Heterocyclic compounds as hedgehog signaling pathway inhibitors

Abstract

This invention relates to novel compounds of formula (I). The compounds of the invention are hedgehog pathway antagonists. Specifically, the compounds of the invention are useful as Smoothened (SMO) inhibitors. The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of the Hedgehog pathway and SMO, for example cancer.

Claims

1. A compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof: ##STR00354## wherein het is selected from the group consisting of substituted or unsubstituted: aziridinylene, azetidinylene, pyrolidinylene, piperidinylene and azepanylene; ##STR00355## wherein two adjacent R.sup.4 groups are both C.sub.1-6 alkyl or both form a ring with the atom to which the R.sup.4 groups are attached forming a fused bicyclic ring system of 8 to 12 atoms, wherein the ring formed by the two R.sup.4 groups is a saturated or unsaturated carbocyclic ring with 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated heterocyclic ring with 4, 5, 6, 7 or 8 atoms or a saturated or unsaturated heterocyclic ring with 4, 5, 6, 7 or 8 atoms containing 1, 2 or 3 heteroatoms; L is selected from the group consisting of a bond, CR.sup.cR.sup.d, CR.sup.cR.sup.dCR.sup.cR.sup.d, C(NR.sup.a), C(O)NR.sup.3 and SO.sub.2; R.sup.1 is selected from the group consisting of OR.sup.5, NR.sup.5R.sup.a, NR.sup.aC(O)R.sup.a, CN, C.sub.1-4 acyl, C(O)R.sup.a, C(O)NR.sup.a, C(O)OR.sup.a, SO.sub.2R.sup.a, SO.sub.3R.sup.a, C.sub.1-6 haloalkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted C.sub.3-8 cycloalkenyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic, wherein R.sup.5 is H, SO.sub.2R.sup.a, SO.sub.2NR.sup.aR.sup.b, substituted or unsubstituted C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted C.sub.3-8 cycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic; R.sup.2 is represented by CR.sup.6R.sup.7R.sup.8, wherein R.sup.6, R.sup.7 and R.sup.8 are independently selected at each occurrence from the group consisting of substituted or unsubstituted: C.sub.1-14 alkyl, C.sub.1-14 haloalkyl, carbocyclic, and heterocyclic, or R.sup.2 is selected from the group consisting of substituted or unsubstituted: C.sub.1-14 haloalkyl, carbocyclic, and heterocyclic; R.sup.3 is selected from the group consisting of H, SO.sub.2R.sup.a, SO.sub.2NR.sup.aR.sup.b, substituted or unsubstituted C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted C.sub.3-8 cycloalkenyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic; R.sup.a and R.sup.b are independently selected at each occurrence from the group consisting of: H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 acyl, C.sub.3-7 cycloalkyl, and C.sub.3-7 halocycloalkyl; R.sup.c and R.sup.d are independently selected from the group consisting of H, halo, OR.sup.a, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 acyl, C.sub.3-7 cycloalkyl, and C.sub.3-7 halocycloalkyl; m is 0, 1 or 2; and when a group is substituted, the group contains 1 to 5 substituents independently selected at each occurrence from the group consisting of: halo, OR.sup.a, SR.sup.a, NR.sup.aR.sup.b, NO.sub.2, O, CN, acyl, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, SO.sub.2R.sup.a, and SO.sub.3R.sup.a, C(OR.sup.a)R.sup.aR.sup.b, C(O)R.sup.a and C(O)OR.sup.a; provided that: (1) LR.sup.2 is not CO(O)tBu; and (2) R.sup.1 is not a substituted or unsubstituted thiadiazolinyl group when ##STR00356##

2. The compound of any preceding claim, wherein het is selected from the group consisting of substituted or unsubstituted: ##STR00357##

3. The compound of claim 1, wherein het is selected from the group consisting of substituted or unsubstituted: ##STR00358##

4. The compound of claim 1, wherein the compound of formula (Ia) is a compound according to formula (II), (IIa) or (IIb) and pharmaceutically acceptable salts and solvates thereof: ##STR00359##

5. The compound of claim 1, wherein ##STR00360## is selected from the group consisting of: ##STR00361##

6. The compound of claim 1, wherein ##STR00362## is ##STR00363##

7. The compound of claim 1, wherein the compound of formula (Ia) is a compound according to formula (Va) or (Vb), or a pharmaceutically acceptable salt or solvate thereof: ##STR00364##

8. The compound of claim 1, wherein L is selected from the group consisting of a bond, CH.sub.2, CH.sub.2CH.sub.2, CH(CH.sub.3), C(NH), C(O)NH, C(O)N(CH.sub.3) and SO.sub.2.

9. The compound of claim 1, wherein R.sup.1 is selected from the group consisting of OR.sup.5, NR.sup.5R.sup.a, NR.sup.aC(O)R.sup.a, CN, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic.

10. The compound of claim 9, wherein R.sup.1 is selected from the group consisting of hydroxyl, methoxy, N-methylamino, Me.sub.2N(CH.sub.2)NH, nitrile, phenyloxy and substituted or unsubstituted: pyrazolyl, pyridyl, morpholinyl, pyrazinyl, pyrimidinyl, piperazinyl, pyridazinyl, pyrolidin-yl-one, imidazolin-yl-one, or pyridazinyl.

11. The compound of claim 10, wherein R.sup.1 is selected from the group consisting of substituted or unsubstituted: pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl.

12. The compound of claim 11, wherein R.sup.1 is substituted or unsubstituted pyrazolyl.

13. The compound of claim 9, wherein R.sup.1 is selected from the group consisting of: ##STR00365##

14. The compound of claim 9, wherein R.sup.1 is: ##STR00366##

15. The compound of 9, wherein R.sup.1 is selected from the group consisting of OMe, OPh, OC.sub.1-4 alkyl, N(CH.sub.3)CH.sub.3, NHCH.sub.2CH.sub.2N(CH.sub.3).sub.2, NHSO.sub.2CH.sub.3, N(CH.sub.3)SO.sub.2CH.sub.3, NHSO.sub.2NCH.sub.3, N(CH.sub.3)SO.sub.2CH.sub.3, NC(O)R.sup.a, and CN.

16. The compound of claim 1, wherein R.sup.2 is represented by CR.sup.6R.sup.7R.sup.8, wherein R.sup.6, R.sup.7 and R.sup.8 are independently selected at each occurrence from the group consisting of substituted or unsubstituted: C.sub.1-14 alkyl, C.sub.1-14 haloalkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocycloalkyl, phenyl, toluenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, and isothiazolyl.

17. The compound of claim 16, wherein R.sup.6, R.sup.7 and R.sup.8 are all one of the groups selected from the group consisting of: methyl, trifluoromethyl, cyclohexanyl and phenyl.

18. The compound of claim 1, wherein R.sup.2 is selected from the group consisting of substituted or unsubstituted: C.sub.1-14 alkyl, C.sub.1-14 haloalkyl, carbocyclic, and heterocyclic.

19. The compound of claim 18, wherein R.sup.2 is selected from the group consisting of substituted or unsubstituted: C.sub.1-14 alkyl, C.sub.1-14 haloalkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocycloalkyl, phenyl, toluenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, and isothiazolyl.

20. The compound of claim 18, wherein R.sup.2 is selected from the group consisting of tert-butyl or substituted or unsubstituted: cyclopropyl, phenyl, toluenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, and isothiazolyl.

21. The compound of claim 18, wherein R.sup.2 is selected from the group consisting of substituted or unsubstituted phenyl, toluenyl and pyridinyl.

22. The compound of claim 1, wherein R.sup.2 is substituted by 1 to 5 substituents, optionally 1, 2 or 3 substituents, independently selected at each occurrence from the group consisting of halo, OR.sup.a, NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(OR.sup.a)R.sup.aR.sup.b, SC.sub.1-4 alkyl, C(O)R.sub.aR.sub.b, N(CO)R.sub.a, and CN.

23. The compound of claim 22, wherein R.sup.2 is substituted by: trifluoromethyl; OCF.sub.3; C(OH)(CH.sub.3)CH.sub.3; methyl; fluoro; chloro; CN; fluoro and trifluoromethyl; fluoro and OCF.sub.3; or fluoro and methyl.

24. The compound of claim 18, wherein R.sup.2 is: ##STR00367##

25. The compound of claim 1, wherein all occurrences of R.sup.a and R.sup.b are hydrogen.

26. The compound of claim 1, wherein all occurrences of R.sup.c and R.sup.d are hydrogen.

27. The compound of claim 1, wherein m is 0 or 1.

28. The compound of claim 1, wherein the compound of formula (Ia) is selected from the group consisting of: ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385##

29. The compound of claim 1, wherein the compound of formula (Ia) is selected from the group consisting of: ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396## ##STR00397##

30. A pharmaceutical composition, wherein the composition comprises a compound of claim 1 and a pharmaceutically acceptable excipient.

31. A method of modulating the Hedgehog signalling pathway, wherein the method comprises administering a therapeutic amount of a compound of claim 1 to a patient in need thereof.

32. The method of treatment of claim 31, wherein the condition which is modulated by the Hedgehog signalling pathway is selected from the group consisting of: carcinoma, blastoma, leukemia and haematological malignancies.

33. The method of treatment of claim 31, wherein the condition is selected from the group consisting of: basal cell carcinoma, medulloblastoma, chondrosarcoma, small-cell lung cancer, non-small-cell lung cancer, multiple myeloma, esophagus cancer, breast cancer, prostate cancer, pancreatic cancer, acute leukemia, chronic leukemia, and ovarian cancer.

34. A method of inhibiting stem cell production, inhibiting stem cell renewal, and/or inhibiting and/or modulating stem cell differentiation, wherein the method comprises administering a therapeutic amount of a compound of claim 1 to a patient in need thereof.

35. A method of treatment of a condition selected from the group consisting of carcinoma, blastoma, and leukemia, comprising administering a therapeutically effective amount of a compound of claim 1 simultaneously, sequentially or separately with an additional anti-tumour agent to a patient in need thereof.

36. A compound of claim 1, wherein L is C(O)NH or C(O)N(CH.sub.3).

37. A compound of claim 1, wherein the compound of formula (Ia) is a compound according to formula (XIII) or a pharmaceutically acceptable salt or solvate thereof: ##STR00398## wherein ##STR00399## is selected from the group consisting of: ##STR00400## het is: ##STR00401## R.sup.1 is substituted or unsubstituted pyrazolyl, R.sup.2 is substituted or unsubstituted phenyl, toluenyl or pyridinyl, R.sup.3 is H, methyl or C(O)CF.sub.3, R.sup.c and R.sup.d are independently selected from the group consisting of H, halo, OR.sup.a, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 acyl, C.sub.3-7 cycloalkyl, and C.sub.3-7 halocycloalkyl, and m is 0 or 1, wherein when a group is substituted, the group contains 1 to 5 substituents independently selected at each occurrence from the group consisting of: halo, OR.sup.a, SR.sup.a, NR.sup.aR.sup.b, NO.sub.2, CN, acyl, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, SO.sub.2R.sup.a, and SO.sub.3R.sup.a, C(OR.sup.a)R.sup.aR.sup.b, C(O)R.sup.a and C(O)OR.sup.a; and R.sup.a and R.sup.b are independently selected at each occurrence from the group consisting of: H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 acyl, C.sub.3-7 cycloalkyl, and C.sub.3-7 halocycloalkyl.

Description

DETAILED DESCRIPTION

(1) Given below are definitions of terms used in this application. Any term not defined herein takes the normal meaning as the skilled person would understand the term.

(2) The term halo refers to one of the halogens, group 17 of the periodic table. In particular the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

(3) The term C.sub.1-6 alkyl refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Similarly, C.sub.1-4 alkyl refers to a linear or branched hydrocarbon chain containing 1, 2, 3 or 4 carbon atoms and C.sub.1-14 alkyl refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Alkylene groups may likewise be linear or branched and may have two places of attachment to the remainder of the molecule. Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. The alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C.sub.1-6 alkoxy.

(4) The term C.sub.1-6 alkoxy refers to an alkyl group which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched and may contain 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Therefore, the alkoxy group may be methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy. The alkyl part of the alkoxy group may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C.sub.1-6 alkoxy.

(5) The term C.sub.1-6 haloalkyl refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine. Similarly, C.sub.1-4 haloalkyl refers to a linear or branched hydrocarbon chain containing 1, 2, 3 or 4 carbon atoms and C.sub.1-14 haloalkyl refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. The halogen atom may be present at any position on the hydrocarbon chain. For example, C.sub.1-6 haloalkyl may refer to chloromethyl, flouromethyl, trifluoromethyl, chloroethyl e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g. 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

(6) The term C.sub.2-6 alkenyl refers to a branched or linear hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, the C.sub.2-6 alkenyl may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

(7) The term C.sub.2-6 alkynyl refers to a branded or linear hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond may be at any possible position of the hydrocarbon chain. For example, the C.sub.2-6 alkynyl may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

(8) The term C.sub.1-6 heteroalkyl refers to a branded or linear hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S positioned between any carbon in the chain or at an end of the chain. For example, the hydrocarbon chain may contain one or two heteroatoms. The C.sub.1-6 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom. For example, the C.sub.1-6 heteroalkyl may be C.sub.1-6 N-alkyl, C.sub.1-6 N,N-alkyl, or C.sub.1-6 O-alkyl.

(9) The term carbocyclic refers to a saturated or unsaturated carbon containing ring system. A carbocyclic system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic. A carbocyclic moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. Carbocyclic encompasses cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems and fused ring systems including an aromatic portion. Carbocyclic may be C.sub.3-8 cycloalkyl or C.sub.5-6 aryl.

(10) The term heterocyclic refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, O or S. A heterocyclic system may contain 1, 2, 3 or 4 heteroatoms, for example 1 or 2. A heterocyclic system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic. A heterocyclic moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. Heterocyclic encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties and heteroaromatic moieties. Heterocyclic groups may be C.sub.3-8 heterocycloalkyl, C.sub.5-6 heteroaryl. For example, the heterocyclic group may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

(11) The term C.sub.3-8 cycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. For example, the C.sub.3-8 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

(12) The term C.sub.3-8 cycloalkenyl refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. The ring may contain more than one double bond. For example, the C.sub.3-8 cycloalkyl may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

(13) The term C.sub.3-8 heterocycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. The C.sub.3-8 heterocycloalkyl may be bonded to the rest of the molecule through any carbon atom or heteroatom. The C.sub.3-8 heterocycloalkyl may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the C.sub.3-8 heterocycloalkyl may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

(14) The term C.sub.3-8 heterocycloalkenyl refers to an unsaturated hydrocarbon ring system, containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. The C.sub.3-8 heterocycloalkenyl may be bonded to the rest of the molecule through any carbon atom or heteroatom. The C.sub.3-8 heterocycloalkenyl may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the C.sub.3-8 heterocycloalkyl may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.

(15) The term aryl refers to an aromatic hydrocarbon ring system. The ring system has 4n+2 electrons in a conjugated system within a ring where all atoms contributing to the conjugated system are in the same plane. For example, the aryl may be phenyl and napthyl. The aryl system itself may be substituted with other groups.

(16) The term heteroaryl refers to an aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused ring system, selected from O, N and S. The ring or ring system has 4n+2 electrons in a conjugated system where all atoms contributing to the conjugated system are in the same plane. For example, the heteroaryl may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

(17) The term alkaryl refers to an aryl group, as defined above, bonded to a C.sub.1-4 alkyl, where the C.sub.1-4 alkyl group provides attachment to the remainder of the molecule.

(18) The term alkheteroaryl refers to a heteroaryl group, as defined above, bonded to a C.sub.1-4 alkyl, where the alkyl group provides attachment to the remainder of the molecule.

(19) The term halogen herein includes reference to F, Cl, Br and I. Halogen may be Cl. Halogen may be F.

(20) A bond terminating in a represents that the bond is connected to another atom that is not shown in the structure. A bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.

(21) Throughout the specification A.sup.1, A.sup.2, A.sup.3 and A.sup.4 may collectively be referred to as A groups. One of the A groups may generally be described as an A group. The unsaturated ring containing A.sup.1, A.sup.2, A.sup.3 and A.sup.4 may be referred to as the A ring.

(22) Where a moiety is substituted, it may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements. The moiety may be substituted by one or more substitutents, e.g. 1, 2, 3 or 4 substituents; optionally there are 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different. The substituent(s) may be selected from: OH, NHR.sup.9, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(O)H, acyl, acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, nitro, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl or alkaryl. Where the group to be substituted is an alkyl group the substituent may be O. Where the moiety is substituted with two or more substituents and two of the substituents are adjacent the adjacent substituents may form a C.sub.4-8 ring along with the atoms of the moiety on which the substituents are substituted, wherein the C.sub.4-8 ring is a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms or a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms and 1, 2 or 3 heteroatoms.

(23) Substituents are only present at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort which substitutions are chemically possible and which are not.

(24) Ortho, meta and para substitution are well understood terms in the art. For the absence of doubt, ortho substitution is substitution at a location adjacent to the position of attachment to the rest of the molecule, for example the two groups below are ortho substituted by fluorine:

(25) ##STR00137##

(26) Meta substitution is substitution on the second atom away from the atom where the group is attached to the rest of the molecule, for example the two groups below are meta substituted by fluorine:

(27) ##STR00138##

(28) Para substitution is substitution on the second atom away from the atom where the group is attached to the rest of the molecule, for example the group below is para substituted by fluorine:

(29) ##STR00139##

(30) By acyl is meant an organic radical derived from, for example, an organic acid by the removal of the hydroxyl group, e.g. a radical having the formula RC(O), where R may be selected from H, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C.sub.1-3 alkyl. In one embodiment acyl is alkyl-carbonyl. Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl and butyryl. A particular acyl group is acetyl.

(31) The invention contemplates pharmaceutically acceptable salts of the compounds of formula (I). These may include the acid addition and base salts of the compounds.

(32) Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

(33) Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

(34) Preferably the salt is an acid addition salt. The salts may be formate or hydrochloride.

(35) Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods: (i) by reacting the compound of formula (I) with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

(36) All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

(37) The compounds of the invention may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term hydrate is employed when said solvent is water.

(38) Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non-ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

(39) Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

(40) The compounds of the invention include compounds of a number of formula as herein defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of the invention.

(41) Before purification, the compounds of the present invention may exist as a mixture of enantiomers depending on the synthetic procedure used. The enantiomers can be separated by conventional techniques known in the art. Thus the invention covers individual enantiomers as well as mixtures thereof.

(42) For some of the steps of the process of preparation of the compounds of formula (I), it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can be used. In particular methods of protection and deprotection such as those described by T. W. GREENE (Protective Groups in Organic Synthesis, A. WileyInterscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used. All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.

(43) Also, the compounds of the present invention as well as intermediates for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.

(44) The method of treatment or the compound for use in the treatment of cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia as defined hereinbefore may be applied as a sole therapy or be a combination therapy with an additional active agent.

(45) The method of treatment or the compound for use in the treatment of cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following specific anti-tumour agents listed below or anti-tumour agents from one or more of the categories of listed below:

(46) (i) antiproliferative/antineoplastic drugs and combinations thereof, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustin, melphalan, chlorambucil, busulphan, capecitabine temozolamide, ifosamide, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, carmustine, estramustine, fotemustine, gulfosfamide, KW-2170, mafosfamide, mitolactol, etaplatin, lobaplatin, nedaplatin, strrplatin and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, 6-mercaptopurine riboside, leucovarin, UFT, doxifluridine, carmoflur, cytarabine, enocitabine S-1, 5-azacitidine, cepecitabine, clofarabine, decitabine, eflornithine, ethynlcytidine, TS-1, nelarabine, nolatrexed, ocosfate, pelitrexol, triapine, trimetrexate, vidarabine, and hydroxyurea); antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, aclarubicin, actinomycin D, amrubicin, annamycin, elsamitrucin, galarubicin, nemorubicin, neocarzinostatin, peplomycin, piarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin and zinostatin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol, docetaxol (Taxotere), and paclitaxel and polokinase inhibitors); proteasome inhibitors, for example carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, aclarubicin, amonafide, belotecan, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, edotecarin, exatecan, gimatecan, lurtotecan, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, amsacrine, topotecan, mitoxantrone and camptothecin) and adjuvants used in combination with these therapies, for example folinic acid;
(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, lasofoxifeneand iodoxyfene), antiandrogens (for example bicalutamide, mifepristone, flutamide, nilutamide, casodex and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5-reductase such as finasteride;
(iii) anti-invasion agents, for example dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase;
(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies, for example the anti-erbB2 antibody trastuzumab [Herceptin], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); ErbB2 inhibitors (for example GW-28297, Herceptin, 2C4, pertuzumab, TAK-165, GW-572016, AR-209, and 2B-1); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (for example Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib, tipifarnib and lonafarnib), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitors and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin); COXII inhibitors (for example Arcoxia (etoricoxib), Bextra (valdecoxib), Celebrex (celecoxib), Paracoxib Vioxx (rofecoxib)); MMP inhibitors (for example MMP-2 inhibitors, MMP-9 inhibitors, AG-3340, RO 32-3555, and RS 13-0830); thalidomide; lenalidomide; and for example, a VEGF receptor (for example SU-11248, SU-5416, SU-6668, and angiozyme) tyrosine kinase inhibitor (such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib); acitretin; fenretinide; zoledronic acid; angiostatin; aplidine; cilengtide; A-4; endostatin; halofuginome; rebimastat; removab; revlimid; squalamine; ukrain; and vitaxincombretastatin;
(vi) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2;
(vii) immunotherapy approaches, including for example antibody therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin) and ofatumumab; interferons such as interferon ; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); interferons, such as interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, and interferon gamma-n; PF3512676; Filgrastim (Neupogen); lentinan; sizofilan; TheraCys; ubenimex; WF-10; BAM-002; dacarbazine; daclizumab; denileukin; gemtuzumab; ozogamicin; imiquimod; lenograstim; melanoma vaccine (Corixa); molgramostim; OncoVAX-CL; sargramostim; tasonermin; tecleukin; thymalasin; tositumomab; Virulizin; Z-100; epratuzumab; mitumomab; oregovomab; pemtumomab; and toll-like receptor modulators for example TLR-7 or TLR-9 agonists; and
(viii) cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (Nipent) edotecarin, SU-11248, paclitaxel, Erbitux, and irinotecan;
(ix) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph;
(x) targeted therapies, for example PI3Kd inhibitors, for example idelalisib and perifosine;
(xi) and additional active agents such as estramustine phosphate, fludarabine phosphate, farnesyl transferase inhibitors, PDGFr, streptozocin, strontium-89, suramin, hormonal therapies (for example Lupron, doxercalciferol, fadrozole, formestane and trelstar), supportive care products (for example, Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi and Emend), biological response modifiers (e.g. Krestin, lentinan, sizofiran, picibanil and ubenimex), alitretinoin, ampligen, atrasenten, bexarotene, bosentan, calcitriol, exisulind, fotemustine, ibandronic acid, miltefosine, 1-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, tazarotne, TLK-286, Velcade, Tarceva, tretinoin.

