 31 , wherein ¹R is selected from ₁C - C4 alkyl , C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , C9 - C10 bicyclic aryl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , phenoxy , and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , wherein said alkyl , cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , C9 - Cbicyclic aryl , heteroaryl , bicyclic heteroaryl , phenoxy and heteroaryloxy are each optionally 648 LO substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and C1 - C4 alkyl .

Clause 33. The compound of any one of clauses 1 to 3 or 20 to 32 , wherein R1 is selected from C1 - C4 alkyl , C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1 R1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - Calkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl - ª1RN R1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

Clause 34. The compound of any one of clauses 1 to 3 or 20 to 33 , wherein R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , 649 LO CN , ³¹Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

Clause 35. The compound of any one of clauses 1 to 3 or 20 to 34 , wherein R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ³¹Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , -₁C C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , phenoxy , halophenoxy , 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and C1 - C4 alkyl .

Clause 36. The compound of any one of clauses 1 to 5 or 20 to 35 , wherein ¹R is selected from ₁C - C4 alkyl , ³C - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1 R1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C650 alkoxy , C1 - C4 haloalkoxy , ₁C - C4 alkyl - b1R³¹RN , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , halophenoxy , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and C1 - C4 alkyl .

Clause 37. The compound of any one of clauses 1 to 5 , 20 to 34 or 36 , wherein R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ª1RN R1b , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , -₁C C4 alkyl - b¹Rª¹RN , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , halophenoxy , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and C1 - C4 alkyl .

Clause 38. The compound of any one of clauses 1 to 5 or 20 to 37 , wherein R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ³¹Rª¹RN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C1 - C4 haloalkoxy , -₁C C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , halophenoxy , and ₁C - C4 alkyl substituted by 651 LO a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

Clause 39. The compound of any one of clauses 1 to 5 , 8 , 20 to 33 , or 36 , wherein ¹R is selected from ₁C - C4 alkyl , ³C - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , and phenoxy , wherein said alkyl , cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , bicyclic heteroaryl , and phenoxy are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , C1 - C4 alkyl - NR1aR1b , C3 - C8 cycloalkyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl . Clause 40 .

The compound of any one of clauses 1 to 5 , 8 , 20 to 33 , 36 , 37 or 39 , wherein R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- b1Ra¹RN , C3 - C8 cycloalkyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

Clause 41. The compound of any one of clauses 1 to 5 , 8 or 20 to 40 , wherein 652 LO R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- NR1aR1b , C3 - C8 cycloalkyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , benzyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

Clause 42. The compound of any one of clauses 1 to 5 , 8 , 11 , 20 to 34 , 36 , 37 , 39 or 40 , wherein R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and C1 - C4 alkyl .

Clause 43. The compound of any one of clause 1 to 5 , 8 , 11 or 20 to 42 , wherein R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring mambers selected from N , O , S and SO2 , wherein said cycloalkyl , bicyclic cycloalkyl , heterocycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are 653 LO each optionally substituted by one or more substituents independently selected from halogen , CN , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - C4 haloalkoxy , ₁C - C4 alkyl- NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

Clause 44 . The compound of any one of clauses 1 to 5 , 8 , 11 , 14 , 20 to 34 , 36 , 37 , 39 , or 42 , wherein R1 is selected from C3 - C8 cycloalkyl , C7 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , C1 - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy .

Clause 45. The compound of any one of clauses 1 to 5 , 8 , 11 , 14 or 20 to 44 , wherein R1 is selected from C3 - C8 cycloalkyl , C8 - C11 bicyclic cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , phenyl , 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , wherein said cycloalkyl , heterocycloalkyl , bicyclic cycloalkyl , bicyclic heterocycloalkyl , phenyl , heteroaryl , and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , and ₁C - C4 haloalkoxy .

Clause 46. The compound of any one of clauses 1 to 6 , 20 to 33 or 36 , wherein R1 is selected from : ₁C - C4 haloalkyl ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1 R1b , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - Chaloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , 654 benzyl , C3 - C8 cycloalkyl , halophenoxy , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - b¹Rª¹RN , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substitutents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy optionally substituted by one or more ₁C - C4 alkyl ; wherein a¹R and R1b are each independently selected from H and C1 - C4 alkyl .

Clause 47. The compound of any one of clauses 1 to 7 , 20 to 33 , 36 or 46 , wherein R1 is selected from : C1 - C4 haloalkyl ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , ₁C - C4 alkoxy , and ₁C - Chaloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , halophenoxy , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , and ₁C - C4 alkyl substituted by a 5- or - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 655 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , C1 - C4 alkyl - NR1aR1b , and 5- or 6- membered heteroaryl having one or more ring members selected from N , O , S and SO2 ( e.g having one or more ring members selected from N , O and S ) ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and ₁C - C4 haloalkyl ; 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substitutents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy substituted by one or more ₁C - C4 alkyl ; wherein a¹R and R1b are each independently selected from H and ₁C - C4 alkyl .

Clause 48. The compound of any one of clauses 1 to 6 , 8 , 9 , 20 to 33 , 36 , 39 or wherein R1 is selected from : ₁C - C4 haloalkyl ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , C1 - C4 alkyl , C1 - C4 alkoxy , and C1 - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; 656 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy optionally substituted by one or more ₁C - C4 alkyl ; wherein R1a and R1b are each independently selected from H and C1 - C4 alkyl .

Clause 49. The compound of any one of clauses 1 to 10 , 20 to 33 , 36 , 39 , 46 and 47 , wherein R1 is selected from : ₁C - C4 haloalkyl ; C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , CN , C1 - C4 alkyl , C1 - C4 alkoxy , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , benzyl , C3 - C8 cycloalkyl , and ₁C - C4 alkyl substituted by a 5- or 6 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - NR1a R1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from C1- C4 alkyl and ₁C - C4 haloalkyl ; 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; and phenoxy substituted by one or more ₁C - C4 alkyl ; wherein a¹R and R1b are each independently selected from H and ₁C - C4 alkyl .

Clause 50 . The compound of any one of clauses 1 to 6 , 8 , 9 , 11 , 12 , 20 to 34 , 36 , 37 , , 40 , 42 , 46 or 48 , wherein R1 is selected from : 657 LO C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , CN , ₁C - C4 alkyl , and C1 - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , and ₁C - Calkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and C1 - C4 alkyl ; wherein a¹R and R1b are each independently selected from H and ₁C - C4 alkyl .

Clause 51 . The compound of any one of clauses 1 to 13 , 20 to 34 , 36 , 37 , 39 , 40 , 42 or to 50 , wherein R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , CN , ₁C - C4 alkyl , and C1 - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 haloalkyl , and ₁C - Calkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , ₁C - C4 alkoxy , ₁C - C4 alkyl - NR1aR1b , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; 658 LO - or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; wherein a¹R and R1b are each independently selected from H and C1 - C4 alkyl .

Clause 52 . The compound of any one of clauses 1 to 6 , 8 , 9 , 11 , 12 , 14 , 15 , 20 to 34 , , 37 , 39 , 40 , 42 , 44 , 46 , 48 or 50 , wherein R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and ₁C - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl .

Clause 53 .

The compound of any of clauses 1 to 15 , 20 to 34 , 36 , 37 , 39 , 40 , 42 , to 52 , wherein R1 is selected from : 44 or C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl , and ₁C - C4 haloalkoxy ; C7 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and C1 - C4 alkoxy ; 659 LO 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen , ₁C - C4 alkyl and ₁C - C4 alkoxy ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl .

Clause 54 . The compound of any one of clauses 1 to 6 , 8 , 9 , 11 , 12 , 14 , 15 , 17 , 18 , to 46 , 48 , 50 or 52 , wherein R1 is selected from : C3 - C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4 haloalkoxy ; C8 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl and ₁C - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl optionally substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from ₁C - C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , optionally substituted substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl .

Clause 55. The compound of any of preceding clause , wherein R1 is selected from : 660 = C3 - C8 cycloalkyl substituted by one or more substituents independently selected from halogen and C1 - C4 haloalkoxy ; C8 - C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl and ₁C - C4 alkoxy ; 3- to 8 - membered heterocycloalkyl having one or more ring members selected from N , O , S and SO2 ; 8- to 11 - membered bicyclic heterocycloalkyl having one or more ring members selected from N , O , S and SO2 , optionally substituted by one or more substituents independently selected from halogen ; phenyl substituted by one or more substituents independently selected from halogen and C1 - C4 alkyl ; 5- or 6 - membered heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from -₁C C4 alkyl and ₁C - C4 haloalkyl ; and 8- to 10 - membered bicyclic heteroaryl having one or more ring members selected from N , O , S and SO2 , substituted by one or more substituents independently selected from halogen and ₁C - C4 alkyl .

Clause 56. The compound of any one of clauses 1 to 7 , 20 to 33 , 36 , 46 or 47 , wherein R1 is selected from the following groups : ﺱﻯ ; ; F F.

M ; F LL F F.

F + H3C F3C F F F F3CO ; 05 $ 2, .N .

N ; H3C ; Cl CH N H3C da ; ' ; F ca F3C F- N ; H3C CI ; a 9 , 20CH3 CH + H3C- -N N a H3C a ' ; H3C A H3C NC . ; 663 H3C H3C H3C viv N.

N ; ; ww ; CF M H3C H3C CHCH IN ; ; ; H3C ww H3C viv .CI 8089 IN N H3C F3C w CH 3 H3C N CH FL N N ; ww CH; ; viv ; IL F ד .

CF m CH ﺲﻛﺭ H3C F F ; ; CFF F F viv ; ; CH ; F F F F # 00 to F Br ww CH; ﭺھ ھٹ ; CI 00 , of F N ; F F F 00,00.

N CH F v ; 667 viv F F viv F F F F F ; viv ; viv ; F F ; ; N ' N ' S. ﻼﻣﺮﻣﺓ ﺐﻟﺓ ; ; ; ; viv F ; H3C Ja 20,; H3C CH; F po po of viv F ; viv F ; CH3 F HO 1000 2 F F 00,F F 000H3C CH; ; F S F F ; and F F indicates the point of attachment to the rest of the compound .

F ; wherein Clause 57. The compound of any one of clauses 1 to 7 , 20 to 33 , 36 , 46 , 47 or 52 , wherein R1 is selected from the following groups : 670 F.

F.

H3C F F H3C ; ד . F F3C ; ﻡا F F ﻝﺄﻣﺎﻧﺓ F3CO .N . ww OCF3 ww .N .

Mw ; N 100+ 700+ C ; ; CI . ; ; ; lllC₂H ....

F3C N IZ H3C ; CI m CH ; H3C H3C H3C ; ; ' CH FIII- CH F CH £ £ £ ; ; CH H3C H3C H3C NC -N C₂H . ; a m H3C H3C Z H3C- H3C " m NC ... ﻊﺒﻳﺭ CF ; ; viv ; 100+ 674 ww IZ Z CH ww Z Z IZ IN m O H3C Z www Z 675 ww HOIIII ...

CH E m ; F3C ; H3C H3C CH HOIII- m CI ; ; N 80.00 N vi 676 CH E & Q H3C H3C ― N CHF -CF F- FL F- F ; CFF viv ; m .CH ; F F viv CH ; ; ; Ox CH F. to viv ; F. F to of CI F 00,w F. F Br F.

F F F .N .

; ; F 60 , 00.

N CH; ; ; ; F F F F w F ; F F ; F F ; ; .F ; Ja .F ; N ; 679 CI S ; ; ; to to go ; .F F ﺲﺗﺭ F ; ; CH; LL F LL F F ; H3C Ja £ 0.OH ; .F CH; 100 F ; 00.

.F 00 $ 0 $ ' N ' ; S ; ; ; ; 681 H3C CH Ja F F ; wherein ﻯ and indicates the point of attachment to the rest of the compound .

Clause 58. The compound of any one of clauses 1 to 10 , 20 to 33 , 36 , 39 , 46 to 49 or , wherein R1 is selected from the following groups : www ; w ; L F 、 ; F + FL H3C ; F. F.

; ; F3C m F3CO F F ﻡﺓ ﻝﺎﻨﻫ .N . ; CI ; ; CH N H3C 02- H3C ; ; F F3C ; H3C CI 9, CH3 CH ; a ; H3C ﻲﻫ + A F- H3C- N N -a H3C a ' H3C NC . ; 684 H3C H3C H3C viv N.

N ; ; ﺱﻯ ; CF M H3C H3C CHCH ; IN ; ; .N N H3C ' N ' HO F3C ; F H3C F F viv ; F F m .CH CH viv CH; LL F F CFF FL LL F viv ; a to of CI ` CH 3 ; F Br ; F 0700,F F ; N CH 687 F F F F v viv ; viv ; F F F ; ; F F F viv ; LO ' N ' S 00:00: N CI ; ; to to to viv ; 6; .F F to por go S ; F ; viv F ; FL CH; F vir 100 a ; H3C H3C CH OH ; ; ; F HO 1000 2 F F 00,F F 000 F H3C CH; ffor Ja S F F ; and F F F ; wherein ; indicates the point of attachment to the rest of the compound .

Clause 59 . The compound of any one of clauses 1 to 10 , 20 to 33 , 36 , 39 , 46 to 49 or to 58 , wherein R1 is selected from the following groups : 690 F H3C F ww F H3C ; F F3C Z F ﻱﺩ F3CO OCF3 www F F ; viv viv ; CI . ; Cl ; ; 02,; ; ; 692 0 .

H3C CHH3C H3C N Z.

H3C F F3C FI CH C N FII- CH FI CH3 CH H3C .

A H3C H3C A H3C NG ||||| ...

H3C- .N . a N NC LO H3C H3C H3C viv ' N ; m ; CF m ; M ; IZ ww CH Z H3C H3C CH Z Z m viv H3C IZ H3C Z m Z Z 695 HOM ww F3C ; CH F F H3C F .CH CH HOIII- ww CH F LL F m m ; F LL F www CF F F CH & £ 4,0 to to to of oa LL Br ; CI ww ; F F 00,0 F F ; ; F F .N . 20ba , 0F F F F N CH · F F ﻡ F ; F ﻢﻤﻣ F ; viv ; F F of ; ; F 698 ; .S ; ww ; F ; .F F F xoç so of ; ww F F ; 3050.F ; H3C CH Ja 20.OH ; H3C .F CH 100 20 F ; 00,00 F ; 7 F LL F F ; LO 0050 N ; H3C CH F F the compound .

F ; wherein S.

F F ; and indicates the point of attachment to the rest of Clause 60 . The compound of any one of clauses 1 to 13 , 20 to 34 , 36 , 37 , 39 , 40 , 42 , to 51 , 56 or 58 , wherein R1 is selected from the following groups : ; F F- H3C F F IL F F. m ; ; F ; F F ; ww F3CO ; F3C F ; viv ; N N ww CI .

; CH H3C N H3C 00,0,F H3C ; ∞ , za ; CI ; F3C N CH F CH ; H3C- " A H3C ; ; H3C N H3C H3C H3C F N.

F N H3C ﻊﺒﻳﺭ N ; N ' NC CF M ; viv ; ; F F F CH ; ; 7viv CH ; LL F F F CF F F ; on to of 00,CI CH F Br F ; 0700,F F ; N CH 705 F F F v F viv ; viv ; F F 0 of F ; ; .F F F S ; viv ; 00'00'N ; 706 ﻡﺓ ﻡﺓ ﻒﻳ ; ; CH ; ww F .F F viv F ; ; viv ia OH F ; ; H3C CH H3C F ; HO 100 F F 00,; F F ; ' N ' ; H3C CH; S F F ; and F F ; wherein indicates the point of attachment to the rest of the compound .

Clause 61 . The compound of any one of clauses 1 to 13 , 20 to 24 , 36 , 37 , 39 , 40 , 42 , to 51 or 56 to 60 , wherein F R1 is selected from the following groups : ; F F- ; F F.

F a F H3C F3CO .N .

H3C W F3C N ; F F OC₂F ; viv ; OCFw ; ; ; m ; N ; N 0 CI ; H3C IIII ... ﻊﺒﻳﺭ CI CH H3C N m ﻊﺒﻳﺭ IZ H3C m F H3C H3C F3C N CI 9 , 20CH; CH3 CH FI H3C FI H3C H3C H3C m m H3C- N NC H3C ' ra , H3C ; ; CF ﺱﻯ ; ; H3C N ﻢﻫ F F F viv ; E. F F.

