N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl) butanamide derivatives and related compounds as human CTPS1 inhibitors for the treatment of proliferative diseases
20230086703 · 2023-03-23
Assignee
Inventors
- Abdul Quddus (Nottingham, Nottinghamshire, GB)
- Andrew Novak (Nottingham, Nottinghamshire, GB)
- David Cousin (Nottingham, Nottinghamshire, GB)
- Emma Blackham (Nottingham, Nottinghamshire, GB)
- Ellie Chatzopoulou (Nottingham, Nottinghamshire, GB)
- Geraint Jones (Nottingham, Nottinghamshire, GB)
- Jennifer Thomas (Nottingham, Nottinghamshire, GB)
- Joseph Wrigglesworth (Nottingham, Nottinghamshire, GB)
- Lorna Duffy (Nottingham, Nottinghamshire, GB)
- Louise Birch (Nottingham, Nottinghamshire, GB)
- Pascal George (Paris, FR)
- Saleh Ahmed (Nottingham, Nottinghamshire, GB)
- Gianna Toschi (Nottingham, Nottinghamshire, GB)
Cpc classification
C07D403/12
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
International classification
C07D417/12
CHEMISTRY; METALLURGY
Abstract
Compounds of formula (I) wherein ring B is selected from the group consisting of Formula (B-a) and Formula (B-bc) as human cytidine triphosphate synthase 1 (CTPS 1) inhibitors for the treatment of proliferative diseases, such as e.g. cancer, such as e.g. leukemia and lymphoma, e.g. inflammatory skin diseases such as psoriasis, or e.g. multiple sclerosis. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. page 129 to page 302; examples; biological examples 1 and 2; tables 1-17). Specific examples are e.g.: N-(4-(5-Chloropyridin-3-yl)phenyl)-2-(2-(cyclopropane-sulfonamido) pyrimidin-4-yl)butanamide (Formula P1) or 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)cyclopentanecarboxamide (Formula P2).
##STR00001##
Claims
1.-15. (canceled)
16. A compound of formula (I): ##STR01027## wherein ring B is selected from the group consisting of: ##STR01028## wherein X, Y and Z are as defined below; and ##STR01029## wherein R.sub.3b3c is R.sub.3b or R.sub.3c as defined below; wherein when B is (B-a) the compound of formula (I) is a compound of formula (I-a): ##STR01030## wherein: A.sub.a is A.sub.aa or A.sub.ba; wherein: A.sub.aa is an amine linker having the following structure: —NH—, —CH.sub.2NH— or —NHCH.sub.2—; A.sub.ba is an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—; X is N or CH; Y is N or CR.sub.2a; Z is N or CR.sub.3a; with the proviso that when at least one of X or Z is N, Y cannot be N; R.sub.2a is H, halo, C.sub.1-2alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl or OC.sub.1-2haloalkyl; and R.sub.3a is H, halo, CH.sub.3, OCH.sub.3, CF.sub.3 or OCF.sub.3; wherein at least one of R.sub.2a and R.sub.3a is H; R.sub.1a is R.sub.1aa or R.sub.1ba; wherein: R.sub.1aa is NR.sub.32aR.sub.33a; R.sub.1ba is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa, or R.sub.4ba and R.sub.5ba; wherein: R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21aR.sub.22a; or one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29a; or R.sub.4ba and R.sub.5ba are each independently H, C.sub.1-6alkyl, C.sub.1-6alkylOH, C.sub.1-6haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, or R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl; and when A.sub.a is —NHC(═O)— or —NHCH.sub.2—: R.sub.4ba and R.sub.5ba may additionally be selected from halo, OC.sub.1-6haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-4heterocycloalkyl, OC.sub.1-4alkyl and NR.sub.21aR.sub.22a; Ar1a is a 6-membered aryl or heteroaryl; Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A.sub.a; R.sub.10a is H, halo, C.sub.1-3alkyl, C.sub.1-2haloalkyl, OC.sub.1-2alkyl, OC.sub.1-2haloalkyl or CN; R.sub.11a is H, F, Cl, C.sub.1-2alkyl, CF.sub.3, OCH.sub.3 or CN; R.sub.12a is attached to Ar2 in the ortho or meta position relative to Ar1a and R.sub.12a is H, halo, C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, hydroxy, C.sub.1-4alkylOH, SO.sub.2C.sub.1-2alkyl, C(O)N(C.sub.1-2alkyl).sub.2, NHC(O)C.sub.1-3alkyl or NR.sub.23aR.sub.24a; and when A.sub.a is —NHC(═O)—, —NH— or —NHCH.sub.2—: R.sub.12a may additionally be selected from CN, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2 and a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R.sub.12a together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); R.sub.13a is H or halo; R.sub.21a is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl, C.sub.1-3alkylOC.sub.1-2alkyl, C.sub.1-4haloalkyl, or C.sub.4-6heterocycloalkyl; R.sub.22a is H or CH.sub.3; R.sub.23a is H or C.sub.1-2alkyl; and R.sub.24a is H or C.sub.1-2alkyl R.sub.29a is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, CF.sub.3, N(C.sub.1-3alkyl).sub.2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; R.sub.32a is C.sub.1-3alkyl and R.sub.33 is C.sub.1-3alkyl; or R.sub.32a and R.sub.33a together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl; wherein R.sub.1a is R.sub.1aa; and/or R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa; and/or A.sub.a is A.sub.aa; and wherein when B is (B-bc) and R.sub.3b3c is R.sub.3b, the compound of formula (I) is a compound of formula (I-b): ##STR01031## wherein: A.sub.b is A.sub.ab or A.sub.bb; wherein: A.sub.ab is —NR.sub.6bCH.sub.2— or —NR.sub.6b—; A.sub.bb is —NR.sub.6bC(═O)—; R.sub.1b is R.sub.1ab or R.sub.1bb; wherein: R.sub.1a is NR.sub.32bR.sub.33b; R.sub.1bb is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, C.sub.1-3alkyleneOC.sub.1-2alkyl, or CF.sub.3; R.sub.3b is H, halo, CH.sub.3, OC.sub.1-2alkyl or CF.sub.3; or R.sub.3b together with R.sub.5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; R.sub.4b and R.sub.5b are either R.sub.4ab and R.sub.5ab or R.sub.4bb and R.sup.5bb; wherein: R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-4cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-4heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21bR.sub.22b; or one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-4heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29b; or R.sub.4ab and R.sub.5ab are each independently H, halo, C.sub.1-4alkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-6alkylOH, C.sub.1-6haloalkyl, OC.sub.1-6haloalkyl or NR.sub.21bR.sub.22b, or R.sub.4bb is H and R.sub.5bb together with R3b form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl, or R.sub.4bb and R.sub.5bb together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl, or R.sub.4bb is H and R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring; or R.sub.4bb is O and R.sub.5bb is absent; R.sub.6b is H or C.sub.1-3alkyl, or R.sub.6b together with R.sub.11b when in the ortho-position to group A.sub.b are a C.sub.2alkylene chain forming a 5-membered ring, or R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring and R.sub.4bb is H; Ar1b is 6-membered aryl or heteroaryl; Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para position relative to group A.sub.b; R.sub.10b is H, halo, C.sub.1-3alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl, OC.sub.1-2haloalkyl or CN; R.sub.11b is H, F, Cl, CH.sub.3, ethyl, OCH.sub.3, CF.sub.3, OCF.sub.3 or CN, or R.sub.11b, when in the ortho-position to group A.sub.b, together with R.sub.6b are a C.sub.2alkylene chain forming a 5-membered ring; R.sub.12b is attached to Ar2b in the ortho or meta position relative to Ar1b and R.sub.12b is H, halo, C.sub.1-4alkyl, C.sub.2-4alkynyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, OH, C.sub.1-4alkylOH, CN, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, C(═O)C.sub.1-2alkyl, NR.sub.23bR.sub.24b, SO.sub.2C.sub.1-4alkyl, SOC.sub.1-4alkyl, SC.sub.1-4alkyl, SH, C(O)N(CH.sub.3).sub.2, NHC(O)C.sub.1-3alkyl, C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R.sub.12b together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); R.sub.13b is H, halo, CH.sub.3 or OCH.sub.3; R.sub.21b is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl, C.sub.1-3alkylOC.sub.1-2alkyl, C.sub.1-4haloalkyl, or C.sub.4-6heterocycloalkyl; R.sub.22b is H or CH.sub.3; R.sub.23b is H or C.sub.1-2alkyl; R.sub.24b is H or C.sub.1-2alkyl; R.sub.29b is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, CF.sub.3, N(C.sub.1-3alkyl).sub.2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and R.sub.32b is C.sub.1-3alkyl and R.sub.33b is C.sub.1-3alkyl; or R.sub.32b and R.sub.33b together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl; wherein: R.sub.1b is R.sub.1ab; and/or R.sub.4b and R.sub.5b are R.sub.4ab and R.sub.5ab; and/or A is A.sub.ab; or wherein when B is (B-bc) and R.sub.3b3c is R.sub.3c, the compound of formula (I) is a compound of formula (I-c): ##STR01032## wherein: A.sub.c is A.sub.ac or A.sub.bc; wherein: A.sub.ac is —CH.sub.2NR.sub.6c—; A.sub.bc is —C(═O)NR.sub.6c—; R.sub.1c is R.sub.1ac or R.sub.1bc; wherein: R.sub.1ac is NR.sub.32cR.sub.33c; R.sub.1bc is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, C.sub.1-3alkyleneOC.sub.1-2alkyl, or CF.sub.3; R.sub.3c is H, CH.sub.3, halo, OC.sub.1-2alkyl or CF.sub.3; R.sub.4c and R.sub.5c are either R.sub.4ac and R.sub.5ac or R.sub.4bc and R.sub.5bc; wherein: R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21cR.sub.22c; or one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29c; or R.sub.4bc and R.sub.5bc are each independently H, C.sub.1-6alkyl, C.sub.0-2alkyleneC.sub.3-4cycloalkyl, C.sub.0-2alkyleneC.sub.3-4heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-4alkylOH or C.sub.1-6haloalkyl, or R.sub.4bc and R.sub.5bc together with the carbon atom to which they are attached form a C.sub.3-4cycloalkyl or C.sub.3-4heterocycloalkyl ring; R.sub.6c is H or C.sub.1-3alkyl; Ar1c is a 6-membered aryl or heteroaryl; Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group A.sub.c; R.sub.10c is H, halo, C.sub.1-3alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl, OC.sub.1-2haloalkyl or CN; R.sub.11c is H, F, Cl, CH.sub.3, ethyl, OCH.sub.3, CF.sub.3, OCF.sub.3 or CN; R.sub.12c is attached to Ar2c in the meta or ortho position relative to Ar1c and R.sub.12c is H, halo, C.sub.1-4alkyl, C.sub.2-4alkynyl, C(═O)C.sub.1-2alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, CN, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, OH, C.sub.1-4alkylOH, NR.sub.23cR.sub.24c, SO.sub.2CH.sub.3, C(O)N(CH.sub.3).sub.2, NHC(O)C.sub.1-3alkyl, or a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R.sub.12c together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); R.sub.21c is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl, C.sub.1-3alkylOC.sub.1-2alkyl, C.sub.1-4haloalkyl, or C.sub.4-6heterocycloalkyl; R.sub.22c is H or CH.sub.3; R.sub.23c is H or C.sub.1-2alkyl; R.sub.24c is H or C.sub.1-2alkyl; R.sub.29c is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, CF.sub.3, N(C.sub.1-3alkyl).sub.2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and R.sub.32c is C.sub.1-3alkyl and R.sub.33c is C.sub.1-3alkyl; or R.sub.32c and R.sub.33c together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl; wherein: R.sub.1c is R.sub.1ac; and/or R.sub.4c and R.sub.5c are R.sub.4ac and R.sub.5ac; and/or A.sub.c is A.sub.ac; or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof.
17. The compound according to claim 16 which is a compound of formula (I): ##STR01033## wherein ring B is selected from the group consisting of: ##STR01034## wherein X, Y and Z are as defined below; and: ##STR01035## wherein R.sub.3b3c is R.sub.3b or R.sub.3c as defined below; wherein when B is (B-a) the compound of formula (I) is a compound of formula (I-a): ##STR01036## wherein: A.sub.a is A.sub.aa or A.sub.ba; wherein: A.sub.aa is an amine linker having the following structure: —NH—, —CH.sub.2NH— or —NHCH.sub.2—; A.sub.ba is an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—; X is N or CH; Y is N or CR.sub.2a; Z is N or CR.sub.3a; with the proviso that when at least one of X or Z is N, Y cannot be N; R.sub.2a is H, halo, C.sub.1-2alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl or OC.sub.1-2haloalkyl; and R.sub.3a is H, halo, CH.sub.3, OCH.sub.3, CF.sub.3 or OCF.sub.3; wherein at least one of R.sub.2a and R.sub.3a is H; R.sub.1a is R.sub.1aa or R.sub.1ba; wherein: R.sub.1aa is NR.sub.32aR.sub.33a; R.sub.1ba is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa, or R.sub.4ba and R.sub.5ba; wherein: R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21aR.sub.22a; or one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29a; or R.sub.4ba and R.sub.5ba are each independently H, C.sub.1-4alkyl, C.sub.1-4alkylOH, C.sub.1-4haloalkyl, C.sub.0-2alkyleneC.sub.3-4cycloalkyl, C.sub.0-2alkyleneC.sub.3-4heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, or R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl; and when A.sub.a is —NHC(═O)— or —NHCH.sub.2—: R.sub.4ba and R.sub.5ba may additionally be selected from halo, OC.sub.1-6haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-4alkyl and NR.sub.21aR.sub.22a; Ar1a is a 6-membered aryl or heteroaryl; Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A.sub.a; R.sub.10a is H, halo, C.sub.1-3alkyl, C.sub.1-2haloalkyl, OC.sub.1-2alkyl, OC.sub.1-2haloalkyl or CN; R.sub.11a is H, F, Cl, C.sub.1-2alkyl, CF.sub.3, OCH.sub.3 or CN; R.sub.12a is attached to Ar2 in the ortho or meta position relative to Ar1a and R.sub.12a is H, halo, C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, hydroxy, C.sub.1-4alkylOH, SO.sub.2C.sub.1-2alkyl, C(O)N(C.sub.1-2alkyl).sub.2, NHC(O)C.sub.1-3alkyl or NR.sub.23aR.sub.24a; and when A.sub.a is —NHC(═O)—, —NH— or —NHCH.sub.2—: R.sub.12a may additionally be selected from CN, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2 and a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R.sub.12a together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); R.sub.13a is H or halo; R.sub.21a is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl; R.sub.22a is H or CH.sub.3; R.sub.23a is H or C.sub.1-2alkyl; and R.sub.24a is H or C.sub.1-2alkyl R.sub.29a is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; R.sub.32a is C.sub.1-3alkyl and R.sub.33 is C.sub.1-3alkyl; or R.sub.32a and R.sub.33a together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl; wherein R.sub.1a is R.sub.1aa; and/or R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa; and/or A.sub.a is A.sub.aa; and wherein when B is (B-bc) and R.sub.3b3c is R.sub.3b, the compound of formula (I) is a compound of formula (I-b): ##STR01037## wherein: A.sub.b is A.sub.ab or A.sub.bb; wherein: A.sub.ab is —NR.sub.6bCH.sub.2— or —NR.sub.6b—; A.sub.bb is —NR.sub.6bC(═O)—; R.sub.1b is R.sub.1ab or R.sub.1bb; wherein: R.sub.1b is NR.sub.32bR.sub.33b; R.sub.1bb is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, C.sub.1-3alkyleneOC.sub.1-2alkyl, or CF.sub.3; R.sub.3b is H, halo, CH.sub.3, OC.sub.1-2alkyl or CF.sub.3; or R.sub.3b together with R.sub.5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; R.sub.4b and R.sub.5b are either R.sub.4b and R.sub.5a or R.sub.4bb and R.sub.5bb; wherein: R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-4heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21bR.sub.22b; or one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-4heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29b; or R.sub.4ab and R.sub.5ab are each independently H, halo, C.sub.1-4alkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-6alkylOH, C.sub.1-6haloalkyl, OC.sub.1-6haloalkyl or NR.sub.21bR.sub.22b, or R.sub.4bb is H and R.sub.5bb together with R3b form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl, or R.sub.4bb and R.sub.5bb together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl, or R.sub.4bb is H and R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring; or R.sub.4bb is O and R.sub.5bb is absent; R.sub.6b is H or C.sub.1-3alkyl, or R.sub.6b together with R.sub.11b when in the ortho-position to group A.sub.b are a C.sub.2alkylene chain forming a 5-membered ring, or R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring and R.sub.4bb is H; Ar1b is 6-membered aryl or heteroaryl; Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para position relative to group A.sub.b; R.sub.10b is H, halo, C.sub.1-3alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl, OC.sub.1-2haloalkyl or CN; R.sub.11b is H, F, Cl, CH.sub.3, ethyl, OCH.sub.3, CF.sub.3, OCF.sub.3 or CN, or R.sub.11b, when in the ortho-position to group A.sub.b, together with R.sub.6b are a C.sub.2alkylene chain forming a 5-membered ring; R.sub.12b is attached to Ar2b in the ortho or meta position relative to Ar1b and R.sub.12b is H, halo, C.sub.1-4alkyl, C.sub.2-4alkynyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, OH, C.sub.1-4alkylOH, CN, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, C(═O)C.sub.1-2alkyl, NR.sub.23bR.sub.24b, SO.sub.2C.sub.1-4alkyl, SOC.sub.1-4alkyl, SC.sub.1-4alkyl, SH, C(O)N(CH.sub.3).sub.2, NHC(O)C.sub.1-3alkyl, C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R.sub.12b together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); R.sub.13b is H, halo, CH.sub.3 or OCH.sub.3; R.sub.21b is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl; R.sub.22b is H or CH.sub.3; R.sub.23b is H or C.sub.1-2alkyl; R.sub.24b is H or C.sub.1-2alkyl; R.sub.29b is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; and R.sub.32b is C.sub.1-3alkyl and R.sub.33b is C.sub.1-3alkyl; or R.sub.32b and R.sub.33b together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl; wherein: R.sub.1b is R.sub.1ab; and/or R.sub.4b and R.sub.5b are R.sub.4ab and R.sub.5ab; and/or A.sub.b is A.sub.ab; or wherein when B is (B-bc) and R.sub.3b3c is R.sub.3c, the compound of formula (I) is a compound of formula (I-c): ##STR01038## wherein: A.sub.c is A.sub.ac or A.sub.bc; A.sub.ac is —CH.sub.2NR.sub.6c—; A.sub.bc is —C(═O)NR.sub.6—; R.sub.1c is R.sub.1ac or R.sub.1bc; wherein: R.sub.1ac is NR.sub.32cR.sub.33c; R.sub.1bc is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, C.sub.1-3alkyleneOC.sub.1-2alkyl, or CF.sub.3; R.sub.3c is H, CH.sub.3, halo, OC.sub.1-2alkyl or CF.sub.3; R.sub.4c and R.sub.5c are either R.sub.4ac and R.sub.5ac or R.sub.4bc and R.sub.5bc; wherein: R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21cR.sub.22c; or one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29c; or R.sub.4bc and R.sub.5bc are each independently H, C.sub.1-4alkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-4alkylOH or C.sub.1-6haloalkyl, or R.sub.4bc and R.sub.5bc together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl ring; R.sub.6c is H or C.sub.1-3alkyl; Ar1c is a 6-membered aryl or heteroaryl; Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group A.sub.c; R.sub.10c is H, halo, C.sub.1-3alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl, OC.sub.1-2haloalkyl or CN; R.sub.11c is H, F, Cl, CH.sub.3, ethyl, OCH.sub.3, CF.sub.3, OCF.sub.3 or CN; R.sub.12c is attached to Ar2c in the meta or ortho position relative to Ar1c and R.sub.12c is H, halo, C.sub.1-4alkyl, C.sub.2-4alkynyl, C(═O)C.sub.1-2alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, CN, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, OH, C.sub.1-4alkylOH, NR.sub.23cR.sub.24c, SO.sub.2CH.sub.3, C(O)N(CH.sub.3).sub.2, NHC(O)C.sub.1-3alkyl, or a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R.sub.12c together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); R.sub.21c is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl; R.sub.22c is H or CH.sub.3; R.sub.23c is H or C.sub.1-2alkyl; R.sub.24c is H or C.sub.1-2alkyl; R.sub.29c is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; and R.sub.32c is C.sub.1-3alkyl and R.sub.33c is C.sub.1-3alkyl; or R.sub.32c and R.sub.33c together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl; wherein: R.sub.1c is R.sub.1ac; and/or R.sub.4c and R.sub.5c are R.sub.4ac and R.sub.5ac; and/or A.sub.c is A.sub.ac; or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof.
18. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 16.
19. The pharmaceutically acceptable salt according to claim 16.
20. The solvate according to claim 16.
21. The compound, pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof according to claim 16 wherein the compound of formula (I) is a compound of formula (I-a).
22. The compound, pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof according to claim 16 wherein the compound of formula (I) is a compound of formula (I-b).
23. The compound, pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof according to claim 16 wherein the compound of formula (I) is a compound of formula (I-c).
24. The compound, pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof according to claim 21 wherein R.sub.1a is R.sub.1aa, R.sub.1b is R.sub.1ab or R.sub.1c is R.sub.1ac.
25. The compound, pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof according to claim 21 wherein R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa, R.sub.4b and R.sub.5b are R.sub.4ab and R.sub.5ab or R.sub.4c and R.sub.5c are R.sub.4ac and R.sub.5ac.
26. The compound, pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof according to claim 21 wherein A.sub.a is A.sub.aa, A.sub.b is A.sub.ab or A.sub.c is A.sub.ac.
27. A compound, pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof according to claim 16 which is selected from the group consisting of: 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-oxocyclohexanecarboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide (diastereomer 2); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 2); N-(4-(1-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propyl)pyrimidin-2-yl)cyclopropanesulfonamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4,4-difluorocyclohexane-1-carboxamide; 8-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide; 4-(2-((N,N-dimethylsulfamoyl)amino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; N-(4-(1-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)cyclopropyl)pyrimidin-2-yl)cyclopropanesulfonamide; N-(4-(1-((4-(6-ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)cyclopropyl)pyrimidin-2-yl)cyclopropanesulfonamide; N-(4-(4-(((4-(6-ethoxypyrazin-2-yl)phenyl)amino)methyl)tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl)cyclopropanesulfonamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-5,8-dioxaspiro[3.4]octane-2-carboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxycyclohexane-1-carboxamide; N-(4-(1-((4-(6-ethoxypyrazin-2-yl)phenyl)amino)propyl)pyrimidin-2-yl)cyclopropanesulfonamidearboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(2-methoxyacetyl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(cyclopropylsulfonyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(N,N-dimethylsulfamoyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-((trifluoromethyl)sulfonyl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidine-4-carboxamide; 1-(cyanomethyl)-4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide; ethyl 2-(4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)carbamoyl)piperidin-1-yl)acetate; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(2-methoxyacetyl)piperidine-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; 1-(Cyclopropylsulfonyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)piperidine-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidine-4-carboxamide; 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-4-methoxycyclohexane-1-carboxamide (diastereomer 1); 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-4-methoxycyclohexane-1-carboxamide (diastereomer 2); 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 2); 4-amino-1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-morpholinocyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-morpholinocyclohexane-1-carboxamide (diastereomer 2); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(methyl(oxetan-3-yl)amino)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-((2-methoxyethyl)(methyl)amino)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-((2-methoxyethyl)(methyl)amino)cyclohexane-1-carboxamide (diastereomer 2); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((2,2-difluoroethyl)(methyl)amino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide (diastereomer 2); 4-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; N-(4-(1-((2-fluoro-4-(pyridin-3-yl)phenyl)amino)-2-methylpropan-2-yl)thiazol-2-yl)cyclopropanesulfonamide; N-(4-(2-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide; and N-(4-(2-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide; and pharmaceutically acceptable salts and/or solvates and/or derivatives of any one thereof.
28. The compound according to claim 27, which is N-(4-(1-((2-fluoro-4-(pyridin-3-yl)phenyl)amino)-2-methylpropan-2-yl)thiazol-2-yl)cyclopropanesulfonamide, or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof.
29. A pharmaceutical composition comprising the compound, pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof according to claim 16.
30. A method of treating or preventing a disease associated with the reduction of T-cell and/or B-cell proliferation in a subject; inflammatory skin diseases such as psoriasis or lichen planus; acute and/or chronic GVHD such as steroid resistant acute GVHD; acute lymphoproliferative syndrome (ALPS); systemic lupus erythematosus, lupus nephritis or cutaneous lupus; transplantation; myasthenia gravis, multiple sclerosis or scleroderma/systemic sclerosis; cancer; or a method of enhancing recovery from vascular injury or surgery and reducing morbidity and mortality associated with neointima and restenosis in a subject, said methods comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt and/or solvate and/or derivative thereof according to claim 16.
31. The method according to claim 30, wherein the method is a method for treating cancer, by administering to a subject in need thereof a compound, pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof according to claim 16.
32. The method according to claim 31, wherein the cancer is a haematological cancer, such as Acute myeloid leukemia, Angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet Syndrome, T-cell Non-Hodgkins lymphoma (including natural killer/T-cell lymphoma, adult T-cell leukaemia/lymphoma, enteropathy type T-cell lymphoma, hepatosplenic T-cell lymphoma and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell Non-Hodgkins lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, Follicular lymphoma, Mantle cell lymphoma, Marginal Zone lymphoma), Hairy Cell Leukemia, Hodgkin lymphoma, Lymphoblastic lymphoma, Lymphoplasmacytic lymphoma, Mucosa-associated lymphoid tissue lymphoma, Multiple myeloma, Myelodysplastic syndrome, Plasma cell myeloma, Primary mediastinal large B-cell lymphoma, chronic myeloproliferative disorders (such as chronic myeloid leukemia, primary myelofibrosis, essential thrombocytemia, polycytemia vera) or chronic lymphocytic leukemia.
33. The method according to claim 31, wherein the cancer is a non-haematological cancer, such as selected from the group consisting of bladder cancer, breast, melanoma, neuroblastoma, malignant pleural mesothelioma, and sarcoma.
34. A compound which is selected from the group consisting of: a compound of formula (I-a): ##STR01039## wherein R is H, C.sub.1-6alkyl (e.g. methyl and ethyl) or benzyl; a compound of formula (XX-a): ##STR01040## wherein P is a nitrogen protecting group such as para-methoxybenzyl; a compound of formula (XXIV-a): ##STR01041## wherein P is a nitrogen protecting group such as para-methoxybenzyl; a compound of formula (XXXI-a): ##STR01042## a compound of formula (XXXXII-a): ##STR01043## a compound of formula (LI-a): ##STR01044## wherein X.sub.1 is Cl or Br; a compound of formula (LXXIII-a): ##STR01045## a compound of formula (LXXIV-a): ##STR01046## a compound of formula (LXXXIII-a): ##STR01047## wherein alkyl is C.sub.1-4alkyl such as methyl or ethyl, e.g. methyl; a compound of formula (XXXIV-a): ##STR01048## wherein alkyl is C.sub.1-4alkyl such as methyl or ethyl, e.g. methyl; a compound of formula (LVIII-a): ##STR01049## a compound of formula (XXXIII-a): ##STR01050## wherein alkyl is C.sub.1-4alkyl such as methyl or ethyl, e.g. methyl; a compound of formula (LXXI-a): ##STR01051## a compound of formula (LXXII-a): ##STR01052## a compound of formula (II-b) ##STR01053## a compound of formula (IV-b) ##STR01054## wherein R is C.sub.1-4alkyl (e.g. methyl, ethyl) or benzyl; a compound of formula (II-c): ##STR01055## a compound of formula (VIII-c): ##STR01056## wherein R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.10, R.sub.11, R.sub.12, R.sub.13, A, Ar1, Ar2, X, Y and Z are as defined in claim 16; and salts of any one thereof.
35. A process for the preparation of a compound of formula (I) or a salt, such as a pharmaceutically acceptable salt, and/or solvate thereof and/or derivative thereof, wherein the process comprises the step of: reacting a compound of formula (I)—ketone or a salt thereof with a compound of formula (I)—amine or a salt thereof: ##STR01057## wherein R.sub.1, B, A, Ar1, Ar2, R.sub.21, R.sub.22, X, Y and Z are as defined in claim 16, and m is 2 and n is 2; or wherein: the compound of formula (I) is a compound of formula (I-a) or a salt, such as a pharmaceutically acceptable salt, and/or solvate thereof and/or derivative thereof and wherein the process comprises the step of: reacting a compound of formula (II) or a salt thereof with a compound of formula (III) or a salt thereof: ##STR01058## or reacting a compound of formula (XXXXII) or a salt thereof with a compound of formula (XXXXIII) or a salt thereof: ##STR01059## or reacting a compound of formula (LXXIV) or a salt thereof with a compound of formula (VI) or a salt thereof: ##STR01060## wherein R.sub.1, R.sub.3, R.sub.4, R.sub.5, Ar1, Ar2, X, Y and Z are as defined in claim 16; or wherein: the compound of formula (I) is a compound of formula (I-b) or a salt, such as a pharmaceutically acceptable salt, and/or solvate thereof and/or derivative thereof and wherein the process comprises the step of: reacting a compound of formula (X) or a salt thereof with a compound of formula (XI) or a salt thereof: ##STR01061## or reacting a compound of formula (II) or a salt thereof with a compound of formula (III) or a salt thereof: ##STR01062## wherein R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6, Ar1 and Ar2 are as defined in claim 16; or wherein: the compound of formula (I) is a compound of formula (I-c) or a salt, such as a pharmaceutically acceptable salt, and/or solvate thereof and/or derivative thereof and wherein the process comprises the step of reacting a compound of formula (XIII) or a salt thereof with a compound of formula (XII) or a salt thereof: ##STR01063## wherein R.sub.1, R.sub.3, R.sub.4, R.sub.5, Ar1 and Ar2 are as defined in claim 16.
Description
DETAILED DESCRIPTION OF THE INVENTION
[0170] In one embodiment there is provided a compound of formula (I) as described above, or a salt such as a pharmaceutically acceptable and/or solvate and/or derivative thereof.
[0171] Suitably, the invention provides a compound of formula (I):
##STR00009##
[0172] wherein ring B is selected from the group consisting of:
##STR00010## [0173] wherein X, Y and Z are as defined below; and
##STR00011## [0174] wherein R.sub.3b3c is R.sub.3b or R.sub.3c as defined below;
[0175] wherein when B is (B-a) the compound of formula (I) is a compound of formula (I-a):
##STR00012## [0176] wherein: [0177] A.sub.a is A.sub.aa or A.sub.ba; [0178] wherein: [0179] A.sub.aa is an amine linker having the following structure: —NH—, —CH.sub.2NH— or —NHCH.sub.2—; [0180] A.sub.ba is an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—; [0181] X is N or CH; [0182] Y is N or CR.sub.2a; [0183] Z is N or CR.sub.3a; [0184] with the proviso that when at least one of X or Z is N, Y cannot be N; [0185] R.sub.2a is H, halo, C.sub.1-2alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl or OC.sub.1-2haloalkyl; and [0186] R.sub.3a is H, halo, CH.sub.3, OCH.sub.3, CF.sub.3 or OCF.sub.3; [0187] wherein at least one of R.sub.2a and R.sub.3a is H; [0188] R.sub.1a is R.sub.1aa or R.sub.1ba; [0189] wherein: [0190] R.sub.1aa is NR.sub.32aR.sub.33a; [0191] R.sub.1ba is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; [0192] R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa or R.sub.4ba and R.sub.5ba; [0193] wherein: [0194] R.sub.4a and R.sub.5a together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [0195] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3 alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21aR.sub.22a; or [0196] one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3 alkyl or OC.sub.1-3alkyl; or [0197] R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [0198] R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29a; or [0199] R.sub.4ba and R.sub.5ba are each independently H, C.sub.1-6alkyl, C.sub.1-6alkylOH, C.sub.1-6haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, or R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6 cycloalkyl or C.sub.3-6heterocycloalkyl; and [0200] when A.sub.a is —NHC(═O)— or —NHCH.sub.2—: [0201] R.sub.4ba and R.sub.5ba may additionally be selected from halo, OC.sub.1-6haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-6alkyl and NR.sub.21aR.sub.22a; [0202] Ar1a is a 6-membered aryl or heteroaryl; [0203] Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A.sub.a; [0204] R.sub.10a is H, halo, C.sub.1-3alkyl, C.sub.1-2haloalkyl, OC.sub.1-2alkyl, OC.sub.1-2haloalkyl or CN; [0205] R.sub.11a is H, F, Cl, C.sub.1-2alkyl, CF.sub.3, OCH.sub.3 or CN; [0206] R.sub.12a is attached to Ar2 in the ortho or meta position relative to Ar1a and R.sub.12a is H, halo, C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, hydroxy, C.sub.1-4alkylOH, SO.sub.2C.sub.1-2alkyl, C(O)N(C.sub.1-2alkyl).sub.2, NHC(O)C.sub.1-3alkyl or NR.sub.23aR.sub.24a; and [0207] when A.sub.a is —NHC(═O)—, —NH— or —NHCH.sub.2—: [0208] R.sub.12a may additionally be selected from CN, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2 and a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R.sub.12a together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); [0209] R.sub.13a is H or halo; [0210] R.sub.21a is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl; [0211] R.sub.22a is H or CH.sub.3; [0212] R.sub.23a is H or C.sub.1-2alkyl; and [0213] R.sub.24a is H or C.sub.1-2alkyl [0214] R.sub.29a is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; [0215] R.sub.32a is C.sub.1-3alkyl and R.sub.33 is C.sub.1-3alkyl; or [0216] R.sub.32a and R.sub.33a together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl;
[0217] wherein [0218] R.sub.1a is R.sub.1aa; and/or [0219] R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa; and/or [0220] A.sub.a is A.sub.aa; and
wherein when B is (B-bc) and R.sub.3b3c is R.sub.3b, the compound of formula (I) is a compound of formula (I-b):
##STR00013## [0221] wherein: [0222] A.sub.b is A.sub.ab or A.sub.bb; [0223] wherein: [0224] A.sub.ab is —NR.sub.6bCH.sub.2— or —NR.sub.6b—; [0225] A.sub.bb is —NR.sub.6bC(═O)—; [0226] R.sub.1b is R.sub.1ab or R.sub.1bb; [0227] wherein: [0228] R.sub.1ab is NR.sub.32bR.sub.33b; [0229] R.sub.1bb is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, C.sub.1-3alkyleneOC.sub.1-2alkyl, or CF.sub.3; [0230] R.sub.3b is H, halo, CH.sub.3, OC.sub.1-2alkyl or CF.sub.3; [0231] or R.sub.3b together with R.sub.5b forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; [0232] R.sub.4b and R.sub.5b are either R.sub.4ab and R.sub.5ab or R.sub.4bb and R.sub.5bb; [0233] wherein: [0234] R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [0235] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3 alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21bR.sub.22b; or [0236] one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3 alkyl or OC.sub.1-3alkyl; or [0237] R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [0238] R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29b; or [0239] R.sub.4bb and R.sub.5bb are each independently H, halo, C.sub.1-6alkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-6alkyl, OC.sub.0-2alkyleneC.sub.3-4cycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-6alkylOH, C.sub.1-6haloalkyl, OC.sub.1-6haloalkyl or NR.sub.21bR.sub.22b, [0240] or R.sub.4bb is H and R.sub.5bb together with R.sub.3b form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl, [0241] or R.sub.4bb and R.sub.5bb together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl, [0242] or R.sub.4bb is H and R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring; [0243] or R.sub.4bb is O and R.sub.5bb is absent; [0244] R.sub.6b is H or C.sub.1-3alkyl, [0245] or R.sub.6b together with R.sub.11b when in the ortho-position to group A.sub.b are a C.sub.2alkylene chain forming a 5-membered ring, [0246] or R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring and R.sub.4bb is H; [0247] Ar1b is 6-membered aryl or heteroaryl; [0248] Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para position relative to group A.sub.b; [0249] R.sub.10b is H, halo, C.sub.1-3alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl, OC.sub.1-2haloalkyl or CN; [0250] R.sub.11b is H, F, Cl, CH.sub.3, ethyl, OCH.sub.3, CF.sub.3, OCF.sub.3 or CN, [0251] or R.sub.11b when in the ortho-position to group A.sub.b, together with R.sub.6b are a C.sub.2alkylene chain forming a 5-membered ring; [0252] R.sub.12b is attached to Ar2b in the ortho or meta position relative to Ar1b and R.sub.12b is H, halo, C.sub.1-4alkyl, C.sub.2-4alkynyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, OH, C.sub.1-4alkylOH, CN, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, C(═O)C.sub.1-2alkyl, NR.sub.23bR.sub.24b, SO.sub.2C.sub.1-4alkyl, SOC.sub.1-4alkyl, SC.sub.1-4alkyl, SH, C(O)N(CH.sub.3).sub.2, NHC(O)C.sub.1-3alkyl, C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R.sub.12b together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); [0253] R.sub.13b is H, halo, CH.sub.3 or OCH.sub.3; [0254] R.sub.21b is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl; [0255] R.sub.22b is H or CH.sub.3; [0256] R.sub.23b is H or C.sub.1-2alkyl; [0257] R.sub.24b is H or C.sub.1-2alkyl; [0258] R.sub.29b is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; and [0259] R.sub.32a is C.sub.1-3alkyl and R.sub.33b is C.sub.1-3alky; or [0260] R.sub.32b and R.sub.33b together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl;
[0261] wherein: [0262] R.sub.1b is R.sub.1ab; and/or [0263] R.sub.4b and R.sub.5b are R.sub.4ab and R.sub.5ab; and/or [0264] A is A.sub.ab; or
[0265] wherein when B is (B-bc) and R.sub.3b3c is R.sub.3c, the compound of formula (I) is a compound of formula (I-c):
##STR00014##
[0266] wherein: [0267] A.sub.c is A.sub.ac or A.sub.bc; [0268] A.sub.ac is —CH.sub.2NR.sub.6c—; [0269] A.sub.bc is —C(═O)NR.sub.6c—; [0270] R.sub.1c is R.sub.1ac or R.sub.1bc; [0271] wherein: [0272] R.sub.1ac is NR.sub.32cR.sub.33c; [0273] R.sub.1bc is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, C.sub.1-3alkyleneOC.sub.1-2alkyl, or CF.sub.3; [0274] R.sub.3c is H, CH.sub.3, halo, OC.sub.1-2alkyl or CF.sub.3; [0275] R.sub.4c and R.sub.5c are either R.sub.4ac and R.sub.5ac or R.sub.4bc and R.sub.5bc; [0276] wherein: [0277] R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [0278] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3 alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-4heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21cR.sub.22c; or [0279] one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3 alkyl or OC.sub.1-3alkyl; or [0280] R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [0281] R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29c; or [0282] R.sub.4bc and R.sub.5bc are each independently H, C.sub.1-6alkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-6alkylOH or C.sub.1-6haloalkyl, [0283] or R.sub.4bc and R.sub.5bc together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl ring; [0284] R.sub.6c is H or C.sub.1-3alkyl; [0285] Ar1c is a 6-membered aryl or heteroaryl; [0286] Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the pare position relative to group A.sub.c; [0287] R.sub.10c is H, halo, C.sub.1-3alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl, OC.sub.1-2haloalkyl or CN; [0288] R.sub.11c is H, F, Cl, CH.sub.3, ethyl, OCH.sub.3, CF.sub.3, OCF.sub.3 or CN; [0289] R.sub.12c is attached to Ar2c in the meta or ortho position relative to Ar1c and R.sub.12c is H, halo, C.sub.1-4alkyl, C.sub.2-4alkynyl, C(═O)C.sub.1-2alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, CN, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, OH, C.sub.1-4alkylOH, NR.sub.23cR.sub.24c, SO.sub.2CH.sub.3, C(O)N(CH.sub.3).sub.2, NHC(O)C.sub.1-3alkyl, or a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R.sub.12c together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); [0290] R.sub.21c is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl; [0291] R.sub.22c is H or CH.sub.3; [0292] R.sub.23c is H or C.sub.1-2alkyl; [0293] R.sub.24c is H or C.sub.1-2alkyl; [0294] R.sub.29c is C.sub.1-3 alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; and [0295] R.sub.32c is C.sub.1-3alkyl and R.sub.33c is C.sub.1-3alkyl; or [0296] R.sub.32c and R.sub.33c together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl;
wherein: [0297] R.sub.1c is R.sub.1ac; and/or [0298] R.sub.4c and R.sub.5c are R.sub.4ac and R.sub.5ac; and/or [0299] A.sub.c is A.sub.ac.
[0300] More suitably, there is provided a compound of formula (I-a).
[0301] Alternatively, there is provided a compound of formula (I-b).
[0302] Alternatively, there is provided a compound of formula (I-c).
[0303] Compounds of Formula (I-a)
[0304] The invention provides a compound of formula (I-a):
##STR00015##
[0305] wherein: [0306] A.sub.a is A.sub.aa or A.sub.ba; [0307] wherein: [0308] A.sub.aa is an amine linker having the following structure: —NH—, —CH.sub.2NH— or —NHCH.sub.2—; [0309] A.sub.ba is an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—; [0310] X is N or CH; [0311] Y is N or CR.sub.2a; [0312] Z is N or CR.sub.3a; [0313] with the proviso that when at least one of X or Z is N, Y cannot be N; [0314] R.sub.1a is R.sub.1aa or R.sub.1ba; [0315] wherein: [0316] R.sub.1aa is NR.sub.32aR.sub.33a; [0317] R.sub.1ba is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; [0318] R.sub.2a is H, halo, C.sub.1-2alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl or OC.sub.1-2haloalkyl; [0319] R.sub.3a is H, halo, CH.sub.3, OCH.sub.3, CF.sub.3 or OCF.sub.3; [0320] wherein at least one of R.sub.2a and R.sub.3a is H; [0321] R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa, or R.sub.4ba and R.sub.5ba; [0322] wherein: [0323] R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [0324] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-4cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-4heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21aR.sub.22a; or [0325] one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3 alkyl or OC.sub.1-3alkyl; or [0326] R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [0327] R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29a; or [0328] R.sub.4ba and R.sub.5ba are each independently H, C.sub.1-6alkyl, C.sub.1-6alkylOH, C.sub.1-6haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, or R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl; and [0329] when A.sub.a is —NHC(═O)— or —NHCH.sub.2—: [0330] R.sub.4ba and R.sub.5ba may additionally be selected from halo, OC.sub.1-6haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-4heterocycloalkyl, OC.sub.1-6alkyl and NR.sub.21aR.sub.22a; [0331] Ar1a is a 6-membered aryl or heteroaryl; [0332] Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A.sub.a; [0333] R.sub.10a is H, halo, C.sub.1-3alkyl, C.sub.1-2haloalkyl, OC.sub.1-2alkyl, OC.sub.1-2haloalkyl or CN; [0334] R.sub.11a is H, F, Cl, C.sub.1-2alkyl, CF.sub.3, OCH.sub.3 or CN; [0335] R.sub.12a is attached to Ar2a in the ortho or meta position relative to Ar1a and R.sub.12a is H, halo, C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, hydroxy, C.sub.1-4alkylOH, SO.sub.2C.sub.1-2alkyl, C(O)N(C.sub.1-2alkyl).sub.2, NHC(O)C.sub.1-3alkyl or NR.sub.23aR.sub.24a; and [0336] when A.sub.a is —NHC(═O)—, —NH— or —NHCH.sub.2—: [0337] R.sub.12a may additionally be selected from CN, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2 and a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R.sub.12a together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); [0338] R.sub.13a is H or halo; [0339] R.sub.21a is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl, C.sub.1-5alkylOC.sub.1-2alkyl, C.sub.1-4haloalkyl, or C.sub.4-6heterocycloalkyl; [0340] R.sub.22a is H or CH.sub.3; [0341] R.sub.23a is H or C.sub.1-2alkyl; and [0342] R.sub.24a is H or C.sub.1-2alkyl; [0343] R.sub.29a is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, CF.sub.3, N(C.sub.1-3alkyl).sub.2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; [0344] R.sub.32a is C.sub.1-3alkyl and R.sub.33a is C.sub.1-3alkyl; or [0345] R.sub.32a and R.sub.33a together with the nitrogen atom to which they are attached form a C.sub.3-5 heterocycloalkyl;
[0346] or a salt and/or solvate thereof and/or derivative thereof.
[0347] Suitably, R.sub.1c is R.sub.1ac; and/or R.sub.4c and R.sub.5c are R.sub.4ac and R.sub.5ac; and/or A.sub.c is A.sub.ac.
[0348] The invention also provides a compound of formula (I-a):
##STR00016##
[0349] wherein: [0350] A.sub.a is A.sub.aa or A.sub.ba; [0351] wherein: [0352] A.sub.aa is an amine linker having the following structure: —NH—, —CH.sub.2NH— or —NHCH.sub.2—; [0353] A.sub.ba is an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—; [0354] X is N or CH; [0355] Y is N or CR.sub.2a; [0356] Z is N or CR.sub.3a; [0357] with the proviso that when at least one of X or Z is N, Y cannot be N; [0358] R.sub.1a is R.sub.1aa or R.sub.1ba; [0359] wherein: [0360] R.sub.1aa is NR.sub.32aR.sub.33a; [0361] R.sub.1ba is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; [0362] R.sub.2a is H, halo, C.sub.1-2alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl or OC.sub.1-2haloalkyl; [0363] R.sub.3a is H, halo, CH.sub.3, OCH.sub.3, CF.sub.3 or OCF.sub.3; [0364] wherein at least one of R.sub.2a and R.sub.3a is H; [0365] R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa, or R.sub.4ba and R.sub.5ba; [0366] wherein: [0367] R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [0368] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3 alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21aR.sub.22a; or [0369] one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3 alkyl or OC.sub.1-3alkyl; or [0370] R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6 heterocycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6 heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [0371] R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29a; or [0372] R.sub.4ba and R.sub.5ba, are each independently H, C.sub.1-6alkyl, C.sub.1-6alkylOH, C.sub.1-6haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, or R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl; and [0373] when A.sub.a is —NHC(═O)— or —NHCH.sub.2—: [0374] R.sub.4ba and R.sub.5ba may additionally be selected from halo, OC.sub.1-6haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-6alkyl and NR.sub.21aR.sub.22a; [0375] Ar1a is a 6-membered aryl or heteroaryl; [0376] Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A.sub.a; [0377] R.sub.10a is H, halo, C.sub.1-3alkyl, C.sub.1-2haloalkyl, OC.sub.1-2alkyl, OC.sub.1-2haloalkyl or CN; R.sub.11a is H, F, Cl, C.sub.1-2alkyl, CF.sub.3, OCH.sub.3 or CN; R.sub.12a is attached to Ar2a in the ortho or meta position relative to Ar1a and R.sub.12a is H, halo, C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, hydroxy, C.sub.1-4alkylOH, SO.sub.2C.sub.1-2alkyl, C(O)N(C.sub.1-2alkyl).sub.2, NHC(O)C.sub.1-3alkyl or NR.sub.23aR.sub.24a; and [0378] when A.sub.a is —NHC(═O)—, —NH— or —NHCH.sub.2—: [0379] R.sub.12a may additionally be selected from CN, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2 and a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R.sub.12a together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); [0380] R.sub.13a is H or halo; [0381] R.sub.21a is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl; [0382] R.sub.21a is H or CH.sub.3; [0383] R.sub.23a is H or C.sub.1-2alkyl; and [0384] R.sub.24a is H or C.sub.1-2alky; [0385] R.sub.29a is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; [0386] R.sub.32a is C.sub.1-3alkyl and R.sub.33a is C.sub.1-3alkyl; or [0387] R.sub.32a and R.sub.33a together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl;
[0388] or a salt and/or solvate thereof and/or derivative thereof.
[0389] Suitably, R.sub.1c is R.sub.1ac; and/or R.sub.4c and R.sub.5c are R.sub.4ac and R.sub.5ac; and/or A.sub.c is A.sub.ac.
[0390] The phrase ‘A.sub.ba is an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—’ means the following structures form:
##STR00017##
[0391] Reference to R.sub.4 and R.sub.5 above includes variables R.sub.4a, R.sub.5a, R.sub.4aa, R.sub.5aa, R.sub.4ba and R.sub.5ba, and reference to Ar1 and Ar2 includes variables Ar1a and Ar2a.
[0392] The phrase ‘A.sub.aa is an amine linker having the following structure: —CH.sub.2NH— or —NHCH.sub.2—’ means the following structures form:
##STR00018##
[0393] Reference to R.sub.4 and R.sub.5 above includes variables R.sub.4a, R.sub.5a, R.sub.4aa, R.sub.5aa, R.sub.4ba and R.sub.5ba, and reference to Ar1 and Ar2 includes variables Ar1a and Ar2a.
[0394] In one embodiment, A.sub.ba is —C(═O)NH—. In another embodiment, A.sub.ba is —NHC(═O)—. In an additional embodiment, A.sub.aa is —NH—. In a further embodiment, A.sub.aa is —CH.sub.2NH—. In another embodiment, A.sub.aa is —NHCH.sub.2—.
[0395] In one embodiment X is N. In another embodiment, X is CH.
[0396] In one embodiment, Y is N. In another embodiment, Y is CR.sub.2a.
[0397] In one embodiment. Z is N. In another embodiment, Z is CR.sub.3a.
[0398] Suitably, X is N, Y is CR.sub.2a and Z is CR.sub.3a. Alternatively, X is CH, Y is N and Z is CR.sub.3a. Alternatively, X is CH, Y is CR.sub.2a and Z is CR.sub.3a. Alternatively, X is CH, Y is CR.sub.2a and Z is N. Alternatively, X is N, Y is CR.sub.2a and Z is N.
[0399] In one embodiment of the invention, R.sub.1a is R.sub.1aa, i.e. is NR.sub.32aR.sub.33a. In an embodiment R.sub.32, is C.sub.1-3alkyl, such as methyl or ethyl, e.g. methyl. In an embodiment, R.sub.33a is C.sub.1-3alkyl, such as methyl or ethyl, e.g. methyl. Suitably, R.sub.32a and R.sub.33a are both methyl. Suitably, R.sub.32a and R.sub.33a are both ethyl. Suitably, R.sub.32a is methyl and R.sub.33a is ethyl.
[0400] In another embodiment, R.sub.32a and R.sub.33a together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl. Suitably, the C.sub.3-5heterocycloalkyl is aziridinyl, azetidinyl or pyrrolidinyl.
[0401] Suitably, R.sub.1a is R.sub.1ba.
[0402] In one embodiment of the invention R.sub.1ba is C.sub.1-5alkyl. When R.sub.1ba is C.sub.1-5alkyl, R.sub.1ba may be methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, sec-butyl or tert-butyl) or pentyl (e.g. n-pentyl, sec-pentyl or 3-pentyl).
[0403] In a second embodiment of the invention R.sub.1ba is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3. In some embodiments, R.sub.1ba is C.sub.0-2alkyleneC.sub.3-5cycloalkyl. In other embodiments, R.sub.1ba is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is substituted by CH.sub.3. R.sub.1ba may be C.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1ba may be C.sub.1alkyleneC.sub.3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1ba may be C.sub.2alkyleneC.sub.3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1ba may be C.sub.0-2alkyleneC.sub.3cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1ba may be C.sub.0-2alkyleneC.sub.4cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1ba may be C.sub.0-2alkyleneC.sub.5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. Suitably, where C.sub.0-2alkyleneC.sub.3-5cycloalkyl is optionally substituted by CH.sub.3, the CH.sub.3 is at the point of attachment of the C.sub.3-5cycloalkyl to the C.sub.0-2alkylene.
[0404] In a third embodiment, R.sub.1ba is CF.sub.3.
[0405] Suitably R.sub.1ba is cyclopropyl, cyclopropyl substituted by CH.sub.3 at the point of attachment, cyclobutyl, CH.sub.3 or CH.sub.2CH.sub.3. In particular R.sub.1ba is cyclopropyl, cyclobutyl, CH.sub.3 or CH.sub.2CH.sub.3, especially cyclopropyl.
[0406] In one embodiment, R.sub.2a is H. In a second embodiment, R.sub.2a is halo such as F, Cl or Br, e.g. Cl or Br. In a third embodiment, R.sub.2a is C.sub.1-2alkyl. When R.sub.2a is C.sub.1-2alkyl, R.sub.2a may be methyl or ethyl, such as methyl. In a fourth embodiment, R.sub.2a is OC.sub.1-2alkyl. When R.sub.2a is OC.sub.1-2alkyl, may be OCH.sub.3 or OEt, such as OCH.sub.3. In a fifth embodiment, R.sub.2a is C.sub.1-2haloalkyl. When R.sub.2 is C.sub.1-2haloalkyl, R.sub.2a may be CF.sub.3 or CH.sub.2CF.sub.3, such as CF.sub.3. In a sixth embodiment, R.sub.2a is OC.sub.1-2haloalkyl. When R.sub.2 is OC.sub.1-2 haloalkyl, R.sub.2a may be OCF.sub.3 or OCH.sub.2CF.sub.3, such as OCF.sub.3.
[0407] Suitably, R2 is H, CH.sub.3 or CF.sub.3, such as H or CH.sub.3, in particular H.
[0408] In one embodiment R.sub.3a is H. In a second embodiment R.sub.3a is halo, in particular chloro or fluoro, especially fluoro. In a third embodiment, R.sub.3a is CH.sub.3. In a fourth embodiment, R.sub.3a is OCH.sub.3. In a fifth embodiment, R.sub.3a is CF.sub.3. In a sixth embodiment, R.sub.3a is OCF.sub.3.
[0409] Suitably, R.sub.3a is H, halo in particular chloro or fluoro, especially fluoro, CH.sub.3 or CF.sub.3. More suitably, R.sub.3a is H or F, such as H.
[0410] Suitably, at least one of R.sub.2a and R.sub.3a is H.
[0411] In one embodiment, R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa.
[0412] Suitably, R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3 haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21aR.sub.22a.
[0413] In one embodiment, the C.sub.3-6cycloalkyl is cyclopropyl. In another embodiment, the C.sub.3-6cycloalkyl is cyclobutyl. In another embodiment, the C.sub.3-6cycloalkyl is cyclopentyl. In another embodiment, the C.sub.3-6cycloalkyl is cyclohexyl.
[0414] In one embodiment the C.sub.3-6cycloalkyl is substituted by one substituent. In a second embodiment the C.sub.3-6cycloalkyl is substituted by two substituents.
[0415] In one embodiment, the substituent is C.sub.1-3alkyl. Suitably, the substituent is methyl. Suitably, the substituent is ethyl. Suitably, the substituent is n-propyl. Suitably, the substituent is iso-propyl.
[0416] In a second embodiment, the substituent is C.sub.1-3alkylOH. Suitably, the substituent is CH.sub.2OH.
[0417] Suitably, the substituent is CH.sub.2CH.sub.2OH. Suitably, the substituent is CH.sub.2CH.sub.2CH.sub.2OH.
[0418] In a third embodiment, the substituent is C.sub.1-3haloalkyl. Suitably the C.sub.1-3alkyl group is substituted by one, two or three, such as one, halogen atom. Suitably, the halogen atom is fluoro or chloro such as fluoro. Suitably, the substituent is C.sub.1haloalkyl such as CF.sub.3. Suitably, the substituent is C.sub.2haloalkyl such as CH.sub.2CF.sub.3.
[0419] In a fourth embodiment, the substituent is C.sub.0-2alkyleneC.sub.3-6cycloalkyl, in particular C.sub.0-2alkyleneC.sub.3-5cycloalkyl, such as C.sub.3-5cycloalkyl, C.sub.1alkyleneC.sub.3-5cycloalkyl or C.sub.0-2alkyleneC.sub.3-5cycloalkyl.
[0420] In a fifth embodiment, the substituent is C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as C.sub.0-2alkyleneC.sub.3heterocycloalkyl, C.sub.0-2alkyleneC.sub.4heterocycloalkyl, C.sub.0-2alkyleneC.sub.5heterocycloalkyl, C.sub.0-2alkyleneC.sub.6heterocycloalkyl, C.sub.0alkyleneC.sub.3-6heterocycloalkyl, C.sub.1alkyleneC.sub.3-6heterocycloalkyl and C.sub.2alkyleneC.sub.3-6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring.
[0421] Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring may be substituted (such as one nitrogen atom is substituted), for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.1-3heterocycloalkyl ring is not substituted.
[0422] In a sixth embodiment, the substituent is C.sub.1-3alkyleneOC.sub.1-3alkyl, in particular C.sub.1-2alkyleneOC.sub.1-2alkyl such as C.sub.1alkyleneOC.sub.1alkyl, C.sub.2alkyleneOC.sub.1alkyl, C.sub.1alkyleneOC.sub.2alkyl or C.sub.2alkyleneOC.sub.2alkyl.
[0423] In a seventh embodiment, the substituent is halo, in particular fluoro or chloro such as chloro.