(47) The combination therapies defined above may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

(48) According to a further aspect of the invention there is provided a pharmaceutical product comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined hereinbefore and an additional active agent for the treatment of a condition which is modulated by the Hedgehog signalling pathway. The additional active agent may be an anti-tumour agent as defined hereinbefore.

(49) In an embodiment there is provided a pharmaceutical product comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined hereinbefore and an additional active agent for the treatment of a condition which is modulated by Smo. The additional active agent may be an anti-tumour agent as defined hereinbefore.

(50) According to a further aspect of the invention there is provided a method of treatment of a condition modulated by the Hedgehog signalling pathway comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-tumour agent, as defined hereinbefore, to a patient in need thereof.

(51) In an embodiment the condition is a condition modulated by Smo.

(52) According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately with an additional anti-tumour agent as defined hereinbefore, in the treatment of a condition modulated by the Hedgehog signalling pathway. In an embodiment the condition is a condition modulated by Smo.

(53) According to another aspect of the invention there is provided a use of the compound of formula (I) in combination with an anti-tumour agent as hereinbefore described. The compound of formula (I) may be used simultaneously, sequentially or separately with the additional anti-tumour agent The use may be in a single combination product comprising the compound of formula (I) and the anti-tumour agent.

(54) According to a further aspect there is provided a method of providing a combination product, wherein the method comprises providing a compound of formula (I) simultaneously, sequentially or separately with an anti-tumour agent, as defined hereinbefore. The method may comprise combining the compound of formula (I) and the anti-tumour agent in a single dosage form. Alternatively the method may comprise providing the anti-tumour agent as separate dosage forms.

(55) The condition modulated by the Hedgehog signalling pathway or Smo described above may be cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia. More specifically the condition modulated by BTK may be selected from: cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia. Specific conditions treatable by the inhibition of the Hedgehog signalling pathway or Smo may be selected from: basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, chondrosarcoma, melanoma, small-cell lung cancer, non-small-cell lung cancer, B-cell lymphoma, multiple myeloma, brain cancer, esophagus cancer, breast cancer, ovarian cancer, stomach cancer, colorectal cancer, liver cancer, kidney cancer, head and neck cancer, mesothelioma, soft tissue sarcomas, bone sarcomas, testicular cancer, prostate cancer, pancreatic cancer, bone cancer, bone metastasis, acute leukemia, chronic leukemia, glioma, hodgkin's disease, cutaneous melanoma, bladder cancer, endocrine system cancer, parathyroid gland cancer, thyroid gland cancer, cervical cancer, endometrium cancer, ovarian cancer, skin cancer, renal cell carcinoma, pituitary adenoma, spinal axis tumours, uterine cancer, gastric cancer and biliary tract cancer.

(56) Conditions also treatable by the inhibition of the Hedgehog signalling pathway or Smo may be selected from inhibiting stem cell production, inhibiting stem cell renewal, inhibiting and/or modulating stem cell differentiation, benign prostatic hyperplasia, psoriasis and osteoporosis.

(57) For the above-mentioned compounds of the invention the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (g/kg) to 100 milligrams per kilogram body weight (mg/kg).

(58) A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, PharmaceuticalsThe Science of Dosage Form Designs, M. E. Aulton, Churchill Livingstone, 1988.

(59) Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99% w (percent by weight) compounds of the invention, more preferably from 0.05 to 80% w compounds of the invention, still more preferably from 0.10 to 70% w compounds of the invention, and even more preferably from 0.10 to 50% w compounds of the invention, all percentages by weight being based on total composition.

(60) The pharmaceutical compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories or enemas; or by inhalation in the form of an aerosol.

(61) For oral administration the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

(62) For the preparation of soft gelatine capsules, the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

(63) For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

(64) The size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

(65) Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient. The standard duration of treatment with compounds of the invention is expected to vary between one and seven days for most clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.

EXAMPLES AND SYNTHESIS

(66) As used herein the following terms have the meanings given: Boc refers to tert-butoxycarbonyl; CV refers to column volumes, DCM refers to dichloromethane; DIPEA refers to N,N-Diisopropylethylamine; LCMS refers to liquid chromatography/mass spectrometry; MIM refers to monoisotopic mass; min refers to minutes; NMP refers to N-methylpyrrolidinone; TLC refers to thin layer chromatography; Rf refers to Retention factor; RT refers to retention time; SCX refers to strong cation exchange; TFA refers to trifluoroacetic acid; THF refers to tetrahydrofuran; and TBME refers to tert-Butyl methyl ether.

(67) The compounds of the invention may be synthesised by analogy with the following reaction route.

(68) ##STR00140##

(69) The steps within the route shown above may be performed in the order shown above or in a different order. For example, as the skilled person would appreciate, the Suzuki coupling could be carried out after the reductive amination or after the urea formation etc. Protecting groups may be present or absent as necessary. For example a nitrogen atom may be protected or unprotected.

(70) Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at room temperature unless otherwise stated. Compound identity and purity confirmations were performed by LCMS UV using a Waters Acquity SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detector wavelength was 254 nM and the MS was in positive and negative electrospray mode (m/z: 150-800). A 2 L aliquot was injected onto a guard column (0.2 m2 mm filters) and UPLC column (C18, 502.1 mm, <2 m) in sequence maintained at 40 C. The samples were eluted at a flow rate of 0.6 mL/min with a mobile phase system composed of A (0.1% (v/v) Formic Acid in Water) and B (0.1% (v/v) Formic Acid in Acetonitrile) according to the gradients outlined in Table 1 below. Retention times RT are reported in minutes.

(71) TABLE-US-00001 TABLE 1 Time (min) % A % B Method 1 0 95 5 1.1 95 5 6.1 5 95 7 5 95 7.5 95 5 8 95 5 Method 2 0 95 5 0.3 95 5 2 5 95 2.6 95 5 3 95 5

(72) NMR was also used to characterise final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay with 5 mm BBFO probe. Optionally, compound Rf values on silica thin layer chromatography (TLC) plates were measured.

(73) Compound purification was performed by flash column chromatography on silica or by preparative LCMS. LCMS purification was performed using a Waters 3100 Mass detector in positive and negative electrospray mode (m/z: 150-800) with a Waters 2489 UV/Vis detector. Samples were eluted at a flow rate of 20 mL/min on a XBridge prep C18 5 M OBD 19100 mm column with a mobile phase system composed of A (0.1% (v/v) Formic Acid in Water) and B (0.1% (v/v) Formic Acid in Acetonitrile) according to the gradient outlined in Table 2 below.

(74) TABLE-US-00002 TABLE 2 Time (min) % A % B 0 90 10 1.5 90 10 11.7 5 95 13.7 5 95 14 90 90 15 90 90

(75) Chemical names in this document were generated using mol2namStructure to Name Conversion by OpenEye Scientific Software. Starting materials were purchased from commercial sources or synthesised according to literature procedures.

(76) Certain starting materials in the synthesis of compounds of formula (I) can be produced by the following procedures:

Procedure A

Pyrido[3,4-d]pyridazine-1,4-diol

(77) ##STR00141##

(78) Pyridine-3,4-dicarboxylic acid (3.10 g, 18.6 mmol) and acetic anhydride (7.0 mL, 74.2 mmol) were added to a 50 mL round bottomed flask and heated to reflux at 140 C. The white suspension turned into a black solution. The reaction was heated at this temperature for 3 hours. The reaction was cooled and the acetic anhydride was taken off by rotary evaporation to afford crude 3,4-pyridinedicarboxylic anhydride (2.68 g, 18.0 mmol, 97%) as brown crystals which was taken onto the next step without further purification.

(79) To a round bottomed flask were added 3,4-pyridinedicarboxylic anhydride (690 mg, 4.6 mmol) and acetic acid (8.9 mL). To this was added hydrazine hydrate (1.6 mL, 18.5 mmol) dropwise with ice bath cooling. The yellow suspension was refluxed at 100 C. overnight. Analytical LCMS indicated formation of product and the reaction was cooled. The resultant cream solid was filtered and washed with water. The product was then dried by rotary evaporation to afford pyrido[3,4-d]pyridazine-1,4-diol (600 mg, 3.7 mmol, 79.5%).

(80) .sup.1H NMR (400 MHz, d6 DMSO) /ppm: 11.9 (s (br), 2H), 9.34 (s (br), 1H), 9.03 (d, J 5.3 Hz, 1H), 7.90 (s (br), 1H).

(81) MS Method 2: RT: 0.54 min, ES.sup.+ m/z 164.0 [M+H].sup.+.

1,4-Dichloropyrido[3,4-d]pyridazine

(82) ##STR00142##

(83) Pyrido[3,4-c]pyridazine-1,4-diol (1.83 g, 11.2 mmol) and phosphorus oxychloride (8.4 mL, 89.7 mmol) were added to a round bottomed flask. To this was added DIPEA (2.0 mL, 11.2 mmol) slowly. The suspension was then heated for 1 hour at 100 C. The reaction turned into a brown solution. The phosphorus oxychloride was then removed by rotary evaporator. The resulting brown residue was dissolved in DCM and added dropwise to a mixture of ice and saturated NaHCO.sub.3 solution (aq). Saturated NaHCO.sub.3 solution (aq) was added until the aqueous layer was neutral. The organic and aqueous layers were separated and the aqueous layer was further extracted with DCM (500 mL). The organic layers were combined and dried (MgSO.sub.4) and then concentrated in vacuo to afford 1,4-dichloropyrido[3,4-c]pyridazine (1.74 g, 8.7 mmol, 77.6%).

(84) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 9.78 (d, J 0.9 Hz, 1H), 9.27 (d, J 5.7 Hz, 1H), 8.09 (dd, J 5.7 Hz, 0.9 Hz, 1H).

(85) MS Method 2: RT: 1.16 min, ES.sup.+ m/z 200.0/202.0 [M+H].sup.+.

(86) Similarly prepared were:

1,4-Dichloro-6,7-dihydro-5H-cyclopenta[c]pyridazine

(87) ##STR00143##

(88) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 3.13 (t, J 7.8 Hz, 2H), 2.27 (m, J 7.8 Hz, 4H).

3,6-Dichloro-4,5-dimethyl-pyridazine

(89) ##STR00144##

(90) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 2.46 (s, 6H).

Procedure B

Preparation of 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine and related compounds, intermediates in the synthesis of compounds of formula (I)

(91) ##STR00145##

tert-Butyl N-[1-(4-chlorophthalazin-1-yl)-4-piperidyl]carbamate

(92) ##STR00146##

(93) 1,4 Dichlorophthalazine (4.80 g, 24.1 mmol) and 4-Boc-aminopiperidine (5.00 g, 25.0 mmol) were combined in NMP at room temperature and potassium carbonate (3.67 g, 26.5 mmol) was added followed by activated molecular sieves. Then the reaction was heated to 100 C. overnight. The reaction was cooled to room temperature and poured over ice water, creating an off white semisolid precipitate. The products were extracted into ethyl acetate (3) and then back washed with more water. The combined organics were washed with brine, dried (MgSO.sub.4) and then concentrated in vacuo to afford tert-butyl N-[1-(4-chlorophthalazin-1-yl)-4-piperidyl]carbamate (7.08 g 19.5 mmol, 80%) as an off white/fawn coloured amorphous solid.

(94) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.27-8.22 (m, 1H), 8.06-8.01 (m, 1H), 7.94-7.88 (m, 2H), 4.59 (s (br), 1H), 3.87 (m (br), 2H), 3.79 (s (br), 1H), 3.25 (m (br), 2H), 2.2-2.13 (m, 2H), 1.80-1.68 (m, 2H), 1.49 (s, 9H).

(95) MS Method 1: RT: 3.94 min, ES.sup.+ m/z 363.3 [M+H].sup.+

tert-Butyl N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]carbamate

(96) ##STR00147##

(97) tert-Butyl N-[1-(4-chlorophthalazin-1-yl)-4-piperidyl]carbamate (2.0 g, 5.5 mmol) was dissolved in toluene (45 mL) (required heating) and a solution of catalyst generated from triphenylphosphine (0.52 g, 2.0 mmol) and palladium acetate (112 mg, 0.5 mmol) in toluene (5 mL) and ethanol (15 mL) was added. 1-Methyl-1H-pyrazole-5-boronic acid, pinacolester (1.67 g, 8.0 mmol) was then added followed by water (15 mL) and the sodium carbonate (1.75 g 16.5 mmol). The solution was de-gassed under vacuum and purged with nitrogen three times before heating to 95 C. overnight. LCMS confirmed the presence of the desired product hence the reaction was cooled to room temperature and diluted with ethyl acetate and water. The organic and aqueous layers were separated and the organic layer washed with brine, dried (MgSO.sub.4) and then concentrated in vacuo to afford a dark brown oil/gum. Purification by silica flash chromatography using 10% 3M NH.sub.3/MeOH: 30% ethyl acetate: 60% heptane afforded tert-butyl N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]carbamate (1.99 g 4.87 mmol, 88%) as an off-white solid.

(98) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.11-8.06 (m, 2H), 7.90-7.81 (m, 2H), 7.67 (d, J 1.9 Hz, 1H), 6.60 (d, J 1.9 Hz, 1H), 4.61 (s (br), 1H), 4.07 (s, 3H), 4.00 (m (br), 2H), 3.82 (s (br), 1H), 3.32 (m (br), 2H), 2.24-2.17 (m, 2H), 1.84-1.73 (m, 2H), 1.50 (s, 9H).

(99) MS Method 1: RT: 3.65 min, ES.sup.+ m/z 409.4 [M+H].sup.+

1-[4-(2-Methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine

(100) ##STR00148##

(101) A solution containing tert-butyl N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]carbamate (6.0 g, 14.7 mmol) and trifluoroacetic acid (12.6 mL, 176 mmol) in DCM (40 mL) was prepared and stirred overnight. The reaction mixture was concentrated in vacuo. The crude material was purified by SCX with MeOH washings followed by 2M NH.sub.3 in MeOH to elute the product. The resulting solution was concentrated under reduced pressure to afford 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (2.82 g, 9.1 mmol, 62% yield) as an oil.

(102) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.11-8.02 (m, 2H), 7.88-7.78 (m, 2H), 7.65 (d, J 1.9 Hz, 1H), 6.58 (d, J 1.9 Hz, 1H), 4.04 (s, 3H), 4.00 (m (br), 2H), 3.22 (m (br), 2H), 3.02 (tt, J 10.5 hz, 4.2 Hz 1H), 2.10-2.01 (m, 2H), 1.77-1.67 (m, 2H).

(103) MS Method 2: RT: 0.91 min. m/z 309.2 [M+H].sup.+

(104) Similarly prepared was:

N-Methyl-1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]piperidin-4-amine

(105) ##STR00149##

(106) To a round bottomed flask were added tert-butyl piperidin-4-ylmethylcarbamate (0.29 mL, 55 mmol), 1,4-dichloropyrido[3,4-c]pyridazine (13.48 mL, 50 mmol), N,N-diisopropylethylamine (26 mL, 150 mmol), NMP (50 mL) and heated to 100 C. for 1 hour. The reaction was diluted with EtOAc and washed with water (5100 mL). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The resulting residue was purified by silica flash chromatography using 30% EtOAc in heptane using a slow isocratic elution and concentrated in vacuo to afford the major regioisomer tert-butyl N-[1-(1-chloropyrido[3,4-d]pyridazin-4-yl)-4-piperidyl]-N-methyl-carbamate (1.1 g, 2.9 mmol, 5.8%, 98% purity). Further mixed fractions of lower purity were also obtained.

(107) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 9.46 (s, 1H), 9.03 (d, J 5.6 Hz, 1H), 7.94 (d, J 5.6 Hz, 1H), 4.33 (m (br), 1H), 4.22-4.12 (m (br), 2H), 3.29 (t, J 12.5 Hz, 2H), 2.83 (s, 3H), 2.11-1.97 (m, 2H), 1.90-1.81 (m, 2H), 1.50 (s, 9H).

(108) MS Method 2: RT: 1.73 min. m/z 378.9[M+H].sup.+

(109) Split between 210-20 mL microwave vials was added tert-butyl N-[1-(1-chloropyrido[3,4-d]pyridazin-4-yl)-4-piperidyl]-N-methyl-carbamate (2.03 g, 5.38 mmol), toluene (12 mL), ethanol (8 mL), water (4 mL), 1-methyl-1H-pyrazole-5-boronic acid, pinacolester (1.57 g, 7.53 mmol) and sodium carbonate (1.09 g, 10.8 mmol. The mixture was purged with nitrogen for 10 minutes. To the reaction vials was then added Palladium (0) tetrakis(triphenylphosphine) (935 mg, 0.81 mmol) and the vials were immediately capped and heated in the microwave for 1 hour at 150 C. The contents of the vials were combined and diluted with EtOAc and partitioned with water. The organic layer was washed with 350 mL of water. The organic layer was dried over sodium sulphate, filtered and then concentrated to give a brown oil. The resulting residue was then purified by silica flash chromatography using 0% EtOAc in heptane to 90% ethyl acetate in heptane followed by a slow isocratic elution at 90% ethyl acetate in heptane to afford tert-butyl N-methyl-N-[1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]-4-piperidyl]carbamate (1.50 g, 3.54 mmol, 65.9%) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 9.54 (s, 1H), 8.96 (d, J5.7 Hz, 1H), 7.87 (d, J5.7 Hz, 1H), 7.69 (d, J2.0 Hz, 1H), 6.63 (d, J2.0 Hz, 1H), 4.49-4.27 (m (br), 3H), 4.12 (s, 3H), 3.38 (t, J12.5 Hz, 2H), 2.85 (s, 3H), 2.15-2.01 (m, 2H), 1.95-1.87 (m, 2H).

(110) MS Method 2: RT: min. m/z 378.9[M+H].sup.+

(111) To a round bottomed flask was added tert-butyl N-methyl-N-[1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]-4-piperidyl]carbamate (1.50 g, 3.54 mmol) and trifluoroacetic acid (4. mL, 52 mmol) and stirred at room temperature for 2 hours. The reaction was concentrated in vacuo and the resulting red oil was purified by SCX with MeOH washings followed by 2M NH.sub.3 in MeOH to elute the product. The resulting solution was concentrated under reduced pressure to afford N-methyl-1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]piperidin-4-amine (947 mg, 2.93 mmol, 82.7%).

(112) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 9.53 (d, J0.9 Hz, 1H), 8.95 (d, J5.7 Hz, 1H), 7.85 (dd, J5.7 Hz, 0.9 Hz, 1H), 7.69 (d, J2.0 Hz, 1H), 6.62 (d, J2.0 Hz, 1H), 4.26-4.18 (m, 2H), 4.11 (s, 3H), 3.42-3.34 (m, 2H), 2.77 (tt, J 10.1 hz, 4.0 Hz, 1H), 2.55 (s, 3H), 2.23-2.14 (m, 2H), 1.79-1.67 (m, 2H).