F -CH N F ; CF F ww ; ﻢﻴﻧ ; ww ; ; CHviv ; ; F m Ox CH F. to viv ; F. F to of CI F 00,w F. F Br F.

F F F .N .

; ; F 60 , 00.

N CH; ; ; ; F F F F ; F F ; F F ; Ja .; N ' N ' F ; ; .F ; ; CI S ; F ; ; .S F CH; ; .F ; LL F LL F F ; Ja £ 0.OH H3C .F CH; 100 F ; 00.

.F 00 $ 0 $ ; S ; ; ; ; 717 H3C CH ﻯ Ja F ; and F F ; wherein indicates the point of attachment to the rest of ד . F.

Clause 62 . The compound of any one of clauses 1 to 16 , 20 to 34 , 36 , 37 , 39 , 40 , 42 , , 46 to 53 , 56 , 58 or 60 , wherein R1 is selected from the following groups : the compound .

F ww M M L ; M ; F LL F F.

F + H3C F3C F F F F3CO ; 05 $ 2, .N .

N ; H3C ; Cl CH N H3C da ; ' ; F3C F Z CHCH F H3C CI 7 Z F w Br LL F ד . F CF viv F CH; viv ; F 7,001ww CH; F ; CI F F ; ; ; F N F 60,00.

· F N CHF pa po F ; viv F F F ; ; ; F F S ; F 2000'viv ; ; ; ﻡﺓ ﻡﺓ ﻒﻳ ; ; ; ww CH3 ' N ' ; F .F F viv F viv H3C F ; ; ; CH; H3C .F 100,0HO ; .

.F ; F F 100 70 For Ja ; and F F the point of attachment to the rest of the compound .

Clause 63 .

F ; wherein indicates The compound of any one of clauses 1 to 16 , 20 to 34 , 36 , 37 , 39 , 40 , 42 , , 46 to 53 or 56 to 62 , wherein ¹R is selected from the following groups : ; ; 724 H3C F.

F.

F F H3C 7 ; ; F3C ד . F ﻡا F F ; viv F3CO CI .N . OCF ; ; .N .

Mw ; CI- 000+ ; ; H3C CHH3C F ; H3C m C H3C ... ; a ﻊﺒﻳﺭ ; F3C a LL F O CH m ; CI ; CH ₤ ....

E FI m ; ; CH ' N ' F ; F F CF F CH; viv ; F s & t F ww ; on to to CH; to of F ; ﻡا 728 CI 00,00 , F Br F F F .N .

F ; ; F 60,00.

N CH F ; -F ; ; ; F F F viv ; F ; ; F F S.

Sa 00 CI 50 50 730 S ; ; F F 2; ; CH ﻢﻃﺮﻳﺓ F H3C H3C CH; ; 731 F LL F ﺱﻯ viv HO F 50 to ; S F F F ; F F S ; F ; and F F ; wherein indicates the point of attachment to the rest of the compound .

Clause 64. The compound of any one of clauses 1 to 56 , 58 , 60 , 62 , wherein R1 is selected from the following groups : 732 F F- H3C F F IL F F. m ; ; F ; F F ; ww F3CO ; F3C F ; viv ; N CI . 100 + 80 + N ; CH N H3C 00 - da H3C ; F 100.0 N to of CI ; F 00,Br ; ; 734 F N 0760,09 . F F N CH F F vi viv ; ; F F F 0 of F F ; F 00.00 ; ; ; 735 F F CI viv ; viv F ; ﻁﺮﻣﺓ ﻂﻳﺭ LL F ; ; F H3C 100, F ; HO 100xF ; 00 , 70 % F ; ; For Ja ; and F F the point of attachment to the rest of the compound .

Clause 65. The compound of any preceding clause , wherein F ; wherein R1 is selected from the following groups : F ; F LL F ; S F H3C F 、 ; F.

; LL F 、 ; ; indicates ' H3C F3CO ; N + CI ; ; Cl .

; F F viv ; ; F3C lloC₂F ...

; ; ; H3C CH N H3C daa ; F ada to ; viv F to too F ; F ; F So to as CI F F ; 00,00 , Br ; ; ; 739 F F F N F. F F ; ; N F F ; CHF ; F ; ; F F ; F F F bo go F ; .F CI F ; ; F F por go to ww ; ; N ; ; LL F IL vr LL F H3C ; .0HO ; ; F to to F F ; and ; ; F F the compound .

FL ; wherein indicates the point of attachment to the rest of 742 LO Clause 66 . The compound of clause 1 or clause 2 , wherein R1 , R2 and L1 and the nitrogen atom to which R2 and L1 are attached form a heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl or bicyclic heteroaryl , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , NR1aR1b , alkyl , haloalkyl , alkoxy , haloalkoxy and alkyl - NR1aR1b ; and R1a and R1b are each independently selected from H and alkyl .

Clause 67 .

The compound of any one of clauses 1 , 2 or 66 , wherein R1 , R2 and L1 and the nitrogen atom to which R2 and L1 are attached form a 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11- membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , or 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S , wherein said heterocycloalkyl , bicyclic heterocycloalkyl , heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , b1Rª¹RN , ₁C - C4 alkyl , C1 - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - Chaloalkoxy and ₁C - C4 alkyl - NR1aR1b ; and R1a and R1b are each independently selected from H and ₁C - C4 alkyl .

Clause 68 . The compound of any one of clauses 1 , 2 , 66 or 67 , wherein R1 , R2 and L1 and the nitrogen atom to which R2 and L1 are attached form a 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 8- to 11- membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S , or 8- to 10 - membered bicyclic heteroaryl having one or more heteroatoms selected from N , O and S.

Clause 69 .

The compound of any one of clauses 1 , 2 or 66 to 68 , wherein R1 , R2 and L1 and the nitrogen atom to which R2 and L1 are attached form a 8- to 11- membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N , O and S.

Clause 70. The compound of any one of clauses 1 , 2 or 66 to 69 , wherein R1 , R2 and L1 and the nitrogen atom to which R2 and L ' are attached form the following bicyclic heterocycloalkyl group : 743 N M ; wherein indicates the point of attachment to the rest of the compound .

Clause 71. The compound of any one of clauses 1 to 4 or 20 to 65 , wherein ²R is selected from H , ₁C - C4 alkyl and C3 - C8 cycloalkyl .

Clause 72. The compound of any one of clauses 1 to 4 or 20 to 71 , wherein ²R is selected from H and ₁C - C4 alkyl .

Clause 73 . ²R is H. The compound of any preceding clause , wherein Clause 74. The compound of any one of clauses 1 to 3 or 20 to 73 , wherein ³R is selected from H , OH , CN , b³R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , ³C - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkoxy - ₁C - C4 alkyl , C1 - C4 alkyl - S - ₁C - C4 alkyl , and C1 - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , C1 - C4 alkyl , -₁C C4 alkoxy , and d³Rc³RN ; a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and C1 - C4 alkyl - f³Rе³RN ; R3b , R3c , d³R , e³R and f³R are each independently selected from H and C1 - C4 alkyl .

Clause 75. The compound of any one of clauses 1 to 3 or 20 to 74 , wherein ³R is selected from H , CN , NR3R3b , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and C1 - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , -₁C C4 alkyl , C1 - C4 alkoxy , and d³Rc³RN ; a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³Re³RN ; 744 LO R3b , R3c , d³R , e³R and f³R are each independently selected from H and C1 - C4 alkyl .

Clause 76. The compound of any one of clauses 1 to 3 or 20 to 75 , wherein ³R is selected from H , CN , b3R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , C1 - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , зC - Ccycloalkyl - ₁C - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , ₁C - C4 alkyl , C1 - Calkoxy , and ³RN ¢ d³R ; 3a a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³R³RN ; R3b , R3 , R3d , e³R and f³R are each independently selected from H and C1 - C4 alkyl .

Clause 77 .

The compound of any one of clauses 1 to 3 or 20 to 76 , wherein ³R is selected from NR 3R 3b , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - ₁C - C4 alkoxy , and ₁C - C4 alkyl - S - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , CN , C1 - C4 alkyl , C1 - C4 alkoxy , and ³RN ¢ d³R ; a³R is selected from H , ₁C - C4 alkyl , ₁C - C4 alkyl - OH , and ₁C - C4 alkyl - f³R³RN ; R3b , R3 , R3d , e³R and f³R are each independently selected from H and ₁C - C4 alkyl .