[0424] In an eighth embodiment, the substituent is OC.sub.1-3haloalkyl. Suitably the OC.sub.1-3alkyl group is substituted by one two or three, such as one, halogen atom. Suitably, the halogen atom is fluoro or chloro such as fluoro. Suitably, the substituent is OC.sub.1haloalkyl such as OCF.sub.3. Suitably, the substituent is OC.sub.2haloalkyl such as OCH.sub.2CF.sub.3.
[0425] In a ninth embodiment, the substituent is OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, such as OC.sub.3-6cycloalkyl, OC.sub.1alkyleneC.sub.3-6cycloalkyl or OC.sub.2alkyleneC.sub.3-6cycloalkyl.
[0426] In a tenth embodiment, the substituent is OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as OC.sub.0-2alkyleneC.sub.3heterocycloalkyl, C.sub.0-2alkyleneC.sub.4heterocycloalkyl, OC.sub.0-2alkyleneC.sub.5heterocycloalkyl, OC.sub.0-2alkyleneC.sub.6heterocycloalkyl, OC.sub.0alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1alkyleneC.sub.3-6heterocycloalkyl and OC.sub.2alkyleneC.sub.3-6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) (such as one nitrogen atom) in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4 alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4 haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3 alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted.
[0427] In an eleventh embodiment, the substituent is OC.sub.1-3alkyl, such as OCH.sub.3 or OCH.sub.2CH.sub.3.
[0428] In a twelfth embodiment, the substituent is NR.sub.21aR.sub.22a wherein R.sub.21a and R.sub.22a are defined elsewhere herein.
[0429] In an embodiment the substituent is oxo.
[0430] In another embodiment the substituent is OH.
[0431] Suitably, the one or two substituents, in particular one substituent, are independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, halo, OC.sub.1-3haloalkyl, OC.sub.1-3alkyl and NR.sub.21aR.sub.22a.
[0432] More suitably, the substituent is independently selected from the group consisting of oxo, OH, halo, OC.sub.1-3alkyl and NR.sub.21aR.sub.22a.
[0433] Most suitably, the substituent is independently selected from the group consisting of oxo, OH, fluoro and NR.sub.21aR.sub.22a.
[0434] When the substituent is NR.sub.21aR.sub.22a, in one embodiment R.sub.21a is H. In a second embodiment R.sub.21a is C.sub.1-5alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R.sub.21a is C(O)C.sub.1-5alkyl, such as C(O)CH.sub.3. In a fourth embodiment R.sub.21a is C(O)OC.sub.1-2alkyl, such as C(O)OCH.sub.3 or C(O)Otert-butyl. In a fifth embodiment R.sub.21a is C.sub.1-3alkylOC.sub.1-2alkyl such as C.sub.1alkylOC.sub.1alkyl, C.sub.2alkylOC.sub.1alkyl or C.sub.3alkylOC.sub.1alkyl e.g. C.sub.2alkylOC.sub.1alkyl. In a sixth embodiment, R.sub.21a is C.sub.1-4haloalkyl, such as CF.sub.3, CH.sub.2CF.sub.3 or CH.sub.2CHF.sub.2 e.g. CH.sub.2CHF.sub.2. In a seventh embodiment R.sub.21a is C.sub.4-6heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.
[0435] When the substituent is NR.sub.21aR.sub.22a, in one embodiment R.sub.22a is H. In a second embodiment R.sub.22a is methyl.
[0436] Suitably, R.sub.21a is C(O)OCH.sub.3 and R.sub.22a is H. Suitably, R.sub.21a is C(O)CH.sub.3 and R.sub.22a is H. Suitably, R.sub.21a and R.sub.22a are both CH.sub.3. Suitably, R.sub.21a and R.sub.22a are both H.
[0437] Alternatively, R.sub.4aa and R.sub.5aa suitably together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl and one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl.
[0438] In one embodiment the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached is unsubstituted. In a second embodiment the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached is substituted by one or two substituents, in particular one substituent. Suitably, each substituent being independently selected from the group consisting of C.sub.1-2alkyl or OCH.sub.3.
[0439] Suitably one of the carbons of the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached is a C.sub.4-6cycloalkyl. Suitably the further C.sub.3-6heterocycloalkyl is an oxygen containing C.sub.3-6heterocycloalkyl.
[0440] Alternatively, R.sub.4aa and R.sub.5aa suitably together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3 alkyl or OC.sub.1-3alkyl.
[0441] In one embodiment the C.sub.3-6heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached is unsubstituted. In a second embodiment the C.sub.3-6heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached is substituted by one or two substituents, in particular one substituent. Suitably, each substituent being independently selected from the group consisting of C.sub.1-2alkyl or OCH.sub.3.
[0442] In an embodiment, R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29a.
[0443] Suitably, the C.sub.3-6heterocycloalkyl is selected from the group consisting of azirdinyl, azetidinyl, pyrrolidinyl and piperidinyl such as piperidinyl.
[0444] Suitably, when the C.sub.3-6heterocycloalkyl is piperidinyl, the nitrogen atom is in the 4-position relative to the quaternary carbon:
##STR00019##
[0445] The C.sub.3-6heterocycloalkyl may be other groups as defined elsewhere herein.
[0446] In an embodiment, R.sub.29a is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3. In one embodiment, R.sub.29a is C.sub.1-3alkyl such as methyl. In another embodiment, R.sub.29a is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3. In some embodiments, R.sub.29a is C.sub.0-2alkyleneC.sub.3-5cycloalkyl. In other embodiments, R.sub.29a is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is substituted by CH.sub.3. R.sub.29a may be C.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29a may be C.sub.1alkyleneC.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29a may be C.sub.2alkyleneC.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29a may be C.sub.0-2alkyleneC.sub.3cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29a may be C.sub.0-2alkyleneC.sub.4cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29a may be C.sub.0-2alkyleneC.sub.5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. Suitably, where C.sub.0-2alkyleneC.sub.3-5cycloalkyl is optionally substituted by CH.sub.3, the CH.sub.3 is at the point of attachment of the C.sub.3-5cycloalkyl to the C.sub.0-2alkylene. In another embodiment, R.sub.29a is CF.sub.3. In another embodiment, R.sub.29a is N(C.sub.1-3alkyl).sub.2 such as N(CH.sub.3).sub.2. In another embodiment, R.sub.29a is a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl. In one embodiment, the 5 or 6 membered heteroaryl is substituted by methyl. In one embodiment, the 5 or 6 membered heteroaryl is not substituted by methyl. In one embodiment, R.sub.29a is a 5-membered heteroaryl such as pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, such as pyrazolyl. Suitably the pyrazolyl is substituted by methyl. In another embodiment, R.sub.29a is a 6-membered heteroaryl such as pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.
[0447] In another embodiment, R.sub.4a and R.sub.5a are R.sub.4ba and R.sub.5ba.
[0448] In one embodiment, R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl in particular cyclopropyl or cyclopentyl. In a second embodiment, R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl, such as a heterocyclohexyl, in particular a tetrahydropyranyl. Any nitrogen atom such as one nitrogen atom in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4 alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted. In a third embodiment, R.sub.4ba is C.sub.1-6alkyl, in particular C.sub.1-4alkyl such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-buty). In a fourth embodiment, R.sub.4ba is C.sub.1-3alkyleneOC.sub.1-3alkyl, in particular C.sub.1-2alkyleneOC.sub.1-2alkyl such as C.sub.1alkyleneOC.sub.1alkyl, C.sub.2alkyleneOC.sub.1alkyl, C.sub.1alkyleneOC.sub.2alkyl or C.sub.2alkyleneOC.sub.2alkyl. In a fifth embodiment, R.sub.4ba is H. In a sixth embodiment, R.sub.4ba is halo, such as chloro or fluoro, especially fluoro. In a seventh embodiment, R.sub.4ba is C.sub.1-6haloalkyl, such as CF.sub.3 or CH.sub.2CF.sub.3. In an eighth embodiment, R.sub.4ba is C.sub.0-2alkyleneC.sub.3-6cycloalkyl such as C.sub.3-6cycloalkyl, C.sub.1alkyleneC.sub.3-6cycloalkyl, C.sub.2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3cycloalkyl, C.sub.0-2alkyleneC.sub.4cycloalkyl, C.sub.0-2alkyleneC.sub.5cycloalkyl or C.sub.0-2alkyleneC.sub.6cycloalkyl. In a ninth embodiment, R.sub.4ba is C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as C.sub.3-6heterocycloalkyl, C.sub.1alkyleneC.sub.3-6heterocycloalkyl, C.sub.2alkyleneC.sub.3-6heterocycloalkyl, C.sub.0-2alkyleneC.sub.3heterocycloalkyl, C.sub.0-2alkyleneC.sub.4hetero-cycloalkyl, C.sub.0-2alkyleneC.sub.5heterocycloalkyl or C.sub.0-2alkyleneC.sub.6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl.
[0449] Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as one nitrogen atom in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted. In a tenth embodiment, R.sub.4ba is C.sub.1-6alkylOH, such as CH.sub.2OH or CH.sub.2CH.sub.2OH. In an eleventh embodiment, R.sub.4ba is OC.sub.1-6haloalkyl, such as OC.sub.1-4haloalkyl, such as OCF.sub.3 or OCHF.sub.2. In a twelfth embodiment, R.sub.4ba is OC.sub.0-2alkyleneC.sub.3-6cycloalkyl such as OC.sub.3-6cycloalkyl, OC.sub.1alkyleneC.sub.3-6cycloalkyl, OC.sub.2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3cycloalkyl, OC.sub.0-2alkyleneC.sub.4cycloalkyl, OC.sub.0-2alkyleneC.sub.5cycloalkyl or OC.sub.0-2alkyleneC.sub.6cycloalkyl. In a thirteenth embodiment, R.sub.4ba is OC.sub.1-6alkyl, in particular OC.sub.1-4alkyl such as methoxy, ethoxy, propoxy (n-propoxy or isopropoxy) or butoxy (n-butoxy, isobutoxy, sec-butoxy or tert-butoxy). In a fourteenth embodiment, R.sub.4ba is OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as OC.sub.3-6heterocycloalkyl, OC.sub.1alkyleneC.sub.3-6heterocycloalkyl, OC.sub.2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.0-2alkyleneC.sub.3heterocycloalkyl, OC.sub.0-2alkyleneC.sub.4hetero-cycloalkyl, OC.sub.0-2alkyleneC.sub.5heterocycloalkyl or OC.sub.0-2alkyleneC.sub.6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as one nitrogen atom in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted. In a fifteenth embodiment, R.sub.4ba is NR.sub.21aR.sub.22a.
[0450] When A.sub.a is —NHC(═O)— or —C(═O)NH—, suitably, R.sub.4ba is H, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkylOH, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, or R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl. When A.sub.a is —NHC(═O)—, suitably R.sub.4ba may additionally be selected from halo, OC.sub.1-6haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-6alkyl or NR.sub.21aR.sub.22a.
[0451] When A.sub.a is —NH—, —CH.sub.2NH— or —NHCH.sub.2—, suitably, R.sub.4ba is H, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkylOH, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, or R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl. When A.sub.a is —NHCH.sub.2—, suitably R.sub.4ba may additionally be selected from halo, OC.sub.1-6haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-6alkyl or NR.sub.21aR.sub.22a.
[0452] Suitably R.sub.4ba is H, fluoro, CH.sub.3, ethyl, OCH.sub.3 or CH.sub.2CH.sub.2OCH.sub.3, such as fluoro, ethyl, OCH.sub.3 or CH.sub.2CH.sub.2OCH.sub.3.
[0453] Suitably R.sub.4ba is H, CH.sub.3, ethyl or CH.sub.2CH.sub.2OCH.sub.3, in particular CH.sub.3 or ethyl.
[0454] Suitably R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a cyclopropyl or cyclopentyl, in particular a cyclopentyl.
[0455] Suitably R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a heterocyclohexyl, such as tetrahydropyranyl or piperidinyl, especially tetrahydropyranyl. Any nitrogen atom such as one nitrogen atom in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-2alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted.
[0456] Suitably R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a heterocyclobutyl, such as azetidinyl. Any nitrogen atom such as one nitrogen atom in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted.
[0457] When R.sub.4ba is NR.sub.21aR.sub.22a, in one embodiment R.sub.21a is H. In a second embodiment R.sub.21a is C.sub.1-5alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R.sub.21a is C(O)C.sub.1-5alkyl, such as C(O)CH.sub.3. In a fourth embodiment R.sub.21a is C(O)OC.sub.1-5alkyl, such as C(O)OCH.sub.3 or C(O)Otert-butyl. In a fifth embodiment R.sub.21a is C.sub.1-3alkylOC.sub.1-2alkyl such as C.sub.1alkylOC.sub.1alkyl, C.sub.2alkylOC.sub.1alkyl or C.sub.3alkylOC.sub.1alkyl e.g. C.sub.2alkylOC.sub.1alkyl. In a sixth embodiment, R.sub.21a is C.sub.1-4haloalkyl, such as CF.sub.3, CH.sub.2CF.sub.3 or CH.sub.2CHF.sub.2 e.g. CH.sub.2CHF.sub.2. In a seventh embodiment R.sub.21a is C.sub.4-6heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.
[0458] When R.sub.4ba is NR.sub.21aR.sub.22a, in one embodiment R.sub.22a is H. In a second embodiment R.sub.22a is methyl.
[0459] For example, R.sub.4ba is NH.sub.2, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHC(O)OCH.sub.3, NHC(O)Otert-butyl and CH.sub.2CH.sub.2OH, especially, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHC(O)OCH.sub.3.
[0460] Suitably, R.sub.21a is C(O)OCH.sub.3 and R.sub.22a is H. Suitably, R.sub.21a is C(O)CH.sub.3 and R.sub.22a is H. Suitably, R.sub.21a and R.sub.22a are both CH.sub.3. Suitably, R.sub.21a and R.sub.22a are both H.
[0461] In one embodiment R.sub.5ba is C.sub.1-6alkyl, in particular C.sub.1-4alkyl such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a second embodiment R.sub.5ba is C.sub.1-3alkyleneOC.sub.1-3alkyl, in particular C.sub.1-2alkyleneOC.sub.1-2alkyl such as C.sub.1alkyleneOC.sub.1alkyl, C.sub.2alkyleneOC.sub.1alkyl, C.sub.1alkyleneOC.sub.2alkyl or C.sub.2alkyleneOC.sub.2alkyl. In a third embodiment R.sub.5ba is H. In a fourth embodiment, R.sub.5ba is halo, such as chloro or fluoro, especially fluoro. In a fifth embodiment, R.sub.5ba is C.sub.1-6haloalkyl, such as CF.sub.3 or CH.sub.2CF.sub.3. In a sixth embodiment, R.sub.5ba is C.sub.0-2alkyleneC.sub.3-6cycloalkyl such as C.sub.3-6cycloalkyl, C.sub.1alkyleneC.sub.3-6cycloalkyl, C.sub.2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3cycloalkyl, C.sub.0-2alkyleneC.sub.4cycloalkyl, C.sub.0-2alkyeneC.sub.5cycloalkyl or C.sub.0-2alkyleneC.sub.6cycloalkyl. In a seventh embodiment, R.sub.5ba is C.sub.0-2alkyleneC.sub.3-4heterocycloalkyl such as C.sub.3-6heterocycloalkyl, C.sub.1alkyleneC.sub.3-6heterocycloalkyl, C.sub.2alkyleneC.sub.3-6heterocycloalkyl, C.sub.0-2alkyleneC.sub.6heterocycloalkyl, C.sub.0-2alkyleneC.sub.4hetero-cycloalkyl, C.sub.0-2alkyleneC.sub.5heterocycloalkyl or C.sub.0-2alkyleneC.sub.6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as one nitrogen atom in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4 alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted. In an eighth embodiment, R.sub.5ba is C.sub.1-6alkylOH, such as CH.sub.2OH or CH.sub.2CH.sub.2OH. In a ninth embodiment, R.sub.5ba is OC.sub.1-6haloalkyl, such as OC.sub.1-4haloalkyl, such as OCF.sub.3 or OCHF.sub.2. In a tenth embodiment, R.sub.5ba is OC.sub.0-2alkyleneC.sub.3-6cycloalkyl such as OC.sub.3-6cycloalkyl, OC.sub.1alkyleneC.sub.3-6cycloalkyl, OC.sub.2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3cycloalkyl, OC.sub.0-2alkyleneC.sub.4cycloalkyl, OC.sub.0-2alkyleneC.sub.5cycloalkyl or OC.sub.0-2alkyleneC.sub.6cycloalkyl. In an eleventh embodiment, R.sub.5ba is OC.sub.1-6alkyl, in particular OC.sub.1-4alkyl such as methoxy, ethoxy, propoxy (n-propoxy or isopropoxy) or butoxy (n-butoxy, isobutoxy, sec-butoxy or tert-butoxy). In a twelfth embodiment, R.sub.5ba is OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as OC.sub.3-6heterocycloalkyl, OC.sub.1alkyleneC.sub.3-6heterocycloalkyl, OC.sub.2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.0-2alkyleneC.sub.3heterocycloalkyl, C.sub.0-2alkyleneC.sub.4hetero-cycloalkyl, OC.sub.0-2alkyleneC.sub.5heterocycloalkyl or OC.sub.0-2alkyleneC.sub.6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as one nitrogen atom in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted. In a thirteenth embodiment, R.sub.5ba is NR.sub.21aR.sub.22a.
[0462] When A.sub.a is —NHC(═O)— or —C(═O)NH—, suitably, R.sub.5ba is H, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkylOH, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, or R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl. When A.sub.a is —NHC(═O)—, suitably R.sub.5ba may additionally be selected from halo, OC.sub.1-6haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-6alkyl or NR.sub.21aR.sub.22a.
[0463] When A.sub.a is —NH—, —CH.sub.2NH— or —NHCH.sub.2—, suitably, R.sub.5ba is H, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkylOH, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, or R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl. When A.sub.a is —NHCH.sub.2—, suitably R.sub.5ba may additionally be selected from halo, OC.sub.1-6haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-6alkyl or NR.sub.21aR.sub.22a.
[0464] When R.sub.5ba is NR.sub.21aR.sub.22a, in one embodiment R.sub.21a is H. In a second embodiment R.sub.21a is C.sub.1-5alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R.sub.21a is C(O)C.sub.1-5alkyl, such as C(O)CH.sub.3. In a fourth embodiment R.sub.21a is C(C)OC.sub.1-5alkyl, such as C(O)OCH.sub.3 or C(O)Otert-butyl. In a fifth embodiment R.sub.21a is C.sub.1-3alkylOC.sub.1-2alkyl such as C.sub.1alkylOC.sub.1alkyl, C.sub.2alkylOC.sub.1alkyl or C.sub.3alkylOC.sub.1alkyl e.g. C.sub.2alkylOC.sub.1alkyl. In a sixth embodiment, R.sub.21a is C.sub.1-4 haloalkyl, such as CF.sub.3, CH.sub.2CF.sub.3 or CH.sub.2CHF.sub.2 e.g. CH.sub.2CHF.sub.2. In a seventh embodiment R.sub.21a is C.sub.4-6heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.
[0465] When R.sub.5ba is NR.sub.21aR.sub.22a, in one embodiment R.sub.22a is H. In a second embodiment R.sub.22a is methyl.
[0466] For example, R.sub.5ba is NH.sub.2, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHC(O)OCH.sub.3, NHC(O)Otert-butyl and CH.sub.2CH.sub.2OH, especially, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHC(O)OCH.sub.3.
[0467] Suitably, R.sub.21a is C(O)OCH.sub.3 and R.sub.22a is H. Suitably, R.sub.21a is C(O)CH.sub.3 and R.sub.22a is H. Suitably, R.sub.21a and R.sub.22a are both CH.sub.3. Suitably, R.sub.21a and R.sub.22a are both H.
[0468] Suitably R.sub.5ba is H, F, CH.sub.3 or ethyl such as H, CH.sub.3 or ethyl.
[0469] Suitably R.sub.4ba is H, CH.sub.3, ethyl or CH.sub.2CH.sub.2OCH.sub.3 and R.sub.5ba is H, CH.sub.3 or ethyl, in particular R.sub.4ba is CH.sub.3, or ethyl and R.sub.5ba is H, methyl or ethyl. For example, R.sub.4ba and R.sub.5ba are H, R.sub.4ba and R.sub.5ba are methyl, R.sub.4ba and R.sub.5ba are ethyl or R.sub.4ba is CH.sub.2CH.sub.2OCH.sub.3 and R.sub.5ba is H.
[0470] Suitably, R.sub.4ba is F and R.sub.5ba is ethyl.
[0471] Suitably, R.sub.4ba is F and R.sub.5ba is F.
[0472] Suitably, R.sub.4ba is ethyl and R.sub.5ba is H.
[0473] Suitably R.sub.4ba and R.sub.5ba are arranged in the following configuration:
##STR00020##
[0474] wherein R.sub.4 and R.sub.5 include variables R.sub.4a, R.sub.5a, R.sub.4aa, R.sub.5aa, R.sub.4ba and R.sub.5ba.
[0475] In one embodiment Ar1a is a 6-membered aryl, i.e. phenyl. In a second embodiment Ar1a is a 6-membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl).
[0476] In particular Ar1a is phenyl, 2-pyridyl or 3-pyridyl, such as phenyl or 2-pyridyl.
[0477] In one embodiment R.sub.10a is H. In a second embodiment R.sub.10a is halo, for example fluoro or chloro. In a third embodiment R.sub.10a is C.sub.1-3alkyl such as C.sub.1-2alkyl, such as CH.sub.3 or ethyl. In a fourth embodiment R.sub.10a is OC.sub.1-2alkyl, such as OCH.sub.3 or ethoxy. In a fifth embodiment R.sub.10a is OC.sub.1-2haloalkyl, such as OCF.sub.3. In a sixth embodiment R.sub.10a is CN. In a seventh embodiment, R.sub.10a is C.sub.1-2 haloalkyl such as CF.sub.3.
[0478] Suitably R.sub.10a is H, fluoro, chloro, CH.sub.3, CF.sub.3, OCH.sub.3, OCF.sub.3 or CN, such as H, fluoro, chloro, CH.sub.3, OCH.sub.3, OCF.sub.3 or CN, in particular H, fluoro, chloro, OCH.sub.3, OCF.sub.3 or CN especially H or fluoro.
[0479] Suitably, R.sub.10a is H, F or CH.sub.3.
[0480] In one embodiment R.sub.11a is H. In a second embodiment R.sub.11a is F. In a third embodiment, R.sub.11a is C.sub.1-2alkyl such as CH.sub.3 or Et, such as CH.sub.3. In a fourth embodiment R.sub.11a is OCH.sub.3. In a fifth embodiment, R.sub.11a is Cl. In a sixth embodiment, R.sub.11a is Et. In a seventh embodiment, R.sub.11a is CF.sub.3. In an eighth embodiment, R.sub.11a is CN.
[0481] Suitably, R.sub.11a is H, F, CH.sub.3 or OCH.sub.3, such as H, F or CH.sub.3, such as H or F, such as H.
[0482] In one embodiment, R.sub.10a is in the ortho position with respect to group Aa. In another embodiment, R.sub.10a is in the meta position with respect to group Aa. Suitably R.sub.10a is in the ortho position with respect to group Aa.
[0483] In one embodiment, R.sub.11a is in the ortho position with respect to group Aa. In another embodiment, R.sub.11a is in the meta position with respect to group Aa. Suitably R.sub.11a is in the ortho position with respect to group Aa.
[0484] In one embodiment Ar2a is a 6-membered aryl, i.e. phenyl. In a second embodiment Ar2a is a 6-membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl).
[0485] In particular Ar2a is 3-pyridyl or 2,5-pyrazinyl, especially 2,5-pyrazinyl.
[0486] In one embodiment R.sub.12a is H. In a second embodiment R.sub.12a is halo, for example fluoro or chloro. In a third embodiment R.sub.12a is C.sub.1-4alkyl, such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment R.sub.12a is OC.sub.1-4alkyl, such as OCH.sub.3, ethoxy, isopropoxy or n-propoxy. In a fifth embodiment R.sub.12a is OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, such as OC.sub.3-5cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OC.sub.1alkyleneC.sub.3-5cycloalkyl or OC.sub.2alkyleneC.sub.3-5cycloalkyl. In a sixth embodiment R.sub.12a is CN. In a seventh embodiment R.sub.12a is C.sub.1-4haloalkyl, such as CF.sub.3. In an eighth embodiment R.sub.12a is OC.sub.1-4haloalkyl, such as OCF.sub.3, OCHF.sub.2 or OCH.sub.2CF.sub.3. In a ninth embodiment, R.sub.12a is C.sub.2-4alkenyl such as C(═CH.sub.2)CH.sub.3. In a tenth embodiment, R.sub.12a is C.sub.0-2alkyleneC.sub.3-5cycloalkyl such as C.sub.3-5cycloalkyl, C.sub.1alkyleneC.sub.3-5cycloalkyl, C.sub.2alkyleneC.sub.3-5cycloalkyl, C.sub.0-2alkyleneC.sub.3cycloalkyl, C.sub.0-2alkyleneC.sub.4cycloalkyl or C.sub.0-2alkyleneC.sub.5cycloalkyl. In an eleventh embodiment, R.sub.12a is hydroxy. In a twelfth embodiment, R.sub.12a is C.sub.1-4alkylOH such as CH.sub.2OH. In a thirteenth embodiment, R.sub.12a is SO.sub.2C.sub.1-2alkyl such as SO.sub.2CH.sub.3. In a fourteenth embodiment, R.sub.12a is C(O)N(C.sub.1-2alkyl).sub.2 such as C(O)N(CH.sub.3).sub.2. In a fifteenth embodiment, R.sub.12a is NHC(O)C.sub.1-3alkyl. In a sixteenth embodiment, R.sub.12a is NR.sub.23aR.sub.24a. In a seventeenth embodiment, R.sub.12a is OCH.sub.2CH.sub.2N(CH.sub.3).sub.2. In an eighteenth embodiment, R.sub.12a is a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is pyrrolidinyl. Suitably, the heterocyclohexyl ring is piperidinyl or piperazinyl. Any nitrogen atom such as one nitrogen atom in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted. In a nineteenth embodiment, R.sub.12a together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−).
[0487] When Aa is —NHC(═O)— or —C(═O)NH—, suitably, R.sub.12a is attached to Ar2a in the ortho or meta position relative to Ar1a and R.sub.12a is H, halo, C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, hydroxy, C.sub.1-4alkylOH, SO.sub.2C.sub.1-2alkyl, C(O)N(C.sub.1-2alkyl).sub.2, NHC(O)C.sub.1-3alkyl or NR.sub.23aR.sub.24a.
[0488] When Aa is —NHC(═O)—, suitably R.sub.12a may additionally be selected from CN, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2 and a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R.sub.12a together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−).
[0489] When Aa is —NH—, —CH.sub.2NH— or —NHCH.sub.2—, suitably, R.sub.12a is attached to Ar2a in the ortho or meta position relative to Ar1a and R.sub.12a is H, halo, C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, hydroxy, C.sub.1-4alkylOH, SO.sub.2C.sub.1-2alkyl, C(O)N(C.sub.1-2alkyl).sub.2, NHC(O)C.sub.1-3alkyl or NR.sub.23aR.sub.24a.
[0490] When Aa is —NH— or —NHCH.sub.2—, suitably R.sub.12a may additionally be selected from CN, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2 and a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R.sub.12a together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−).
[0491] R.sub.12a is suitably H, F, Cl, CH.sub.3, OCH.sub.3, OEt, OiPr, OCyclopropyl, CN, CF.sub.3, OCHF.sub.2 or OCH.sub.2CF.sub.3. In particular, R.sub.12a is Cl, CN, CF.sub.3, OCHF.sub.2, OCH.sub.2CF.sub.3, OCH.sub.3, OEt, OiPr, OCyclopropyl, such as CF.sub.3, OCHF.sub.2, OCH.sub.2CF.sub.3, OCH.sub.3, OEt, OiPr, OCyclopropyl, e.g. OEt.
[0492] R.sub.12a is suitably H, F, Cl, CH.sub.3, iPr, OCH.sub.3, OEt, OiPr, OCyclopropyl, CN, CF.sub.3, OCHF.sub.2, OCH.sub.2CF.sub.3, C.sub.3cycloalkyl or C(═CH.sub.2)CH.sub.3. In particular, R.sub.12a is Cl, iPr, OCH.sub.3, OEt, OiPr, OCyclopropyl, CN, CF.sub.3, OCHF.sub.2, OCH.sub.2CF.sub.3, C.sub.3cycloalkyl or C(═CH.sub.2)CH.sub.3, such as Cl, OCH.sub.3, OEt, OiPr, OCyclopropyl, CF.sub.3, OCHF.sub.2, OCH.sub.2CF.sub.3 or C.sub.3cycloalkyl, e.g. OEt.
[0493] When Aa is —C(═O)NH—, suitably R.sub.12a is CF.sub.3, OEt or OiPr, such as OEt or OiPr.
[0494] Suitably R.sub.12a is in the meta position of Ar2a. Alternatively, R.sub.12a is in the ortho position of Ar2a.
[0495] In one embodiment, R.sub.13a is H. In another embodiment, R.sub.13a is halo such as F or Cl, suitably F.
[0496] In one embodiment, R.sub.13a is in the ortho position with respect to Ar1a. In another embodiment, R.sub.13a is in the para position with respect to Ar1a. In another embodiment, R.sub.13a is in the meta position with respect to Ar1a.
[0497] In one embodiment, R.sub.23a is H. In another embodiment, R.sub.23a is C.sub.1-2alkyl such as methyl.
[0498] In one embodiment, R.sub.24a is H. In another embodiment R.sub.24a is C.sub.1-2alkyl such as methyl.
[0499] Suitably, R.sub.23a is H and R.sub.24a is ethyl. Suitably, R.sub.23a is CH.sub.3 and R.sub.24a is CH.sub.3.
[0500] Desirably, a compound of formula (I) does not include 2-(6-(methylsulfonamido)pyrazin-2-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide.
[0501] In one embodiment, at least one of R.sub.10a, R.sub.11a, R.sub.12a and R.sub.13a is other than H.
[0502] Suitably, at least one of R.sub.4a, R.sub.5a, R.sub.10a, R.sub.11a, R.sub.12a and R.sub.13a is other than H.
[0503] More suitably, when R.sub.1a is methyl, at least one of R.sub.4a, R.sub.5a, R.sub.10a, R.sub.11a, R.sub.12a and R.sub.13a is other than H.
[0504] The present invention provides the compounds described in any one of Examples P226, P227, P228, P229, P230, P235, P242, P244, P248, P251, P254, P255, P256, P258, P260 and P261.
[0505] The present invention also provides the compounds described in any one of Examples P288, P289, P290, P291, P292, P293, P294, P295, P296, P297, P298, P299, P300, P301, P302, P303, P304, P305, P306, P307, P308, P309, P310, P311, P312, P313, P314, P315, P316, P317 and P318.
[0506] The present invention provides the following compounds: [0507] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-4-oxocyclohexanecarboxamide; [0508] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-4-hydroxycyclohexanecarboxamide; [0509] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-4-hydroxycyclohexanecarboxamide (diastereomer 1); [0510] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-4-hydroxycyclohexanecarboxamide (diastereomer 2); [0511] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)cyclohexane-1-carboxamide; [0512] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyidin-2-yl)cyclohexane-1-carboxamide (diastereomer 1); [0513] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyidin-2-yl)cyclohexane-1-carboxamide (diastereomer 2); [0514] N-(4-(1-((4-(6-Ethoxypyrazin-2-yq)-2-fluorobenzyl)amino)propy)pyrimidin-2-yl)cyclopropanesulfonamide; [0515] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-4,4-difluorocyclohexane-1-carboxamide; [0516] 8-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide; [0517] 4-(2-((N,N-dimethylsulfamoyl)amino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide; [0518] 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; [0519] N-(4-(1-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)cyclopropyl)pyrimidin-2-yl)cyclopropanesulfonamide; [0520] N-(4-(1-((4-(6-ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)cyclopropyl)pyrimidin-2-yl)cyclopropanesulfonamide; [0521] N-(4-(4-(((4-(6-ethoxypyrazin-2-yl)phenyl)amino)methyl)tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl)cyclopropanesulfonamide; [0522] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-5,8-dioxaspiro[3.4]octane-2-carboxamide; [0523] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-4-methoxycyclohexane-1-carboxamide; and [0524] N-(4-(1-((4-(6-ethoxypyrazin-2-yl)phenyl)amino)propyl)pyrimidin-2-yl)cyclopropanesulfonamidearboxamide.
[0525] The present invention also provides the following compounds: [0526] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-1-(2-methoxyacetyl)piperidine-4-carboxamide; [0527] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; [0528] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(cyclopropylsulfonyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide; [0529] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(N,N-dimethylsulfamoyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide; [0530] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-1-((trifluoromethyl)sulfonyl)piperidine-4-carboxamide; [0531] 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidine-4-carboxamide; [0532] 1-(cyanomethyl)-4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyidin-2-yl)piperidine-4-carboxamide; [0533] ethyl 2-(4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)carbamoyl)piperidin-1-yl)acetate; [0534] N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(2-methoxyacetyl)piperidine-4-carboxamide; [0535] N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; [0536] N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; [0537] 1-(Cyclopropylsulfonyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)piperidine-4-carboxamide; [0538] N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidine-4-carboxamide; [0539] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-4-methoxycyclohexane-1-carboxamide (diastereomer 1); [0540] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-4-methoxycyclohexane-1-carboxamide (diastereomer 2); [0541] 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 1); [0542] 1-(2-(Cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 2); [0543] 4-amino-1-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1); [0544] 1-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-morpholinocyclohexane-1-carboxamide (diastereomer 1); [0545] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-morpholinocyclohexane-1-carboxamide (diastereomer 2); [0546] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(methyl(oxetan-3-yl)amino)cyclohexane-1-carboxamide (diastereomer 1); [0547] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-((2-methoxyethyl)(methyl)amino)cyclohexane-1-carboxamide (diastereomer 1); [0548] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-((2-methoxyethyl)(methyl)amino)cyclohexane-1-carboxamide (diastereomer 2); [0549] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((2,2-difluoroethyl)(methyl)amino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1); [0550] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide (diastereomer 1); [0551] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide (diastereomer 2); [0552] 4-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; [0553] 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; [0554] 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; [0555] 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; and [0556] 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide.
[0557] Compounds of Formula (I-b)
[0558] The invention provides a compound of formula (I-b):
##STR00021##
wherein [0559] A.sub.b is A.sub.ab or A.sub.bb; [0560] A.sub.ab is —NR.sub.6bCH.sub.2— or —NR.sub.6b—; [0561] A.sub.bb is —NR.sub.6bC(═O)—; [0562] R.sub.1b is R.sub.1ab or R.sub.1bb; [0563] wherein: [0564] R.sub.1ab is NR.sub.32aR.sub.33b; [0565] R.sub.1bb is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, C.sub.1-3alkyleneOC.sub.1-2alkyl, or CF.sub.3; [0566] R.sub.3b is H, halo, CH.sub.3, OC.sub.1-2alkyl or CF.sub.3; [0567] or R.sub.3b together with R.sub.5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; [0568] R.sub.4b and R.sub.5b are either R.sub.4ab and R.sub.5ab or R.sub.4bb and R.sub.5bb; [0569] wherein: [0570] R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [0571] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3 alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21bR.sub.22b; or [0572] one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3 alkyl or OC.sub.1-3alkyl; or [0573] R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [0574] R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29b; or [0575] R.sub.4bb and R.sub.5bb are each independently H, halo, C.sub.1-6alkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-6alkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-6alkylOH, C.sub.1-6haloalkyl, OC.sub.1-6haloalkyl or NR.sub.21bR.sub.22b, [0576] or R.sub.4bb is H and R.sub.5bb together with R.sub.3b form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl, [0577] or R.sub.4bb and R.sub.5bb together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl, [0578] or R.sub.4bb is H and R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring; [0579] or R.sub.4bb is O and R.sub.5bb is absent; [0580] R.sub.6b is H or C.sub.1-3alkyl, [0581] or R.sub.6b together with R.sub.11b when in the ortho-position to group A.sub.b are a C.sub.2alkylene chain forming a 5-membered ring, [0582] or R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring and R.sub.4bb is H; [0583] Ar1b is 6-membered aryl or heteroaryl; [0584] Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para position relative to group A.sub.b; [0585] R.sub.10b is H, halo, C.sub.1-3alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl, OC.sub.1-2haloalkyl or CN; [0586] R.sub.11b is H, F, Cl, CH.sub.3, ethyl, OCH.sub.3, CF.sub.3, OCF.sub.3 or CN, [0587] or R.sub.11b, when in the ortho-position to group A.sub.b, together with R.sub.6b are a C.sub.2alkylene chain forming a 5-membered ring; [0588] R.sub.12b is attached to Ar2b in the ortho or meta position relative to Ar1b and R.sub.12b is H, halo, C.sub.1-4alkyl, C.sub.2-4alkynyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, OH, C.sub.1-4alkylOH, CN, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-4haloalkyl, OC.sub.1-4 haloalkyl, C(═O)C.sub.1-2alkyl, NR.sub.23bR.sub.24b, SO.sub.2C.sub.1-4alkyl, SOC.sub.1-4alkyl, SC.sub.1-4alkyl, SH, C(O)N(CH.sub.3).sub.2, NHC(O)C.sub.1-3alkyl, C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R.sub.12b together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); [0589] R.sub.13b is H, halo, CH.sub.3 or OCH.sub.3; [0590] R.sub.21b is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl, C.sub.1-5alkylOC.sub.1-2alkyl, C.sub.1-4haloalkyl, or C.sub.4-6heterocycloalkyl; [0591] R.sub.22b is H or CH.sub.3; [0592] R.sub.23b is H or C.sub.1-2alkyl; [0593] R.sub.24b is H or C.sub.1-2alkyl; [0594] R.sub.29b is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, CF.sub.3, N(C.sub.1-3alkyl).sub.2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and [0595] R.sub.32b is C.sub.1-3alkyl and R.sub.33b is C.sub.1-3alkyl; or [0596] R.sub.32b and R.sub.33b together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl; [0597] or a salt and/or solvate thereof and/or derivative thereof.
[0598] Suitably, R.sub.1b is R.sub.1a; and/or R.sub.4b and R.sub.5b are R.sub.4ab and R.sub.5ab; and/or A is A.sub.ab.
[0599] The invention also provides a compound of formula (I-b):
##STR00022##
wherein [0600] A.sub.b is A.sub.ab or A.sub.bb; [0601] A.sub.ab is —NR.sub.6bCH.sub.2— or —NR.sub.6b—; [0602] A.sub.bb is —NR.sub.6bC(═O)—; [0603] R.sub.1b is R.sub.1ab or R.sub.1bb; [0604] wherein: [0605] R.sub.1ab is NR.sub.32aR.sub.33b; [0606] R.sub.1bb is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, C.sub.1-3alkyleneOC.sub.1-2alkyl, or CF.sub.3; [0607] R.sub.3b is H, halo, CH.sub.3, OC.sub.1-2alkyl or CF.sub.3; [0608] or R.sub.3b together with R.sub.5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; [0609] R.sub.4b and R.sub.5b are either R.sub.4ab and R.sub.5ab or R.sub.4bb and R.sub.5bb; [0610] wherein: [0611] R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [0612] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3 alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21bR.sub.22b; or [0613] one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3 alkyl or OC.sub.1-3alkyl; or [0614] R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [0615] R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29b; or [0616] R.sub.4bb and R.sub.5bb are each independently H, halo, C.sub.1-6alkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-6alkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-6alkylOH, C.sub.1-6haloalkyl, OC.sub.1-6haloalkyl or NR.sub.21bR.sub.22b, [0617] or R.sub.4bb is H and R.sub.5bb together with R.sub.3b form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl, [0618] or R.sub.4bb and R.sub.5bb together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl, [0619] or R.sub.4bb is H and R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring; [0620] or R.sub.4bb is O and R.sub.5bb is absent; [0621] R.sub.6b is H or C.sub.1-3alkyl, [0622] or R.sub.6b together with R.sub.11b when in the ortho-position to group A.sub.b are a C.sub.2alkylene chain forming a 5-membered ring, [0623] or R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring and R.sub.4bb is H; [0624] Ar1b is 6-membered aryl or heteroaryl; [0625] Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the pare position relative to group A.sub.b; [0626] R.sub.10b is H, halo, C.sub.1-3alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl, OC.sub.1-2haloalkyl or CN; [0627] R.sub.11b is H, F, Cl, CH.sub.3, ethyl, OCH.sub.3, CF.sub.3, OCF.sub.3 or CN, [0628] or R.sub.11b, when in the ortho-position to group A.sub.b, together with R.sub.6b are a C.sub.2alkylene chain forming a 5-membered ring; [0629] R.sub.12a is attached to Ar2b in the ortho or meta position relative to Ar1b and R.sub.12a is H, halo, C.sub.1-4alkyl, C.sub.2-4alkynyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, OH, C.sub.1-4alkylOH, CN, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-4haloalkyl, OC.sub.1-4 haloalkyl, C(═O)C.sub.1-2alkyl, NR.sub.23bR.sub.24b, SO.sub.2C.sub.1-4alkyl, SOC.sub.1-4alkyl, SC.sub.1-4alkyl, SH, C(O)N(CH.sub.3).sub.2, NHC(O)C.sub.1-3alkyl, C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R.sub.12a together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); [0630] R.sub.13b is H, halo, CH.sub.3 or OCH.sub.3; [0631] R.sub.21b is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl; [0632] R.sub.22b is H or CH.sub.3; [0633] R.sub.23b is H or C.sub.1-2alkyl; [0634] R.sub.24b is H or C.sub.1-2alky; [0635] R.sub.29b is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; and [0636] R.sub.32a is C.sub.1-3alkyl and R.sub.33b is C.sub.1-3alkyl; or [0637] R.sub.32b and R.sub.33b together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl; [0638] or a salt and/or solvate thereof and/or derivative thereof.
[0639] Suitably, R.sub.1b is R.sub.1ab; and/or R.sub.4b and R.sub.5b are R.sub.4ab and R.sub.5ab; and/or A is A.sub.ab.
[0640] In one embodiment of the invention, R.sub.1b is R.sub.1ab, i.e. is NR.sub.32bR.sub.33b. In an embodiment, R.sub.32b is C.sub.1-3 alkyl, such as methyl or ethyl, e.g. methyl. In an embodiment, R.sub.33b is C.sub.1-3alkyl, such as methyl or ethyl, e.g. methyl. Suitably, R.sub.32b and R.sub.33b are both methyl. Suitably, R.sub.32a and R.sub.33b are both ethyl. Suitably, R.sub.32b is methyl and R.sub.33b is ethyl.
[0641] In another embodiment, R.sub.32b and R.sub.33b together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl. Suitably, the C.sub.3-5heterocycloalkyl is aziridinyl, azetidinyl or pyrrolidinyl.
[0642] Suitably, R.sub.1b is R.sub.1bb.
[0643] In one embodiment of the invention R.sub.1bb is C.sub.1-5alkyl. When R.sub.1bb is C.sub.1-5alkyl, R.sub.1bb may be methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, sec-butyl or tert-butyl) or pentyl (e.g. n-pentyl, sec-pentyl or 3-pentyl). Suitably, when R.sub.1bb is C.sub.1-5alkyl, R.sub.1bb may be methyl, ethyl, propyl (e.g. isopropyl) or butyl (e.g. sec-butyl or tert-butyl), especially methyl, ethyl or isopropyl and in particular methyl.
[0644] In a second embodiment of the invention R.sub.1bb is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3. In some embodiments, R.sub.1bb is C.sub.0-2alkyleneC.sub.3-5cycloalkyl. In other embodiments, R.sub.1bb is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is substituted by CH.sub.3. R.sub.1bb may be C.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bb may be C.sub.1alkyleneC.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bb may be C.sub.2alkyleneC.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bb may be C.sub.0-2alkyleneC.sub.3cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bb may be C.sub.0-2alkyleneC.sub.4cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bb may be C.sub.0-2alkyleneC.sub.5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. Suitably, where C.sub.0-2alkyleneC.sub.3-5cycloalkyl is optionally substituted by CH.sub.3, the CH.sub.3 is at the point of attachment of the C.sub.3-5cycloalkyl to the C.sub.0-2alkylene.
[0645] In a third embodiment of the invention R.sub.1bb is CF.sub.3.
[0646] In a fourth embodiment of the invention R.sub.1bb is C.sub.1-3alkyleneOC.sub.1-2alkyl such as C.sub.1-2alkyleneOC.sub.1-2alkyl. When R.sub.1bb is C.sub.1-3alkyleneOC.sub.1-2alkyl, R.sub.1bb may be methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxymethyl or propoxyethyl. When R.sub.1bb is C.sub.1-2alkyleneOC.sub.1-2alkyl, R.sub.1bb may be methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl.
[0647] Suitably R.sub.1bb is cyclopropyl, cyclopropyl substituted by CH.sub.3 at the point of attachment, cyclobutyl, CH.sub.3, isopropyl, sec-butyl, tert-butyl or CF.sub.3. In particular R.sub.1bb is cyclopropyl, cyclopropyl substituted by CH.sub.3 at the point of attachment, cyclobutyl, CH.sub.3, isopropyl, sec-butyl or tert-butyl, especially cyclopropyl, cyclopropyl substituted by CH.sub.3 at the point of attachment, cyclobutyl or isopropyl, such as cyclopropyl or cyclopropyl substituted by CH.sub.3 at the point of attachment.
[0648] Additionally of interest is when R.sub.1bb is cyclopentyl, methyl, ethyl, cyclopropylmethylene and methoxyethyl, in particular cyclopentyl, methyl, ethyl and cyclopropylmethylene, especially ethyl and methyl, such as methyl.
[0649] Consequently, suitably R.sub.1bb is cyclopropyl, cyclopropyl substituted by CH.sub.3 at the point of attachment, cyclopropylmethylene, cyclobutyl, cyclopentyl, CH.sub.3, ethyl, isopropyl, sec-butyl, tert-butyl, methoxyethyl or CF.sub.3. In particular R.sub.1bb is cyclopropyl, cyclopropyl substituted by CH.sub.3 at the point of attachment, cyclopropylmethylene, cyclobutyl, cyclopentyl, CH.sub.3, ethyl, isopropyl, sec-butyl or tert-butyl, especially cyclopropyl, cyclopropyl substituted by CH.sub.3 at the point of attachment, cyclobutyl, CH.sub.3, ethyl or isopropyl, such as cyclopropyl, cyclopropyl substituted by CH.sub.3 at the point of attachment, ethyl or methyl such as cyclopropyl, cyclopropyl substituted by CH.sub.3 at the point of attachment or methyl.
[0650] In one embodiment R.sub.3b is H. In a second embodiment R.sub.3b is halo, in particular chloro or fluoro, especially chloro. In a third embodiment R.sub.3b is CH.sub.3. In a fourth embodiment R.sub.3b is CF.sub.3. In a fifth embodiment R.sub.3b together with R.sub.5bb forms a 5- or 6-membered cycloalkyl, in particular a 5-membered cycloalkyl. In a sixth embodiment R.sub.3b is OC.sub.1-2alkyl such as OCH.sub.3. In a seventh embodiment R.sub.3b together with R.sub.5bb forms a 5- or 6-membered oxygen-containing heterocycloalkyl, in particular a 5-membered heterocycloalkyl.
[0651] The phrase ‘R.sub.3b together with R.sub.5bb forms a 5- or 6-membered cycloalkyl’ means that compounds with the following exemplary substructure are formed:
##STR00023##
[0652] The phrase ‘R.sub.3b together with R.sub.5bb forms a 5- or 6-membered oxygen containing heterocycloalkyl’ means that compounds with the following substructure are formed:
##STR00024##
[0653] In particular R.sub.3b is H, CH.sub.3 or R.sub.3b together with R.sub.5bb forms a 5- or 6-membered cycloalkyl, especially H, CH.sub.3 or R.sub.3b together with R.sub.5bb forms a 5-membered cycloalkyl, such as R.sub.3b is H or CH.sub.3, e.g. H.
[0654] In one embodiment, R.sub.4b and R.sub.5b are R.sub.4ab and R.sub.5ab.
[0655] Suitably, R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [0656] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21bR.sub.22a.
[0657] In one embodiment, the C.sub.3-6cycloalkyl is cyclopropyl. In another embodiment, the C.sub.3-6cycloalkyl is cyclobutyl. In another embodiment, the C.sub.3-6cycloalkyl is cyclopentyl. In another embodiment, the C.sub.3-6cycloalkyl is cyclohexyl.
[0658] In one embodiment the C.sub.3-6cycloalkyl is substituted by one substituent. In a second embodiment the C.sub.3-6cycloalkyl is substituted by two substituents.
[0659] In one embodiment, the substituent is C.sub.1-3alkyl. Suitably, the substituent is methyl. Suitably, the substituent is ethyl. Suitably, the substituent is n-propyl. Suitably, the substituent is iso-propyl.
[0660] In a second embodiment, the substituent is C.sub.1-2alkylOH. Suitably, the substituent is CH.sub.2OH. Suitably, the substituent is CH.sub.2CH.sub.2OH. Suitably, the substituent is CH.sub.2CH.sub.2CH.sub.2OH.
[0661] In a third embodiment, the substituent is C.sub.1-3haloalkyl. Suitably the C.sub.1-3alkyl group is substituted by one two or three, such as one, halogen atom. Suitably, the halogen atom is fluoro or chloro such as fluoro. Suitably, the substituent is C.sub.1haloalkyl such as CF.sub.3. Suitably, the substituent is C.sub.2haloalkyl such as CH.sub.2CF.sub.3.
[0662] In a fourth embodiment, the substituent is C.sub.0-2alkyleneC.sub.3-6cycloalkyl, in particular C.sub.0-2alkyleneC.sub.3-5cycloalkyl, such as C.sub.3-5cycloalkyl, C.sub.1alkyleneC.sub.3-5cycloalkyl or C.sub.2alkyleneC.sub.3-5cycloalkyl.
[0663] In a fifth embodiment, the substituent is C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as C.sub.0-2alkyleneC.sub.3heterocycloalkyl, C.sub.0-2alkyleneC.sub.4heterocycloalkyl, C.sub.0-2alkyleneC.sub.5heterocycloalkyl, C.sub.0-2alkyleneC.sub.6heterocycloalkyl, C.sub.0alkyleneC.sub.3-6heterocycloalkyl, C.sub.1alkyleneC.sub.3-6heterocycloalkyl and C.sub.2alkyleneC.sub.3-6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring may be substituted (such as one nitrogen atom is substituted), for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3 alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted.
[0664] In a sixth embodiment, the substituent is C.sub.1-3alkyleneOC.sub.1-3alkyl, in particular C.sub.1-2alkyleneOC.sub.1-2alkyl such as C.sub.1alkyleneOC.sub.1alkyl, C.sub.2alkyleneOC.sub.1alkyl, C.sub.1alkyleneOC.sub.2alkyl or C.sub.2alkyleneOC.sub.2alkyl.
[0665] In a seventh embodiment, the substituent is halo, in particular fluoro or chloro such as chloro.
[0666] In an eighth embodiment, the substituent is OC.sub.1-3haloalkyl. Suitably the OC.sub.1-3alkyl group is substituted by one two or three, such as one, halogen atom. Suitably, the halogen atom is fluoro or chloro such as fluoro. Suitably, the substituent is OC.sub.1haloalkyl such as OCF.sub.3. Suitably, the substituent is OC.sub.2haloalkyl such as OCH.sub.2CF.sub.3.
[0667] In a ninth embodiment, the substituent is OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, such as OC.sub.3-6cycloalkyl, OC.sub.1alkyleneC.sub.3-6cycloalkyl or OC.sub.2alkyleneC.sub.3-6cycloalkyl.
[0668] In a tenth embodiment, the substituent is OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as OC.sub.0-2alkyleneC.sub.3heterocycloalkyl, OC.sub.0-2alkyleneC.sub.4heterocycloalkyl, OC.sub.0-2alkyleneC.sub.5heterocycloalkyl, OC.sub.0-2alkyleneC.sub.6heterocycloalkyl, OC.sub.0alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1alkyleneC.sub.3-6heterocycloalkyl and OC.sub.2alkyleneC.sub.3-6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) (such as one nitrogen atom) in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4 alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4 alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4 haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3 alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted.
[0669] In an eleventh embodiment, the substituent is OC.sub.1-3alkyl, such as OCH.sub.3 or OCH.sub.2CH.sub.3.
[0670] In a twelfth embodiment, the substituent is NR.sub.21bR.sub.22b.
[0671] In one embodiment R.sub.21b is H. In a second embodiment R.sub.21b is C.sub.1-5alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R.sub.21b is C(O)C.sub.1-5alkyl, such as C(O)CH.sub.3. In a fourth embodiment R.sub.21b is C(O)OC.sub.1-5alkyl, such as C(O)OCH.sub.3 or C(O)Otert-butyl. In a fifth embodiment R.sub.21b is C.sub.1-3alkylOC.sub.1-2alkyl such as C.sub.1alkylOC.sub.1alkyl, C.sub.2alkylOC.sub.1alkyl or C.sub.3alkylOC.sub.1alkyl e.g. C.sub.2alkylOC.sub.1alkyl. In a sixth embodiment, R.sub.21b is C.sub.1-4haloalkyl, such as CF.sub.3, CH.sub.2CF.sub.3 or CH.sub.2CHF.sub.2 e.g. CH.sub.2CHF.sub.2. In a seventh embodiment R.sub.21b is C.sub.4-6heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.
[0672] When the substituent is NR.sub.21bR.sub.22b, in one embodiment R.sub.22b is H. In a second embodiment R.sub.22b is methyl.
[0673] Suitably, R.sub.21b is C(O)OCH.sub.3 and R.sub.22b is H. Suitably, R.sub.21b is C(O)CH.sub.3 and R.sub.22b is H. Suitably, R.sub.21b and R.sub.22b are both CH.sub.3. Suitably, R.sub.21b and R.sub.22b are both H.
[0674] In a thirteenth embodiment, the substituent is oxo.
[0675] In a fourteenth embodiment, the substituent is OH.
[0676] Suitably, the one or two substituents, in particular one substituent, are independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, halo, OC.sub.1-3haloalkyl, OC.sub.1-3alkyl and NR.sub.21bR.sub.22b.
[0677] More suitably, the substituent is independently selected from the group consisting of oxo, OH, halo, OC.sub.1-3alkyl and NR.sub.21bR.sub.22b.
[0678] Most suitably, the substituent is independently selected from the group consisting of oxo, OH, fluoro, NR.sub.21bR.sub.22b.
[0679] Alternatively, R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl and one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl.
[0680] In one embodiment the C.sub.3-6cycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached is unsubstituted. In a second embodiment the C.sub.3-6cycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached is substituted by one or two substituents, in particular one substituent. Suitably, each substituent is independently selected from the group consisting of C.sub.1-2alkyl or OCH.sub.3.
[0681] Suitably one of the carbons of the C.sub.3-6cycloalkyl which is formed by R.sub.4ab and R.sub.5ab is a spiro centre such that a spirocyclic ring system is formed, wherein the C.sub.3-6cycloalkyl which is formed by R.sub.4ab and R.sub.5ab is a C.sub.4-6cycloalkyl. Suitably the C.sub.3-5heterocycloalkyl is an oxygen containing C.sub.3-6heterocycloalkyl. Suitably, the C.sub.3-6heterocycloalkyl is an oxygen comprising, such as containing, C.sub.3-6heterocycloalkyl ring, such as a C.sub.5cycloalkyl ring.
[0682] In an embodiment, R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl. Suitably, each substituent is independently selected from the group consisting of C.sub.1-2alkyl or OCH.sub.3.
[0683] Suitably one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed containing further ring C, wherein C is a C.sub.4-6heterocycloalkyl. Suitably the C.sub.4-6heterocycloalkyl is an oxygen containing C.sub.4-6heterocycloalkyl such as tetrahydropyranyl or 1,3-dioxolanyl.
[0684] In an embodiment, R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29b.
[0685] Suitably, the C.sub.3-6heterocycloalkyl is selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl such as piperidinyl.
[0686] Suitably, when the C.sub.3-6heterocycloalkyl is piperidinyl, the nitrogen atom is in the 4-position relative to the quaternary carbon:
##STR00025##
[0687] The C.sub.3-6heterocycloalkyl may be other groups as defined elsewhere herein.
[0688] In an embodiment, R.sub.29b is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3. In one embodiment, R.sub.29b is C.sub.1-3alkyl such as methyl. In another embodiment, R.sub.29b is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3. In some embodiments, R.sub.2 is C.sub.0-2alkyleneC.sub.3-5cycloalkyl. In other embodiments, R.sub.29a is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is substituted by CH.sub.3. R.sub.29b may be C.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29b may be C.sub.1alkyleneC.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29b may be C.sub.2alkyleneC.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29b may be C.sub.0-2alkyleneC.sub.3cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29b may be C.sub.0-2alkyleneC.sub.4cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29b may be C.sub.0-2alkyleneC.sub.5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. Suitably, where C.sub.0-2alkyleneC.sub.3-5cycloalkyl is optionally substituted by CH.sub.3, the CH.sub.3 is at the point of attachment of the C.sub.3-5cycloalkyl to the C.sub.0-2alkylene. In another embodiment, R.sub.29b is CF.sub.3. In another embodiment, R.sub.29b is N(C.sub.1-3alkyl).sub.2 such as N(CH.sub.3).sub.2. In another embodiment, R.sub.29b is a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl. In one embodiment, the 5 or 6 membered heteroaryl is substituted by methyl. In one embodiment, the 5 or 6 membered heteroaryl is not substituted by methyl. In one embodiment, R.sub.29b is a 5-membered heteroaryl such as pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, such as pyrazolyl. Suitably the pyrazolyl is substituted by methyl. In another embodiment, R.sub.29b is a 6-membered heteroaryl such as pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.
