NZ732394B2 - Parg inhibitory compounds - Google Patents

Parg inhibitory compounds

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Publication number
NZ732394B2
NZ732394B2 NZ732394A NZ73239415A NZ732394B2 NZ 732394 B2 NZ732394 B2 NZ 732394B2 NZ 732394 A NZ732394 A NZ 732394A NZ 73239415 A NZ73239415 A NZ 73239415A NZ 732394 B2 NZ732394 B2 NZ 732394B2
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NZ
New Zealand
Prior art keywords
methyl
methylcyclopropyl
oxo
benzimidazolesulfonamide
alkyl
Prior art date
Application number
NZ732394A
Other versions
NZ732394A (en
Inventor
Niall M Hamilton
James R Hitchin
Colin P Hutton
Allan M Jordan
Alison E Mcgonagle
Kate M Smith
Ian D Waddell
Bohdan Waszkowycz
Original Assignee
Cancer Research Technology Limited
Filing date
Publication date
Application filed by Cancer Research Technology Limited filed Critical Cancer Research Technology Limited
Priority claimed from PCT/GB2015/054064 external-priority patent/WO2016097749A1/en
Publication of NZ732394A publication Critical patent/NZ732394A/en
Publication of NZ732394B2 publication Critical patent/NZ732394B2/en

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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The present invention relates to compounds of formula I that function as inhibitors of PARG (Poly ADP-ribose glycohydrolase) enzyme activity: wherein R1a, R1b, R1c, R1d, R1e, W, X1, X2, X3, X4, X5, X6, X7, c are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which PARG activity is implicated.

Claims (26)

1. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structural formula (II) shown below: wherein: R1a is selected from , chloro, cyano, formyl, (1-2C)alkyl, (1-2C) haloalkyl, (2C)alkenyl, or (2C)alkynyl; 10 R1b, R1c, R1d, and R1e are each independently selected from H, fluoro or ; X1 is selected from CR2 or N; wherein R2 is H or fluoro; X2 is selected from CR3 or N; wherein R3 is H or fluoro; X3 is selected form CR4 or N; wherein R4 is H, halo, cyano, (1-2C)alkyl, (1-2C) kyl, (1- 2C)alkoxy, (1-2C)haloalkoxy or (2C)alkynyl; or 15 R4 is ed from a group of the formula: -L4-L4C-Q4C wherein L4 is absent or (1-3C)alkylene optionally substituted by (1-2C)alkyl or 20 L4C is absent or selected from O, S, SO, SO2, N(R4b), C(O), C(O)O, OC(O), C(O)N(R4b), N(R4b)C(O), N(R4b)C(O)N(R4c), S(O)2N(R4b), or N(R4b)SO2, wherein R4b and R4c are each independently selected from en or (1-2C)alkyl; and 20458597_1 (GHMatters) P106062.NZ Q4C is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q4C is optionally substituted by one or more tuents selected from halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, 5 NR4dR4e, OR4d, C(O)R4d, C(O)OR4d, OC(O)R4d, C(O)N(R4e)R4d, N(R4e)C(O)R4d, 4d (where y is 0, 1 or 2), SO2N(R4e)R4d, N(R4e)SO2R4d or (CH2)zNR4eR4d (where z is 1, 2 or 3), wherein R4d and R4e are each independently selected from H or (1-4C)alkyl; HET is a fused 5-membered ted, partially saturated or rated heterocyclic ring of 10 formula: wherein bond a is optionally a double bond; R5 is H, (1-4C)alkyl or a group of the formula: 15 -L1-L5-Q5 wherein L1 is absent or selected from (1-3C)alkylene optionally substituted by (1- 2C)alkyl or oxo, or a (2-3C)alkenylene or (2-3C)alkynylene linker that is optionally substituted by (1-2C)alkyl; 20 L5 is absent or selected from C(O), C(O)O, OC(O), C(O)N(Ra), N(Ra)C(O), N(Ra)C(O)N(Rb), S(O)2N(Ra), or O2, wherein Ra and Rb are each independently selected from hydrogen or (1-2C)alkyl; and Q5 is selected from hydrogen, (1-4C)alkyl, aryl, 5-6 membered heteroaryl, (4- 6C)cycloalkyl, cycloalkenyl, (2C)alkenyl or 5-6 membered heterocyclyl; 25 and wherein Q5 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, amino, cyano, carboxy, oyl, sulphamoyl, trifluoromethoxy, haloalkyl, NRcRd, ORc, C(O)Rc, C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, N(Rc)C(O)Rd, S(O)yRc (where y is 0, 1 or 2), c)Rd, 20458597_1 (GHMatters) P106062.NZ N(Rc)SO2Rd or (CH2)zNRcRd (where z is 1, 2 or 3), wherein Rc and Rd are each independently selected from H or (1-4C)alkyl; or Q5 is ally substituted by a group of the formula; -W5-Y5-Z5 5 wherein W5 is absent or selected from (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo, or a (2-3C)alkenylene or (2-3C)alkynylene linker that is optionally substituted by (1-2C)alkyl; Y5 is absent or selected from C(O), C(O)O, OC(O), Re), 10 N(Re)C(O), N(Re)C(O)N(Rf), S(O)2N(Re), or N(Re)SO2, wherein Re and Rf are each independently selected from hydrogen or alkyl; and Z5 is selected from hydrogen, (1-4C)alkyl, phenyl, 5 or 6-membered heterocyclyl or a 5-6 membered heteroaryl; and wherein Z5 is optionally substituted by one or more substituents selected from (1- 15 yl, halo, haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1- 4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl or moyl; X4 is selected from C(=O), CHR6c when bond a is a single bond, or CR6c or N when bond a is a double bond; 20 wherein R6c is selected from hydrogen, or a group of the formula: -L6-L6C-Q6C wherein L6 is absent or (1-3C)alkylene optionally substituted by (1-2C)alkyl or 25 oxo; L6C is absent or selected from