Clause 78. The compound of any one of clauses 1 to 5 or 20 to 75 , wherein ³R is selected from H , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , C1 - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and NR3c R3d a³R is selected from H , ₁C - C4 alkyl , and C1 - C4 alkyl - f³Re³RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; 745 LO R3d is selected from C1 - C4 alkyl ; and e³R and f³R are each independently selected from ₁C - C4 alkyl .

Clause 79. The compound of any one of clauses 1 to 5 or 20 to 76 , wherein ³R is selected from H , CN , b³R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and d³Rc³RN ; 3a a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Re³RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; and e³R and f³R are each independently selected from C1 - C4 alkyl .

Clause 80. The compound of any one of clauses 1 to 5 or 20 to 79 , wherein ³R is selected from NR 3R 3b , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , C1 - Calkoxy - ₁C - C4 alkyl , C1 - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - C1 - C4 alkyl , C3 - Ccycloalkyl - C1 - C4 alkoxy , and ₁C - C4 alkyl - S - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH , ₁C - C4 alkyl , and d³RC3RN ; a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³Rе³RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from ₁C - C4 alkyl ; and e³R and f³R are each independently selected from ₁C - C4 alkyl .

Clause 81. The compound of any one of clauses 1 to 5 , 8 , 20 to 75 , or 78 wherein ³R is selected from H , CN , ³Rª³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , зC - Ccycloalkyl - C1 - C4 alkoxy , ₁C - C4 alkyl - S - C1 - C4 alkyl , and C1 - C4 alkyl - SO2 - C1 - C4 alkyl , wherein 746 LO said alkyl , cycloalkyl , heterocycloalkyl , phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³RC³RN ; R3a is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; and R3d is selected from ₁C - C4 alkyl .

Clause 82. The compound of any one of clauses 1 to 5 , 8 , 20 to 76 , 78 , 79 , or 81 , wherein ³R is selected from H , CN , b³R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl - ₁C - C4 alkoxy , C1 - Chaloalkoxy - C1 - C4 alkyl , ₁C - C4 alkyl - S - C1 - C4 alkyl , and ₁C - C4 alkyl - SO2 - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³Rc³RN ; 3a aзR is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; and R3d is selected from ₁C - C4 alkyl .

Clause 83. The compound of any one of clauses 1 to 5 , 8 or 20 to 82 , wherein ³R is selected from b³R³RN , ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - Ccycloalkoxy - C1 - C4 alkyl , C3 - C8 cycloalkyl - ₁C - C4 alkoxy , ₁C - C4 haloalkoxy - C1 - C4 alkyl , and -₁C C4 alkyl - S - C1 - C4 alkyl , wherein said alkyl , cycloalkyl , heterocycloalkyl , and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen , OH and d³Rc³RN ; aзR is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; and R3d is selected from ₁C - C4 alkyl .

Clause 84. The compound of any one of clauses 1 to 5 , 8 , 11 , 14 , 20 to 76 , 78 , 79 , 81 , or 82 , wherein 747 LO ³R is selected from H , CN , ³Rª³RN , ₁C - C4 alkyl optionally substituted by OH , ³C - Ccycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl- ₁C - C4 alkoxy , ₁C - C4 haloalkoxy - ₁C - C4 alkyl , ₁C - C4 alkyl - S - ₁C - C4 alkyl , and ₁C - C4 alkyl - SO2- ₁C - C4 alkyl ; R3a is H ; and R3b is selected from ₁C - C4 alkyl .

Clause 85. The compound of any one of clauses 1 to 5 , 8 , 11 , 14 , 17 , or 20 to 84 , wherein ³R is selected from NR 3R 3b , ₁C - C4 alkyl substituted by one or more substituents independently selected from OH and NR 3c R3d , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S , ₁C - Calkoxy - C1 - C4 alkyl , C3 - C8 cycloalkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl - ₁C - C4 alkoxy , C1 - Chaloalkoxy - C1 - C4 alkyl , and C1 - C4 alkyl - S - C1 - C4 alkyl ; a³R is H ; R3b is selected from ₁C - C4 alkyl .

Clause 86. The compound of any one of clauses 1 to 7 , 20 to 75 , or 78 , wherein ³R is selected from : - H ; CN ; NR3aR3b : ₁C - C4 alkyl optionally substituted by one of more substituents selected from OH and NR3cR3d C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , optionally substituted by one or more C1 - C4 alkyl ; phenyl optionally substituted by one or more halogen ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkoxy - C1 - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; 748 LO wherein ₁C - C4 alkyl - S - C1 - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; a³R is selected from H , ₁C - C4 alkyl , and ₁C - C4 alkyl - f³R³RN ; R3b is selected from H and ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; R3d is selected from C1 - C4 alkyl ; and e³R and f³R are each independently selected from ₁C - C4 alkyl .

Clause 87. The compound of any one of clauses 1 to 10 , 20 to 75 , 78 , 81 , or 86 , wherein R3 is selected from : H ; CN ; b³Ra3RN ₁C - C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR3CR3d . C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; phenyl substituted by one or more halogen ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; wherein ₁C - C4 alkyl - S - C1 - C4 alkyl ; and C1 - C4 alkyl - SO2 - C1 - C4 alkyl ; a³R is selected from H and ₁C - C4 alkyl ; R3b is selected from ₁C - C4 alkyl ; R3c is selected from H and ₁C - C4 alkyl ; and R3d is selected from ₁C - C4 alkyl .

Clause 88 . The compound of any one of clauses 1 to 16 , 20 to 76 , 78. 79 , 81 , 82 , 84 , , or 87 , wherein R3 is selected from : 749 H ; CN : - wherein NR3aR3b . ₁C - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; ₁C - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - C1 - C4 alkyl ; ₁C - C4 alkyl - S - ₁C - C4 alkyl ; and ₁C - C4 alkyl - SO2 - ₁C - C4 alkyl ; R3a is H ; and R3b is selected from ₁C - C4 alkyl .

Clause 89. The compound of any preceding clause , wherein ³R is selected from : - b³Ra3RN ' wherein C1 - C4 alkyl optionally substituted by OH ; C3 - C8 cycloalkyl ; 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S ; 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; C1 - C4 alkoxy - ₁C - C4 alkyl ; C3 - C8 cycloalkyl - ₁C - C4 alkoxy ; C3 - C8 cycloalkoxy - ₁C - C4 alkyl ; ₁C - C4 haloalkoxy - ₁C - C4 alkyl ; and ₁C - C4 alkyl - S - ₁C - C4 alkyl ; R3a is H ; and R3b is selected from ₁C - C4 alkyl . 750 Clause 90. The compound of any preceding clause , wherein ³R is selected from ₁C - Calkoxy - C1 - C4 alkyl .

Clause 91. The compound of any preceding clause , wherein ³R is selected from methoxymethyl .

Clause 92. The compound of any one of clauses 1 to 75 , or 78 , wherein ³R is selected from the following groups : LO viv viv .CH vir CH CN viv viv IN CH viv ; F viv CH; N ' N ' CH CH viv viv N ' N ' vi .CH viv CH; ZI viv .CH viv CH ; . 2H H ; ; CH ; N. ; 72H 2H CH -N . · CH3 ; viv CH ; COH viv CH .CH ; CHviv viv H3C CH viv OH ; CH; and indicates the point of attachment to the rest of the compound .

CH; wherein Clause 93. The compound of any one of clauses 1 to 75 , 78 , 81 , or 92 , wherein R3 is selected from the following groups : viv viv CH CH ; CN viv viv CH CH N viv F viv ' N ' CH CH viv N ' N ' viv N ZI .CH viv .CH vir CH viv H .N . CH viv .CH3 ﻊﻧﻯ viv viv OH ; viv viv CHS 2H viv 2H -2H .CH ; viv CHviv viv CH; and F ; and CH3 H3C viv OH CH; wherein indicates the point of attachment to the rest of the compound . Clause 94 . The compound of any one of clauses 1 to 76 , 78 , 79 , 81 , 82 , 84 , 86 to 88 , , or 93 , wherein R3 is selected from the following groups : viv .CH CH .CN viv IN CH CHN viv iv .CH CHviv H viv 2H 2H 2H F OH ; and ; wherein indicates the point of attachment to the rest of the compound .