[0689] In another embodiment, R.sub.4b and R.sub.5b are R.sub.4bb and R.sub.5bb.
[0690] In one embodiment R.sub.4bb is O and R.sub.5bb is absent. The person skilled in the art will appreciate that in this embodiment, the following moiety forms, in order to retain the correct carbon valency of 4:
##STR00026##
[0691] In a second embodiment, R.sub.4bb and R.sub.5bb together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl. In a third embodiment R.sub.4bb is C.sub.1-6alkyl, in particular C.sub.1-4alkyl such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment R.sub.4bb is C.sub.0-2alkyleneC.sub.3-6cycloalkyl, in particular C.sub.0-2alkyleneC.sub.3-5cycloalkyl, such as C.sub.3-5cycloalkyl, C.sub.1alkyleneC.sub.3-5cycloalkyl or C.sub.2alkyleneC.sub.3-5cycloalkyl. In a fifth embodiment R.sub.4bb is OC.sub.1-6alkyl, in particular OC.sub.1-4alkyl, such as methoxy, ethoxy, propoxy (n-propoxy or isopropoxy) or butoxy (n-butoxy, isobutoxy, sec-butoxy or tert-butoxy). In a sixth embodiment R.sub.4bb is OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, such as OC.sub.3-6cycloalkyl, OC.sub.1alkyleneC.sub.3-6cycloalkyl or OC.sub.2alkyleneC.sub.3-6cycloalkyl. In a seventh embodiment R.sub.4bb is C.sub.1-3alkyleneOC.sub.1-3alkyl, in particular C.sub.1-2alkyleneOC.sub.1-2alkyl such as C.sub.1alkyleneOC.sub.1alkyl, C.sub.2alkyleneOC.sub.1alkyl, C.sub.1alkyleneOC.sub.2alkyl or C.sub.2alkyleneOC.sub.2alkyl. In an eighth embodiment R.sub.4bb is C.sub.1-6haloalkyl, in particular C.sub.1-44haloalkyl. In a ninth embodiment R.sub.4bb is OC.sub.1-6haloalkyl, in particular OC.sub.1-4haloalkyl. In a tenth embodiment R.sub.4bb is H. In an eleventh embodiment R.sub.4bb is halo such as fluoro. In a twelfth embodiment R.sub.4bb is C.sub.1-6alkylOH, such as CH.sub.2OH or CH.sub.2CH.sub.2OH, in particular CH.sub.2CH.sub.2OH. In a thirteenth embodiment R.sub.4bb is NR.sub.21bR.sub.22b. In a fourteenth embodiment, R.sub.4bb is C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as C.sub.0-2alkyleneC.sub.3heterocycloalkyl, C.sub.0-2alkyleneC.sub.4heterocycloalkyl, C.sub.0-2alkyleneC.sub.5heterocycloalkyl, C.sub.0-2alkyleneC.sub.6heterocycloalkyl, C.sub.0alkyleneC.sub.3-6heterocycloalkyl, C.sub.1alkyleneC.sub.3-6heterocycloalkyl and C.sub.2alkyleneC.sub.3-6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) (such as one nitrogen atom) in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted. In a fifteenth embodiment, R.sub.4bb and R.sub.5bb together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl, such as tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl, such as tetrahydrofuranyl or piperidinyl. If the C.sub.3-6heterocycloalkyl group comprises (e.g. contains) a nitrogen atom, independently the nitrogen atom(s) may be unsubstituted (NH) or the nitrogen atom(s) may be substituted, for example substituted by a group selected from the following: C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. In a fifteenth embodiment, R.sub.4bb is H and R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring. In a sixteenth embodiment, R.sub.4bb is OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as OC.sub.0-2alkyleneC.sub.3heterocycloalkyl, OC.sub.0-2alkyleneC.sub.4heterocycloalkyl, OC.sub.0-2alkyleneC.sub.5heterocycloalkyl, C.sub.0-2alkyleneC.sub.6heterocycloalkyl, OC.sub.0alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1alkyleneC.sub.3-6heterocycloalkyl and OC.sub.2alkyleneC.sub.3-6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) (such as one nitrogen atom) in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4 alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4 alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4 haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3 alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted.
[0692] When R.sub.4bb is H and R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring, suitably a 5-membered ring, compounds comprising one of the following moieties are formed:
##STR00027##
[0693] When R.sub.4bb is NR.sub.21bR.sub.22b, in one embodiment R.sub.21b is H. In a second embodiment R.sub.21b is C.sub.1-5alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R.sub.21b is C(O)C.sub.1-5alkyl, such as C(O)CH.sub.3. In a fourth embodiment R.sub.21b is C(O)OC.sub.1-5alkyl, such as C(O)OCH.sub.3 or C(O)Otert-butyl. In a fifth embodiment R.sub.21b is C.sub.1-3alkylOC.sub.1-2alkyl such as C.sub.1alkylOC.sub.1alkyl, C.sub.2alkylOC.sub.1alkyl or C.sub.3alkylOC.sub.1alkyl e.g. C.sub.2alkylOC.sub.1alkyl. In a sixth embodiment, R.sub.21b is C.sub.1-4 haloalkyl, such as CF.sub.3, CH.sub.2CF.sub.3 or CH.sub.2CHF.sub.2 e.g. CH.sub.2CHF.sub.2. In a seventh embodiment R.sub.21b is C.sub.4-6heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.
[0694] When R.sub.4bb is NR.sub.21bR.sub.22b, in one embodiment R.sub.22b is H. In a second embodiment R.sub.22b is methyl.
[0695] Suitably R.sub.4bb is H, CH.sub.3, ethyl, isopropyl, fluoro, OCH.sub.3, isopropoxy or CH.sub.2CH.sub.2OCH.sub.3, in particular H, CH.sub.3, ethyl, fluoro, OCH.sub.3, isopropoxy or CH.sub.2CH.sub.2OCH.sub.3, especially H, CH.sub.3, ethyl, OCH.sub.3 or CH.sub.2CH.sub.2OCH.sub.3.
[0696] Additionally of interest is when R.sub.4bb is NH.sub.2, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHC(O)OCH.sub.3, NHC(O)Otert-butyl and CH.sub.2CH.sub.2OH, especially, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHC(O)OCH.sub.3.
[0697] Suitably, R.sub.21b is C(O)OCH.sub.3 and R.sub.22b is H. Suitably, R.sub.21b is C(O)CH.sub.3 and R.sub.22b is H. Suitably, R.sub.21b and R.sub.22b are both CH.sub.3. Suitably, R.sub.21b and R.sub.22b are both H.
[0698] Consequently, suitably R.sub.4bb is H, CH.sub.3, ethyl, isopropyl, fluoro, OCH.sub.3, isopropoxy, CH.sub.2CH.sub.2OCH.sub.3, NH.sub.2, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHC(O)OCH.sub.3, NHC(O)Otert-butyl or CH.sub.2CH.sub.2OH, in particular H, CH.sub.3, ethyl, fluoro, OCH.sub.3, isopropoxy, CH.sub.2CH.sub.2OCH.sub.3, NH.sub.2, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHC(O)OCH.sub.3, NHC(O)Otert-butyl or CH.sub.2CH.sub.2OH, especially H, CH.sub.3, ethyl, OCH.sub.3, CH.sub.2CH.sub.2OCH.sub.3, N(CH.sub.3).sub.2, NHC(O)CH.sub.3 or NHC(O)OCH.sub.3.
[0699] Suitably R.sub.4bb may be C═O and R.sub.5bb is absent.
[0700] Suitably R.sub.4bb and R.sub.5bb together with the carbon atom to which they are attached form a cyclopropyl or cyclopentyl, in particular a cyclopentyl.
[0701] Suitably R.sub.4bb is H and R.sub.3b together with R.sub.5bb forms a 5- or 6-membered cycloalkyl, in particular a 5-membered cycloalkyl, especially R.sub.4bb is H and R.sub.3b together with R.sub.5bb forms a 5- or 6-membered cycloalkyl, such as a 5-membered cycloalkyl.
[0702] In one embodiment R.sub.5bb is C.sub.1-6alkyl, in particular C.sub.1-4alkyl, such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a second embodiment R.sub.5bb is C.sub.0-2alkyleneC.sub.3-6cycloalkyl, in particular C.sub.0-2alkyleneC.sub.3-5cycloalkyl, such as C.sub.3-5cycloalkyl, C.sub.1alkyleneC.sub.3-5cycloalkyl or C.sub.2alkyleneC.sub.3-5cycloalkyl. In a third embodiment R.sub.5bb is OC.sub.1-6alkyl, in particular OC.sub.1-4alkyl, such as methoxy, ethoxy, propoxy (n-propoxy or isopropoxy) or butoxy (n-butoxy, isobutoxy, sec-butoxy or tert-butoxy). In a fourth embodiment R.sub.5bb is OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, such as OC.sub.3-6cycloalkyl, OC.sub.1alkyleneC.sub.3-6cycloalkyl or OC.sub.2alkyleneC.sub.3-6cycloalkyl. In a fifth embodiment R.sub.5bb is C.sub.1-3alkyleneOC.sub.1-3alkyl, in particular C.sub.1-2alkyleneOC.sub.1-2alkyl such as C.sub.1alkyleneOC.sub.1alkyl, C.sub.2alkyleneOC.sub.1alkyl, C.sub.1alkyleneOC.sub.2alkyl or C.sub.2alkyleneOC.sub.2alkyl. In a sixth embodiment R.sub.5bb is C.sub.1-6haloalkyl, in particular C.sub.1-4haloalkyl. In a seventh embodiment R.sub.5bb is OC.sub.1-6haloalkyl, in particular OC.sub.1-4haloalkyl. In an eighth embodiment R.sub.5bb is H. In a ninth embodiment R.sub.5bb is halo such as fluoro. In a tenth embodiment R.sub.5bb is C.sub.1-6alkylOH, such as CH.sub.2OH or CH.sub.2CH.sub.2OH, in particular CH.sub.2CH.sub.2OH. In an eleventh embodiment R.sub.5bb is NR.sub.21bR.sub.22b. In a twelfth embodiment, R.sub.5bb is C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.0-2alkyleneC.sub.4heterocycloalkyl, C.sub.0-2alkyleneC.sub.5heterocycloalkyl, C.sub.0-2alkyleneC.sub.6heterocycloalkyl, C.sub.0alkyleneC.sub.3-6heterocycloalkyl, C.sub.1alkyleneC.sub.3-6heterocycloalkyl and C.sub.2alkyleneC.sub.3-6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring may be substituted (such as one nitrogen atom is substituted), for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4 alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted. In a thirteenth embodiment, R.sub.5bb is OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as OC.sub.0-2alkyleneC.sub.3heterocycloalkyl, OC.sub.0-2alkyleneC.sub.4heterocycloalkyl, OC.sub.0-2alkyleneC.sub.5heterocycloalkyl, OC.sub.0-2alkyleneC.sub.6heterocycloalkyl, OC.sub.0alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1alkyleneC.sub.3-6heterocycloalkyl and OC.sub.2alkyleneC.sub.3-6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) (such as one nitrogen atom) in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-4heterocycloalkyl ring is not substituted.
[0703] Suitably R.sub.5bb is H, CH.sub.3, ethyl, isopropyl or fluoro, in particular R.sub.5bb is H, methyl or ethyl.
[0704] Suitably R.sub.4bb is H, CH.sub.3, ethyl, fluoro, OCH.sub.3, propoxy or CH.sub.2CH.sub.2OCH.sub.3 and R.sub.5bb is H, CH.sub.3, ethyl or fluoro, in particular R.sub.4bb is H, CH.sub.3, ethyl or OCH.sub.3 and R.sub.5bb is H, methyl or ethyl. For example, R.sub.4bb and R.sub.5bb are H, R.sub.4bb and R.sub.5bb are methyl, R.sub.4bb and R.sub.5bb are ethyl, R.sub.4bb is CH.sub.2CH.sub.2OCH.sub.3 and R.sub.5bb is H or R.sub.4bb and R.sub.5bb are fluoro.
[0705] Suitably, when R.sub.4bb is other than H, methyl, ethyl or fluoro, then R.sub.5bb is H.
[0706] In one embodiment, A.sub.b is A.sub.ab. Suitably, A.sub.ab is —NR.sub.6bCH.sub.2—. Alternatively, A.sub.ab is —NR.sub.6b—.
[0707] In another embodiment, A.sub.b is A.sub.bb i.e. —NR.sub.6bC(═O)—.
[0708] In one embodiment R.sub.6b is H. In a second embodiment R.sub.6b is C.sub.1-3alkyl, in particular methyl. In a third embodiment R.sub.6b together with R.sub.11b in the ortho-position to group A.sub.b are a C.sub.2alkylene chain forming a 5-membered ring. In a fourth embodiment, R.sub.4bb is H and R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring in particular a 5-membered ring.
[0709] Suitably R.sub.6b is H, methyl or R.sub.6b together with R.sub.11b when in the ortho-position to group A.sub.b are a C.sub.2alkylene chain forming a 5-membered ring. In particular R.sub.6b is H or R.sub.6b together with R.sub.11b in the ortho-position to group A.sub.b are a C.sub.2alkylene chain forming a 5-membered ring, especially R.sub.6b is H.
[0710] The term ‘R.sub.6b together with R.sub.11b in the ortho-position to group A.sub.b are a C.sub.2alkylene chain forming a 5-membered ring’ as used herein means that compounds with the following exemplary substructure are formed:
##STR00028##
[0711] wherein W may be N or CR.sub.10a.
[0712] In one embodiment Ar1b is a 6-membered aryl, i.e. phenyl. In a second embodiment Ar1b is a 6-membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl).
[0713] In particular Ar1b is phenyl, 2-pyridyl, 3-pyridyl or 2,6-pyrimidinyl, especially phenyl, 2-pyridyl or 3-pyridyl, such as phenyl or 2-pyridyl.
[0714] In one embodiment R.sub.10b is H. In a second embodiment R.sub.10b is halo, for example fluoro or chloro. In a third embodiment R.sub.10b is C.sub.1-3alkyl, such as CH.sub.3, ethyl or isopropyl, in particular C.sub.1-2alkyl, such as CH.sub.3 or ethyl. In a fourth embodiment R.sub.10b is OC.sub.1-2alkyl, such as OCH.sub.3 or ethoxy. In a fifth embodiment R.sub.10b is C.sub.1-2haloalkyl, such as CF.sub.3. In a sixth embodiment R.sub.10b is OC.sub.1-2haloalkyl, such as OCF.sub.3. In a seventh embodiment R.sub.10b is CN.
[0715] Suitably R.sub.10b is H, fluoro, chloro, CH.sub.3, OCH.sub.3, ethoxy, OCF.sub.3 or CN, in particular H, fluoro, chloro, CH.sub.3, OCH.sub.3, ethoxy or OCF.sub.3, especially or H, fluoro, chloro, CH.sub.3, OCH.sub.3 or OCF.sub.3, such as H, fluoro or CH.sub.3.
[0716] Additionally of interest are compounds wherein R.sub.10b is ethyl, isopropyl and CF.sub.3, in particular isopropyl and CF.sub.3. Additionally of interest are compounds when R.sub.10b is CN.
[0717] Consequently, suitably R.sub.10b is H, fluoro, chloro, CH.sub.3, ethyl, isopropyl, OCH.sub.3, ethoxy, OCF.sub.3, CF.sub.3 or CN, in particular H, fluoro, chloro, CH.sub.3, isopropyl, OCH.sub.3, ethoxy, OCF.sub.3 or CF.sub.3, especially or H, fluoro, chloro, CH.sub.3, isopropyl, OCH.sub.3, OCF.sub.3 or CF.sub.3, such as H, fluoro or CH.sub.3.
[0718] In one embodiment R.sub.11b is H. In a second embodiment R.sub.11b is F. In a third embodiment, R.sub.11b is CH.sub.3. In a fourth embodiment R.sub.6b together with R.sub.11b in the ortho-position to group A.sub.b are a C.sub.2alkylene chain forming a 5-membered ring. In a fifth embodiment R.sub.11b is ethyl. In a sixth embodiment R.sub.11b is Cl. In a seventh embodiment R.sub.11b is OCH.sub.3. In an eighth embodiment, R.sub.11, is CF.sub.3. In a ninth embodiment, R.sub.11b is OCF.sub.3. In a tenth embodiment, R.sub.11b is CN. In an eleventh embodiment R.sub.6b together with R.sub.11b in the ortho-position to group A.sub.b are a C.sub.2alkylene chain forming a 5-membered ring.
[0719] Suitably, R.sub.10b and R.sub.11b are both CH.sub.3. Suitably, R.sub.10b and R.sub.11b are both H. Suitably, R.sub.10b and R.sub.11b are both fluoro.
[0720] In one embodiment, R.sub.10b is in the ortho position with respect to group A.sub.b. In another embodiment, R.sub.10b is in the meta position with respect to group A.sub.b. Suitably R.sub.10b is in the ortho position with respect to group A.sub.b.
[0721] In one embodiment, R.sub.11b is in the ortho position with respect to group A.sub.b. In another embodiment, R.sub.11b is in the meta position with respect to group A.sub.b. Suitably R.sub.11b is in the ortho position with respect to group A.sub.b.
[0722] In one embodiment Ar2b is a 6-membered aryl, i.e. phenyl. In a second embodiment Ar2b is a 6-membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl).
[0723] In particular Ar2b is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyridazinyl, 3,4-pyridazinyl, 3,5-pyrimidinyl or 2,5-pyrazinyl, especially 3-pyridyl, 3,5-pyrimidinyl or 2,5-pyrazinyl, such as 3-pyridyl or 2,5-pyrazinyl.
[0724] In one embodiment R.sub.12b is H. In a second embodiment R.sub.12b is halo, for example fluoro or chloro. In a third embodiment R.sub.12b is C.sub.1-4alkyl, such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment R.sub.12b is C.sub.2-4alkynyl, such as C≡CH. In a fifth embodiment R.sub.12b is C.sub.0-2alkyleneC.sub.3-5cycloalkyl, such as C.sub.3-5cycloalkyl (e.g. cyclopropyl), C.sub.1alkyleneC.sub.3-5cycloalkyl or C.sub.2alkyleneC.sub.3-5cycloalkyl. In a sixth embodiment R.sub.12b is OC.sub.1-4alkyl, such as OCH.sub.3, ethoxy, isopropoxy or n-propoxy. In a seventh embodiment R.sub.12b is OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, such as OC.sub.3-5cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OC.sub.1alkyleneC.sub.3-5cycloalkyl or OC.sub.2alkyleneC.sub.3-5cycloalkyl. In an eighth embodiment R.sub.12b is OCH.sub.2CH.sub.2N(CH.sub.3).sub.2. In a ninth embodiment R.sub.12b is C.sub.1-4alkylOH, such as CH.sub.2OH or C(CH.sub.3).sub.2OH. In a tenth embodiment R.sub.12b is CN. In an eleventh embodiment R.sub.12b is C.sub.1-3alkyleneOC.sub.1-3alkyl. In a twelfth embodiment R.sub.12b is C.sub.1-4haloalkyl, such as CF.sub.3. In a thirteenth embodiment R.sub.12b is OC.sub.1-4 haloalkyl, such as OCF.sub.3, OCHF.sub.2 or OCH.sub.2CF.sub.3. In a fourteenth embodiment R.sub.12b is NR.sub.23bR.sub.24b such as N(CH.sub.3).sub.2. In a fifteenth embodiment R.sub.12b is S(O).sub.2C.sub.1-4alkyl such as SO.sub.2CH.sub.3. In a sixteenth embodiment R.sub.12b is C(O)N(CH.sub.3).sub.2. In a seventeenth embodiment R.sub.12b is NHC(O)C.sub.1-3alkyl such as NHC(O)CH.sub.3. In an eighteenth embodiment R.sub.12b is a C.sub.3-6heterocyloalkyl comprising one nitrogen located at the point of attachment to Ar2b, such as a C.sub.5heterocycloalkyl, in particular pyrrolidinyl, or a C.sub.6heterocycloalkyl such as morpholinyl. In a nineteenth embodiment R.sub.12b is OH. In a twentieth embodiment R.sub.12b is C(═O)C.sub.1-2alkyl. In a twenty first embodiment R.sub.12b is S(O)C.sub.1-4alkyl. In a twenty second embodiment R.sub.12b is SC.sub.1-4alkyl. In a twenty third embodiment R.sub.12b is SH. In a twenty fourth embodiment, R.sub.12b together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−).
[0725] R.sub.12b is suitably H, fluoro, chloro, CH.sub.3, cyclopropyl, C≡CH, OCH.sub.3, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CF.sub.3, OCF.sub.3, OCHF.sub.2, OCH.sub.2CF.sub.3, CH.sub.2OH, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, SO.sub.2CH.sub.3, C(O)N(CH.sub.3).sub.2 or pyrrolidinyl, in particular H, fluoro, chloro, CH.sub.3, cyclopropyl, C≡CH, OCH.sub.3, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CF.sub.3, OCF.sub.3, OCHF.sub.2, OCH.sub.2CF.sub.3, CH.sub.2OH, C(O)N(CH.sub.3).sub.2 or pyrrolidinyl, especially H, fluoro, chloro, CH.sub.3, cyclopropyl, C≡CH, OCH.sub.3, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF.sub.3, OCHF.sub.2, OCH.sub.2CF.sub.3 or pyrrolidinyl, such as H, fluoro, chloro, CH.sub.3, C≡CH, OCH.sub.3, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF.sub.3, OCHF.sub.2 or OCH.sub.2CF.sub.3.
[0726] Additionally of interest are ethyl, 2-methoxyisopropyl and OH, especially ethyl.
[0727] In one embodiment, R.sub.23b is H. In another embodiment, R.sub.23b is C.sub.1-2alkyl such as methyl.
[0728] In one embodiment, R.sub.24b is H. In another embodiment R.sub.24b is C.sub.1-2alkyl such as methyl.
[0729] Suitably, R.sub.23b is H and R.sub.24b is ethyl. Suitably, R.sub.23b is CH.sub.3 and R.sub.24b is CH.sub.3.
[0730] Consequently, suitably R.sub.12b is H, fluoro, chloro, CH.sub.3, ethyl, cyclopropyl, C≡CH, OCH.sub.3, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CF.sub.3, OCF.sub.3, OCHF.sub.2, OCH.sub.2CF.sub.3, OH, CH.sub.2OH, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, SO.sub.2CH.sub.3, C(O)N(CH.sub.3).sub.2 or pyrrolidinyl, in particular H, fluoro, chloro, CH.sub.3, ethyl, cyclopropyl, C≡CH, OCH.sub.3, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CF.sub.3, OCF.sub.3, OCHF.sub.2, OCH.sub.2CF.sub.3, CH.sub.2OH, C(O)N(CH.sub.3).sub.2 or pyrrolidinyl, especially H, fluoro, chloro, CH.sub.3, ethyl, cyclopropyl, C≡CH, OCH.sub.3, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF.sub.3, OCHF.sub.2, OCH.sub.2CF.sub.3 or pyrrolidinyl, such as H, fluoro, chloro, CH.sub.3, C≡CH, OCH.sub.3, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF.sub.3, OCHF.sub.2 or OCH.sub.2CF.sub.3.
[0731] Suitably R.sub.12b is suitably in the meta position of Ar2b. Alternatively, R.sub.12b is in the ortho position of Ar2b.
[0732] In one embodiment R.sub.13b is methyl. In a second embodiment R.sub.13b is H. In a third embodiment R.sub.13b is methoxy. In a fourth embodiment R.sub.13b is halo such as fluoro.
[0733] In one embodiment, R.sub.13b is in the ortho position with respect to Ar1b. In another embodiment, R.sub.13b is in the para position with respect to Ar1b.
[0734] The present invention provides compound T466.
[0735] The present invention provides the following compound:
N-(4-(1-((2-fluoro-4-(pyridin-3-yl)phenyl)amino)-2-methylpropan-2-yl)thiazol-2-yl)cyclopropanesulfonamide
Compounds of Formula (I-c)
[0736] The invention provides a compound of formula (I-c):
##STR00029##
[0737] wherein [0738] A.sub.c is A.sub.ac or A.sub.bc; [0739] A.sub.ac is —CH.sub.2NR.sub.6c—; [0740] A.sub.bc is —C(═O)NR.sub.6c—; [0741] R.sub.1c is R.sub.1ac or R.sub.1bc; [0742] wherein: [0743] R.sub.1ac is NR.sub.32cR.sub.33c; [0744] R.sub.1bc is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, C.sub.1-3alkyleneOC.sub.1-2alkyl, or CF.sub.3; [0745] R.sub.3c is H, CH.sub.3, halo, OC.sub.1-2alkyl or CF.sub.3; [0746] R.sub.4c and R.sub.5c are either R.sub.4ac and R.sub.5ac or R.sub.4bc and R.sub.5bc; [0747] wherein: [0748] R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [0749] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3 alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21cR.sub.22c; or [0750] one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [0751] R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [0752] R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29c; or [0753] R.sub.4ba and R.sub.5bc are each independently H, C.sub.1-6alkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-6alkylOH or C.sub.1-6haloalkyl, or R.sub.4bc and R.sub.5bc together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl ring; [0754] R.sub.6c is H or C.sub.1-3alkyl; [0755] Ar1c is a 6-membered aryl or heteroaryl; [0756] Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group A.sub.c; [0757] R.sub.10c is H, halo, C.sub.1-3alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl, OC.sub.1-2haloalkyl or CN; [0758] R.sub.11c is H, F, Cl, CH.sub.3, ethyl, OCH.sub.3, CF.sub.3, OCF.sub.3 or CN; [0759] R.sub.12c is attached to Ar2c in the meta or ortho position relative to Ar1c and R.sub.12c is H, halo, C.sub.1-4alkyl, C.sub.2-4alkynyl, C(═O)C.sub.1-2alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, C.sub.1-3 alkyleneOC.sub.1-3alkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, CN, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, OH, C.sub.1-4alkylOH, NR.sub.23cR.sub.24c, SO.sub.2CH.sub.3, C(O)N(CH.sub.3).sub.2, NHC(O)C.sub.1-3alkyl, or a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R.sub.12c together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); [0760] R.sub.21c is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl, C.sub.1-3alkylOC.sub.1-2alkyl, C.sub.1-4haloalkyl, or C.sub.4-6heterocycloalkyl; [0761] R.sub.22c is H or CH.sub.3; [0762] R.sub.23c is H or C.sub.1-2alkyl; [0763] R.sub.24c is H or C.sub.1-2alkyl; [0764] R.sub.29c is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, CF.sub.3, N(C.sub.1-3alkyl).sub.2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and [0765] R.sub.32c is C.sub.1-3alkyl and R.sub.33c is C.sub.1-3alkyl; or [0766] R.sub.32c and R.sub.33c together with the nitrogen atom to which they are attached form a C.sub.3-6heterocycloalkyl;
[0767] or a salt and/or solvate thereof and/or derivative thereof.
[0768] Suitably, R.sub.1c is R.sub.1ac; and/or R.sub.4c and R.sub.5c are R.sub.4ac and R.sub.5ac; and/or A.sub.c is A.sub.ac.
[0769] The invention also provides a compound of formula (I-c):
##STR00030##
[0770] wherein [0771] A.sub.c is A.sub.ac or A.sub.bc; [0772] A.sub.ac is —CH.sub.2NR.sub.6c—; [0773] A.sub.bc is —C(═O)NR.sub.6c—; [0774] R.sub.1c is R.sub.1ac or R.sub.1bc; [0775] wherein: [0776] R.sub.1ac is NR.sub.32cR.sub.33c; [0777] R.sub.1bc is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, C.sub.1-3alkyleneOC.sub.1-2alkyl, or CF.sub.3; [0778] R.sub.3c is H, CH.sub.3, halo, OC.sub.1-2alkyl or CF.sub.3; [0779] R.sub.4c and R.sub.5c are either R.sub.4ac and R.sub.5ac or R.sub.4bc and R.sub.5bc; [0780] wherein: [0781] R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [0782] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21cR.sub.22c; or [0783] one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3 alkyl or OC.sub.1-3alkyl; or [0784] R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [0785] R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29c; or [0786] R.sub.4bc and R.sub.5bc are each independently H, C.sub.1-6alkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-6alkylOH or C.sub.1-6haloalkyl, [0787] or R.sub.4bc and R.sub.5bc together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl ring; [0788] R.sub.6c is H or C.sub.1-3alkyl; [0789] Ar1c is a 6-membered aryl or heteroaryl; [0790] Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group A.sub.c; [0791] R.sub.10c is H, halo, C.sub.1-3alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl, OC.sub.1-2haloalkyl or CN; [0792] R.sub.11c is H, F, Cl, CH.sub.3, ethyl, OCH.sub.3, CF.sub.3, OCF.sub.3 or CN; [0793] R.sub.12c is attached to Ar2c in the meta or ortho position relative to Ar1c and R.sub.12c is H, halo, C.sub.1-4alkyl, C.sub.2-4alkynyl, C(═O)C.sub.1-2alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, C.sub.1-3 alkyleneOC.sub.1-3alkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, CN, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, OH, C.sub.1-4alkylOH, NR.sub.23cR.sub.24c, SO.sub.2CH.sub.3, C(O)N(CH.sub.3).sub.2, NHC(O)C.sub.1-3alkyl, or a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R.sub.12c together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); [0794] R.sub.21c is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl; [0795] R.sub.22c is H or CH.sub.3; [0796] R.sub.23c is H or C.sub.1-2alkyl; [0797] R.sub.24c is H or C.sub.1-2alkyl; [0798] R.sub.29c is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; and [0799] R.sub.32c is C.sub.1-3alkyl and R.sub.33c is C.sub.1-3alkyl; or [0800] R.sub.32c and R.sub.33 together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl;
[0801] or a salt and/or solvate thereof and/or derivative thereof.
[0802] Suitably, R.sub.1c is R.sub.1ac; and/or R.sub.4c and R.sub.5c are R.sub.4ac and R.sub.5ac; and/or A.sub.c is A.sub.ac.
[0803] When R.sub.4bc and/or R.sub.5bc is C.sub.0alkyleneC.sub.3-6heterocycloalkyl, any heteroatom in the heterocycloalkyl may not be directly connected to the carbon to which R.sub.4bc and R.sub.5bc are connected.
[0804] In one embodiment of the invention, R.sub.1c is R.sub.1ac, i.e. is NR.sub.32cR.sub.33c. In an embodiment, R.sub.32c is C.sub.1-3 alkyl, such as methyl or ethyl, e.g. methyl. In an embodiment, R.sub.33c is C.sub.1-3alkyl, such as methyl or ethyl, e.g. methyl. Suitably, R.sub.32c and R.sub.33c are both methyl. Suitably, R.sub.32c and R.sub.33c are both ethyl. Suitably, R.sub.32c is methyl and R.sub.33c is ethyl.
[0805] In another embodiment, R.sub.32c and R.sub.33c together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl. Suitably, the C.sub.3-5heterocycloalkyl is aziridinyl, azetidinyl or pyrrolidinyl.
[0806] Suitably, R.sub.1c is R.sub.1bc.
[0807] In one embodiment of the invention R.sub.1bc is C.sub.1-5alkyl such as C.sub.1-4alkyl. When R.sub.1bc is C.sub.1-5alkyl, R.sub.1bc is methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, sec-butyl or tert-butyl) or pentyl (e.g. n-pentyl, sec-pentyl, 3-pentyl, sec-isopentyl or active pentyl). When R.sub.1bc is C.sub.1-4alkyl, R.sub.1bc is methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl).
[0808] In a second embodiment of the invention R.sub.1bc is C.sub.1-3alkyleneOC.sub.1-2alkyl such as C.sub.1-2alkyleneOC.sub.1-2alkyl. R.sub.1bc may be C.sub.1alkyleneOC.sub.1alkyl. R.sub.1bc may be C.sub.1alkyleneOC.sub.2alkyl. R.sub.1bc may be C.sub.2alkyleneOC.sub.1alkyl. R.sub.1bc may be C.sub.2alkyleneOC.sub.2alkyl. R.sub.1bc may be C.sub.3alkyleneOC.sub.1alkyl. R.sub.1bc may be C.sub.3alkyleneOC.sub.2alkyl.
[0809] In a third embodiment of the invention R.sub.1bc is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3 such as C.sub.0-1alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3. In some embodiments, R.sub.1bc is C.sub.0-2alkyleneC.sub.3-5cycloalkyl such as C.sub.0-1alkyleneC.sub.3-4cycloalkyl. In other embodiments, R.sub.1bc is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is substituted by CH.sub.3 such as C.sub.0-1alkyleneC.sub.3-4cycloalkyl which cycloalkyl is substituted by CH.sub.3. R.sub.1bc may be C.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3 such as C.sub.3-4cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bc may be C.sub.1alkyleneC.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bc may be C.sub.1alkyleneC.sub.3-4cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bc may be C.sub.2alkyleneC.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bc may be C.sub.2alkyleneC.sub.3-4cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bc may be C.sub.0-2alkyleneC.sub.3cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bc may be C.sub.0-1alkyleneC.sub.3cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bc may be C.sub.0-2alkyleneC.sub.4cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bc may be C.sub.0-1alkyleneC.sub.4cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bc may be C.sub.0-2alkyleneC.sub.5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.1bc may be C.sub.0-1alkyleneC.sub.5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. Suitably, where C.sub.0-2alkyleneC.sub.3-5cycloalkyl such as C.sub.0-1alkyleneC.sub.3-4cycloalkyl is optionally substituted by CH.sub.3, the CH.sub.3 is at the point of attachment of the C.sub.3-5cycloalkyl to the C.sub.0-2alkylene such as at the point of attachment of the C.sub.3-4cycloalkyl to the C.sub.0-1alkylene.
[0810] Suitably R.sub.1bc is cyclopropyl.
[0811] In a fourth embodiment of the invention, R.sub.1bc is CF.sub.3.
[0812] In one embodiment R.sub.3c is H. In a second embodiment R.sub.3c is CH.sub.3. In a third embodiment, R.sub.3c is halo. In an example, R.sub.3c is F. In a second example, R.sub.3c is Cl. In a fourth embodiment, R.sub.3c is OC.sub.1-2alkyl. Suitably R.sub.3c is OCH.sub.3. Suitably, R.sub.3c is OCH.sub.2CH.sub.3. In a fifth embodiment, R.sub.3c is CF.sub.3.
[0813] Suitably, R.sub.3c is H.
[0814] In one embodiment, R.sub.4c and R.sub.5c are R.sub.4ac and R.sub.5ac.
[0815] Suitably, R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [0816] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21cR.sub.22c.
[0817] In one embodiment, the C.sub.3-6cycloalkyl is cyclopropyl. In another embodiment, the C.sub.3-6cycloalkyl is cyclobutyl. In another embodiment, the C.sub.3-6cycloalkyl is cyclopentyl. In another embodiment, the C.sub.3-6cycloalkyl is cyclohexyl.
[0818] In one embodiment the C.sub.3-6cycloalkyl is substituted by one substituent. In a second embodiment the C.sub.3-6cycloalkyl is substituted by two substituents.
[0819] In one embodiment, the substituent is C.sub.1-3alkyl. Suitably, the substituent is methyl. Suitably, the substituent is ethyl. Suitably, the substituent is n-propyl. Suitably, the substituent is iso-propyl.
[0820] In a second embodiment, the substituent is C.sub.1-3alkylOH. Suitably, the substituent is CH.sub.2OH. Suitably, the substituent is CH.sub.2CH.sub.2OH. Suitably, the substituent is CH.sub.2CH.sub.2CH.sub.2OH.
[0821] In a third embodiment, the substituent is C.sub.1-3haloalkyl. Suitably the C.sub.1-3alkyl group is substituted by one two or three, such as one, halogen atom. Suitably, the halogen atom is fluoro or chloro such as fluoro. Suitably, the substituent is C.sub.1haloalkyl such as CF.sub.3. Suitably, the substituent is C.sub.2haloalkyl such as CH.sub.2CF.sub.3.
[0822] In a fourth embodiment, the substituent is C.sub.0-2alkyleneC.sub.3-6cycloalkyl, in particular C.sub.0-2alkyleneC.sub.3-5cycloalkyl, such as C.sub.3-5cycloalkyl, C.sub.1alkyleneC.sub.3-5cycloalkyl or C.sub.2alkyleneC.sub.3-5cycloalkyl.
[0823] In a fifth embodiment, the substituent is C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as C.sub.0-2alkyleneC.sub.3heterocycloalkyl, C.sub.0-2alkyleneC.sub.4heterocycloalkyl, C.sub.0-2alkyleneC.sub.5heterocycloalkyl, C.sub.0-2alkyleneC.sub.6heterocycloalkyl, C.sub.0alkyleneC.sub.3-6heterocycloalkyl, C.sub.1alkyleneC.sub.3-6heterocycloalkyl and C.sub.2alkyleneC.sub.3-6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring may be substituted (such as one nitrogen atom is substituted), for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3 alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted.
[0824] In a sixth embodiment, the substituent is C.sub.1-3alkyleneOC.sub.1-3alkyl, in particular C.sub.1-2alkyleneOC.sub.1-2alkyl such as C.sub.1alkyleneOC.sub.1alkyl, C.sub.2alkyleneOC.sub.1alkyl, C.sub.1alkyleneOC.sub.2alkyl or C.sub.2alkyleneOC.sub.2alkyl.
[0825] In a seventh embodiment, the substituent is halo, in particular fluoro or chloro such as chloro.
[0826] In an eighth embodiment, the substituent is OC.sub.1-3haloalkyl. Suitably the OC.sub.1-3alkyl group is substituted by one two or three, such as one, halogen atom. Suitably, the halogen atom is fluoro or chloro such as fluoro. Suitably, the substituent is OC.sub.1haloalkyl such as OCF.sub.3. Suitably, the substituent is OC.sub.2haloalkyl such as OCH.sub.2CF.sub.3.
[0827] In a ninth embodiment, the substituent is OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, such as OC.sub.3-6cycloalkyl, OC.sub.1alkyleneC.sub.3-6cycloalkyl or OC.sub.2alkyleneC.sub.3-6cycloalkyl.
[0828] In a tenth embodiment, the substituent is OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as OC.sub.0-2alkyleneC.sub.3heterocycloalkyl, OC.sub.0-2alkyleneC.sub.4heterocycloalkyl, OC.sub.0-2alkyleneC.sub.5heterocycloalkyl, OC.sub.0-2alkyleneC.sub.6heterocycloalkyl, OC.sub.0alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1alkyleneC.sub.3-6heterocycloalkyl and OC.sub.2alkyleneC.sub.3-6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) (such as one nitrogen atom) in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4 haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted.
[0829] In an eleventh embodiment, the substituent is OC.sub.1-3alkyl, such as OCH.sub.3 or OCH.sub.2CH.sub.3.
[0830] In a twelfth embodiment, the substituent is NR.sub.21cR.sub.22c. In one embodiment R.sub.21c is H. In a second embodiment R.sub.21c is C.sub.1-5alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R.sub.21c is C(O)C.sub.1-5alkyl, such as C(O)CH.sub.3. In a fourth embodiment R.sub.21c is C(O)OC.sub.1-5alkyl, such as C(O)OCH.sub.3 or C(O)Otert-butyl. In a fifth embodiment R.sub.21c is C.sub.1-3alkylOC.sub.1-2alkyl such as C.sub.1alkylOC.sub.1alkyl, C.sub.2alkylOC.sub.1alkyl or C.sub.3alkylOC.sub.1alkyl e.g. C.sub.2alkylOC.sub.1alkyl. In a sixth embodiment, R.sub.21c is C.sub.1-4haloalkyl, such as CF.sub.3, CH.sub.2CF.sub.3 or CH.sub.2CHF.sub.2 e.g. CH.sub.2CHF.sub.2. In a seventh embodiment R.sub.21c is C.sub.4-6heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.
[0831] When the substituent is NR.sub.21cR.sub.22c, in one embodiment R.sub.22c is H. In a second embodiment R.sub.22c is methyl.
[0832] Suitably, R.sub.21c is C(O)OCH.sub.3 and R.sub.22c is H. Suitably, R.sub.21c is C(O)CH.sub.3 and R.sub.22c is H. Suitably, R.sub.21c and R.sub.22c are both CH.sub.3. Suitably, R.sub.21c and R.sub.22c are both H.
[0833] In a thirteenth embodiment, the substituent is oxo.
[0834] In a fourteenth embodiment, the substituent is OH.
[0835] Suitably, the one or two substituents, in particular one substituent, are independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, halo, OC.sub.1-3haloalkyl, OC.sub.1-3alkyl and NR.sub.21cR.sub.22c.
[0836] More suitably, the substituent is independently selected from the group consisting of oxo, OH, halo, OC.sub.1-3alkyl and NR.sub.21cR.sub.22c.
[0837] Most suitably, the substituent is independently selected from the group consisting of oxo, OH, fluoro, NR.sub.21cR.sub.22c.
[0838] Alternatively, R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl and one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl.
[0839] In one embodiment the C.sub.3-6cycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached is unsubstituted. In a second embodiment the C.sub.3-6cycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached is substituted by one or two substituents, in particular one substituent. Suitably, each substituent is independently selected from the group consisting of C.sub.1-2alkyl or OCH.sub.3.
[0840] Suitably one of the carbons of the C.sub.3-6cycloalkyl which is formed by R.sub.4ac and R.sub.5ac is a spiro centre such that a spirocyclic ring system is formed, wherein the C.sub.3-6cycloalkyl which is formed by R.sub.4ac and R.sub.5ac is a C.sub.4-6cycloalkyl. Suitably the C.sub.3-6heterocycloalkyl is an oxygen containing C.sub.3-6heterocycloalkyl. Suitably, the C.sub.3-6heterocycloalkyl is an oxygen comprising, such as containing, C.sub.3-6heterocycloalkyl ring, such as a C.sub.5cycloalkyl ring.
[0841] In an embodiment, R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl. Suitably, each substituent is independently selected from the group consisting of C.sub.1-2alkyl or OCH.sub.3.
[0842] Suitably one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed containing further ring C, wherein C is a C.sub.4-6heterocycloalkyl. Suitably the C.sub.4-6heterocycloalkyl is an oxygen containing C.sub.4-6heterocycloalkyl such as tetrahydropyranyl or 1,3-dioxolanyl.
[0843] As stated above, when a heterocycloalkyl is formed from R.sub.4c and R.sub.5c together with the carbon atom to which they are attached, suitably any heteroatom is not directly connected to the carbon to which R.sub.4c and R.sub.5c are attached.
[0844] In an embodiment, R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29c.
[0845] Suitably, the C.sub.3-6heterocycloalkyl is selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl such as piperidinyl.
[0846] Suitably, when the C.sub.3-6heterocycloalkyl is piperidinyl, the nitrogen atom is in the 4-position relative to the quaternary carbon:
##STR00031##
[0847] The C.sub.3-6 heterocycloalkyl may be other groups as defined elsewhere herein.
[0848] In an embodiment, R.sub.29c is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3. In one embodiment, R.sub.29c is C.sub.1-3alkyl such as methyl. In another embodiment, R.sub.29c is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3. In some embodiments, R.sub.29c is C.sub.0-2alkyleneC.sub.3-5cycloalkyl. In other embodiments, R.sub.29c is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is substituted by CH.sub.3. R.sub.29c may be C.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29c may be C.sub.1alkyleneC.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29c may be C.sub.2alkyleneC.sub.3-5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29c may be C.sub.0-2alkyleneC.sub.3cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29c may be C.sub.0-2alkyleneC.sub.4cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. R.sub.29c may be C.sub.0-2alkyleneC.sub.5cycloalkyl, which cycloalkyl is optionally substituted by CH.sub.3. Suitably, where C.sub.0-2alkyleneC.sub.3-5cycloalkyl is optionally substituted by CH.sub.3, the CH.sub.3 is at the point of attachment of the C.sub.3-5cycloalkyl to the C.sub.0-2alkylene. In another embodiment, R.sub.29c is CF.sub.3. In another embodiment, R.sub.29c is N(C.sub.1-3alkyl).sub.2 such as N(CH.sub.3).sub.2. In another embodiment, R.sub.29c is a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl. In one embodiment, the 5 or 6 membered heteroaryl is substituted by methyl. In one embodiment, the 5 or 6 membered heteroaryl is not substituted by methyl. In one embodiment, R.sub.29c is a 5-membered heteroaryl such as pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, such as pyrazolyl. Suitably the pyrazolyl is substituted by methyl. In another embodiment, R.sub.29c is a 6-membered heteroaryl such as pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.
[0849] In another embodiment, R.sub.4c and R.sub.5c are R.sub.4bc and R.sub.5bc.
[0850] In one embodiment, R.sub.4bc is H. In a second embodiment R.sub.4bc is C.sub.1-6alkyl such as C.sub.1-4alkyl, i.e. methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). R.sub.4bc may also be pentyl (e.g. n-pentyl, sec-pentyl, 3-pentyl, sec-isopentyl or active pentyl) or hexyl (e.g. n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl). In a third embodiment, R.sub.4bc is C.sub.0-2alkyleneC.sub.3-6cycloalkyl such as C.sub.0-2alkyleneC.sub.3-5cycloalkyl, such as C.sub.0-2alkyleneC.sub.3cycloalkyl, C.sub.0-2alkyleneC.sub.4cycloalkyl, C.sub.0-2alkyleneC.sub.5cycloalkyl, C.sub.0alkyleneC.sub.3-5 cycloalkyl, C.sub.1alkyleneC.sub.3-5cycloalkyl and C.sub.2alkyleneC.sub.3-5cycloalkyl. R.sub.4bc may also be C.sub.0-2alkyleneC.sub.6cycloalkyl, C.sub.0alkyleneC.sub.3-6cycloalkyl, C.sub.1alkyleneC.sub.3-6cycloalkyl and C.sub.2alkyleneC.sub.3-6cycloalkyl. In a fourth embodiment R.sub.4bc is C.sub.1-3alkyleneOC.sub.1-3alkyl, in particular C.sub.1-2alkyleneOC.sub.1-2 alkyl such as C.sub.1alkyleneOC.sub.1alkyl, C.sub.2alkyleneOC.sub.1alkyl, C.sub.1alkyleneOC.sub.2alkyl or C.sub.2alkyleneOC.sub.2alkyl. In a fifth embodiment R.sub.4bc is C.sub.1-6alkylOH such as C.sub.1-4alkylOH such as C.sub.1alkylOH, C.sub.2alkylOH, C.sub.3alkylOH or C.sub.4alkylOH wherein C.sub.1-4alkyl is methyl, ethyl, propyl (n-propyl or isopropyl) and butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). R.sub.4bc may also be C.sub.5alkylOH or C.sub.6alkylOH. In a sixth embodiment, R.sub.4bc is C.sub.1-6haloalkyl such as C.sub.1-4haloalkyl such as C.sub.1haloalkyl (e.g. CF.sub.3), C.sub.2haloalkyl (e.g. CH.sub.2CF.sub.3), C.sub.3haloalkyl (e.g. CH.sub.2CH.sub.2CF.sub.3) or C.sub.4haloalkyl (e.g. CH.sub.2CH.sub.2CH.sub.2CF.sub.3). R.sub.4bc may also be C.sub.5haloalkyl (e.g. CH.sub.2CH.sub.2CH.sub.2CH.sub.2CF.sub.3) or C.sub.6haloalkyl (e.g. CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CF.sub.3). In a seventh embodiment, R.sub.4bc is C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as C.sub.0-2alkyleneC.sub.3heterocycloalkyl, C.sub.0-2alkyleneC.sub.4heterocycloalkyl, C.sub.0-2alkyleneC.sub.5heterocycloalkyl, C.sub.0-2alkyleneC.sub.6heterocycloalkyl, C.sub.0alkyleneC.sub.3-6heterocycloalkyl, C.sub.1alkyleneC.sub.3-6heterocycloalkyl and C.sub.2alkyleneC.sub.3-6heterocycloalkyl. Suitably the heterocycloalkyl of a C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl group is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as one nitrogen atom in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted. In an eighth embodiment, R.sub.4bc and R.sub.5bc together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl ring. Suitably R.sub.4bc and R.sub.5bc together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl ring, such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. Suitably R.sub.4bc and R.sub.5bc together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl ring, such as a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as one nitrogen atom in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted.
[0851] Suitably R.sub.4bc is H, CH.sub.3 or ethyl, in particular CH.sub.3 or ethyl. Suitably, R.sub.4bc and R.sub.5bc together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl ring, such as a cyclopropyl ring.
[0852] In one embodiment, R.sub.5bc is H. In a second embodiment R.sub.5bc is C.sub.1-6alkyl such as C.sub.1-4alkyl, i.e. methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). R.sub.5bc may also be pentyl (e.g. n-pentyl, sec-pentyl, 3-pentyl, sec-isopentyl and active pentyl) or hexyl (e.g. n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl). In a third embodiment, R.sub.5bc is C.sub.0-2alkyleneC.sub.3-6cycloalkyl such as C.sub.0-2alkyleneC.sub.3-5cycloalkyl, such as C.sub.0-2alkyleneC.sub.3cycloalkyl, C.sub.0-2alkyleneC.sub.4cycloalkyl, C.sub.0-2alkyleneC.sub.5cycloalkyl, C.sub.0alkyleneC.sub.3-5 cycloalkyl, C.sub.1alkyleneC.sub.3-5cycloalkyl and C.sub.2alkyleneC.sub.3-5cycloalkyl. R.sub.5bc may also be C.sub.0-2alkyleneC.sub.6cycloalkyl, C.sub.0alkyleneC.sub.3-6cycloalkyl, C.sub.1alkyleneC.sub.3-6cycloalkyl and C.sub.2alkyleneC.sub.3-6cycloalkyl. In a fourth embodiment R.sub.5bc is C.sub.1-3alkyleneOC.sub.1-3alkyl, in particular C.sub.1-2alkyleneOC.sub.1-2 alkyl such as C.sub.1alkyleneOC.sub.1alkyl, C.sub.2alkyleneOC.sub.1alkyl, C.sub.1alkyleneOC.sub.2alkyl or C.sub.2alkyleneOC.sub.2alkyl. In a fifth embodiment R.sub.5bc is C.sub.1-6alkylOH such as C.sub.1-4alkylOH such as C.sub.1alkylOH, C.sub.2alkylOH, C.sub.3alkylOH or C.sub.4alkylOH wherein C.sub.1-4alkyl is methyl, ethyl, propyl (n-propyl or isopropyl) and butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). R.sub.5bc may also be C.sub.5alkylOH or C.sub.6alkylOH. In a sixth embodiment, R.sub.5bc is C.sub.1-6haloalkyl such as C.sub.1-4haloalkyl such as C.sub.1haloalkyl (e.g. CF.sub.3), C.sub.2haloalkyl (e.g. CH.sub.2CF.sub.3), C.sub.3haloalkyl (e.g. CH.sub.2CH.sub.2CF.sub.3), C.sub.4haloalkyl (e.g. CH.sub.2CH.sub.2CH.sub.2CF.sub.3). R.sub.5bc may also be C.sub.5haloalkyl (e.g. CH.sub.2CH.sub.2CH.sub.2CH.sub.2CF.sub.3) or C.sub.6haloalkyl (e.g. CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CF.sub.3). In a seventh embodiment, R.sub.5bc is C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl such as C.sub.0-2alkyleneC.sub.3heterocycloalkyl, C.sub.0-2alkyleneC.sub.4heterocycloalkyl, C.sub.0-2alkyleneC.sub.5heterocycloalkyl, C.sub.0-2alkyleneC.sub.6heterocycloalkyl, C.sub.0alkyleneC.sub.3-6heterocycloalkyl, C.sub.1alkyleneC.sub.3-6heterocycloalkyl and C.sub.2alkyleneC.sub.3-6heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as one nitrogen in the C.sub.3-6heterocycloalkyl ring may be substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Suitably, any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted.
[0853] Suitably R.sub.5bc is H, CH.sub.3 or ethyl, in particular CH.sub.3 or ethyl. Suitably, R.sub.4bc and R.sub.5bc together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl ring, such as a cyclopropyl ring.
[0854] Suitably R.sub.4bc is H, CH.sub.3 or ethyl and R.sub.5bc is H, CH.sub.3 or ethyl, in particular R.sub.4bc is CH.sub.3 or ethyl and R.sub.5bc is CH.sub.3 or ethyl. For example, R.sub.4bc and R.sub.5bc are H, R.sub.4bc and R.sub.5bc are methyl or R.sub.4bc and R.sub.5bc are ethyl.
[0855] Suitably, R.sub.4bc is CH.sub.2CH.sub.2OCH.sub.3 and R.sub.5bc is H.
[0856] In one embodiment, A.sub.c is A.sub.ac i.e. —CH.sub.2NR.sub.6c—.
[0857] In another embodiment, A.sub.c is A.sub.bc i.e. —C(═O)NR.sub.6c—.
[0858] In one embodiment, R.sub.6c is H. In another embodiment, R.sub.6c is C.sub.1-3alkyl, in particular CH.sub.3.
[0859] In one embodiment Ar1c is a 6-membered aryl, i.e. phenyl. In a second embodiment Ar1c is a 6-membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl).
[0860] In particular Ar1c is phenyl or 2-pyridyl, such as phenyl.
[0861] In one embodiment R.sub.10c is H. In a second embodiment R.sub.10c is halo, for example fluoro or chloro. In a third embodiment R.sub.10c is C.sub.1-3alkyl, i.e. CH.sub.3, ethyl or propyl (e.g. n-propyl or iso-propyl). In a fourth embodiment R.sub.10c is OC.sub.1-2alkyl, such as OCH.sub.3 or ethoxy. In a fifth embodiment, R.sub.10c is C.sub.1-2 haloalkyl, such as CF.sub.3 or CH.sub.2CF.sub.3. In a sixth embodiment R.sub.10c is OC.sub.1-2haloalkyl, such as OCF.sub.3. In a seventh embodiment R.sub.10c is CN.
[0862] Suitably R.sub.10c is H, fluoro, OCH.sub.3, CH.sub.3 or CF.sub.3, in particular H or fluoro, especially H.
[0863] Suitably R.sub.10c is attached at the ortho position of Ar1c relative to group A.sub.c(i.e. proximal to group A.sub.c).
[0864] In one embodiment R.sub.11c is H. In a second embodiment R.sub.11c is F. In a third embodiment, R.sub.11c is Cl. In a fourth embodiment R.sub.11c is CH.sub.3. In a fifth embodiment R.sub.11c is CH.sub.2CH.sub.3. In a sixth embodiment R.sub.11c is OCH.sub.3. In a seventh embodiment R.sub.11c is CF.sub.3. In an eighth embodiment R.sub.11c is OCF.sub.3. In a ninth embodiment R.sub.11c is CN.
[0865] In one embodiment, R.sub.11c is in the ortho position relative to group A.sub.c. In another embodiment R.sub.11c is in the meta position relative to group A.sub.c.
[0866] In one embodiment Ar2c is a 6-membered aryl, i.e. phenyl. In a second embodiment Ar2c is a 6-membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl).
[0867] In particular Ar2c is 3-pyridyl or 2,5-pyrazinyl, especially 2,5-pyrazinyl.