(113) MS Method 2: RT: 0.87 min. m/z 324.2[M+H].sup.+

(114) And similarly prepared was:

1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-methyl-piperidin-4-amine

(115) ##STR00150##

(116) tert-Butyl piperidin-4-ylmethylcarbamate (3.81 g, 17.8 mmol), 3,6-dichloro-4,5-dimethyl-pyridazine (3.0 g, 17.0 mmol), NMP (14 mL) and N,N-Diisopropylethylamine (4.43 mL, 25.4 mmol) were added to a round bottom flask and heated to 150 C. for 5 h. The mixture was partitioned between EtOAc (100 mL) and 1M Na.sub.2CO.sub.3 aq. (50 mL). The organic layer was washed with 1M Na.sub.2CO.sub.3 aq. (50 mL), water (270 mL), brine (70 mL), before passage through a hydrophobic frit and concentrated in vacuo to give an orange/brown solid. The crude material was purified by silica flash chromatography using 0% EtOAc in heptane with tri ethylamine 1% with a gradient increasing to 30% ethyl acetate. Fractions containing product were combined and concentrated in vacuo to afford tert-butyl N-[1-(6-chloro-4,5-dimethyl-pyridazin-3-yl)-4-piperidyl]-N-methyl-carbamate (1.8 g, 5.1 mmol, 30% yield).

(117) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 4.34-3.84 (m, 2H), 3.56-3.47 (m (br), 2H), 3.00 (t (br), J12.0 Hz, 2H), 2.78 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 1.93-1.80 (m, 2H), 1.78-1.71 (m (br), 2H), 1.47 (s, 9H).

(118) MS Method 2: RT: 1.88 min, m/z 355.9 [M+H].sup.+

(119) The reaction was carried out in 320 mL microwave tubes: 1-methyl-1H-pyrazole-5-boronic acid, pinacolester (5.28 g, 25.4 mmol), tert-butyl N-[1-(6-chloro-4,5-dimethyl-pyridazin-3-yl)-4-piperidyl]-N-methyl-carbamate (6.0 g, 16.9 mmol), palladium(0) tetrakis(triphenylphosphine) (0.98 g, 0.85 mmol) were combined in 1,2-dimethoxyethane (30. mL, 16.91 mmol) and a solution of potassium hydrophosphate (5.9 g, 33.8 mmol in 15 mL water) was added, The vessels were sealed, the reaction mixture degassed with nitrogen and heated to 120 C. in the microwave for 2 hrs. Further 1-methyl-1H-pyrazole-5-boronic acid, pinacolester (2.14 g, 12.7 mmol), palladium(0) tetrakis(triphenylphosphine) (0.49 g, 0.425 mmol) and potassium hydrophosphate (2.85 g, 16.9 mmol in 7.5 mL water) were added and the vessels were resealed, the reaction mixture was again degassed with nitrogen and heated to 120 C. in the microwave for 2 hrs. The reaction was cooled to room temperature, the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate (3). The organic layers were combined, dried over brine and sodium sulphate. Filtered and evaporated in vacuo to a dark brown gum. The crude material was purified by silica flash chromatography using 100% heptane with a gradient to 40% ethyl acetate in heptane then an isocratic flow of 40% ethyl acetate in heptane for 4 column volumes before increasing the gradient to 100% ethyl acetate. Fractions containing the product were combined and evaporated in vacuo to afford tert-butyl N-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]-N-methyl-carbamate (5.2 g, 13 mmol, 76.8%)

(120) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 7.56 (d, J1.9 Hz, 1H), 6.35 (d, J1.9 Hz, 1H), 4.36-3.93 (m (br), 1H), 3.92 (s, 3H), 3.68-3.61 (m (br), 2H), 3.09 (t, J12.1 Hz, 2H), 2.81 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 1.97-1.85 (m, 2H), 1.83-1.76 (m (br), 2H), 1.49 (s, 9H).

(121) MS Method 2: RT: 1.66 min, m/z 401.3 [M+H].sup.+

(122) Trifluoroacetic acid (3.0 mL, 39.2 mmol) was added dropwise to a stirring solution of tert-butyl N-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]-N-methyl-carbamate (2.0 g, 4.99 mmol) in DCM (30 mL) at room temperature and the reaction was stirred for 2 h. Further TFA (0.8 mL) was added and the reaction was stirred overnight. The mixture was concentrated in vacuo and then the resulting residue was loaded onto a primed SCX-2 cartridge, which was eluted with methanol (5 CV) to remove impurities and then 1M NH.sub.3/MeOH (2CV) to isolate the product. The latter fraction was concentrated in vacuo to afford an orange oil that solidified on standing, 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-methyl-piperidin-4-amine (1.12 g, 3.73 mmol, 74.7% yield).

(123) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 7.56 (d, J1.9 Hz, 1H), 6.35 (d, J1.9 Hz, 1H), 3.91 (s, 3H), 3.61-3.54 (m (br), 3H), 3.03 (t, J12.2 Hz, 2H), 2.61 (tt, J10.5 Hz, 4.3 Hz, 1H), 2.50 (s, 3H), 2.27 (s, 3H), 2.21 (s, 3H), 2.09-2.02 (m (br), 2H), 1.61-1.49 (m, 2H).

(124) MS Method 2: RT: 0.92 min, m/z 301.2 [M+H].sup.+

(125) And similarly prepared were:

N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine

(126) ##STR00151##

(127) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.10 (d, J 8.1 Hz, 1H), 8.08 (d, J 8.1 Hz, 1H), 7.90-7.80 (m, 2H), 7.67 (d, J 1.9 Hz, 1H), 6.60 (d, J 1.9 Hz, 1H), 4.07 (s, 3H), 4.07-4.01 (m (br), 2H), 3.28-3.20 (m (br), 2H), 2.73 (tt, J 10.5 Hz, 3.9 Hz, 1H), 2.55 (s, 3H), 2.20-2.13 (m, 2H), 1.78-1.67 (m, 2H).

1-[1-(2-Methylpyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-4-yl]piperidin-4-amine

(128) ##STR00152##

(129) .sup.1H NMR (400 MHz, MeOD) /ppm: 7.56 (d, J 2.0 Hz, 1H), 6.55 (d, 1H), 4.14-4.08 (m (br), 2H), 4.02 (s, 3H), 3.11-3.02 (m, 4H), 3.00-2.92 (m, 3H), 2.17-2.10 (m, 2H), 2.03-1.96 (m, 2H), 1.59-1.48 (m, 2H).

(130) MS Method 2: RT: 0.89 min m/z 299.3 [M+H].sup.+

racemic [1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]pyrrolidin-3-yl]methanamine

(131) ##STR00153##

(132) .sup.1H NMR (400 MHz, MeOD) /ppm: 8.53-8.49 (m, 1H), 7.95-7.81 (m, 3H), 7.69 (d, J2.0 Hz, 1H), 6.63 (d, J2.0 Hz, 1H), 4.17-4.00 (m, 3H), 3.88 (s, 3H), 3.80 (dd, J10.8 Hz, 8.0 Hz, 1H), 2.87 (d, J7.0 Hz, 2H), 2.58-2.46 (m, 1H), 2.33-2.25 (m, 1H), 1.91-1.80 (m, 1H).

(133) MS Method 2: RT: 0.60 min m/z 309.2 [M+H].sup.+

(134) Also prepared was:

1-(4-morpholinophthalazin-1-yl)piperidin-4-amine

(135) ##STR00154##

(136) tert-Butyl N-[1-(4-chlorophthalazin-1-yl)-4-piperidyl]carbamate (150. mg, 0.4100 mmol), morpholine (0.05 mL, 0.62 mmol) and triethylamine (0.07 mL, 0.50 mmol) were dissolved in NMP (0.50 mL) and heated in microwave at 150 C. for 1 hour. LCMS. Water (5 mL) was added resulting in the precipitation of a white solid, the suspension was stirred rapidly for 10 minutes before filtering, the collected solid was washed with more water and dried under suction to yield tert-butyl N-[1-(4-morpholinophthalazin-1-yl)-4-piperidyl]carbamate (140 mg, 0.3386 mmol, 81.898% yield). as an off white solid.

(137) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.07-7.98 (m, 2H), 7.80-7.75 (m, 2H), 4.56 (s (br), 1H), 3.99-3.95 (m, 4H), 3.78-3.70 (m, 3H), 3.46-3.41 (m, 4H), 3.16 (t, J12.0 Hz, 2H), 2.17-2.08 (m, 2H), 1.78-1.67 (m, 2H), 1.47 (s, 9H)

(138) MS Method 2: RT: 1.29 min, m/z 414.4 [M+H].sup.+

(139) tert-Butyl N-[1-(4-morpholinophthalazin-1-yl)-4-piperidyl]carbamate (140 mg, 0.34 mmol) was dissolved in DCM (3 mL) and trifluoroacetic acid (0.26 mL, 3.39 mmol) was added. The solution was stirred for 1 hour. The reaction mixture was concentrated in vacuo to a brown oil which was desalted on a 5 g SCX cartridge washing with methanol then eluting with 10% (7M NH.sub.3 in MeOH) in MeOH to afford 1-(4-morpholinophthalazin-1-yl)piperidin-4-amine (106 mg, 0.34 mmol, 99.9% yield) as a white solid.

(140) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.08-8.04 (m, 2H), 7.82-7.77 (m, 2H), 4.01-3.98 (m, 4H), 3.83-3.76 (m (br), 2H), 3.48-3.44 (m, 4H), 3.11 (t, J12.5 Hz, 2H), 2.98 (tt, J10.5 Hz, 4.4 Hz, 1H), 2.07-2.00 (m (br), 2H), 1.76-1.65 (m, 2H).

(141) MS Method 2: RT: 0.78 min, m/z 314.3 [M+H].sup.+

Procedure C

Preparation of N-[[4-Fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-piperidin-4-amine an intermediate in the synthesis of compounds of formula (I)

(142) ##STR00155##

(143) 1-Boc-4-(methylamino)piperidine (800 mg, 3.7 mmol), and 4-fluoro-2-(trifluoromethyl)benzaldehyde (0.56 mL, 4.1 mmol) were dissolved in DCM (12 mL) (plus molecular sieves) and stirred for 2 hours at room temperature. To the clear solution was added sodium triacetoxyborohydride (1.18 g, 5.6 mmol) and the reaction was stirred over the weekend at room temperature. The reaction was diluted with DCM and then quenched with saturated NaHCO.sub.3 solution (aq). The organic and aqueous layers were separated and the aqueous layer further extracted with DCM. The organic layers were combined and concentrated in vacuo to give 1.6 g of crude product as a yellow oil. Purification by silica flash chromatography using 0% EtOAc in heptane with a gradient increasing to 50% ethyl acetate afforded tert-butyl 4-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl-methyl-amino]piperidine-1-carboxylate (1.15 g, 2.9 mmol, 79%) as a pale yellow/clear oil.

(144) tert-Butyl 4-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl-methyl-amino]piperidine-1-carboxylate (1.15 g, 2.95 mmol) and trifluoroacetic acid (4.5 mL, 58.9 mmol) were combined and stirred at room temperature for 4 hours. The solution turned from to clear to light pink. The reaction was concentrated in vacuo and the resulting pink oil was dissolved in methanol and loaded onto a methanol primed SCX cartridge and washed with methanol (3 column volumes) and triethylamine in methanol (3 column volumes). The triethylamine wash was then concentrated in vacuo to afford N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-piperidin-4-amine (750 mg, 2.6 mmol, 88%).

(145) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 7.84 (dd, J 8.5 Hz, 5.8 Hz 1H), (dd, J 5.8 Hz, 2.7 Hz 1H), 7.22 (td, J 8.5 Hz, 2.7 Hz, 1H), 3.73 (s (br), 2H), 3.24-3.18 (m (br), 2H), 2.85 (s (br), 1H), 2.63 (td, J12.2 Hz, 2.4 Hz, 2H), 2.56 (tt, J 11.5 Hz, 3.6 Hz, 1H), 2.22 (s, 3H), 1.89-1.82 (m (br), 2H), 1.56 (qd, J 12.1 Hz, 3.9 Hz, 2H)

(146) MS Method 2: RT: 0.73 min, m/z 291.3 [M+H].sup.+

(147) Similarly prepared was:

(148) ##STR00156##

(149) MS Method 2: RT: 1.34 min, m/z 317.3 [M+H].sup.+

Procedure D

Preparation of 2,2,2-trifluoro-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-(4-piperidyl)acetamide hydrochloride an intermediate in the synthesis of compounds of formula (I)

(150) ##STR00157##

tert-butyl 4-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]piperidine-1-carboxylate

(151) ##STR00158##

(152) 4-Fluoro-2-(trifluoromethyl)phenyl]methanamine (28.0 g, 145 mmol) and 1-Boc-4-piperidone (28.9 g, 145 mmol) were mixed in dry toluene (250 mL). The reaction was flushed with nitrogen and stirred at room temperature under an atmosphere of nitrogen for 30 min before heating overnight under dean stark conditions to distil off the water formed. The reaction was cooled and concentrated in vacuo to give a dark orange oil. The crude oil was taken up in methanol (250 mL) and sodium borohydride (25 g, 290 mmol) was added portionwise over ten minutes with ice bath cooling. The reaction was then allowed to warm to room temperature and stirred for 3 days and left to stand for 1 day. The methanol was concentrated in vacuo and the residue partitioned between ethyl acetate and water and stirred. Solid ammonium chloride was added to aid separation. The aqueous layer was extracted with ethyl acetate and the combined organics were further washed with water then brine, then dried (MgSO.sub.4), filtered then concentrated in vacuo to afford an orange oil (55 g). The crude material was purified by silica flash chromatography using 10% ethyl acetate in heptane with a gradient increasing to 100% ethyl acetate to afford tert-butyl 4-[[4-fluoro-2-(trifluoromethyl)benzyl]amino]piperidine-1-carboxylate (24.58 g, 65 mmol, 55%) as a yellow oil.

(153) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 7.68 (dd, J 8.4 Hz, 5.6 Hz, 1H), 7.35 (dd, J 5.0, 2.5, 1H), 7.24 (td, J 8.4 Hz, 2.5 Hz, 1H), 4.03 (s (br), 2H), 3.95 (s, 2H), 2.84 (t (br), J 12.1 Hz, 2H), 2.69 (tt, J 10.9 Hz, 3.1 Hz, 1H), 1.92-1.84 (m, 1H), 1.48 (s, 9H), 1.37-1.25 (m, 4H).

tert-butyl 4-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl-(2,2,2-trifluoroacetyl)amino]piperidine-1-carboxylate

(154) ##STR00159##

(155) tert-Butyl 4-[[4-fluoro-2-(trifluoromethyl)phenyl]methylamino]piperidine-1-carboxylate (1.87 g, 4.97 mmol) and triethylamine (1.38 mL, 9.94 mmol) were dissolved in DCM (40 mL) and the reaction mixture cooled to 0 C. Trifluoroacetic anhydride (0.69 mL, 4.97 mmol) was added dropwise and the mixture was gradually allowed to warm to room temperature over 2 hours. The reaction mixture was washed with water (320 mL) then with brine (30 mL). The organics were dried (MgSO.sub.4), filtered then concentrated in vacuo to give a yellow oil (2.3 g). This was purified using silica flash column chromatography eluting using 0% ethyl acetate in heptane with a gradient increasing to 50% ethyl acetate to afford tert-butyl 4-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl-(2,2,2-trifluoroacetyl)amino]piperidine-1-carboxylate (1.47 g, 3.11 mmol, 63% yield) as a pale straw coloured oil.

(156) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 7.45-7.40 (m, 1H), 7.39-7.34 (m, 0.3H, rotamer), 7.32-7.26 (m, 0.3H, rotamer), 7.22 (td, J 8.1 Hz, 2.4 Hz, 0.7H, rotamer), 7.11 (dd, J 8.5 Hz, 5.2 Hz, 0.7H, rotamer), 4.77 (s, 2H), 4.36-4.04 (m, 3H), 2.74 (s (br), 2H), 1.73-1.54 (m, 4H), 1.46 (s, 6.3H, rotamer), 1.45 (s, 2.7H, rotamer).

2,2,2-trifluoro-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-(4-piperidyl)acetamide hydrochloride

(157) ##STR00160##

(158) tert-Butyl 4-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl-(2,2,2-trifluoroacetyl)amino]piperidine-1-carboxylate (1.47 g, 3.11 mmol) was taken up in a solution of 4M hydrogen chloride in dioxane (10 mL, 40 mmol) and stirred at room temperature for 90 min. The excess hydrogen chloride and solvent were removed in vacuo and the resulting solid was washed twice with DCM to remove any traces of HCl to afford 2,2,2-trifluoro-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-(4-piperidyl)acetamide hydrochloride (1.5 g, 3.67 mmol, quantitative) as an off-white solid. This was used without further purification.

(159) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 9.96-9.60 (m, 2H), 7.48-7.40 (m, 1H), 7.34-7.26 (m, 1H, rotamers), 7.25-7.17 (m, 0.5H, rotamer), 7.06-7.01 (m, 0.5H, rotamer), 4.82 (s, 2H), 4.36-4.14 (m, 1H), 3.61-3.49 (m, 2H), 3.03-2.83 (m, 2H), 2.39-2.25 (m, 2H), 1.90 (dd, J 23.2 Hz, 13.8 Hz, 2H).

(160) MS Method 2: RT: 1.25 min, m/z 373.2 [M+H].sup.+

(161) Compounds produced in the Procedures described above may take part in reactions to produce compounds of the invention, such as those exemplified below.

Example 1

(162) Compounds produced in Procedure B described above can be used in the preparation of N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine a compound of formula (I).

(163) ##STR00161##

(164) 1-[4-(2-Methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (228 mg, 0.74 mmol) and 4-fluoro-2-(trifluoromethyl)benzaldehyde (142 mg, 0.74 mmol) were added to Methanol (15 mL). Molecular sieves were added and the reaction mixture stirred at room temperature under an atmosphere of nitrogen overnight. The reaction mixture was filtered and the resulting reaction mixture passed through the H-Cube using a 10% Pd/C CatCart cartridge at 1.0 mL/min at 40 C. The crude material was purified in the silica flash chromatography eluting with 0% DCM-heptane with a gradient increasing to 25% DCM followed by 0% MeOH-DCM with a gradient increasing to 10% MeOH. Fractions containing the product were combined and concentrated in vacuo to give an off white solid. This material was further purified by flash column chromatography eluting with 0% MeOH-DCM with a gradient to 5% MeOH to afford N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (100 mg, 0.21 mmol, 28%) as an off white solid.

(165) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.12 (d, J 8.1 Hz, 1H), 8.06 (d, J 8.1 Hz, 1H), 7.90-7.80 (m, 2H), 7.77 (d, J 8.4 Hz, 5.6 Hz, 1H), 7.67 (d, J 1.9 Hz, 1H), 7.39 (dd, J 9.1 Hz, 2.6 Hz, 1H), 7.3-7.25 (m, 1H), 6.60 (d, J 1.9 Hz, 1H), 4.07 (s, 3H), 4.05 (s, 2H), 4.07-4.01 (m, 2H), 3.30-3.22 (m, 2H), 2.97-2.88 (m, 1H), 2.22-2.15 (m, 2H), 1.85-1.75 (m, 2H).

(166) MS Method 2: RT: 1.24 min, m/z 485.3 [M+H].sup.+

Example 2

(167) The compound of Example 1 may be used as a starting material in the preparation of another compound of formula (I), N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine.

(168) ##STR00162##

(169) N-[[4-Fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (23 mg, 0.05 mmol) and formaldehyde solution (36.5-38%) in water (0.01 mL, 0.24 mmol) were dissolved in methanol (5 mL) and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (30.3 mg, 0.14 mmol) was added and the reaction left to stir at room temperature overnight. LCMS analysis confirmed formation of product. The reaction mixture was concentrated under reduced pressure to give a crude oil. The crude material was dissolved in ethyl acetate (20 mL), washed with saturated NaHCO3 solution (aq) (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure. Purification by SCX with MeOH washings followed by 2M NH3 in MeOH to elute the product afforded a colourless oil. The resulting colourless oil was dissolved in 1:1 MeCN:H2O and the solvent removed under vacuum to give N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (18.4 mg, 0.04 mmol, 77%) as a white crystalline solid.

(170) 1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.14 (d, J 8.3 Hz, 1H), 8.07 (d, J 8.3 Hz, 1H), 7.90-7.81 (m, 3H), 7.68 (d, J 2.0 Hz, 1H), 7.37 (dd, J 9.1 Hz, 2.6 Hz, 1H), 7.29-7.23 (m, 1H), 6.61 (d, J 2.0 Hz, 1H), 4.17-4.11 (m (br), 2H), 4.08 (s, 3H), 3.83 (s, 2H), 3.24-3.16 (m (br), 2H), 2.85-2.77 (m, 1H), 2.32 (s, 3H), 2.11-1.93 (m, 4H).