Clause 95. The compound of any one of clauses 1 to 89 or 92 to 94 , wherein R3 is selected from the following groups : viv .CH ; CH ; viv viv viv viv viv viv N CH; CH CH CH viv viv viv F and ﻊﻧﻯ ; CH viv compound .

CH; wherein Clause 96 .

N .CH OH viv viv viv ; ; viv 2H 2H 2H .CH CH; and indicates the point of attachment to the rest of the The compound of any one of clauses 1 to 3 , or 20 to 95 , wherein 754 LO R4 is selected from C ( O ) OH , C ( O ) b4Rª4RN , C ( S ) NR ª4 R4 and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; and R4a and R4b are each independently selected from H and alkyl .

Clause 97. The compound of any one of clauses 1 to 3 or 20 to 96 , wherein R4 is selected from C ( O ) 4Rª4RN and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; and R4a and R4b are each independently selected from H and alkyl .

Clause 98. The compound of any one of clauses 1 to 7 or 20 to 96 , wherein R4 is selected from C ( O ) OH , C ( O ) NR4R4b , C ( S ) NR ª4 R4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S ; R4a is selected from H and ₁C - C4 alkyl ; and R4b is H.

Clause 99. The compound of any one of clauses 1 to 7 , 20 to 96 or 98 , wherein R4 is selected from C ( O ) OH , C ( O ) NR ª4 R4b , and C ( S ) b4Rª4RN ; Ra is selected from H and ₁C - C4 alkyl ; and R4b is H.

Clause 100. The compound of any one of clauses 1 to 10 or 20 to 99 , wherein R4 is selected from C ( O ) OH , C ( O ) NR4R4b and C ( S ) ª4RN R4b ; and R4a and R4b are each H.

Clause 101. The compound of any preceding clause , wherein R4 is C ( O ) NR4aR4b ; and R4a and R4b are each H.

Clause 102. The compound of any one of clauses 1 to 7 , or 20 to 96 , wherein R4 is selected from the following groups : 755 viv .OH NH NH ; wherein ' viv N viv CHN ; ; and indicates the point of attachment to the rest of the compound .

Clause 103. The compound of any one of clauses 1 to 10 , 20 to 98 , or 102 wherein R4 is selected from the following groups : viv .OH .NH S ; ; viv NH ; and CH wherein indicates the point of attachment to the rest of the compound .

Clause 104. The compound of any one of clauses 1 to 10 , 20 to 100 , 102 , or 103 wherein R4 is selected from the following groups : .OH viv .NHviv NH S ; and point of attachment to the rest of the compound . ; wherein Clause 105. The compound of any preceding clause , wherein R4 is indicates the viv compound .

NH ; wherein indicates the point of attachment to the rest of the Clause 106 . The compound of any one of clauses 1 to 4 or 20 to 105 , wherein R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , C1 - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycle having one or more heteroatoms selected from N , O and S.

Clause 107 . The compound of any one of clauses 1 to 4 or 20 to 106 , wherein R5 and R6 are each independently selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - Chaloalkyl , ₁C - C4 alkoxy , ₁C - C4 alkoxy - ₁C - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl and 5- or 6 - membered heteroaryl having one or more heteroatoms selected from N , O and S ; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycle having one or more heteroatoms selected from N and O.

Clause 108. The compound of any one of clauses 1 to 4 or 20 to 107 , wherein R5 is selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , ₁C - Calkoxy - C1 - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

Clause 109. The compound of any one of clauses 1 to 10 or 20 to 108 , wherein R5 is selected from H , ₁C - C4 alkyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

Clause 110. The compound of any one of clauses 1 to 13 or 20 to 101 , wherein R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S. 757 LO Clause 111. The compound of any one of clauses 1 to 10 or 20 to 110 , wherein R5 is selected from the following groups : HN H H3C . ; and wherein ' indicates the point of attachment to the rest of the compound .

Clause 112. The compound of any one of clauses 1 to 13 or 20 to 111 , wherein R5 is selected from the following groups : N H ; and HN ; wherein rest of the compound . Clause 113 . R5 is H. A compound of any preceding clause , wherein indicates the point of attachment to the Clause 114. The compound of any one of clauses 1 to 4 or 20 to 113 , wherein R6 is selected from H , halogen , OH , CN , ₁C - C4 alkyl , ₁C - C4 haloalkyl , ₁C - C4 alkoxy , C1 - Calkoxy - C1 - C4 alkyl , C3 - C8 cycloalkyl , 3- to 8 - membered heterocycloalkyl having one or more heteroatoms selected from N , O and S , phenyl , and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N , O and S.

Clause 115. The compound of any one of clauses 1 to 13 or 20 to 114 , wherein R6 is selected from H , ₁C - C4 alkyl , ₁C - C4 alkoxy , and C1 - C4 alkoxy - ₁C - C4 alkyl .

Clause 116. The compound of any one of clauses 1 to 16 or 20 to 115 , wherein R6 is selected from H and ₁C - C4 alkyl .

Clause 117. The compound of any one of clauses 1 to 13 or 20 to 115 , wherein R6 is selected from the following groups : 758 H H3C H3C .

; H3C ; and ; wherein indicates the point of attachment to the rest of the compound .

The compound of any one of clauses 1 to 16 or 20 to 117 , wherein Clause 118 . R6 is H or methyl .

Clause 119 . R6 is H. The compound of any preceding clause , wherein Clause 120. The compound of any one of clauses 1 to 4 , or 20 to 106 , wherein R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycle having one or more heteroatoms selected from N , O and S.

Clause 121. The compound of any one of clauses 1 to 4 , 20 to 107 , or 120 , wherein R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycle having one or more heteroatoms selected from N and O.

Clause 122. The compound of any one of clauses 1 to 4 , 20 to 107 , 20 , or 121 , wherein R5 and R6 together with the carbon atoms to which they are attached form a 5 - membered heterocycle containing one O atom .

Clause 123. A compound according to any preceding clause , wherein R7 , R8 , ºR , º¹R , R11 , and R12 are each H.

Clause 124. A compound of formula ( 2 ) : 759 R' L ' N. x2 ' A ( N / R R( 2 ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein : X1 , X2 , X3 , X4 , and X5 are as defined in clause 1 ; X7 is selected from CR10 , O , and N ; and q , L1 , R1 , R2 , R3 , R4 , and R10 are as defined in any preceding clause ; wherein when q is 0 , X7 is O or N , and when q is 1 , X7 is CR 10 .

Clause 125. A compound of formula ( 2a ) : 760 R R R N.

+ % N R+ ' N ' ( 2a ) R -R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein X1 , X5 , L1 , ¹R , R2 , R3 , R4 , R5 and R6 are as defined in any one of clauses 1 to 123 ; wherein one of X1 and X5 is C and the other is N.

Clause 126. A compound of formula ( 2aa ) : RL N. R RN R' N ' N R ³R- LO ( 2aa ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein L1 , R1 , ²R , ³R , R4 , R5 and R6 are as defined in any one of clauses 1 to 123 .

Clause 127 A compound of formula ( 2ab ) : R RN.

RN R' N ' ( 2ab ) R -R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein ¹L , ¹R , ²R , ³R , R4 , R5 and R6 are as defined in any one of clauses 1 to 123 .

Clause 128. A compound of formula ( 2ac ) : 762 R' L N R ' N ' .N .

N -R ( 2ac ) R including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein L ' , ¹R , ²R , ³R and R4 are as defined in any one of clauses 1 to 123 .

Clause 129. A compound of formula ( 2ad ) : R R R N.

N N ( 2ad ) R -R3 LO Including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein L1 , R1 , R2 , ³R , R4 , and R5 are as defined in any one of clauses 1 to 123 .

Clause 130. A compound of formula ( 2b ) : RL ' .N . R RN. R R' N ' R R( 2b ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein q , L1 , R1 , R2 , ³R , R4 , R5 , R6 and R10 are as defined in any of clauses 1 to 123 .

Clause 131. A compound of formula ( 3 ) : 764 RL RN N N R ³R- R( 3 ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein ¹L , R1 , R2 , ³R , R4 and R7 are as defined in any one of clauses 1 to 123 .