[0868] In one embodiment R.sub.12c is H. In a second embodiment R.sub.12c is halo, for example fluoro or chloro. In a third embodiment R.sub.12c is C.sub.1-4alkyl, i.e. methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment, R.sub.12c is C.sub.2-4alkynyl such as C.sub.2alkynyl (i.e. C≡CH). In a fifth embodiment, R.sub.12c is C(═O)C.sub.1-2alkyl, such as C(═O)C.sub.1alkyl or C(═O)C.sub.2alkyl. In a sixth embodiment R.sub.12c is OC.sub.1-2alkyleneC.sub.3-5cycloalkyl, such as OC.sub.3-5cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OC.sub.1alkyleneC.sub.3-5cycloalkyl or OC.sub.2alkyleneC.sub.3-5cycloalkyl. In a seventh embodiment R.sub.12c is OC.sub.1-4alkyl, such as OCH.sub.3-5ethoxy, iso-propoxy or n-propoxy. In an eighth embodiment, R.sub.12c is C.sub.1-3alkyleneOC.sub.1-3alkyl in particular C.sub.1-2alkyleneOC.sub.1-2alkyl such as C.sub.1alkyleneOC.sub.1alkyl, C.sub.2alkyleneOC.sub.1alkyl, C.sub.1alkyleneOC.sub.2alkyl or C.sub.2alkyleneOC.sub.2alkyl. In a ninth embodiment R.sub.12c is C.sub.1-4haloalkyl, such as CF.sub.3. In a tenth embodiment R.sub.12c is OC.sub.1-4haloalkyl, such as OCF.sub.3, OCHF.sub.2 or OCH.sub.2CF.sub.3. In an eleventh embodiment R.sub.12c is CN. In an eleventh embodiment R.sub.12c is OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, such as OC.sub.3-5cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OC.sub.1alkyleneC.sub.3-5cycloalkyl or OC.sub.2alkyleneC.sub.3-5cycloalkyl. In a twelfth embodiment R.sub.12c is OCH.sub.2CH.sub.2N(CH.sub.3).sub.2. In a thirteenth embodiment R.sub.12c is OH. In a fourteenth embodiment R.sub.12c is C.sub.1-4alkylOH, such as CH.sub.2OH or C(CH.sub.3).sub.2OH. In a fifteenth embodiment R.sub.12c is NR.sub.23cR.sub.24c. In a sixteenth embodiment R.sub.12c is SO.sub.2CH.sub.3. In a seventeenth embodiment R.sub.12c is C(O)N(CH.sub.3).sub.2. In an eighteenth embodiment R.sub.12c is NHC(O)C.sub.1-3alkyl such as NHC(O)CH.sub.3. In a nineteenth embodiment R.sub.12c is a C.sub.3-6heterocycloalkyl comprising (such as containing) one nitrogen located at the point of attachment to Ar2c, such as a C.sub.5heterocycloalkyl, in particular pyrrolidinyl, or a C.sub.6heterocycloalkyl such as morpholinyl. In a twentieth embodiment, R.sub.12c together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−).
[0869] In one embodiment, R.sub.23c is H. In another embodiment, R.sub.23c is C.sub.1-2alkyl i.e. CH.sub.3 or CH.sub.2CH.sub.3.
[0870] In one embodiment, R.sub.24c is H. In another embodiment, R.sub.24c is C.sub.1-2alkyl i.e. CH.sub.3 or CH.sub.2CH.sub.3.
[0871] R.sub.12c is suitably H, fluoro, chloro, CH.sub.3, Et, OCH.sub.3, OEt, OiPr, CF.sub.3 or OCH.sub.2CF.sub.3. In particular, R.sub.12c is fluoro, chloro, CH.sub.3, OCH.sub.3, OEt, OiPr or CF.sub.3, for example chloro, OEt, OiPr or CF.sub.3 such as chloro, OEt or CF.sub.3.
[0872] R.sub.12c is suitably attached at the meta position of Ar2c. Alternatively, R.sub.12c is attached at the ortho position of Ar2c.
[0873] The present invention provides compounds R94 and R95.
[0874] The present invention provides the following compounds: [0875] N-(4-(2-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide; and [0876] N-(4-(2-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide.
General Terms and Definitions
[0877] In this section reference to variables and compounds of formula (I) are taken to generically cover variables wherein the suffix “a”, “b” or “c” has been added. For example, reference to R.sub.4 is taken to include reference to R.sub.4a, R.sub.4b and R.sub.4c as well as sub-groups within these variables. The same applies for all other variables discussed in this section. Similarly, reference to compounds of formula (I) is taken to include compounds of formula (I-a), (I-b) and/or (I-c).
[0878] The term ‘alkyl’ as used herein, such as in C.sub.1-3alkyl, C.sub.1-4alkyl, C.sub.1-5alkyl or C.sub.1-6alkyl e.g. C.sub.1-3alkyl, C.sub.1-4alkyl or C.sub.1-5alkyl, or such as in C.sub.1-2alkyl, C.sub.1-3alkyl or C.sub.1-4alkyl whether alone or forming part of a larger group such as an Oalkyl group (e.g. OC.sub.1-3alkyl, OC.sub.1-4alkyl and OC.sub.1-5alkyl or OC.sub.1-2alkyl, OC.sub.1-3alkyl or OC.sub.1-4alkyl), is a straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. Examples of alkyl groups include the C.sub.1-5alkyl groups methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and n-pentyl, sec-pentyl and 3-pentyl, in particular the C.sub.1-3alkyl groups methyl, ethyl, n-propyl and iso-propyl. Examples of alkyl groups also include the C.sub.1-4alkyl groups methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl, in particular the C.sub.1-3alkyl groups methyl, ethyl, n-propyl and iso-propyl such as C.sub.1-2alkyl groups methyl and ethyl. Reference to “propyl” includes n-propyl and iso-propyl, and reference to “butyl” includes n-butyl, isobutyl, sec-butyl and tert-butyl. Examples of Oalkyl groups include the OC.sub.1-4alkyl groups methoxy, ethoxy, propoxy (which includes n-propoxy and iso-propoxy) and butoxy (which includes n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy). C.sub.5alkyl groups as used herein, whether alone or forming part of a larger group such as an OC.sub.5alkyl group is a straight or a branched fully saturated hydrocarbon chain containing five carbon atoms. Examples of C.sub.5alkyl groups include n-pentyl, sec-pentyl, 3-pentyl, sec-isopentyl and active pentyl. C.sub.5alkyl groups as used herein, whether alone or forming part of a larger group such as an OC.sub.6alkyl group is a straight or a branched fully saturated hydrocarbon chain containing six carbon atoms. Examples of C.sub.6alkyl groups include n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.
[0879] The term ‘alkylene’ as used herein, such as in C.sub.0-2alkyleneC.sub.3-5cycloalkyl, C.sub.1-3alkyleneOC.sub.1-2alkyl C.sub.1-2alkyleneOC.sub.1-2alkyl or OC.sub.0-2alkyleneC.sub.3-5cycloalkyl is a bifunctional straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. Examples of C.sub.0-2alkylene groups are where the group is absent (i.e. C.sub.0), methylene (C.sub.1) and ethylene (C.sub.2). Examples of C.sub.1-3alkylene groups are where the group is methylene (C.sub.1), ethylene (C.sub.2) and propylene (C.sub.3). Examples of C.sub.1-2alkylene groups are where the group is methylene (C.sub.1) and ethylene (C.sub.2). Examples of C.sub.0-1alkylene groups are where the group is absent (C.sub.0) and methylene (C.sub.1).
[0880] The term ‘alkenyl’ as used herein, such as in C.sub.2-4alkenyl, is a straight or branched hydrocarbon chain containing the specified number of carbon atoms and a carbon-carbon double bond.
[0881] The term ‘alkynyl’ as used herein, such as in C.sub.2-4alkynyl such as in C.sub.2alkynyl is an unbranched hydrocarbon chain containing the specified number of carbons (e.g. 2, 3 or 4 carbons, such as two carbons), two of which carbon atoms are linked by a carbon-carbon triple bond.
[0882] The term ‘cycloalkyl’ as used herein, such as in C.sub.3-4cycloalkyl, C.sub.3-5cycloalkyl or C.sub.3-6cycloalkyl, whether alone or forming part of a larger group such as OC.sub.3-5cycloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl or C.sub.0-1alkyleneC.sub.3-4cycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms. Examples of cycloalkyl groups include the C.sub.3-6cycloalkyl groups cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, in particular the C.sub.3-5cycloalkyl groups cyclopropyl, cyclobutyl and cyclopentyl:
##STR00032##
[0883] When B is B-a, the term ‘heterocycloalkyl’ as used herein, such as in C.sub.3-6heterocycloalkyl or C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms, wherein at least one of the carbon atoms in the ring is replaced by a heteroatom such as N, S or O. When B is B-bc, the term ‘heterocycloalkyl’ as used herein, such as in C.sub.3-6heterocycloalkyl or C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of ring atoms and includes the ring atom through which the heterocycloalkyl group is attached, wherein at least one of the atoms in the ring is a heteroatom such as O, N or S.
[0884] As required by valency, the nitrogen atom(s) may be connected to a hydrogen atom to form an NH group. Alternatively the nitrogen atom(s) may be substituted (such as one nitrogen atom is substituted), for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. Wherein a ring heteroatom is S, the term ‘heterocycloalkyl’ includes wherein the S atom(s) is substituted (such as one S atom is substituted) by one or two oxygen atoms (i.e. S(O) or S(O).sub.2). Alternatively, any sulphur atom(s) in the C.sub.3-6heterocycloalkyl ring is not substituted.
[0885] Examples of C.sub.3-6heterocycloalkyl groups include those comprising one heteroatom such as containing one heteroatom (e.g. oxygen) or containing two heteroatoms (e.g. two oxygen atoms or one oxygen atom and one nitrogen atom). Other examples of C.sub.3-6heterocycloalkyl include those comprising one heteroatom atom such as containing one heteroatom (e.g. one oxygen atom or one nitrogen atom) or containing two heteroatoms (e.g. two nitrogen atoms or one nitrogen atom and one oxygen atom). Particular examples of C.sub.3-6heterocycloalkyl comprising one nitrogen atom include pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, especially piperidinyl, pyrrolidinyl and morpholinyl. Particular examples of C.sub.3-6heterocycloalkyl comprising one oxygen atom include oxiranyl, oxetanyl, 3-dioxolanyl, morpholinyl, 1,4-oxathianyl, tetrahydropyranyl, 1,4-thioxanyl and 1,3,5-trioxanyl. Examples of C.sub.3-6heterocycloalkyl include those comprising one oxygen atom such as containing one oxygen atom, or containing two oxygen atoms. Particular examples of C.sub.3-6heterocycloalkyl comprising one oxygen atom include oxiranyl, oxetanyl, 3-dioxolanyl, morpholinyl, 1,4-oxathianyl, tetrahydropyranyl, 1,4-thioxanyl and 1,3,5-trioxanyl. Particular examples of C.sub.3-6heterocycloalkyl comprising one nitrogen atom include piperidinyl. Other examples of C.sub.3-6heterocycloalkyl comprising one nitrogen atom include pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, such as piperidinyl.
[0886] In one embodiment and when B is B-a, the term ‘heterocycloalkyl’ as used herein, such as in C.sub.3-6heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms, wherein at least one of the carbon atoms in the ring is replaced by a heteroatom such as N, S or O. Examples of C.sub.3-6heterocycloalkyl groups include those comprising one heteroatom such as containing one heteroatom (e.g. oxygen) or containing two heteroatoms (e.g. two oxygen atoms or one oxygen atom and one nitrogen atom).
[0887] When B is B-bc and the compound is a compound of formula (I-b), the term ‘heterocycloalkyl’ as used herein, such as in C.sub.3-6heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of ring atoms and includes the ring atom through which the heterocycloalkyl group is attached, wherein at least one of the atoms in the ring is a heteroatom such as O, N or S. Examples of C.sub.3-6heterocycloalkyl include those comprising one nitrogen atom such as containing one heteroatom (i.e. nitrogen) or containing two heteroatoms (e.g. two nitrogen atoms or one nitrogen atom and one oxygen atom).
[0888] The term ‘5- or 6-membered oxygen-containing heterocycloalkyl’ as used herein, is a fully saturated hydrocarbon ring containing the specified number of ring atoms (i.e. 5 or 6), wherein at least one ring atom is an oxygen atom and the ring does not contain heteroatoms other than oxygen. Examples of oxygen-containing heterocycloalkyl groups are oxiranyl, oxetanyl, tetrahydrofuranyl, 3-dioxolanyl, tetrahydropyranyl, and 1,3,5-trioxanyl, such as tetrahydrofuranyl and tetrahydropyranyl. An example of a nitrogen-containing heterocycloalkyl group is piperidinyl.
[0889] The heterocycloalkyl groups may have any one of the following structures:
##STR00033##
[0890] wherein each Q is independently selected from O, N or S, such as O or N. When Q is N, as required by valency, the nitrogen atom(s) may be connected to a hydrogen atom to form an NH group. Alternatively the nitrogen atom(s) may be substituted (such as one nitrogen atom is substituted), for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. When any Q is S, the S atoms can be substituted (such as one S atom is substituted) by one or two oxygen atoms (i.e. S(O) or S(O).sub.2). When R.sub.4 and R.sub.5 are R.sub.4a and R.sub.5a, Q is N substituted by S(O).sub.2R.sub.29. Alternatively, any sulphur atom(s) in the C.sub.3-6heterocycloalkyl ring is not substituted.
[0891] When A.sub.a is —C(═O)NH—, —NH— or —CH.sub.2NH— and R.sub.4a and/or R.sub.5a is C.sub.0alkyleneC.sub.3-6heterocycloalkyl, or when R.sub.4a and R.sub.5a together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl, any heteroatom in the heterocycloalkyl may not be directly connected to the carbon to which R.sub.4a and R.sub.5a are connected.
[0892] When B is B-a, suitably, heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms wherein at least one of the carbon atoms is replaced by a heteroatom such as N, S or O wherein as required by valency, any nitrogen atom is connected to a hydrogen atom, and wherein the S atom is not present as an oxide.
[0893] When B is B-bc and the compound is a compound of formula (I-b), suitably, heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of ring atoms and includes the ring atom through which the heterocycloalkyl group is attached, wherein at least one of the atoms in the ring is a heteroatom such as O, N or S. Suitably, as required by valency, any nitrogen atom is connected to a hydrogen atom. Suitably any S atom is not present as an oxide. In particular, any nitrogen atom is connected to a hydrogen atom and any S atom is not present as an oxide.
[0894] When B is B-bc and the compound is a compound of formula (I-c), and when the heterocycloalkyl is formed from R.sub.4 and R.sub.5 together with the carbon atom to which they are attached, suitably any heteroatom is not directly connected to the carbon to which R.sub.4 and R.sub.5 are attached. Thus suitably, when the heterocycloalkyl is formed from R.sub.4 and R.sub.5 together with the carbon atom to which they are attached, the heterocycloalkyl may be:
##STR00034##
[0895] wherein each Q is independently O, N or S such as O or N. When Q is N, as required by valency, the nitrogen atom(s) may be connected to a hydrogen atom to form an NH group. Alternatively the nitrogen atom (s) may be substituted (such as one nitrogen atom is substituted), for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C.sub.3-6heterocycloalkyl ring include C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3 alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3. When any Q is S, the S atom(s) can be substituted (such as one S atom is substituted) by one or two oxygen atoms (i.e. S(O) or S(O).sub.2). When R.sub.4 and R.sub.5 are R.sub.4a and R.sub.5a, Q is N substituted by —S(O).sub.2R.sub.29. Alternatively, any sulphur atom(s) in the C.sub.3-6heterocycloalkyl ring is not substituted.
[0896] The term ‘halo’ or ‘halogen’ as used herein, refers to fluorine, chlorine, bromine or iodine. Particular examples of halo are fluorine and chlorine, especially fluorine.
[0897] The term ‘haloalkyl’ as used herein, such as in C.sub.1-6haloalkyl, such as in C.sub.1-4haloalkyl or C.sub.1-2 haloalkyl, whether alone or forming part of a larger group such as an Ohaloalkyl group, such as in OC.sub.1-6haloalkyl, such as in OC.sub.1-4haloalkyl or OC.sub.1-2haloalkyl, is a straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms and at least one halogen atom, such as fluoro or chloro, especially fluoro. An example of haloalkyl is CF.sub.3. Further examples of haloalkyl are CHF.sub.2 and CH.sub.2CF.sub.3. Another example of haloalkyl is CH.sub.2CHF.sub.2. Examples of Ohaloalkyl include OCF.sub.3, OCHF.sub.2 and OCH.sub.2CF.sub.3.
[0898] The term ‘6-membered aryl’ as used herein refers to a phenyl ring.
[0899] The term ‘6-membered heteroaryl’ as used herein refers to 6-membered aromatic rings containing at least one heteroatom (e.g. nitrogen). Exemplary 6-membered heteroaryls include one nitrogen atom (pyridinyl), two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl) and three nitrogen atoms (triazinyl).
[0900] The phrase ‘in the para position relative to group A’ as used herein, such as in relation to the position of Ar2, means that compounds with the following substructure are formed:
##STR00035##
[0901] wherein when B is B-a, W.sub.1 may be N, CH, CR.sub.10a or CR.sub.11a, and W.sub.2 may be N, CH or CR.sub.12a as allowed by the definitions provided for compounds of formula (I). W.sub.2 may also be CR.sub.13a as allowed by the definitions provided for compounds of formula (I-a); and
[0902] when B is B-bc and the compound is a compound of formula (I-b), compounds with the following substructure are formed:
##STR00036##
[0903] wherein W may be N, CH, CR.sub.10b or CR.sub.11b, and Y may be N, CH, CR.sub.12b or CR.sub.13b as allowed by the definitions provided for compounds of formula (I-b);
[0904] and when B is B-bc and the compound is a compound of formula (I-c), compounds with the following substructure are formed:
##STR00037##
[0905] wherein W may be N, CH or CR.sub.10c, and Y may be N, CH or CR.sub.12c as required by the definitions provided for compounds of formula (I-c). W may also be CR.sub.11c as allowed by the definitions provided for compounds of formula (I-c).
[0906] The terms ‘ortho’ and ‘meta’ as used herein, such as when used in respect of defining the position of R.sub.12 on Ar2 is with respect to Ar1, means that the following structures may form:
[0907] when B is B-a:
##STR00038##
[0908] when B is B-bc and the compound is a compound of formula (I-b):
##STR00039##
[0909] wherein X represents a substituent e.g. R.sub.12b; and
[0910] when B is B-bc and the compound is a compound of formula (I-c):
##STR00040##
[0911] wherein all variables listed above are as defined elsewhere herein.
[0912] When a spirocyclic ring system is said to form, e.g. when R.sub.4aa and R.sub.5aa, R.sub.4ab and R.sub.5ab, or R.sub.4ac and R.sub.5ac, suitably together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl and one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, the following spirocyclic groups are encompassed (which may optionally be substituted as mentioned above):
##STR00041##
[0913] wherein C is a C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, as defined elsewhere herein. In one embodiment C is a C.sub.3-6cycloalkyl ring. In a second embodiment C is a C.sub.3-6heterocycloalkyl ring.
[0914] For example, one of the carbons is quaternary and is attached to a 5-membered dioxalane ring to form the following structure:
##STR00042##
[0915] wherein m is 1 or 2 and n is 0, 1 or 2. Suitably m is 2 and n is 2.
[0916] Alternatively, when a spirocyclic ring system is said to form, e.g. when R.sub.4aa and R.sub.5aa, R.sub.4ab and R.sub.5ab, or R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, the following spirocyclic groups are encompassed (which may optionally be substituted as mentioned above):
##STR00043##
[0917] wherein C is a C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, as defined elsewhere herein, and HC is a C.sub.3-6heterocycloalkyl ring formed by R.sub.4a and R.sub.5a (i.e. R.sub.4aa and R.sub.5aa, R.sub.4ab and R.sub.ab, or R.sub.4ac and R.sub.5ac) as defined elsewhere herein. In one embodiment C is a C.sub.3-6cycloalkyl ring. In a second embodiment C is a C.sub.3-6heterocycloalkyl ring.
[0918] Throughout the specification Ar1 and Ar2 may be depicted as follows:
##STR00044##
[0919] All depictions with respect to Ar1 are equivalent and all depictions with respect to Ar2 are equivalent, unless the context requires otherwise, depictions of Ar1 and Ar2 should not be taken to exclude the presence of heteroatoms or substitutions. Ar1 encompasses the variables Ar1 a, Ar1b and Ar1c. Ar2 encompasses the variables Ar2a, Ar2b and Ar2c.
[0920] The present invention provides N-oxides of the compound of formula (I). Suitably, when R.sub.12 together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−), the example following structures are formed:
##STR00045##
[0921] The position numbering for Ar1 is in respect of group A, with the carbon at the point of attachment designated position 1 and other numbers providing the relative location of the nitrogen atoms, for example:
##STR00046##
[0922] The position numbering for Ar2 is in respect of the point of attachment to Ar1, for example:
##STR00047##
[0923] Reference to compounds of formula (I) throughout the application is intended to encompass reference to compounds of formulae (I-a), (I-b) and (I-c).
[0924] The compounds of the invention may be provided in the form of a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof. In particular, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt and/or solvate, such as a pharmaceutically acceptable salt Compounds of the invention of particular interest are those demonstrating an IC.sub.50 of 1 uM or lower, especially 100 nM or lower, in respect of CTPS1 enzyme, using the methods of the examples (or comparable methods).
[0925] Compounds of the invention of particular interest are those demonstrating a selectivity for CTPS1 over CTPS2 of 2-30 fold, suitably >30-60 fold or more suitably >60 fold, using the methods of the examples (or comparable methods). Desirably the selectivity is for human CTPS1 over human CTPS2.
[0926] It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Non-pharmaceutically acceptable salts of the compounds of formula (I) may be of use in other contexts such as during preparation of the compounds of formula (I). Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art.
[0927] Pharmaceutically acceptable salts include those described by Berge et al. (1977). Such pharmaceutically acceptable salts include acid and base addition salts. Pharmaceutically acceptable acid additional salts may be formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g. oxalates or formates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.
[0928] Certain of the compounds of formula (I) may form acid or base addition salts with one or more equivalents of the acid or base. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
[0929] The compounds of formula (I) may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, e.g. as the hydrate. This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water).
[0930] It will be understood that the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and that these are included within the scope of the invention.
[0931] As used herein “pharmaceutically acceptable derivative” includes any pharmaceutically acceptable prodrug such as an ester or salt of such ester of a compound of formula (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
[0932] It is to be understood that the present invention encompasses all isomers of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
[0933] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exist as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or >99% by number of the atoms of that atomic number (the latter embodiment referred to as an “isotopically enriched variant form”). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
[0934] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (.sup.2H or D), carbon-11 (.sup.11C), carbon-13 (.sup.13C), carbon-14 (.sup.14C), nitrogen-13 (.sup.13N), nitrogen-15 (.sup.15N), oxygen-15 (.sup.15O), oxygen-17 (.sup.17O), oxygen-18 (.sup.19O), phosphorus-32 (.sup.32P), sulphur-35 (.sup.35S), chlorine-36 (.sup.36Cl), chlorine-37 (.sup.37Cl), fluorine-18 (.sup.18F) iodine-123 (.sup.123I), iodine-125 (.sup.125I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
[0935] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. .sup.3H, and carbon-14, i.e. .sup.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e. .sup.2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as .sup.11C, .sup.18F, .sup.15O and .sup.13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
[0936] In one embodiment, the compounds of the invention are provided in a natural isotopic form.
[0937] In one embodiment, the compounds of the invention are provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e. .sup.2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.
[0938] In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.
[0939] Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the Examples. Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.
[0940] In general, the compounds of formula (I) may be made according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth below, those in the Examples, and modifications thereof.
[0941] General Routes:
[0942] In this section reference to variables and compounds of formula (I) are taken to generically cover variables wherein the suffix “a”, “b” or “c” has been added. For example, reference to R.sub.4 is taken to include reference to R.sub.4a, R.sub.4b and R.sub.4c as well as sub-groups within these variables. The same applies for all other variables discussed in this section. Reference to compounds of formula (I) is taken to include compounds of formula (I-a), (I-b) and/or (I-c).
[0943] Generic and specific routes by which compounds disclosed herein and compound examples of the invention may be conveniently prepared are disclosed in WO2019/106156, WO2019/106146, WO2019/179652, WO02019/180244 and WO2020/083975, each of which is herein incorporated in its entirety by reference, as well as those routes summarised below, and adaptations thereof.
[0944] Compounds of Formula (I-a)
[0945] Compounds of formula (I-a) may be synthesised according to general and specific methods disclosed in WO2019/179652, WO2019/180244 and WO02020/083975. For the avoidance of doubt, reference to variables in each of the schemes in this section encompasses variables specific to compounds of formula (I-a). For example, R.sub.1 includes R.sub.1a. Furthermore, reference to intermediates in each of the schemes in this section encompasses corresponding intermediates for compounds of formula (I-a). For example, reference to compounds of formula (II) encompasses compounds of formula (II-a).
##STR00048##
##STR00049##
[0946] Suitably, R.sub.2 is H, (IX) is converted to (X) using a base and alkyl halide or X—CH.sub.2—(CH.sub.2)n-X wherein n=1,2,3 and the compounds of general formula (I) are obtained by a five step process.
[0947] In general and as illustrated in Schemes 1a and 1b, compounds of general formula (I) may be obtained by a five or six step process from a 2,4-dichloropyrimidine derivative of general formula (VIII). Firstly, the derivative (VIII) can be reacted with an unsymmetrical malonate ester as shown in Schemes 1a, 1b of WO2019/179652, or 1a or 1b herein. For example, the unsymmetrical malonate ester can be treated with a base such as Cs.sub.2CO.sub.M in the presence of di-chloropyrimidine (VIII) in a solvent such as DMF and heated to an elevated temperature such as 80° C., followed by an aqueous work-up to obtain compounds of formula (VII). This intermediate compound can then be deprotected at this stage via a decarboxylation, initiated by the use of a strong acid such as TFA to yield intermediate derivative (IX). Certain intermediates such as (IX) where R.sub.3=H, are commercially available. Reaction of a methyl 2-(2-chloropyrimidin-4-yl)acetate derivative of general formula (IX) with an inorganic base such as potassium carbonate, in the presence of an alkylating agent leads to alkylation alpha to the ester. It will be understood by persons skilled in the art that both mono- and dialkylation may be achieved with careful control of the reaction conditions, but for a more reliable synthesis of the monoalkylated product, an alternative procedure should be considered (as in Scheme 1a of WO2019179652). R.sub.4 and R.sub.5 can be connected to form a C.sub.3-6cycloalkyl ring as defined above ((IX) to (X)). Such compounds may be prepared by double alkylation with a dihaloalkane, such as 1,2-dibromoethane or 1,3-dibromobutane in the presence of an inorganic base such as sodium hydroxide. For compounds of general formula (I) wherein R.sub.4 and R.sub.5 together with the carbon to which they are attached form a C.sub.3-6heterocycloalkyl, double alkylation of intermediates (IX) using a di-haloheteroalkane (such as BrCH.sub.2CH.sub.2OCH.sub.2CH.sub.2Br) in the presence of a base such as Cs.sub.2CO.sub.3 in a solvent such as MeCN at an elevated temperature such as 60° C. followed by direct column chromatography can be used to provide compounds of formula (X).
[0948] Palladium catalysed sulfamination of intermediate (X) may be achieved using a catalyst such as [t-BuXPhosPd(allyl)]OTf or t-BuXPhos-Pd-G3 and substituted sulfonamide nucleophile (VI), in the presence of an inorganic base, for example potassium carbonate to form intermediate derivative (II). Alternatively, sulfamination of intermediate (X) may be achieved using a substituted sulfonamide nucleophile (VI), in the presence of an inorganic base, for example Cs.sub.2CO.sub.3 and a solvent such as N-methyl pyrrolidinone to form intermediates (II) which may be obtained by precipitation following dilution in aqueous 4M HCl.
[0949] Final transformation to compounds of general formula (I) can be prepared by conversion of intermediate (II) by activation of the ester moiety using trimethylaluminium (usually a 2.0 M solution in toluene or heptane) and addition of amine (ill) (commercially available or prepared as in Schemes 6a, 6b, 7a or 7b of WO2019179652). Alternatively, compounds of formula (I) may be obtained by a strong base-mediated amide formation between compounds (II) and (III) at room temperature using bases such as iPrMgCl, UHMDS or KOtBu.
[0950] Compounds of the general formula (VII) where R.sub.2 is O-alkyl may be accessed in two steps from commercial 2,4,6-trichloropyrimidine derivatives such as (VIII) where R.sub.2 is Cl. Reaction of an unsymmetrical malonate ester can yield compounds such as (VII) which can then be treated with an alkoxide base such as sodium methoxide to displace the more reactive chloride to give compounds of general formula (VII) where R.sub.2=O-alkyl. Such compounds can then be progressed to final compounds of formula (I) following the steps previously described in Schemes 1a or 1b.
[0951] Compounds of general formula (I) where R1, Ar1 and Ar2 are defined above and R.sub.4 and R.sub.5 together with the carbon to which they are attached form a C.sub.3-6heterocycloalkyl, may be prepared in five steps starting from intermediate of general formula (VIII). Firstly, alkyl esters of general formula (XXVII) can be treated with a strong base such as LIHMDS then reacted with 2,4-dichloropyrimidines such as derivative (VIII). Such compounds can then be converted to final compounds using the methods described in Scheme 1b. If any protecting groups remain after amide coupling, treatment with a strong acid such as TFA may yield final compounds of formula (I).
[0952] Following deprotection compounds of general formula (I) where R.sub.1, Ar1 and Ar2 are defined above and R.sub.4 and R.sub.5 together with the carbon to which they are attached form a C.sub.3-6aminocycloalkyl, may be further elaborated by treatment with a suitable electrophile such as an acid chloride or an isocyanate, to yield the corresponding amide or urea. Such compounds may also undergo reductive amination in the presence of a suitable aldehyde or ketone followed by treatment with sodium triacetoxyborohydride.
##STR00050##
[0953] Intermediates of formula (III) wherein Ar1, R.sub.10, R.sub.11, R.sub.12 and R.sub.13 are defined above and Ar2 is an unsubstituted or substituted 3-pyridyl ring, may be synthesised by coupling under Suzuki conditions of a boronate of general formula (XII), wherein R.sub.12 and R.sub.13 are defined above and Z represents a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group, to a substituted pyridine of formula (XI) where X denotes a halide. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water.
##STR00051##
[0954] Intermediates of formula (III) wherein Ar1, R.sub.10, R.sub.11, R.sub.12 and R.sub.13 are defined above and Ar2 is an unsubstituted or substituted 2,5-pyrazinyl ring, may be synthesised by coupling under Suzuki conditions of an aromatic halide of general formula (XII) and Z represents a halide, to a boronate of general formula (XI) where X denotes a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium or [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II) and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water.
[0955] Benzamide Pyrimidines
##STR00052##
[0956] Compounds of general formula (I) may be obtained by a four step process, as shown in Scheme 4. 2-Chloropyrimidine-4-carbonitrile (XXXIX) can be converted to the corresponding sulfonamide (XXXX) using palladium catalysed sulfamination conditions previously reported in Scheme 1a and 1b of WO2019179652. Reduction of the nitrile group using sodium borohydride in the presence of nickel (II) chloride and di-tert-butyl dicarbonate may yield the protected benzylamine derivative of general formula (XXXXI). Deprotection can be carried out by acid hydrolysis using HCl in dioxane to yield benzylamine derivative of general formula (XXXXII). Amide coupling conditions may then be employed to convert the benzylamine derivative (XXXXII) to amides of general formula (I) by employing a coupling reagent together with a biaryl carboxylic acid (XXXXIII) (commercially available or prepared as in Scheme 19 of WO2019179652 or Scheme 6 herein).
[0957] Compounds of general formula (I) where A is an amine linker such as —CH.sub.2NH—, where R.sub.1, Ar.sub.1 and Ar.sub.2 are defined above, R.sub.4 is C.sub.1-6alkyl and R.sub.5 is H or C.sub.1-6alkyl or R.sub.4 and R.sub.5 together with the carbon to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl may be accessed in one step from benzyl amines such as (XXXXII). Reaction of (XXXXII) with aromatic aldehydes (LXXII) in the presence of a hydride source such as sodium triacetoxyborohydride may yield amines of formula (I).
##STR00053##
[0958] Compounds of general formula (I) where R.sub.1, Ar.sub.1 and Ar.sub.2 are defined above, R.sub.4 is C.sub.1-6alkyl and R.sub.5 is H or C.sub.1-6alkyl or R.sub.4 and R.sub.5 together with the carbon to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl may be obtained by a six step process, as shown in Scheme 5. Firstly, the carboxylic acid (LVXII) can be obtained by hydrolysis of methyl ester (XXXIII) using an alkali metal base such as lithium hydroxide. Curtius rearrangement can be carried out, for example, using diphenylphosphoryl azide in the presence of propylphosphonic anhydride, triethylamine and tert-butanol to yield carbamates such as (LVXIII). Deprotection can be carried out by acid hydrolysis using HCl in dioxane to yield benzylamine derivative of general formula (LVXIX). Amide coupling conditions may then be employed to convert the benzylamine derivative (LVXIX) to amides of general formula (LXX) by employing a coupling reagent together with a biaryl carboxylic acid (XXXXIII) (commercially available or prepared as in Scheme 19 of WO02019179652). Compound of formula (LXX) can then be progressed to compounds of formula (I) following the oxidation, displacement sequence described in Scheme 9a.
##STR00054##
[0959] Intermediates of formula (LXXII) where Ar.sub.2 is an unsubstituted or substituted 2-pyrazine ring or 3-pyridyl ring, may be synthesised as shown in Scheme 6, in a one-pot, two step procedure starting with borylation of (XI), where X denotes a halogen such as Br or Cl. followed by coupling under Suzuki conditions with an aromatic halide of general formula (XII), of which R.sub.12 and R.sub.13 are defined above and Z represents Br or Cl. Initially compounds such as (XI), can be converted to the corresponding boronate using a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH.sub.2Cl.sub.2 adduct and an inorganic base such as potassium acetate in a solvent such as dioxane. Aromatic halide (XII) may then be added to the reaction mixture along with an aqueous solution of an inorganic base such as caesium carbonate to yield alcohols of formula (LXXI). The aldehydes of general formula (LXXII) are obtained by treatment with an oxidant such as manganese dioxide.
##STR00055##
[0960] In general compounds of formula (I) where R.sub.4 and R.sub.5 together with the carbon to which they are attached form a 1,4-dioxaspiro[4.5]decane (i.e. m and n are 2) may be treated with a strong acid, such as HCl, to yield cyclic ketones of formula (I). Such ketones may then be treated with a hydride source, such as sodium borohydride, to yield the corresponding exocyclic alcohol or reacted with an amine, such as dimethylamine, followed by sodium triacetoxyborohydride to yield exocydic amines of formula (I).
##STR00056##
[0961] Compounds of formula (I) wherein A is —NR.sub.6CH.sub.2— can be obtained from compounds of formula (I) wherein A is —NR.sub.6C(═O)—, by the reduction of the amide to the amine using a reducing agent such as LiAlH.sub.4 in a solvent such as THF.
##STR00057##
[0962] In general and as illustrated in Scheme 9a, compounds of formula (I) wherein R.sub.1, Ar1 and Ar2 are as defined above, alkyl is C.sub.1-4alkyl such as methyl or ethyl, e.g. methyl, and for example, R.sub.4 and R.sub.5 together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl ring may be prepared starting from a general intermediate of formula (XXXIII). Intermediates such as (LXXIV) may be obtained by subjecting compounds such as (XXXIII) to amide coupling conditions such as those described in Scheme 9 of WO2019179652 using iPrMgCl. Thioethers of the general formula (LXXIII) may be transformed to sulfoxides or sulfones (LXXIV) in the presence of an oxidising agent such as mCPBA. Displacement of the sulfone group with a primary sulphonamide (VI) in the presence of a base such as Cs.sub.2CO.sub.3 and a solvent such as N-methyl pyrrolidone gives compounds of formula (I).
[0963] Compounds of formula (I) may also be accessed by oxidation of (XXXIII) to form sulphone (LXXXIII), which can be coupled with (VI), and then (III) using standard conditions disclosed elsewhere herein to give compounds of formula (I).
##STR00058##
[0964] In general and as illustrated in Scheme 9b, compounds of formula (I) wherein R.sub.1, Ar1 and Ar2 are as defined above, alkyl is C.sub.1-4alkyl such as methyl or ethyl, e.g. methyl, and for example, R.sub.4 and R.sub.5 together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl ring may be prepared starting from a general intermediate of formula (LXXX). Intermediates such as (LXXXI) may be obtained by subjecting compounds such as (LXXX) and (III) to reductive amination conditions such as those described in Scheme 7. Thioethers of the general formula (LXXXI) may be transformed to sulfoxides or sulfones (LXXXII) in the presence of an oxidising agent such as mCPBA. Displacement of the sulfone group with a primary sulphonamide (VI) in the presence of a base such as Cs.sub.2CO.sub.3 and a solvent such as N-methyl pyrrolidone gives compounds of formula (I).
##STR00059##
[0965] wherein R is H, C.sub.1-4alkyl (e.g. methyl and ethyl) or benzyl. In general and as illustrated in Scheme 9c, compounds of formula (I) wherein R.sub.1, X, Y, Z, Ar1 and Ar2 are as defined above and K is C.sub.1-4 alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu, C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3, may be prepared in five steps from compounds of formula (LVX). An intermediate of formula (XXXVI) may be coupled to a compound of formula (LVX) in the presence of a base such as LiHMDS to give a compound of formula (XXXIII). Thioethers of the general formula (XXXIII) may be transformed to a sulfoxide of formula (XXXIV) or a sulfone of formula (LXXXIII) in the presence of an oxidising agent such as mCPBA. The skilled person will appreciate that formation of the sulfoxide or sulfone can be controlled by varying the number of equivalents of oxidising agent used, the length of reaction and/or the temperature of the reaction. Displacement of the sulfoxide group or the sulfone group with a primary sulfonamide (VI) in the presence of a base such as Cs.sub.2CO.sub.3 and a solvent such as N-methyl pyrrolidone gives compounds of formula (II). Compounds of formula (I) may be obtained by a strong base-mediated amide formation between compounds (II) and (III) at room temperature using bases such as iPrMgCl, UHMDS or KOtBu, to give compounds of formula (I-P), followed by removal of the Boc group using a strong acid such as TFA, and introduction of the N-substituent K. Introduction of K may be performed by reaction of the free NH group with K-LG wherein LG is a leaving group such as halo e.g. chloro or bromo, under standard conditions known to the skilled person, or by any other N-substituent forming conditions known to the skilled person (such as Mitsunobu conditions, reductive amination or N-acylation), to give a compound of formula (I).
##STR00060##
[0966] In general and as illustrated in Scheme 10, compounds of formula (I) wherein R.sub.1, Ar1 and Ar2 are as defined above, alkyl is C.sub.1-4alkyl such as methyl or ethyl, e.g. methyl, and for example, R.sub.4 and R.sub.5 together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl ring may be prepared starting from chloro-pyrimidine (LXXV). Intermediates (XXXVII) are coupled to chloro-pyrimidine (LXXV) in the presence of a base such as LIHMDS to give intermediates (LXXVI). Thioethers of the general formula (LXXVI) may then be transformed to compounds of formula (I) following the route described in Scheme 9a of WO2019179652.
##STR00061##
[0967] In general and as illustrated in Scheme 11, compounds of formula (I) wherein R1, Ar1 and Ar2 are as defined above, R.sub.4 and R.sub.5 together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl ring may be prepared starting from alcohols (LXXI), which as oxidised to aldehydes (LXXII) in the presence of MnO.sub.2 in a non-protic solvent such as DCM. Reductive coupling of amine (LXXIX) and aldehyde (LXXII) in the presence of a hydride source such as sodium triacetoxyborohydride in an aprotic solvent such as DCM in the presence of a proton source such as acetic acid affords compounds of formula (I) following the route described in Scheme 11.
##STR00062##
[0968] Compounds of formula (I) wherein A is —NH— and R.sub.4 or R.sub.5 is H may be prepared by reductive coupling of the appropriate amine and aldehyde in the presence of a hydride source such as sodium triacetoxyborohydride.
[0969] Compounds of Formula (I-b)
[0970] Compounds of formula (I-b) may be synthesised by general and specific methods disclosed in WO2019/106156 and those disclosed below. For the avoidance of doubt, reference to variables in each of the schemes in this section encompasses variables specific to compounds of formula (I-b). For example, R.sub.1 includes R.sub.1b. Furthermore, reference to intermediates in each of the schemes in this section encompasses corresponding intermediates for compounds of formula (I-b). For example, reference to compounds of formula (II) encompasses compounds of formula (II-b).
##STR00063##
[0971] Compounds of formula (I) may be obtained by a general process whereby a carboxylic acid precursor (II), or a suitably protected derivative thereof, is reacted with an activating agent, to generate a reactive, electrophilic carboxylic acid derivative, followed by subsequent reaction with an amine of formula (IX). Intermediates of formula (X) are then converted to a compound of the invention of general formula (I) by coupling under Suzuki conditions with an aromatic halide or boronate of general formula (XI), of which X is defined above and represents usually a bromide, a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as bis(diphenylphosphino)ferrocene]dichloropalladium(II) and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water. It will be understood by persons skilled in the art that many catalysts and conditions can be employed for such couplings.
##STR00064##
[0972] Intermediates of formula (III) where Ar2 is an unsubstituted or substituted 3-pyridyl ring, may be synthesised by coupling under Suzuki conditions of a boronate of general formula (XI), of which R.sup.12 and R.sup.13 are defined above and Z represents a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group, to a substituted pyridine of formula (IX) of which R.sup.10 and R.sup.11 are defined above and where X denotes a halide. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and an inorganic base such as potassium carbonate in a solvent mixture of 1,4-dioxane and water.
##STR00065##
[0973] Intermediates of formula (III) where Ar2 is an unsubstituted or substituted 2-pyrazine ring, may be synthesised by coupling under Suzuki conditions of an aromatic halide of general formula (XI), of which R.sup.12 and R.sup.13 are defined above and Z represents a halide, to a boronate of general formula (IX) of which R.sup.10 and R.sup.11 are defined above and where X denotes a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium or [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water.
##STR00066##
[0974] Compound of general formula (XVII) may be prepared by conversion of a suitable 2-(2-aminothiazol-4-yl)acetate derivative, such as a methyl or ethyl derivative, by a Sandmeyer type reaction using an organic nitrite, such as n-butylnitrite, in the presence of a halide source, such as Cu(I)Br in acetonitrille. Such reactions can be undertaken at temperatures of RT to 60° C.
[0975] Introduction of R.sub.4/R.sub.5can be undertaken by two alternative methods at this stage. Firstly, alkylation of compounds of general formula (XVII) can be undertaken by addition of a suitable base, for example, LiHMDS, together with an alkylating agent, such as iodomethane which results in dialkylation alpha to the ester moiety to yield compounds of formula (XVIII), where R.sub.4b=R.sub.5b=Me. Secondly, diazotisation of compounds of general formula (XVII) with the use of an diazo transfer reagent, such as 4-acetamidobenzenesulfonyl azide, under basic conditions, followed by treatment with rhodium and subsequent insertion of the corresponding nucleophile, such as isopropyl alcohol, gives intermediates of general formula (XVIII) where R.sub.4b=Oisopropoxy and R.sub.5b=H.
[0976] Introduction of the sulfonamide group in the preparation of compounds of formula (IV) may be achieved by an Ullmann coupling reaction i.e. Cu mediated coupling conditions using amines of formula (XXIV) and a copper catalyst, such as Cu(I)I, in the presence of an inorganic base, potassium carbonate, and a diamine ligand in dioxane. Such reactions are typically carried out at elevated temperatures such as 80° C. Alternatively, conversion of compounds of formula (XVIII) to (IV) can be achieved via a palladium mediated coupling, for example using a catalyst such as [t-BuXPhos Pd(allyl)]OTf and substituted sulfonamide nucleophile (XXIV), in the presence of an inorganic base, for example potassium carbonate to form compounds of formula (IV). Palladium meditated coupling conditions are particularly useful when R.sub.4 and R.sub.5 together with the carbon atom to which they are attached form a 5- or 6-membered heterocycloalkyl, such as a tetrahydropyranyl. The alkyl esters of formula (IV) may be conveniently converted to compounds of formula (I) according to synthetic steps reported in Scheme 13.
##STR00067##
[0977] wherein halo is, for example, bromo. Compounds of formula (XXVII), for example, when R.sub.4b is H and R.sub.5b and R.sub.6 are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring, can be accessed in three steps from compounds of formula (XXV). Acylation of compounds of formula (XXV) in the presence of a strong base such as LDA followed by a quench with an .sup.−OAc source such as EtOAc provides compounds of formula (XXVI). Compounds of formula (XXVII) can be made from (XXVI) following addition of bromine and quench with a suitable thiourea, before a coupling with sulfonyl chlorides of formula (VI) to give compounds of formula (XXVIII). Compounds of formula (I) may be accessed using conditions set out in Scheme 14.
##STR00068##
[0978] In general compounds of formula (I) where R.sub.4 and R.sub.5 together with the carbon to which they are attached form a 1,4-dioxaspiro[4.5]decane (i.e. m is 2 and n is 2) may be treated with a strong acid such as HCl to yield cyclic ketones of formula (I). Such ketones may then be treated with a hydride source such as sodium borohydride to yield the corresponding exocyclic alcohol or reacted with an amine such as dimethylamine followed by sodium triacetoxyborohydride to yield exocyclic amines of formula (I).
##STR00069##
[0979] Compounds of formula (I) wherein A is —NR.sub.6CH.sub.2— can be obtained from compounds of formula (I) wherein A is —NR.sub.6C(═O)—, by the reduction of the amide to the amine using a reducing agent such as LiAlH.sub.4 in a solvent such as THF.
##STR00070##
[0980] Compounds of formula (I) wherein A is —NR.sub.6— and R.sub.5 or R.sub.4 are H can be obtained in a single step by a reductive amination between ketones of formula (XXIX) and amines of formula (III) in the presence of a hydride source such as sodium triacetoxyborohydride.
[0981] Compounds of Formula (I-c)
[0982] Compounds of formula (I-c) may be synthesised by general and specific methods disclosed in WO02019/106148 and those disclosed below. For the avoidance of doubt, reference to variables in each of the schemes in this section encompasses variables specific to compounds of formula (I-c). For example, R.sub.1 includes R.sub.1c. Furthermore, reference to intermediates in each of the schemes in this section encompasses corresponding intermediates for compounds of formula (I-c). For example, reference to compounds of formula (II) encompasses compounds of formula (II-c).
##STR00071##
[0983] Compounds of formula (XIII) may be obtained by a general process as shown in Scheme 21 whereby a carboxylic acid precursor (XIV) is reacted with an activating agent such as HATU, T3P or Ghosez's reagent, to generate a reactive, electrophilic carboxylic acid derivative, followed by subsequent reaction with an amine of formula (II). Intermediates of formula (XIII) are then converted to a compound of general formula (I) by coupling under Suzuki conditions with an aromatic halide of general formula (XII), of which X is defined in Scheme 21 and represents a dihydroxyboryl or dialkyloxyboryl group, such as a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH.sub.2Cl.sub.2 adduct and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water under an inert atmosphere such as a nitrogen atmosphere. It will be understood by persons skilled in the art that many catalysts and conditions can be employed for such couplings.
##STR00072##
[0984] Intermediates of formula (III) where Ar.sub.2 is an unsubstituted or substituted 2-pyrazine ring or 3-pyridyl ring, may be synthesised as shown in Scheme 22 by coupling under Suzuki conditions of an aromatic halide of general formula (XII), of which R.sub.10 and R.sub.12 are defined above and Z represents a halide such as Br or Cl, to a boronate of general formula (XVI) where X denotes a dihydroxyboryl or dialkyloxyboryl group, such as a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH.sub.2Cl.sub.2 adduct and an inorganic base such as cesium carbonate in a solvent mixture of dioxane and water under an inert atmosphere such as a nitrogen atmosphere. The carboxylic acids of general formula (III) are obtained by either deprotection of the t-butyl ester using a strong acid, such as TFA in a solvent of CH.sub.2Cl.sub.2, hydrolysis of the methyl ester using an alkali metal hydroxide such as NaOH in a solvent mixture such as THF/MeOH or hydrolysis of the nitrile using a strong acid such as concentrated HCl. Compounds of formula (III-A) may also be made using this method.
##STR00073##
[0985] Compounds of formula (I) wherein A.sub.a is —CH.sub.2NR.sub.6— can be accessed in two steps from compounds of formula (XXII). Oxidation of the alcohol (XXII) under standard oxidation conditions such as MnO.sub.2 gives aldehyde (XXIII). A reductive amination using a hydride source such as sodium tiacetoxyborohydride between aldehyde (XXIII) and amine (II) gives compounds of formula (I).
##STR00074##
[0986] In general compounds of the formula (I) where R.sub.4a and R.sub.5a together with the carbon to the which they are attached form a C.sub.3-6cycloalkyl wherein one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a C.sub.3-6heterocycloalkyl ring, such as a 1,4-dioxaspiro[4.5]decane moiety (m is 2 and n is 2), may be treated with a strong acid such as HCl to yield cyclic ketones of formula (I). Such ketones may then be treated with a hydride source such as sodium borohydride to yield the corresponding exocyclic alcohol or reacted with an amine such as dimethylamine followed by sodium triacetoxyborohydride to yield exocyclic amines of formula (I).
Intermediates of the Invention
[0987] Compounds of Formula (I-a)
[0988] The present invention also relates to novel intermediates in the synthesis of compounds of formula (I-a) such as compounds of formula (II-a) to (LVIX-a) such as compounds of formula (II-a) to (XXV-a), such as compounds of formula (II-a)-(XX-a). Particular intermediates of interest are those of the following general formulae, wherein the variable groups and associated preferences are as defined previously for compounds of formula (I-a): [0989] a compound of formula (II-a):
##STR00075##
[0990] wherein R is H, C.sub.1-6alkyl (e.g. methyl and ethyl) or benzyl; [0991] a compound of formula (XX-a):
##STR00076##
[0992] wherein P is a nitrogen protecting group such as para-methoxybenzyl; [0993] a compound of formula (XXIV-a):
##STR00077##
[0994] wherein P is a nitrogen protecting group such as para-methoxybenzyl; [0995] a compound of formula (XXXI-a):
##STR00078## [0996] a compound of formula (XXXXII-a):
##STR00079## [0997] a compound of formula (LI-a):
##STR00080##
[0998] wherein X.sub.1 is Cl or Br. [0999] a compound of formula (LVIII-a):
##STR00081## [1000] a compound of formula (LXXIII-a):
##STR00082##
[1001] wherein alkyl is C.sub.1-4alkyl such as methyl or ethyl, e.g. methyl; [1002] a compound of formula (LXXIII-a)
##STR00083## [1003] a compound of formula (LXXIV-a):
##STR00084## [1004] a compound of formula (LXXXIII-a):
##STR00085## [1005] a compound of formula (XXXIV-a):
##STR00086## [1006] a compound of formula (LXXI-a):
##STR00087## [1007] a compound of formula (LXXII-a):
##STR00088##
[1008] Suitably, at least one of R.sub.10, R.sub.11 and R.sub.12 is other than H.
[1009] There is also provided protected derivatives of a compound of formula (I). There is also provided protected derivatives of any one of the above intermediates, such as (II-a), (XX-a), (XXIV-a), (XXXI-a), (XXXXII-a), (LI-a), (LVIII-a), (XXXIII-a), (LXXIII-a), (LXXIV-a) and (LXXXIII-a). For example, if the compound of formula (I) comprises a heterocyclyl group comprising a nitrogen atom, for example, when R.sub.4ba and R.sub.5ba join to form a piperidinyl ring, the nitrogen atom may be protected with a suitable nitrogen protecting group such as Boc. Also provided are compounds of formula (I) or any one of the above mentioned intermediates in which the protecting group, such as the Boc group has been removed.
[1010] Compounds of formula (I) may be considered intermediates for further compounds of formula (I), as described in the Examples below.
[1011] Included as an aspect of the invention are all novel intermediates described in the examples, including: [1012] Intermediates INTC186 to INTC218; and [1013] Intermediates INTC232 to INTC247.
[1014] Included as an aspect of the invention are salts such as pharmaceutically acceptable salts of any one of the intermediates disclosed herein, such as any one of compounds of formulae (II-a)-(LXXVII-a).
[1015] Compounds of Formula (I-b)
[1016] The present invention also relates to novel intermediates in the synthesis of compounds of formula (I-b) such as compounds of formula (II-b), (IV-b), (V-b), (VI-b), (VII-b), (X-b), (XII-b), (XVIII-b), (XIX-b), (XX-b), (XXI-b), (XXII-b) and (XXIII-b). Particular intermediates of interest are those of the following general formulae, wherein the variable groups and associated preferences are as defined previously for compounds of formula (I-b): [1017] Compounds of formula (II-b)
##STR00089##
[1018] wherein R.sub.1, R.sub.3, R.sub.4 and R.sub.5 are as defined herein; [1019] Compounds of formula (IV-b)
##STR00090##
[1020] wherein R is C.sub.1-6alkyl (e.g. methyl, ethyl) or benzyl.
[1021] Suitably, the intermediate is not:
##STR00091##
[1022] Suitably, when the compound is a compound of formula (IV-b), R.sub.4b and R.sub.5b cannot both be H when R.sub.1b is CH.sub.3.
[1023] Included as an aspect of the invention are salts such as pharmaceutically acceptable salts of any one of the intermediates disclosed herein, such as any one of compounds of formulae (II-b), (IV-b), (V-b), (VI-b), (VII-b), (X-b), (XII-b), (XVIII-b), (XIX-b), (XX-b), (XXI-b), (XXII-b) and (XXIII-b).
[1024] Other intermediates of interest include those disclosed in WO2019/106156 such as INTA92, INTA93, INTA94, INTA95, INTA96, INTA97, INTA98, INTA103, INTA104, INTA105, INTA107, INTA3, INTA47, INTA48, INTA72, INTA106, INTB37, INTB38, INTB43.
[1025] Compounds of Formula (I-c)
[1026] The present invention also relates to novel intermediates in the synthesis of compounds of formula (I-c) such as compounds of formula (II-c), (IV-c), (V-c), (VI-c), (VIII-c), (IX-c), (X-c), (XI-c), (XIII-c), (XVIII-c), (XIX-c), (XX-c) and (XXI-c). Particular intermediates of interest are those of the following general formulae, wherein the variable groups and associated preferences are as defined previously for compounds of formula (I-c): [1027] a compound of formula (II-c):
##STR00092## [1028] a compound of formula (VIII-c):
##STR00093##
[1029] Included as an aspect of the invention are salts such as pharmaceutically acceptable salts of any one of the intermediates disclosed herein, such as any one of compounds of formulae (II-c), (IV-c), (V-c), (VI-c), (VIII-c), (IX-c), (X-c), (XI-c), (XIII-c), (XVIII-c), (XIX-c), (XX-c) and (XXI-c).
[1030] Therapeutic Methods
[1031] In the following section, reference to compounds of formula (I) encompasses compounds of formula (I-a), (I-b) and (I-c).
[1032] Compounds of formula (I) of the present invention have utility as inhibitors of CTPS1.
[1033] Therefore, the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof, for use as a medicament, in particular in the treatment or prophylaxis of a disease or disorder wherein an inhibitor of CTPS1 is beneficial, for example those diseases and disorders mentioned herein below.
[1034] The invention provides a method for the treatment or prophylaxis of a disease or disorder wherein an inhibitor of CTPS1 is beneficial, for example those diseases and disorders mentioned herein below, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof.
[1035] The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof (e.g. salt) and/or derivative, in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder wherein an inhibitor of CTPS1 is beneficial, for example those diseases and disorders mentioned herein below.
[1036] More suitably, the disease or disorder wherein an inhibitor of CTPS1 is beneficial is a disease or disorder wherein a reduction in T-cell and/or B-cell proliferation would be beneficial.
[1037] The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof, for use in the inhibition of CTPS1 in a subject.
[1038] The invention provides a method for the inhibition of CTPS1 in a subject, which comprises administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof.
[1039] The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof (e.g. salt) and/or derivative, in the manufacture of a medicament for the inhibition of CTPS1 in a subject
[1040] The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof, for use in the reduction of T-cell and/or B-cell proliferation in a subject
[1041] The invention provides a method for the reduction of T-cell and/or B-cell proliferation in a subject, which comprises administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof.
[1042] The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof (e.g. salt) and/or derivative, in the manufacture of a medicament for the reduction of T-cell and/or B-cell proliferation in a subject More suitably, the disease or disorder wherein an inhibitor of CTPS1 is beneficial is a disease or disorder wherein a reduction in T-cell and/or B-cell proliferation would be beneficial.
[1043] The term ‘treatment’ or ‘treating’ as used herein includes the control, mitigation, reduction, or modulation of the disease state or its symptoms.
[1044] The term ‘prophylaxis’ or ‘preventing’ is used herein to mean preventing symptoms of a disease or disorder in a subject or preventing recurrence of symptoms of a disease or disorder in an afflicted subject and is not limited to complete prevention of an affliction.
[1045] Suitably, the disease or disorder is selected from rejection of transplanted cells and tissues, Graft-related diseases or disorders, allergies and autoimmune diseases.
[1046] In one embodiment the disease or disorder is the rejection of transplanted cells and tissues. The subject may have been transplanted with a graft selected from the group consisting of heart, kidney, lung, liver, pancreas, pancreatic islets, brain tissue, stomach, large intestine, small intestine, cornea, skin, trachea, bone, bone marrow (or any other source of hematopoietic precursor cells and stem cells including hematopoietic cells mobilized from bone marrow into peripheral blood or umbilical cord blood cells), muscle, or bladder. The compounds of the invention may be of use in preventing or suppressing an immune response associated with rejection of a donor tissue, cell, graft or organ transplant in a subject In a further embodiment the disease or disorder is a Graft-related disease or disorder. Graft-related diseases or disorders include graft versus host disease (GVHD), such as GVHD associated with bone marrow transplantation, and immune disorders resulting from or associated with rejection of organ, tissue, or cell graft transplantation (e.g., tissue or cell allografts or xenografts), including, e.g., grafts of skin, muscle, neurons, islets, organs, parenchymal cells of the liver, etc, and Host-Versus-Graft-Disease (HVGD). The compounds of the invention may be of use in preventing or suppressing acute rejection of such transplant in the recipient and/or for long-term maintenance therapy to prevent rejection of such transplant in the recipient (e.g., inhibiting rejection of insulin-producing islet cell transplant from a donor in the subject recipient suffering from diabetes). Thus the compounds of the invention have utility in preventing Host-Versus-Graft-Disease (HVGD) and Graft-Versus-Host-Disease (GVHD).