(171) MS Method 2: RT: 1.23 min, m/z 499.4 [M+H].sup.+

Example 3

(172) The compound of Example 1 may be used as a starting material in the preparation of another compound of formula (I),

N-[[4-Fluoro-2-(trifluoromethyl)phenyl]methyl]-N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]acetamide

(173) ##STR00163##

(174) N-[[4-Fluoro-2-(trifluoromethyl)phenyl]methyl]-N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]acetamide was prepared from N-[[4-Fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (45 mg, 0.090 mmol) using acetylation methods known to those skilled in the art. The crude product was purified using silica flash chromatography eluting with 0% methanol in DCM with a gradient to 10% methanol to afford N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]acetamide (18.8 mg, 0.034 mmol, 38%) as an off white solid

(175) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.10-8.02 (m, 2H), 7.92-7.80 (m, 2H), 7.69-7.66 (m, 1H), 7.52-7.21 (m, 3H), 6.61-6.59 (m, 1H), 4.99-4.89 (m, 0.6H, rotamer), 4.85 (s, 0.8H, rotamer), 4.75 (s, 1.2H, rotamer), 4.12-4.02 (m, 2.4H, including rotamer), 4.06 (s, 3H), 3.35-3.16 (m, 2H), 2.42 (s, 1.2H, rotamer), 2.07 (s, 1.8H, rotamer), 2.14-1.84 (m, 4H).

(176) MS Method 2: RT: 1.65 min, m/z 527.3 [M+H].sup.+

Example 4

(177) Compounds produced in Procedure A and Procedure E described above can be used in the preparation of N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]piperidin-4-amine a compound of formula (I).

(178) ##STR00164##

N-[1-(1-chloropyrido[3,4-c]pyridazin-4-yl)-4-piperidyl]-2,2,2-trifluoro-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]acetamide

(179) ##STR00165##

(180) To a 50 mL round bottomed flask were added 1,4-dichloropyrido[3,4-d]pyridazine (200 mg, 1 mmol), potassium carbonate (0.37 mL, 2 mmol), 2,2,2-trifluoro-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-(4-piperidyl)acetamide (409 mg, 1.1 mmol), NMP (3.0 mL) and the reaction was refluxed at 100 C. overnight. The reaction was cooled and diluted with ethyl acetate. The organic layer was washed with water (520 mL). The organic layer was dried (MgSO.sub.4) and concentrated in vacuo to afford N-[1-(1-chloropyrido[3,4-d]pyridazin-4-yl)-4-piperidyl]-2,2,2-trifluoro-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]acetamide (480 mg, 0.90 mmol, 90%) which was used without further purification.

(181) MS Method 2: RT: 1.94 min, m/z 536.2/538.2 [M+H].sup.+

2,2,2-trifluoro-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-[1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]-4-piperidyl]acetamide

(182) ##STR00166##

(183) To a 10-20 mL microwave vial were added Palladium (0) tetrakis(triphenylphosphine) (0.14 mL, 0.09 mmol), 1-methyl-1H-pyrazole-5-boronic acid, pinacolester (280 mg, 1.34 mmol), sodium carbonate (193 mg, 1.8 mmol), water (3.3 mL), ethanol (3.3 mL) and toluene (3.3 mL) and the reaction was degassed with a flow of nitrogen for 10 min. N-[1-(1-chloropyrido[3,4-d]pyridazin-4-yl)-4-piperidyl]-2,2,2-trifluoro-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]acetamide (480 mg, 0.90 mmol) was then added and heated in the microwave for 40 min at 100 C. The reaction was concentrated in vacuo and then taken up in DCM. The organic layer was washed with water. The aqueous layer was extracted with DCM (310 mL). The organic layers were combined and concentrated. The resulting brown oil was purified by silica flash chromatography using 0% ethyl acetate in heptane with a gradient increasing to 100% ethyl acetate to afford 2,2,2-trifluoro-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-[1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-c]pyridazin-4-yl]-4-piperidyl]acetamide (150 mg, 0.26 mmol, 29%).

(184) MS Method 2: RT: 1.81 min, m/z 582.4 [M+H].sup.+

N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-c]pyridazin-4-yl]piperidin-4-amine

(185) ##STR00167##

(186) To a round bottomed flask were added phenyl]methyl]-N-[1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-c]pyridazin-4-yl]-4-piperidyl]acetamide (150 mg, 0.26 mmol), sodium hydroxide (1.0 mL, 1.0 mmol), Methanol (1 mL) and the reaction was stirred at room temperature over the weekend. The reaction mixture was concentrated in vacuo and purified by silica flash chromatography using 0% methanol in ethyl acetate with a gradient to 20% methanol to afford N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]piperidin-4-amine (23.6 mg, 0.05 mmol, 19%).

(187) MS Method 2: RT: 1.17 min, m/z 486.3[M+H].sup.+

(188) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 9.44 (d, J 0.9 Hz, 1H), 8.86 (d, J 5.7 Hz, 1H), 7.77 (dd, J 5.7 Hz, 0.9 Hz, 1H), 7.66 (dd, J8.5 Hz, 5.7 Hz, 1H), 7.60 (d, J 1.9 Hz, 1H), 7.30 (dd, J 9.2 Hz, 2.8 Hz, 1H), 7.22-7.16 (m, 1H), 6.52-6.53 (d, J1.9 Hz, 1H) 4.17-4.10 (m (br), 2H), 4.02 (s, 3H), 3.96 (s (br), 2H), 3.35-3.27 (m, 2H), 2.92-2.83 (m, 1H), 2.15-2.07 (m (br), 2H), 1.77-1.65 (m, 2H).

Example 5

(189) In a similar way to Example 1, but using different conditions, compounds of formula (I) can be prepared by the General Method A1, shown below. General Method A1 may be carried out using the compound prepared by Procedure B or another appropriate method for producing the compound.

(190) ##STR00168##

1-[4-(2-Methylpyrazol-3-yl)phthalazin-1-yl]-N-[[4-(trifluoromethyl)phenyl]methyl]piperidin-4-amine

(191) ##STR00169##

(192) 1-[4-(2-Methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (100 mg, 0.32 mmol) and 4-(trifluoromethyl)benzaldehyde (44 uL, 0.32 mmol) were dissolved in dry methanol (5 mL) and stirred at room temperature under an atmosphere of nitrogen overnight. Sodium borohydride (14.7 mg, 0.39 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction mixture was loaded onto an SCX cartridge, washed with 2 column volumes of methanol and then eluted with 2 column volumes of 2N ammonia in methanol. The ammonia in methanol was then removed in vacuo to afford a crude oil which was purified by preparative LCMS to afford the formate salt. This was then dissolved in methanol and loaded onto a carbonate column which was eluted with 2 column volumes of MeOH to produce the free base of 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[4-(trifluoromethyl)phenyl]methyl]piperidin-4-amine (16.4 mg, 0.032 mmol, 10%).

(193) .sup.1H NMR (400 MHz, MeOD) /ppm: 8.26 (d, J 8.2 Hz, 1H), 8.05-8.00 (m, 1H), 7.98-7.95 (m, 2H), 7.71 (d, J 2.0 Hz, 1H), 7.68 (d, J 8.3 Hz, 2H), 7.63 (d, J 8.3 Hz, 2H), 6.70 (d, J2.1 Hz, 1H), 4.10-4.04 (m (br), 2H), 3.99 (s, 2H), 3.91 (s, 3H), 3.23-3.15 (m, 2H), 2.86 (m, 1H), 2.24-2.17 (m, 2H), 1.88-1.77 (m, 2H).

(194) MS Method 1: RT: 2.83 min, m/z 467.3 [M+H].sup.+

(195) The compounds shown below in Table 3 were similarly prepared by varying the aldehyde shown in the reaction scheme for General Method A1:

(196) TABLE-US-00003 TABLE 3 m/z COMPOUND COMPOUND NAME LCMS RT MIM 0 1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[(2- methylsulfanylphenyl)methyl] piperidin-4-amine 2.74 min (Method 1) 445.3 [M + H].sup.+ N-[(2-chloro-4-fluoro- phenyl)methyl]-1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 2.68 min (Method 1) 451.3 [M + H].sup.+ 1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[[4- (trifluoromethoxy)phenyl]methyl] piperidin-4-amine 2.92 min (Method 1) 483.3 [M + H].sup.+ N-[[2-(difluoromethoxy) phenyl]methyl]-1-[4-(2- methylpyrazol-3-yl)phthalazin- 1-yl]piperidin-4-amine 2.72 min (Method 1) 465.3 [M + H].sup.+ 1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[[3- (trifluoromethoxy)phenyl] methyl]piperidin-4-amine 4.19 min (Method 1) 483.3 [M + H].sup.+ N-[(4-chlorophenyl)methyl]-1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 3.95 min (Method 1) 433.3 [M + H].sup.+ 1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[[2- (trifluoromethoxy)phenyl]methyl] piperidin-4-amine 4.18 min (Method 1) 483.3 [M + H].sup.+ N-[(2-chlorophenyl)methyl]-1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 3.94 min (Method 1) 433.3 [M + H].sup.+ 1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[[3- (trifluoromethyl)phenyl]methyl] piperidin-4-amine 2.99 min (Method 1) 467.3 [M + H].sup.+ 1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[[2- (trifluoromethyl)phenyl]methyl] piperidin-4-amine 2.94 min (Method 1) 467.3 [M + H].sup.+ 0 N-[(2-isopropylphenyl)methyl]-1-[4- (2-methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 3.02 min (Method 1) 441.1 [M + H].sup.+ 1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-(o- tolylmethyl)piperidin-4-amine 2.66 min (Method 1) 413.4 [M + H].sup.+ N-[(2-ethoxyphenyl)methyl]-1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 2.85 min (Method 1) 443.4 [M + H].sup.+ N-benzyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]piperidin-4-amine 2.69 min (Method 1) 399.4 [M + H].sup.+ 4-[[[1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-4- piperidyl]amino]methyl]benzonitrile 3.49 min (Method 1) 424.3 [M + H].sup.+ 3-[[[1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-4- piperidyl]amino]methyl]benzonitrile 2.89 min (Method 1) 424.3 [M + H].sup.+ N-[(2-methoxyphenyl)methyl]-1-[4- (2-methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 3.03 min (Method 1) 429.4 [M + H].sup.+ N-[(3-methoxyphenyl)methyl]-1-[4- (2-methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 3.63 min (Method 1) 429.4 [M + H].sup.+ N-[(4-methoxyphenyl)methyl]-1-[4- (2-methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 2.95 min (Method 1) 429.4 [M + H].sup.+ N-[(2-fluorophenyl)methyl]-1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 3.69 min (Method 1) 417.3 [M + H].sup.+ 0 N-[(3-fluorophenyl)methyl]-1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 2.97 min (Method 1) 417.3 [M + H].sup.+ N-[(2,4-difluorophenyl)methyl]-1-[4- (2-methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 3.79 min (Method 1) 435.3 [M + H].sup.+ N-[(4-fluorophenyl)methyl]-1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 2.95 min (Method 1) 417.3 [M + H].sup.+ 1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[(2- methylsulfonylphenyl)methyl] piperidin-4-amine 2.41 min (Method 1) 477.3 [M + H].sup.+ N-[(2,3-difluorophenyl)methyl]-1-[4- (2-methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 2.57 min (Method 1) 435.3 [M + H].sup.+

(197) In cases where ketones rather than aldehydes are used it may be necessary to perform the reaction with a Lewis acid as further activation for example:

racemic N-[1-[4-Fluoro-2-(trifluoromethyl)phenyl]ethyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine

(198) ##STR00195##

(199) 1-[4-(2-Methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (50 mg, 0.16 mmol) and 4-fluoro-2-trifluoromethylacetophenone (0.05 mL, 0.32 mmol) were combined in DCM (1.6 mL) with 4 molecular sieves. Titanium(IV) isopropoxide (0.1 mL, 0.32 mmol) was added and the reaction stirred at room temperature overnight. Reaction heated in the microwave at 80 C. for 20 min. Addition of further 4-Fluoro-2-trifluoromethylacetophenone (0.05 mL, 0.32 mmol) and titanium(IV) isopropoxide (0.1 mL, 0.32 mmol) and the reaction was heated in the microwave at 100 C. for 1 h. A solution of sodium borohydride (24.5 mg, 0.65 mmol) in methanol (1.6 mL) was made up under nitrogen and the reaction solution from the microwave was added to it. The reaction was stirred at room temperature for a further hour. Addition of further sodium borohydride (24.5 mg, 0.65 mmol). Reaction stirred for 1 h then quenched by addition of water. The reaction mixture was extracted into DCM, the organic and aqueous layers were separated by hydrophobic frit and then concentrated in vacuo. The crude oil was purified by preparative LCMS to afford N-[1-[4-fluoro-2-(trifluoromethyl)phenyl]ethyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (5.2 mg, 0.0104 mmol, 6.4% yield)

(200) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.09-8.02 (m, 2H), 7.93-7.79 (m, 3H), 7.66 (d, J1.9 Hz, 1H), 7.37-7.29 (m, 2H), 6.59 (d, J1.9 Hz, 1H), 4.48 (q, J6.4 Hz, 1H), 4.05 (s, 3H), 4.04-3.90 (m, 2H), 3.18-3.08 (2H), 2.66-2.58 (m, 1H), 2.24-2.16 (m (br), 1H), 1.92-1.85 (m (br), 1H), 1.73-1.57 (m, 2H), 1.44 (d, J6.4 Hz, 3H).

(201) MS Method 1: RT: 3.02 min m/z 499.4 [M+H].sup.+

Example 6

(202) In a similar way to Example 2, but using different conditions, compounds of formula (I) can be prepared by the General Method A2, shown below. General Method A2 may be carried out using the compound prepared by Procedure B as starting material or another appropriate method for producing the starting material may be used.

(203) ##STR00196##

N-Methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[4 (trifluoromethyl)phenyl]methyl]piperidin-4-amine

(204) ##STR00197##

(205) 1-[4-(2-Methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (100 mg, 0.32 mmol) and 4-(trifluoromethyl)benzaldehyde (44.3 uL, 0.32 mmol) were dissolved in dry methanol (5 mL) and stirred at room temperature under an atmosphere of nitrogen overnight. Sodium borohydride (14.7 mg, 0.39 mmol) was added and the reaction stirred until completion (LCMS). Formaldehyde solution (36.5-38%) in water (0.09 mL, 3.24 mmol) was added to the reaction mixture and the reaction was stirred overnight. Sodium borohydride (14.72 mg, 0.39 mmol) was added and the reaction was monitored by LCMS. On completion, the reaction mixture was loaded onto an SCX cartridge before being washed with 2 column volumes of methanol followed by elution with 2 column volumes of 2N ammonia in methanol. The ammonia in methanol was then removed in vacuo and the crude product purified by preparative LCMS to afford N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[4 (trifluoromethyl)phenyl]methyl]piperidin-4-amine (31.3 mg, 0.065 mmol, 20%).

(206) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.14 (d, J 8.1 Hz, 1H), 8.07 (d, J 8.1 Hz, 1H), 7.91-7.81 (m, 2H), 7.68 (d, J 2.0 Hz, 1H), 7.61 (AABB, d, J 8.1 Hz, 2H), 7.52 (AABB, d, J 8.1 Hz, 2H), 6.61 (d, J 2.0 Hz, 1H), 4.19-4.12 (m (br), 2H), 4.08 (s, 3H), 3.76 (s, 2H), 3.25-3.17 (dt, J12.0 Hz, 2.1 Hz, 2H), 2.81 (tt, J 11.0, 4.0 Hz, 1H), 2.32 (s, 3H), 2.13-1.95 (m, 4H).

(207) MS Method 2: RT: 1.28 min, m/z 481.3 [M+H].sup.+

(208) The compounds shown below in Table 4 were similarly prepared by varying the aldehyde shown in the reaction scheme for General Method A2:

(209) TABLE-US-00004 TABLE 4 m/z Compound Compound name LCMS RT MIM N-methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[[3- (trifluoromethyl)phenyl]methyl]piperidin- 4-amine 1.28 min (Method 2) 481.3 [M + H].sup.+ N-methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[[2- (trifluoromethyl)phenyl]methyl]piperidin- 4-amine 1.26 min (Method 2) 481.3 [M + H].sup.+ 00 N-[[2-(difluoromethoxy)phenyl]methyl]- N-methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]piperidin-4-amine 2.80 (Method 1) 479.3 [M + H].sup.+ 01 N-methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[(2- methylsulfanylphenyl)methyl]piperidin- 4-amine 2.80 min (Method 2) 459.3 [M + H].sup.+ 02 N-[(2-isopropylphenyl)methyl]-N- methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]piperidin-4-amine 1.30 min (Method 2) 455.3 [M + H].sup.+ 03 N-methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-(o- tolylmethyl)piperidin-4-amine 3.07 min (Method 1) 427.4 [M + H].sup.+ 04 N-[(4-fluorophenyl)methyl]-N-methyl-1- [4-(2-methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 2.90 min (Method 1) 431.4 [M + H].sup.+ 05 N-benzyl-N-methyl-1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]piperidin-4-amine 2.95 min (Method 1) 413.4 [M + H].sup.+ 06 4-[[methyl-[1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-4- piperidyl]amino]methyl]benzonitrile 2.84 min (Method 1) 438.4 [M + H].sup.+ 07 N-[(2-methoxyphenyl)methyl]-N- methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]piperidin-4-amine 3.24 min (Method 1) 443.4 [M + H].sup.+ 08 N-[(3-methoxyphenyl)methyl]-N- methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]piperidin-4-amine 2.93 min (Method 1) 443.4 [M + H].sup.+ 09 (4-methoxyphenyl)methyl-methyl-[1-[4- (2-methylpyrazol-3-yl)phthalazin-1-yl]- 4-piperidyl]ammonium 3.04 min (Method 1) 443.4 [M + H].sup.+ 0 (2-fluorophenyl)methyl-methyl-[1-[4-(2- methylpyrazol-3-yl)phthalazin-1-yl]-4- piperidyl]ammonium 2.93 min (Method 1) 431.4 [M + H].sup.+ (3-fluorophenyl)methyl-methyl-[1-[4-(2- methylpyrazol-3-yl)phthalazin-1-yl]-4- piperidyl]ammonium 3.02 min (Method 1) 431.4 [M + H].sup.+ N-[(2,4-difluorophenyl)methyl]-N- methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]piperidin-4-amine 1.90 min (Method 2) 449.3 [M + H].sup.+ N-[(2-chloro-4-fluoro-phenyl)methyl]-N- methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]piperidin-4-amine 2.74 min (Method 1) 465.3 [M + H].sup.+ N-methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[[2- (trifluoromethoxy)phenyl]methyl]piperidin- 4-amine 2.90 min (Method 1) 497.4 [M + H].sup.+

Example 7

(210) In a similar way to Example 2, but using different conditions, compounds of formula (I) can be prepared by the General Method A3, shown below. General Method A3 may be carried out using the compound prepared by Procedure B as starting material or another appropriate method for producing the starting material may be used. Those skilled in the art will appreciate that in cases where step i) alone is performed with one equivalent of aldehyde the procedure can be used to afford the resulting secondary amine products.

(211) ##STR00215##

N-[(2,6-difluoro-3-pyridyl)methyl]-N-methyl-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]amine

(212) ##STR00216##

(213) To a solution of 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (135 mg, 0.44 mmol) and 2,6-difluoropyridine-3-carbaldehyde (63 mg, 0.44 mmol) in DCM (2 mL) at room temperature was added sodium triacetoxyborohydride (131 mg, 0.62 mmol). The reaction mixture was stirred at room temperature under nitrogen for 72 h. The reaction was quenched with a saturated NaHCO.sub.3 solution (aq) and extracted with ethyl acetate. The organic layer was concentrated in vacuo. Purification by silica flash column chromatography with 10% ethyl acetate in heptane with a gradient increasing to 80% ethyl acetate followed by 2% DCM in methanol with a gradient increasing to 10% MeOH afforded the crude product as a brown oil. Further purification by preparative LCMS afforded N-[(2,6-difluoro-3-pyridyl)methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (50 mg, 0.11 mmol, 26%) as a colourless oil.

(214) .sup.1H NMR (400 MHz, MeOD) /ppm: 8.25 (d, J 8.2 Hz, 1H), 8.2-8.14 (dd, J 8.0 Hz, .sup.3J.sub.HF 17.0 Hz, 1H), 8.04-7.99 (m, 1H), 7.97-7.94 (m, 2H), 7.70 (d, J 2.0 Hz, 1H), 7.01 (dd, J 8.2 Hz, 2.5 Hz, 1H), 6.69 (d, J 2.0 Hz, 1H) 4.10-4.03 (m (br), 2H), 3.94 (s, 2H), 3.91 (s, 3H), 3.25-3.27 (m, 2H), 2.87 (tt, J 10.7 Hz, 4.1 Hz, 1H), 2.24-2.17 (m (br), 2H), 1.87-1.76 (m, 2H).