Clause 132. A compound of formula ( 4 ) : R RN.

+A X R R3 LO ( 4 ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein : X1 , X2 , X3 , X4 , and X5 are as defined in clause 1 ; X6 is selected from CR8R9 and O ; X7 is selected from CR11 R12 and O ; and ¹L , q , R1 , R2 , ³R , R4 , R8 , ºR , 1¹R , and R12 are as defined in any one of clauses 1 to 123 ; wherein when q is 0 , X7 is O ; and when X7 is O and q is 1 , X6 is CR8R9 .

Clause 133. A compound of formula ( 4a ) : R N. R R R' N ' ( 4a ) R ³R- including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein : ¹L , q , R1 , R2 , ³3R , R4 , and R6 are as defined in any one of clauses 1 to 123 .

Clause 134. A compound of formula ( 4b ) : 766 R RN.

R RR ³R R R ( 4b ) Including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein q , ¹L , ¹R , ²R , ³R , R4 , R5 , R6 , R11 and R12 are as defined in any one of clauses 1 to 123 .

Clause 135. A compound of formula ( 4c ) : R .N . R R R R⁹R R ³R LO ( 4c ) including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , wherein q , ¹L , ¹R , ²R , ³R , R4 , R5 , R6 , R8 and R ° are as defined in any one of clauses 1 to 123 .

Clause 136. The compound of clause 1 , wherein the compound is selected from compounds 1 to 242 as shown in Table 1 .

Clause 137 .

Clause 138 .

The compound of any of clauses 1 to 136 for use in medicine .

The compound for use of clause 137 , wherein the use is in the treatment or prophylaxis of a cancer or proliferative disease or disorder .

Clause 139. The compound for use of clause 137 , wherein the use is in the treatment or prophylaxis of fibrotic disease or inflammatory disease .

Clause 140. A pharmaceutical composition comprising a compound of any of clauses to 136 , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , and at least one pharmaceutically acceptable diluent , excipient or carrier .

Clause 141. The pharmaceutical composition of clause 140 for use according to any of clauses 137 to 140 .

Clause 142. A method of treatment comprising administration of a therapeutically effective amount of a compound of any of clauses 1 to 136 , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , to a patient in need thereof .

Clause 143. The method of clause 142 , wherein the patient has a cancer or proliferative disease or disorder . Clause 144. The method of clause 143 , wherein the patient has fibrotic disease or inflammatory disease . 768 LO Clause 145. A method of treating a cancer or proliferative disease or disorder , comprising administering one or more compound ( s ) according to any of clauses 1 to 136 , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , to a subject in need thereof .

Clause 146. A method of treating fibrotic disease or inflammatory disease , comprising administering one or more compound ( s ) according to any of clauses 1 to 136 , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , to a subject in need thereof .

Clause 147. The use of a compound according to any of clauses 1 to 136 , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for the manufacture of a medicament .

Clause 148. The use of a compound according to any of clauses 1 to 136 , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for the manufacture of a medicament for the treatment or prophylaxis of a cancer or proliferative disease or disorder .

Clause 149. The use of a compound according to any of clauses 1 to 136 , or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers , tautomer , isotopic form , pharmaceutically acceptable salt , solvate , prodrug , or pharmaceutically active metabolite thereof , or combinations thereof , for the manufacture of a medicament for the treatment or prophylaxis of fibrotic disease or inflammatory disease .

As used herein , it should be appreciated that the expression " selected from A , B or C " ( or analogous ) is intended to mean that a selection from the group of A , B and C is made ; and that the group may comprise or consist of the specified elements A , B and C. Similarly , the 769 LO phrase " selected from A , B and C " " ( or analogous ) is intended to mean that a selection from the group of A , B and C is made . Thus , no difference is intended by the inclusion of ‘ or ' or ' and ' in such phrases , unless otherwise stated or clear from the context of the disclosure . As will be appreciated , the phrase " selected from at least one of A , B or C " and the phrase " selected from at least one of A , B and C " are intended to include all combinations of one or more of the specified elements and no difference is intended by the inclusion of ‘ or ' or ' and ' , unless otherwise stated or clear from the context of the disclosure . Generally , it is intended that a recited list of alternatives , such as defined by e.g. the group of " A , B and C " , means . that the group is exclusive of additional alternatives , and so in preferred embodiments can be read to mean " selected from the group consisting of A , B and C " ( or analogously ) , unless otherwise stated .

Many modifications may be made to the above examples without departing from the scope of the present invention as defined in the accompanying claims . 770

Claims

CLAIMS:

1. A compound of formula (1): including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers, tautomer, isotopic form, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or combinations thereof, wherein:Q is 0 or S;X1 is selected from C and N;X2 is selected from CR5 and N;X3 is selected from CR6 and N;X4 is selected from CR7 and N;X5 is selected from C and N;wherein X1, X2, X3, X4 and X5 are selected so that the ring labelled A is aromatic;X6 is selected from CR8R9, 0 and N;X7 is selected from CR10, CR11R12, 0 and N;q is 0 or 1;wherein when q is 0, X7 is 0 or N; and when X7 is 0 or N and q is 1, X6 is CR8R9;L1 is a bond, C1-C6 alkylene, C1-Cehaloalkylene, C3-C6 cycloalkylene, or a 5-or 6-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S; 771 R1 is selected from C1-C4 alkyl, C3-Cs cycloalkyl, C7-C11 bicyclic cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more ring members selected from N, 0, S and SO2, 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N, 0, S and SO2, phenyl, C9-C10 bicyclic aryl, 5- or 6- membered heteroaryl having one or more ring members selected from N, 0, S and SO2, 8- to 10-membered bicyclic heteroaryl having one or more ring members selected from N, O, S and SO2, phenoxy, and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N, O and S, wherein said alkyl, cycloalkyl, bicyclic cycloalkyl, heterocycloalkyl, bicyclic heterocycloalkyl, phenyl, bicyclic aryl, heteroaryl, bicyclic heteroaryl, phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen, OH, CN, NR1aR1b, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4alkyl-NR1aR1b, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl, 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S, benzyl, phenoxy, halophenoxy, 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N, O and S, and C1-C4 alkyl substituted by a 5- or 6-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S;R1a and R1b are each independently selected from H and C1-C4 alkyl;R2 is selected from H, C1-C4 alkyl and C3-C8 cycloakyl;or R1, R2 and L1 and the nitrogen atom to which R2 and L1 are attached form a 3- to 8- membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, 8- to 11 -membered bicyclic heterocycloalkyl having one or more heteroatoms selected from N, and S, 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S, or 8- to 10-membered bicyclic heteroaryl having one or more heteroatoms selected from N, O and S, wherein said heterocycloalkyl, bicyclic heterocycloalkyl, heteroaryl and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, OH, CN, NR1aR1b, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-Chaloalkoxy and C1-C4 alkyl-NR1aR1b;R3 is selected from H, OH, CN, NR3aR3b, C1-C4 alkyl, C3-Cg cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl, and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S, Cr C4 alkoxy-C1-C4 alkyl, C1-C4 haloalkoxy-C1-C4 alkyl, C3-C8 cycloalkoxy-C1-C4 alkyl, C3-Ccycloalkyl-C1-C4alkoxy, C1-C4 alkyl-S-C1-C4 alkyl, and C1-C4 alkyl-SO2- C1-C4 alkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, OH, CN, C1-C4 alkyl, and NR3cR3d;R3a is selected from H, C-C4 alkyl, C-C4 alkyl-OH, and C1-C4 alkyl-NR3eR3f;772 R3b, R3c, R3d, R3e and R3f are each independently selected from H and C1-C4 alkyl;R4 is selected from C(O)OH, C(O)NR4aR4b, C(S)NR4aR4b and 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S;R4a and R4b are each independently selected from H and C1-C4 alkyl;R5 and R6 are each independently selected from H, halogen, OH, CN, C1-C4 alkyl, C1-Chaloalkyl, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N, O and S; and R7, R8, R9, R10, R11, and R12 are each independently selected from H, halogen, OH, CN, Cr C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S.