[1047] A CTPS1 inhibitor may be administered to the subject before, after transplantation and/or during transplantation. In some embodiments, the CTPS1 inhibitor may be administered to the subject on a periodic basis before and/or after transplantation.
[1048] In another embodiment, the disease or disorder is an allergy.
[1049] In additional embodiments the immune related disease or disorder is an autoimmune disease. As used herein, an “autoimmune disease” is a disease or disorder directed at a subject's own tissues. Examples of autoimmune diseases include, but are not limited to Addison's Disease, Adult-onset Still's disease, Alopecia Areata, Alzheimer's disease, Anti-neutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis, Ankylosing Spondylitis, Anti-phospholipid Syndrome (Hughes' Syndrome), A plastic Anemia, Arthritis, Asthma, Atherosclerosis, Atherosclerotic plaque, Atopic Dermatitis, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis, Autoimmune Hypophysitis (Lymphocytic Hypophysitis), Autoimmune Inner Ear Disease, Autoimmune Lymphoproliferative Syndrome, Autoimmune Myocarditis, Autoimmune Neutropenia, Autoimmune Oophoritis, Autoimmune Orchitis, Auto-Inflammatory Diseases requiring an immunosuppressive treatment, Azoospermia, Bechet's Disease, Berger's Disease, Bullous Pemphigoid, Cardiomyopathy, Cardiovascular disease, Celiac disease including Refractory Celiac Disease (type I and type II), Chronic Fatigue Immune Dysfunction Syndrome (CFIDS), Chronic Idiopathic Polyneuritis, Chronic Inflammatory Demyelinating Polyneuropathy (CIPD), Chronic Relapsing Polyneuropathy (Guillain-Barré syndrome), Churg-Strauss Syndrome (CSS), Cicatricial Pemphigoid, Cold Agglutinin Disease (CAD), chronic obstructive pulmonary disease (COPD), CREST Syndrome, Cryoglobulin Syndromes, Cutaneous Lupus, Dermatitis Herpetiformis, Dermatomyositis, Eczema, Epidermolysis Bullosa Acquisita, Essential Mixed Cryoglobulinemia, Evan's Syndrome, Exophthalmos, Fibromyalgia, Goodpasture's Syndrome, Grave's disease, Hemophagocytic Lymphohistiocytosis (HLH) (including Type 1 Hemophagocytic Lymphohistiocytosis), Histiocytosis/Histiocytic Disorders, Hashimoto's Thyroiditis, Idiopathic Pulmonary Fibrosis, Idiopathic Thrombocytopenia Purpura (ITP), IgA Nephropathy, Immunoproliferative Diseases or Disorders, Inflammatory Bowel Disease (IBD), Interstitial Lung Disease, Juvenile Arthritis, Juvenile Idiopathic Arthritis (JIA), Kawasaki's Disease, Lambert-Eaton Myasthenic Syndrome, Lichen Planus, Localized Scleroderma, Lupus Nephritis, Méniére's Disease, Microangiopathic Hemoytic Anemia, Microscopic Polyangitis, Miller Fischer Syndrome/Acute Disseminated Encephalomyeloradiculopathy, Mixed Connective Tissue Disease, Multiple Sclerosis (MS), Muscular Rheumatism, Myalgic Encephalomyelitis (ME), Myasthenia Gravis, Ocular Inflammation, Pemphigus Foliaceus, Pemphigus Vulgaris, Pernicious Anemia, Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes (Whitaker's syndrome), Polymyalgia Rheumatica, Polymyositis, Primary Agammaglobulinemia, Primary Biliary Cirrhosis/Autoimmune Cholangiopathy, Primary Glomerulonephritis, Primary Sclerosing Cholangitis, Psoriasis, Psoriatic Arthritis, Pure Red Cell Anemia, Raynaud's Phenomenon, Reiter's Syndrome/Reactive Arthritis, Relapsing Polychondritis, Restenosis, Rheumatic Fever, Rheumatic Disease, Rheumatoid Arthritis, Sarcoidosis, Schmidt's Syndrome, Scleroderma/Systemic Sclerosis, Sjörgen's Syndrome, Stiff-Man Syndrome, The Sweet Syndrome (Febrile Neutrophilic Dermatosis), Systemic Lupus Erythematosus (SLE), Systemic Scleroderma, Takayasu Arteritis, Temporal Arteritis/Giant Cell Arteritis, Thyroiditis, Type 1 diabetes, Type 2 diabetes, Uveitis, Vasculitis, Vitiligo, Wegener's Granulomatosis, and X-linked lymphoproliferative disease.
[1050] Of particular interest are diseases and disorders which are mainly driven by T-cell activation and proliferation, including: [1051] diseases and disorders which are not linked to alloreactivity including: [1052] Alopecia areata, atopic dermatitis, eczema, psoriasis, lichen planus, psoriatic arthritis, vitiligo; [1053] Uveitis; [1054] Ankylosing spondylitis, Reiter's syndrome/reactive arthritis; [1055] Aplastic anemia, autoimmune lymphoproliferative syndrome/disorders, hemophagocytic lymphohistiocytosis; [1056] Type 1 diabetes; and [1057] Refractory celiac disease; [1058] Acute rejection of grafted tissues and transplanted organs; acute graft versus host disease (GVHD) after transplantation of bone marrow cells or any other source of allogenic cells including hematopoietic precursors cells and/or stem cells.
[1059] Also of interest are diseases and disorders which are driven by both T- and B-cell activation and proliferation, with an important involvement of B-cells, including: [1060] diseases and disorders for which the involvement of pathogenic auto-antibodies is well characterized, including: [1061] a Allergy; [1062] Cicatricial pemphigoid, bullous pemphigoid, epidermolysis bullosa acquisita, pemphigus foliaceus, pemphigus vulgaris, dermatitis herpetiformis; [1063] ANCA-associated vasculitis and microscopic polyangitis, vasculitis, Wegener's granulomatosis; Churg-Strauss syndrome (CSS), polyarteritis nodosa, cryoglobulin syndromes and essential mixed cryglobulinemia; [1064] Systemic lupus erythematosus (SLE), antiphospholipid syndrome (Hughes' syndrome), cutaneous lupus, lupus nephritis, mixed connective tissue disease; a Thyroiditis, Hashimoto thyroiditis, Grave's disease, exophthalmos; [1065] Autoimmune hemolytic anemia, autoimmune neutropenia, ITP, pernicious anaemia, pure red cell anaemia, micro-angiopathic hemolytic anemia; [1066] Primary glomerulonephritis, Berger's disease, Goodpasture's syndrome, IgA nephropathy; and [1067] Chronic idiopathic polyneuritis, chronic inflammatory demyelinating polyneuropathy (CIPD), chronic relapsing polyneuropathy (Guillain-Barré syndrome), Miller Fischer syndrome, Stiff man syndrome, Lambert-Eaton myasthenic syndrome, myasthenia gravis. [1068] diseases and disorders for which the involvement of B-cells is less clearly characterized (although sometimes illustrated by the efficacy of anti-CD20 monoclonal antibodies or intravenous immunoglobulin infusions) and may not correspond or be limited to the production of pathogenic antibodies (nevertheless, non-pathogenic antibodies are sometimes described or even often present and used as a diagnosis biomarker), including: [1069] Addison's disease, autoimmune oophoritis and azoospermia, polyglandular syndromes (Whitaker's syndrome), Schmidt's syndrome; [1070] Autoimmune myocarditis, cardiomyopathy, Kawasaki's disease; [1071] Rheumatoid arthritis, Sjögren's syndrome, mixed connective tissue disease, polymyositis and dermatomyositis; polychondritis; [1072] Primary glomerulonephritis; [1073] Multiple sclerosis; [1074] Autoimmune hepatitis, primary biliary cirrhosis/autoimmune cholangiopathy, [1075] Hyper acute rejection of transplanted organs; [1076] Chronic rejection of graft or transplants; [1077] Chronic Graft versus Host reaction/disease after transplantation of bone marrow cells or hematopoietic precursor cells.
[1078] Additionally of interest are diseases and disorders for which the mechanism is shared between activation/proliferation of T-cells and activation/proliferation of innate immune cells and other inflammatory cellular subpopulations (including myeloid cells such as macrophages or granulocytes) and resident cells (such as fibroblasts and endothelial cells), including: [1079] COPD, idiopathic pulmonary fibrosis, interstitial lung disease, sarcoidosis; [1080] Adult onset Still's disease, juvenile idiopathic arthritis, Systemic sclerosis, CREST syndrome where B cells and pathogen antibodies may also play a role; the Sweet syndrome; Takayasu arteritis, temporal arteritis/giant cell arteritis; [1081] Ulcerative cholangitis, inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis, primary sclerosing cholangitis.
[1082] Also of interest are diseases and disorders for which the mechanism remains poorly characterized but involves the activation and proliferation of T-cells, including: [1083] Alzheimer's disease, cardiovascular syndrome, type 2 diabetes, restenosis, chronic fatigue immune dysfunction syndrome (CFIDS). [1084] Autoimmune Lymphoproliferative disorders, including: [1085] Autoimmune Lymphoproliferative Syndrome and X-linked lymphoproliferative disease.
[1086] Suitably the disease or disorder is selected from: inflammatory skin diseases such as psoriasis or lichen planus; acute and/or chronic GVHD such as steroid resistant acute GVHD; acute lymphoproliferative syndrome; systemic lupus erythematosus, lupus nephritis or cutaneous lupus; or transplantation. In addition, the disease or disorder may be selected from myasthenia gravis, multiple sclerosis, and scleroderma/systemic sclerosis.
[1087] The compounds of formula (I) may be used in the treatment of cancer.
[1088] Thus, in one embodiment there is provided a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof, for use in the treatment of cancer.
[1089] Further, there is provided a method for treating cancer in a subject, by administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof.
[1090] Additionally provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof, in the manufacture of a medicament for the treatment of cancer in a subject.
[1091] Suitably the cancer is a haematological cancer, such as Acute myeloid leukemia, Angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet Syndrome, T-cell Non-Hodgkins lymphoma (including natural killer/T-cell lymphoma, adult T-cell leukaemia/lymphoma, enteropathy type T-cell lymphoma, hepatosplenic T-cell lymphoma and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell Non-Hodgkins lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, Follicular lymphoma, Mantle cell lymphoma, Marginal Zone lymphoma), Hairy Cell Leukemia, Hodgkin lymphoma, Lymphoblastic lymphoma, Lymphoplasmacytic lymphoma, Mucosa-associated lymphoid tissue lymphoma, Multiple myeloma, Myelodysplastic syndrome, Plasma cell myeloma, Primary mediastinal large B-cell lymphoma, chronic myeloproliferative disorders (such as chronic myeloid leukemia, primary myelofibrosis, essential thrombocytemia, polycytemia vera) or chronic lymphocytic leukemia.
[1092] Alternatively, the cancer is a non-haematological cancer, such as selected from the group consisting of bladder cancer, breast, melanoma, neuroblastoma, malignant pleural mesothelioma, and sarcoma.
[1093] In addition, compounds of formula (I) may be used in enhancing recovery from vascular injury or surgery and reducing morbidity and mortality associated with neointima and restenosis in a subject. For example, the compounds of formula (I) may be used in preventing, reducing, or inhibiting neointima formation. A medical device may be treated prior to insertion or implantation with an effective amount of a composition comprising a compound of formula (I) in order to prevent, reduce, or inhibit neointima formation following insertion or implantation of the device or graft into the subject. The device can be a device that is inserted into the subject transiently, or a device that is implanted permanently. In some embodiments, the device is a surgical device.
[1094] Examples of medical devices include, but are not limited to, needles, cannulas, catheters, shunts, balloons, and implants such as stents and valves.
[1095] Suitably the subject is a mammal, in particular the subject is a human.
[1096] Pharmaceutical Compositions
[1097] In the following section, reference to compounds of formula (I) encompasses compounds of formula (I-a), (I-b) and (I-c).
[1098] For use in therapy the compounds of the invention are usually administered as a pharmaceutical composition. The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof, and a pharmaceutically acceptable carrier or excipient.
[1099] In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof, for use in the treatment or prophylaxis of a disease or disorder as described herein.
[1100] In a further embodiment, there is provided a method for the prophylaxis or treatment of a disease or disorder as described herein, which comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof.
[1101] The invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof (e.g. salt) and/or derivative thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder as described herein.
[1102] The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates and/or derivatives thereof may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration, and the pharmaceutical compositions adapted accordingly.
[1103] The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates and/or derivatives thereof may be administered topically, for example to the eye, gut or skin. Thus, in an embodiment there is provided a pharmaceutical composition comprising a compound of the invention optionally in combination with one or more topically acceptable diluents or carriers.
[1104] A pharmaceutical composition of the invention may be delivered topically to the skin. Compositions suitable for transdermal administration include ointments, gels and patches. Such a pharmaceutical composition may also suitably be in the form of a cream, lotion, foam, powder, paste or tincture.
[1105] The pharmaceutical composition may suitably include vitamin D3 analogues (e.g. calcipotriol and maxacalcitol), steroids (e.g. fluticasone propionate, betamethasone valerate and clobetasol propionate), retinoids (e.g. tazarotene), coal tar and dithranol. Topical medicaments are often used in combination with each other (e.g. a vitamin D3 and a steroid) or with further agents such as salicylic acid.
[1106] A pharmaceutical composition of the invention may be delivered topically to the eye. Such a pharmaceutical composition may suitably be in the form of eye drops or an ointment.
[1107] A pharmaceutical composition of the invention may be delivered topically to the gut. Such a pharmaceutical composition may suitably be delivered orally, such as in the form of a tablet or a capsule, or rectally, such as in the form of a suppository.
[1108] Suitably, delayed release formulations are in the form of a capsule.
[1109] The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates and/or derivatives thereof which are active when given orally can be formulated as liquids or solids, e.g. as syrups, suspensions, emulsions, tablets, capsules or lozenges.
[1110] A liquid formulation will generally consist of a suspension or solution of the active ingredient (such as a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof) in a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
[1111] A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.
[1112] A composition in the form of a capsule can be prepared using routine encapsulation procedures, e.g. pellets containing the active ingredient (such as a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof) can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
[1113] Typical parenteral compositions consist of a solution or suspension of the active ingredient (such as a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof) in a sterile aqueous carrier or parenterally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
[1114] Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active ingredient in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas e.g. air, or an organic propellant such as a fluoro-chloro-hydrocarbon or hydrofluorocarbon. Aerosol dosage forms can also take the form of pump-atomisers.
[1115] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
[1116] Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
[1117] Suitably, the composition is in unit dose form such as a tablet, capsule or ampoule.
[1118] The composition may for example contain from 0.1% to 100% by weight, for example from 10 to 60% by weight, of the active material, depending on the method of administration. The composition may contain from 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration. The composition may contain from 0.05 mg to 2000 mg, for example from 1.0 mg to 500 mg, of the active material, depending on the method of administration. The composition may contain from 50 mg to 1000 mg, for example from 100 mg to 400 mg of the carrier, depending on the method of administration. The dose of the compound used in the treatment or prophylaxis of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 mg to 1000 mg, more suitably 1.0 mg to 500 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
[1119] The invention provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable, salt, solvate and/or derivative thereof (e.g. a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof) together with a further pharmaceutically acceptable active ingredient or ingredients.
[1120] The invention provides a compound of formula (I), for use in combination with a further pharmaceutically acceptable active ingredient or ingredients.
[1121] When the compounds are used in combination with other therapeutic agents, the compounds may be administered separately, sequentially or simultaneously by any convenient route.
[1122] Optimal combinations may depend on the disease or disorder. Possible combinations include those with one or more active agents selected from the list consisting of: 5-aminosalicylic acid, or a prodrug thereof (such as sulfasalazine, olsalazine or bisalazide); corticosteroids (e.g. prednisolone, methylprednisolone, or budesonide); immunosuppressants (e.g. cyclosporin, tacrolimus, sirolimus, methotrexate, azathioprine mycophenolate mofetil, leflunomide, cyclophosphamide, 6-mercaptopurine or anti-lymphocyte (or thymocyte) globulins); anti-TNF-alpha antibodies (e.g., infliximab, adalimumab, certolizumab pegol or golimumab); anti-IL12/IL23 antibodies (e.g., ustekinumab); anti-IL6 or anti-IL6R antibodies, anti-IL17 antibodies or small molecule IL12/IL23 inhibitors (e.g., apilimod); Anti-alpha-4-beta-7 antibodies (e.g., vedolizumab); MAdCAM-1 blockers (e.g., PF-00547659); antibodies against the cell adhesion molecule alpha-4-integrin (e.g., natalizumab); antibodies against the IL2 receptor alpha subunit (e.g., daclizumab or basiliximab); JAK inhibitors including JAK1 and JAK3 inhibitors (e.g., tofacitinib, baricitinib, R348); Syk inhibitors and prodrugs thereof (e.g., fostamatinib and R-406); Phosphodiesterase-4 inhibitors (e.g., tetomilast); HMPL-004; probiotics; Dersalazine; semapimod/CPSI-2364; and protein kinase C inhibitors (e.g. AEB-071).
[1123] For cancer, the further pharmaceutically acceptable active ingredient may be selected from anti-mitotic agents such as vinblastine, paclitaxel and docetaxel; alkylating agents, for example cisplatin, carboplatin, dacarbazine and cyclophosphamide; antimetabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea; intercalating agents for example adriamycin and bleomycin; topoisomerase inhibitors for example etoposide, topotecan and irinotecan; thymidylate synthase inhibitors for example raltitrexed; PI3 kinase inhibitors for example idelalisib; mTor inhibitors for example everolimus and temsirolimus; proteasome inhibitors for example bortezomib; histone deacetylase inhibitors for example panobinostat or vorinostat; and hedgehog pathway blockers such as vismodegib.
[1124] The further pharmaceutically acceptable active ingredient may be selected from tyrosine kinase inhibitors such as, for example, axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib and sunitinib.
[1125] Anticancer antibodies may be included in a combination therapy and may be selected from the group consisting of olaratumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtansine, pertuzumab, obinutuzumab, brentuximab, ofatumumab, panitumumab, catumaxomab, bevacizumab, cetuximab, tositumomab, traztuzumab, gentuzumab ozogamycin and rituximab.
[1126] Compounds or pharmaceutical compositions of the invention may also be used in combination with radiotherapy.
[1127] Some of the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. The individual components of combinations may also be administered separately, through the same or different routes.
[1128] When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
[1129] Medical Devices
[1130] In the following section, reference to compounds of formula (I) encompasses compounds of formula (I-a), (I-b) and (I-c).
[1131] In an embodiment, compounds of the invention or pharmaceutical compositions comprising said compounds may be formulated to permit incorporation into the medical device, thus providing application of the compound or composition directly to the site to prevent or treat conditions disclosed herein.
[1132] In an embodiment, the compounds of the invention or pharmaceutical composition thereof is formulated by including it within a coating onto the medical device. There are various coatings that can be utilized such as, for example, polymer coatings that can release the compound over a prescribed time period. The compound, or a pharmaceutical composition thereof, can be embedded directly within the medical device. In some embodiments, the compound is coated onto or within the device in a delivery vehicle such as a microparticle or liposome that facilitates its release and delivery. In some embodiments, the compound or pharmaceutical composition is miscible in the coating.
[1133] In some embodiments, the medical device is a vascular implant such as a stent. Stents are utilized in medicine to prevent or eliminate vascular restrictions. The implants may be inserted into a restricted vessel whereby the restricted vessel is widened. Excessive growth of the adjacent cells following vascular implantation results in a restriction of the vessel particularly at the ends of the implants which results in reduced effectiveness of the implants. If a vascular implant is inserted into a human artery for the elimination of for example an arteriosclerotic stenosis, intima hyperplasia can occur within a year at the ends of the vascular implant and results in renewed stenosis (“restenosis”).
[1134] Accordingly, in some embodiments, the stents are coated or loaded with a composition including a compound of the invention or pharmaceutical composition thereof and optionally a targeting signal, a delivery vehicle, or a combination thereof. Many stents are commercially available or otherwise know in the art.
[1135] In some embodiments, the stent is a drug-eluting stent. Various drug eluting stents that simultaneously deliver a therapeutic substance to the treatment site while providing artificial radial support to the wall tissue are known in the art. Endoluminal devices including stents are sometimes coated on their outer surfaces with a substance such as a drug releasing agent, growth factor, or the like. Stents have also been developed having a hollow tubular structure with holes or ports cut through the sidewall to allow drug elution from a central lumen. Although the hollow nature of the stent allows the central lumen to be loaded with a drug solution that is delivered via the parts or holes in the sidewall of the stent, the hollow tubular structure may not have suitable mechanical strength to provide adequate scaffolding in the vessel.
[1136] In some embodiments, the devices are also coated or impregnated with a compound of the invention, or pharmaceutical composition thereof and one or more additional therapeutic agents, including, but not limited to, antiplatelet agents, anticoagulant agents, anti-inflammatory agents, antimicrobial agents, antimetabolic agents, additional anti-neointima agents, additional antiproliferative agents, immunomodulators, antiproliferative agents, agents that affect migration and extracellular matrix production, agents that affect platelet deposition or formation of thrombis, and agents that promote vascular healing and re-endothelialization, such as those and others described in Sousa et al. (2003) and Salu et al. (2004).
[1137] Examples of antithrombin agents include, but are not limited to, Heparin (including low molecular heparin), R-Hirudin, Hirulog, Argatroban, Efegatran, Tick anticoagulant peptide, and Ppack.
[1138] Examples of antiproliferative agents include, but are not limited to, Paclitaxel (Taxol), QP-2 Vincristin, Methotrexat, Angiopeptin, Mitomycin, BCP 678, Antisense c-myc, ABT 578, Actinomycin-D, RestenASE, 1-Chlor-deoxyadenosin, PCNA Ribozym, and Celecoxib.
[1139] Examples of anti-restenosis agents include, but are not limited to, immunomodulators such as Sirolimus (Rapamycin), Tacrolimus, Biorest, Mizoribin, Cyclosporin, Interferon-γ Ib, Leflunomid, Tranilast, Corticosteroide, Mycophenolic acid and Biphosphonate.
[1140] Examples of anti-migratory agents and extracellular matrix modulators include, but are not limited to Halofuginone, Propyl-hydroxylase-Inhibitors, C-Proteinase-Inhibitors, MMP-Inhibitors, Batimastat, Probucol.
[1141] Examples of antiplatelet agents include, but are not limited to, heparin.
[1142] Examples of wound healing agents and endothelialization promoters include vascular epithelial growth factor (“VEGF”), 17-Estradiol, Tkase-Inhibitors, BCP 671, Statins, nitric oxide (“NO”)-Donors, and endothelial progenitor cell (“EPC”)-antibodies.
[1143] Besides coronary applications, drugs and active agents may be incorporated into the stent or stent coating for other indications. For example, in urological applications, antibiotic agents may be incorporated into the stent or stent coating for the prevention of infection. In gastroenterological and urological applications, active agents may be incorporated into the stent or stent coating for the local treatment of carcinoma. It may also be advantageous to incorporate in or on the stent a contrast agent, radiopaque markers, or other additives to allow the stent to be imaged in vivo for tracking, positioning, and other purposes. Such additives could be added to the absorbable composition used to make the stent or stent coating, or absorbed into, melted onto, or sprayed onto the surface of part or all of the stent. Preferred additives for this purpose include silver, iodine and iodine labelled compounds, barium sulfate, gadolinium oxide, bismuth derivatives, zirconium dioxide, cadmium, tungsten, gold tantalum, bismuth, platinum, iridium, and rhodium. These additives may be, but are not limited to, micro- or nano-sized particles or nano particles. Radio-opacity may be determined by fluoroscopy or by x-ray analysis.
[1144] A compound of the invention and one or more additional agents, or pharmaceutical composition thereof, can be incorporated into the stent, either by loading the compound and one or more additional agents, or pharmaceutical composition thereof into the absorbable material prior to processing, and/or coating the surface of the stent with the agent(s). The rate of release of agent may be controlled by a number of methods including varying the following: the ratio of the absorbable material to the compound and one or more additional agents, or pharmaceutical composition, the molecular weight of the absorbable material, the composition of the compound and one or more additional agents, or pharmaceutical composition, the composition of the absorbable polymer, the coating thickness, the number of coating layers and their relative thicknesses, and/or the compound and one or more additional agents, or pharmaceutical composition concentration. Top coats of polymers and other materials, including absorbable polymers, may also be applied to active agent coatings to control the rate of release. For example, P4HB can be applied as a top coat on a metallic stent coated with P4HB including an active agent to retard the release of the active agent.
[1145] The invention is further exemplified by the following non-limiting examples.
EXAMPLES
[1146] Abbreviations used herein are defined below. Any abbreviations not defined are intended to convey their generally accepted meaning.
Abbreviations
[1147] Ac acetyl (C(O)CH.sub.3) [1148] AcOH glacial acetic acid [1149] AlMe.sub.3 trimethylaluminium [1150] aq aqueous [1151] Ar Aromatic ring [1152] BEH ethylene bridged hybrid [1153] Bispin Bis(pinacolato)diboron; 4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi-1,3,2-dioxaborolane [1154] Bz benzyl (CH.sub.2-phenyl) [1155] Boc tert-butyloxycarbonyl protecting group [1156] Cs.sub.2CO.sub.3 Cesium carbonate [1157] CSH charged surface hybrid [1158] d doublet [1159] DABAL-Me.sub.3 adduct of trimethylaluminum and 1,4-diazabicyclo[2.2.2]octane [1160] DCM dichloromethane [1161] DIPEA N, N-diisopropylethylamine [1162] dioxane 1,4-dioxane [1163] DMAP 4-dimethylaminopyridine [1164] DME dimethoxyethane [1165] DMF N,N-dimethylformamide [1166] DMSO dimethyl sulfoxide [1167] DMP Dess-Martin Periodinane [1168] DPPA diphenylphosphoryl azide [1169] dppf 1,1′-bis(diphenylphosphino)ferrocene [1170] (ES.sup.+) electrospray ionisation, positive mode [1171] (ES.sup.−) electrospray ionisation, negative mode [1172] ESI electrospray ionisation [1173] Et ethyl [1174] EtI Ethyl iodide [1175] EtOAc ethyl acetate [1176] EtOH ethanol [1177] g grams [1178] Hal halogen [1179] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate [1180] HPLC high performance liquid chromatography [1181] hr(s) hour(s) [1182] IC.sub.50 50% inhibitory concentration [1183] iPr iso-propyl [1184] iPrMgCl iso-propyl magnesium chloride [1185] K.sub.2CO.sub.3 potassium carbonate [1186] LCMS liquid chromatography-mass spectrometry [1187] LiHMDS lithium hexamethyldisilazide [1188] LiOH lithium hydroxide [1189] (M+H).sup.+ protonated molecular ion [1190] (M−H).sup.− unprotonated molecular ion [1191] M molar concentration [1192] mCPBA Meta-chloroperoxybenzoic acid [1193] mL millilitre [1194] mm millimiter [1195] mmol millimole [1196] Me methyl [1197] MeCN acetonitrile [1198] MeI iodomethane [1199] MeOH methanol [1200] MesCl methanesulfonyl chloride [1201] MHz megahertz [1202] min(s) minute(s) [1203] MSD mass selective detector [1204] m/z mass-to-charge ratio [1205] N.sub.2 nitrogen gas [1206] NH.sub.3 ammonia [1207] NH.sub.4Cl ammonium chloride [1208] NaH sodium hydride [1209] NaHCO.sub.3 sodium bicarbonate [1210] NaBH(OAc).sub.3 Sodium triacetoxyborohydride [1211] nm nanometre [1212] NMR nuclear magnetic resonance (spectroscopy) [1213] NSFI N-fluorobenzenesulfonimide [1214] P4HB poly-4-hydroxybutyrate [1215] PDA photodiode array [1216] Pd 170 chloro(crotyl)(2-dicyclohexylphosphino-2′,4′,6′-triisopropybiphenyl)palladium(II) or XPhos Pd(crotyl)Cl [1217] Pd 174 allyl(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium(II) triflate or [tBuXPhosPd(allyl)]OTf [1218] [Pd(allyl)Cl.sub.2].sub.2 bis(allyl)dichlorodipalladium [1219] PdCl.sub.2(dppf) [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [1220] Pd(PPh.sub.3).sub.4 tetrakis(triphenylphosphine)palladium(0) [1221] PMB 4-methoxybenzyl [1222] prep HPLC preparative high performance liquid chromatography [1223] Ph phenyl [1224] pos/neg positive/negative [1225] q quartet [1226] RF/MS RapidFire Mass Spectrometry [1227] RT room temperature [1228] Rt retention time [1229] RP reverse phase [1230] s singlet [1231] S.sub.NAr nucleophilic aromatic substitution [1232] sat saturated [1233] SCX solid supported cation exchange (resin) [1234] Selectfluor N-chloromethyl-N′-fluorotriethylenediammonium bis(tetrafluoroborate) [1235] t triplet [1236] tBu tert-butyl [1237] T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide [1238] TBME tert-butyl methyl ether [1239] TFA Trifluoroacetic acid [1240] [t-BuXPhos Pd(allyl)]OTf allyl(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium(II) triflate [1241] THF tetrahydrofuran [1242] TMP 2,2,6,6-tetramethylpiperidinyl [1243] TMSOK potassium trimethylsilanolate [1244] TTIP titanium tetraisopropoxide [1245] UPLC ultra performance liquid chromatography [1246] UV ultraviolet [1247] v/v volume/volume [1248] VWD variable wave detector [1249] wt weight [1250] um micrometre [1251] uL microlitre [1252] ° C. degrees Celsius
General Procedures
[1253] All starting materials and solvents were obtained either from commercial sources or prepared according to the literature. Unless otherwise stated all reactions were stirred. Organic solutions were routinely dried over anhydrous magnesium sulfate. Hydrogenations were performed on a Thales H-cube flow reactor under the conditions stated.
[1254] Column chromatography was performed on pre-packed silica (230-400 mesh, 40-63 um) cartridges using the amount indicated. SCX was purchased from Supelco and treated with 1M hydrochloric acid prior to use. Unless stated otherwise the reaction mixture to be purified was first diluted with MeOH and made acidic with a few drops of AcOH. This solution was loaded directly onto the SCX and washed with MeOH. The desired material was then eluted by washing with 0.7 M NH.sub.3 in MeOH.
[1255] Preparative Reverse Phase High Performance Liquid Chromatography
[1256] Prep HPLC
[1257] Acidic Prep
[1258] Waters X-Select CSH column C18, 5 um (19×50 mm), flow rate 28 mL min.sup.−1 eluting with a H.sub.2O-MeCN gradient containing 0.1% v/v formic acid over 8.5 min using UV detection at 254 nm.
[1259] Basic Prep
[1260] Waters X-Bridge Prep column C18, 5 um (19×50 mm), flow rate 28 mL min.sup.−1 eluting with a 10 mM NH.sub.4HCO.sub.3-MeCN gradient over 6.5 min using UV detection at 254 nm.
[1261] Analytical Methods
[1262] Reverse Phase HPLC Conditions for the LCMS Analytical Methods
[1263] HPLC acidic: Acidic LCMS 4 minute (5-95%)
[1264] Analytical LCMS was carried out using a Waters X-Select CSH C18, 2.5 um, 4.6×30 mm column eluting with a gradient of 0.1% Formic acid in MeCN in 0.1% Formic acid in water. The gradient from 5-95% 0.1% Formic acid in MeCN occurs between 0.00-3.00 minutes at 2.5 mL/min with a flush from 3.01-3.5 minutes at 4.5 mL/min. A column re-equilibration to 5% MeCN is from 3.60-4.00 minutes at 2.5 mL/min. UV spectra of the eluted peaks were measured using an Agilent 1260 Infinity VWD at 254 nm. Mass spectra were measured using an Agilent 6120 MSD running with positive/negative switching.
[1265] HPLC basic: Basic LCMS 4 minute (5-95%)
[1266] Analytical LCMS was carried out using a Waters X-Select BEH C18, 2.5 um, 4.6×30 mm column eluting with a gradient of MeCN in aqueous 10 mM ammonium bicarbonate. The gradient from 5-95% MeCN occurs between 0.00-3.00 minutes at 2.5 mL/min with a flush from 3.01-3.5 minutes at 4.5 mL/min. A column re-equilibration to 5% MeCN is from 3.60-4.00 minutes at 2.5 mL/min. UV spectra of the eluted peaks were measured using an Agilent 1260 Infinity VWD at 254 nm. Mass spectra were measured using an Agilent 6120 MSD running with positive/negative switching.
[1267] Reverse Phase HPLC Conditions for the UPLC Analytical Methods
[1268] UPLC acidic: Acidic UPLC 3 minute
[1269] Analytical UPLC/MS was carried out using a Waters Acquity CSH C18, 1.7 um, 2.1×30 mm column eluting with a gradient of 0.1% Formic acid in MeCN in 0.1% Formic acid in water. The gradient is structured with a starting point of 5% MeCN held from 0.0-0.11 minutes. The gradient from 5-95% occurs between 0.11-2.15 minutes with a flush from 2.15-2.56 minutes. A column re-equilibration to 5% MeCN is from 2.56-2.83 minutes. UV spectra of the eluted peaks were measured using an Acquity PDA and mass spectra were recorded using an Acquity QDa detector with ESI pos/neg switching.
[1270] Acidic UPLC 2 Acidic UPLC 1 Minute
[1271] Analytical UPLC/MS was carried out using a Waters Acquity CSH C18, 1.7 um, 2.1×30 mm column eluting with a gradient of 0.1% Formic acid in MeCN in 0.1% Formic acid in water. The gradient is structured with a starting point of 5% MeCN held from 0.0-0.08 minutes. The gradient from 5-95% occurs between 0.08-0.70 minutes with a flush from 0.7-0.8 minutes. A column re-equilibration to 5% MeCN is from 0.8-0.9 minutes. UV spectra of the eluted peaks were measured using an Acquity PDA and mass spectra were recorded using an Acquity QDa detector with ESI pos/neg switching.
[1272] UPLC Basic: Basic UPLC 3 Minute
[1273] Analytical UPLC/MS was carried out using a Waters Acquity BEH C18, 1.7 um, 2.1×30 mm column eluting with a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate. The gradient is structured with a starting point of 5% MeCN held from 0.0-0.11 minutes. The gradient from 5-95% occurs between 0.11-2.15 minutes with a flush from 2.15-2.56 minutes. A column re-equilibration to 5% MeCN is from 2.56-2.83 minutes. UV spectra of the eluted peaks were measured using an Acquity PDA and mass spectra were recorded using an Acquity QDa detector with ESI pos/neg switching.
[1274] Basic UPLC 2 Basic UPLC 1 minute Analytical UPLC/MS was carried out using a Waters Acquity BEH C18, 1.7 um, 2.1×30 mm column eluting with a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate. The gradient is structured with a starting point of 5% MeCN held from 0.0-0.08 minutes. The gradient from 5-95% occurs between 0.08-0.70 minutes with a flush from 0.7-0.8 minutes. A column re-equilibration to 5% MeCN is from 0.8-0.9 minutes. UV spectra of the eluted peaks were measured using an Acquity PDA and mass spectra were recorded using an Acquity QDa detector with ESI pos/neg switching.
[1275] Column temperature is 40° C. in all runs. Injection volume is 3 uL and the flow rate is 0.77 mL/min.
[1276] PDA scan from 210-400 nm on all runs.
[1277] Normal Phase HPLC Conditions for the Chiral Analytical Methods
[1278] Chiral IC3 method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6×250 mm, 1.0 mL/min, 25-70% EtOH (0.2% TFA) in iso-hexane (0.2% TFA)
[1279] Chiral IC4 method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6×250 mm, 1.0 mL/min, 40% EtOH (0.2% TFA) in 4:1 heptane/chloroform (0.2% TFA).
[1280] Chiral IC5 method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6×250 mm, 1.0 mL/min, 20% EtOH (0.2% TFA) in iso-hexane (0.2% TFA).
[1281] Reverse Phase HPLC Conditions for the Chiral Analytical Methods
[1282] Chiral IC6 method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6×250 mm, 1.0 mL/min, 50% MeCN (0.1% formic acid) in water (0.1% formic acid).
[1283] Chiral IC7 method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6×250 mm, 1.0 mL/min, 5-95% MeCN (0.1% formic acid) in water (0.1% formic acid).
[1284] .sup.1H NMR Spectroscopy
[1285] .sup.1H NMR spectra were acquired on a Bruker Avance III spectrometer at 400 MHz or Bruker Avance III HD spectrometer at 500 MHz using residual undeuterated solvent as reference and unless specified otherwise were run in DMSO-d6.
Preparation of Intermediates
[1286] Known synthetic intermediates were procured from commercial sources or were obtained using published literature procedures. Additional intermediates were prepared by the representative synthetic processes described herein.
[1287] Compounds of Formula (I-a)—Intermediates
[1288] Any one of Methods 1-1q (referred to later herein) or A-N and Q-R may be used in the synthesis of the compounds of formula (I). For example, a scheme which is shown using a compound wherein X=N, Y=CR.sub.2 and Z=CR.sub.3 may also be used in the synthesis of compounds wherein X, Y and Z are as defined in the claims.
[1289] The synthesis of INTC1 to INTC179 and INTD1 to INTD86 is disclosed in at least one of WO02019/179852, VNO2019/180244 and VNO2020/083975, each of which is herein incorporated in its entirety by reference.
[1290] Method A: Decarboxylation of Chloro-Heterocycles Such as Chloro-Pyrimidines
##STR00094##
[1291] TFA (10 eq) was added dropwise to an ice-cooled, stirred solution of malonate derivative (1 eq) in DCM (15 volumes). The reaction vessel was stirred at RT for 18 hrs and then concentrated. The crude product was purified by normal phase chromatography.
[1292] Method B: Alkylation
##STR00095##
[1293] Base (2.5-5 eq) was added to an ice-cooled, stirred mixture of methyl 2-(2-chloropyrimidin-4-yl)acetate (1 eq) in appropriate polar aprotic solvent such as DMF or acetone (10 volumes). After 20 min, alkyl halide (1-5 eq) was added. The reaction vessel was stirred at 0° C. for 30 mins then at RT for 2 hrs. The reaction was quenched with NH.sub.4Cl (aq) or 1M HCl (aq), stirred for 20 mins then extracted with EtOAc. The organic phases were died (phase separator) and concentrated. The crude product was purified by normal phase chromatography.
[1294] Method C: Formation of Sulfonamides from Aromatic Halides
##STR00096##
[1295] 2-Chloropyrimidine intermediate (1 eq), sulfonamide (1.2 eq) and base (2 eq) were dissolved in dioxane (40 volumes). The mixture was degassed (N.sub.2, 5 mins) then catalyst (5 mol %) was added. The resulting mixture was heated under nitrogen at 90° C. for 2 hrs. The mixture was filtered, washing with EtOAc or DCM and the resulting filtrate was concentrated. The crude product was purified by normal phase chromatography or trituration using a suitable solvent.
[1296] Method D: Decarboxylation of Pyrimidines Bearing Sulfonamides
##STR00097##
[1297] TFA (10 eq) was added dropwise to an ice-cooled, stirred solution of malonate derivative (1 eq) in DCM (15 volumes). The reaction vessel was stirred at RT for 18 hrs and then concentrated. The crude product was purified by normal phase chromatography.
[1298] Method H: Benzylic Fluorination of Hetero-Aromatic Esters
##STR00098##
[1299] A solution of hetero-aromatic ester (1 eq) in THF (10 volumes) was cooled to −78° C. to which was added LiHMDS (1.25 eq 1M in THF). The reaction mixture was then warmed to RT for 1 hr. The solution was cooled to −78° C. and a solution (in THF) of, or solid, NSFI (1.25 eq) was added dropwise then warmed to RT for 2 hrs. The solution was diluted with sat NaHCO.sub.3 (aq) and the product was extracted into EtOAc. The crude product was purified by normal phase chromatography.
[1300] Method I: Buchwald Coupling—Sulfonylation
##STR00099##
[1301] 2-Bromopyridine intermediate (1 eq), sulfonamide (1.2 eq) and base (2 eq) were dissolved in dioxane (40 volumes). The mixture was degassed (N.sub.2, 5 mins) then catalyst (5 mol %) was added. The resulting mixture was heated under nitrogen at 90° C. for 2 hrs. The mixture was filtered, washing with EtOAc or DCM and the resulting filtrate was concentrated. The crude product was purified by normal phase chromatography.
[1302] Method J: Hydrolysis
##STR00100##
[1303] 2M LiOH (aq, 2 eq) was added into a solution of ester (1 eq) in MeOH (3 volumes) and THF (3 volumes) and the resulting reaction mixture was stirred at 50° C. for 2 hrs. The solvent was removed under reduced pressure and then was acidified with 1M HCl (aq) until pH 3. The solution was extracted with EtOAc, the organic phase was passed through a phase separator and the solvent was removed. The compound was used crude or purified by reverse phase chromatography.
Amine Intermediate Preparation
[1304] Method E: Suzuki Coupling of Halo Anilines with Heteroaromatic Boronates
##STR00101##
[1305] A solution of Ar1-X (1 eq) and Ar2-Z (1 eq) in solvent (3 volumes) and base (2.5 eq) was degassed (N.sub.2, 5 min) and heated to 40° C. whereupon Pd catalyst (3 mol %) was added and the reaction mixture further degassed (N.sub.2, 5 min) before being heated to 90° C. for 90 mins. The reaction mixture was allowed to cool to RT. In general, the desired compound was purified by column chromatography.
[1306] Method F: Suzuki Coupling of Heteroaromatic Halides with Aniline Boronates
##STR00102##
[1307] Pd catalyst (5 mol %) was added to a degassed (N.sub.2, 5 mins) solution of Ar1-X (1 eq), Ar2-Z (1 eq) and base (3 eq, 6.85 mmol) in solvent (3 volumes). The solution was then degassed further (N.sub.2, 5 mins) and then heated to 90° C. for 2 hrs then allowed to cool to RT. In general, the desired compound was purified by column chromatography.
[1308] Method G: Telescoped Boronate Formation and Suzuki Coupling
##STR00103##
[1309] Bispin (1.1 eq) and KOAc (4 eq) were added to Ar1-Hal (1 eq) in dioxane (5 volumes). The reaction was heated to 60° C. and degassed (N.sub.2, 5 mins). PdCl.sub.2(dppf) (5 mol %) was added to the reaction mixture and the temperature was increased to 90° C. for 1 hr. The reaction mixture was then cooled to RT and a solution of Ar2-Hal (1 eq) in dioxane (3 volumes) was added, followed by a solution of K.sub.2CO.sub.3 (4 eq) in water (2 volumes). The temperature was then increased to 90° C. for 18 hrs. The reaction was cooled to RT, an aqueous work up was performed and the crude compound was purified by normal phase chromatography.
[1310] Anilines
[1311] Method K: Suzuki Coupling
##STR00104##
[1312] A solution of boronic acid (1 eq), aryl halide (1.05 eq.) and Cs.sub.2CO.sub.3 (3 eq.) in a mixture of dioxane (40 volumes) and water (6 volumes) was degassed (N.sub.2, 5 mins). PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (5 mol %) was added and the reaction was further degassed (N.sub.2) before being heated to 90° C. for 18 hrs. The reaction mixture was filtered through celite before an aqueous workup was undertaken, followed by purification by normal phase chromatography.
[1313] Method L: Ester Deprotection with TFA
##STR00105##
[1314] A solution of the ester (1 eq) in DCM (20 volumes) was treated with TFA (10 eq.) and stirred at RT for 3 hrs. The reaction mixture was then concentrated and azeotroped with MeOH and MeCN. No further purification was undertaken.
[1315] Method M: Ester Deprotection with Base
##STR00106##
[1316] A solution of the ester (1 eq) in a mixture of THF/MeOH (4/1 volumes) was treated with LiOH (2.2-6 eq.) and stirred between RT and 50° C. for between 3 hrs and 18 hrs. The organic solvents were removed in vacuo then acidified with 1 M HCl and extracted with EtOAc. The organic phases were combined, dried (Na.sub.2SO.sub.4), filtered and concentrated. The products were used directly in the next step with no further purification undertaken.
[1317] Method N: Potassium Salt Formation
##STR00107##
[1318] A solution of the ester (1 eq.) in THF (4 volumes) was treated with TMSOK (1 eq.) and stirred at RT for 2 hrs before the reaction mixtures were filtered and washed with iso-hexanes. The products were used directly in the next step with no further purification undertaken.
[1319] Method P: SNAR using 4-chloro-2-(methylthio)-heterocycles
##STR00108##
[1320] A solution of hetero-aromatic chloride (1 eq) and ester (1 eq) in THF (5-20 volumes) was warmed to 30° C. to which was added UHMDS (1.25 eq 1-1.5M in THF). The reaction mixture was stirred at this temperature for up to 3 hrs, then was poured into water and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO.sub.4), filtered and the solvent removed in vacuo to afford the desired compound. If required, the crude product was purified by normal phase chromatography.
TABLE-US-00001 TABLE 1 The following intermediates were made according to Method P. Name/Structure Synthesis (All examples containing Method, [LCMS chiral centres are Method], m/z .sup.1H NMR Chemical Shift Data INTC racemates unless stated) (M + H).sup.+, (Rt/min) (DMSO-d6 unless stated) INTC186
Ethyl 4-(2-(methylthio)pyrimidin-4-yl)piperidine-4-carboxylate INTC191
[1321] ##STR00115##
[1322] To a solution of 1-tert-butyl 4-ethyl 4-(2-(methylthio)pyrimidin-4-yl)piperidine-1,4-dicarboxylate (4 g, 9.44 mmol) INTC187 in DCM (30 mL) at RT was added TFA (5 mL). The reaction mixture was stirred at RT for 1 hr. Additional TFA (5 mL) added and the reaction was stirred at RT for a further 1 hr. The reaction mixture was quenched by addition of NaHCO.sub.3 (aq, 100 mL), gas evolved, and was diluted with DCM (50 mL). The organics were isolated and dried (MgSO.sub.4), filtered and solvent removed in vacuo to afford ethyl 4-(2-(methylthio)pyrimidin-4-yl)piperidine-4-carboxylate (2.6 g, 9.15 mmol, 97% yield) as a brown oil. Rt 0.97 min (HPLC, acidic); m/z 282 (M+H).sup.+ (ES+); No NMR data collected.
Ethyl 1-(methylsulfonyl)-4-(2-(methylthio)pyrimidin-4-yl)piperidine-4-carboxylate INTC192
[1323] ##STR00116##
[1324] To a stirred solution of ethyl 4-(2-(methylthio)pyrimidin-4-yl)piperidine-4-carboxylate (1.3 g, 4.62 mmol) INTC191 in DCM (15 mL) at RT was added TEA (1.42 mL, 10.16 mmol) and then MesCl (0.37 mL, 5.08 mmol). After 1 hr, 1 M HCl (aq, 50 mL) and DCM (30 mL) were added. The organic layer was isolated by passage through a phase separation cartridge and then concentrated in vacuo to afford ethyl 1-(methylsulfonyl)-4-(2-(methylthio)pyrimidin-4-yl)piperidine-4-carboxylate (1.21 g, 3.37 mmol, 73% yield) as a brown oil. Rt 1.93 min (HPLC, acidic); m/z 360 (M+H).sup.+ (ES+); No NMR data collected.
[1325] Amide Formation
(4-(2-(Methylthio)pyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)methanol INTC197
[1326] ##STR00117##
[1327] LiCl (0.95 g, 22.4 mmol) followed by NaBH.sub.4 (0.85 g, 22.4 mmol) and EtOH (15 mL) was added into a stirring solution of methyl 4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxylate INTC178 (3 g, 11.2 mmol) in THF (15 mL). The resulting reaction mixture was stirred at RT for 18 hrs. The reaction mixture was acidified with 1M HCl (aq, 20 mL) and the volatiles were removed in vacuo. The residue was extracted with DCM (3×150 mL). The organic extract was dried (MgSO.sub.4), filtered and solvent removed in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-100% EA/iso-hexanes) to afford (4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)methanol (2.3 g, 9.09 mmol, 81% yield) as a colourless gum. Rt 0.80 min (UPLC acidic); m/z 241 (M+H).sup.+ (ES+). .sup.1H NMR (500 MHz, DMSO-d6) δ 8.54 (d, J=5.3 Hz, 1H), 7.23 (d, J=5.3 Hz, 1H), 4.73 (t, J=5.6 Hz, 1H), 3.74-3.67 (m, 2H), 3.49 (d, J=5.7 Hz, 2H), 3.35-3.27 (m, 2H), 2.50 (s, 3H), 2.19-2.10 (m, 2H), 1.77-1.67 (m, 2H).
4-(2-(Methylthio)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carbaldehyde INTC198
[1328] ##STR00118##
[1329] DMP (1.77 g, 4.16 mmol) was added portionwise into a stirring solution of (4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)methanol INTC197 (1 g, 4.16 mmol) in DCM (25 ml). The resulting reaction mixture was stirred at RT for 1 hr. The reaction mixture was poured into sat. NaHCO.sub.3 (aq, 100 mL) and extracted with DCM (3×100 mL). The organic extract was sequentially washed with saturated sat. NaHCO.sub.3 (aq, 100 mL), and brine (100 mL). The organic extract was dried (MgSO.sub.4), filtered and solvent in vacuo to afford 4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carbaldehyde (900 mg, 3.40 mmol, 82% yield) as a colorless oil. Rt 1.61 min (HPLC acidic); m/z 239 (M+H).sup.+ (ES.sup.+). .sup.1H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.65 (d, J=5.2 Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 3.68-3.59 (m, 2H), 3.56-3.48 (m, 2H), 2.51 (s, 3H), 2.28-2.20 (m, 2H), 2.16-2.09 (m, 2H).
4-(6-Ethoxypyrazin-2-yl)-N-((4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)methyl)aniline INTC199
[1330] ##STR00119##
[1331] NaBH(OAc).sub.3 (1.07 g, 5.04 mmol) was added into a suspension of 4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carbaldehyde INTC198 (400 mg, 1.68 mmol) and 4-(6-ethoxypyrazin-2-yl)aniline INTD18 (542 mg, 2.52 mmol) in DCM (10 ml) and the resulting reaction mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was diluted with DCM (100 mL) and sequentially washed with sat. NaHCO.sub.3 (aq, 2×100 mL) and brine (100 mL), dried (MgSO.sub.4), filtered and solvent removed in vacuo. The crude product was purified by chromatography on silica gel (25 g cartridge, 0-100% EtOAc/iso-hexanes) to afford 4-(6-ethoxypyrazin-2-yl)-N-((4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)methyl)aniline (312 mg, 0.706 mmol, 42% yield) as a yellow gum. Rt 2.49 min (HPLC acidic); m/z 438 (M+H).sup.+ (ES.sup.+). .sup.1H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 7.99 (s, 1H), 7.81-7.74 (m, 2H), 7.29 (d, J=5.3 Hz, 1H), 6.66-6.57 (m, 2H), 6.00 (t, J=6.6 Hz, 1H), 4.42 (q, J=7.0 Hz, 2H), 3.80-3.70 (m, 2H), 3.38 (d, J=6.6 Hz, 2H), 3.32-3.26 (m, 2H), 2.52 (s, 3H), 2.32-2.26 (m, 2H), 1.89-1.80 (m, 2H), 1.38 (t, J=7.0 Hz, 3H).
[1332] Method Q: Oxidation of Thioethers to Sulfones or Sulfoxides
##STR00120##
[1333] mCPBA (2.2 eq) was portionwise to a stirred solution of thiother (1 eq) in DCM (20-50 volumes) maintaining the internal temperature at RT. The resulting mixture was stirred at RT for a further 3 hrs. The reaction mixture was poured into sat aq. Na.sub.2SO.sub.3 and extracted with DCM. The organic extract was sequentially washed with sat aq. NaHCO.sub.3 and brine, dried (MgSO.sub.4), filtered and solvent removed in vacuo to afford the desire compound.
TABLE-US-00002 TABLE 2 The following intermediates were made according to Method Q. Synthesis Method, Name/Structure [LCMS (All examples containing chiral Method], m/z centres are racemates unless (M + H).sup.+, .sup.1H NMR Chemical Shift Data INTC stated) (Rt/min) (DMSO-d6 unless stated) INTC203
[1334] Method R: Formation of Sulfonamides from Aromatic Sulfones
##STR00128##
[1335] To a solution of sulfone (1.0 eq) and primary sulfonamide (1.1-2.0 eq) in polar aprotic solvent such as NMP (5-100 volumes) was added an inorganic base (3 eq) such as cesium carbonate and heated to 40-90° C. for 1-3 hrs. The reaction mixture was cooled to RT and diluted with water (50-100 volumes) and the mixture was washed with MTBE (100 volumes) and the aqueous was slowly acidified to pH 5 or lower using an appropriate acid such as HCl. The resulting precipitate was filtered to afford desired sulfonamide product.
TABLE-US-00003 TABLE 3 The following intermediates were made according to Method R. Synthesis Method, [LCMS Method], .sup.1H NMR Chemical Shift Name/Structure m/z Data (All examples containing chiral (M + H).sup.+, (DMSO-d6 unless Base, INTC centres are racemates unless stated) (Rt/min) stated) Solvent INTC214
N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)piperidine-4-carboxamide hydrochloride INTC235
[1336] ##STR00136##
[1337] This compound was prepared by Boc-deprotection with HCl of INTC234, [HPLC acidic], 513, (2.72).
4-(6-(Cydopropanesulfonamido) pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide hydrochloride INTC240
[1338] ##STR00137##
[1339] This compound was prepared by Boc-deprotection with HCl of INTC239, [UPLC Acidic], 525, (0.83); .sup.1H NMR (DMSO-d6) 11.18 (s, 1H), 10.39 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.94-8.73 (m, 3H), 8.52 (dd, J=8.8, 2.4 Hz, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.23 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 4.47 (q, J=7.0 Hz, 2H), 3.37-3.22 (m, 2H), 3.15-3.11 (m, 3H), 2.74-2.68 (m, 2H), 2.43-2.40 (m, 2H), 1.39 (t, J=7.0 Hz, 3H), 1.09-1.03 (m, 2H), 0.91-0.82 (m, 2H).
4-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide hydrochloride INTC245
[1340] ##STR00138##
[1341] This compound was prepared by Boc-deprotection with HCl of INTC244, [HPLC Acidic], 521, (1.30); .sup.1H NMR (DMSO-d6) 11.42 (s, 1H), 10.23 (s, 1H), 9.03-8.96 (m, 2H), 8.89-8.70 (m, 2H), 8.63-8.57 (m, 2H), 8.52-8.48 (m, 1H), 8.21 (d, J=8.8 Hz, 1H), 6.89 (d, J=5.7 Hz, 1H), 3.29-3.07 (m, 5H), 2.53 (s, 2H), 2.29-2.22 (m, 1H), 1.13-1.06 (m, 6H), 0.95-0.89 (m, 2H). 2H not observed potentially obscured broad H.sub.2O peak.
4-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide hydrochloride INTC247
[1342] ##STR00139##
[1343] This compound was prepared by Boc-deprotection with HCl of INTC246, [HPLC Acidic], 521, (1.30).
[1344] Method 13: t-BuOK Mediated Amide Coupling from Ester
##STR00140##
[1345] A stirred solution of ester (1.0 eq) and amine (1.1 eq) in THF (10-50 volumes) and DMSO (5 volumes) was cooled to 0° C. under an inert atmosphere. To the reaction mixture was added a solution of f-BuOK (3.3 eq) as a solution THF (10-50 volumes) over 15-80 mins. After addition was complete the reaction was warmed to RT for 1 hr. Reaction was quenched by the addition of aqueous acid either acetic acid or dilute HCl (1 M) until acidic pH was achieved. The reaction was diluted with water and extracted with EtOAc. The organics were combined, dried (phase separator) and concentrated in vacuo. The crude product was purified by reverse or normal phase chromatography or a combination of both.
TABLE-US-00004 Synthesis .sup.1H NMR Chemical Shift Name/Structure Method, [LCMS Data (All examples containing chiral centres Method], m/z (DMSO-d6 unless INTC are racemates unless stated) (M + H).sup.+, (RT/Min) stated) INTC232
(4-(6-Ethoxypyrazin-2-yl)-2-fluorophenyl)methanol INTD87
[1346] ##STR00142##
[1347] Prepared as for INTD84 using (4-bromo-2-fluorophenyl)methanol (205 mg, 1.00 mmol) and 2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine (250 mg, 1.00 mmol) to afford (4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)methanol (260 mg, 0.995 mmol, quantitative yield) was isolated as a yellow gum. Rt 1.25 min (UPLC, acidic); m/z 249 (M+H).sup.+(ES.sup.+); .sup.1H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.26 (s, 1H), 7.99 (dd, J=8.0, 1.7 Hz, 1H), 7.91 (dd, J=11.6, 1.7 Hz, 1H), 7.66-7.57 (m, 1H), 5.37 (t, J=5.8 Hz, 1H), 4.62 (d, J=5.8 Hz, 2H), 4.49 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H).