O, S, SO, SO2, N(Rg), C(O), C(O)O, OC(O), C(O)N(Rg), N(Rg)C(O), N(Rg)C(O)N(Rh), S(O)2N(Rg), or N(Rg)SO2, wherein Rg and Rh are each independently selected from hydrogen or alkyl; and 20458597_1 (GHMatters) P106062.NZ Q6C is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or aryl, each of which is optionally substituted by one or more tuents selected from (1-2C)alkyl, halo or trifluoromethyl; X5 is selected from C(=O), C(=NH), C(=S), CHR7c or N-R7N when bond a is a single bond, or 5 CR7c or N when bond a is a double bond; wherein R7c is selected from hydrogen, cyano, halo or a group of the formula: -L7-L7C-Q7C 10 L7 is absent or (1-3C)alkylene optionally tuted by (1-2C)alkyl or L7C is absent or selected from O, S, SO, SO2, N(Ro), C(O), C(O)O, OC(O), C(O)N(Ro), N(Ro)C(O), N(Ro)C(O)N(Rp), S(O)2N(Ro), or N(Ro)SO2, wherein Ro and Rp are each independently selected from 15 hydrogen or (1-2C)alkyl; and Q7C is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3- 6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q7C is optionally substituted by one or more tuents selected from (1- 4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, nitro, 20 y, carboxy, carbamoyl, sulphamoyl, NRqRr, ORq, C(O)Rq, C(O)ORq, OC(O)Rq, C(O)N(Rq)Rr, N(Rq)C(O)Rr, S(O)yRq (where y is 0, 1 or 2), SO2N(Rq)Rr, O2Rr or (CH2)zNRqRr (where z is 1, 2 or 3), wherein Rq and Rr are each independently selected from H or (1- 4C)alkyl; or 25 Q7C is optionally substituted by a group of the formula: -W7C-L7’-Z7C wherein W7C is absent or (1-3C)alkylene substituted by (1-2C)alkyl or 30 L7’ is absent or selected from C(O), C(O)O, OC(O), C(O)N(Rs), N(Rs)C(O), N(Rs)C(O)N(Rt), S(O)2N(Rs), or O2, wherein 20458597_1 (GHMatters) P106062.NZ Rs and Rt are each ndently selected from hydrogen or (1- 2C)alkyl; and Z7C is phenyl or 5-6 membered heteroaryl; each of which is optionally substituted by one or more substituents selected from 5 (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1- 4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl or sulphamoyl; R7N is selected from hydrogen or a group of the formula: -L7-L7N-Q7N 10 wherein L7 is absent or (1-3C)alkylene optionally substituted by (1- 2C)alkyl; L7N is absent or selected from O, S, SO, SO2, N(Ru), C(O), C(O)O, OC(O), C(O)N(Ru), N(Ru)C(O), N(Ru)C(O)N(Rv), 15 S(O)2N(Ru), or N(Ru)SO2, n Ru and Rv are each independently selected from en or (1-2C)alkyl; and Q7N is en, cyano, (1-6C)alkyl, (2C)alkynyl, (2- 3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more 20 substituents selected from (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, moyl, NRwRx, ORw, , C(O)ORw, OC(O)Rw, C(O)N(Rw)Rx, N(Rw)C(O)Rx, S(O)yRw (where y is 0, 1 or 2), w)Rx, N(Rw)SO2Rx or (CH2)zNRwRx (where z is 1, 2 or 25 3), wherein Rw and Rx are each independently selected from H or (1-4C)alkyl; or Q7N is optionally substituted by a group of the formula: -W7N-L7’-Z7N wherein 30 W7N is absent or (1-3C)alkylene ally substituted by (1-3C)alkyl; 20458597_1 (GHMatters) P106062.NZ L7’ is absent or selected from C(O), C(O)O, OC(O), C(O)N(Ry), N(Ry)C(O), N(Ry)C(O)N(Rz), S(O)2N(Ry), or N(Ry)SO2, wherein Ry and Rz are each independently selected from hydrogen or (1-2C)alkyl; and 5 Z7N is phenyl or 5-6 membered aryl; each of which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, haloalkyl, (1- 4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, oyl or sulphamoyl; 10 with the proviso that: (i) only one or two of R1b-e can be selected from any substituent other than H; (ii) only one or two of X1, X2 or X3 can be N; (iii) Het may only comprise up to 2 ring nitrogen atoms; and (iv) only one of X4 or X5 can be selected from C(=O), C(=NH) or C(=S).
2. A compound according to claim 1, wherein R1a is selected from fluoro, cyano, formyl, (1-2C)alkyl, (1-2C) haloalkyl or (2C)alkynyl.
3. A compound according to claim 2, n R1a is selected from cyano or alkyl.
4. A compound according to any one of claims 1-3, wherein X1 is CR2; wherein R2 is H or fluoro.
5. A compound according to claim 4, wherein X1 is C-H.
6. A compound according to any preceding claim, wherein X2 is CR3; n R3 is H or fluoro.
7. A compound according to any preceding claim, wherein X3 is selected from CR4 or N; 30 wherein R4 is H, halo, cyano or (1-2C)haloalkyl. 97_1 (GHMatters) P106062.NZ
8. A compound according to any one of claims 1 to 6, wherein X3 is selected from CR4 or N; wherein R4 has the formula: -L4-L4C-Q4C 5 wherein L4 is absent or (1-3C)alkylene optionally tuted by (1-2C)alkyl or oxo; L4C is absent or selected from O, S, SO, SO2, N(R4b), C(O), C(O)O, OC(O), C(O)N(R4b), N(R4b)C(O), C(O)N(R4c), S(O)2N(R4b), or N(R4b)SO2, wherein R4b and R4c are each independently selected from hydrogen or (1-2C)alkyl; and 10 Q4C is hydrogen, (1-6C)alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q4C is optionally substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, e, OR4d, C(O)R4d, C(O)OR4d, OC(O)R4d, C(O)N(R4e)R4d, N(R4e)C(O)R4d, S(O)yR4d (where y is 0, 1 or 2), SO2N(R4e)R4d, SO2R4d or (CH2)zNR4eR4d (where z is 1, 2 or 3), 15 wherein R4d and R4e are each independently selected from H or (1-4C)alkyl.