2. The compound of claim 1, whereinL1 is a bond, C1-C6 alkylene, C1-Cehaloalkylene, C3-C6 cycloalkylene, or a 5-or 6-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S;R1 is selected from C1-C4 alkyl, C3-Cg cycloalkyl, C7-C11 bicyclic cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more ring members selected from N, O, S and SO2, 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N, 0, S and SO2, phenyl, C9-C10 bicyclic aryl, 5- or 6- membered heteroaryl having one or more ring members selected from N, 0, S and SO2, 8- to 10-membered bicyclic heteroaryl having one or more ring members selected from N, O, S and SO2, phenoxy, and 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N, O and S, wherein said alkyl, cycloalkyl, bicyclic cycloalkyl, heterocycloalkyl, bicyclic heterocycloalkyl, phenyl, bicyclic aryl, heteroaryl, bicyclic heteroaryl, phenoxy and heteroaryloxy are each optionally substituted by one or more substituents independently selected from halogen, OH, CN, NR1aR1b, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4alkyl-NR1aR1b, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl, 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S, benzyl, phenoxy, halophenoxy, 5- or 6- membered heteroaryloxy having one or more heteroatoms selected from N, O and S, and C1-C4 alkyl substituted by a 5- or 6-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S;R1a and R1b are each independently selected from H and C1-C4 alkyl;R2 is selected from H, C1-C4 alkyl and C3-C8 cycloakyl;773 R3 is selected from H, OH, CN, NR3aR3b, C1-C4 alkyl, C3-Cs cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl, and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S, Cr C4 alkoxy-C1-C4 alkyl, C1-C4 haloalkoxy-C1-C4 alkyl, C3-C8 cycloalkoxy-C1-C4 alkyl, C3-Ccycloalkyl-C1-C4alkoxy, C1-C4 alkyl-S-C1-C4 alkyl, and C1-C4 alkyl-SO2- C1-C4 alkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, OH, CN, C1-C4 alkyl, and NR3cR3d;R3a is selected from H, C1-C4 alkyl, C1-C4 alkyl-OH, and C1-C4 alkyl-NR3eR3f;R3b, R3c, R3d, R3e and R3f are each independently selected from H and C1-C4 alkyl;R4 is selected from C(O)OH, C(O)NR4aR4b, C(S)NR4aR4b and 5- or 6-membered heteroaryl having one or more heteroatoms selected from N, O and S;R4a and R4b are each independently selected from H and C1-C4 alkyl;R5 and R6 are each independently selected from H, halogen, OH, CN, C1-C4 alkyl, C1-Chaloalkyl, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S; or R5 and R6 together with the carbon atoms to which they are attached form a 5- or 6- membered heterocycloalkyl having one or more heteroatoms selected from N, O and S; and R7, R8, R9, R10, R11, and R12 are each independently selected from H, halogen, OH, CN, Cr C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S.

3. The compound of claim 1 or claim 2, whereinL1 is a bond, C1-C6 alkylene, C1-Cehaloalkylene, C3-C6 cycloalkylene, or a 5-or 6-memberedheterocycloalkyl having one or more heteroatoms selected from N, O and S;R1 is selected from C1-C4 alkyl, C3-Cg cycloalkyl, C7-C11 bicyclic cycloalkyl, 3- to 8-memberedheterocycloalkyl having one or more ring members selected from N, O, S and SO2, 8- to 11-membered bicyclic heterocycloalkyl having one or more ring members selected from N, 0,S and SO2, phenyl, 5- or 6- membered heteroaryl having one or more ring members selectedfrom N, 0, S and SO2, 8- to 10-membered bicyclic heteroaryl having one or more ringmembers selected from N, O, S and SO2, and phenoxy, wherein said alkyl, cycloalkyl, heterocycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, phenyl, heteroaryl, bicyclic heteroaryl, and phenoxy are each optionally substituted by one or more substituents independently selected from halogen, OH, CN, NR1aR1b, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 haloalkoxy, C1-C4 alkyl-NR1aR1b, C3-C8 cycloalkyl, 3- to 8-membered774 heterocycloalkyl having one or more heteroatoms selected from N, 0 and S, 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S, benzyl, halophenoxy, and C1-C4 alkyl substituted by a 5- or 6-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S;R1a and R1b are each independently selected from H and C1-C4 alkyl;R2 is H;R3 is selected from H, CN, NR3aR3b, C1-C4 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl, 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S, C1-Calkoxy-C1-C4 alkyl, C1-C4 haloalkoxy-C1-C4 alkyl, C3-C8 cycloalkoxy-C1-C4 alkyl, C3-Cg cycloalkyl-C1-C4alkoxy, C1-C4 alkyl-S-C1-C4 alkyl, and C1-C4 alkyl-SO2-C1-C4 alkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, OH, C1-C4 alkyl, and NR3cR3d;R3a is selected from H, C1-C4 alkyl, and C1-C4 alkyl-NR3eR3f;R3b is selected from H and C1-C4 alkyl;R3c is selected from H and C1-C4 alkyl;R3d is selected from C1-C4 alkyl;R3e and R3f are each independently selected from C1-C4 alkyl;R4 is selected from C(O)OH, C(O)NR4aR4b, C(S)NR4aR4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S;R4a is selected from H and C1-C4 alkyl;R4b is H;R5 is selected from H, C1-C4 alkyl, and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S;R6 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4alkoxy-C1-C4alkyl; andR7, R8, R9, R10, R11, and R12 are each H.

4. The compound of any preceding claim, whereinL1 is a bond, C1-C6 alkylene, C1-Cehaloalkylene, or C3-C6 cycloalkylene;R1 is selected from C1-C4 alkyl, C3-Cg cycloalkyl, C7-C11 bicyclic cycloalkyl, 3- to 8-memberedheterocycloalkyl having one or more ring members selected from N, O, S and SO2, 8- to 11-membered bicyclic heterocycloalkyl having one or more ring members selected from N, 0,S and SO2, phenyl, 5- or 6- membered heteroaryl having one or more ring members selectedfrom N, O, S and SO2, 8- to 10-membered bicyclic heteroaryl having one or more ringmembers selected from N, O, S and SO2, and phenoxy, wherein said alkyl, cycloalkyl,heterocycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, phenyl, heteroaryl, bicyclic775 heteroaryl, and phenoxy are each optionally substituted by one or more substituents independently selected from halogen, CN, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkyl-NR1aR1b, C3-Ce cycloalkyl, 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S, benzyl, and C1-C4 alkyl substituted by a 5- or 6-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S;R1a and R1b are each independently selected from H and C1-C4 alkyl;R2 is H;R3 is selected from H, CN, NR3aR3b, C1-C4 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl, 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S, C1-Calkoxy-C1-C4 alkyl, C1-C4 haloalkoxy-C1-C4 alkyl, C3-C8 cycloalkoxy-C1-C4 alkyl, C3-Cg cycloalkyl-C1-C4alkoxy, C1-C4 alkyl-S-C1-C4 alkyl, and C1-C4 alkyl-SO2-C1-C4 alkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, OH and NR3cR3d;R3a is selected from H and C1-C4 alkyl;R3b is selected from C1-C4 alkyl;R3c is selected from H and C1-C4 alkyl;R3d is selected from C1-C4 alkyl;R4 is selected from C(O)OH, C(O)NR4aR4b, C(S)NR4aR4b and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S;R4a is selected from H and C1-C4 alkyl;R4b is H ;R5 is selected from H, C1-C4 alkyl, and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S;R6 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4alkoxy-C1-C4alkyl; and R7, R8, R9, R10, R11, and R12 are each H.