(215) MS Method 1: RT: 2.89 min, m/z 436.4 [M+H].sup.+

(216) N-[(2,6-Difluoro-3-pyridyl)methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (153. mg, 0.35 mmol) was taken up in THF (5 mL) and formaldehyde solution (36.5-38%) in water (0.05 mL, 1.76 mmol) and acetic acid (0.2 mL, 3.5 mmol) were added. This mixture was stirred at room temperature for 1 hour then sodium borohydride (18.6 mg, 0.49 mmol) was added and the mixture stirred for a further 2 hours then analysed by LCMS which showed the reaction had gone to completion. The mixture was quenched with a saturated solution of sodium carbonate (10 mL) then extracted with DCM (320 mL). The organics were combined, washed with brine (25 mL), dried (NaSO.sub.4), filtered then concentrated in vacuo to give a yellow oil. The crude product was purified by preparative LCMS to afford the formate salt: (2,6-difluoro-3-pyridyl)methyl-methyl-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]ammonium formate (10 mg, 0.02 mmol, 6%) as a white solid.

(217) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.23 (s, 1H), 8.20-8.06 (m, 3H), 7.93-7.83 (m, 2H), 7.69 (d, J 1.9 Hz, 1H), 6.90 (dd, J 8.0 Hz, 2.7 Hz, 1H), 6.61 (d, J 1.9 Hz, 1H), 4.22-4.15 (m (br), 2H), 4.07 (s, 3H), 3.89 (s, 2H), 3.28-3.19 (m (br), 2H), 3.06-2.96 (m (br), 1H), 2.45 (3H), 2.19-2.00 (m (br), 4H).

(218) MS Method 1: RT: 2.48 min, m/z 450.3 [M+H].sup.+

(219) The compounds shown below in Table 5 were similarly prepared by varying the aldehyde shown in the reaction scheme for General Method A3. Where a compound in Table 4 does not possess the N-methyl as in the final compound in the scheme depicted for General Method A3 then the compound has been obtained by carrying out step i) of the General Method A3 and not the second step, step ii). In cases where a secondary amine starting material such as N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine is used then step i) alone can be used to obtain the final products.

(220) TABLE-US-00005 TABLE 4 LCMS m/z Compound Compound Name RT MIM 1-[4,5-dimethyl-6-(2- methylpyrazol-3- yl)pyridazin-3-yl]-N-[[4-fluoro-2- (trifluoromethyl)phenyl] methyl]piperidin- 4-amine 1.23 min (Method 2) 463.3 [M + H].sup.+ 4-fluoro-3-[[[1-[4-(2- methylpyrazol-3- yl)phthalazin-1-yl]-4- piperidyl]amino]methyl] benzonitrile 2.45 min (Method 1) 442.3 [M + H].sup.+ 2-fluoro-5-[[[1-[4-(2- methylpyrazol-3- yl)phthalazin-1-yl]-4- piperidyl]amino]methyl] benzonitrile 2.53 (Method 1) 442.3 [M + H].sup.+ 0 N-[(2,6-difluoro-3-pyridyl) methyl]-1-[4-(2- methylpyrazol-3-yl) phthalazin-1- yl]piperidin-4-amine 2.89 (Method 1) 436.4 [M + H].sup.+ methyl 6-[[[1-[4-(2- methylpyrazol-3- yl)phthalazin-1-yl]-4- piperidyl]amino]methyl] pyridine-3- carboxylate 2.44 (Method 1) 458.3 [M + H].sup.+ N-[(5-fluoro-2-pyridyl)methyl]- 1-[4-(2-methylpyrazol- 3-yl)phthalazin-1- yl]piperidin-4-amine 1.06 min (Method 2) 418.4 [M + H].sup.+ 1-[4-(2-methylpyrazol-3-yl) phthalazin-1-yl]-N-[[3- (trifluoromethyl)-4- pyridyl]methyl]piperidin- 4-amine 2.55 min (Method 1) 468.4 [M + H].sup.+ N-ethyl-N-[[4-fluoro-2- (trifluoromethyl)phenyl]methyl]- 1-[4-(2-methylpyrazol- 3-yl)phthalazin-1- yl]piperidin-4-amine 3.18 min (Method 1) 513.3 [M + H].sup.+ N-[[4-fluoro-2- (trifluoromethyl)phenyl] methyl]-1-(4- morpholinophthalazin-1-yl) piperidin-4-amine 1.10 min (Method 2) 490.3 [M + H].sup.+ 1-[4-(2-methylpyrazol-3-yl) phthalazin-1- yl]-N-[[4-(trifluoromethyl)-3- pyridyl]methyl]piperidin-4-amine 2.50 min (Method 1) 468.3 [M + H].sup.+ N-[[4-fluoro-2- (trifluoromethyl)phenyl] methyl]-N-methyl-1- [1-(2-methylpyrazol-3-yl)-6,7- dihydro-5H-cyclopenta[d] pyridazin-4-yl]piperidin- 4-amine 2.92 min (Method 1) 489.4 [M + H].sup.+ 3-[[methyl-[1-[1-(2-methylpyrazol- 3-yl)-6,7-dihydro-5H- cyclopenta[d]pyridazin- 4-yl]-4-piperidyl] amino]methyl]benzonitrile 2.49 min (Method 1) 428.5 [M + H].sup.+ 1-[4,5-dimethyl-6-(2- methylpyrazol-3- yl)pyridazin-3-yl]-N-methyl- N-[[2-methyl- 4-(trifluoromethyl)thiazol-5- yl]methyl]piperidin-4-amine 2.68 min (Method 1) 480.4 [M + H].sup.+ 0 N-methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-(pyridazin-4- ylmethyl)piperidin-4-amine 2.15 min (Method 1) 415.4 [M + H].sup.+ N-methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[(2- methylsulfanylpyrimidin-4- yl)methyl]piperidin-4-amine 2.51 min (Method 1) 461.3 [M + H].sup.+ 1-[4,5-dimethyl-6-(2- methylpyrazol-3- yl)pyridazin-3-yl]-N-methyl-N-[(2- methylsulfanylpyrimidin-4- yl)methyl]piperidin-4-amine 2.47 min (Method 1) 439.4 [M + H].sup.+ 1-[4,5-dimethyl-6-(2- methylpyrazol-3- yl)pyridazin-3-yl]-N-methyl-N- (pyridazin-4-ylmethyl) piperidin-4-amine 2.05 min (Method 1) 393.4 [M + H].sup.+ 1-[4,5-dimethyl-6-(2- methylpyrazol-3-yl) pyridazin-3-yl]-N-methyl-N-[(2- methylsulfanylphenyl)methyl] piperidin-4-amine 2.73 min (Method 1) 437.4 [M + H].sup.+ 1-[4,5-dimethyl-6-(2- methylpyrazol-3-yl)pyridazin- 3-yl]-N-methyl-N-[2- (trifluoromethoxy)phenyl]methyl] piperidin-4-amine 2.90 min (Method 1) 475.4 [M + H].sup.+ 2-[[[1-[4,5-dimethyl-6-(2- methylpyrazol-3-yl)pyridazin- 3-yl]-4-piperidyl]-methyl- amino]methyl]benzonitrile 2.47 min (Method 1) 416.4 [M + H].sup.+ 1-[4,5-dimethyl-6-(2- methylpyrazol-3-yl)pyridazin- 3-yl]-N-methyl-N-[[3- (trifluoromethyl)-2- pyridyl]methyl]piperidin- 4-amine 2.49 min (Method 1) 460.4 [M + H].sup.+ 1-[4,5-dimethyl-6-(2- methylpyrazol-3-yl) pyridazin-3-yl]-N-methyl- N-[[3-(trifluoromethoxy) phenyl]methyl]piperidin- 4-amine 2.89 min (Method 1) 475.4 [M + H].sup.+ 1-[4,5-dimethyl-6-(2- methylpyrazol-3- yl)pyridazin-3-yl]-N-[(2- isopropylphenyl)methyl]-N- methyl-piperidin-4-amine 2.91 min (Method 1) 433.4 [M + H].sup.+ 0 1-[4,5-dimethyl-6-(2- methylpyrazol-3-yl) pyridazin-3-yl]-N-methyl- N-[[2-(trifluoromethyl) phenyl]methyl]piperidin- 4-amine 2.81 min (Method 1) 459.4 [M + H].sup.+ N-methyl-1-[4-(2-methylpyrazol- 3-yl)phthalazin- 1-yl]-N-(pyrimidin-4- ylmethyl)piperidin-4-amine 2.17 min (Method 1) 415.4 [M + H].sup.+ 1-[4,5-dimethyl-6-(2- methylpyrazol-3-yl)pyridazin- 3-yl]-N-methyl-N-[(2- nitrophenyl)methyl]piperidin- 4-amine 2.49 min (Method 1) 436.4 [M + H].sup.+ 1-[4-fluoro-2-(trifluoromethyl) phenyl]-N-[[1-[4-(2- methylpyrazol-3-yl)phthalazin- 1-yl]pyrrolidin-3-yl]methyl] methanamine 1.04 min (Method 2) 485.3 [M + H].sup.+ N-[[4-fluoro-2- (trifluoromethyl)phenyl]methyl]-N- methyl-1-[5-(2-methylpyrazol-3- yl)pyrido[2,3-d]pyridazin-8-yl] piperidin-4-amine 1.20 min (Method 2) 500.3 [M + H].sup.+ N-[[4-fluoro-2- (trifluoromethyl)phenyl]methyl]-N- methyl-1-[8-(2-methylpyrazol-3- yl)pyrido[2,3-d]pyridazin-5-yl] piperidin-4-amine 1.19 min (Method 2) 500.3 [M + H].sup.+ 2-fluoro-5-[[[1-(2-methylpyrazol- 3-yl)-6,7-dihydro- 5H-cyclopenta[d]pyridazin- 4-yl]-4-piperidyl] amino]methyl]benzonitrile 2.48 min (Method 2) 476.4 [M + H].sup.+ N-[[4-fluoro-2- (trifluoromethyl)phenyl]methyl]- 1-[6-(6-methoxy-3- pyridyl)-4,5-dimethyl- pyridazin-3-yl]piperidin-4-amine 1.29 min (Method 2) 490.4 [M + H].sup.+ N-[[4-fluoro-2- (trifluoromethyl)phenyl]methyl]- 1-[6-(2-methoxy-4- pyridyl)-4,5-dimethyl- pyridazin-3-yl]piperidin-4-amine 1.28 min (Method 2) 490.4 [M + H].sup.+ 1-[4,5-dimethyl-6-(2-methyl-4- pyridyl)pyridazin-3-yl]-N-[[4- fluoro-2-(trifluoromethyl) phenyl]methyl]piperidin- 4-amine 1.03 min (Method 2) 474.4 [M + H].sup.+ 0 1-[4,5-dimethyl-6-(4-pyridyl) pyridazin-3-yl]-N-[[4- fluoro-2- (trifluoromethyl)phenyl] methyl]piperidin-4-amine 1.07 min (Method 2) 460.3 [M + H].sup.+ 1-[4-(2-methylpyrazol-3-yl) phthalazin-1-yl]-N-[[3- (trifluoromethyl)-2- pyridyl]methyl]piperidin-4-amine 2.61 min (Method 1) 468.3 [M + H].sup.+ 3-[[[1-[1-(2-methylpyrazol- 3-yl)-6,7-dihydro-5H- cyclopenta[d]pyridazin-4-yl]- 4-piperidyl]amino]methyl] benzonitrile 2.40 min (Method 1) 414.3 [M + H].sup.+ N-[[4-fluoro-2- (trifluoromethyl)phenyl]methyl]- 1-[1-(2-methylpyrazol- 3-yl)-6,7-dihydro-5H- cyclopenta[d]pyridazin-4-yl] piperidin-4-amine 2.74 min (Method 1) 475.4 [M + H].sup.+ N-methyl-1-[4-(2- methylpyrazol-3-yl) phthalazin-1-yl]-N-[[3- (trifluoromethyl)-2- pyridyl]methyl]piperidin-4-amine 2.66 min (Method 1) 482.3 [M + H].sup.+ N-[[4-fluoro-2- (trifluoromethyl)phenyl]methyl]- 1-[5-(2-methylpyrazol- 3-yl)pyrido[2,3- d]pyridazin-8-yl]piperidin- 4-amine 1.18 min (Method 2) 486.3 [M + H].sup.+ N-methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[[2-methyl-4- (trifluoromethyl)thiazol-5- yl]methyl]piperidin-4-amine 2.78 min (Method 1) 502.3 [M + H].sup.+ 1-[4,5-dimethyl-6-(2-methylpyrazol- 3-yl)pyridazin-3-yl]-N-methyl-N- [[2-methyl- 5-(trifluoromethyl)oxazol-4- yl]methyl]piperidin-4-amine 2.63 min (Method 1) 464.4 [M + H].sup.+ N-methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[[2-methyl-5- (trifluoromethyl)oxazol-4- yl]methyl]piperidin-4-amine 2.65 min (Method 1) 486.4 [M + H].sup.+

Example 8

(221) Compounds of formula (I) can be prepared by the General Method A4, shown below.

(222) ##STR00259##

(223) 2-Fluoro-5-[[[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]amino]methyl]benzonitrile (175 mg, 0.40 mmol) was dissolved in a mixture of formaldehyde solution (36.5-38%) in water (5.0 mL, 0.40 mmol) and formic acid (5.0 mL, 109 mmol). The reaction was then heated at 80 C. for 1.5 hours. The reaction was cooled, saturated NaHCO.sub.3 solution (aq) was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed a further three times with saturated NaHCO.sub.3 solution (aq). The organic layer was separated and dried (NaSO.sub.4) and concentrated in vacuo to afford 0.108 g of crude product. Purification by preparative LCMS afforded the formate salt of 2-fluoro-5-[[methyl-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]amino]methyl]benzonitrile (36 mg, 0.079 mmol, 20%) as a white solid.

(224) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.16 (s, 1H), 8.13 (d, J 8.0 Hz, 1H), 8.07 (d, J 8.0 Hz, 1H), 7.93-7.83 (m, 2H), 7.72-7.65 (m, 2H), 7.69 (d, J 1.9 Hz, 1H), 7.23 (t, J 8.6 Hz, 1H), 6.61 (d, J 1.9 Hz, 1H), 4.20-4.14 (m (br), 2H), 4.07 (s, 3H), 3.78 (s, 2H), 3.26-3.18 (m, 2H), 2.92 (tt, J 11.3 Hz, 4.0 Hz, 1H), 2.35 (s, 3H), 2.14-1.97 (m, 4H).

(225) MS Method 1: RT: 2.60 min, m/z 456.3 [M+H].sup.+

(226) The compounds shown below in Table 5 were similarly prepared by General Method A4.

(227) TABLE-US-00006 TABLE 5 m/z Structure Name LCMS RT MIM 0 4-fluoro-3-[[methyl-[1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]-4- piperidyl]amino]methyl]benzonitrile 1.10 min (Method 2) 456.3 [M + H].sup.+ N-[(2-ethoxyphenyl)methyl]-N- methyl-1-[4-(2-methylpyrazol-4- yl)phthalazin-1-yl]piperidin-4- amine 2.89 min (Method 1) 457.4 [M + H].sup.+ [4-fluoro-2- (trifluoromethyl)phenyl]-methyl-[1- [4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-4- piperidyl]ammonium 4.38 min (Method 1) 485.3 [M + H].sup.+ 1-[4-fluoro-2- (trifluoromethyl)phenyl]-N-methyl- N-[[1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]pyrrolidin-3- yl]methyl]methanamine 1.09 min (Method 2) 499.3 [M + H].sup.+ N-[[4-fluoro-2- (trifluoromethyl)phenyl]methyl]-N- methyl-1-(4- morpholinophthalazin-1- yl)piperidin-4-amine 1.14 min (Method 2) 504.3 [M + H].sup.+ N-methyl-1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[[4- (trifluoromethyl)-3- pyridyl]methyl]piperidin-4-amine 2.59 min (Method 1) 482.4 [M + H].sup.+ N-[[4-fluoro-2- (trifluoromethyl)phenyl]methyl]-1- [6-(6-methoxy-3-pyridyl)-4,5- dimethyl-pyridazin-3-yl]-N-methyl- piperidin-4-amine 1.31 min (Method 2) 504.4 [M + H].sup.+

Example 9

(228) Compounds of formula (I) can be prepared by the General Method B, shown below. General Method B may be carried out using compounds prepared by Procedure A and Procedure D as starting materials or another appropriate method for producing the starting materials may be used.

(229) ##STR00267##

1-(6-chloro-4,5-dimethyl-pyridazin-3-yl)-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-piperidin-4-amine

(230) ##STR00268##

(231) 3,6-Dichloro-4,5-dimethyl-pyridazine (153 mg, 0.86 mmol), N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-piperidin-4-amine (250 mg, 0.86 mmol) and sodium carbonate (100 mg, 0.95 mmol) were added to NMP (4 mL) and stirred at 120 C. for 2 days. LCMS analysis showed consumption of starting material and formation of product with desired mass. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL), washed with saturated NaHCO.sub.3 (20 mL), washed with water (220 mL) and brine (10 mL). The EtOAc layer was dried (MgSO.sub.4), filtered and concentrated under reduced pressure to give a crude brown oil. The crude material was purified by silica flash chromotography eluting with 0% EtOAc in heptane with a gradient to 30% EtOAc. Fractions containing the product were combined and concentrated under reduced pressure to give 1-(6-chloro-4,5-dimethyl-pyridazin-3-yl)-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-piperidin-4-amine (113 mg, 0.26 mmol, 30%) as a white solid.

(232) MS Method 2: RT: 1.37 min, m/z 431.3 [M+H].sup.+

1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-piperidin-4-amine

(233) ##STR00269##

(234) 1-(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-piperidin-4-amine (251 mg, 0.58 mmol), 1-methyl-1H-pyrazole-5-boronic acid, pinacolester (182 mg, 0.87 mmol), Tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.060 mmol) and sodium carbonate (185 mg, 1.75 mmol) were added to PhMe:EtOH:H.sub.20 (4:2:1) (3.5 mL). The reaction mixture was degassed and stirred at reflux overnight. The reaction mixture was cooled and filtered through a plug of Celite eluting with MeOH:DCM (10%). The eluent was concentrated under reduced pressure to give the crude dark brown oil. The crude material was purified by silica flash chromotography eluting with 0% EtOAc in heptane with a gradient to 30% EtOAc to afford a gum. The product was further purified by SCX washing with MeOH followed by elution with 2M NH.sub.3 MeOH to afford 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-piperidin-4-amine (54 mg, 0.11 mmol, 20%) as a gum.

(235) .sup.1H NMR (400 MHz, DMSO-d6) /ppm: 7.9-7.85 (m, 1H), 7.59-7.51 (m, 3H), 6.45 (d, J 1.7 Hz, 1H), 3.75 (s, 2H), 3.73 (s, 3H), 3.63-3.55 (d (br), 2H), 2.93-2.83 (m (br), 2H), 2.73-2.64 (m, 1H), 2.26 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H), 1.94-1.87 (m (br), 2H), 1.80-1.68 (m, 2H).

(236) MS Method 2: RT: 1.26 min, m/z 477.3 [M+H].sup.+

(237) Those skilled in the art will appreciate that there are several alternative metal mediated cross coupling reactions which can be used as an alternative to the Suzuki-Miyura cross coupling of a boronic acid described above, for example the Stille or Kumada, or Negishi or Hiyama or Heck-Matsuda coupling.

(238) The compounds shown below in Table 6 were similarly prepared by varying General Method B.

(239) TABLE-US-00007 TABLE 6 m/z Structure Name LCMS RT MIM 0 methyl 2-[[methyl-[1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]-4- piperidyl]amino]methyl]benzoate 1.20 min (Method 2) 471.3 [M + H].sup.+ N-[[4-fluoro-2- (trifluoromethyl)phenyl]methyl]- N-methyl-1-[6-(2-methylpyrazol- 3-yl)pyridazin-3-yl]piperidin-4- amine 1.16 min (Method 2) 449.3 [M + H].sup.+ N-[[4-fluoro-2- (trifluoromethyl)phenyl]methyl]- N-methyl-1-[1-(2-methylpyrazol- 3-yl)pyrido[3,4-d]pyridazin-4- yl]piperidin-4-amine 1.19 min (Method 2) 500.3 [M + H].sup.+ N-cyclopropyl-N-[[4-fluoro-2- (trifluoromethyl)phenyl]methyl]- 1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]piperidin-4- amine 3.97 min (Method 1) 525.4 [M + H].sup.+

Example 10

(240) Compounds of formula (I) can be prepared by the General Method C, shown below. General Method C may be carried out using compounds prepared by Procedure B as starting materials or another appropriate method for producing the starting materials may be used.

(241) ##STR00274##

2-[[methyl-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]amino]methyl]benzonitrile

(242) ##STR00275##

(243) N-Methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (120 mg, 0.37 mmol), 2-(bromomethyl)benzonitrile (88 mg, 0.45 mmol) and potassium carbonate (77 mg, 0.56 mmol) were combined in acetonitrile and stirred for four days at room temperature. The reaction solvent was evaporated, the material partitioned between water and ethyl acetate and the product extracted with ethyl acetate (3). The organic layer was washed with brine then dried (NaSO.sub.4) and concentrated in vacuo to afford the crude product as a brown-orange gum. The crude material was purified by silica column chromatography using 100% DCM with a gradient to 5% methanol in DCM to elute the product. Concentration in vacuo afforded 2-[[methyl-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]amino]methyl]benzonitrile (109 mg, 0.25 mmol, 67%) as a yellow gum.