9. A compound according to claim 7, wherein X3 is C-H or C-F.
10. A compound ing to any one of the preceding , wherein R1b, R1c, R1d and 20 R1e are H.
11. A compound according to any one of the preceding claims, wherein R5 is H, (1- 4C)alkyl or a group of the formula: -L1-L5-Q5 25 wherein L1 is absent or selected from (1-3C)alkylene optionally substituted by (1- yl or oxo; L5 is absent or selected from C(O), C(O)O, OC(O), C(O)N(Ra), or N(Ra)C(O), wherein Ra is selected from hydrogen or (1-2C)alkyl; and 20458597_1 (GHMatters) P106062.NZ Q5 is selected from hydrogen, (1-4C)alkyl, aryl, 5-6 ed heteroaryl, (4- loalkyl, (4-6C)cycloalkenyl, (2C)alkenyl or 5-6 membered heterocyclyl; and wherein Q5 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, amino, cyano, carboxy, carbamoyl, sulphamoyl, 5 trifluoromethoxy, haloalkyl, NRcRd, ORc, , C(O)ORc, OC(O)Rc, C(O)N(Rc)Rd, (O)Rd, wherein Rc and Rd are each independently selected from H or alkyl; or Q5 is optionally substituted by a group of the formula; -W5-Y5-Z5 10 wherein W5 is absent or selected from (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo, or a (2-3C)alkenylene or (2-3C)alkynylene linker that is optionally substituted by (1-2C)alkyl; Y5 is absent or ed from C(O), C(O)O, OC(O), C(O)N(Re), 15 N(Re)C(O), N(Re)C(O)N(Rf), S(O)2N(Re), or N(Re)SO2, wherein Re and Rf are each independently selected from hydrogen or (1-2C)alkyl; and Z5 is selected from hydrogen, (1-4C)alkyl, phenyl, 5 or ered cyclyl or a 5-6 membered heteroaryl; and wherein Z5 is optionally substituted by one or more substituents selected from (1- 20 yl, halo, (1-2C)haloalkyl, haloalkoxy, (1-2C)alkoxy, (1- 2C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl or sulphamoyl.
12. A compound of any one of the preceding claims, wherein R5 is H, (1-4C)alkyl or a 25 group of the formula: -L1-L5-Q5 wherein L1 is absent or (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo; L5 is absent or selected from C(O), C(O)O, OC(O), C(O)N(Ra), or N(Ra)C(O), 30 wherein Ra and Rb are each independently selected from hydrogen or (1- 2C)alkyl; and 20458597_1 (GHMatters) P106062.NZ Q5 is ed from hydrogen, (1-4C)alkyl, aryl, 5-6 membered heteroaryl, (4- 6C)cycloalkyl, cycloalkenyl, (2C)alkenyl or 5-6 membered heterocyclyl; and wherein Q5 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, amino, cyano, haloalkyl, NRcRd, ORc, C(O)Rc, wherein 5 Rc and Rd are each independently ed from H or (1-2C)alkyl; or Q5 is optionally substituted by a group of the formula; -W5-Y5-Z5 wherein W5 is absent or (1-3C)alkylene; 10 Y5 is absent or selected from C(O), C(O)O, OC(O), or Re), wherein Re is selected from en or (1-2C)alkyl; and Z5 is selected from hydrogen, (1-4C)alkyl, , or a 5-6 membered heteroaryl; and wherein Z5 is optionally substituted by one or more substituents selected from (1-2C)alkyl or halo.
13. A compound of any one of the ing , wherein R5 is a 5- or 6-membered heteroaryl, optionally substituted by one or more substituents selected from (1-2C)alkyl, halo, amino, cyano, carboxy, carbamoyl, CF3, CHF2, NRcRd, ORc or C(O)Rc, wherein Rc and Rd are each independently selected from H or (1-2C)alkyl.
14. A compound according to claim 13, wherein the 5-membered heteroaryl is selected from pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups and the 6- membered heteroaryl group is selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and 25 triazinyl.
15. A compound of any one of the ing claims, wherein R5 is a thiadiazole or oxadiazole, optionally substituted by one or more substituents ed from alkyl, halo, amino, cyano, carboxy, carbamoyl, CF3, CHF2, NRcRd, ORc or C(O)Rc, wherein Rc and 30 Rd are each independently selected from H or (1-2C)alkyl. 20458597_1 (GHMatters) P106062.NZ
16. A compound according to any one of the preceding claims, wherein X5 is selected from C(=O), C(=NH), C(=S), CHR7c or N-R7N when bond a is a single bond, or CR7c or N when bond a is a double bond; wherein 5 R7c is selected from hydrogen, cyano, halo or a group of the a: -L7-L7C-Q7C L7 is absent or alkylene optionally substituted by (1-2C)alkyl or 10 L7C is absent or selected from O, S, SO, SO2, N(Ro), C(O), C(O)O, OC(O), C(O)N(Ro), N(Ro)C(O), wherein Ro is selected from hydrogen or (1-2C)alkyl; and Q7C is hydrogen, cyano, (1-4C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3- 6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q7C is 15 optionally substituted by one or more substituents selected from (1- 2C)alkyl, halo, trifluoromethyl, oromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl or sulphamoyl; R7N is selected from hydrogen or a group of the formula: -L7-Q7N 20 wherein L7 is absent or (1-3C)alkylene optionally substituted by (1- 2C)alkyl; Q7N is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2- 3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl or aryl, 25 each of which is optionally tuted by one or more substituents selected from alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NRwRx, ORw, C(O)Rw, C(O)ORw, OC(O)Rw, C(O)N(Rw)Rx, N(Rw)C(O)Rx, wherein Rw and Rx are each 30 ndently selected from H or (1-4C)alkyl. 20458597_1 (GHMatters) P106062.NZ
17. A compound according to any one of the preceding claims, wherein X5 is ed from C(=O), CHR7c or N-R7N when bond a is a single bond, or CR7c or N when bond a is a double bond; wherein 5 R7c is selected from hydrogen or a group of the formula: -L7-L7C-Q7C wherein L7 is absent or (1-3C)alkylene optionally tuted by (1-2C)alkyl or 10 L7C is absent or selected from O, S, N(Ro), C(O), C(O)O, C(O)N(Ro), N(Ro)C(O), wherein Ro is selected from hydrogen or (1-2C)alkyl; and Q7C is hydrogen, cyano, (1-2C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3- 6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q7C is optionally substituted by one or more substituents selected from (1- 15 2C)alkyl, halo, trifluoromethyl, amino or cyano; R7N is selected from en or a group of the formula: -L7-Q7N wherein L7 is absent or (1-3C)alkylene optionally substituted by (1- 20 2C)alkyl; Q7N is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2- 3C)alkenyl, cycloalkyl, aryl, cyclyl or heteroaryl, each of which is optionally substituted by one or more substituents ed from (1-2C)alkyl, halo, trifluoromethyl, 25 amino, cyano, carbamoyl, NRwRx, ORw, C(O)N(Rw)Rx, (O)Rx, wherein Rw and Rx are each independently selected from H or (1-2C)alkyl.