4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzaldehyde INTD88
[1348] ##STR00143##
[1349] Prepared as for INTD85 using (4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)methanol INTD87 (1.00 g, 4.03 mmol) to afford 4-(6-ethoxypyrazin-2-yl)-2-fluorobenzaldehyde (448 mg, 1.78 mmol, 44% yield) as a colourless solid. Rt 0.67 min (UPLC 2, acidic); m/z 247 (M+H).sup.+(ES.sup.+); .sup.1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.98 (s, 1H), 8.37 (s, 1H), 8.22-8.13 (m, 2H), 7.99 (dd, J=8.3, 7.3 Hz, 1H), 4.52 (q, J=7.0 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H).
[1350] Compounds of Formula (I-a)—Examples
[1351] The synthesis of a number of known CTPS1 inhibitors is disclosed in WO2019/179652, WO2019/180244 and WO2020/083975 (see compounds P1 to P225). Such compounds are made using general methods disclosed herein and represent further examples of compounds which are CTPS1 inhibitors. The full synthetic methods and characterising data for compounds P1 to P225 are provided in WO2019/179652, WO2019/180244 and WO2020/083975, each of which is herein incorporated in its entirety by reference.
[1352] Amide Formation
[1353] Method 1: Amide Coupling Using HATU
##STR00144##
[1354] To a stirred suspension of the acid or the potassium salt (1 eq, X=H or K) and DIPEA (6 eq) in DMF (15 vol) the aniline (1 eq) and HATU (1.5 eq) were added. The reaction was stirred at RT for 18 hrs then concentrated in vacuo. MeOH and 2M NaOH (aq) were added. The mixture was stirred for 30 min then concentrated in vacuo. The aqueous phase acidified to pH 6 with 1M HCl (aq) and the product extracted into DCM. The organics were combined, dried (phase separator) and concentrated in vacuo.
[1355] The crude product was purified by reverse or normal phase chromatography or a combination of both.
N-(4-(5-Chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide P1
[1356] ##STR00145##
[1357] Method 2: AlMe.sub.3 Mediated Amide Coupling from Ester
##STR00146##
[1358] To an ice cooled solution of aniline (2 eq) in toluene (40 volumes) was added AlMe.sub.3 (2.0 M in heptane, 2 eq). The mixture was stirred at this temperature for 5 mins then at RT for 10 mins. To this solution was added ester (1 eq) in one portion and the resultant mixture heated and stirred at 80° C. for 2 hrs. The reaction mixture was cooled in an ice bath and carefully quenched with MeOH (10 volumes). After stirring for 20 mins the mixture was diluted in a mixture of DCM/MeOH (10 volumes), filtered through celite and the filtrate concentrated. The crude product was purified by reverse or normal phase chromatography.
1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)cyclopentanecarboxamide P2
[1359] ##STR00147##
2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)-2-methylpropanamide P3
[1360] ##STR00148##
2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)propanamide P4
[1361] ##STR00149##
2-Methyl-N-(2-methyl-4-(6-methylpyrazin-2-yl)phenyl)-2-(2-(methylsulfonamido)pyrimidin-4-yl)propanamide P5
[1362] ##STR00150##
[1363] Method 2b: DABALMe.sub.3 Mediated Amide Coupling from Ester
##STR00151##
[1364] To a solution of ester (1 eq) and aniline (1.5 eq) in toluene (30 volumes) was added DABAL-Me.sub.3 (1.5 eq) and the resulting mixture was heated at 100° C. for 4 h. The reaction mixture was cooled to 0° C. and quenched by careful addition of 1 M HCl (aq, 20 volumes). The aqueous phase was extracted with EtOAc (3×20 volumes). The combined organics were washed with 1 M HCl (aq, 2×10 volumes), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by reverse or normal phase chromatography.
[1365] Method 3: Amide Coupling from Potassium Salt Using T3P
##STR00152##
[1366] Pyridine (10 eq) followed by T3P (50 wt % in DMF, 2 eq) was added to a stirring solution of amine (1.1 eq) and potassium 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanoate (1 eq) in DMF (16 volumes). The resulting reaction was stirred at RT for 24 hrs. The crude reaction mixture was concentrated in vacuo then diluted with NH.sub.4Cl (sat. aq) and extracted with DCM. The combined organic extracts were dried (phase separator) and the solvent removed. The crude product was purified by reverse or normal phase chromatography.
2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(pyrazin-2-yl)phenyl)butanamide P6
[1367] ##STR00153##
2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)butanamide P7
[1368] ##STR00154##
2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide P8
[1369] ##STR00155##
[1370] Method 4: Amide Coupling from Lithium Salt Using T3P
N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-yl)butanamide INTC51
[1371] ##STR00156##
[1372] Method 5: NH-Amide Formation Via Amide Deprotection and/or Decarboxylation
##STR00157##
[1373] To a solution of the protected amide in DCM a mixture of TFA (88 eq) and triflic acid (1-6 eq) was added and the mixture left stirring at RT for 18-36 hrs and then concentrated in vacuo. The crude product was purified by column chromatography on silica gel or by RP chromatography.
[1374] Method 6: Deprotection of Sulfonamide
##STR00158##
[1375] Method 7: Sulfonylation from Aromatic Chloride
##STR00159##
[1376] 2-Chloro-heteroaromatic intermediate (1 eq), sulfonamide (1.2 eq) and base (2 eq) were dissolved in dioxane (40 volumes). The mixture was degassed (evacuated and backfilled with N.sub.2×3) then catalyst (10 mol %) was added. The resulting mixture was heated under nitrogen at 90° C. for 2 hrs. The mixture was cooled to RT, diluted with sat. NH.sub.4Cl (aq, 80 volumes) and DCM (80 volumes). The phases were separated and the aqueous was extracted with further DCM (2×80 volumes). The combined organics were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by normal phase chromatography or trituration using a suitable solvent.
[1377] Method 8: Amide Coupling Using 1-chloro-N,N,2-trimethylprop-1-en-1-amine
##STR00160##
[1378] 1-Chloro-N,N,2-trimethylprop-1-en-1-amine (2 eq) was added to a solution of carboxylic acid (1 eq) in DCM (20 volumes). The reaction mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated in vacuo and the residue redissolved in DCM (20 volumes) before addition of pyridine (2 mL) followed by addition of the appropriate amine (1.1 eq). The reaction mixture was stirred at RT for 2 hrs. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.
[1379] Method 9: Suzuki ArBr
##STR00161##
[1380] To a suspension of Ar1-Br (1 eq) in dioxane (10 volumes) was added arylboronic acid or ester (1 eq) and a solution of K.sub.2CO.sub.3 (2 eq) in water (5 volumes). The resulting suspension was degassed (N.sub.2, 5 mins). PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct or other appropriate catalyst (10 mol %) was added and the reaction mixture was stirred at 80° C. for 2 hrs. The reaction mixture was then cooled to RT. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.
[1381] Method 10: T3P with Free Acid
##STR00162##
[1382] Pyridine (10 eq) followed by T3P (50 wt % in DMF, 2 eq) was added to a stirring solution of amine (1.1 eq) and carboxylic acid (1 eq) in DMF (16 volumes). The resulting reaction was stirred at RT for 24 hrs. The crude reaction mixture was concentrated in vacuo then diluted with NH.sub.4Cl (sat. aq) and extracted with DCM. The combined organic extracts were dried (phase separator) and the solvent removed. The crude product was purified by reverse or normal phase chromatography.
TABLE-US-00005 TABLE 4 Compounds P9-P115, P117-P225 Name/Structure (All examples containing chiral centres are racemates unless P stated) P9 2-(2- (cyclopropanesulfonamido)pyrimidin- 4-yl)-N-(5-(6-isopropoxypyrazin-2- yl)pyridin-2-yl)-2-methylpropanamide
2-(2-(Cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-isopropylpyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide P116
[1383] ##STR00378##
[1384] A solution of 2-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(5-(6-(prop-1-en-2-yl)pyrazin-2-yl)pyridin-2-yl)propanamide P122 (77 mg, 0.161 mmol) in MeOH/DCM (4:1, 10 mL) was hydrogenated using the H-Cube flow hydrogenation apparatus (10% Pd/C, 30×4 mm, Full hydrogen, 25° C., 1 mL/min). The crude product was purified by chromatography on silica gel (12 g column, 50-100% EtOAc/iso-hexane) to afford 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-isopropylpyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide (21 mg, 0.043 mmol, 27% yield) as a white solid. Rt 2.22 mins (HPLC acidic); m/z 482 (M+H).sup.+ (ES.sup.+); .sup.1H NMR (500 MHz, DMSO-d6) δ 11.23 (s, 1H), 10.15 (s, 1H), 9.10 (s, 1H), 9.03 (dd, J=2.4, 0.8 Hz, 1H), 8.59 (d, J=5.3 Hz, 1H), 8.56 (s, 1H), 8.52 (dd, J=8.8, 2.5 Hz, 1H), 8.21 (dd, J=8.8, 0.8 Hz, 1H), 7.19 (d, J=5.3 Hz, 1H), 3.23-3.10 (m, 2H), 1.61 (s, 6H), 1.32 (d, J=6.9 Hz, 6H), 1.04-0.97 (m, 2H), 0.80-0.72 (m, 2H).
[1385] The following compounds were prepared using the methods described herein and below. Numbering of certain intermediates refers either to intermediates disclosed herein, or intermediates disclosed in WO02019/179852, WO2019/180244 and/or WO2020/083975.
1-(2-(Cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-oxocyclohexanecarboxamide P226
[1386] ##STR00379##
[1387] A solution of HCl (1N in water) (17.19 mL, 17.19 mmol) was added into a stirring solution of 8-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide P244 (1.0 g, 1.72 mmol) in THF (30 mL). The resulting reaction mixture was stirred at 30° C. for 14 days. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (100 mL) and brine (100 mL). The organic extract was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/iso-hexanes) to afford 1-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-oxocyclohexanecarboxamide (414 mg, 0.762 mmol, 44% yield) as a white solid. Rt 2.03 min (HPLC acidic); m/z 538 (M+H).sup.+(ES.sup.+). .sup.1H NMR (500 MHz, DMSO-d6) δ 11.32 (s, 1H), 10.33 (s, 1H), 9.03 (d, J=2.5 Hz, 1H), 8.85 (s, 1H), 8.64 (d, J=5.3 Hz, 1H), 8.51 (dd, J=8.8, 2.5 Hz, 1H), 8.31-8.20 (m, 2H), 7.30 (d, J=5.3 Hz, 1H), 4.48 (q, J=7.0 Hz, 2H), 3.28-3.21 (m, 1H), 2.78-2.68 (m, 2H), 2.60-2.41 (m, 4H (obscured by DMSO)), 2.39-2.32 (m, 2H), 1.40 (t, J=7.0 Hz, 3H), 110-1.02 (m, 2H), 0.92-0.82 (m, 2H).
1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexane-1-carboxamide
[1388] ##STR00380##
[1389] NaBH.sub.4 (10.6 mg, 0.28 mmol) was added into a stirring suspension of 1-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-oxocyclohexanecarboxamide P226 (100 mg, 0.186 mmol) in EtOH (20 mL) and stirred at RT for 3 hrs. The reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on RP Flash C18 (24 g column, 0-100% MeCN/Water 0.1% formic acid) to afford two diastereoisomers of the title compound.
[1390] P227—First Eluting Peak from Column
[1391] 1-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide (26 mg, 0.048 mmol, 26% yield) as a white solid. Rt 1.85 min (HPLC, acidic); m/z 540 (M+H).sup.+ (ES.sup.+); .sup.1H NMR (500 MHz, DMSO-d6) δ 11.24 (s, 1H), 10.05 (s, 1H), 9.06-8.98 (m, 1H), 8.85 (s, 1H), 8.57 (d, J=5.3 Hz, 1H), 8.51 (dd, J=8.8, 2.5 Hz, 1H), 8.26 (s, 1H), 8.23-8.20 (m, 1H), 7.19 (d, J=5.3 Hz, 1H), 4.58 (d, J=4.7 Hz, 1H), 4.48 (q, J=7.0 Hz, 2H), 3.56-3.45 (m, 1H), 3.29-3.22 (m, 1H), 2.60 (d, J=13.6 Hz, 2H), 1.91-1.77 (m, 4H), 1.52-1.37 (m, 5H), 1.07-0.99 (m, 2H), 0.88-0.78 (m, 2H).
[1392] P228—Second Eluting Peak from Column
[1393] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide (23 mg, 0.042 mmol, 22% yield) as a white solid. Rt 1.95 min (HPLC, acidic); m/z 540 (M+H).sup.+(ES.sup.+); .sup.1H NMR (500 MHz, DMSO-d6) δ 11.31 (s, 1H), 9.75 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.83 (s, 1H), 8.62 (s, 1H), 8.48 (dd, J=8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.29 (s, 1H), 4.51-4.44 (m, 3H), 3.70-3.62 (m, 1H), 3.29-3.20 (m, 1H), 2.22-2.11 (m, 2H), 1.80-1.68 (m, 2H), 1.41-1.29 (m, 7H), 1.11-1.05 (m, 2H), 0.96-0.88 (m, 2H).
1-(2-(Cydopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide
[1394] ##STR00381##
[1395] NaH(BOAc).sub.3 (118 mg, 0.558 mmol) was added into a suspension of 1-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-oxocyclohexanecarboxamide (100 mg, 0.186 mmol) P226 and dimethylamine (2M in THF) (0.93 mL, 1.86 mmol) in DCM (10 mL) and the resulting reaction mixture was stirred at RT for 18 hrs. The reaction mixture was concentrated in vacuo and the crude product was purified by preparative HPLC (Acidic prep method (5-95% MeCN in water) to afford two diastereoisomers of the title compound.
[1396] P229—First Eluting Peak from Prep HPLC
[1397] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (22 mg, 0.037 mmol, 20% yield) as a white solid. Rt 1.40 min (HPLC, acidic); m/z 567 (M+H).sup.+(ES.sup.+); .sup.1H NMR (500 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.84 (s, 1H), 8.60-8.44 (m, 2H), 8.25 (s, 1H), 8.22-8.20 (m, 2H), 7.09 (d, J=5.3 Hz, 1H), 4.48 (q, J=7.0 Hz, 2H), 3.28-3.20 (m, 1H), 2.72 (d, J=13.4 Hz, 2H), 2.32 (s, 6H), 2.25 (s, 1H), 1.91 (d, J=12.3 Hz, 2H), 1.79 (t, J=12.6 Hz, 2H), 1.51 (q, J=12.2 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H), 1.03-0.98 (m, 2H), 0.87-0.73 (m, 2H).
[1398] P230—Second Eluting Peak from Prep HPLC
[1399] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (26 mg, 0.045 mmol, 24% yield) as a white solid. Rt 1.48 min (HPLC, acidic); m/z 567 (M+H).sup.+(ES.sup.+); .sup.1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.83 (s, 1H), 8.55 (d, J=5.2 Hz, 1H), 8.48 (dd, J=8.8, 2.4 Hz, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.19 (d, J=5.3 Hz, 1H), 4.47 (q, J=7.0 Hz, 2H), 3.25-3.18 (m, 1H), 2.78-2.67 (m, 2H), 2.48-2.39 (m, 1H), 2.26 (s, 6H), 2.02 (t, J=12.4 Hz, 2H), 1.87-1.77 (m, 2H), 1.42-1.29 (m, 5H), 1.07-1.00 (m, 2H), 0.97-0.85 (m, 2H).
[1400] Method 11: i-PrMgCl mediated amide coupling from ester
##STR00382##
[1401] To an ice cooled solution of aniline (1.1 eq) in THF (10-50 volumes) was added i-PrMgCl (2.0 M in THF, 2.0 eq) dropwise over 5-15 mins to maintain an internal temperature of less than 10° C. The reaction mixture was warmed to RT over 45 mins, then a solution of ester (1.0 eq) in THF (5-20 volumes) was added dropwise over 5-15 min. The reaction mixture was stirred at ambient temperature for 5-15 mins then further i-PrMgCl (2.0 M in THF, 2.0 eq) was added dropwise over 5-20 min. The reaction mixture was stirred at RT for 30 mins and then the solution was slowly poured into 1M HCl (aq) and extracted with EtOAc. The organics were combined, dried (phase separator) and concentrated in vacuo. The crude product was purified by reverse or normal phase chromatography or a combination of both.
[1402] Reductive Amination General Method:
[1403] Method 12: Reductive Amination
##STR00383##
[1404] To a suspension of aldehyde (1.5 eq) and amine (HCl salt can be used, 1.0 eq) in an organic solvent such as DCM (2-10 volumes) was added AcOH (1.0 eq) at RT and stirred for up to 1 hr. NaBH(OAc).sub.3 (1-2 eq) was then added and stirring continued for up to 24 hrs and monitored by LCMS. On completion 1% NH.sub.3 in MeOH (10 volumes) was added and the volatiles removed in vacuo. The crude product was purified by reverse or normal phase chromatography or a combination of both.
N-(4-(1-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propyl)pyrimidin-2-yl)cyclopropanesulfonamide P235
[1405] ##STR00384##
[1406] A suspension of 4-(6-ethoxypyrazin-2-yl)-2-fluorobenzaldehyde INTD88 (259 mg, 1.05 mmol) and N-(4-(1-aminopropyl)pyrimidin-2-yl)cyclopropanesulfonamide INTC162 (300 mg, 1.05 mmol) in DCM (2 mL) was treated with AcOH (0.065 mL, 1.14 mmol) and stirred for 15 mins then NaBH(OAc).sub.3 (223 mg, 1.06 mmol) was added and the reaction mixture was stirred at RT for 3 hrs. To the reaction mixture was added 1% NH.sub.3 in MeOH (2 mL) and the volatiles were removed in vacuo. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 15-70% MeCN/10 mM ammonium bicarbonate). The crude material was purified by capture and release on SCX (1 g) eluting with MeOH (20 mL) then removing product with 1% NH.sub.3 in MeOH (30 mL). The crude material was finally purified a second time by chromatography on RP Flash C18 (12 g cartridge, 10-50% MeCN/10 mM Ammonium Bicarbonate) to afford N-(4-(1-((4-(6-ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propyl)pyrimidin-2-yl)cyclopropanesulfonamide (20 mg, 0.031 mmol, 3% yield) as a yellow gum. Rt 2.02 min (HPLC, basic); m/z 487 (M+H).sup.+(ES.sup.+); .sup.1H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.27-8.26 (m, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.87 (d, J=11.4 Hz, 1H), 7.67-7.58 (m, 1H), 7.23 (d, J=5.1 Hz, 1H), 5.38 (t, J=5.7 Hz, 1H), 4.62 (d, J=5.8 Hz, 2H), 4.49 (q, J=7.1 Hz, 2H), 3.52-3.50 (m, 1H), 1.71-1.67 (m, 2H), 1.41 (t, J=7.0 Hz, 3H), 1.13-1.09 (m, 2H), 1.04-1.01 (m, 2H), 0.84 (t, J=7.4 Hz, 3H). Two exchangeable protons not observed.
TABLE-US-00006 TABLE 5 Preparation methods and characterisation data of certain intermediates and examples P242 onwards Synthesis Method, [LCMS Method], .sup.1H NMR Chemical Shift INTC# m/z (M + H).sup.+, Data (DMSO-d6 unless or P# Name/Structure (All examples containing chiral centres are racemates unless stated) (Rt/Min) stated) INTC 246
[1407] Compounds of Formula (I-b)—Intermediates
[1408] The synthesis of intermediates INTA1 to INTA117 and INTB1 to INTB120 is disclosed in WO2019/106156, which is herein incorporated in its entirety by reference, and uses the general methods shown below.
[1409] Method A: Formation of Thiazole Amines from Ketoesters
##STR00429##
[1410] To a solution of ketoester (1 eq) in an alcoholic solvent such as MeOH or EtOH (1 volume) at 0° C. was added bromine (1.5 eq) dropwise over 10 mins. The reaction was stirred at 0° C. for 10 mins. The reaction mixture was then heated at 30° C. for 2 hrs. After cooling to RT the reaction mixture was diluted with water. The product was extracted using an appropriate solvent such as EtOAc. The combined organics were dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The resulting compound was dissolved in alcoholic solvent such as MeOH or EtOH (1 volume) and thiourea (1 eq) was added. The reaction mixture was heated at 40° C. for 1 hr, then stirred at RT for 18 hrs. The reaction mixture was concentrated in vacuo and purified by normal phase chromatography or via trituration with an appropriate solvent.
[1411] Method B: Formation of Sulfonamides from Sulfonyl Chlorides
##STR00430##
[1412] A solution of amine (1.0 eq) and appropriate sulfonyl chloride (1.1 eq) in pyridine (3M volumes) was warmed to 40° C. and stirred for 18 hrs. The reaction mixture was purified by normal or reverse phase chromatography or via trituration with an appropriate solvent.
[1413] Method C: Formation of Sulfonamides from Heterocyclic Halides
##STR00431##
[1414] A suspension of (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.2 eq), bromothiazole intermediate (1 eq), alkylsulfonamide (1 eq), and K.sub.2CO.sub.3 (1.1 eq) in dioxane (10 volumes) at 40° C. was degassed (N.sub.2, 5 mins) then copper(I) iodide (0.1 equiv.) was added. The solution was again degassed (N.sub.2, 5 mins) before being warmed to 80° C. The reaction was progressed for 2 hrs before being allowed to cool to RT. 1M HCl (aq) was added and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude material was purified by normal phase chromatography.
[1415] Method D: Formation of Acids from Esters
##STR00432##
[1416] To a solution of ester (1.0 eq.) in THF/MeOH (2:1) was added a solution of appropriate base (2.0 eq. of LiOH or NaOH aq solutions at 1-2M). The reaction was stirred at RT or with heating up to 50° C. The reaction was concentrated in vacuo to half volume and was acidified with 1M HCl. The product was extracted using an appropriate organic solvent (EtOAc). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give the desired compound.
[1417] Aniline Intermediate Preparation
[1418] Method E: Suzuki Coupling of Halo Anilines with Heteroaromatic Boronates
##STR00433##
[1419] A solution of Ar1-X (1 eq) and Ar2-Z (1 eq) in solvent (3 volumes) and base (2.5 eq) was degassed (N.sub.2, 5 min) and heated to 40° C. whereupon Pd catalyst (3 mol %) was added and the reaction mixture further degassed (N.sub.2, 5 min) before being heated to 90° C. for 90 mins. The reaction mixture was allowed to cool to RT. In general, the desired compound is purified by column chromatography.
[1420] Method F: Suzuki Coupling of Heteroaromatic Halides with Aniline Boronates
##STR00434##
[1421] Pd catalyst (5 mol %) was added to a degassed (N.sub.2, 5 mins) solution of Ar1-X (1 eq), Ar2-Z (1 eq) and base (3 eq, 6.85 mmol) in solvent (3 volumes). The solution was then degassed further (N.sub.2, 5 mins) and then heated to 90° C. for 2 hrs then allowed to cool to RT. In general, the desired compound is purified by column chromatography.
[1422] Method G: Telescoped Boronate Formation and Suzuki Coupling
##STR00435##
[1423] Bispin (1.1 eq) and KOAc (4 eq) were added to Ar1-Hal (1 eq) in dioxane (5 volumes). The reaction was heated to 60° C. and degassed (N.sub.2, 5 mins). PdCl.sub.2(dppf)-DCM adduct (5 mol %) was added to the reaction mixture and the temperature was increased to 90° C. for 1 hr. The reaction mixture was then cooled to RT and a solution of Ar2-Hal (1 eq) in dioxane (3 volumes) was added, followed by a solution of K.sub.2CO.sub.3 (4 eq) in water (2 volumes). The temperature was then increased to 90° C. for 18 hrs. The reaction was cooled to RT, an aqueous work up was performed and the crude compound was purified by normal phase chromatography.
[1424] Method H: Suzuki Coupling of Halo Pyrimidines with Heteroaromatic Boronates
##STR00436##
[1425] A solution of 5-bromo-2-chloropyrimidine (1.2 eq) and Ar2-Z (1 eq) in solvent (3 volumes) and base (4 eq) was degassed (N.sub.2, 5 min) and heated to 40° C. whereupon Pd catalyst (5 mol %) was added and the reaction mixture further degassed (N.sub.2, 5 min) before being heated to 90° C. for up to 24 hrs. The reaction mixture was allowed to cool to RT and an aqueous work-up was performed. In general, the desired compound is purified by column chromatography.
[1426] Compounds of Formula (I-b)—Examples
[1427] The synthesis of a number of known CTPS1 inhibitors is disclosed in WO2019/106156 (see compounds T1 to T465). Such compounds are made using general methods disclosed herein and represent further examples of compounds which are CTPS1 inhibitors. The full synthetic methods and characterising data for compounds T1 to T465 are provided in WO2019/106156.
[1428] Amide Couplings
##STR00437##
[1429] Method 1: HATU (1.2 eq) was added to a solution of appropriate acid (1 eq), amine (1 eq) and DIPEA (3 eq) in DCM (10 volumes) at RT. The reaction was stirred at RT for 18 hrs. The solvent was removed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.
[1430] Method 1b: 1-chloro-N,N,2-trimethylprop-1-en-1-amine (2 eq) was added to a solution of 2-(2-(cydopropanesulfonamido)thiazol-4-yl)-2-methylpropanoic acid (1 eq) in DCM (20 volumes). The reaction mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated in vacuo and the residue redissolved in pyridine (2 mL) before addition of the appropriate amine (1.1 eq). The reaction mixture was stirred at RT for 2 hrs. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent
[1431] Method 1c: T3P (50% in EtOAc, 2.5 eq) was added to a solution of appropriate acid (1 eq), amine (1 eq) and pyridine (3 eq) in a mixture of EtOAc (20 volumes) and DMF (10 volumes). The reaction was stirred for 1 hr at RT. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.
[1432] Method 1e: Thionyl chloride (2 eq) was added to a solution of an appropriate acid (1 eq) in toluene (20 volumes) at 70° C. The reaction mixture was stirred at 70° C. for 1 hr. The reaction mixture was cooled to RT and concentrated to dryness. The resulting intermediate was redissolved in EtOAc (10 volumes) and a solution of amine (1.1 eq) in EtOAc (20 volumes) was added followed by triethylamine (2 eq). The reaction mixture was stirred at 40° C. for 16 hrs. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent
[1433] Suzuki Couplings
[1434] Method 2: Suzuki Coupling of Ar1-Bromide with Heteroaromatic Boronates
##STR00438##
[1435] To a suspension of Ar1-Br (1 eq) in dioxane (10 volumes) was added arylboronic acid or ester (1 eq) and 2M K.sub.2PO.sub.4 (2 eq). The resulting suspension was heated to 60° C. and degassed (N.sub.2, 5 mins). Pd 170 or other appropriate catalyst (5 mol %) was added and the reaction mixtures were stirred at 60° C. for 16 hrs. The reaction mixture was then cooled to RT. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.
[1436] Method 2b: Suzuki Coupling of Ar1-B(OR).sub.2 with Heteroaromatic Halides
##STR00439##
[1437] PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (10 mol %) or other appropriate catalyst was added to a degassed (N.sub.2, 5 mins) solution of Ar1-B(OR).sub.2 (1 eq), Ar2-halide (1.2 eq) and K.sub.2CO.sub.3 (5 eq) in dioxane (10 volumes) and water (15 volumes). The solution was then degassed further (N.sub.2, 5 mins) and then heated to 90° C. for 1-2 hrs. The reaction mixture was allowed to cool to RT. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.
[1438] Method 3: Coupling of Primary Amides with 2-Chloropyrimidines
##STR00440##
[1439] To a solution of amide (1 eq) and 2-chloropyrimidine (1 eq) in dioxane (30 volumes) was added Cs.sub.2CO.sub.3 (1.5 eq). The reaction mixture was heated to 60° C. and degassed (N.sub.2, 5 mins). Pd 177 (10 mol %) was added to the reaction mixture and the temperature was increased to 90° C. After 2 hrs, the reaction was stirred for 16 hrs at 60° C. The reaction mixture was cooled to RT and an aqueous work up was performed. The crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.
N-([1,1′-biphenyl]-4-yl)-2-(2-(methylsulfonamido)thiazol-4-yl)acetamide T1
[1440] ##STR00441##
N-([1,1′-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide T2
[1441] ##STR00442##
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(5-(pyrazin-2-yl)pyridin-2-yl)butanamide T3
[1442] ##STR00443##
[1443] Prepared as Method 1b from INTB41 and 5-(pyrazin-2-yl)pyridin-2-amine (Cheng et al., 2016).
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyrimidin-2-yl)phenyl)propanamide T4
[1444] ##STR00444##
2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)butanamide T5
[1445] ##STR00445##
[1446] The racemate T5 (180 mg) was separated by chiral preparative HPLC (Gilson, iso-hexane+0.2% TFA: DCM, 4:1 with EtOH 30%). A salt exchange (TFA to HCl) was undertaken by adding 1.25M HCl (EtOH, 2 mL×5) and removing solvent to afford:
[1447] Peak A: Stereochemistry of Product was not Assigned [1448] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)butanamide.HCl T6.
[1449] Peak B: Stereochemistry of Product was not Assigned [1450] 2-(2-(cydopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)butanamide.HCl T7. [1451] N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cydopropanesulfonamido)thiazol-4-yl)butanamide T8
##STR00446##
[1452] Prepared as Method 1 from INTB38.
[1453] The racemate T8 was separated by chiral preparative HPLC (30% EtOH vs 4:1 isoehexanes+0.2% TFA:DCM IA column). A salt exchange (TFA to HCl) was undertaken by adding 1.25M HCl (EtOH, 2 mL×5) and removing solvent to afford:
[1454] Peak A: Stereochemistry of Product was not Assigned [1455] N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide.HCl.
[1456] Peak B: Stereochemistry of Product was not Assigned [1457] N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide.HCl T10. [1458] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(pyrimidin-5-yl)phenyl)butanamide T11
##STR00447##
[1459] Prepared as Method 1 from INTB40. [1460] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(pyridin-3-yl)phenyl)butanamide T12
##STR00448##
[1461] Prepared as Method 1 from INTB40 and 4-(pyridin-3-yl)aniline (Xing-Li et al, 2009)
[1462] The racemate T12 was separated by chiral preparative HPLC (Gilson, iso-hexane+0.2% TFA: DCM, 4:1 with EtOH 30%). A salt exchange (TFA to HCl) was undertaken by adding 1.25M HCl (EtOH, 2 mL×5) and removing solvent to afford:
[1463] Peak A: Stereochemistry of Product was not Assigned [1464] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(pyridin-3-yl)phenyl)butanamide.HCl T13.
[1465] Peak B: Stereochemistry of Product was not Assigned [1466] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(pyridin-3-yl)phenyl)butanamide.HCl T14. [1467] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-methoxypyridin-3-yl)phenyl)-2-methylpropanamide T15
##STR00449## [1468] N-(2-chloro-4-(pyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide T16
##STR00450## [1469] 2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide T17
##STR00451## [1470] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyrimidin-5-yl)phenyl)propanamide T18
##STR00452## [1471] 6-(4-(2-(2-(cydopropanesulfonamido)thiazol-4-yl)-2-methylpropanamido)phenyl)-N,N-dimethylpyrazine-2-carboxamide T19
##STR00453## [1472] N-(5-(5-cyanopyridin-3-yl)pyrimidin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide T20
##STR00454## [1473] N-([1,1′-biphenyl]4-yl)-2-(5-chloro-2-(cydopropanesulfonamido)thiazol-4-yl)acetamide T21
##STR00455## [1474] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethynylpyrazin-2-yl)phenyl)butanamide T22
##STR00456##
TABLE-US-00007 TABLE 6 Compounds T23-T322, T422-T443 and T445-T465. Name/Structure (All examples containing chiral centres are racemates unless T# stated) T23 2-(2- (cyclopropanesulfonamido)thiazol-4- yl)-N-(6-(pyrimidin-5-yl)pyridin-3- yl)acetamide
[1475] Method 2c: Telescoped Boronate Formation and Suzuki Coupling on Sulfonamide Scaffold
##STR00795##
[1476] A suspension of Ar1-Br (1 eq), bispin (1.1 eq.) and KOAc (2 eq) in dioxane (50 volumes) was degassed (N.sub.2, 5 mins, ×3) then charged with PdCl.sub.2(dppo)-DCM adduct (5 mol %) and again degassed (N.sub.2, 5 mins, ×3). The reaction mixture was heated to 90° C. for 1 hr and then the reaction was allowed to cool to RT. Ar2-Z (1 eq) and 2M K.sub.2CO.sub.3 (aq, 2 eq) were added and the reaction was then heated to 90° C. for 18 hrs. The reaction was allowed to cool to RT, an aqueous work up was performed and the crude compound was purified by normal phase chromatography. [1477] 2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)acetamide T325
##STR00796## [1478] 2-acetamido-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)acetamide T326
##STR00797## [1479] methyl (1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-((4-(6-ethoxypyrazin-2-yl)phenyl)amino)-2-oxoethyl)carbamate T327
##STR00798## [1480] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)acetamide T328
##STR00799## [1481] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-hydroxybutanamide T329
##STR00800##
[1482] The racemate T410 was separated by chiral preparative HPLC [Chiralpak® IB (Daicel Ltd.) column (4.6 mm×25 mm), flow rate 0.5 mL min.sup.−1 eluting with a mixture of (30% of ethanol) ethanol in heptane+0.2% Et.sub.2NH, UV detection at 254 nm followed by SCX (300 mg) purification (elution with MeOH) to afford: [1483] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide T410
##STR00801##
[1484] The racemate T410 was prepared using Method 1b was separated by chiral preparative HPLC using a Diacel Chiralpak IB column (30% EtOH (0.1% DEA) in iso-hexane (0.2% DEA) to afford:
[1485] Peak 1: Stereochemistry of Product was Unassigned [1486] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide T330.
[1487] Peak 2: Stereochemistry of Product was Unassigned [1488] 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide T331.
TABLE-US-00008 TABLE 7 Compounds T332-T416 Name/Structure (All examples containing chiral T# centres are racemates unless stated) T332 2-(2-((2- methoxyethyl)sulfonamido)thiazol-4-yl)-2- methyl-N-(5-(6-(trifluoronnethyl)pyrazin-2- yl)pyridin-2-yl)propanamide
##STR00887## [1490] 2-Amino-2-(2-(cyclopropanesulfonamido)thiazolyl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)acetamide hydrochloride T417
##STR00888## [1491] 2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)acetamide hydrochloride T419
##STR00889## [1492] 2-Amino-2-(2-(cyclopropanesulifonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide T418
##STR00890## [1493] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide T420
##STR00891## [1494] 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)acetamide T421
##STR00892## [1495] N-(4-(1-((2-fluoro-4-(pyridin-3-yl)phenyl)amino)-2-methylpropan-2-yl)thiazol-2-yl)cyclopropanesulfonamide T466
##STR00893##
[1496] LiAlH.sub.4 (0.870 mL, 1.74 mmol) was added into a solution of 2-(2-(cydopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)-2-methylpropanamide T42 (200 mg, 0.434 mmol) in THF (20 mL, 0.434 mmol) and the resulting solution was stirred at RT for 16 hrs. The reaction mixture was quenched with sat. NH.sub.4Cl (aq, 50 mL) and extracted with EtOAc (3×50 mL). The organic extract was dried (MgSO.sub.4), filtered and solvent removed in vacuo. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 5-100% MeCN/10 mM ammonium bicarbonate) to afford N-(4-(1-((2-fluoro-4-(pyridin-3-yl)phenyl)amino)-2-methylpropan-2-yl)thiazol-2-yl)cyclopropanesulfonamide (23 mg, 0.050 mmol, 12% yield) as a white solid. Rt 1.83 min (HPLC basic); m/z 447 (M+H).sup.+ (ES.sup.+). .sup.1H NMR (500 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.82 (d, J=2.4 Hz, 1H), 8.47-8.43 (m, 1H), 8.00-7.95 (m, 1H), 7.46 (dd, J=13.4, 2.2 Hz, 1H), 7.39 (dd, J=8.0, 4.7 Hz, 1H), 7.35-7.31 (m, 1H), 6.92 (t, J=8.9 Hz, 1H), 6.40 (s, 1H), 5.50 (t, J=4.4 Hz, 1H), 3.36-3.28 (m, 2H (obscured by water peak)), 2.56-2.51 (m, 1H, (obscured by DMSO peak)), 1.27 (s, 6H), 0.90-0.79 (m, 4H).
[1497] Compounds of Formula (I-c)—Intermediates
[1498] Known synthetic intermediates were procured from commercial sources or were obtained using published literature procedures. Additional intermediates were prepared by the representative synthetic processes described herein.
[1499] The synthesis of INTE1 to INTE39 and INTF1 to INTF53 is disclosed in WO2019/106146 and uses the general methods disclosed below.
[1500] Method A: Reductive Amination
##STR00894##
[1501] A solution of aldehyde/ketone (1 eq.) in THF was treated with AcOH (1 eq.), amine (1 eq.) and a reducing agent such as STAB (1.2 eq.) and stirred at RT for 1 hr. The reaction mixture was quenched by addition of MeOH then loaded directly on to SCX (1 g/mmol of substrate), washed with MeOH and the product was eluted with 1 M NH.sub.3 in MeOH. The crude product was then concentrated onto silica and purified by normal phase chromatography.
[1502] Method B: Benzylamine Deprotection (TFA)
##STR00895##
[1503] Benzylamine derivative (1 eq.) was dissolved in TFA (50 eq.) and heated to 70° C. for 1-24 hrs. The reaction was allowed to cool to RT, then was loaded on to SCX (1 g/mmol of substrate) and washed with MeOH. The required compound was eluted with 1% NH.sub.3 in MeOH.
[1504] Method D: Ester Deprotection with TFA
##STR00896##
[1505] A solution of the ester (1 eq) in DCM (20 volumes) was treated with TFA (10 eq.) and stirred at RT for 3 hrs. The reaction mixture was then concentrated and azeotroped with MeOH and MeCN. No further purification was undertaken.
[1506] Method E: Ester Deprotection with Base
##STR00897##
[1507] A solution of the ester (1 eq) in a mixture of THF/MeOH (4/1 volumes) was treated with LiOH (2.2-6 eq.) and stirred between RT and 50° C. for between 3 hrs and 18 hrs. The organic solvents were removed in vacuo then acidified with 1 M HCl and extracted with EtOAc. The organic phases were combined, dried (Na.sub.2SO.sub.4), filtered and concentrated. The products were used directly in the next step with no further purification undertaken.
[1508] Method F: Potassium Salt Formation
##STR00898##
[1509] A solution of the ester (1 eq.) in THF (4 volumes) was treated with TMSOK (1 eq.) and stirred at RT for 2 hrs before the reaction mixtures were filtered and washed with iso-hexanes. The products were used directly in the next step with no further purification undertaken.
[1510] Compounds of Formula (I-c)—Examples
[1511] The synthesis of a number of known CTPS1 inhibitors is disclosed in VNO2019/106146 (see compounds R1 to R93). Such compounds are made using general methods disclosed herein and represent further examples of compounds which are CTPS1 inhibitors. The full synthetic methods and characterising data for compounds R1 to R93 are provided in WO2019/106146, which is herein incorporated in its entirety by reference.
[1512] Method 1: Amide Coupling
##STR00899##
[1513] Method 1a: HATU (1.2 eq.) was added to a solution of appropriate acid (1 eq.), amine (1 eq.) and DIPEA (3 eq.) in DMF (10 volumes) at RT. The reaction was stirred at RT for 18 hrs. The solvent was removed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.
[1514] Method 1b: 1-chloro-N,N,2-trimethylprop-1-en-1-amine (2 eq.) was added to a solution of appropriate acid (1 eq.) in DCM (20 volumes). The reaction mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated in vacuo and the residue dissolved in DCM (20 volumes) before addition of DIPEA (3 eq.) and the appropriate amine (1 eq). The reaction mixture was stirred at RT for 2 hrs. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.
[1515] Method 1c: T3P (50 wt % in EtOAc, 2.5 eq.) was added to a solution of appropriate acid (1 eq.), amine (1 eq.) and pyridine (3 eq.) in a mixture of EtOAc (20 volumes) and DMF (10 volumes). The reaction was stirred for 1 hr at RT. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.
[1516] Method 2a: Suzuki [ArB(OR).sub.2 Core]
##STR00900##
[1517] PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (10 mol %) or other appropriate catalyst was added to a degassed (N.sub.2, 5 mins) solution of Ar1-B(OR).sub.2 (1 eq.), Ar2-halide (1 eq.) and K.sub.2CO.sub.3 (3 eq.) in dioxane (10 volumes) and water (1 volumes). The solution was then degassed further (N.sub.2, 5 mins) and heated to 90° C. for 1-2 hrs. The reaction mixture was allowed to cool to RT. An aqueous workup was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.
[1518] Method 2b: Telescoped Miyaura Borylation/Suzuki Protocol
##STR00901##
[1519] A suspension of Ar1-Br (1 eq.), Bispin (1.1 eq.) and KOAc (2 eq.) in dioxane (50 volumes) was degassed (N.sub.2) then charged with PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (5 mol %) and again degassed (N.sub.2). The reaction mixture was heated to 90° C. for 1-24 hrs, recharging the Pd-catalyst if required. On formation of the boronate ester the reaction was allowed to cool to RT. Ar2-Z (1 eq.) and 2 M K.sub.2CO.sub.3 (eq, 2 eq.) were added, degassed (N.sub.2) and the reaction was then heated to 90° C. for 18 hrs. The reaction was allowed to cool to RT, an aqueous work up was performed and the crude compound was purified by normal phase chromatography.
[1520] Representative for Method 1a [1521] N-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-4-(pyridin-3-yl)benzamide R1
##STR00902##
[1522] Representative for Method 1b [1523] N-(1-(2-(cydopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide R2
##STR00903##
[1524] The racemic mixture R2 was separated by chiral preparative HPLC using chiral method A. A salt exchange (TFA to HCl) was undertaken by adding 1.25 M HCl (EtOH, 2 mL×5) and removing solvent to afford:
[1525] Peak 1: Stereochemistry of Product was not Defined R3 [1526] N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide. HCl R3.
[1527] Peak 2: Stereochemistry of Product was not Defined R4 [1528] N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide. HCl R4.
[1529] Representative for Method 1c [1530] N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide R5
##STR00904##
[1531] Representative for Method 2a [1532] N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide R6
##STR00905##
[1533] Representative for Method 2b [1534] N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2-methoxybenzamide R7
##STR00906##
TABLE-US-00009 TABLE 8 Compounds R8 to R93 Name/Structure (All examples containing chiral R centres are racemic unless stated) R8 N-((2-(cyclopropanesulfon- amido)thiazol-4-yl)methyl)-5- phenylpicolinamide
##STR00993##
[1536] A solution of 4-(6-ethoxypyrazin-2-yl)-2-fluorobenzaldehyde (75 mg, 0.305 mmol) INTF57 and N-(4-(2-aminopropan-2-yl)thiazol-2-yl)cyclopropanesulfonamide INTE14 (80 mg, 0.305 mmol) in DCM (2 mL) was treated with AcOH (0.02 mL, 0.35 mmol) and stirred for 1 hr whereupon sodium tiacetoxyborohydride (70 mg, 0.33 mmol) was added and the reaction mixture was stirred at RT for 4 hrs. The reaction mixture was treated with 1% NH.sub.3 in MeOH (2 mL) and concentrated in vacuo. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 15-70% MeCN/10 mM Ammonium Bicarbonate) to N-(4-(2-((4-(6-ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide (30 mg, 0.056 mmol, 18% yield) was isolated as a colourless solid. Rt 0.95 min (UPLC acidic); m/z 492 (M+H).sup.+ (ES.sup.+). .sup.1H NMR (500 MHz, DMSO-d6) δ 8.86-8.81 (m, 1H), 8.28-8.18 (m, 1H), 7.96-7.93 (m, 1H), 7.91-7.82 (m, 1H), 7.67-7.50 (m, 1H), 6.49-6.14 (v. br. m., 3H), 4.49 (q, J=7.1 Hz, 2H), 3.59-3.48 (m, 2H), 2.50-2.39 (m, 1H), 1.48-1.14 (m, 9H), 0.91-0.59 (m, 4H). [1537] N-(4-(2-(((5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide R95
##STR00994##
[1538] Prepared as for R94 using 5-(6-ethoxypyrazin-2-yl)picolinaldehyde (70 mg, 0.305 mmol) INTF55 and N-(4-(2-aminopropan-2-yl)thiazol-2-yl)cyclopropanesulfonamide INTE14 (80 mg, 0.305 mmol) to afford N-(4-(2-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide (36 mg, 0.073 mmol, 24% yield) as a red solid. Rt 0.81 min (UPLC acidic); m/z 475 (M+H).sup.+ (ES.sup.+). .sup.1H NMR (500 MHz, DMSO-d6) δ 9.21 (d, J=2.3 Hz, 1H), 8.88 (s, 1H), 8.44 (dd, J=8.2, 2.4 Hz, 1H), 8.30 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 6.50 (s, 1H), 4.49 (q, J=7.0 Hz, 2H), 3.68 (s, 2H), 2.59-2.53 (m, 1H), 1.45-1.37 (m, 9H), 0.92-0.82 (m, 4H), 2×N−H not observed.
BIOLOGICAL EXAMPLES
Biological Example 1—Human CTPS1 Enzyme Inhibition
[1539] The enzyme inhibitory activities of compounds invented against the target of interest were determined using the ADP-Glo™ Max assay (Promega, UK). Assays for human CTPS1 were performed in 1× assay buffer containing 50 mM Tris, 10 mM MgCl.sub.2, 0.01% Tween-20, pH to 8.0 accordingly. Finally, immediately before use, L-cysteine was added to the 1× assay buffer to a final concentration of 2 mM. All reagents are from Sigma-Aldrich unless specified otherwise. Human full length active C-terminal FLAG-His.sub.8-tag CTPS1 (UniProtKB—P17812, CTPS1[1-591]-GGDYKDDDDKGGHHHHHHHH (CTPS1[1-591]—SEQ ID NO: 1)) was obtained from Proteros biostructures GmbH.
[1540] Assay Procedure
[1541] 3× human CTPS1 protein was prepared in 1× assay buffer to the final working protein concentration required for the reaction. A 2 uL volume per well of 3× human CTPS1 protein was mixed with 2 uL per well of 3× test compound (compound prepared in 1× assay buffer to an appropriate final 3× compound concentration respective to the concentration response curve designed for the compounds under test) for 10 minutes at 25° C. The enzymatic reaction was then initiated by addition of a 2 uL per well volume of a pre-mixed substrate mix (UltraPure ATP from ADP-Glo™ Max kit (0.31 mM), GTP (0.034 mM), UTP (0.48 mM) and L-glutamine (0.186 mM)) and the mixture was incubated for an appropriate amount of time within the determined linear phase of the reaction at 25° C. under sealed plate conditions with constant agitation at 500 revolutions per minute (rpm). ADP-Glo™ Max reagent was added for 60 minutes (6 μL per well) and subsequently ADP-Glo™ Max development reagent was added for 60 minutes (12 uL per well) prior to signal detection in a microplate reader (EnVision® Multilabel Reader, Perkin Elmer). Following each reagent addition over the course of the assay, assay plates were pulse centrifuged for 30 seconds at 500 rpm.
[1542] In all cases, the enzyme converts ATP to ADP and the ADP-Glo™ Max reagent subsequently depletes any remaining endogenous ATP in the reaction system. The ADP-Glo™ Max detection reagent converts the ADP that has been enzymatically produced back into ATP and using ATP as a substrate together with luciferin for the enzyme luciferase, light is generated which produces a detectable luminescence. The luminescent signal measured is directly proportional to the amount of ADP produced by the enzyme reaction and a reduction in this signal upon compound treatment demonstrates enzyme inhibition. The percentage inhibition produced by each concentration of compound was calculated using the equation shown below:
[1543] Percentage inhibition was then plotted against compound concentration, and the 50% inhibitory concentration (IC.sub.50) was determined from the resultant concentration-response curve.
[1544] The data for compounds of formula (I) tested are presented below.
TABLE-US-00010 TABLE 9 Human CTPS1 Enzyme Inhibition data grouped by potency range (± indicates IC.sub.50 in the range of >10 to 20 micromolar, + indicates IC.sub.50 in the range >1 to 10 micromolar, ++ indicates IC.sub.50 in the range >0.1 to 1 micromolar, +++ indicates IC.sub.50 of ≤0.1 micromolar) P CTPS1 P1 ++ P2 +++ P3 +++ P4 ++ P5 + P6 ++ P7 ++ P8 +++ P9 +++ P10 +++ P11 +++ P12 +++ P13 ++ P14 ++ P15 + P16 ++ P17 + P18 +++ P19 +++ P20 +++ P21 +++ P22 ++ P23 ++ P24 ++ P25 ++ P26 ++ P27 +++ P28 ++ P29 + P30 +++ P31 +++ P32 +++ P33 +++ P34 +++ P35 ++ P36 + P37 +++ P38 +++ P39 +++ P40 ++ P41 +++ P42 + P43 ++ P44 ++ P45 ++ P46 ++ P47 +++ P48 ++ P49 +++ P50 + P51 ++ P52 ++ P53 ++ P54 ++ P55 +++ P56 ++ P57 ++ P58 ++ P59 + P60 + P61 + P62 + P63 ± P64 +++ P65 +++ P66 ++ P67 +++ P68 ++ P69 ++ P70 + P71 + P72 ++ P73 ++ P74 ++ P75 ++ P76 ++ P77 + P78 ++ P79 ++ P80 ++ P81 +++ P82 + P83 +++ P84 ++ P85 ++ P86 + P87 +++ P88 +++ P89 +++ P90 ++ P91 ++ P92 ++ P93 + P94 +++ P95 +++ P96 +++ P97 +++ P98 +++ P99 ++ P100 ++ P101 ++ P102 ++ P103 ++ P104 ++ P105 +++ P106 +++ P107 +++ P108 +++ P109 ++ P110 +++ P111 ++ P112 +++ P113 +++ P114 +++ P115 +++ P116 ++ P117 +++ P118 +++ P122 ++ P123 ++ P124 ++ P125 ++ P126 +++ P128 ++ P129 ++ P130 ++ P131 ++ P132 ++ P133 + P134 ++ P135 ++ P136 +++ P137 +++ P138 ++ P139 ++ n = 4 +++ n = 6 P140 ++ P141 ++ P142 ++ P143 +++ P144 +++ P145 +++ P146 +++ P147 ++ P148 +++ P149 +++ P150 +++ P151 +++ P152 +++ P153 +++ P154 +++ P155 +++ P156 +++ P157 +++ P158 ++ P159 +++ P160 +++ P161 +++ P162 +++ P163 +++ P164 +++ P165 +++ P166 +++ P167 ++ P168 ++ P169 ++ P170 ++ P171 + P172 ++ P173 +++ P174 + P175 + P176 + P177 + P178 + P179 + P180 + P181 + P182 ++ P183 ++ P184 ++ P185 + P186 +++ P187 ++ P188 +++ P189 + P190 ++ P191 ++ P192 + P193 + P194 58.6 uM P195 +++ P196 +++ P197 +++ P198 +++ P199 ++ P200 +++ P201 +++ P202 +++ P203 +++ P204 +++ P205 +++ P206 +++ P207 +++ P208 +++ P209 ++ P210 ++ P211 ++ P212 ++ P213 ++ P214 ++ P215 ++ P216 +++ P217 ++ P218 +++ P219 ++ P220 ++ P221 ++ P222 ++ P223 ++ P224 ++ P225 +++
TABLE-US-00011 TABLE 10 Human CTPS1 Enzyme Inhibition data grouped by potency range (± indicates IC.sub.50 in the range of >10 to 20 micromolar, + indicates IC.sub.50 in the range >1 to 10 micromolar, ++ indicates IC.sub.50 in the range >0.1 to 1 micromolar, +++ indicates IC.sub.50 of ≤0.1 micromolar) T # CTPS1 T1 + T2 ++ T3 ++ T4 + T5 +++ T6 ++ T7 +++ T8 +++ T9 +++ T10 +++ T11 ++ T12 ++ T13 ++ T14 ++ T15 ++ T16 ++ T17 ++ T18 +++ T19 ++ T20 ++ T21 + T22 +++ T23 ++ T24 ++ T25 + T26 ++ T27 ++ T28 ++ T29 +++ T30 +++ T31 + T32 +++ T33 +++ T34 ++ T35 +++ T36 ++ T37 ++ T38 +++ T39 ++ T40 +++ T41 ++ T42 +++ T43 ++ T44 ++ T45 ++ T46 + T47 +++ T48 +++ T49 ++ T50 +++ T51 +++ T52 +++ T53 + T54 ++ T55 +++ T56 +++ T57 +++ T58 +++ T59 +++ T60 ++ T61 +++ T62 ++ T63 ++ T64 ++ T65 ++ T66 ++ T67 ++ T68 ++ T69 + T70 ++ T71 +++ T72 +++ T73 +++ T74 ++ T75 +++ T76 +++ T77 +++ T78 +++ T79 ++ T80 +++ T81 +++ T82 +++ T83 + T84 ++ T85 ++ T86 + T87 ++ T88 ++ T89 +++ T90 +++ T91 +++ T92 +++ T93 +++ T94 +++ T95 +++ T96 +++ T97 ++ T98 ++ T99 +++ T100 ++ T101 + T102 +++ T103 ++ T104 ++ T105 + T106 +++ T107 +++ T108 +++ T109 +++ T110 ++ T111 +++ T112 +++ T113 + T114 ++ T115 +++ T116 ++ T117 ++ T118 +++ T119 +++ T120 +++ T121 +++ T122 +++ T123 +++ T124 +++ T125 +++ T126 +++ T127 +++ T128 +++ T129 +++ T130 +++ T131 +++ T132 ++ T133 +++ T134 +++ T135 ++ T136 +++ T137 +++ T138 +++ T139 +++ T140 ++ T141 ++ T142 +++ T143 +++ T144 ++ T145 +++ T146 ++ T147 +++ T148 ++ T149 +++ T150 ++ T151 ++ T152 ++ T153 ++ T154 ++ T155 +++ T156 +++ T157 +++ T158 +++ T159 +++ T160 +++ T161 ++ (n = 2) + (n = 6) T163 ++ T164 + T169 ++ T170 ++ T171 +++ T172 +++ T173 +++ T174 +++ T175 +++ T176 +++ T177 +++ T178 + T179 +++ T180 +++ T181 ++ T182 +++ T183 +++ T184 + T185 +++ (n = 1) ++ (n = 2) T186 +++ T187 +++ T188 ++ T189 +++ T190 +++ T191 +++ T192 +++ T193 +++ T194 +++ T195 +++ T196 +++ T197 +++ T198 +++ T199 +++ T200 +++ T201 +++ T202 +++ T203 +++ T204 +++ T205 +++ T206 +++ T207 +++ T208 +++ T209 +++ T210 +++ T211 +++ (n = 1) ++ (n = 2) T212 +++ T213 ++ T214 +++ T215 +++ T216 ++ T217 +++ T218 ++ T219 +++ T220 +++ T221 +++ T222 ++ T223 +++ T224 +++ T225 +++ T226 +++ T227 ++ T228 +++ T229 +++ T230 +++ T231 + T232 ++ T233 + T234 + T235 ++ T236 ++ T237 + T238 + T239 ++ T240 ++ T241 ++ T242 + T243 + T244 ++ T245 + T246 ++ T247 ++ T248 + T249 +++ T250 + T251 + T252 +++ T253 +++ T254 ++ T255 + T256 +++ T257 ++ T258 ++ T259 +++ T260 + T261 +++ T262 +++ T263 + T264 ++ T265 +++ T266 +++ T267 +++ T268 ++ T269 ++ T270 ++ T271 + T272 +++ T273 +++ T274 +++ T275 +++ T276 ++ T277 ++ T278 +++ T279 + T280 + T281 ++ T282 ++ T283 ++ T284 + T285 +++ T286 +++ T287 +++ T288 ++ T289 ++ T290 +++ T291 +++ T292 ++ T293 ++ T294 ++ T295 ++ T296 ++ T297 + T298 +++ T299 ++ T300 ++ T301 +++ T302 ++ T303 + T304 ++ T305 ++ T306 ++ T307 +++ T308 ++ T309 + T310 + T311 + T312 ++ T313 ++ T314 ++ T315 ++ T316 ++ T317 ++ T318 + T319 + T320 ++ T321 +++ T322 ++ T325 +++ T326 +++ T327 +++ T328 +++ T329 +++ T330 +++ T331 +++ T332 ++ T333 + T334 ++ T335 ++ T336 ++ T337 +++ T338 + T339 + T340 ++ T341 +++ T342 +++ T343 +++ T344 +++ T345 +++ T346 ++ T347 +++ T348 ++ T349 ++ T350 ++ T351 ++ (n = 1) +++ (n = 2) T352 ++ T353 ++ T354 ++ T355 + T356 +++ T357 +++ T358 +++ T359 +++ T360 ++ T361 ++ T362 +++ T363 +++ T364 ++ T365 +++ T366 ++ T367 +++ T368 +++ T369 ++ T370 + T371 +++ T372 ++ T373 +++ T374 + T375 ++ T376 ++ T377 ++ T378 + T379 + T380 +++ T381 +++ T382 +++ T383 +++ T384 ++ T385 +++ T386 ++ T387 +++ T388 +++ T389 ++ T390 +++ T391 +++ T392 +++ T393 ++ T394 +++ T395 +++ T396 ++ T397 ++ T398 +++ T399 +++ T400 +++ T401 ++ T402 + T403 ++ T404 ++ T405 +++ T406 ++ T407 +++ T408 +++ T409 +++ T410 +++ T411 +++ T412 +++ T413 +++ T414 +++ T415 ++ T416 +++ T417 ++ T418 ++ T419 +++ T420 +++ T421 +++ T422 ++ T423 +++ T424 +++ T425 +++ T426 ++ T427 ++ T428 ++ T429 +++ T430 ++ T431 +++ T432 ++ T433 +++ T434 +++ T435 +++ T436 +++ T437 +++ T438 +++ T439 +++ T440 +++ T441 +++ T442 +++ T443 +++ T444 +++ T445 +++ T446 +++ T447 +++ T448 +++ T449 +++ T450 +++ T451 +++ T452 +++ T453 +++ T454 +++ T455 +++ T456 +++ T457 +++ T458 +++ T459 +++ T463 ++ T464 +++ T465 +
TABLE-US-00012 TABLE 11 Human CTPS1 Enzyme Inhibition data grouped by potency range (± indicates IC.sub.50 in the range of >10 to 21 micromolar, + indicates IC.sub.50 in the range >1 to 10 micromolar, ++ indicates IC.sub.50 in the range >0.1 to 1 micromolar, +++ indicates IC.sub.50 of ≤0.1 micromolar) R CTPS1 R1 ++ R2 ++ R3 ++ R4 +++ R5 +++ R6 +++ R7 ++ R8 + R9 + R10 +++ R11 +++ R12 +++ R13 +++ R14 +++ R15 +++ R16 ++ R17 ++ R18 ++ R19 +++ R20 +++ R21 +++ R22 ++ R23 ++ R24 ++ R25 ++ R26 ++ R27 ± R28 +++ R29 +++ R30 ++ R31 ++ R32 ++ R33 + R34 + R35 +++ R36 ++ R37 +++ R38 ++ R39 ++ R40 ++ R41 ++ R42 +++ R43 +++ R44 ++ R45 ++ R46 ++ R47 ++ R48 ++ R49 ++ R50 + R51 +++ R52 +++ R53 ++ R54 +++ R55 +++ R56 +++ R57 ++ R58 ++ R59 ++ R60 ++ R61 ++ R62 ++ R63 ++ R64 ++ R65 +++ R66 ++ R67 ++ R68 + R69 +++ R70 ++ R71 +++ R72 + R73 + R74 ++ R75 ++ R76 ++ R77 + R78 ++ R79 ++ R80 +++ R81 ++ R82 +++ R83 +++ R84 +++ R85 ++ R86 ++ R87 ++ R88 ++ R89 +++ R90 +++ R91 +++ R92 +++ R93 +++
[1545] All compounds disclosed in Tables 9 to 11 were found to demonstrate inhibition of CTPS1 enzyme in this assay. Consequently, these compounds may be expected to have utility in the inhibition of CTPS1. The compounds of the invention are also expected to have utility as research tools, for example, for use in CTPS assays.