(244) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.14 (d, J 8.1 Hz, 1H), 8.06 (d, J 8.1 Hz, 1H), 7.91-7.81 (t, J 7.1 Hz, 1H), 7.84-7.81 (t, J7.1 Hz, 1H), 7.70-7.57 (m, 4H), 7.41-7.36 (m, 1H), 6.60 (d, J 2.0 Hz, 1H), 4.19-4.13 (m (br), 2H), 4.07 (s, 3H), 3.90 (s, 2H), 3.24-3.16 (m, 2H), 2.91-2.83 (m, 1H), 2.33 (s, 3H), 2.16-1.98 (m, 4H).

(245) MS Method 1: RT: 2.52 min, m/z 438.3 [M+H].sup.+

(246) The compounds shown below in Table 7 were similarly prepared by varying the bromide used in General Method C.

(247) TABLE-US-00008 TABLE 7 Compound Compound Name LCMS RT m/z 1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[(2- nitrophenyl)methyl]piperidin- 4-amine 1.14 min (Method 2) 444.3 [M + H].sup.+ N-[[6-chloro-2- (trifluoromethyl)-3- pyridyl]methyl]-N-methyl-1-[4- (2-methylpyrazol-3- yl)phthalazin-1-yl]piperidin-4- amine 3.04 min (Method 1) 516.2 [M + H].sup.+ N-[[6-chloro-2- (trifluoromethyl)-3- pyridyl]methyl]-1-[4-(2- methylpyrazol-3- yl)phthalazin-1-yl]piperidin-4- amine 2.88 (Method 1) 502.3 [M + H].sup.+ N-methyl-1-[4-(2- methylpyrazol-3- yl)phthalazin-1-yl]-N-[(2- nitrophenyl)methyl]piperidin- 4-amine 2.57 min (Method 1) 458.3 [M + H].sup.+ 0 N-methyl-1-[4-(2- methylpyrazol-3- yl)phthalazin-1-yl]-N-[[2- (trifluoromethyl)-3- pyridyl]methyl]piperidin-4- amine 2.61 min (Method 1) 482.3 [M + H].sup.+ 1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-N-[[2- (trifluoromethyl)-3- pyridyl]methyl]piperidin-4- amine 2.52 min (Method 1) 468.4 [M + H].sup.+

Example 11

(248) Compounds of formula (I) can be prepared by the General Method D, shown below. General Method D may be carried out using compounds prepared by Procedure B as starting materials or another appropriate method for producing the starting materials may be used.

(249) ##STR00282##

4-Fluoro-N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]-2-(trifluoromethyl)benzenesulfonamide

(250) ##STR00283##

(251) 1-[4-(2-Methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (297 mg, 0.96 mmol) was taken up in pyridine (0.5 mL, 6.2 mmol) and cooled to 0 C. 4-Fluoro-2-(trifluoromethyl)benzenesulfonyl chloride (230 mg, 0.88 mmol) was added in portions and the mixture stirred for 1 hour slowly warming to room temperature. The mixture was left to stir for another hour at room temperature. The reaction mixture was diluted in DCM (20 mL) and washed with brine (20 mL). The organics were collected, dried (MgSO.sub.4), and concentrated in vacuo to afford 250 mg of crude product as a yellow oil. Purification by silica column chromatography using 30% ethyl acetate in heptane with a gradient to 100% ethyl acetate afforded 250 mg of crude yellow oil. 40 mg of the crude oil was purified by preparative LCMS. Fractions containing product were evaporated to dryness then further dried in the vacuum oven for 2 hours to give 4-fluoro-N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]-2-(trifluoromethyl)benzenesulfonamide (18 mg) as a white solid.

(252) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.38 (dd, J 8.9 Hz, 5.4 Hz, 1H), 8.09-8.03 (m, 2H), 7.90-7.81 (m, 2H), 7.67 (d, J 2.0 Hz, 1H), 7.64 (dd, J 8.9 Hz, 2.6 Hz, 1H), 7.49-7.42 (m, 1H), 6.59 (d, 1.9 Hz, 1H), 4.78 (d (br), J 7.6 Hz, 1H), 4.05 (s, 3H), 3.97-3.91 (m (br), 2H), 3.63-3.52 (m, 1H), 3.27-3.19 (m, 2H), 2.07-1.99 (m, 2H), 1.89-1.78 (m, 2H).

(253) MS Method 1: RT: 3.75 min, m/z 535.3 [M+H].sup.+

4-Fluoro-N-methyl-N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]-2-(trifluoromethyl)benzenesulfonamide

(254) ##STR00284##

(255) 4-Fluoro-N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]-2-(trifluoromethyl)benzenesulfonamide (286 mg, 0.54 mmol) was taken up in THF (2 mL) and cooled to 0 C. Sodium Hydride 60% In Oil (15.4 mg, 0.64 mmol) was added and the mixture stirred at this temperature for 40 minutes at which point Iodomethane (70 uL, 1.07 mmol) was added. The mixture was allowed to reach room temperature and then left to stir overnight at room temperature. The reaction was quenched by the addition of water followed by extraction with ethyl acetate (320 mL). The organics were combined, washed with brine (20 mL), dried over sodium sulfate, filtered then evaporated to dryness to give the crude product as an orange solid. Purification with silica column chromatography using ethyl acetate in heptane with a gradient to 100% ethyl acetate afforded 60 mg of a yellow oil. Further purification was performed on the preparative LCMS to give 4-Fluoro-N-methyl-N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]-2-(trifluoromethyl)benzenesulfonamide (26.4 mg, 0.05 mmol, 9.0%) as a white solid.

(256) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.29 (dd, 8.8 Hz, 5.5 Hz, 1H), 8.10-8.06 (m, 2H), 7.91-7.82 (m, 2H), 7.67 (d, J 1.9 Hz, 1H), 7.63 (dd, J 9.0 Hz, 2.6 Hz, 1H), 7.45-7.40 (m, 1H), 6.60 (d, J 1.9 Hz, 1H), 4.18-4.11 (m (br), 3H), 4.07 (s, 3H), 3.32-3.23 (m, 2H), 2.88 (s, 3H), 2.16 (qd, J 12.3 Hz, 3.9 Hz, 2H), 1.90-1.83 (m, 2H).

(257) MS Method 1: RT: 3.97 min, m/z 549.3 [M+H].sup.+

(258) The compounds shown below in Table 8 were similarly prepared by varying the sulphonyl chloride used in General Method D.

(259) TABLE-US-00009 TABLE 8 m/z Structure Name LCMS RT MIM N-[1-[4,5-dimethyl-6-(2-methylpyrazol- 3-yl)pyridazin-3-yl]-4-piperidyl]-4- fluoro-2- (trifluoromethyl)benzenesulfonamide 1.60 min (Method 2) 513.3 [M + H].sup.+ 2,4-difluoro-N-methyl-N-[1-[1-(2- methylpyrazol-3-yl)pyrido[3,4- d]pyridazin-4-yl]-4- piperidyl]benzenesulfonamide 1.57 min (Method 2) 500.4 [M + H].sup.+ 2,4-difluoro-N-[1-[1-(2-methylpyrazol- 3-yl)-6,7-dihydro-5H- cyclopenta[d]pyridazin-4-yl]-4- piperidyl]benzenesulfonamide 1.43 min (Method 2) 475.3 [M + H].sup.+ 4-fluoro-N-methyl-N-[1-[5-(2- methylpyrazol-3-yl)pyrido[2,3- d]pyridazin-8-yl]-4-piperidyl]-2- (trifluoromethyl)benzenesulfonamide 1.63 min (Method 2) 550.3 [M + H].sup.+ 4-fluoro-N-[1-[6-(6-methoxy-3-pyridyl)- 4,5-dimethyl-pyridazin-3-yl]-4- piperidyl]-2- (trifluoromethyl)benzenesulfonamide 1.64 min (Method 2) 540.3 [M + H].sup.+ 0 N-[1-[4,5-dimethyl-6-(2-methyl-4- pyridyl)pyridazin-3-yl]-4-piperidyl]-4- fluoro-2- (trifluoromethyl)benzenesulfonamide 1.37 min (Method 2) 524.3 [M + H].sup.+ N-[1-[4,5-dimethyl-6-(4- pyridyl)pyridazin-3-yl]-4-piperidyl]-4- fluoro-2- (trifluoromethyl)benzenesulfonamide 1.41 min (Method 2) 510.3 [M + H].sup.+ 4-fluoro-N-[1-[1-(2-methylpyrazol-3- yl)pyrido[3,4-b]pyridazin-4-yl]-4- piperidyl]-2- (trifluoromethyl)benzenesulfonamide 1.57 min (Method 2) 536.4 [M + H].sup.+ 4-fluoro-N-methyl-N-[1-[1-(2- methylpyrazol-3-yl)pyrido[3,4- d]pyridazin-4-yl]-4-piperidyl]-2- (trifluoromethyl)benzenesulfonamide 1.68 min (Method 2) 550.4 [M + H].sup.+ 4-fluoro-N-[1-[1-(2-methylpyrazol-3- yl)-6,7-dihydro-5H- cyclopenta[d]pyridazin-4-yl]-4- piperidyl]-2- (trifluoromethyl)benzenesulfonamide 3.59 min (Method 1) 525.3 [M + H].sup.+ 4-fluoro-N-methyl-N-[1-[1-(2- methylpyrazol-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyridazin-4-yl]-4- piperidyl]-2- (trifluoromethyl)benzenesulfonamide 1.67 min (Method 2) 539.3 [M + H].sup.+

Example 12

(260) Compounds of formula (I) can be prepared by the General Method E, shown below. General Method E may be carried out using compounds prepared by Procedure B as starting materials or another appropriate method for producing the starting materials may be used.

(261) ##STR00296##

1-[4-Fluoro-2-(trifluoromethyl)phenyl]-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]urea

(262) ##STR00297##

(263) In dried glassware DIPEA (0.06 mL, 0.34 mmol), DCM (1 mL) and 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (0.05 mL, 0.23 mmol) were combined. The suspension was cooled to 0 C. and to this was added 4-fluoro-2-(trifluoromethyl)phenyl isocyanate (0.04 mL, 0.2500 mmol) dropwise. The reaction was stirred at 0 C. and then stirred overnight at room temperature. An off-white precipitate formed. The reaction was filtered and the solid was washed with DCM. The white solid was then dried in the vacuum oven overnight to afford 1-[4-fluoro-2-(trifluoromethyl)phenyl]-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]urea (57.7 mg, 0.11 mmol, 50%).

(264) .sup.1H NMR (400 MHz, DMSO-d6) /ppm: 8.19 (d, J 8.2 Hz, 1H), 8.05-7.92 (m, 4H), 7.80 (s, 1H), 7.66 (d, J 1.9 Hz, 1H), 7.55-7.47 (m, 2H), 7.15 (d, J 7.5 Hz, 1H), 6.69 (d, J 1.9 Hz, 1H), 3.89-3.82 (m (br), 3H), 3.87 (s, 3H), 3.34-3.26 (m, 2H), 2.14-2.06 (m, 2H), 1.82-1.71 (m, 2H).

(265) MS Method 2: RT: 1.48 min, m/z 514.3 [M+H].sup.+

3-[4-fluoro-2-(trifluoromethyl)phenyl]-1-methyl-1-[1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]-4-piperidyl]urea

(266) ##STR00298##

(267) To a solution of N-methyl-1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]piperidin-4-amine (947 mg, 2.93 mmol) and N,N-diisopropylethylamine (0.76 mL, 4.39 mmol) in DCM (30 mL) (dried over 4 MS) was added 4-fluoro-2-(trifluoromethyl)phenyl isocyanate (0.42 mL, 2.93 mmol) dropwise at 0 C. The reaction was stirred at this temperature for 30 minutes and then stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous. sodium bicarbonate and diluted with DCM, The mixture was passed through a phase separator and the aqueous layer was re-extracted several times with DCM, the organic layers were combined and concentrated. The resulting residue was purified by silica flash chromatography using 0% methanol in ethyl acetate with a gradient increasing to 20% methanol in ethyl acetate to afford 3-[4-fluoro-2-(trifluoromethyl)phenyl]-1-methyl-1-[1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]-4-piperidyl]urea (920 mg, 1.74 mmol, 59.5% yield) as a yellow solid. The product was then dried in the vacuum oven for 4 days.

(268) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 9.53 (s, 1H), 8.95 (d, J5.7 Hz, 1H), 8.11 (dd, J9.0 Hz, 5.0 Hz, 1H), 7.86 (d, J5.7 Hz, 1H), 7.68 (d, J1.9 Hz, 1H), 7.33-7.23 (m, 2H), 6.73 (s, 1H), 6.61 (d, J1.9 Hz, 1H), 4.66-4.55 (m, 1H), 4.39-4.31 (m (br), 2H), 4.11 (s, 3H), 3.47-3.37 (m, 2H), 2.99 (s, 3H), 2.16-2.04 (m, 2H), 1.99-1.92 (m, 2H).

(269) MS Method 1: RT: 3.41 min, m/z 529.4 [M+H].sup.+

(270) And similarly prepared was:

3-[4-fluoro-2-(trifluoromethyl)phenyl]-1-methyl-1-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]urea

(271) ##STR00299##

(272) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.17-8.07 (m, 3H), 7.92-7.82, (m, 2H), 7.68 (d, J1.9 Hz, 1H), 7.34-7.25 (m, 2H), 6.76 (s, 1H), 6.61 (d, J1.9 Hz, 1H), 4.61-4.51 (m, 1H), 4.24-4.16 (m (br), 2H), 4.08 (s, 3H), 3.40-3.30 (t, J 12.5 Hz, 2H), 3.02 (s, 3H), 2.20-2.08 (m, 2H), 1.98-1.91 (m, 2H).

(273) MS Method 1: RT: 3.47 min, m/z 528.3 [M+H].sup.+

(274) And similarly prepared was:

1-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]-3-[4-fluoro-2-(trifluoromethyl)phenyl]-1-methyl-urea

(275) ##STR00300##

(276) .sup.1H NMR (400 MHz, CDCl.sub.3) /ppm: 8.15-8.09 (m, 1H), 7.57 (d, J2.0 Hz, 1H), 7.31-7.21 (m, 2H), 6.72 (s, 1H), 6.36 (d, J2.0 Hz, 1H), 4.48-4.37 (m, 1H), 3.93 (s, 3H), 3.74-3.67 (m (br), 2H), 3.16 (t, J12.8 Hz, 2H), 2.96 (s, 3H), 2.30 (s, 3H), 2.23 (s, 3H), 2.03-1.91 (m, 2H), 1.90-1.83 (m, 2H).

(277) MS Method 1: RT: 3.63 min, m/z 506.3 [M+H].sup.+

(278) The compounds shown below in Table 9 were also similarly prepared by varying the isocyanate used in General Method E.

(279) TABLE-US-00010 TABLE 9 Structure Name LCMS RT m/z MIM 01 1-(2,4-difluorophenyl)-3-[1-[4- (2-methylpyrazol-3- yl)phthalazin-1-yl]-4- piperidyl]urea 1.37 min (Method 2) 464.3 [M + H].sup.+ 02 1-(4-fluorophenyl)-3-[1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]-4-piperidyl]urea 1.33 min (Method 2) 446.3 [M + H].sup.+ 03 1-tert-butyl-3-[1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]-4-piperidyl]urea 1.24 min (Method 2) 408.3 [M + H].sup.+ 04 1-cyclohexyl-3-[1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]-4-piperidyl]urea 1.32 min (Method 2) 434.3 [M + H].sup.+ 05 1-[1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-4-piperidyl]- 3-[3-(trifluoromethyl)phenyl]urea 1.53 min (Method 2) 496.3 [M + H].sup.+ 06 1-[1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-4-piperidyl]- 3-[4-(trifluoromethyl)phenyl]urea 1.54 min (Method 2) 497.1 [M + H].sup.+ 07 1-(2-methoxyphenyl)-3-[1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]-4-piperidyl]urea 1.37 min (Method 2) 458.3 [M + H].sup.+ 08 1-(3-fluorophenyl)-3-[1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]-4-piperidyl]urea 1.37 min (Method 2) 446.3 [M + H].sup.+ 09 1-[1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-4-piperidyl]- 3-[2-(trifluoromethyl)phenyl]urea 1.46 min (Method 2) 496.3 [M + H].sup.+ 0 1-(3-cyanophenyl)-3-[1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]-4-piperidyl]urea 1.33 min (Method 2) 453.3 [M + H].sup.+ 1-(3-methoxyphenyl)-3-[1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]-4-piperidyl]urea 1.33 min (Method 2) 458.2 [M + H].sup.+ 1-[1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-4-piperidyl]- 3-[2- (trifluoromethyl)phenyl]urea 1.54 min (Method 2) 512.4 [M + H].sup.+ 1-[4-(difluoromethoxy)phenyl]-3- [1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-4- piperidyl]urea 1.41 min (Method 2) 494.3 [M + H].sup.+ 1-(4-cyanophenyl)-3-[1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]-4-piperidyl]urea 1.32 min (Method 2) 453.2 [M + H].sup.+ 1-(4-methoxyphenyl)-3-[1-[4-(2- methylpyrazol-3-yl)phthalazin- yl]-4-piperidyl]urea 1.29 min (Method 2) 458.3 [M + H].sup.+ 1-(2-fluorophenyl)-3-[1-[4-(2- methylpyrazol-3-yl)phthalazin-1- yl]-4-piperidyl]urea 1.35 min (Method 2) 446.3 [M + H].sup.+ 3-tert-butyl-1-methyl-1-[1-[1-(2- methylpyrazol-3-yl)-6,7-dihydro- 5H-cyclopenta[d]pyridazin-4-yl]- 4-piperidyl]urea 1.32 min (Method 2) 412.4 [M + H].sup.+ 1-tert-butyl-3-[1-[1-(2- methylpyrazol-3-yl)-6,7-dihydro- 5H-cyclopenta[d]pyridazin-4-yl]- 4-piperidyl]urea 2.74 min (Method 1) 398.4 [M + H].sup.+ 3-(2,4-difluorophenyl)-1-methyl- 1-[1-[8-(2-methylpyrazol-3- yl)pyrido[2,3-d]pyridazin-5-yl]-4- piperidyl]urea 3.09 min (Method 1) 479.4 [M + H].sup.+ 0 3-(2,4-difluorophenyl)-1-methyl- 1-[1-[5-(2-methylpyrazol-4- yl)pyrido[2,3-d]pyridazin-8-yl]-4- piperidyl]urea 3.02 min (Method 1) 479.4 [M + H].sup.+ 1-[1-[4,5-dimethyl-6-(2- methylpyrazol-3-yl)pyridazin-3- yl]-4-piperidyl]-3-[4-fluoro-2- (trifluoromethyl)phenyl]urea 3.56 min (Method 1) 492.4 [M + H].sup.+ 1-[4-fluoro-2- (trifluoromethyl)phenyl]-3-[1-[1- (4-pyridyl)pyrido[3,4- d]pyridazin-4-yl]-4- piperidyl]urea 2.98 min (Method 1) 512.4 [M + H].sup.+ 3-tert-butyl-1-methyl-1-[1-[8-(2- methylpyrazol-3-yl)pyrido[2,3- d]pyridazin-5-yl]-4- piperidyl]urea 1.32 min (Method 2) 423.3 [M + H].sup.+ 3-(2,4-difluorophenyl)-1-methyl- 1-[1-[4-(2-methylpyrazol-3- yl)phthalazin-1-yl]-4- piperidyl]urea 3.16 min (Method 1) 478.4 [M + H].sup.+ 1-(2,4-difluorophenyl)-3-[1-[1- (2-methylpyrazol-3-yl)-6,7- dihydro-5H- cyclopenta[d]pyridazin-4-yl]-4- piperidyl]urea 3.04 min (Method 1) 454.3 [M + H].sup.+ 3-[4-fluoro-2- (trifluoromethyl)phenyl]-1- methyl-1-[1-[5-(2-methylpyrazol- 3-yl)pyrido[2,3-d]pyridazin-8-yl]- 4-piperidyl]urea 1.44 min (Method 2) 529.3 [M + H].sup.+ 3-(2,4-difluorophenyl)-1-[1-[4,5- dimethyl-6-(2-methylpyrazol-3- yl)pyridazin-3-yl]-4-piperidyl]-1- methyl-urea 3.31 min (Method 1) 456.4 [M + H].sup.+ 1-[1-[4,5-dimethyl-6-(2- methylpyrazol-3-yl)pyridazin-3- yl]-4-piperidyl]-3-(2- fluorophenyl)-1-methyl-urea 3.28 min (Method 1) 438.4 [M + H].sup.+ 3-[4-fluoro-2- (trifluoromethyl)phenyl]-1- methyl-1-[1-[1-(2-methylpyrazol- 3-yl)-6,7-dihydro-5H- cyclopenta[d]pyridazin-4-yl]-4- piperidyl]urea 1.47 min (Method 2) 518.4 [M + H].sup.+ 0 1-tert-butyl-3-[1-[4,5-dimethyl-6- (2-methylpyrazol-3-yl)pyridazin- 3-yl]-4-piperidyl]urea 1.32 min (Method 2) 386.4 [M + H].sup.+ 3-(2,4-difluorophenyl)-1-methyl- 1-[1-[1-(2-methylpyrazol-3- yl)pyrido[3,4-d]pyridazin-4-yl]-4- piperidyl]urea 3.07 min (Method 1) 479.4 [M + H].sup.+ 1-[1-[4,5-dimethyl-6-(2- methylpyrazol-3-yl)pyridazin-3- yl]-4-piperidyl]-3-(4- fluorophenyl)-1-methyl-urea 3.29 min (Method 1) 438.4 [M + H].sup.+ 1-(2,4-difluorophenyl)-3-[1-[1- (2-methylpyrazol-3- yl)pyrido[3,4-d]pyridazin-4-yl]-4- piperidyl]urea 3.11 min (Method 1) 465.4 [M + H].sup.+ 1-[4-fluoro-2- (trifluoromethyl)phenyl]-3-[1-[1- (2-methylpyrazol-3- yl)pyrido[3,4-d]pyridazin-4-yl]-4- piperidyl]urea 3.37 min (Method 1) 515.4 [M + H].sup.+ 3-[4-fluoro-2- (trifluoromethyl)phenyl]-1- methyl-1-[1-[8-(2-methylpyrazol- 3-yl)pyrido[2,3-d]pyridazin-5-yl]- 4-piperidyl]urea 3.41 min (Method 1) 529.4 [M + H].sup.+ 3-tert-butyl-1-[1-[4,5-dimethyl-6- (2-methylpyrazol-3-yl)pyridazin- 3-yl]-4-piperidyl]-1-methyl-urea 1.44 min (Method 2) 400.4 [M + H].sup.+ 1-[1-[4-(2-methylpyrazol-2- yl)phthalazin-1-yl]-4-piperidyl]- 3-[1- (trifluoromethyl)cyclopropyl]urea 1.25 min (Method 2) 460.4 [M + H].sup.+

(280) In cases where the isocyanate is not readily commercially available it can be prepared in situ via various methods known to those skilled In the art for example, similarly prepared was:

1-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]-1-methyl-3-[5-(trifluoromethyl)pyridazin-4-yl]urea

(281) ##STR00338##

(282) To a solution of 5-(trifluoromethyl)pyridazine-4-carboxylic acid (96 mg, 0.50 mmol) and triethylamine (0.1 mL, 0.75 mmol) in toluene (4 mL) was added diphenyl phosphoryl azide (137.6 mg, 0.50 mmol). The reaction was stirred for 1 h, then heated to 100 C. and maintained at this temperature for 2 h. A solution of 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-methyl-piperidin-4-amine (150 mg, 0.50 mmol) in toluene (4 mL) was added, and stirring at 100 C. continued for 30 min. The reaction was concentrated in vacuo and then purified by silica flash chromatography using 0% methanol in ethyl acetate with a gradient to 80% methanol and the fractions containing the desired product were concentrated in vacuo. Further purification by prep LC/MS, repeated twice, afforded a the formate salt of 1-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]-1-methyl-3-[5-(trifluoromethyl)pyridazin-4-yl]urea (4.0 mg, 0.0073 mmol, 10.5%) as a colourless oil.