18. A compound according to claim 1, selected from one of the following: 30 1-[(2,6-dichlorophenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 20458597_1 (GHMatters) P106062.NZ 1-(cyclopropylmethyl)methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 1-benzylmethyl-N-(1-methylcyclopropyl)oxo-benzimidazolesulfonamide; 1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)oxophenyl-benzimidazole 5 sulfonamide; 3-methyl-N-(1-methylcyclopropyl)oxo(3-pyridylmethyl)benzimidazolesulfonamide; 1-[(2,2-difluorocyclopropyl)methyl]methyl-N-(1-methylcyclopropyl)oxobenzimidazolesulfonamide 1-isobutylmethyl-N-(1-methylcyclopropyl)oxo-benzimidazolesulfonamide; 10 3-methyl-N-(1-methylcyclopropyl)[(2-methylcyclopropyl)methyl]oxo-benzimidazole amide; 3-methyl-N-(1-methylcyclopropyl)[(1-methylcyclopropyl)methyl]oxo-benzimidazole sulfonamide; 3-methyl-N-(1-methylcyclopropyl)[(3-methyloxetanyl)methyl]oxo-benzimidazole 15 sulfonamide; 1-(cyclobutylmethyl)methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 1-(cyclohexylmethyl)methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 20 3-methyl-N-(1-methylcyclopropyl)oxo(4-pyridylmethyl)benzimidazolesulfonamide; N-(1-methylcyclopropyl)[2-(2-oxooxazolidinyl)acetyl]indolinesulfonamide; -dimethylpropyl)methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 1-(cyclopentylmethyl)methyl-N-(1-methylcyclopropyl)oxo-benzimidazole 25 sulfonamide; 3-methyl-N-(1-methylcyclopropyl)oxopropynyl-benzimidazolesulfonamide; 1-allylmethyl-N-(1-methylcyclopropyl)oxo-benzimidazolesulfonamide; 1-(2-cyclopropylethyl)methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 30 yl-N-(1-methylcyclopropyl)[(5-methylfuryl)methyl]oxo-benzimidazole sulfonamide; N-(1-methylcyclopropyl)[2-(2-oxoimidazolidinyl)acetyl]indolinesulfonamide; 2-[3-methyl[(1-methylcyclopropyl)sulfamoyl]oxo-benzimidazolyl]ethyl acetate; 3-methyl-N-(1-methylcyclopropyl)[(1-methylpyrazolyl)methyl]oxo-benzimidazole- 35 5-sulfonamide; 3-acetylmethyl-N-(1-methylcyclopropyl)oxo-benzimidazolesulfonamide; 20458597_1 (GHMatters) P106062.NZ N-(1-methylcyclopropyl)[2-(3-methyloxo-imidazolidinyl)acetyl]indoline sulfonamide; 1-methyl-N-(1-methylcyclopropyl)oxo(3-thienyl)benzimidazolesulfonamide; 3-benzoylmethyl-N-(1-methylcyclopropyl)oxo-benzimidazolesulfonamide; 5 3-(cyclohexanecarbonyl)methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 1-methyl(4-methylbenzoyl)-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 1-methyl(3-methylbenzoyl)-N-(1-methylcyclopropyl)oxo-benzimidazole 10 sulfonamide; 1-methyl(2-methylbenzoyl)-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; lmethyl[(1-methylcyclopropyl)sulfamoyl]oxo-benzimidazolecarboxamide; 3-methyl-N-(1-methylcyclopropyl)(m-tolylmethyl)oxo-benzimidazolesulfonamide; 15 3-methyl-N-(1-methylcyclopropyl)oxo(p-tolylmethyl)benzimidazolesulfonamide; 1-[(2-methoxyphenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 1-[(3-methoxyphenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 20 1-[(4-methoxyphenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 1-[(3-chlorophenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 1-[(4-chlorophenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole 25 sulfonamide; 1-[(2-fluorophenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 1-[(3-fluorophenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 30 1-[(4-fluorophenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 1-[(2-cyanophenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 1-[(3-cyanophenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole 35 sulfonamide; 1-[(4-cyanophenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole amide; 20458597_1 (GHMatters) P106062.NZ 3-methyl-N-(1-methylcyclopropyl)oxo[[2- (trifluoromethyl)phenyl]methyl]benzimidazolesulfonamide; 1-[(2,6-difluorophenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 5 1-[(3,5-dichlorophenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 1-[(3,5-dimethylphenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 1-[(3,5-dimethoxyphenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole- 10 5-sulfonamide; 1-[(3,5-difluorophenyl)methyl]methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; 3-(2-furyl)methyl-N-(1-methylcyclopropyl)oxo-benzimidazolesulfonamide; 1-methyl-N-(1-methylcyclopropyl)oxothiazolyl-benzimidazolesulfonamide; 15 3-(5-formylthienyl)methyl-N-(1-methylcyclopropyl)oxo-benzimidazole sulfonamide; methyl[(1-methylcyclopropyl)sulfamoyl]oxo-benzimidazolecarboxamide; 6-fluoro-1,3-dimethyl-N-(1-methylcyclopropyl)oxo-benzimidazolesulfonamide; 