5. The compound of any preceding claim, whereinL1 is a bond, C1-C6 alkylene, C1-Cehaloalkylene, or C3-C6 cycloalkylene;R1 is selected from C3-C8 cycloalkyl, C7-C11 bicyclic cycloalkyl, 3- to 8-memberedheterocycloalkyl having one or more ring members selected from N, 0, S and SO2, 8- to 11-membered bicyclic heterocycloalkyl having one or more ring members selected from N, 0,S and SO2, phenyl, 5- or 6- membered heteroaryl having one or more ring members selectedfrom N, O, S and SO2, and 8- to 10-membered bicyclic heteroaryl having one or more ringmembers selected from N, 0, S and SO2, wherein said cycloalkyl, bicyclic cycloalkyl, heterocycloalkyl, bicyclic heterocycloalkyl, phenyl, heteroaryl, and bicyclic heteroaryl are776 each optionally substituted by one or more substituents independently selected from halogen, CN, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkyl- NR1aR1b, and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S;R1a and R1b are each independently selected from H and C1-C4 alkyl;R2 is H;R3 is selected from H, CN, NR3aR3b, C1-C4 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, phenyl, 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S, C1-Calkoxy-C1-C4 alkyl, C1-C4 haloalkoxy-C1-C4 alkyl, C3-C8 cycloalkoxy-C1-C4 alkyl, C3-Cg cycloalkyl-C1-C4alkoxy, C1-C4 alkyl-S-C1-C4 alkyl, and C1-C4 alkyl-SO2-C1-C4 alkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, OH and NR3cR3d;R3a is selected from H and C1-C4 alkyl;R3b is selected from C1-C4 alkyl;R3c is selected from H and C1-C4 alkyl;R3d is selected from C1-C4 alkyl;R4 is selected from the following groups: O ; S ; anc| O ; and ° wherein •ל indicates the point of attachment to the rest of the compound;R5 is selected from H and 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S;R6 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4alkoxy-C1-C4alkyl; andR7, R8, R9, R10, R11, and R12 are each H.

6. The compound of any preceding claim, whereinL1 is a bond, C1-C6 alkylene, or C3-C6 cycloalkylene;R1 is selected from C3-C8 cycloalkyl, C7-C11 bicyclic cycloalkyl, 3- to 8-memberedheterocycloalkyl having one or more ring members selected from N, O, S and SO2, 8- to 11-membered bicyclic heterocycloalkyl having one or more ring members selected from N, 0,S and SO2, phenyl, 5- or 6- membered heteroaryl having one or more ring members selectedfrom N, O, S and SO2, and 8- to 10-membered bicyclic heteroaryl having one or more ring 777 members selected from N, 0, S and SO2, wherein said cycloalkyl, heterocycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, phenyl, heteroaryl, and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy;R2 is H;R3 is selected from H, CN, NR3aR3b, C1-C4 alkyl optionally substituted by OH, C3-Ca cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S, C1-C4alkoxy-C1-C4alkyl, C3-C8cycloalkyl-C1-C4 alkoxy, C1-C4 haloalkoxy- C1-C4 alkyl״ C1-C4 alkyl-S-C1-C4 alkyl, and C1-C4 alkyl-SO2-C1-C4 alkyl;R3a is H;R3b is selected from C1-C4 alkyl;R4 is selected from the following groups: O ; S ; anc| O ; wherein indicates the point of attachment to the rest of the compound;R5 is H;R6 is selected from H and C1-C4 alkyl; andR7, R8, R9, R10, R11, and R12 are each H.

7. The compound of any preceding claim, whereinL1 is either a bond or C1-Ce alkylene;R1 is selected from C3-C8 cycloalkyl, Ca-C11 bicyclic cycloalkyl, 3- to 8-membered heterocycloalkyl having one or more ring members selected from N, 0, S and SO2, 8- to 11- membered bicyclic heterocycloalkyl having one or more ring members selected from N, 0,S and SO2, phenyl, 5- or 6- membered heteroaryl having one or more ring members selected from N, O, S and SO2, and 8- to 10-membered bicyclic heteroaryl having one or more ring members selected from N, 0, S and SO2, wherein said cycloalkyl, bicyclic cycloalkyl, heterocycloalkyl, bicyclic heterocycloalkyl, phenyl, heteroaryl, and bicyclic heteroaryl are each optionally substituted by one or more substituents independently selected from halogen, OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy;R2 is H;R3 is selected from NR3aR3b, C1-C4 alkyl optionally substituted by one or more substituents independently selected from OH and NR3cR3d, C3-C8 cycloalkyl, 3- to 8-membered 778 heterocycloalkyl having one or more heteroatoms selected from N, 0 and S, 5- or 6- membered heteroaryl having one or more heteroatoms selected from N, O and S, C3-Ccycloalkoxy-C1-C4 alkyl, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 haloalkoxy-C1-C4 alkyl, C3-Cg cycloalkyl-C1-C4alkoxy, and alkyl-S-C1-C4 alkyl;R3a is H;R3b is selected from C1-C4 alkyl;R4 is selected from the following groups: O ؛ S ؛ and O ; wherein J indicates the point of attachment to the rest of the compoundR5, R7, R8, R9, R10, R11, and R12 are each H; andR6 is selected from H and C1-C4 alkyl.

8. The compound of any preceding claim, wherein Q is O.

9. The compound of any preceding claim, wherein L1 is either a bond or methylene.

10. The compound of any preceding claim, whereinR1 is selected from:C3 -C8 cycloalkyl optionally substituted by one or more substituents independently selected from halogen and C1-C4 haloalkoxy;C8 -C11 bicyclic cycloalkyl optionally substituted by one or more substituents independently selected from halogen, OH, C1-C4 alkyl and C1-C4 alkoxy;3- to 8-membered heterocycloalkyl having one or more ring members selected from N, O, S and SO2;8- to 11-membered bicyclic heterocycloalkyl having one or more ring members selected from N, O, S and SO2, optionally substituted by one or more substituents independently selected from halogen;ph enyl optionally substituted by one or more substituents independently selected from halogen and C1-C4 alkyl;5- or 6- membered heteroaryl having one or more ring members selected from N, O, S and SO2, optionally substituted by one or more substituents independently selected from C1-C4 alkyl and C1-C4 haloalkyl; and 779 8- to 10-membered bicyclic heteroaryl having one or more ring members selected from N, 0, S and SO2, optionally substituted substituted by one or more substituents independently selected from halogen and C1-C4 alkyl.

11. The compound of any preceding claim, wherein R2 is H.

12. The compound of any preceding claim, whereinR3 is selected from:- NR3aR3b;C1-C4 alkyl optionally substituted by OH;C3-C8 cycloalkyl;3- to 8-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S;5- or 6- membered heteroaryl having one or more heteroatoms selected from N, and S;C1-C4alkoxy-C1-C4 alkyl;C3-C8 cycloalkyl-C1-C4 alkoxy;C3-C8cycloalkoxy-C1-C4 alkyl;C1-C4haloalkoxy-C1-C4alkyl; andC1-C4 alkyl-S-C1-C4 alkyl;whereinR3a is H; andR3b is selected from C1-C4 alkyl.

13. The compound of any preceding claim, wherein R3 is selected from C1-C4alkoxy-C1- C4 alkyl.

14. The compound of any one of claims 1 to 3 or 8 to 13, whereinR4 is selected from the following groups: 780

15. S , wherein j indicates the point of attachment to the rest of thecompound. 5 15. A compound of any preceding claim, whereinR5 is H.

16. The compound of any preceding claim, wherein R6 is H or methyl.

17. A compound according to any preceding claim, wherein R7, R8, R9, R10, R11, and R12 are each H.

18. A compound of formula (2a): 15(2a) 781 including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers, tautomer, isotopic form, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or combinations thereof, wherein X1, X5, L1, R1, R2, R3, R4, R5 and R6 are as defined in any one of claims 1 to 16;wherein one of X1 and X5 is C and the other is N.

19. A compound of formula (2aa): 10 including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers, tautomer, isotopic form, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or combinations thereof, wherein L1, R1, R2, R3, R4, R5 and R6 are as defined in any one of claims 1 to 16. 15

20. A compound of formula (2ab): 782 (2ab)including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers, tautomer, isotopic form, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or combinations thereof, wherein L1, R1, R2, R3, R4, R5 and R6 are as defined in any one of claims 1 to 16.

21. A compound of formula (2ad): 783 Including any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers, tautomer, isotopic form, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or combinations thereof, wherein L1, R1, R2, R3, R4, and R5 are as defined in any one of claims 1 to 16.

22. The compound of claim 1, wherein the compound is selected from compounds 1 to 242.

23. The compound of any of claims 1 to 22 for use in medicine.

24. The compound for use of claim 23, wherein the use is in the treatment or prophylaxisof a cancer or proliferative disease or disorder.

25. The compound for use of claim 23, wherein the use is in the treatment or prophylaxis of fibrotic disease or inflammatory disease.

26. A pharmaceutical composition comprising a compound of any of claims 1 to 22, or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers, tautomer, isotopic form, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or combinations thereof, and at least one pharmaceutically acceptable diluent, excipient or carrier.

27. The pharmaceutical composition of claim 26 for use according to any of claims 23 to25. 784