(283) MS Method 2: RT: 1.39 min, m/z 490.4 [M+H].sup.+

(284) Similarly prepared was:

1-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]-3-[1-(trifluoromethyl)cyclopropyl]urea

(285) ##STR00339##

(286) To a solution of 1,1-Carbonyldiimidazole (55.5 mg, 0.34 mmol) in DCM (1 mL) was added 1-trifluoromethyl-1-cyclopropylamine (0.03 mL, 0.30 mmol), the reaction vessel was sealed and the reaction was left to stir at room temperature for three days. After this 4A MS were added, followed by 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]piperidin-4-amine (28. mg, 0.10 mmol) and triethylamine (0.07 mL, 0.49 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 1 hour then quenched by the addition of saturated aqueous NaHCO.sub.3. The organic and aqueous layers were separated, the reaction mixture was extracted with DCM3 and the combined organic extracts were concentrated in vacuo to afford the crude material which was then purified by silica flash chromatography using 0% methanol in ethyl acetate with a gradient to 10% methanol and the fractions containing the desired product were concentrated in vacuo. Further purification by preparative LCMS was performed to afford 1-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]-3-[1-(trifluoromethyl)cyclopropyl]urea (12 mg, 0.0274 mmol, 28.1% yield) as a white solid.

(287) .sup.1H NMR (400 MHz, DMSO-d6) /ppm: 7.58 (d, J1.9 Hz, 1H), 6.37 (d, J1.9 Hz, 1H), 5.26 (s, 1H), 5.00 (d, J7.9 Hz, 1H), 4.01-3.90 (m, 1H), 3.92 (s, 3H), 3.60-3.52 (m, 2H), 3.21-3.12 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 2.16-2.08 (m, 2H), 1.71-1.60 (m, 2H). 1.39-1.34 (m, 2H), 1.19-1.14 (m, 2H).

(288) MS Method 2: RT: 1.35 min, m/z 438.4 [M+H].sup.+

Example 13

(289) Compounds of formula (I) can be prepared by the General Method F, shown below. General Method F may be carried out using compounds prepared by Procedure B as starting materials or another appropriate method for producing the starting materials may be used.

(290) ##STR00340##

[4-fluoro-2-(trifluoromethyl)phenyl]-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]ammonium formate

(291) ##STR00341##

(292) A solution of 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (0.05 g, 0.17 mmol), 1-bromo-4-fluoro-2-(trifluoromethyl)benzene (24 uL, 0.17 mmol), caesium carbonate (110 mg, 0.34 mmol), (+/) BINAP (10 mg, 0.02 mmol) and Pd.sub.2(dba).sub.3 (7.71 mg, 0.0100 mmol) in 1,4-dioxane (1.5 mL) was prepared, degassed with nitrogen and heated at 110 C. overnight. The reaction mixture was cooled and then concentrated in vacuo. The crude material was purified by preparative LCMS to afford the formate salt: [4-fluoro-2-(trifluoromethyl)phenyl]-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]ammonium formate (11.6 mg, 0.02 mmol, 13%) as an oil.

(293) .sup.1H NMR (400 MHz, MeOD) /ppm: 8.57 (s, 1H), 8.28 (d, J 8.2 Hz, 1H) 8.05-7.95 (m, 3H), 7.71 (d, J 1.87 Hz, 1H), 7.24 (d, J 8.2 Hz, 1H), 7.24 (m, 1H), 7.02-7.02 (m, 1H), 6.71 (d, J 1.8 Hz, 1H), 4.08-4.01 (m (br), 2H), 3.92 (s, 3H), 3.85-3.76 (m, 1H), 3.39-3.345 (m, 2H), 2.17-2.11 (m (br), 2H), 1.97-1.86 (m, 2H)

(294) MS Method 2: RT: 4.42 min, m/z 471.3 [M+H].sup.+

(295) The compounds shown below in Table 10 were similarly prepared by varying the aryl halide used in General Method F.

(296) TABLE-US-00011 TABLE 10 Structure Name LCMS RT m/z MIM 5-fluoro-N-[1-[4-(2- methylpyrazol-3-yl)phthalazin- 1-yl]-4-piperidyl]-3- (trifluoromethyl)pyridin-2- amine 2.54 min (Method 1) 458.3 [M + H].sup.+ N-[4-fluoro-2- (trifluoromethyl)phenyl]-1-[1-(2- methylpyrazol-3-yl)-6,7- dihydro-5H- cyclopenta[d]pyridazin-4- yl]piperidin-4-amine 1.85 min (Method 2) 461.3 [M + H].sup.+

Example 14

(297) Compounds of formula (I) can be prepared by the General Method G, shown below. Shown is a procedure to prepare N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]pyrrolidin-3-amine.

(298) ##STR00344##

tert-butyl 3-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl-methyl-amino]pyrrolidine-1-carboxylate

(299) ##STR00345##

(300) Potassium carbonate (1.0 g, 7.49 mmol) was added to a solution of tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (500 mg, 2.5 mmol) and 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (642 mg, 2.5 mmol) in MeCN (30 mL) and stirred overnight at room temperature. The potassium carbonate was filtered off and the filtrate was concentrated and purified by silica flash column chromatography eluting with 0% ethyl acetate in heptane with a gradient to 50% ethyl acetate to afford tert-butyl 3-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl-methyl-amino]pyrrolidine-1-carboxylate (751 mg, 2.0 mmol, 80% yield) as an oil.

(301) MS Method 2: RT: 1.51 min, m/z 399.2 [M+Na].sup.+

N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-pyrrolidin-3-amine

(302) ##STR00346##

(303) Trifluoroacetic acid (1.7 mL, 23.94 mmol) was added to a solution of tert-butyl 3-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl-methyl-amino]pyrrolidine-1-carboxylate (751 mg, 2.0 mmol) in DCM (15 mL) and stirred overnight. The reaction mixture was concentrated under reduced pressure. The resulting oil was loaded onto an SCX cartridge using MeOH then washed using 2 column volumes of methanol followed by elution with 2 column volumes of 1M ammonia in methanol solution. The fractions were then concentrated to afford N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-pyrrolidin-3-amine (421 mg, 1.52 mmol, 76%) as an oil which was used directly in the next reaction.

(304) MS Method 2: RT: 1.09 min, m/z 277.2 [M+H].sup.+

1-(4-chlorophthalazin-1-yl)-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-pyrrolidin-3-amine

(305) ##STR00347##

(306) A solution containing 1,4-dichlorophthalazine (334 mg, 1.68 mmol), N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-pyrrolidin-3-amine (421 mg, 1.52 mmol) and potassium carbonate (241 mg, 1.74 mmol) in NMP (5 mL) was prepared and stirred at 80 C. overnight. The reaction was cooled to room temperature and water was added to the reaction mixture at which point a cloudying of the mixture was observed. The NMP and water mixture was extracted with ethyl acetate several times and the organic layer was then concentrated in vacuo to afford the crude product. The crude material was purified by silica flash chromatography eluting with 10% ethyl acetate in heptane with a gradient to 60% ethyl acetate to afford 1-(4-chlorophthalazin-1-yl)-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-pyrrolidin-3-amine (226 mg, 0.52 mmol, 33.8% yield) as an oil which was used directly in the next reaction

(307) MS Method 2: RT: 1.47 min, m/z 439.2 [M+H].sup.+

N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]pyrrolidin-3-amine

(308) ##STR00348##

(309) 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (536 mg, 2.57 mmol), 1-(4-chlorophthalazin-1-yl)-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-pyrrolidin-3-amine (226 mg, 0.51 mmol), sodium carbonate (109 mg, 1.03 mmol) and tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) were combined in a microwave vial which was sealed and flushed with nitrogen. A solution of toluene (1.8 mL), ethanol (0.60 mL) and water (0.60 mL) was also prepared and degassed, then transferred into the microwave vial. The reaction was then heated in the microwave at 150 C. for 10 min. The reaction mixture was extracted with DCM and washed with brine. The organic layer was concentrated in vacuo to afford the crude product. This material was purified by silica flash column chromatography eluting with 0% 2M NH.sub.3 in methanol, in DCM with a gradient to 5% 2M NH.sub.3 in methanol to afford an oil which was further purified by preparative LCMS. Fractions containing the desired product were combined and concentrated. The product was desalted by SCX cartridge. The product was loaded and washed with methanol then eluted with 2M ammonia methanol solution to afford N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]pyrrolidin-3-amine (108 mg, 0.22 mmol, 43% yield).

(310) .sup.1H NMR (400 MHz, MeOD) /ppm: 8.41-8.37 (m, 1H), 7.95-7.80 (m, 4H), 7.67 (d, J 1.9 Hz, 1H), 7.36 (dd, J 9.2 Hz, 2.6 Hz, 1H), 7.30 (td, J 8.3 Hz, 2.6 Hz, 1H), 6.62 (d, J 1.9 Hz, 1H), 4.13-4.06 (m, 3H), 3.97 (dd, J 10.4 Hz, 8.0 Hz, 1H), 3.86 (s, 3H), 3.84 (d, J 14.6 Hz, 1H), 3.77 (d, J 14.6 Hz, 1H), 3.32-3.25 (m, 1H), 2.38-2.30 (m, 1H), 2.29 (s, 3H), 2.17-2.06 (m, 1H)

(311) MS Method 1: RT: 3.66 min, m/z 485.3 [M+H].sup.+

(312) The compounds shown below in Table 11 were similarly prepared by varying the isocyanate used in General Method G.

(313) TABLE-US-00012 TABLE 11 Structure Name LCMS RT m/z MIM N-[[4-fluoro-2- (trifluoromethyl)phenyl]methyl]- N-methyl-1-[4-(2-methylpyrazol- 3-yl)phthalazin-1-yl]piperidin-3- amine 3.51 min (Method 1) 499.4 [M + H].sup.+

Example 15

(314) Compounds of formula (I) can be prepared by the General Method H, shown below.

(315) ##STR00350##

N-[[6-Fluoro-2-(trifluoromethyl)-3-pyridyl]methyl]-N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine

(316) ##STR00351##

(317) N-[[6-chloro-2-(trifluoromethyl)-3-pyridyl]methyl]-N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (36 mg, 0.0700 mmol), potassium fluoride (Spray dried) (64 mg, 0.42 mmol) (ground in a pestle and mortar) and 18-crown-6 (2 mg, 0.01 mmol) were added to sulfolane (1 mL) and heated in a microwave vial at 220 C. for 7 h. The mixture was cooled, and taken up in water (20 mL) and filtered. The filtrate was extracted with TBME (2) and the combined extracts washed with water (2), dried (Na.sub.2SO.sub.4) and concentrated in vacuo, then purified by preparative HPLC, and passed through a carbonate cartridge to afford N-[[6-fluoro-2-(trifluoromethyl)-3-pyridyl]methyl]-N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine as the partial formate salt (4 mg, 0.008 mmol; 11%).

(318) .sup.1H NMR (400 MHz, MeOH) /ppm: 8.48 (t, J 8.0 Hz, 1H), 8.28 (d, J 8.2 Hz, 1H), 8.15 (s, 0.78H), 8.05-8.00 (m, 1H), 7.98-7.95 (m, 2H), 7.71 (d, J 2.0 Hz, 1H), 7.37 (dd, J 8.5 Hz, 3.1 Hz, 1H), 6.70 (d, J 2.0 Hz, 1H), 4.20-4.17 (m, 2H), 3.96 (s, 2H), 3.91 (s, 3H), 3.24-3.14 (m, 2H), 2.96-2.87 (m, 1H), 2.36 (s, 3H), 2.16-2.00 (m, 4H).

(319) MS Method 2: RT: 1.24 min. m/z 500.3 [M+H].sup.+

(320) Similarly prepared were:

N-[[6-Fluoro-4-(trifluoromethyl)-3-pyridyl]methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine

(321) ##STR00352##

(322) Partial formate salt (43% by nmr) of N-[[6-fluoro-4-(trifluoromethyl)-3-pyridyl]methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine (9 mg, 0.017 mmol, 25%).

(323) .sup.1H NMR (400 MHz, MeOH) /ppm: 8.66 (s, 1H), 8.57 (s, 0.43H), 8.26 (d, J 8.2 Hz, 1H), 8.05-7.99 (m, 1H), 7.97-7.94 (m, 2H), 7.71 (d, J 2.0 Hz, 1H), 7.44 (d, J 2.2 Hz, 1H), 6.70 (d, J 2.0 Hz, 1H), 4.09 (s, 2H), 4.06 (m, 2H), 3.91 (s, 3H), 3.28-3.20 (m, 2H), 2.96-2.89 (m, 1H), 2.22-2.20 (m, 2H), 1.89-1.76 (m, 2H).

(324) MS Method 1: RT: 2.58 min. m/z 486.3 [M+H].sup.+

N-[[6-fluoro-2-(trifluoromethyl)-3-pyridyl]methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine

(325) ##STR00353##

(326) 4 mg, 0.008 mmol; 12%.

(327) .sup.1H NMR (400 MHz, MeOH) /ppm: 8.31 (t, J 8.0 Hz, 1H), 8.14 (d, J 8.2 Hz, 1H), 7.93-7.88 (m, 1H), 7.87-7.83 (m, 2H), 7.59 (d, J 2.0 Hz, 1H), 7.29 (dd, J 8.5 Hz, 3.1 Hz, 1H), 6.58 (d, J 2.0 Hz, 1H), 4.03 (s, 2H), 4.00-3.92 (m, 2H), 3.79 (s, 3H), 3.16-3.08 (m, 2H), 2.93-2.82 (m, 1H), 2.14-2.06 (m, 2H), 1.80-1.67 (m, 2H).

(328) MS Method 1: RT: 2.71 min. m/z 486.3 [M+H].sup.+

Example 16

(329) In vitro biological evaluation of compounds of the invention was carried out using the procedure detailed below. The procedure provides activity data for the compounds of the invention against the Hedgehog signalling pathway. The activity is represented as IC50 values in Table 12 below.

(330) The Gli-reporter NIH3T3 cell line (BPS Biosciences) was grown according to the suppliers recommendations. Briefly, cells were maintained in growth medium (DMEM supplemented with 10% calf serum, 1% Penicillin/Streptomycin, and 500 g/mL of Geneticin) and grown at 37 C., 5% CO.sub.2. In order to passage cells they were first rinsed with phosphate buffered saline before the addition of 0.05% Trypsin/EDTA. Fresh growth media was added and the cells were transferred to a centrifuge tube, spun and resuspended at an appropriate cell density.

(331) Gli-reporter NIH-3T3 cells were seeded at 20,000 cells/well into 96 well, poly-D-lysine coated white clear bottomed full area TC plates in growth media (without geneticin). Three wells were left with just media as cell free controls. Cells were then incubated for 24 hours at 37 C. in a 5% CO.sub.2.

(332) Serial dilutions of the test compounds were prepared in 100% DMSO. 10 l of compound or DMSO from each well was pipetted into a sterile, 0.5 ml deep well conical bottomed 96 well plate (intermediate plate). 190 l of warmed assay media (Opti-MEM supplemented with 0.5% calf serum, 1% non-essential amino acids, 1 mM sodium pyruvate, 10 mM HEPES, 1% penicillin/Streptomycin) was then added to each well and mixed five times at 180 l by electronic pipette to ensure homogeneity of the compound solution. This 1:20 dilution gives a top concentration of 50 M in 5% DMSO, 95% assay media. 10 l was pipetted from each well of the intermediate plate into a second deep well sterile plate. 490 l of warm assay media was then added to each well and mixed five times at 300 l. This gives a final top concentration of 1 M in 0.1% DMSO.

(333) After the 24 hour incubation, media was carefully removed by pipette and replaced with 45 l of compound dilutions in triplicate. This was incubated for one hour at 37 C. in a 5% CO.sub.2. After an hour, 5 l 10 g/mL recombinant mouse sonic hedgehog (R&D Systems) was added to each well and the plates were incubated for a further 24 hours at 37 C., 5% CO.sub.2.

(334) After 24 hours, plates were removed from the incubator and left to acclimatise to room temperature for 20 minutes. 50 l of OneGLO assay reagent (Promega) was then added to each well and the plates gently shaken for a further 30 minutes. Plates were then read for luminescence on the EnVision plate reader (PerkinElmer).

(335) The results of the in vitro biological data for certain compounds of the invention are given in Table 12 below. The table shows the Hedgehog pathway inhibition activity of each compound characterised based on the IC50 value of the compound as +, ++ and +++. The category + refers to compounds with an IC50 of 200 nM to 2 M. The category ++ refers to compounds with an IC50 of 10 nM to 200 nM. The category +++ refers to compounds with an IC50 of <10 nM.