3-methyl-N-(1-methylcyclopropyl)oxophenyl-benzimidazolesulfonamide; 20 1-[(4-cyanofluoro-phenyl)methyl]methyl-N-(1-methylcyclopropyl)oxobenzimidazolesulfonamide methyl[(1-methylcyclopropyl)sulfamoyl]oxo-benzimidazol yl]methyl]benzamide; N-methyl[[3-methyl[(1-methylcyclopropyl)sulfamoyl]oxo-benzimidazol 25 yl]methyl]-1,2,4-oxadiazolecarboxamide; 3-[[3-methyl[(1-methylcyclopropyl)sulfamoyl]oxo-benzimidazol hyl]benzamide; 3-methyl-N-(1-methylcyclopropyl)[(5-nitrofuryl)methyl]oxo-benzimidazole sulfonamide; 30 N-[4-[[3-methyl[(1-methylcyclopropyl)sulfamoyl]oxo-benzimidazol yl]methyl]phenyl]acetamide; 3-methyl-N-(1-methylcyclopropyl)[(2-methylpyrazolyl)methyl]oxo-benzimidazole- 5-sulfonamide; 3-methyl-N-(1-methylcyclopropyl)[(2-methylthiazolyl)methyl]oxo-benzimidazole 35 sulfonamide; ethyl 3-methyl[(1-methylcyclopropyl)sulfamoyl]oxo-benzimidazolecarboxylate; (E)[5-[3-methyl[(1-methylcyclopropyl)sulfamoyl]oxo-benzimidazolyl] furyl]propenoic acid; 20458597_1 (GHMatters) P106062.NZ 1-methyl-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)oxo-benzimidazole- 5-sulfonamide; (E)[2-[3-methyl[(1-methylcyclopropyl)sulfamoyl]oxo-benzimidazolyl]thiazol yl]propenoic acid; 5 3-[2-[3-methyl[(1-methylcyclopropyl)sulfamoyl]oxo-benzimidazolyl]thiazol yl]propanoic acid; N,N-dimethyl[2-[3-methyl[(1-methylcyclopropyl)sulfamoyl]oxo-benzimidazol yl]thiazolyl]propanamide; 1-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)oxo-3H-benzimidazole 10 sulfonamide; 1-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl) oxo-benzimidazolesulfonamide; N-methyl[2-[3-methyl[(1-methylcyclopropyl)sulfamoyl]oxo-benzimidazol yl]thiazolyl]propanamide; 15 ethyl fluorophenyl)methyl][(1-methylcyclopropyl)sulfamoyl]oxo-benzimidazole- oxylate; 1-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)oxothiazolyl-benzimidazole sulfonamide; 1-methyl-N-(1-methylcyclopropyl)oxo(1,3,4-thiadiazolyl)benzimidazole 20 sulfonamide; 1-methyl-N-(1-methylcyclopropyl)oxo[5-(trifluoromethyl)-1,3,4-thiadiazol yl]benzimidazolesulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazolyl]methyl-N-(1-methylcyclopropyl)oxobenzimidazolesulfonamide 25 N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)oxo-1H-benzimidazole sulfonamide; 3-(5-amino-1,3,4-thiadiazolyl)methyl-N-(1-methylcyclopropyl)oxo-benzimidazole- 5-sulfonamide; 1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)oxo- 30 benzimidazolesulfonamide; N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)[(2-methylthiazolyl)methyl]- benzimidazolesulfonamide; 1-[(2,5-dimethylpyrazolyl)methyl]-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazol- 2-yl)oxo-benzimidazolesulfonamide; 35 1-[2-(dimethylamino)ethyl]-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl) oxo-benzimidazolesulfonamide; 1-[(4-methoxyphenyl)methyl]-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl) oxo-benzimidazolesulfonamide; 4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazol- 40 2-yl)oxo-benzimidazolesulfonamide; 20458597_1 (GHMatters) P106062.NZ 3-[5-(difluoromethyl)-1,3,4-thiadiazolyl][(2,4-dimethylthiazolyl)methyl]-N-(1- methylcyclopropyl)oxo-benzimidazolesulfonamide; 1-[(2,4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)oxo-3H-benzimidazole sulfonamide; 5 1-[(2,4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)oxo(1,2,4-thiadiazol yl)benzimidazolesulfonamide; 1-[(2,4-dimethylthiazolyl)methyl](1H-imidazolyl)-N-(1-methylcyclopropyl)oxobenzimidazolesulfonamide 1-[(2,4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)oxo(1H-pyrazol 10 yl)benzimidazolesulfonamide; 1-[(2,4-dimethylthiazolyl)methyl]isothiazolyl-N-(1-methylcyclopropyl)oxobenzimidazolesulfonamide N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl)oxo-1H-benzimidazole sulfonamide; 15 1-[(2,4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)oxothiazolylbenzimidazolesulfonamide 1-[(2,4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)(1-methylpyrazolyl) oxo-benzimidazolesulfonamide; 1-[(2,4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)oxothiazolyl- 20 benzimidazolesulfonamide; yl-N-(1-methylcyclopropyl)oxo(1,2,4-thiadiazolyl)benzimidazole sulfonamide; 1-[(2,4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazol- 2-yl)oxo-benzimidazolesulfonamide; 25 N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)oxopropynylbenzimidazolesulfonamide N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)(oxazolylmethyl)oxobenzimidazolesulfonamide N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)oxo(1H-pyrazol 30 ylmethyl)benzimidazolesulfonamide; N-(1-methylcyclopropyl)[(5-methylfuryl)methyl](5-methyl-1,3,4-thiadiazolyl) oxo-benzimidazolesulfonamide; N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)[(5-methylthienyl)methyl]- benzimidazolesulfonamide; 