[1546] The data for all compounds of formula (I) (including (I-a), (I-b) and (I-c) tested wherein R.sub.1 is R.sub.1a; and/or R.sub.4 and R.sub.5 are R.sub.4a and R.sub.5a; and/or A is A.sub.a are presented below.
TABLE-US-00013 TABLE 12 Human CTPS1 Enzyme Inhibition data grouped by potency range (± indicates IC.sub.50 in the range of >10 to 20 micromolar, + indicates IC.sub.50 in the range >1 to 10 micromolar, ++ indicates IC.sub.50 in the range >0.1 to 1 micromolar, +++ indicates IC.sub.50 of ≤0.1 micromolar) P CTPS1 P226 +++ P227 +++ P228 +++ P229 +++ P230 + P235 ++ P242 +++ P244 +++ P248 ++ P251 +++ P254 ++ P255 ++ P256 ++ P258 +++ P260 +++ P261 ++ P288 +++ P289 +++ P290 +++ P291 +++ P292 +++ P293 +++ P294 +++ P295 +++ P296 +++ P297 +++ P298 +++ P299 +++ P300 +++ P301 +++ P302 +++ P303 ++ P304 +++ P305 ++ P306 +++ P307 +++ P308 +++ P309 ++ P310 +++ P311 ++ P312 +++ P313 +++ P314 +++ P315 +++ P316 +++ P317 +++ P318 +++
TABLE-US-00014 TABLE 13 Human CTPS1 Enzyme Inhibition data grouped by potency range (+++ indicates IC.sub.50 of ≤0.1 micromolar) R CTPS1 T466 ±
TABLE-US-00015 TABLE 14 Human CTPS1 Enzyme Inhibition data grouped by potency range (+++ indicates IC.sub.50 of ≤0.1 micromolar) R CTPS1 R94 +++
[1547] All compounds of the invention which have been tested were found to demonstrate inhibition of CTPS1 enzyme in this assay (see Tables 12 to 14). Consequently, these compounds may be expected to have utility in the inhibition of CTPS1.
[1548] In particular, activity is retained following reduction of the amide (group A) to the amine derivative (see Examples R94 and T466).
Biological Example 2—RapidFire/MS-Based Enzyme Selectivity Assays
[1549] Human CTPS1 Versus CTPS2 Selectivity Assessment by RapidFire/MS Analysis.
[1550] The enzyme inhibitory activities against each target isoform of interest may be determined for the compounds of the invention using an optimised RapidFire high-throughput mass spectrometry (RF/MS) assay format. RF/MS assays for both human CTPS1 and CTPS2 may be performed in assay buffer consisting of 50 mM HEPES (Merck), 20 mM MgCl.sub.2, 5 mM KCl, 1 mM DTT, 0.01% Tween-20, pH to 8.0 accordingly. Human full-length active C-terminal FLAG-His-tag CTPS1 (UniProtKB—P17812, CTPS1[1-591]-GGDYKDDDDKGGHHHHHHHH (CTPS1[1-591]-SEQ ID NO: 1)) may be obtained from Proteros biostructures GmbH. Human full length active C-terminal FLAG-His-Avi tagged CTPS2 (UniProtKB—Q9NRF8, CTPS2 [1-586]-DYKDDDDKHHHHHHGLNDIFEAQKIEWHE (CTPS2 [1-586]—SEQ ID NO: 2)) may be obtained from Harker Bio.
[1551] Assay Procedure
[1552] Human CTPS (1 or 2) protein may be prepared in 1× assay buffer to the final working protein concentration required for the reaction. A 2 uL volume per well of 2×CTPS (1 or 2) protein may be mixed with 40 nL of compound using acoustic (ECHO) delivery and incubated for 10 minutes at 25° C. Each isoform enzymatic reaction may be subsequently initiated by addition of 2 uL per well of a 2× substrate mix in assay buffer. For hCTPS1: ATP (0.3 mM), UTP (0.2 mM), GTP (0.07 mM) and L-glutamine (0.1 mM). For hCTPS2: ATP (0.1 mM), UTP (0.04 mM), GTP (0.03 mM) and L-glutamine (0.1 mM). Each mixture may be incubated for an appropriate amount of time per isoform within the determined linear phase of the reaction at 25° C. A 80 uL volume of stop solution (1% formic acid with 0.5 uM .sup.13C.sub.9-.sup.15N.sub.3-CTP in H.sub.2O) may be added and the plate immediately heat-sealed and centrifuged for 10 minutes at 4,000 rpm. Following centrifugation, plates may be loaded onto the Agilent RapidFire microfluidic solid phase extraction system coupled to an API4000 triple quadrupole mass spectrometer (RF/MS) for analysis.
[1553] In all cases, the enzyme converts UTP to CTP. Highly specific and sensitive multiple reaction monitoring (MRM) MS methods may be optimised for the detection of the enzymatic reaction product, CTP, and the stable isotope labelled product standard .sup.13C.sub.9-.sup.15N.sub.3-CTP. Readout for data analysis may be calculated as the ratio between the peak area of the product CTP and the internal standard .sup.13C.sub.9-.sup.15N.sub.3-CTP. For data reporting, the following equation may be used:
[1554] (R=ratio/readout, P=product signal area, IS=internal standard signal area)
[1555] For each screening plate, the means of the negative (DMSO) and positive control values were used for the calculation of the respective assay window (S/B) and Z′ values. The median of the respective control values was used for calculation of percent inhibition according to the following equation:
[1556] (I=Inhibition, R.sub.neq=median of negative control readout values, R.sub.pos=median of positive control readout values, R.sub.sample=sample readout value)
[1557] Percentage inhibition was then plotted against compound concentration, and the 50% inhibitory concentration (IC.sub.50) was determined from the resultant concentration-response curve.
[1558] Fold selectivity between CTPS1 and CTPS2 was subsequently calculated according to the following equation:
[1559] The data for all compounds disclosed herein that were tested in Biological Example 2 are presented below.
TABLE-US-00016 TABLE 15 Selectivity data split into grouping of 2-30 fold (+), >30-60 fold (++) or >60 fold (+++) P Selectivity P1 + P2 +++ P9 +++ P12 ++ P16 ++ P18 ++ P21 ++ P31 +++ P34 + P38 + P39 + P59 + P65 ++ P68 ++ P70 + P74 ++ P76 ++ P83 +++ P87 ++ P88 +++ P89 +++ P95 + P96 + P98 +++ P103 + P105 ++ P108 +++ P110 ++ P112 ++ P113 + P114 +++ P115 +++ P118 +++ P125 ++ P128 + P132 ++ P136 +++ P143 +++ P145 +++ P146 +++ P151 +++ P155 + P158 + P159 +++ P161 + P162 ++ P163 +++ P164 + P188 ++ P191 ++ P195 +++ P196 +++ P197 +++ P198 +++ P200 ++ P201 +++ P202 +++ P205a +++ P205b ++ P206 +++ P207 + P216 +++ P221 + P222 +
TABLE-US-00017 TABLE 16 Selectivity data split into grouping of 2-30 fold (+), >30-60 fold (++) or >60 fold (+++) R Selectivity R5 + R6 ++ R7 ++ R11 ++ R19 ++ R23 ++ R25 ++ R26 +++ R41 ++ R42 ++ R43 ++ R45 ++ R46 + R47 + R48 ++ R51 ++ R52 +++ R54 + R55 +++ R56 +++ R62 +++ R63 + R64 ++ R68 ++ R69 +++ R70 +++ R71 +++ R73 + R74 ++ R75 +++ R76 + R78 ++ R79 + R80 +++ R82 +++ R83 +++ R84 +++ R86 +++ R87 ++ R88 +++ R89 +++ R90 ++ R91 +++ R92 +++ R93 +++
[1560] The data for all compounds of formula (I) tested wherein R.sub.1 is R.sub.1a; and/or R.sub.4 and R.sub.5 are R.sub.4a and R.sub.5a; and/or A is A.sub.a are presented in Table 17.
TABLE-US-00018 TABLE 17 Selectivity data split into grouping of 2-30 fold (+), >30-60 fold (++) or >60 fold (+++) P Selectivity P226 +++ P227 +++ P228 +++ P229 +++ P230 + P242 +++ P244 +++ P248 +++ P251 +++ P289 +++ P290 +++ P291 +++ P292 +++ P293 +++ P294 +++ P297 +++ P298 +++ P299 +++ P300 +++ P301 +++ P302 +++ P303 +++ P305 +++ P306 +++ P307 +++ P308 +++ P309 +++ P312 +++ P313 +++ P314 +++ P315 +++ P316 +++ P317 +++ P318 +++
[1561] All compounds tested in the assay described in Biological Assay 2 were found to have at least 2 fold selectivity for CTPS1 over CTPS2, with many compounds having a selectivity for CTPS1 of over 60 fold. In particular, these compounds may be expected to have utility in the treatment of diseases whereby a selective CTPS1 compound is beneficial.
[1562] The compounds of the invention are also expected to have utility as research tools, for example, for use in CTPS assays.
[1563] Throughout the specification and the claims and clauses which follow, unless the context requires otherwise, the word ‘comprise’, and variations such as ‘comprises’ and ‘comprising’, will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.
[1564] The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the claims which follow.
[1565] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
CLAUSES OF THE INVENTION
[1566] Clause 1. A compound of formula (I):
##STR00995##
[1567] wherein ring B is selected from the group consisting of:
##STR00996## [1568] wherein X, Y and Z are as defined below; and
##STR00997## [1569] wherein R.sub.3b3c is R.sub.3b or R.sub.3c as defined below;
[1570] wherein when B is (B-a) the compound of formula (I) is a compound of formula (I-a):
##STR00998## [1571] wherein: [1572] A.sub.a is A.sub.aa or A.sub.ba; [1573] wherein: [1574] A.sub.aa is an amine linker having the following structure: —NH—, —CH.sub.2NH— or —NHCH.sub.2—; [1575] A.sub.ba is an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—; [1576] X is N or CH; [1577] Y is N or CR.sub.2a; [1578] Z is N or CR.sub.3a; [1579] with the proviso that when at least one of X or Z is N, Y cannot be N; [1580] R.sub.2a is H, halo, C.sub.1-2alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl or OC.sub.1-2haloalkyl; and [1581] R.sub.3a is H, halo, CH.sub.3, OCH.sub.3, CF.sub.3 or OCF.sub.3; [1582] wherein at least one of R.sub.2a and R.sub.3a is H; [1583] R.sub.1a is R.sub.1aa or R.sub.1ba; [1584] wherein: [1585] R.sub.1aa is NR.sub.32aR.sub.33a; [1586] R.sub.1ba is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; [1587] R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa, or R.sub.4ba and R.sub.5ba; [1588] wherein: [1589] R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [1590] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkykeneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21aR.sub.22a; or [1591] one of the carbons of the C.sub.3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [1592] R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29a; or [1593] R.sub.4ba and R.sub.5ba are each independently H, C.sub.1-6alkyl, C.sub.1-6alkylOH, C.sub.1-6haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, or R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl; and [1594] when A.sub.a is —NHC(═O)— or —NHCH.sub.2—: [1595] R.sub.4ba and R.sub.5ba may additionally be selected from halo, OC.sub.1-6haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-6alkyl and NR.sub.21aR.sub.22a; [1596] Ar1a is a 6-membered aryl or heteroaryl; [1597] Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A.sub.a; [1598] R.sub.10a is H, halo, C.sub.1-3alkyl, C.sub.1-2haloalkyl, OC.sub.1-2alkyl, OC.sub.1-2haloalkyl or CN; [1599] R.sub.11a is H, F, Cl, C.sub.1-2alkyl, CF.sub.3, OCH.sub.3 or CN; [1600] R.sub.12a is attached to Ar2 in the ortho or meta position relative to Ar1a and R.sub.12a is H, halo, C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, hydroxy, C.sub.1-4alkylOH, SO.sub.2C.sub.1-2alkyl, C(O)N(C.sub.1-2alkyl).sub.2, NHC(O)C.sub.1-3alkyl or NR.sub.23aR.sub.24a; and [1601] when A.sub.a is —NHC(═O)—, —NH— or —NHCH.sub.2—: [1602] R.sub.12a may additionally be selected from CN, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2 and a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R.sub.12a together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O—); [1603] R.sub.13a is H or halo; [1604] R.sub.21a is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl, C.sub.1-3alkylOC.sub.1-2alkyl, C.sub.1-4haloalkyl, or C.sub.4-6heterocycloalkyl; [1605] R.sub.22a is H or CH.sub.3; [1606] R.sub.23a is H or C.sub.1-2alkyl; and [1607] R.sub.24a is H or C.sub.1-2alkyl [1608] R.sub.29a is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, CF.sub.3, N(C.sub.1-3alkyl).sub.2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; [1609] R.sub.32a is C.sub.1-3alkyl and R.sub.33 is C.sub.1-3alkyl; or [1610] R.sub.32a and R.sub.33a together with the nitrogen atom to which they are attached form a C.sub.3-5 heterocycloalkyl; [1611] wherein: [1612] R.sub.1a is R.sub.1aa; and/or [1613] R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa; and/or [1614] A.sub.a is A.sub.aa; and
[1615] wherein when B is (B-bc) and R.sub.3a3c is R.sub.3b, the compound of formula (I) is a compound of formula (I-b):
##STR00999## [1616] A.sub.b is A.sub.ab or A.sub.bb; [1617] wherein: [1618] A.sub.ab is —NR.sub.6bCH.sub.2— or —NR.sub.6b—; [1619] A.sub.bb is —NR.sub.6bC(═O)—; [1620] R.sub.1b is R.sub.1ab or R.sub.1bb; [1621] wherein: [1622] R.sub.1ab is NR.sub.32bR.sub.33b; [1623] R.sub.1bb is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, C.sub.1-3alkyleneOC.sub.1-2alkyl, or CF.sub.3; [1624] R.sub.3b is H, halo, CH.sub.3, OC.sub.1-2alkyl or CF.sub.3; [1625] or R.sub.3b together with R.sub.5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; [1626] R.sub.4b and R.sub.5b are either R.sub.4ab and R.sub.5ab or R.sub.4bb and R.sub.5bb; [1627] wherein: [1628] R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [1629] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21bR.sub.22a; or [1630] one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3 alkyl or OC.sub.1-3alkyl; or [1631] R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [1632] R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29b; or [1633] R.sub.4bb and R.sub.5bb are each independently H, halo, C.sub.1-6alkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-6alkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-6alkylOH, C.sub.1-6haloalkyl, OC.sub.1-6haloalkyl or NR.sub.21bR.sub.22b, [1634] or R.sub.4bb is H and R.sub.5bb together with R.sub.3b form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl, [1635] or R.sub.4bb and R.sub.5bb together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl, [1636] or R.sub.4bb is H and R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring; [1637] or R.sub.4bb is O and R.sub.5bb is absent; [1638] R.sub.6b is H or C.sub.1-3alkyl, [1639] or R.sub.6b together with R.sub.11b when in the ortho-position to group A.sub.b are a C.sub.2alkylene chain forming a 5-membered ring, [1640] or R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring and R.sub.4bb is H; [1641] Ar1b is 6-membered aryl or heteroaryl; [1642] Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the pare position relative to group A.sub.b; [1643] R.sub.10b is H, halo, C.sub.1-3alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl, OC.sub.1-2haloalkyl or CN; [1644] R.sub.11b is H, F, Cl, CH.sub.3, ethyl, OCH.sub.3, CF.sub.3, OCF.sub.3 or CN, [1645] or R.sub.11b, when in the ortho-position to group A.sub.b, together with R.sub.6b are a C.sub.2alkylene chain forming a 5-membered ring; [1646] R.sub.12b is attached to Ar2b in the ortho or meta position relative to Ar1b and R.sub.12b is H, halo, C.sub.1-4alkyl, C.sub.2-4alkynyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, OH, C.sub.1-4alkylOH, CN, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, C(═O)C.sub.1-2alkyl, NR.sub.23bR.sub.24b, SO.sub.2C.sub.1-4alkyl, SOC.sub.1-4alkyl, SC.sub.1-4alkyl, SH, C(O)N(CH.sub.3).sub.2, NHC(O)C.sub.1-3alkyl, C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R.sub.12b together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); [1647] R.sub.13b is H, halo, CH.sub.3 or OCH.sub.3; [1648] R.sub.21b is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl, C.sub.1-3alkylOC.sub.1-2alkyl, C.sub.1-4haloalkyl, or C.sub.4-6heterocycloalkyl; [1649] R.sub.22a is H or CH.sub.3; [1650] R.sub.22b is H or C.sub.1-2alkyl; [1651] R.sub.24b is H or C.sub.1-2alkyl; [1652] R.sub.29b is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, CF.sub.3, N(C.sub.1-3alkyl).sub.2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and [1653] R.sub.32b is C.sub.1-3alkyl and R.sub.33b is C.sub.1-3alkyl; or [1654] R.sub.32b and R.sub.33b together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl; [1655] wherein: [1656] R.sub.1b is R.sub.1ab; and/or [1657] R.sub.4b and R.sub.5b are R.sub.4ab and R.sub.5ab; and/or [1658] A is A.sub.ab; or
[1659] wherein when B is (B-bc) and R.sub.3b3c is R.sub.3c, the compound of formula (I) is a compound of formula (I-c):
##STR01000##
[1660] wherein: [1661] A.sub.c is A.sub.ac or A.sub.bc; [1662] wherein: [1663] A.sub.ac is —CH.sub.2NR.sub.6c—; [1664] A.sub.bc is —C(═O)NR.sub.6c—; [1665] R.sub.1c is R.sub.1ac or R.sub.1bc; [1666] wherein: [1667] R.sub.1ac is NR.sub.32cR.sub.33c; [1668] R.sub.1bc is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, C.sub.1-3alkyleneOC.sub.1-2alkyl, or CF.sub.3; [1669] R.sub.3c is H, CH.sub.3, halo, OC.sub.1-2alkyl or CF.sub.3; [1670] R.sub.4c and R.sub.5c are either R.sub.4ac and R.sub.5bc or R.sub.4bc and R.sub.5bc; [1671] wherein: [1672] R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [1673] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21cR.sub.22c; or [1674] one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3 alkyl or OC.sub.1-3alkyl; or [1675] R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [1676] R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29c; or [1677] R.sub.4bc and R.sub.5bc are each independently H, C.sub.1-6alkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, C.sub.1-6alkylOH or C.sub.1-6haloalkyl, [1678] or R.sub.4bc and R.sub.5bc together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl ring; [1679] R.sub.6c is H or C.sub.1-3alkyl; [1680] Ar1c is a 6-membered aryl or heteroaryl; [1681] Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group A.sub.c; [1682] R.sub.10c is H, halo, C.sub.1-3alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl, OC.sub.1-2haloalkyl or CN; [1683] R.sub.11c is H, F, Cl, CH.sub.3, ethyl, OCH.sub.3, CF.sub.3, OCF.sub.3 or CN; [1684] R.sub.12c is attached to Ar2c in the meta or ortho position relative to Ar1c and R.sub.12c is H, halo, C.sub.1-4alkyl, C.sub.2-4alkynyl, C(═O)C.sub.1-2alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, C.sub.1-3 alkyleneOC.sub.1-3alkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, CN, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, OH, C.sub.1-4alkylOH, NR.sub.23cR.sub.24c, SO.sub.2CH.sub.3, C(O)N(CH.sub.3).sub.2, NHC(O)C.sub.1-3alkyl, or a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R.sub.12c together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); [1685] R.sub.21c is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl, C.sub.1-3alkylOC.sub.1-2alkyl, C.sub.1-4haloalkyl, or C.sub.4-6heterocycloalkyl; [1686] R.sub.22c is H or CH.sub.3; [1687] R.sub.23c is H or C.sub.1-2alkyl; [1688] R.sub.24c is H or C.sub.1-2alkyl; [1689] R.sub.29c is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, CF.sub.3, N(C.sub.1-3alkyl).sub.2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and [1690] R.sub.32c is C.sub.1-3alkyl and R.sub.33c is C.sub.1-3alkyl; or [1691] R.sub.32c and R.sub.33c together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl;
[1692] wherein: [1693] R.sub.1c is R.sub.1ac; and/or [1694] R.sub.4c and R.sub.5c are R.sub.4ac and R.sub.5ac; and/or [1695] A.sub.c is A.sub.ac;
[1696] or a salt and/or solvate thereof and/or derivative thereof.
[1697] Clause 2. A compound of formula (I) according to clause 1 wherein the compound of formula (I) is a compound of formula (I-a).
[1698] Clause 3. A compound of formula (I) according to clause 1 or clause 2 wherein the compound of formula (I) is a compound of formula (I-a):
##STR01001##
[1699] wherein [1700] A.sub.a is A.sub.aa or A.sub.ba; [1701] wherein [1702] A.sub.aa is an amine linker having the following structure: —NH—, —CH.sub.2NH— or —NHCH.sub.2—; [1703] A.sub.ba is an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—; [1704] X is N or CH; [1705] Y is N or CR.sub.2a; [1706] Z is N or CR.sub.3a; [1707] with the proviso that when at least one of X or Z is N, Y cannot be N; [1708] R.sub.1a is R.sub.1aa or R.sub.1ba; [1709] wherein [1710] R.sub.1aa is NR.sub.32aR.sub.33a; [1711] R.sub.1ba is C.sub.1-5alkyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; [1712] R.sub.2a is H, halo, C.sub.1-2alkyl, OC.sub.1-2alkyl, C.sub.1-2haloalkyl or OC.sub.1-2haloalkyl; [1713] R.sub.3a is H, halo, CH.sub.3, OCH.sub.3, CF.sub.3 or OCF.sub.3; [1714] wherein at least one of R.sub.2a and R.sub.3a is H; [1715] R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa, or R.sub.4ba and R.sub.5ba; [1716] wherein [1717] R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is: [1718] substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21aR.sub.22a; or [1719] one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [1720] R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl; or [1721] R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29a; or [1722] R.sub.4ba and R.sub.5ba are each independently H, C.sub.1-6alkyl, C.sub.1-6alkylOH, C.sub.1-6haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, or R.sub.4a and R.sub.5a together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl; and [1723] when A.sub.a is —NHC(═O)— or —NHCH.sub.2—: [1724] R.sub.4ba and R.sub.5ba may additionally be selected from halo, OC.sub.1-6haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-6alkyl and NR.sub.21aR.sub.22a; [1725] Ar1a is a 6-membered aryl or heteroaryl; [1726] Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A.sub.a; [1727] R.sub.10a is H, halo, C.sub.1-3alkyl, C.sub.1-2haloalkyl, OC.sub.1-2alkyl, OC.sub.1-2haloalkyl or CN; [1728] R.sub.11a is H, F, Cl, C.sub.1-2alkyl, CF.sub.3, OCH.sub.3 or CN; [1729] R.sub.12a is attached to Ar2a in the ortho or meta position relative to Ar1a and R.sub.12a is H, halo, C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.0-2alkyleneC.sub.3-5cycloalkyl, OC.sub.1-4alkyl, OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, C.sub.1-4haloalkyl, OC.sub.1-4haloalkyl, hydroxy, C.sub.1-4alkylOH, SO.sub.2C.sub.1-2alkyl, C(O)N(C.sub.1-2alkyl).sub.2, NHC(O)C.sub.1-3alkyl or NR.sub.23aR.sub.24a; and [1730] when A.sub.a is —NHC(═O)—, —NH— or —NHCH.sub.2—: [1731] R.sub.12a may additionally be selected from CN, OCH.sub.2CH.sub.2N(CH.sub.3).sub.2 and a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R.sub.12a together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−); [1732] R.sub.13a is H or halo; [1733] R.sub.21a is H, C.sub.1-5alkyl, C(O)C.sub.1-5alkyl, C(O)OC.sub.1-5alkyl; [1734] R.sub.22a is H or CH.sub.3; [1735] R.sub.23a is H or C.sub.1-2alkyl; and [1736] R.sub.24a is H or C.sub.1-2alkyl; [1737] R.sub.29a is C.sub.1-3alkyl, C.sub.0-2alkyleneC.sub.3-5-cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3, or CF.sub.3; [1738] R.sub.32a is C.sub.1-3alkyl and R.sub.33a is C.sub.1-3alkyl; or [1739] R.sub.32a and R.sub.33a together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl;
[1740] wherein [1741] R.sub.1a is R.sub.1aa; and/or [1742] R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa; and/or [1743] A is A.sub.a;
[1744] or a salt and/or solvate thereof and/or derivative thereof.
[1745] Clause 4. The compound according to any one of clauses 1 to 3 wherein A.sub.a is —C(═O)NH—.
[1746] Clause 5. The compound according to any one of clauses 1 to 3 wherein A.sub.a is —NHC(═O)—.
[1747] Clause 6. The compound according to any one of clauses 1 to 3 wherein A.sub.a is —NH—.
[1748] Clause 7. The compound according to any one of clauses 1 to 3 wherein A.sub.a is —CH.sub.2NH—.
[1749] Clause 8. The compound according to any one of clauses 1 to 3 wherein A.sub.a is —NHCH.sub.2—.
[1750] Clause 9. The compound according to any one of clauses 1 to 8 wherein X is N.
[1751] Clause 10. The compound according to any one of clauses 1 to 8 wherein X is CH.
[1752] Clause 11. The compound according to any one of clauses 1 to 8 or 10 wherein Y is N.
[1753] Clause 12. The compound according to any one of clauses 1 to 10 wherein Y is CR.sub.2a.
[1754] Clause 13. The compound according to any one of clauses 1 to 10 or 12 wherein Z is N.
[1755] Clause 14. The compound according to any one of clauses 1 to 12 wherein Z is CR.sub.3a.
[1756] Clause 15. The compound according to any one of clauses 1 to 8 wherein X is N, Y is CR.sub.2a and Z is N.
[1757] Clause 16. The compound according to any one of clauses 1 to 8 wherein X is N, Y is CR.sub.2a and Z is CR.sub.3a.
[1758] Clause 17. The compound according to any one of clauses 1 to 8 wherein X is CH, Y is N and Z is CR.sub.3a.
[1759] Clause 18. The compound according to any one of clauses 1 to 8 wherein X is CH, Y is CR.sub.2a and Z is CR.sub.3a.
[1760] Clause 19. The compound according to any one of clauses 1 to 8 wherein X is CH, Y is CR.sub.2a and Z is N.
[1761] Clause 20. The compound according to any one of clauses 1 to 19 wherein R.sub.1a is R.sub.1aa.
[1762] Clause 21. The compound according to clause 20 wherein R.sub.1aa is NR.sub.32aR.sub.33a, R.sub.32a is C.sub.1-3alkyl and R.sub.33a is C.sub.1-3alkyl.
[1763] Clause 22. The compound according to clause 21 wherein R.sub.32a is methyl or ethyl, such as methyl.
[1764] Clause 23. The compound according to either clause 21 or 22 wherein R.sub.33a is methyl or ethyl, such as methyl.
[1765] Clause 24. The compound according to clause 21 wherein R.sub.32a is methyl and R.sub.33a is methyl.
[1766] Clause 25. The compound according to clause 20 wherein R.sub.1aa is NR.sub.32aR.sub.33a and wherein R.sub.32a and R.sub.33a together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl.
[1767] Clause 26. The compound according to clause 25 wherein the C.sub.3-5heterocycloalkyl is selected from the group consisting of azirdine, azetidine and pyrrolidine.
[1768] Clause 27. The compound according to any one of clauses 1 to 19 wherein R.sub.1a is R.sub.1ba.
[1769] Clause 28. The compound according to any one of clauses 1 to 19 wherein R.sub.1a is C.sub.1-5alkyl.
[1770] Clause 29. The compound according to any one of clauses 1 to 19 wherein R.sub.1a is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3.
[1771] Clause 30. The compound according to clause 29 wherein R.sub.1a is C.sub.0-2alkyleneC.sub.3-5cycloalkyl.
[1772] Clause 31. The compound according to clause 29 wherein R.sub.1a is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is substituted by CH.sub.3.
[1773] Clause 32. The compound according to any one of clauses 29 to 31 wherein R.sub.1a is C.sub.3-5cycloalkyl optionally substituted by CH.sub.3.
[1774] Clause 33. The compound according to any one of clauses 29 to 31 wherein R.sub.1a is C.sub.1alkyleneC.sub.3-5cycloalkyl optionally substituted by CH.sub.3.
[1775] Clause 34. The compound according to any one of clauses 29 to 31 wherein R.sub.1a is C.sub.2alkyleneC.sub.3-5cycloalkyl optionally substituted by CH.sub.3.
[1776] Clause 35. The compound according to any one of clauses 1 to 19 wherein R.sub.1a is cyclopropyl, cyclopropyl substituted by CH.sub.3 at the point of attachment, cyclobutyl, methyl or ethyl.
[1777] Clause 36. The compound according to clause 35 wherein R.sub.1a is cyclopropyl, methyl or ethyl.
[1778] Clause 37. The compound according to clause 36 wherein R.sub.1a is cyclopropyl.
[1779] Clause 38. The compound according to any one of clauses 1 to 19 wherein R.sub.1a is CF.sub.3.
[1780] Clause 39. The compound according to any one of clauses 1 to 38 wherein R.sub.2a is H.
[1781] Clause 40. The compound according to any one of clauses 1 to 38 wherein R.sub.2a is halo, such as F, Cl or Br e.g. Cl or Br.
[1782] Clause 41. The compound according to any one of clauses 1 to 38 wherein R.sub.2a is C.sub.1-2alkyl such as CH.sub.3.
[1783] Clause 42. The compound according to any one of clauses 1 to 38 wherein R.sub.2a is OC.sub.1-2alkyl such as OCH.sub.3.
[1784] Clause 43. The compound according to any one of clauses 1 to 38 wherein R.sub.2a is C.sub.1-2 haloalkyl such as CF.sub.3.
[1785] Clause 44. The compound according to any one of clauses 1 to 38 wherein R.sub.2a is OC.sub.1-2 haloalkyl such as OCF.sub.3.
[1786] Clause 45. The compound according to any one of clauses 1 to 44 wherein R.sub.3a is H.
[1787] Clause 46. The compound according to any one of clauses 1 to 44 wherein R.sub.3a is halo.
[1788] Clause 47. The compound according to clause 46 wherein R.sub.3a is fluoro.
[1789] Clause 48. The compound according to any one of clauses 1 to 44 wherein R.sub.3a is CH.sub.3.
[1790] Clause 49. The compound according to any one of clauses 1 to 44 wherein R.sub.3a is OCH.sub.3.
[1791] Clause 50. The compound according to any one of clauses 1 to 44 wherein R.sub.3a is CF.sub.3.
[1792] Clause 51. The compound according to any one of clauses 1 to 44 wherein R.sub.3a is OCF.sub.3.
[1793] Clause 52. The compound according to any one of clauses 1 to 51 wherein at least one of R.sub.2a and R.sub.5a is H.
[1794] Clause 53. The compound according to any one of clauses 1 to 52 wherein R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa.
[1795] Clause 54. The compound according to clause 53 wherein R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21aR.sub.22a.
[1796] Clause 55. The compound according to clause 54 wherein R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is substituted by one substituent.
[1797] Clause 56. The compound according to either clause 54 or 55 wherein each substituent is independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3 haloalkyl, halo, OC.sub.1-3haloalkyl, OC.sub.1-3alkyl and NR.sub.21aR.sub.22a.
[1798] Clause 57. The compound according to clause 56 wherein each substituent is independently selected from the group consisting of oxo, OH, halo, OC.sub.1-3alkyl and NR.sub.21aR.sub.22a.
[1799] Clause 58. The compound according to clause 57 wherein each substituent is independently selected from the group consisting of oxo, OH, fluoro and NR.sub.21aR.sub.22a.
[1800] Clause 59. The compound according to clause 53 wherein R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl wherein one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl.
[1801] Clause 60. The compound according to clause 53 wherein R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl.
[1802] Clause 61. The compound according to either clause 59 or 60 wherein R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl which is substituted by one substituent.
[1803] Clause 62. The compound according to either clause 59 or 60 wherein R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6 heterocycloalkyl which is unsubstituted.
[1804] Clause 63. The compound according to any one of clauses 59, 60 or 61 wherein each substituent is independently selected from the group consisting of C.sub.1-2alkyl or OCH.sub.3.
[1805] Clause 64. The compound according to any one of clauses 59 to 63 wherein a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring.
[1806] Clause 65. The compound according to any one of clauses 59 to 63 wherein a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6heterocycloalkyl ring.
[1807] Clause 66. The compound according to any one of clauses 59 or 61 to 65 wherein the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached is cyclopropyl.
[1808] Clause 67. The compound according to any one of clauses 59 or 61 to 65 wherein the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached is cyclobutyl.
[1809] Clause 68. The compound according to any one of clauses 59 or 61 to 65 wherein the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached is cyclopentyl.
[1810] Clause 69. The compound according to any one of clauses 59 or 61 to 65 wherein the C.sub.3-6cycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached is cyclohexyl.
[1811] Clause 70. The compound according to any one of clauses 60 to 65 wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached is heterocyclopropyl.
[1812] Clause 71. The compound according to any one of clauses 60 to 65 wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached is heterocyclobutyl.
[1813] Clause 72. The compound according to any one of clauses 60 to 65 wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached is heterocyclopentyl.
[1814] Clause 73. The compound according to any one of clauses 60 to 65 wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached is heterocyclohexyl.
[1815] Clause 74. The compound according to any one of clauses 59 or 61 to 69 wherein one of the carbons is quaternary and is attached to a 5-membered dioxalane ring to form the following structure:
##STR01002##
[1816] wherein m is 1 or 2 and n is 0, 1 or 2.
[1817] Clause 75. The compound according to any one of clauses 54 to 58 wherein R.sub.21a is H.
[1818] Clause 76. The compound according to any one of clauses 54 to 58 wherein R.sub.21a is C.sub.1-5alkyl, such as methyl, ethyl or propyl.
[1819] Clause 77. The compound according to any one of clauses 54 to 58 wherein R.sub.21a is C(O)C.sub.1-5alkyl, such as C(O)CH.sub.3.
[1820] Clause 78. The compound according to any one of clauses 54 to 58 wherein R.sub.21a is C(O)OC.sub.1-5alkyl, such as C(O)OCH.sub.3 or C(O)Otert-butyl.
[1821] Clause 79. The compound according to any one of clauses 54 to 58 wherein R.sub.21a is C.sub.1-3 alkylOC.sub.1-2alkyl such as CH.sub.2CH.sub.2OCH.sub.3.
[1822] Clause 80. The compound according to any one of clauses 54 to 58 wherein R.sub.21a is C.sub.1-4 haloalkyl such as CH.sub.2CHF.sub.2.
[1823] Clause 81. The compound according to any one of clauses 54 to 58 wherein R.sub.21a is C.sub.4-6heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.
[1824] Clause 82. The compound according to any one of clauses 54 to 58 or 75 to 81 wherein R.sub.22a is H.
[1825] Clause 83. The compound according to any one of clauses 54 to 58 or 75 to 81 wherein R.sub.22a is CH.sub.3.
[1826] Clause 84. The compound according to clause 53 wherein R.sub.4aa and R.sub.5aa together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29a.
[1827] Clause 85. The compound according to clause 84 wherein the C.sub.3-6heterocycloalkyl is piperidinyl and the nitrogen atom is in the 4-position relative to the quaternary carbon:
##STR01003##
[1828] Clause 86. The compound according to either clause 84 or 85 wherein R.sub.29a is C.sub.1-3alkyl.
[1829] Clause 87. The compound according to clause 86 wherein R.sub.29a is methyl.
[1830] Clause 88. The compound according to either clause 84 or 85 wherein R.sub.29a is N(C.sub.1-3alkyl).sub.2 e.g. N(CH.sub.3).sub.2.
[1831] Clause 89. The compound according to either clause 84 or 85 wherein R.sub.29a is 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl such as pyrazolyl substituted by methyl.
[1832] Clause 90. The compound according to any one of clauses 1 to 52 wherein R.sub.4a and R.sub.5a are R.sub.4ba and R.sub.5ba.
[1833] Clause 91. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is H.
[1834] Clause 92. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is C.sub.1-6alkyl.
[1835] Clause 93. The compound according to clause 92 wherein R.sub.4ba is methyl or ethyl.
[1836] Clause 94. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is C.sub.1-6alkylOH.
[1837] Clause 95. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is C.sub.1-6haloalkyl such as CF.sub.3.
[1838] Clause 96. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is C.sub.0-2alkyleneC.sub.3-6cycloalkyl.
[1839] Clause 97. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl.
[1840] Clause 98. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is C.sub.1-3 alkyleneOC.sub.1-3alkyl.
[1841] Clause 99. The compound according to clause 98 wherein R.sub.4ba is C.sub.2alkyleneOC.sub.1-3alkyl.
[1842] Clause 100. The compound according to clause 99 wherein R.sub.4ba is CH.sub.2CH.sub.2OCH.sub.3.
[1843] Clause 101. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is halo.
[1844] Clause 102. The compound according to clause 101 wherein R.sub.4ba is fluoro.
[1845] Clause 103. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is OC.sub.1-6haloalkyl, such as OC.sub.1-4haloalkyl.
[1846] Clause 104. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is OC.sub.0-2alkyleneC.sub.3-6cycloalkyl.
[1847] Clause 105. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl.
[1848] Clause 108. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is OC.sub.1-6alkyl, in particular OC.sub.1-4alkyl.
[1849] Clause 107. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is NR.sub.21aR.sub.22a.
[1850] Clause 108. The compound according to clause 107 wherein R.sub.21a is H, CH.sub.3, C(O)CH.sub.3, C(O)OCH.sub.3 or C(O)Otert-butyl.
[1851] Clause 109. The compound according to clause 107 wherein R.sub.21a is C.sub.1-3alkylOC.sub.1-2alkyl such as CH.sub.2CH.sub.2OCH.sub.3.
[1852] Clause 110. The compound according to clause 107 wherein R.sub.21a is C.sub.1-4haloalkyl such as CH.sub.2CHF.sub.2.
[1853] Clause 111. The compound according to clause 107 wherein R.sub.21a is C.sub.4-8heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.
[1854] Clause 112. The compound according to any one of clauses 107 or 111 wherein R.sub.22a is H or CH.sub.3 such as H.
[1855] Clause 113. The compound according to any one of clauses 107 to 112 wherein R.sub.21a is C(O)OCH.sub.3 and R.sub.22a is H, R.sub.21a is C(O)CH.sub.3 and R.sub.22a is H, R.sub.21a and R.sub.22a are both CH.sub.3, or R.sub.21a and R.sub.22a are both H.
[1856] Clause 114. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is H, C.sub.1-6alkyl, C.sub.1-6alkylOH, C.sub.1-6haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, or R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl.
[1857] Clause 115. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba is halo, OC.sub.1-6haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-6alkyl or NR.sub.21aR.sub.22a.
[1858] Clause 116. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is H.
[1859] Clause 117. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is C.sub.1-6alkyl.
[1860] Clause 118. The compound according to clause 117 wherein R.sub.5ba is methyl or ethyl.
[1861] Clause 119. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is C.sub.1-6alkylOH.
[1862] Clause 120. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is C.sub.1-6haloalkyl such as CF.sub.3.
[1863] Clause 121. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is C.sub.0-2alkyleneC.sub.3-6cycloalkyl.
[1864] Clause 122. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl.
[1865] Clause 123. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is C.sub.1-3alkyleneOC.sub.1-3alkyl, such as C.sub.2alkyleneOC.sub.1-3alkyl e.g. CH.sub.2CH.sub.2OCH.sub.3.
[1866] Clause 124. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is halo.
[1867] Clause 125. The compound according to clause 124 wherein R.sub.5ba is fluoro.
[1868] Clause 126. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is OC.sub.1-6haloalkyl, such as OC.sub.1-4haloalkyl.
[1869] Clause 127. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is OC.sub.0-2alkyleneC.sub.3-6cycloalkyl.
[1870] Clause 128. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl.
[1871] Clause 129. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is OC.sub.1-6alkyl, in particular OC.sub.1-4alkyl.
[1872] Clause 130. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is NR.sub.21aR.sub.22a.
[1873] Clause 131. The compound according to clause 130 wherein R.sub.21a is H, CH.sub.3, C(O)CH.sub.3, C(O)OCH, or C(O)Otert-butyl.
[1874] Clause 132. The compound according to clause 130 wherein R.sub.21a is C.sub.1-3alkylOC.sub.1-2alkyl such as CH.sub.2CH.sub.2OCH.sub.3.
[1875] Clause 133. The compound according to clause 130 wherein R.sub.21a is C.sub.1-4haloalkyl such as CH.sub.2CHF.sub.2.
[1876] Clause 134. The compound according to clause 130 wherein R.sub.21, is C.sub.4-6heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.
[1877] Clause 135. The compound according to any one of clauses 130 to 134 wherein R.sub.22a is H or CH.sub.3 such as H.
[1878] Clause 136. The compound according to any one of clauses 130 to 134 wherein R.sub.21a is C(O)OCH.sub.3 and R.sub.22a is H, R.sub.21a is C(O)CH.sub.3 and R.sub.22a is H, R.sub.21a and R.sub.22a are both CH.sub.3, or R.sub.21a and R.sub.22a are both H.
[1879] Clause 137. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is H, C.sub.1-6alkyl, C.sub.1-6alkylOH, C.sub.1-6haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, or R.sub.4 and R.sub.5 together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heterocycloalkyl.
[1880] Clause 138. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R.sub.5ba is halo, OC.sub.1-6haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-6alkyl or NR.sub.21aR.sub.22a.
[1881] Clause 139. The compound according to any one of clauses 1 to 52 or 90 to 116 wherein R.sub.4ba and R.sub.5ba are both H.
[1882] Clause 140. The compound according to any one of clauses 1 to 52, 93 or 118 wherein R.sub.4ba and R.sub.5ba are both methyl.
[1883] Clause 141. The compound according to any one of clauses 1 to 52, 93 or 118 wherein R.sub.4ba and R.sub.5ba are both ethyl.
[1884] Clause 142. The compound according to any one of clauses 1 to 52, 102 or 125 wherein R.sub.4ba and R.sub.5ba, are both fluoro.
[1885] Clause 143. The compound according to any one of clauses 1 to 52,102 or 116 wherein R.sub.4ba is ethyl and R.sub.5ba is H.
[1886] Clause 144. The compound according to any one of clauses 1 to 52, 102 or 118 wherein R.sub.4ba is fluoro and R.sub.5ba is ethyl.
[1887] Clause 145. The compound according to any one of clauses 1 to 52, 100 or 116 wherein R.sub.4ba is CH.sub.2CH.sub.2OCH.sub.3 and R.sub.5ba is H.
[1888] Clause 148. The compound according to any one of clauses 143 to 145 wherein R.sub.4ba and R.sub.5ba are arranged in an S configuration.
[1889] Clause 147. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl.
[1890] Clause 148. The compound according to clause 147 wherein R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a cyclopropyl ring or a cyclopentyl ring, such as a cyclopentyl ring.
[1891] Clause 149. The compound according to any one of clauses 1 to 52 or 90 wherein R.sub.4ba and R.sub.5ba together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl, such as heterocyclohexyl, such as tetrahydropyranal.
[1892] Clause 150. The compound according to any one of clauses 1 to 149 wherein Ar1a is phenyl.
[1893] Clause 151. The compound according to anyone of clauses 1 to 149 wherein Ar1a is 2-pyridyl.
[1894] Clause 152. The compound according to any one of clauses 1 to 149 wherein Ar1a is 3-pyridyl.
[1895] Clause 153. The compound according to any one of clauses 1 to 152 wherein Ar2a is 3-pyridyl.
[1896] Clause 154. The compound according to any one of clauses 1 to 152 wherein Ar2a is 2,5-pyrazinyl.
[1897] Clause 155. The compound according to any one of clauses 1 to 154 wherein R.sub.10a is H.
[1898] Clause 156. The compound according to any one of clauses 1 to 154 wherein R.sub.10a is halo such as fluoro or chloro.
[1899] Clause 157. The compound according to any one of clauses 1 to 154 wherein R.sub.10a is C.sub.1-3alkyl.
[1900] Clause 158. The compound according to clause 157 wherein R.sub.10a is C.sub.1-2alkyl such as CH.sub.3.
[1901] Clause 159. The compound according to any one of clauses 1 to 154 wherein R.sub.10a is C.sub.1-2 haloalkyl such as CF.sub.3.
[1902] Clause 160. The compound according to any one of clauses 1 to 154 wherein R.sub.10a is OC.sub.1-2alkyl such as OCH.sub.3.
[1903] Clause 161. The compound according to any one of clauses 1 to 154 wherein R.sub.10a is OC.sub.1-2 haloalkyl such as OCF.sub.3.
[1904] Clause 162. The compound according to any one of clauses 1 to 154 wherein R.sub.10a is CN.
[1905] Clause 163. The compound according to any one of clauses 1 to 162 wherein R.sub.11a is H.
[1906] Clause 164. The compound according to any one of clauses 1 to 162 wherein R.sub.11a is F.
[1907] Clause 165. The compound according to any one of clauses 1 to 162 wherein R.sub.11a is Cl.
[1908] Clause 166. The compound according to any one of clauses 1 to 162 wherein R.sub.11a is C.sub.1-2 alkyl.
[1909] Clause 167. The compound according to clause 166 wherein R.sub.11a is CH.sub.3.
[1910] Clause 168. The compound according to any one of clauses 1 to 162 wherein R.sub.11a is CF.sub.3.
[1911] Clause 169. The compound according to any one of clauses 1 to 162 wherein R.sub.11a is OCH.sub.3.
[1912] Clause 170. The compound according to any one of clauses 1 to 162 wherein R.sub.11a is CN.
[1913] Clause 171. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is H.
[1914] Clause 172. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is halo such as fluoro or chloro.
[1915] Clause 173. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is C.sub.1-4 alkyl such as CH.sub.3.
[1916] Clause 174. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is C.sub.2-4alkenyl.
[1917] Clause 175. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is C.sub.0-2alkyleneC.sub.3-5cycloalkyl such as C.sub.0alkyleneC.sub.3cycloalkyl.
[1918] Clause 176. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is OC.sub.1-4 alkyl such as methoxy, ethoxy or isopropoxy.
[1919] Clause 177. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is OC.sub.0-2alkyleneC.sub.3-5cycloalkyl such as OC.sub.0alkyleneC.sub.3cycloalkyl.
[1920] Clause 178. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is C.sub.1-4 haloalkyl such as CF.sub.3.
[1921] Clause 179. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is OC.sub.1-4 haloalkyl such as OCH.sub.2CF.sub.3 or OCHF.sub.2.
[1922] Clause 180. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is OH.
[1923] Clause 181. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is C.sub.1-4 alkylOH.
[1924] Clause 182. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is SO.sub.2C.sub.1-2alkyl.
[1925] Clause 183. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is NHC(O)C.sub.1-3alkyl.
[1926] Clause 184. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is NR.sub.23aR.sub.24a.
[1927] Clause 185. The compound according to clause 184 wherein R.sub.24a is H or C.sub.1-2alkyl such as H or CH.sub.3.
[1928] Clause 186. The compound according to clause 184 or 185 wherein R.sub.24a is H or C.sub.1-2alkyl such as CH.sub.3 or ethyl.
[1929] Clause 187. The compound according to any one of clauses 184 to 186 wherein R.sub.23a is H and R.sub.24a is ethyl; or R.sub.23a is CH.sub.3 and R.sub.24 is CH.sub.3.
[1930] Clause 188. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is CN.
[1931] Clause 189. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is OCH.sub.2CH.sub.2N(CH.sub.3).sub.2.
[1932] Clause 190. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a.
[1933] Clause 191. The compound according to any one of clauses 1 to 170 wherein R.sub.12a together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−).
[1934] Clause 192. The compound according to any one of clauses 1 to 170 wherein R.sub.12a is C(O)N(C.sub.1-2alkyl).sub.2.
[1935] Clause 193. The compound according to any one of clauses 1 to 192 wherein R.sub.13a is H.
[1936] Clause 194. The compound according to any one of clauses 1 to 192 wherein R.sub.13a is halo such as fluoro or chloro e.g. fluoro.
[1937] Clause 195. The compound according to any one of clauses 1 to 194 when R.sub.1ba is methyl, at least one of R.sub.4ba, R.sub.5ba, R.sub.10ba, R.sub.11ba, R.sub.12ba and R.sub.13ba is other than H.
[1938] Clause 196. The compound according to any one of clauses 1 to 195 wherein at least one, such as only one, nitrogen atom in any of the C.sub.3-6heterocycloalkyl rings, such as only one of the C.sub.3-6heterocycloalkyl rings is substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl, C(O)NHC.sub.1-4 haloalkyl such as C(O)OtBu, C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, or C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3.
[1939] Clause 197. The compound according to any one of clauses 1 to 195 wherein all nitrogen atoms in all C.sub.3-6heterocycloalkyl rings are not substituted.
[1940] Clause 198. The compound according to any one of clauses 1 to 197 wherein at least one, such as only one, sulphur atom in any of the C.sub.3-6heterocycloalkyl rings, such as only one of the C.sub.3-6heterocycloalkyl rings is substituted, for example by one oxygen atom to form S═O or by two oxygen atoms to form S(O).sub.2.
[1941] Clause 199. The compound according to any one of clauses 1 to 197 wherein all sulphur atoms in all C.sub.3-6heterocycloalkyl rings are not substituted.
[1942] Clause 200. The compound according to any one of clauses 1 to 199 wherein R.sub.1a is R.sub.1aa and R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa.
[1943] Clause 201. The compound according to any one of clauses 1 to 199 wherein R.sub.1a is R.sub.1aa and A.sub.a is —NH—, —CH.sub.2NH— or —NHCH.sub.2—.
[1944] Clause 202. The compound according to any one of clauses 1 to 199 wherein R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa and A.sub.a is —NH—, —CH.sub.2NH— or —NHCH.sub.2—.
[1945] Clause 203. The compound according to any one of clauses 1 to 199 wherein R.sub.1a is R.sub.1aa, R.sub.4a and R.sub.5a are R.sub.4aa and R.sub.5aa and A.sub.a is —NH—, —CH.sub.2NH— or —NHCH.sub.2—.
[1946] Clause 204. A compound of the examples P226, P227, P228, P229, P230, P235, P242, P244, P248, P251, P254, P255, P256, P258, P260, P261, P288, P289, P290, P291, P292, P293, P294, P295, P296, P297, P298, P299, P300, P301, P302, P303, P304, P305, P306, P307, P308, P309, P310, P311, P312, P313, P314, P315, P316, P317 and P318.
[1947] Clause 205. A compound of formula (II-a):
##STR01004##
[1948] wherein R.sub.1, X, Y, Z, R.sub.4 and R.sub.5 are as defined in any preceding clause and R is H, C.sub.1-6alkyl (e.g. methyl and ethyl) or benzyl, or a salt, such as a pharmaceutically acceptable salt, thereof.
[1949] Clause 206. A compound of formula (XX-a):
##STR01005##
[1950] wherein Ar1, Ar2, R.sub.1, X, Y, Z, R.sub.4, R.sub.5, R.sub.10, R.sub.11, R.sub.12 and R.sub.13 are as defined in any preceding clause and P is a nitrogen protecting group such as para-methoxybenzyl, or a salt, such as a pharmaceutically acceptable salt, thereof.
[1951] Clause 207. A compound of formula (XXIV-a):
##STR01006##
[1952] wherein Ar1, Ar2, A, R.sub.1, X, Y, Z, R.sub.4, R.sub.5, R.sub.10, R.sub.11, R.sub.12 and R.sub.13 are as defined in any preceding clause and P is a nitrogen protecting group such as para-methoxybenzyl, or a salt such as a pharmaceutically acceptable salt, thereof.
[1953] Clause 208. A compound of formula (XXXI-a):
##STR01007##
[1954] wherein Ar1, Ar2, A, X, Y, Z, R.sub.4, R.sub.5, R.sub.10, R.sub.11, R.sub.12 and R.sub.13 are as defined in any preceding clause, or a salt, such as a pharmaceutically acceptable salt, thereof.
[1955] Clause 209. A compound of formula (XXXXII-a):
##STR01008##
[1956] wherein R.sub.1, X, Y, Z, R.sub.4 and R.sub.5 are as defined in any preceding clause, or a salt, such as a pharmaceutically acceptable salt, thereof.
[1957] Clause 210. A compound of formula (LI-a):
##STR01009##
[1958] wherein Ar1, Ar2, A, R.sub.4 and R.sub.5 are as defined in any preceding clause and X.sub.1 is Cl or Br, or a salt, such as a pharmaceutically acceptable salt, thereof.
[1959] Clause 211. A compound of formula (LVIII-a):
##STR01010##
[1960] wherein R.sub.1, Ar1, A, X, Y, Z, R.sub.4 and R.sub.5 are as defined in any preceding clause, or a salt, such as a pharmaceutically acceptable salt, thereof.
[1961] Clause 212. A compound of formula (XXXIII-a):
##STR01011##
[1962] wherein X, Y, Z, R.sub.4 and R.sub.5 are as defined in any preceding clause and alkyl is C.sub.1-4alkyl such as methyl or ethyl, e.g. methyl, or a salt, such as a pharmaceutically acceptable salt, thereof.
[1963] Clause 213. A compound of formula (LXXXIII-a):
##STR01012##
[1964] wherein X, Y, Z, R.sub.4 and R.sub.5 are as defined in any preceding clause and alkyl is C.sub.1-4alkyl such as methyl or ethyl, e.g. methyl, or a salt, such as pharmaceutically acceptable salt, thereof.