35 1-[(2,4-dimethylthiazolyl)methyl](3-methoxy-1,2,4-thiadiazolyl)-N-(1- methylcyclopropyl)oxo-benzimidazolesulfonamide; 1-[(2,4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)(4-methylthiazolyl) oxo-benzimidazolesulfonamide; 4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)(5-methylthiazolyl) 40 oxo-benzimidazolesulfonamide; 20458597_1 (GHMatters) P106062.NZ 3-(3-bromo-1,2,4-thiadiazolyl)[(2,4-dimethylthiazolyl)methyl]-N-(1- methylcyclopropyl)oxo-benzimidazolesulfonamide; 1-[(2,4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)oxopyridazinylbenzimidazolesulfonamide 5 1-[(2,4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)oxo(1,3,4-thiadiazol yl)benzimidazolesulfonamide; 1-[(2,4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)oxothiazolylbenzimidazolesulfonamide ethyl 4-dimethylthiazolyl)methyl][(1-methylcyclopropyl)sulfamoyl]oxo- 10 benzimidazolecarboxylate; 3-(cyclopentenyl)[(2,4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)oxobenzimidazolesulfonamide 7-fluoromethyl-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)oxobenzimidazolesulfonamide 15 N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)indolesulfonamide; 6-fluoromethyl-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)oxobenzimidazolesulfonamide N-methyl[[5-[(1-methylcyclopropyl)sulfamoyl](5-methyl-1,3,4-oxadiazolyl)oxobenzimidazolyl ]methyl]-1,2,4-oxadiazolecarboxamide; 20 ethylcyclopropyl)[(3-methylisoxazolyl)methyl](5-methyl-1,3,4-thiadiazol yl)benzimidazolesulfonamide; N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)benzimidazolesulfonamide; N-(1-methylcyclopropyl)[(1-methylpyrazolyl)methyl](5-methyl-1,3,4-thiadiazol yl)benzimidazolesulfonamide; 25 N-(1-methylcyclopropyl)[2-(1-methylpyrazolyl)ethyl](5-methyl-1,3,4-thiadiazol yl)benzimidazolesulfonamide; 2-methyl-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)benzimidazole sulfonamide; 1-methyl-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)oxo 30 (trifluoromethyl)benzimidazolesulfonamide; N-[[6-[(1-methylcyclopropyl)sulfamoyl](5-methyl-1,3,4-thiadiazolyl)benzimidazol yl]methyl]acetamide; 2-(2-aminoethyl)-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)benzimidazole- 5-sulfonamide; 35 3-benzyl-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)indolesulfonamide; 3-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazol yl)indolesulfonamide; 3-(cyclopropylmethyl)-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)indole sulfonamide; 20458597_1 ters) P106062.NZ 3-[(2,4-dimethylthiazolyl)methyl]-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazol- 2-yl)indolesulfonamide; 3-(cyclopropanecarbonyl)-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazol yl)indolesulfonamide; 5 3-(4-fluorobenzoyl)-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)indole sulfonamide; ethyl 3-[(2,4-dimethylthiazolyl)methyl][(1-methylcyclopropyl)sulfamoyl]indole ylate; 1-[3-(dimethylamino)propyl]-N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl) 10 oxo-benzimidazolesulfonamide; 1-(2-methoxyethyl)-N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl)oxobenzimidazolesulfonamide 1-[3-(dimethylamino)propyl]-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl) oxo-benzimidazolesulfonamide; 15 N-(1-methylcyclopropyl)[(1-methylpiperidyl)methyl](5-methyl-1,3,4-thiadiazol yl)oxo-benzimidazolesulfonamide; 1-[2-(dimethylamino)ethyl]-N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl) oxo-benzimidazolesulfonamide; N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl)[(1-methyl 20 piperidyl)methyl]oxo-benzimidazolesulfonamide; N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl)[(1-methyl piperidyl)methyl]oxo-benzimidazolesulfonamide; N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl)oxo[2-(1- piperidyl)ethyl]benzimidazolesulfonamide; 25 N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl)(2-morpholinoethyl)oxobenzimidazolesulfonamide N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl)oxo(2-pyrrolidin ylethyl)benzimidazolesulfonamide; N-(1-methylcyclopropyl)[(1-methylpiperidyl)methyl](5-methyl-1,3,4-thiadiazol 30 yl)oxo-benzimidazolesulfonamide; 3-acetyl-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)indolesulfonamide; 3-(cyclopropanecarbonyl)[5-(difluoromethyl)-1,3,4-thiadiazolyl]-N-(1- methylcyclopropyl)indolesulfonamide; 3-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazol 35 azolesulfonamide; 1-(2-methoxyethyl)-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)oxobenzimidazolesulfonamide 1-(3-methoxypropyl)-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)oxobenzimidazolesulfonamide 20458597_1 (GHMatters) P106062.NZ N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)oxo[2-(1- piperidyl)ethyl]benzimidazolesulfonamide; 1-(3-methoxypropyl)-N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl)oxobenzimidazolesulfonamide 5 3-[5-[(1-methylcyclopropyl)sulfamoyl](5-methyl-1,3,4-oxadiazolyl)oxobenzimidazolyl ]propanamide; N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)(2-morpholinoethyl)oxobenzimidazolesulfonamide N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)oxo(2-pyrrolidin 10 ylethyl)benzimidazolesulfonamide; 3-[5-[(1-methylcyclopropyl)sulfamoyl](5-methyl-1,3,4-thiadiazolyl)oxobenzimidazolyl namide; N-(1-methylcyclopropyl)[(1-methylpyrrolidinyl)methyl](5-methyl-1,3,4-thiadiazol yl)oxo-benzimidazolesulfonamide; 15 N-[1-(fluoromethyl)cyclopropyl]methyl(5-methyl-1,3,4-thiadiazolyl)oxobenzimidazolesulfonamide N-(1-cyanocyclopropyl)(5-methyl-1,3,4-thiadiazolyl)oxo-1H-benzimidazole sulfonamide; N-(1-cyanocyclopropyl)ethyl(5-methyl-1,3,4-thiadiazolyl)oxo-benzimidazole 20 sulfonamide; 1-ethyl-N-[1-(fluoromethyl)cyclopropyl](5-methyl-1,3,4-thiadiazolyl)oxobenzimidazolesulfonamide N-[1-(fluoromethyl)cyclopropyl](2-methoxyethyl)(5-methyl-1,3,4-thiadiazolyl) oxo-benzimidazolesulfonamide; 25 N-(1-cyanocyclopropyl)(2-methoxyethyl)(5-methyl-1,3,4-thiadiazolyl)oxobenzimidazolesulfonamide N-(1-cyanocyclopropyl)[5-(difluoromethyl)-1,3,4-thiadiazolyl](2-methoxyethyl) oxo-benzimidazolesulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazolyl]-N-[1-(fluoromethyl)cyclopropyl](2- 30 methoxyethyl)oxo-benzimidazolesulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazolyl][(2,5-dimethylpyrazolyl)methyl]-N-[1- omethyl)cyclopropyl]oxo-benzimidazolesulfonamide; yanocyclopropyl)[5-(difluoromethyl)-1,3,4-thiadiazolyl][(2,5-dimethylpyrazol- 3-yl)methyl]oxo-benzimidazolesulfonamide; 35 1-(cyanomethyl)-N-(1-methylcyclopropyl)(5-methyl-1,3,4-thiadiazolyl)oxobenzimidazolesulfonamide 3-[5-(difluoromethyl)-1,3,4-thiadiazolyl]fluoro-N-[1-(fluoromethyl)cyclopropyl](2- methoxyethyl)oxo-benzimidazolesulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazolyl]fluoro(2-methoxyethyl)-N-(1- 40 methylcyclopropyl)oxo-benzimidazolesulfonamide; 20458597_1 (GHMatters) P106062.NZ 3-[5-(difluoromethyl)-1,3,4-thiadiazolyl](2-methoxyethyl)-N-(1-methylcyclopropyl) oxo-benzimidazolesulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazolyl][3-(dimethylamino)propyl]-N-[1- (fluoromethyl)cyclopropyl]oxo-benzimidazolesulfonamide; 5 6-fluoromethyl-N-(1-methylcyclopropyl)(3-methyl-1,2,4-thiadiazolyl)oxobenzimidazolesulfonamide 6-fluoro-N-[1-(fluoromethyl)cyclopropyl]methyl(3-methyl-1,2,4-thiadiazolyl)oxobenzimidazolesulfonamide 3-[5-(difluoromethyl)-1,3,4-thiadiazolyl]fluoromethyl-N-(1-methylcyclopropyl) 10 oxo-benzimidazolesulfonamide; difluoromethyl)-1,3,4-thiadiazolyl]fluoro-N-[1-(fluoromethyl)cyclopropyl] methyloxo-benzimidazolesulfonamide; N-[1-(fluoromethyl)cyclopropyl]methyloxo(1,2,4-thiadiazolyl)benzimidazole sulfonamide; 15 1-methyl-N-(1-methylcyclopropyl)(3-methyl-1,2,4-thiadiazolyl)oxo-benzimidazole- 5-sulfonamide; N-[1-(fluoromethyl)cyclopropyl]methyl(3-methyl-1,2,4-thiadiazolyl)oxobenzimidazolesulfonamide 1-(cyanomethyl)-N-[1-(fluoromethyl)cyclopropyl](5-methyl-1,3,4-thiadiazolyl)oxo- 20 benzimidazolesulfonamide; 1-(cyanomethyl)-N-(1-methylcyclopropyl)(3-methyl-1,2,4-thiadiazolyl)oxobenzimidazolesulfonamide 1-(cyanomethyl)-N-[1-(fluoromethyl)cyclopropyl](3-methyl-1,2,4-thiadiazolyl)oxobenzimidazolesulfonamide 25 3-[5-(difluoromethyl)-1,3,4-thiadiazolyl]-N-[1-(fluoromethyl)cyclopropyl]methyloxobenzimidazolesulfonamide 1-(2-methoxyethyl)-N-(1-methylcyclopropyl)(3-methyl-1,2,4-thiadiazolyl)oxobenzimidazolesulfonamide N-[1-(fluoromethyl)cyclopropyl](2-methoxyethyl)oxo(1,2,4-thiadiazol 30 yl)benzimidazolesulfonamide; N-[1-(fluoromethyl)cyclopropyl](2-methoxyethyl)(3-methyl-1,2,4-thiadiazolyl) oxo-benzimidazolesulfonamide; N-[1-(fluoromethyl)cyclopropyl](3-methoxypropyl)(3-methyl-1,2,4-thiadiazolyl) oxo-benzimidazolesulfonamide; 35 1-[2-(dimethylamino)ethyl]-N-[1-(fluoromethyl)cyclopropyl](3-methyl-1,2,4-thiadiazol yl)oxo-benzimidazolesulfonamide; N-[1-(fluoromethyl)cyclopropyl](3-methoxypropyl)(5-methyl-1,3,4-thiadiazolyl) oxo-benzimidazolesulfonamide; 1-[2-(dimethylamino)ethyl]-N-[1-(fluoromethyl)cyclopropyl](5-methyl-1,3,4-thiadiazol 40 oxo-benzimidazolesulfonamide; 20458597_1 ters) P106062.NZ 1-methyl-N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl)oxo-benzimidazole- 