[1965] Clause 214. A compound selected from the group consisting of: [1966] a compound of formula (XXXIV-a):
##STR01013##
[1967] wherein and alkyl is C.sub.1-4alkyl such as methyl or ethyl, e.g. methyl; [1968] a compound of formula (LXXIII-a):
##STR01014##
and [1969] a compound of formula (LXXIV-a):
##STR01015##
[1970] wherein X, Y, Z, R.sub.4, R.sub.5, Ar1 and Ar2 are as defined in any preceding clause;
[1971] and salts such as pharmaceutically acceptable salts, thereof.
[1972] Clause 215. A compound of formula (LXXI-a):
##STR01016##
[1973] wherein Ar1, Ar2, R.sub.10, R.sub.11, R.sub.12 and R.sub.13 are as defined in any preceding clause, or a salt such as a pharmaceutically acceptable salt, thereof.
[1974] Clause 216. A compound of formula (LXXII-a):
##STR01017##
[1975] wherein Ar1, Ar2, R.sub.10, R.sub.11, R.sub.12 and R.sub.13 are as defined in any preceding clause, or a salt such as a pharmaceutically acceptable salt, thereof.
[1976] Clause 217. A compound of INTC186 to INTC218 and INTC232 to INTC247, or salt such as pharmaceutically acceptable salt thereof.
[1977] Clause 218. The compound of formula (I) according to clause 1 wherein the compound of formula (I) is a compound of formula (I-b).
[1978] Clause 219. The compound according to clause 218 wherein R.sub.1b is R.sub.1ab.
[1979] Clause 220. The compound according to clause 219 wherein R.sub.1ab is NR.sub.32bR.sub.33b and wherein R.sub.32b is C.sub.1-3alkyl and R.sub.33b is C.sub.1-3alkyl.
[1980] Clause 221. The compound according to clause 220 wherein R.sub.32b is methyl or ethyl.
[1981] Clause 222. The compound according to clause 221 wherein R.sub.32b is methyl.
[1982] Clause 223. The compound according to any one of clauses 220 or 222 wherein R.sub.33b is methyl or ethyl such as methyl.
[1983] Clause 224. The compound according to any one of clauses 220 to 223 wherein R.sub.32b is methyl and R.sub.33b is methyl.
[1984] Clause 225. The compound according to clause 219 wherein R.sub.1ab is NR.sub.32aR.sub.33b and R.sub.32b and R.sub.33b together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl.
[1985] Clause 226. The compound according to clause 225 wherein the C.sub.3-5heterocycloalkyl is selected from the group consisting of aziridine, azetidine and pyrrolidine.
[1986] Clause 227. The compound according to clause 218 wherein R.sub.1b is R.sub.1bb.
[1987] Clause 228. The compound according to clause 227 wherein R.sub.1bb is C.sub.1-5alkyl such as CH.sub.3 or ethyl.
[1988] Clause 229. The compound according to clause 228 wherein R.sub.1bb is CH.sub.3.
[1989] Clause 230. The compound according to any one of clauses 227 wherein R.sub.1bb is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3.
[1990] Clause 231. The compound according to clause 230, wherein R.sub.1bb is C.sub.0-2alkyleneC.sub.3-5cycloalkyl.
[1991] Clause 232. The compound according to clause 230, wherein R.sub.1bb is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is substituted by CH.sub.3.
[1992] Clause 233. The compound according to any one of clauses 230 to 232, wherein R.sub.1bb is C.sub.3-5cycloalkyl, optionally substituted by CH.sub.3.
[1993] Clause 234. The compound according to any one of clauses 230 to 232, wherein R.sub.1bb is C.sub.1alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3.
[1994] Clause 235. The compound according to any one of clauses 230 to 232, wherein R.sub.1bb is C.sub.2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3.
[1995] Clause 236. The compound according to any one of clauses 230 to 235, wherein R.sub.1bb is C.sub.0-2alkyleneC.sub.3cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3.
[1996] Clause 237. The compound according to any one of clauses 230 to 235 wherein R.sub.1bb is C.sub.0-2alkyleneC.sub.4cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3.
[1997] Clause 238. The compound according to any one of clauses 230 to 235 wherein R.sub.1bb is C.sub.0-2alkyleneC.sub.3cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3.
[1998] Clause 239. The compound according to any one of clauses 230 to 238 wherein R.sub.1bb is cyclopropyl, cyclopropyl substituted by CH.sub.3 at the point of attachment, cyclopropylmethylene, cyclobutyl, cyclopentyl, CH.sub.3, ethyl, isopropyl, sec-butyl or tert-butyl, especially cyclopropyl, cyclopropyl substituted by CH.sub.3 at the point of attachment, cyclobutyl, CH.sub.3, ethyl or isopropyl.
[1999] Clause 240. The compound according to any one of clauses 239 wherein R.sub.1bb is cyclopropyl, cyclopropyl substituted by CH.sub.3 at the point of attachment, cyclobutyl, CH.sub.3, isopropyl, sec-butyl or tert-butyl.
[2000] Clause 241. The compound according to any clause 240 wherein R.sub.1bb is cyclopropyl, cyclopropyl substituted by CH.sub.3 at the point of attachment, cyclobutyl or isopropyl.
[2001] Clause 242. The compound according to any one of clauses 218 to 241 wherein R.sub.3b is H.
[2002] Clause 243. The compound according to any one of clauses 218 to 241 wherein R.sub.3b is chloro or fluoro.
[2003] Clause 244. The compound according to any one of clauses 218 to 241 wherein R.sub.3b is CH.sub.3.
[2004] Clause 245. The compound according to any one of clauses 218 to 241 wherein R.sub.3b is OCH.sub.3.
[2005] Clause 246. The compound according to any one of clauses 218 to 241 wherein R.sub.3b is CF.sub.3.
[2006] Clause 247. The compound according to any one of clauses 218 to 241 wherein R.sub.3b together with R.sub.5bb forms a 5- or 6-membered cycloalkyl.
[2007] Clause 248. The compound according to clause 247 wherein R.sub.b together with Ru forms a 5-membered cycloalkyl.
[2008] Clause 249. The compound according to any one of clauses 218 to 248 wherein R.sub.4b and R.sub.5b are R.sub.4ab and R.sub.5ab.
[2009] Clause 250. The compound according to clause 249 wherein R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21bR.sub.22b.
[2010] Clause 251. The compound according to clause 250 wherein R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is substituted by one substituent.
[2011] Clause 252. The compound according to clause 250 or 251 wherein each substituent is independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3 haloalkyl, halo, OC.sub.1-3haloalkyl, OC.sub.1-3alkyl and NR.sub.21bR.sub.22b.
[2012] Clause 253. The compound according to clause 252 wherein each substituent is independently selected from the group consisting of oxo, OH, halo, OC.sub.1-3alkyl and NR.sub.21bR.sub.22b, such as oxo, OH, fluoro and NR.sub.21bR.sub.22b.
[2013] Clause 254. The compound according to any one of clauses 250 to 253 wherein R.sub.21b is H.
[2014] Clause 255. The compound according to any one of clauses 250 to 253 wherein R.sub.21b is C.sub.1-5alkyl, such as methyl, ethyl or propyl.
[2015] Clause 256. The compound according to any one of clauses 250 to 253 wherein R.sub.21b is C(O)C.sub.1-5alkyl, such as C(O)CH.sub.3.
[2016] Clause 257. The compound according to any one of clauses 250 to 253 wherein R.sub.21b is C(O)OC.sub.1-5alkyl, such as C(O)OCH.sub.3 or C(O)Otert-butyl.
[2017] Clause 258. The compound according to any one of clauses 250 to 253 wherein R.sub.21b is C.sub.1-3 alkylOC.sub.1-2alkyl such as CH.sub.2CH.sub.2OCH.sub.3.
[2018] Clause 259. The compound according to any one of clauses 250 to 253 wherein R.sub.21b is C.sub.1-4 haloalkyl such as CH.sub.2CHF.sub.2.
[2019] Clause 260. The compound according to any one of clauses 250 to 253 wherein R.sub.21b is C.sub.4-6heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.
[2020] Clause 261. The compound according to any one of clauses 250 to 260 wherein R.sub.22b is H.
[2021] Clause 262. The compound according to any one of clauses 250 to 260 wherein R.sub.22b is CH.sub.3.
[2022] Clause 263. The compound according to clause 249 wherein R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl wherein one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl.
[2023] Clause 264. The compound according to clause 249 wherein R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl.
[2024] Clause 265. The compound according to either clause 263 or 264 wherein R.sub.4ab and R.sub.5abtogether with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heteroycloalkyl which is substituted by one substituent.
[2025] Clause 266. The compound according to clause 263 or 264 wherein R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heteroycloalkyl which is unsubstituted.
[2026] Clause 267. The compound according to any one of clauses 263 to 266 wherein each substituent is independently selected from the group consisting of C.sub.1-2alkyl or OCH.sub.3.
[2027] Clause 268. The compound according to any one of clauses 263 to 267 wherein a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl or C.sub.3-6heteroycloalkyl ring and a further C.sub.3-6cycloalkyl ring.
[2028] Clause 269. The compound according to any one of clauses 263 to 267 wherein a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl or C.sub.3-6heteroycloalkyl ring and a further C.sub.3-6heterocycloalkyl ring.
[2029] Clause 270. The compound according to any one of clauses 263 or 265 to 269 wherein the C.sub.3-6cycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached is cyclopropyl.
[2030] Clause 271. The compound according to any one of clauses 263 or 265 to 269 wherein the C.sub.3-6cycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached is cyclobutyl.
[2031] Clause 272. The compound according to any one of clauses 263 or 265 to 269 wherein the C.sub.3-6cycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached is cyclopentyl.
[2032] Clause 273. The compound according to any one of clauses 263 or 265 to 269 wherein the C.sub.3-6cycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached is cyclohexyl.
[2033] Clause 274. The compound according to any one of clauses 264 to 269 wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached is heterocyclopropyl.
[2034] Clause 275. The compound according to any one of clauses 264 to 269 wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached is heterocyclobutyl.
[2035] Clause 276. The compound according to any one of clauses 264 to 269 wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached is heterocyclopentyl.
[2036] Clause 277. The compound according to any one of clauses 264 to 269 wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached is heterocyclohexyl.
[2037] Clause 278. The compound according to any one of clauses 263 or 265 to 273 wherein one of the carbons is quaternary and is attached to a 5-membered dioxalane ring to form the following structure:
##STR01018##
[2038] wherein m is 1 or 2 and n is 0, 1 or 2.
[2039] Clause 279. The compound according to clause 249 wherein R.sub.4ab and R.sub.5ab together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29b.
[2040] Clause 280. The compound according to clause 279 wherein the C.sub.3-6heterocycloalkyl is piperidinyl and the nitrogen atom is in the 4-position relative to the quaternary carbon:
##STR01019##
[2041] Clause 281. The compound according to clause 279 or 280wherein R.sub.29b is C.sub.1-3alkyl.
[2042] Clause 282. The compound according to clause 281 wherein R.sub.29b is methyl.
[2043] Clause 283. The compound according to either clause 279 or 280wherein R is N(C.sub.1-3alkyl).sub.2 e.g. N(CH.sub.3).sub.2.
[2044] Clause 284. The compound according to either clause 279 or 280 wherein R.sub.29b is 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl such as pyrazolyl substituted by methyl.
[2045] Clause 285. The compound according to any one of clauses 218 to 248 wherein R.sub.4b and R.sub.5b are R.sub.4bb and R.sub.5bb.
[2046] Clause 286. The compound according to any one of clauses 218 to 248 and 285 wherein R.sub.4bb is H and R.sub.3b together with R.sub.5bb form a 5- or 6-membered oxygen-containing heterocycloalkyl such as tetrahydrofuranyl or tetrahydropyranyl.
[2047] Clause 287. The compound according to any one of clauses 218 to 246 and 285 wherein R.sub.4bb together with R.sub.5bb form a C.sub.3-6cycloalkyl.
[2048] Clause 288. The compound according to clause 287 wherein R.sub.4bb together with R.sub.5bb form cyclopropyl or cyclopentyl.
[2049] Clause 289. The compound according to any one of clauses 218 to 246 and 285 wherein R.sub.4bb together with R.sub.5bb form a C.sub.3-6heterocycloalkyl.
[2050] Clause 290. The compound according to clause 289 wherein R.sub.4bb together with R.sub.5bb form heterocyclopentyl or heterocyclohexyl, such as tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl such as tetrahydropyranyl or piperidinyl.
[2051] Clause 291. The compound according to any one of clauses 218 to 248 and 285, wherein R.sub.4bb is C.sub.1-6alkyl, in particular C.sub.1-4alkyl such as methyl, ethyl or propyl (n-propyl or isopropyl).
[2052] Clause 292. The compound according to any one of clauses 218 to 248 and 285, wherein R.sub.4bb is C.sub.0-2alkyleneC.sub.3-6cycloalkyl, such as C.sub.3-6cycloalkyl, C.sub.1alkyleneC.sub.3-6cycloalkyl or C.sub.2alkyleneC.sub.3-6cycloalkyl.
[2053] Clause 293. The compound according to any one of clauses 218 to 248 and 285, wherein R.sub.4bb is OC.sub.1-6alkyl, in particular OC.sub.1-4alkyl, such as methoxy or isopropoxy.
[2054] Clause 294. The compound according to any one of clauses 218 to 248 and 285, wherein R.sub.4bb is OC.sub.0-2alkyleneC.sub.3-6cycloalkyl such as OC.sub.3-6cycloalkyl, OC.sub.1alkyleneC.sub.3-6cycloalkyl or OC.sub.2alkyleneC.sub.3-6cycloalkyl.
[2055] Clause 295. The compound according to any one of clauses 218 to 248 and 285, wherein R.sub.4bb is C.sub.1-3alkyleneOC.sub.1-3alkyl, in particular C.sub.1-2alkyleneOC.sub.1-2alkyl, such as CH.sub.2CH.sub.2OCH.sub.3.
[2056] Clause 298. The compound according to any one of clauses 218 to 248 and 285, wherein R.sub.4bb is C.sub.1-6haloalkyl, in particular C.sub.1-4haloalkyl.
[2057] Clause 297. The compound according to any one of clauses 218 to 248 and 285, wherein R.sub.4bb is OC.sub.1-6haloalkyl, in particular OC.sub.1-4haloalkyl.
[2058] Clause 298. The compound according to clause 218 to 248 and 285 wherein R.sub.4bb is H.
[2059] Clause 299. The compound according to clause 218 to 248 and 285 wherein R.sub.4bb is halo such as F.
[2060] Clause 300. The compound according to clause 218 to 248 and 285 wherein R.sub.4bb is C.sub.1-6alkylOH, such as CH.sub.2CH.sub.2OH.
[2061] Clause 301. The compound according to clause 218 to 248 and 285 wherein R.sub.4b is NR.sub.21bR.sub.22b.
[2062] Clause 302. The compound according to clause 301 wherein R.sub.21b is H.
[2063] Clause 303. The compound according to clause 301 wherein R.sub.21b is C.sub.1-5alkyl, such as methyl, ethyl or propyl.
[2064] Clause 304. The compound according to clause 301 wherein R.sub.21b is C(O)C.sub.1-5alkyl, such as C(O)CH.sub.3.
[2065] Clause 305. The compound according to clause 301 wherein R.sub.21b is C(O)OC.sub.1-5alkyl, such as C(O)OCH.sub.3 or C(O)Otert-butyl.
[2066] Clause 308. The compound according to clause 301 wherein R.sub.21b is C.sub.1-3alkylOC.sub.1-2alkyl such as CH.sub.2CH.sub.2OCH.sub.3.
[2067] Clause 307. The compound according to clause 301 wherein R.sub.21b is C.sub.1-4haloalkyl such as CH.sub.2CHF.sub.2.
[2068] Clause 308. The compound according to clause 301 wherein R.sub.21b is C.sub.4-6heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.
[2069] Clause 309. The compound according to clause 301 to 308 wherein R.sub.22b is H.
[2070] Clause 310. The compound according to clause 301 to 308 wherein R.sub.22b is CH.sub.3.
[2071] Clause 311. The compound according to any one of clauses 218 to 248 and 285 wherein R.sub.4bb is C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl.
[2072] Clause 312. The compound according to any one of clauses 218 to 311 wherein any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4 alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu, C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3.
[2073] Clause 313. The compound according to any one of clauses 218 to 311 wherein any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted.
[2074] Clause 314. The compound according to any one of clauses 218 to 313 wherein any sulphur atom in the C.sub.3-6heterocycloalkyl ring is substituted, for example by one oxygen atom to form S═O or by two oxygen atoms to form S(O).sub.2.
[2075] Clause 315. The compound according to any one of clauses 218 to 313 wherein any sulphur atom in the C.sub.3-6heterocycloalkyl ring is not substituted.
[2076] Clause 316. The compound according to any one of clauses 218 to 246 and 285 to 315, wherein R.sub.5bb is H, methyl, ethyl or fluoro e.g. H, methyl or ethyl.
[2077] Clause 317. The compound according to clause 316, wherein R.sub.5bb is H.
[2078] Clause 318. The compound according to any one of clauses 218 to 246 and 285 to 316 wherein R.sub.4bb and R.sub.5bb are methyl.
[2079] Clause 319. The compound according to any one of clauses 218 to 246 and 285 to 316 wherein R.sub.4bb and R.sub.5bb are ethyl.
[2080] Clause 320. The compound according to any one of clauses 218 to 246 and 285 wherein R.sub.4bb is H and R.sub.5bb and R.sub.6b are a C.sub.2-3alkylene chain forming a 5- or 6-membered ring, such as a 5-membered ring.
[2081] Clause 321. The compound according to any one of clauses 218 to 246 and 285 wherein R.sub.4bb is O and R.sub.5bb is absent.
[2082] Clause 322. The compound according to any one of clauses 218 to 246 and 285 wherein R.sub.4bb is ethyl and R.sub.5bb is H and the groups are arranged in the S configuration.
[2083] Clause 323. The compound according to any one of clauses 218 to 322 wherein A.sub.b is A.sub.ab.
[2084] Clause 324. The compound according to clause 323 wherein A.sub.ab is —NR.sub.6bCH.sub.2—.
[2085] Clause 325. The compound according to clause 323 wherein A.sub.ab is —NR.sub.6b—.
[2086] Clause 326. The compound according to any one of clauses 218 to 322 wherein A.sub.b is A.sub.bb.
[2087] Clause 327. The compound according to clause 324 or 325 wherein R.sub.6b is H.
[2088] Clause 328. The compound according to clause 324 or 325 wherein R.sub.6b is C.sub.1-3alkyl such as CH.sub.3.
[2089] Clause 329. The compound according to clause 324 or 325 wherein R.sub.6b together with R.sub.11b in the ortho-position to group A.sub.b are a C.sub.2alkylene chain forming a 5-membered ring.
[2090] Clause 330. The compound according to any one of clauses 218 to 329 wherein Ar1b is phenyl.
[2091] Clause 331. The compound according to any one of clauses 218 to 329 wherein Ar1b is pyridyl.
[2092] Clause 332. The compound according to clause 331 wherein Ar1b is 2-pyridyl.
[2093] Clause 333. The compound according to any one of clauses 218 to 329 wherein Ar1b is pyridazinyl.
[2094] Clause 334. The compound according to any one of clauses 218 to 329 wherein Ar1b is pyrimidinyl.
[2095] Clause 335. The compound according to any one of clauses 218 to 329 wherein Ar1b is pyrazinyl.
[2096] Clause 336. The compound according to any one of clauses 218 to 335 wherein R.sub.10b is H.
[2097] Clause 337. The compound according to any one of clauses 218 to 335 wherein R.sub.10b is chloro or fluoro, such as fluoro.
[2098] Clause 338. The compound according to any one of clauses 218 to 335 wherein R.sub.10b is methoxy or ethoxy such as methoxy.
[2099] Clause 339. The compound according to any one of clauses 218 to 335 wherein R.sub.10b is C.sub.1-3alkyl.
[2100] Clause 340. The compound according to clause 339 wherein R.sub.10b is methyl.
[2101] Clause 341. The compound according to any one of clauses 218 to 335 wherein R.sub.10b is OCF.sub.3.
[2102] Clause 342. The compound according to any one of clauses 218 to 335 wherein R.sub.10b is CF.sub.3.
[2103] Clause 343. The compound according to any one of clauses 218 to 335 wherein R.sub.10b is CN.
[2104] Clause 344. The compound according to any one of clauses 337 to 343 wherein R.sub.10b is in the ortho or meta position with respect to group A.sub.b, such as the ortho position with respect to group A.sub.b.
[2105] Clause 345. The compound according to any one of clauses 218 to 334 wherein R.sub.11b is H.
[2106] Clause 346. The compound according to any one of clauses 218 to 334 wherein R.sub.11b is fluoro.
[2107] Clause 347. The compound according to any one of clauses 218 to 334 wherein R.sub.11b is methyl.
[2108] Clause 348. The compound according to clause 348 or 347 wherein R.sub.11b is in the ortho or meta position with respect to group A.sub.b, such as the ortho position with respect to group A.sub.b.
[2109] Clause 349. The compound according to any one of clauses 218 to 348 wherein Ar2b is phenyl.
[2110] Clause 350. The compound according to any one of clauses 218 to 348 wherein Ar2b is pyridyl.
[2111] Clause 351. The compound according to clause 350 wherein Ar2b is 3-pyridyl.
[2112] Clause 352. The compound according to any one of clauses 218 to 348 wherein Ar2b is pyridazinyl.
[2113] Clause 353. The compound according to any one of clauses 218 to 348 wherein Ar2b is pyrimidinyl.
[2114] Clause 354. The compound according to any one of clauses 218 to 348 wherein Ar2b is pyrazinyl.
[2115] Clause 355. The compound according to any one of clauses 218 to 354 wherein R.sub.12a is H.
[2116] Clause 356. The compound according to any one of clauses 218 to 354 wherein R.sub.12a is halo, such as F or Cl.
[2117] Clause 357. The compound according to any one of clauses 218 to 354 wherein R.sub.12a is C.sub.1-4 alkyl, such as ethyl or methyl, especially methyl.
[2118] Clause 358. The compound according to any one of clauses 218 to 354 wherein R.sub.12a is C.sub.2-4alkynyl, such as C≡CH.
[2119] Clause 359. The compound according to any one of clauses 218 to 354 wherein R.sub.12b is C.sub.0-2alkyleneC.sub.3-5cycloalkyl, such as cyclopropyl.
[2120] Clause 360. The compound according to any one of clauses 218 to 354 wherein R.sub.12a is OC.sub.1-4alkyl such as methoxy, ethoxy, isopropoxy or n-propoxy.
[2121] Clause 361. The compound according to any one of clauses 218 to 354 wherein R.sub.12b is OC.sub.0-2alkyleneC.sub.3-5cycloalkyl, such as cyclopropoxyl or cyclobutoxy.
[2122] Clause 362. The compound according to any one of clauses 218 to 354 wherein R.sub.12a is OCH.sub.2CH.sub.2N(CH.sub.3).sub.2
[2123] Clause 363. The compound according to any one of clauses 218 to 354 wherein R.sub.12b is C.sub.1-4 alkylOH, such as CH.sub.2OH or C(CH.sub.3).sub.2OH.
[2124] Clause 364. The compound according to any one of clauses 218 to 354 wherein R.sub.12b is CN.
[2125] Clause 365. The compound according to any one of clauses 218 to 354 wherein R.sub.12b is C.sub.1-3 alkyleneOC.sub.1-3alkyl.
[2126] Clause 366. The compound according to any one of clauses 218 to 354 wherein R.sub.12b is C.sub.1-4 haloalkyl, such as CF.sub.3.
[2127] Clause 387. The compound according to any one of clauses 218 to 354 wherein R.sub.12b is OC.sub.1-4haloalkyl, such as OCF.sub.3, OCHF.sub.2 or OCH.sub.2CF.sub.3.
[2128] Clause 368. The compound according to any one of clauses 218 to 354 wherein R.sub.12b is C(═O)C.sub.1-2alkyl, such as C(═O)CH.sub.3.
[2129] Clause 369. The compound according to any one of clauses 218 to 354 wherein R.sub.12b is NR.sub.23bR.sub.24b.
[2130] Clause 370. The compound according to clause 369 wherein R.sub.12b is N(CH.sub.3).sub.2.
[2131] Clause 371. The compound according to clause 369 wherein R.sub.12b is N(H)Et.
[2132] Clause 372. The compound according to any one of clauses 218 to 354 wherein R.sub.12b is SO.sub.2C.sub.1-4alkyl.
[2133] Clause 373. The compound according to clause 372 wherein R.sub.12b is SO.sub.2CH.sub.3.
[2134] Clause 374. The compound according to any one of clauses 218 to 354 wherein R.sub.12b is C(O)N(CH.sub.3).sub.2.
[2135] Clause 375. The compound according to any one of clauses 218 to 354 wherein R.sub.12b is NHC(O)C.sub.1-3alkyl such as NHC(O)CH.sub.3.
[2136] Clause 376. The compound according to any one of clauses 218 to 354 wherein R.sub.12b is OH.
[2137] Clause 377. The compound according to any one of clauses 218 to 354 wherein R.sub.12b is C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b such as a C.sub.5heterocycloalkyl or C.sub.6heterocycloalkyl, and in particular pyrrolidinyl.
[2138] Clause 378. The compound according to any one of clauses 218 to 354 wherein R.sub.12b together with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−).
[2139] Clause 379. The compound according to any one of clauses 218 to 378 wherein R.sub.12b is in the meta position of Ar2b.
[2140] Clause 380. The compound according to any one of clauses 218 to 378 wherein R.sub.12b is in the ortho position of Ar2b.
[2141] Clause 381. The compound according to any one of clauses 218 to 380 wherein R.sub.13b is H.
[2142] Clause 382. The compound according to any one of clauses 218 to 380 wherein R.sub.13b is methyl.
[2143] Clause 383. The compound according to clause 382 wherein R.sub.13b is in the ortho position with respect to Ar1b.
[2144] Clause 384. The compound according to clause 382 wherein R.sub.13b is in the para position with respect to Ar1b.
[2145] Clause 385. The compound according to any one of clauses 218 to 384 wherein R.sub.1b is R.sub.1ab and R.sub.4b and R.sub.5b are R.sub.4ab and R.sub.5ab.
[2146] Clause 386. The compound according to any one of clauses 218 to 384 wherein R.sub.1b is R.sub.1ab and A.sub.b is A.sub.ab.
[2147] Clause 387. The compound according to any one of clauses 218 to 384 wherein R.sub.1b and R.sub.1abare R.sub.4ab and R.sub.5ab and A.sub.b is A.sub.ab.
[2148] Clause 388. The compound according to any one of clauses 218 to 384 wherein R.sub.1b is R.sub.1ab, R.sub.4b and R.sub.5b are R.sub.4ab and R.sub.5ab and A.sub.b is A.sub.ab.
[2149] Clause 389. A compound of the example T486.
[2150] Clause 390. A compound of formula (II-b):
##STR01020##
[2151] wherein R.sub.1, R.sub.3, R.sub.4 and R.sub.5 are as defined in any one of clauses 218 to 389 and R is H, C.sub.1-6alkyl (e.g. methyl and ethyl) or benzyl.
[2152] Clause 391. A compound of formula (X-b):
##STR01021##
[2153] wherein Ar1, R.sub.1, R.sub.3, R.sub.4, R.sub.5 and R.sub.a are as defined in any one of clauses 218 to 389.
[2154] Clause 392. A compound of formula (XII-b):
##STR01022##
[2155] wherein R.sub.1, R.sub.3, R.sub.4 and R.sub.5 are as defined in any one of clauses 218 to 389.
[2156] Clause 393. The compound of formula (I) according to clause 1 wherein the compound of formula (I) is a compound of formula (I-c).
[2157] Clause 394. The compound according to clause 393 wherein R.sub.1c is R.sub.1ac.
[2158] Clause 395. The compound according to clause 394 wherein R.sub.1ac is NR.sub.32cR.sub.33c and wherein R.sub.32c is C.sub.1-3alkyl and R.sub.33c is C.sub.1-3alkyl.
[2159] Clause 396. The compound according to clause 395 wherein R.sub.32c is methyl or ethyl.
[2160] Clause 397. The compound according to clause 396 wherein R.sub.32c is methyl.
[2161] Clause 398. The compound according to any one of clauses 395 to 397 wherein R.sub.32c is methyl or ethyl.
[2162] Clause 399. The compound according to clause 398 wherein R.sub.32c is methyl.
[2163] Clause 400. The compound according to any one of clauses 397 to 399 wherein R.sub.32c is methyl and R.sub.33c is methyl.
[2164] Clause 401. The compound according to clause 394 wherein R.sub.1ac is NR.sub.32cR.sub.33c and R.sub.32c and R.sub.33c together with the nitrogen atom to which they are attached form a C.sub.3-5heterocycloalkyl.
[2165] Clause 402. The compound according to clause 401 wherein the C.sub.3-5heterocycloalkyl is selected from the group consisting of aziridine, azetidine and pyrrolidine.
[2166] Clause 403. The compound according to clause 393 wherein R.sub.1c is R.sub.1bc.
[2167] Clause 404. The compound according to clause 403 wherein R.sub.1bc is C.sub.1-5alkyl.
[2168] Clause 405. The compound according to clause 403 wherein R.sub.1bc is C.sub.1-3alkyleneOC.sub.1-2alkyl.
[2169] Clause 406. The compound according to clause 405 wherein R.sub.1bc is C.sub.1-2alkyleneOC.sub.1-2alkyl.
[2170] Clause 407. The compound according to clause 403 wherein R.sub.1bc is C.sub.0-2alkyleneC.sub.3-5cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3.
[2171] Clause 408. The compound according to clause 407 wherein R.sub.1bc is C.sub.0-1alkyleneC.sub.3-4cycloalkyl which cycloalkyl is optionally substituted by CH.sub.3.
[2172] Clause 409. The compound according to clause 408 wherein R.sub.1bc is C.sub.0-1alkyleneC.sub.3-4cycloalkyl.
[2173] Clause 410. The compound according to any one of clauses 407 or 409 wherein R.sub.1bc is C.sub.3-4 cycloalkyl.
[2174] Clause 411. The compound according to clause 410 wherein R.sub.1bc is cyclopropyl.
[2175] Clause 412. The compound according to clause 408 wherein R.sub.1bc is C.sub.0-1alkyleneC.sub.3-4cycloalkyl which cycloalkyl is substituted by CH.sub.3.
[2176] Clause 413. The compound according to any one of clauses 393 to 412 wherein R.sub.3c is H.
[2177] Clause 414. The compound according to any one of clauses 393 to 412 wherein R.sub.3c is Me.
[2178] Clause 415. The compound according to any one of clauses 393 to 412 wherein R.sub.3c is halo.
[2179] Clause 416. The compound according to clause 415 wherein R.sub.3c is F.
[2180] Clause 417. The compound according to clause 415 wherein R.sub.3c is Cl.
[2181] Clause 418. The compound according to any one of clauses 393 to 412 wherein R.sub.3c is OC.sub.1-2 alkyl.
[2182] Clause 419. The compound according to any one of clauses 393 to 412 wherein R.sub.3c is OCF.sub.3.
[2183] Clause 420. The compound according to any one of clauses 393 to 412 wherein R.sub.3c is CF.sub.3.
[2184] Clause 421. The compound according to any one of clauses 393 to 420 wherein R.sub.4c and R.sub.5c are R.sub.4ac and R.sub.5ac.
[2185] Clause 422. The compound according to clause 421 wherein R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, C.sub.0-2alkyleneC.sub.3-6cycloalkyl, C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, C.sub.1-3alkyleneOC.sub.1-3alkyl, halo, OC.sub.1-3haloalkyl, OC.sub.0-2alkyleneC.sub.3-6cycloalkyl, OC.sub.0-2alkyleneC.sub.3-6heterocycloalkyl, OC.sub.1-3alkyl and NR.sub.21cR.sub.22c.
[2186] Clause 423. The compound according to clause 422 wherein R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl which is substituted by one substituent.
[2187] Clause 424. The compound according to clause 422 or 423 wherein each substituent is independently selected from the group consisting of C.sub.1-3alkyl, oxo, OH, C.sub.1-3alkylOH, C.sub.1-3haloalkyl, halo, OC.sub.1-3haloalkyl, OC.sub.1-3alkyl and NR.sub.21cR.sub.22c.
[2188] Clause 425. The compound according to clause 424 wherein each substituent is independently selected from the group consisting of oxo, OH, halo, OC.sub.1-3alkyl and NR.sub.21cR.sub.22c, such as oxo, OH, fluoro and NR.sub.21cR.sub.22c.
[2189] Clause 426. The compound according to any one of clauses 422 to 425 wherein R.sub.21c is H.
[2190] Clause 427. The compound according to any one of clauses 422 to 425 wherein R.sub.21c is C.sub.1-5alkyl, such as methyl, ethyl or propyl.
[2191] Clause 428. The compound according to any one of clauses 422 to 425 wherein R.sub.21c is C(O)C.sub.1-5alkyl, such as C(O)CH.sub.3.
[2192] Clause 429. The compound according to any one of clauses 422 to 425 wherein R.sub.21c is C(O)OC.sub.1-5alkyl, such as C(O)OCH.sub.3 or C(O)Otert-butyl.
[2193] Clause 430. The compound according to any one of clauses 422 to 425 wherein R.sub.21c is C.sub.1-3alkylOC.sub.1-2alkyl such as CH.sub.2CH.sub.2OCH.sub.3.
[2194] Clause 431. The compound according to any one of clauses 422 to 425 wherein R.sub.21c is C.sub.1-4 haloalkyl such as CH.sub.2CHF.sub.2.
[2195] Clause 432. The compound according to any one of clauses 422 to 425 wherein R.sub.21c is C.sub.4-6heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.
[2196] Clause 433. The compound according to any one of clauses 422 to 432 wherein R.sub.22c is H.
[2197] Clause 434. The compound according to any one of clauses 422 to 432 wherein R.sub.22c is CH.sub.3.
[2198] Clause 435. The compound according to clause 421 wherein R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl wherein one of the carbons of the C.sub.3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6cycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl.
[2199] Clause 436. The compound according to clause 421 wherein R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heteroycloalkyl wherein one of the carbons of the C.sub.3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C.sub.3-6heterocycloalkyl ring and a further C.sub.3-6cycloalkyl ring or a C.sub.3-6heterocycloalkyl ring, and wherein the C.sub.3-6heteroycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C.sub.1-3alkyl or OC.sub.1-3alkyl.
[2200] Clause 437. The compound according to either clause 435 or 436 wherein R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heteroycloalkyl which is substituted by one substituent.
[2201] Clause 438. The compound according to clause 435 or 436 wherein R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl or C.sub.3-6heteroycloalkyl which is unsubstituted.
[2202] Clause 439. The compound according to any one of clauses 435 to 438 wherein each substituent is independently selected from the group consisting of C.sub.1-2alkyl or OCH.sub.3.
[2203] Clause 440. The compound according to any one of clauses 435 to 439 wherein a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl or C.sub.3-6heteroycloalkyl ring and a further C.sub.3-6cycloalkyl ring.
[2204] Clause 441. The compound according to any one of clauses 435 to 439 wherein a spirocyclic ring system is formed by the C.sub.3-6cycloalkyl or C.sub.3-6heteroycloalkyl ring and a further C.sub.3-6heterocycloalkyl ring.
[2205] Clause 442. The compound according to any one of clauses 435 or 437 to 441 wherein the C.sub.3-6cycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached is cyclopropyl.
[2206] Clause 443. The compound according to any one of clauses 435 or 437 to 441 wherein the C.sub.3-6cycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached is cyclobutyl.
[2207] Clause 444. The compound according to any one of clauses 435 or 437 to 441 wherein the C.sub.3-6cycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached is cyclopentyl.
[2208] Clause 445. The compound according to any one of clauses 435 or 437 to 441 wherein the C.sub.3-6cycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached is cyclohexyl.
[2209] Clause 446. The compound according to any one of clauses 436 to 441 wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached is heterocyclopropyl.
[2210] Clause 447. The compound according to any one of clauses 436 to 441 wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached is heterocyclobutyl.
[2211] Clause 448. The compound according to any one of clauses 436 to 441 wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached is heterocyclopentyl.
[2212] Clause 449. The compound according to any one of clauses 436 to 441 wherein the C.sub.3-6heterocycloalkyl formed by R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached is heterocyclohexyl.
[2213] Clause 450. The compound according to any one of clauses 435 or 437 to 445 wherein one of the carbons is quaternary and is attached to a 5-membered dioxolane ring to form the following structure:
##STR01023##
[2214] wherein m is 1 or 2 and n is 0, 1 or 2.
[2215] Clause 451. The compound according to clause 421 wherein R.sub.4ac and R.sub.5ac together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by —S(O).sub.2R.sub.29c.
[2216] Clause 452. The compound according to clause 451 wherein the C.sub.3-6heterocycloalkyl is piperidinyl and the nitrogen atom is in the 4-position relative to the quaternary carbon:
##STR01024##
[2217] Clause 453. The compound according to clause 451 or 452 wherein R.sub.29c is C.sub.1-3alkyl.
[2218] Clause 454. The compound according to clause 453 wherein R.sub.29c is methyl.
[2219] Clause 455. The compound according to either clause 451 or 452 wherein R.sub.2 is N(C.sub.1-3 alkyl).sub.2 e.g. N(CH.sub.3).sub.2.
[2220] Clause 456. The compound according to either clause 451 or 452 wherein R.sub.29c is 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl such as pyrazolyl substituted by methyl.
[2221] Clause 457. The compound according to any one of clauses 393 to 420 wherein R.sub.4c and R.sub.5c are R.sub.4bc and R.sub.5bc.
[2222] Clause 458. The compound according to any one of clauses 393 to 420 and 457 wherein R.sub.4bc is H.
[2223] Clause 459. The compound according to any one of clauses 393 to 420 and 457 wherein R.sub.4bc is C.sub.1-4alkyl.
[2224] Clause 460. The compound according to clause 459 wherein R.sub.4bc is C.sub.1-4alkyl.
[2225] Clause 461. The compound according to clause 460 wherein R.sub.4bc is methyl or ethyl.
[2226] Clause 462. The compound according to any one of clauses 393 to 420 and 457 wherein R.sub.4bc is C.sub.0-2alkyleneC.sub.3-6cycloalkyl.
[2227] Clause 463. The compound according to clause 482 wherein R.sub.4bc is C.sub.0-2alkyleneC.sub.3-5cycloalkyl.
[2228] Clause 464. The compound according to any one of clauses 393 to 420 and 457 wherein R.sub.4bc is C.sub.1-6alkyleneOC.sub.1-3alkyl such as CH.sub.2CH.sub.2OCH.sub.3.
[2229] Clause 465. The compound according to any one of clauses 393 to 420 and 457 wherein R.sub.4bc is C.sub.0-2alkyleneC.sub.3-6heterocycloalkyl.
[2230] Clause 466. The compound according to any one of clauses 393 to 420 and 457 wherein R.sub.4bc is C.sub.1-6alkylOH.
[2231] Clause 467. The compound according to clause 466 wherein R.sub.4bc is C.sub.1-4alkylOH.
[2232] Clause 468. The compound according to clause 393 to 420 and 457 wherein R.sub.4bc is C.sub.1-6haloalkyl.
[2233] Clause 469. The compound according to clause 468 wherein R.sub.4bc is C.sub.1-4haloalkyl.
[2234] Clause 470. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R.sub.5bc is H.
[2235] Clause 471. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R.sub.5bc is C.sub.1-6alkyl.
[2236] Clause 472. The compound according to clause 471 wherein R.sub.5bc is C.sub.1-4alkyl.
[2237] Clause 473. The compound according to clause 472 wherein R.sub.5bc is methyl or ethyl.
[2238] Clause 474. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R.sub.5bc is C.sub.0-2alkyleneC.sub.3-6cycloalkyl.
[2239] Clause 475. The compound according to clause 474 wherein R.sub.5bc is C.sub.0-2alkyleneC.sub.3-5cycloalkyl.
[2240] Clause 476. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R.sub.5bc is C.sub.0-2akyleneC.sub.3-6heterocycloalkyl.
[2241] Clause 477. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R.sub.5bc is C.sub.1-3alkyleneOC.sub.1-3alkyl such as CH.sub.2CH.sub.2OCH.sub.3.
[2242] Clause 478. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R.sub.5bc is C.sub.1-6alkylOH.
[2243] Clause 479. The compound according to clause 478 wherein R.sub.5bc is C.sub.1-4alkylOH.
[2244] Clause 480. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R.sub.5bc is C.sub.1-6haloalkyl.
[2245] Clause 481. The compound according to clause 480 wherein R.sub.5bc is C.sub.1-4haloalkyl.
[2246] Clause 482. The compound according to any one of clauses 393 to 420 wherein R.sub.4bc and R.sub.5bc together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl such as cyclopropyl.
[2247] Clause 483. The compound according to any one of clauses 393 to 420 wherein R.sub.4bc and R.sub.5bc together with the carbon atom to which they are attached form a C.sub.3-6heterocycloalkyl such as tetrahydropyranyl or piperidinyl.
[2248] Clause 484. The compound according to any one of clauses 393 to 483 wherein at least one, such as one, nitrogen atom of a C.sub.3-6heterocycloalkyl ring is substituted, for example by C.sub.1-4alkyl, C(O)H, C(O)C.sub.1-4alkyl, C(O)OC.sub.1-4alkyl, C(O)OC.sub.1-4alkylaryl such as C(O)OBz, C(O)NHC.sub.1-4alkyl, C(O)NHC.sub.1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C.sub.1-4haloalkyl, C(O)OC.sub.1-4haloalkyl or C(O)NHC.sub.1-4haloalkyl such as C(O)OtBu, C.sub.1-4alkylCN such as CH.sub.2CN, C(O)C.sub.1-3alkylOC.sub.1-2alkyl such as C(O)CH.sub.2OCH.sub.3, and C.sub.1-2alkylC(O)OC.sub.1-4alkyl such as CH.sub.2C(O)OCH.sub.2CH.sub.3.
[2249] Clause 485. The compound according to any one of clauses 393 to 483 wherein any nitrogen atom in the C.sub.3-6heterocycloalkyl ring is not substituted.
[2250] Clause 486. The compound according to any one of clauses 393 to 485 wherein at least one, such as one, sulphur atom of a C.sub.3-6heterocycloalkyl ring is substituted, for example by one oxygen atom to form S═O or by two oxygen atoms to form S(O).sub.2.
[2251] Clause 487. The compound according to any one of clauses 393 to 485 wherein any sulphur atom in the C.sub.3-6heterocycloalkyl ring is not substituted.
[2252] Clause 488. The compound according to any one of clauses 393 to 470 wherein R.sub.4bc and R.sub.5bc are both H.
[2253] Clause 489. The compound according to any one of clauses 393 to 473 wherein R.sub.4bc and R.sub.5bc are both methyl.
[2254] Clause 490. The compound according to any one of clauses 393 to 473 wherein R.sub.4bc and R.sub.5bc are both ethyl.
[2255] Clause 491. The compound according to any one of clauses 393 to 470 wherein R.sub.4bc is ethyl and R.sub.5bc is H.
[2256] Clause 492. The compound according to clause 491 wherein R.sub.4bc and R.sub.5bc are arranged in an S configuration.
[2257] Clause 493. The compound according to any one of clauses 393 to 492 wherein A.sub.c is —CH.sub.2NR.sub.6c—.
[2258] Clause 494. The compound according to any one of clauses 393 to 492 wherein A.sub.c is A.sub.bc.
[2259] Clause 495. The compound according to clause 493 wherein R.sub.6c is H.
[2260] Clause 496. The compound according to clause 493 wherein R.sub.6c is C.sub.1-3alkyl.
[2261] Clause 497. The compound according to clause 496 wherein R.sub.6c is methyl.
[2262] Clause 498. The compound according to clause 496 wherein R.sub.6c is ethyl.
[2263] Clause 499. The compound according to any one of clauses 393 to 498 wherein Ar1c is phenyl.
[2264] Clause 500. The compound according to any one of clauses 393 to 498 wherein Ar1c is 2-pyridyl.
[2265] Clause 501. The compound according to any one of clauses 393 to 500 wherein Ar2c is 3-pyridyl.
[2266] Clause 502. The compound according to any one of clauses 393 to 500 wherein Ar2c is 2,5-pyrazinyl.
[2267] Clause 503. The compound according to any one of clauses 393 to 502 wherein R.sub.10c is H.
[2268] Clause 504. The compound according to any one of clauses 393 to 502 wherein R.sub.10c is halo such as F.
[2269] Clause 505. The compound according to any one of clauses 393 to 502 wherein R.sub.10 is C.sub.1-3 alkyl such as methyl.
[2270] Clause 506. The compound according to any one of clauses 393 to 502 wherein R.sub.10c is OC.sub.1-2 alkyl such as OCH.sub.3.
[2271] Clause 507. The compound according to any one of clauses 393 to 502 wherein R.sub.10c is C.sub.1-2 haloalkyl such as CF.sub.3.
[2272] Clause 508. The compound according to any one of clauses 393 to 502 wherein R.sub.10c is OC.sub.1-2 haloalkyl.
[2273] Clause 509. The compound according to any one of clauses 393 to 502 wherein R.sub.10c is CN.
[2274] Clause 510. The compound according to any one of clauses 504 to 509 wherein R.sub.10c is ortho to group A.sub.c.
[2275] Clause 511. The compound according to any one of clauses 393 to 510 wherein R.sub.11c is H.
[2276] Clause 512. The compound according to any one of clauses 393 to 510 wherein R.sub.11c is F.
[2277] Clause 513. The compound according to any one of clauses 393 to 510 wherein R.sub.11c is Cl.
[2278] Clause 514. The compound according to any one of clauses 393 to 510 wherein R.sub.11c is CH.sub.3.
[2279] Clause 515. The compound according to any one of clauses 393 to 510 wherein R.sub.11c is ethyl.
[2280] Clause 516. The compound according to any one of clauses 393 to 510 wherein R.sub.11c is OCH.sub.3.
[2281] Clause 517. The compound according to any one of clauses 393 to 510 wherein R.sub.11c is CF.sub.3.
[2282] Clause 518. The compound according to any one of clauses 393 to 510 wherein R.sub.11c is OCF.sub.3.
[2283] Clause 519. The compound according to any one of clauses 393 to 510 wherein R.sub.11c is CN.
[2284] Clause 520. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is H.
[2285] Clause 521. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is halo such as fluoro or chloro.
[2286] Clause 522. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is C.sub.1-4 alkyl such as CH.sub.3 or ethyl.
[2287] Clause 523. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is C.sub.2-4alkynyl.
[2288] Clause 524. The compound according to clause 523 wherein R.sub.12c is C.sub.2alkynyl.
[2289] Clause 525. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is C(═O)C.sub.1-2alkyl such as C(═O)CH.sub.3.
[2290] Clause 526. The compound according to any one of clauses 393 to 519 wherein R.sub.12C is C.sub.0-2alkyleneC.sub.3-5cycloalkyl.
[2291] Clause 527. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is OC.sub.1-4 alkyl such as OCH.sub.3, OEt or OiPr.
[2292] Clause 528. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is C.sub.1-3 alkyleneOC.sub.1-3alkyl.
[2293] Clause 529. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is C.sub.1-4 haloalkyl such as CF.sub.3.
[2294] Clause 530. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is OC.sub.1-4 haloalkyl such as OCH.sub.2CF.sub.3.
[2295] Clause 531. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is CN.
[2296] Clause 532. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is OC.sub.0-2alkyleneC.sub.3-5cycloalkyl.
[2297] Clause 533. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is OCH.sub.2CH.sub.2N(CH.sub.3).sub.2.
[2298] Clause 534. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is OH.
[2299] Clause 535. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is C.sub.1-4 alkylOH.
[2300] Clause 536. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is NR.sub.23cR.sub.24c.
[2301] Clause 537. The compound according to clause 538 wherein R.sub.23c is H.
[2302] Clause 538 The compound according to clause 536 wherein R.sub.23c is C.sub.1-2alkyl such as CH.sub.3.
[2303] Clause 539. The compound according to any one of clauses 536 to 538 wherein R.sub.24c is H.
[2304] Clause 540. The compound according to any one of clauses 536 to 538 wherein R.sub.24c is C.sub.1-2 alkyl such as CH.sub.3.
[2305] Clause 541. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is SO.sub.2CH.sub.3.
[2306] Clause 542. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is C(O)N(CH.sub.3).sub.2.
[2307] Clause 543. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is NHC(O)C.sub.1-3alkyl.
[2308] Clause 544. The compound according to any one of clauses 393 to 519 wherein R.sub.12c is a C.sub.3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c.
[2309] Clause 545. The compound according to any one of clauses 393 to 519 wherein R.sub.12ctogether with a nitrogen atom to which it is attached forms an N-oxide (N.sup.+—O.sup.−).
[2310] Clause 546. The compound according to any one of clauses 521 to 545 wherein R.sub.12c is attached at the meta position of Ar2c.
[2311] Clause 547. The compound according to any one of clauses 521 to 545 wherein R.sub.12c is attached at the ortho position of Ar2c.
[2312] Clause 548. The compound according to any one of clauses 393 to 547 wherein R.sub.1c is R.sub.1ac and R.sub.4c and R.sub.5c are R.sub.4ac and R.sub.5ac.
[2313] Clause 549. The compound according to any one of clauses 393 to 547 wherein R.sub.1c is R.sub.1ac and A.sub.c is A.sub.ac.
[2314] Clause 550. The compound according to any one of clauses 393 to 547 wherein R.sub.4c and R.sub.5care R.sub.4ac and R.sub.5ac and A.sub.c is A.sub.ac.
[2315] Clause 551. The compound according to any one of clauses 393 to 547 wherein R.sub.1c is R.sub.1ac, R.sub.4c and R.sub.5c are R.sub.4ac and R.sub.5ac and A.sub.c is A.sub.ac.
[2316] Clause 552. A compound which is R94 or R95.
[2317] Clause 553. A compound of formula (II-c):
##STR01025##
[2318] wherein R.sub.1, R.sub.3, R.sub.4 and R.sub.6 are as defined in clause 393.
[2319] Clause 554. A compound of formula (VIII-c):
##STR01026##
[2320] wherein R.sub.1, R.sub.3 and R.sub.4 are as defined in clause 393.
[2321] Clause 555. A compound according to any one of clauses 1 to 554 which is in the form of a salt.
[2322] Clause 556. A compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552, for use as a medicament.
[2323] Clause 557. The compound according to clause 556, for use in the inhibition of CTPS1 in a subject.
[2324] Clause 558. The compound according to clause 556, for use in the reduction of T-cell and/or B-cell proliferation in a subject
[2325] Clause 559. The compound according to clause 556, for use in the treatment or prophylaxis of: inflammatory skin diseases such as psoriasis or lichen planus; acute and/or chronic GVHD such as steroid resistant acute GVHD; acute lymphoproliferative syndrome (ALPS); systemic lupus erythematosus, lupus nephritis or cutaneous lupus; or transplantation.
[2326] Clause 560. The compound according to clause 556, for use in the treatment or prophylaxis of myasthenia gravis, multiple sclerosis or scleroderma/systemic sclerosis.
[2327] Clause 561. A compound according to clause 556, for use in the treatment of cancer.
[2328] Clause 562. A method for treating cancer in a subject, by administering to a subject in need thereof a compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552.
[2329] Clause 563. Use of a compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552, in the manufacture of a medicament for the treatment of cancer in a subject.
[2330] Clause 564. The compound according to clause 561, the method according to clause 562 or the use according to clause 563 wherein the cancer is a haematological cancer.
[2331] Clause 565. The compound, method or use according to clause 564 wherein the haematological cancer is selected from the group consisting of Acute myeloid leukemia, Angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet Syndrome, T-cell Non-Hodgkins lymphoma (including natural killer/T-cell lymphoma, adult T-cell leukaemia/lymphoma, enteropathy type T-cell lymphoma, hepatosplenic T-cell lymphoma and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell Non-Hodgkins lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, Follicular lymphoma, Mantle cell lymphoma, Marginal Zone lymphoma), Hairy Cell Leukemia, Hodgkin lymphoma, Lymphoblastic lymphoma, Lymphoplasmacytic lymphoma, Mucosa-associated lymphoid tissue lymphoma, Multiple myeloma, Myelodysplastic syndrome, Plasma cell myeloma, Primary mediastinal large B-cell lymphoma, chronic myeloproliferative disorders (such as chronic myeloid leukemia, primary myelofibrosis, essential thrombocytemia, polycytemia vera) and chronic lymphocytic leukemia.
[2332] Clause 566. The compound according to clause 561, the method according to clause 562 or the use according to clause 563 wherein the cancer is a non-haematological cancer such as bladder cancer, breast cancer, melanoma, neuroblastoma, malignant pleural mesothelioma and sarcoma, such as breast cancer and melanoma.
[2333] Clause 567. The compound according to clause 556, for use in enhancing recovery from vascular injury or surgery and reducing morbidity and mortality associated with neointima and restenosis in a subject.
[2334] Clause 568. A method for enhancing recovery from vascular injury or surgery and reducing morbidity and mortality associated with neointima and restenosis in a subject, by administering to a subject in need thereof a compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552.
[2335] Clause 569. Use of a compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552, in the manufacture of a medicament for enhancing recovery from vascular injury or surgery and reducing morbidity and mortality associated with neointima and restenosis in a subject.
[2336] Clause 570. A method for the inhibition of CTPS1 in a subject, which comprises administering to the subject an effective amount of a compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552.
[2337] Clause 571. Use of a compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552, in the manufacture of a medicament for the inhibition of CTPS1 in a subject.
[2338] Clause 572. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552.
[2339] Clause 573. The compound, method, use or composition according to any one of clauses 556 to 572, for administration to a human subject.
[2340] Clause 574. The compound, method, use or composition according to any one of clauses 556 to 573, for administration in conjunction with a further pharmaceutically acceptable active ingredient or ingredients.
[2341] Clause 575. The compound, method, use or composition according to any one of clauses 556 to 574, for topical administration to the skin, eye or gut.
[2342] Clause 576. The compound according to any one of clauses 1 to 555, which is in natural isotopic form.
REFERENCES
[2343] Evans, D. R. & Guy, H. I. Mammalian pyrimidine biosynthesis: fresh insights into an ancient pathway. J. Biol. Chem. 279, 33035-33038 (2004). [2344] Fairbanks, L D. et al. Importance of ribonucleotide availability to proliferating T-lymphocytes from healthy humans. Disproportionate expansion of pyrimidine pools and contrasting effects of de novo synthesis inhibitors. J. Biol. Chem. 270, 29682-29689 (1995). [2345] Higgins, M. J. et al. Regulation of human cytidine triphosphate synthetase 1 by glycogen synthase kinase 3. J. Biol. Chem. 282, 29493-29503 (2007). [2346] Kursula, P. et al. Structure of the synthetase domain of human CTP synthetase, a target for anticancer therapy. Acta Crystallogr Sect F Struct Biol Cryst Commun. 62 (Pt7): 613-617 (2006). [2347] Ueberman 1. Enzymatic amination of uridine triphosphate to cytidine triphosphate. The J. Biol. Chem. 222 (2): 765-75 (1956). [2348] Martin E. et al. CTP synthase 1 deficiency in humans reveals its central role in lymphocytes proliferation. Nature. June 12; 510(7504):288-92 (2014). Erratum in: Nature. July 17; 511(7509):370 (2014). [2349] McCluskey G D et al., Exploring the Potent Inhibition of CTP Synthase by Gemcitabine-5′-Triphosphate. Chembiochem. 17, 2240-2249 (2016). [2350] Ostrander, D. B. et al. Effect of CTP synthetase regulation by CTP on phospholipid synthesis in Saccharomyces cerevisiae. J. Bio. Chem. 273, 18992-19001 (1998). [2351] Sakamoto K et al. Identification of cytidine-5-triphosphate synthase1-selective inhibitory peptide from random peptide library displayed on T7 phage. Peptides. 2017; 94:56-63 (2017). [2352] Salu et al. Drug-eluting stents: a new treatment in the prevention of restenosis Part I: experimental studies. Acta Cardiol, 59, 51-61 (2004). [2353] Sousa J. E. et al. Drug-Eluting Stents. Circulation, 107 (2003) 2274 (Part I), 2283 (Part II). [2354] Tang R. et al. CTP synthase 1, a smooth muscle-sensitive therapeutic target for effective vascular repair. Arterioscler Thromb Vasc Biol. 33(10), 1-19, (2013). [2355] van den Berg, A. A. et al. Cytidine triphosphate (CTP) synthetase activity during cell cycle progression in normal and malignant T-lymphocytic cells. Eur. J. Cancer 31, 108-112 (1995). [2356] van Kuilenburg, A. B. P. et al. Identification of a cDNA encoding an isoform of human CTP synthetase. Biochimica et Biophysica Acta 1492548-552 (2000).