5-sulfonamide; 1-ethyl-N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl)oxo-benzimidazole sulfonamide; 5 1-(2-fluoroethyl)-N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl)oxobenzimidazolesulfonamide 6-fluoro-N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl)oxo-1H- benzimidazolesulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazolyl]-N-[1-(fluoromethyl)cyclopropyl]oxoprop 10 ynyl-benzimidazolesulfonamide; 6-fluoro-N-[1-(fluoromethyl)cyclopropyl](5-methyl-1,3,4-oxadiazolyl)oxo-1H- benzimidazolesulfonamide; 3-[5-(difluoromethyl)-1,3,4-oxadiazolyl]methyl-N-(1-methylcyclopropyl)oxobenzimidazolesulfonamide 15 difluoromethyl)-1,3,4-oxadiazolyl]-N-[1-(fluoromethyl)cyclopropyl]methyloxobenzimidazolesulfonamide 6-fluoromethyl-N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl)oxobenzimidazolesulfonamide 6-fluoro(2-fluoroethyl)-N-(1-methylcyclopropyl)(5-methyl-1,3,4-oxadiazolyl)oxo- 20 benzimidazolesulfonamide; difluoromethyl)-1,3,4-oxadiazolyl]ethylfluoro-N-(1-methylcyclopropyl)oxobenzimidazolesulfonamide 3-[5-(difluoromethyl)-1,3,4-oxadiazolyl]ethylfluoro-N-[1-(fluoromethyl)cyclopropyl]- 2-oxo-benzimidazolesulfonamide; 25 3-[5-(difluoromethyl)-1,3,4-oxadiazolyl]ethyl-N-(1-methylcyclopropyl)oxobenzimidazolesulfonamide 3-[5-(difluoromethyl)-1,3,4-oxadiazolyl]ethyl-N-[1-(fluoromethyl)cyclopropyl]oxobenzimidazolesulfonamide 6-fluoro-N-[1-(fluoromethyl)cyclopropyl](2-methoxyethyl)(6-methylpyridazinyl) 30 oxo-benzimidazolesulfonamide; 6-fluoro-N-[1-(fluoromethyl)cyclopropyl]methyl(6-methylpyridazinyl)oxobenzimidazolesulfonamide 6-fluoromethyl-N-(1-methylcyclopropyl)(6-methylpyridazinyl)oxobenzimidazolesulfonamide 35 6-fluoro-N-[1-(fluoromethyl)cyclopropyl]methyloxo[6-(trifluoromethyl)pyridazin yl]benzimidazolesulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazolyl]ethylfluoro-N-(1-methylcyclopropyl)oxobenzimidazolesulfonamide 3-[5-(difluoromethyl)-1,3,4-thiadiazolyl]ethylfluoro-N-[1-(fluoromethyl)cyclopropyl]- 40 benzimidazolesulfonamide; 20458597_1 (GHMatters) P106062.NZ 3-[5-(difluoromethyl)-1,3,4-oxadiazolyl]fluoromethyl-N-(1-methylcyclopropyl) oxo-benzimidazolesulfonamide; 3-[5-(difluoromethyl)-1,3,4-oxadiazolyl]fluoro-N-[1-(fluoromethyl)cyclopropyl] methyloxo-benzimidazolesulfonamide; 5 3-[5-(difluoromethyl)-1,3,4-oxadiazolyl]fluoro(2-fluoroethyl)-N-(1- cyclopropyl)oxo-benzimidazolesulfonamide; 3-[5-(difluoromethyl)-1,3,4-oxadiazolyl]fluoro(2-fluoroethyl)-N-[1- omethyl)cyclopropyl]oxo-benzimidazolesulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazolyl]fluoro-N-[1-(fluoromethyl)cyclopropyl]oxo- 10 1-propynyl-benzimidazolesulfonamide; 2-[3-[5-(difluoromethyl)-1,3,4-thiadiazolyl]fluoro[[1- (fluoromethyl)cyclopropyl]sulfamoyl]oxo-benzimidazolyl]acetamide; 1-(cyanomethyl)[5-(difluoromethyl)-1,3,4-thiadiazolyl]fluoro-N-[1- (fluoromethyl)cyclopropyl]oxo-benzimidazolesulfonamide; 15 3-[5-(Difluoromethyl)-1,3,4-thiadiazolyl]fluoro(2-fluoroethyl)-N-[1- (fluoromethyl)cyclopropyl]oxo-benzimidazolesulfonamide; 3-[5-(Difluoromethyl)-1,3,4-thiadiazolyl]fluoro(2-fluoroethyl)-N-(1- methylcyclopropyl)oxo-benzimidazolesulfonamide; or a pharmaceutically acceptable salt or solvate thereof.
19. A compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.
20. A compound as defined in any one of claims 1 to 18, or a ceutically acceptable 25 salt or solvate thereof, for use in the treatment of cancer.
21. A pharmaceutical ition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
22. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically able salt or solvate thereof, in the manufacture of a medicament for treating a proliferative disorder in a patient in need of such treatment, wherein the proliferative disorder is responsive to PARG inhibition.
23. The use of claim 22, wherein the erative disorder is cancer. 20458597_1 (GHMatters) P106062.NZ
24. The compound according to claim 1, substantially as herein described with reference to any one of the Examples.
25. The pharmaceutical composition according to claim 21, substantially as herein 5 described with reference to any one of the Examples.
26. The use according to claim 22, ntially as herein described with reference to any one of the Examples.
NZ732394A 2015-12-17 Parg inhibitory compounds NZ732394B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB201422771 2014-12-19
PCT/GB2015/054064 WO2016097749A1 (en) 2014-12-19 2015-12-17 Parg inhibitory compounds

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NZ732394A NZ732394A (en) 2024-01-26
NZ732394B2 true NZ732394B2 (en) 2024-04-30

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