(336) TABLE-US-00013 TABLE 12 ID No. Compound Category 1 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[4- ++ (trifluoromethyl)phenyl]methyl]piperidin-4-amine 2 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[3- ++ (trifluoromethyl)phenyl]methyl]piperidin-4-amine 3 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[2- +++ (trifluoromethyl)phenyl]methyl]piperidin-4-amine 4 2-fluoro-5-[[methyl-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- ++ piperidyl]amino]methyl]benzonitrile 5 3-[4-fluoro-2-(trifluoromethyl)phenyl]-1-methyl-1-[1-[4-(2- +++ methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]urea 6 2-fluoro-5-[[[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- + piperidyl]amino]methyl]benzonitrile 7 N-[(2-ethoxyphenyl)methyl]-N-methyl-1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]piperidin-4-amine 8 1-(2,4-difluorophenyl)-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]- +++ 4-piperidyl]urea 9 1-(4-fluorophenyl)-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- +++ piperidyl]urea 10 1-tert-butyl-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- +++ piperidyl]urea 11 1-cyclohexyl-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- +++ piperidyl]urea 12 N-[[2-(difluoromethoxy)phenyl]methyl]-N-methyl-1-[4-(2- ++ methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine 13 1-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]-3-[3- +++ (trifluoromethyl)phenyl]urea 14 1-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]-3-[4- +++ (trifluoromethyl)phenyl]urea 15 1-(2-methoxyphenyl)-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]- +++ 4-piperidyl]urea 16 1-(3-fluorophenyl)-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- +++ piperidyl]urea 17 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[(2- ++ methylsulfanylphenyl)methyl]piperidin-4-amine 18 N-[[6-fluoro-2-(trifluoromethyl)-3-pyridyl]methyl]-1-[4-(2- ++ methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine 19 N-[(2-chloro-4-fluoro-phenyl)methyl]-1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]piperidin-4-amine 20 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[4- ++ (trifluoromethoxy)phenyl]methyl]piperidin-4-amine 21 1-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]-3-[2- +++ (trifluoromethyl)phenyl]urea 22 1-(3-cyanophenyl)-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- +++ piperidyl]urea 23 1-[4-fluoro-2-(trifluoromethyl)phenyl]-3-[1-[4-(2-methylpyrazol-3- +++ yl)phthalazin-1-yl]-4-piperidyl]urea 24 1-(3-methoxyphenyl)-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]- +++ 4-piperidyl]urea 25 1-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]-3-[2- +++ (trifluoromethoxy)phenyl]urea 26 1-[4-(difluoromethoxy)phenyl]-3-[1-[4-(2-methylpyrazol-3- +++ yl)phthalazin-1-yl]-4-piperidyl]urea 27 N-[(2,6-difluoro-3-pyridyl)methyl]-N-methyl-1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]piperidin-4-amine 28 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[(2- +++ methylsulfanylphenyl)methyl]piperidin-4-amine 29 N-[(2-isopropylphenyl)methyl]-N-methyl-1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]piperidin-4-amine 30 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-(o- +++ tolylmethyl)piperidin-4-amine 31 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[(2- ++ nitrophenyl)methyl]piperidin-4-amine 32 1-(4-cyanophenyl)-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- +++ piperidyl]urea 33 2-[[methyl-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- ++ piperidyl]amino]methyl]benzonitrile 34 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[3- ++ (trifluoromethoxy)phenyl]methyl]piperidin-4-amine 35 N-[(4-chlorophenyl)methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1- ++ yl]piperidin-4-amine 36 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[2- ++ (trifluoromethoxy)phenyl]methyl]piperidin-4-amine 37 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[4- ++ (trifluoromethyl)phenyl]methyl]piperidin-4-amine 38 N-[(2-chlorophenyl)methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1- ++ yl]piperidin-4-amine 39 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[3- ++ (trifluoromethyl)phenyl]methyl]piperidin-4-amine 40 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[2- +++ (trifluoromethyl)phenyl]methyl]piperidin-4-amine 41 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-[[4-fluoro- ++ 2-(trifluoromethyl)phenyl]methyl]-N-methyl-piperidin-4-amine 42 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-[6-(2- +++ methylpyrazol-3-yl)pyridazin-3-yl]piperidin-4-amine 43 N-[(2-isopropylphenyl)methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin- ++ 1-yl]piperidin-4-amine 44 N-[[6-chloro-2-(trifluoromethyl)-3-pyridyl]methyl]-1-[4-(2- +++ methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine 45 1-(4-methoxyphenyl)-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]- ++ 4-piperidyl]urea 46 1-(2-fluorophenyl)-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- +++ piperidyl]urea 47 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-[1-(2- +++ methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]piperidin-4-amine 48 4-fluoro-N-methyl-N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- +++ piperidyl]-2-(trifluoromethyl)benzenesulfonamide 49 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[1-(2-methylpyrazol- ++ 3-yl)pyrido[3,4-d]pyridazin-4-yl]piperidin-4-amine 50 4-fluoro-N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]-2- +++ (trifluoromethyl)benzenesulfonamide 51 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[3-(trifluoromethyl)-4- ++ pyridyl]methyl]piperidin-4-amine 52 N-[(2-ethoxyphenyl)methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1- ++ yl]piperidin-4-amine 53 N-[4-fluoro-2-(trifluoromethyl)phenyl]-1-[4-(2-methylpyrazol-3- +++ yl)phthalazin-1-yl]piperidin-4-amine 54 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-[4-(2- + methylpyrazol-3-yl)phthalazin-1-yl]piperidin-3-amine 55 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-[4-(2- ++ methylpyrazol-3-yl)phthalazin-1-yl]pyrrolidin-3-amine 56 2,2,2-trifluoro-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-[1-[4- ++ (2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]acetamide 57 N-benzyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4- + amine 58 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-(4- + methoxyphthalazin-1-yl)piperidin-4-amine 59 N-benzyl-N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1- ++ yl]piperidin-4-amine 60 4-[[methyl-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- ++ piperidyl]amino]methyl]benzonitrile 61 N-[(2-methoxyphenyl)methyl]-N-methyl-1-[4-(2-methylpyrazol-3- + yl)phthalazin-1-yl]piperidin-4-amine 62 N-[(3-methoxyphenyl)methyl]-N-methyl-1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]piperidin-4-amine 63 (4-methoxyphenyl)methyl-methyl-[1-[4-(2-methylpyrazol-3- + yl)phthalazin-1-yl]-4-piperidyl]ammonium 64 (2-fluorophenyl)methyl-methyl-[1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]-4-piperidyl]ammonium 65 (3-fluorophenyl)methyl-methyl-[1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]-4-piperidyl]ammonium 66 tert-butyl N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- ++ piperidyl]carbamate 67 N-[(2,4-difluorophenyl)methyl]-N-methyl-1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]piperidin-4-amine 68 4-[[[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- + piperidyl]amino]methyl]benzonitrile 69 N-[(2-methoxyphenyl)methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin- + 1-yl]piperidin-4-amine 70 N-[(3-methoxyphenyl)methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin- ++ 1-yl]piperidin-4-amine 71 N-[(4-methoxyphenyl)methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin- + 1-yl]piperidin-4-amine 72 N-[(2-fluorophenyl)methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1- ++ yl]piperidin-4-amine 73 N-[(3-fluorophenyl)methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1- ++ yl]piperidin-4-amine 74 N-[(2,4-difluorophenyl)methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin- + 1-yl]piperidin-4-amine 75 N-[(4-fluorophenyl)methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1- + yl]piperidin-4-amine 76 N-[(2,6-difluoro-3-pyridyl)methyl]-1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]piperidin-4-amine 77 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-[1-[4-(2- ++ methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]acetamide 78 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-[4-(2- +++ methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine 79 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[4-(2-methylpyrazol- +++ 3-yl)phthalazin-1-yl]piperidin-4-amine

(337) Further results of the in vitro biological evaluation for certain compounds of the invention are given in Table 13 below. The table shows the Hedgehog pathway inhibition activity of each compound characterised based on the IC50 value of the compound as +, ++ and +++. The category + refers to compounds with an IC50 of >200 nM. The category ++ refers to compounds with an IC50 of 10 nM to 200 nM. The category +++ refers to compounds with an IC50 of <10 nM. Compounds that did not exhibit an IC50 value within the upper concentration limit of the assay have been indicated with a .

(338) TABLE-US-00014 TABLE 13 ID Gli luc No. s STRUCTURE_NAME IC50 nM 80 3-[4-fluoro-2-(trifluoromethyl)phenyl]-1-methyl-1-[1-[8-(2-methylpyrazol-3- +++ yl)pyrido[2,3-d]pyridazin-5-yl]-4-piperidyl]urea 81 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-methyl-N-[(2- +++ nitrophenyl)methyl]piperidin-4-amine 82 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-[(2- ++ isopropylphenyl)methyl]-N-methyl-piperidin-4-amine 83 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-methyl-N-[[3- ++ (trifluoromethoxy)phenyl]methyl]piperidin-4-amine 84 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-methyl-N-[[2- ++ (trifluoromethyl)phenyl]methyl]piperidin-4-amine 85 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-methyl-N-[[3- ++ (trifluoromethyl)-2-pyridyl]methyl]piperidin-4-amine 86 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-(pyrimidin-4- + ylmethyl)piperidin-4-amine 87 2-[[[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]- ++ methyl-amino]methyl]benzonitrile 88 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-methyl-N-[(2- + methylsulfanylphenyl)methyl]piperidin-4-amine 89 1-[4,5-dimethyl-6-(2-methylpyrazol-yl)pyridazin-3-yl]-N-methyl-N-[[2- + (trifluoromethoxy)phenyl]methyl]piperidin-4-amine 90 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-methyl-N- + (pyridazin-4-ylmethyl)piperidin-4-amine 91 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-(pyridazin-4- + ylmethyl)piperidin-4-amine 92 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[(2- ++ methylsulfanylpyrimidin-4-yl)methyl]piperidin-4-amine 93 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-methyl-N-[(2- + methylsulfanylpyrimidin-4-yl)methyl]piperidin-4-amine 94 N-cyclopropyl-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[4-(2- + methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine 95 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-methyl-N-[[2- ++ methyl-4-(trifluoromethyl)thiazol-5-yl]methyl]piperidin-4-amine 96 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[2-methyl-4- +++ (trifluoromethyl)thiazol-5-yl]methyl]piperidin-4-amine 97 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-methyl-N-[[2- ++ methyl-5-(trifluoromethyl)oxazol-4-yl]methyl]piperidin-4-amine 98 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[2-methyl-5- ++ (trifluoromethyl)oxazol-4-yl]methyl]piperidin-4-amine 99 1-[4-fluoro-2-(trifluoromethyl)phenyl]-3-[1-[1-(4-pyridyl)pyrido[3,4- +++ d]pyridazin-4-yl]-4-piperidyl]urea 100 1-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]-3-[4- ++ fluoro-2-(trifluoromethyl)phenyl]urea 101 3-(2,4-difluorophenyl)-1-methyl-1-[1-[8-(2-methylpyrazol-3-yl)pyrido[2,3- + d]pyridazin-5-yl]-4-piperidyl]urea 102 2,4-difluoro-N-methyl-N-[1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin- ++ 4-yl]-4-piperidyl]benzenesulfonamide 103 4-fluoro-N-methyl-N-[1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]- ++ 4-piperidyl]-2-(trifluoromethyl)benzenesulfonamide 104 1-(2,4-difluorophenyl)-3-[1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin- ++ 4-yl]-4-piperidyl]urea 105 1-[4-fluoro-2-(trifluoromethyl)phenyl]-3-[1-[1-(2-methylpyrazol-3- +++ yl)pyrido[3,4-d]pyridazin-4-yl]-4-piperidyl]urea 106 4-fluoro-N-[1-[1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]-4- ++ piperidyl]-2-(trifluoromethyl)benzenesulfonamide 107 1-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]-1- + methyl-3-[5-(trifluoromethyl)pyridazin-4-yl]urea 108 1-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]-3-[1- ++ (trifluoromethyl)cyclopropyl]urea 109 1-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]-3-[1- ++ (trifluoromethyl)cyclopropyl]urea 110 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[6-(6-methoxy-3-pyridyl)- ++ 4,5-dimethyl-pyridazin-3-yl]-N-methyl-piperidin-4-amine 111 3-(2,4-difluorophenyl)-1-methyl-1-[1-[1-(2-methylpyrazol-3-yl)pyrido[3,4- ++ d]pyridazin-4-yl]-4-piperidyl]urea 112 3-[4-fluoro-2-(trifluoromethyl)phenyl]-1-methyl-1-[1-[1-(2-methylpyrazol-3- +++ yl)pyrido[3,4-d]pyridazin-4-yl]-4-piperidyl]urea 113 1-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]-3-(4- + fluorophenyl)-1-methyl-urea 114 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[(2- ++ nitrophenyl)methyl]piperidin-4-amine 115 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[(2- ++ methylsulfonylphenyl)methyl]piperidin-4-amine 116 1-tert-butyl-3-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4- ++ piperidyl]urea 117 4-fluoro-N-[1-[6-(6-methoxy-3-pyridyl)-4,5-dimethyl-pyridazin-3-yl]-4- ++ piperidyl]-2-(trifluoromethyl)benzenesulfonamide 118 N-[1-[4,5-dimethyl-6-(2-methyl-4-pyridyl)pyridazin-3-yl]-4-piperidyl]-4- + fluoro-2-(trifluoromethyl)benzenesulfonamide 119 N-[1-[4,5-dimethyl-6-(4-pyridyl)pyridazin-3-yl]-4-piperidyl]-4-fluoro-2- ++ (trifluoromethyl)benzenesulfonamide 120 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[6-(6-methoxy-3-pyridyl)- ++ 4,5-dimethyl-pyridazin-3-yl]piperidin-4-amine 121 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[6-(2-methoxy-4-pyridyl)- + 4,5-dimethyl-pyridazin-3-yl]piperidin-4-amine 122 1-[4,5-dimethyl-6-(2-methyl-4-pyridyl)pyridazin-3-yl]-N-[[4-fluoro-2- + (trifluoromethyl)phenyl]methyl]piperidin-4-amine 123 1-[4,5-dimethyl-6-(4-pyridyl)pyridazin-3-yl]-N-[[4-fluoro-2- ++ (trifluoromethyl)phenyl]methyl]piperidin-4-amine 124 4-fluoro-N-methyl-N-[1-[1-(2-methylpyrazol-3-yl)-6,7-dihydro-5H- ++ cyclopenta[d]pyridazin-4-yl]-4-piperidyl]-2- (trifluoromethyl)benzenesulfonamide 125 3-[4-fluoro-2-(trifluoromethyl)phenyl]-1-methyl-1-[1-[1-(2-methylpyrazol-3- +++ yl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-4-yl]-4-piperidyl]urea 126 1-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]-3-(2- ++ fluorophenyl)-1-methyl-urea 127 3-(2,4-difluorophenyl)-1-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin- + 3-yl]-4-piperidyl]-1-methyl-urea 128 2-fluoro-5-[[[1-[1-(2-methylpyrazol-3-yl)-6,7-dihydro-5H- + cyclopenta[d]pyridazin-4-yl]-4-piperidyl]amino]methyl]benzonitrile 129 3-tert-butyl-1-methyl-1-[1-[8-(2-methylpyrazol-3-yl)pyrido[2,3-d]pyridazin-5- + yl]-4-piperidyl]urea 130 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-[8-(2- + methylpyrazol-3-yl)pyrido[2,3-d]pyridazin-5-yl]piperidin-4-amine 131 3-[[methyl-[1-[1-(2-methylpyrazol-3-yl)-6,7-dihydro-5H- ++ cyclopenta[d]pyridazin-4-yl]-4-piperidyl]amino]methyl]benzonitrile 132 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-[1-(2- ++ methylpyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-4-yl]piperidin-4- amine 133 3-tert-butyl-1-methyl-1-[1-[1-(2-methylpyrazol-3-yl)-6,7-dihydro-5H- ++ cyclopenta[d]pyridazin-4-yl]-4-piperidyl]urea 134 4-fluoro-N-methyl-N-[1-[5-(2-methylpyrazol-3-yl)pyrido[2,3-d]pyridazin-8-yl]- ++ 4-piperidyl]-2-(trifluoromethyl)benzenesulfonamide 135 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-[5-(2- ++ methylpyrazol-3-yl)pyrido[2,3-d]pyridazin-8-yl]piperidin-4-amine 136 3-(2,4-difluorophenyl)-1-methyl-1-[1-[5-(2-methylpyrazol-3-yl)pyrido[2,3- ++ d]pyridazin-8-yl]-4-piperidyl]urea 137 3-[4-fluoro-2-(trifluoromethyl)phenyl]-1-methyl-1-[1-[5-(2-methylpyrazol-3- +++ yl)pyrido[2,3-d]pyridazin-8-yl]-4-piperidyl]urea 138 1-(2,4-difluorophenyl)-3-[1-[1-(2-methylpyrazol-3-yl)-6,7-dihydro-5H- ++ cyclopenta[d]pyridazin-4-yl]-4-piperidyl]urea 139 1-[4-fluoro-2-(trifluoromethyl)phenyl]-N-methyl-N-[[1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]pyrrolidin-3-yl]methyl]methanamine 140 1-[4-fluoro-2-(trifluoromethyl)phenyl]-N-[[1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]pyrrolidin-3-yl]methyl]methanamine 141 2,4-difluoro-N-[1-[1-(2-methylpyrazol-3-yl)-6,7-dihydro-5H- ++ cyclopenta[d]pyridazin-4-yl]-4-piperidyl]benzenesulfonamide 142 N-[4-fluoro-2-(trifluoromethyl)phenyl]-1-[1-(2-methylpyrazol-3-yl)-6,7- ++ dihydro-5H-cyclopenta[d]pyridazin-4-yl]piperidin-4-amine 143 N-[1-[4-fluoro-2-(trifluoromethyl)phenyl]ethyl]-1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]piperidin-4-amine 144 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-(4- + morpholinophthalazin-1-yl)piperidin-4-amine 145 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-(4-morpholinophthalazin-1- + yl)piperidin-4-amine 146 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[5-(2-methylpyrazol-3- + yl)pyrido[2,3-d]pyridazin-8-yl]piperidin-4-amine 147 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[3-(trifluoromethyl)- ++ 2-pyridyl]methyl]piperidin-4-amine 148 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[1-(2-methylpyrazol-3-yl)- ++ 6,7-dihydro-5H-cyclopenta[d]pyridazin-4-yl]piperidin-4-amine 149 3-[[[1-[1-(2-methylpyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-4-yl]- + 4-piperidyl]amino]methyl]benzonitrile 150 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[3-(trifluoromethyl)-2- ++ pyridyl]methyl]piperidin-4-amine 151 1-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]-3-[4- +++ fluoro-2-(trifluoromethyl)phenyl]-1-methyl-urea 152 3-tert-butyl-1-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4- + piperidyl]-1-methyl-urea 153 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-(4-pyrazin-2- + ylphthalazin-1-yl)piperidin-4-amine 154 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[4-(trifluoromethyl)- +++ 3-pyridyl]methyl]piperidin-4-amine 155 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[2-(trifluoromethyl)-3- +++ pyridyl]methyl]piperidin-4-amine 156 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[4-(trifluoromethyl)-3- +++ pyridyl]methyl]piperidin-4-amine 157 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[2-(trifluoromethyl)- +++ 3-pyridyl]methyl]piperidin-4-amine 158 N-[(2-chloro-4-fluoro-phenyl)methyl]-N-methyl-1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]piperidin-4-amine 159 4-fluoro-N-[1-[1-(2-methylpyrazol-3-yl)-6,7-dihydro-5H- +++ cyclopenta[d]pyridazin-4-yl]-4-piperidyl]-2- (trifluoromethyl)benzenesulfonamide 160 N-[[6-fluoro-2-(trifluoromethyl)-3-pyridyl]methyl]-N-methyl-1-[4-(2- +++ methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-amine 161 1-tert-butyl-3-[1-[1-(2-methylpyrazol-3-yl)-6,7-dihydro-5H- ++ cyclopenta[d]pyridazin-4-yl]-4-piperidyl]urea 162 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[2- +++ (trifluoromethoxy)phenyl]methyl]piperidin-4-amine 163 N-[(2,3-difluorophenyl)methyl]-1-[4-(2-methylpyrazol-3-yl)phthalazin-1- ++ yl]piperidin-4-amine 164 N-[[6-fluoro-4-(trifluoromethyl)-3-pyridyl]methyl]-1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]piperidin-4-amine 165 N-[[6-fluoro-2-(trifluoromethyl)-3-pyridyl]methyl]-1-[4-(2-methylpyrazol-3- ++ yl)phthalazin-1-yl]piperidin-4-amine 166 methyl 6-[[[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- + piperidyl]amino]methyl]pyridine-3-carboxylate 167 1-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]-3-[4- +++ (trifluoromethoxy)phenyl]urea 168 3-[[methyl-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- ++ piperidyl]amino]methyl]benzonitrile 169 3-(2,4-difluorophenyl)-1-methyl-1-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1- +++ yl]-4-piperidyl]urea 170 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-(o-tolylmethyl)piperidin-4- ++ amine 171 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-N-methyl-N- (pyrimidin-4-ylmethyl)piperidin-4-amine 172 4-fluoro-N-[1-[6-(2-methoxy-4-pyridyl)-4,5-dimethyl-pyridazin-3-yl]-4- piperidyl]-2-(trifluoromethyl)benzenesulfonamide

(339) Examples of compounds of the invention with values for their IC50 are given in Table 14, below.

(340) TABLE-US-00015 TABLE 14 ID No. Compound Gli Luc nM 3 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[2- 3.94 (trifluoromethyl)phenyl]methyl]piperidin-4-amine 5 3-[4-fluoro-2-(trifluoromethyl)phenyl]-1-methyl-1-[1-[4-(2- 0.05 methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]urea 8 1-(2,4-difluorophenyl)-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]- 0.99 4-piperidyl]urea 9 1-(4-fluorophenyl)-3-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4- 1.33 piperidyl]urea 14 1-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]-3-[4- 0.71 (trifluoromethyl)phenyl]urea 23 1-[4-fluoro-2-(trifluoromethyl)phenyl]-3-[1-[4-(2-methylpyrazol-3- 0.66 yl)phthalazin-1-yl]-4-piperidyl]urea 42 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N-methyl-1-[6-(2- 0.04 methylpyrazol-3-yl)pyridazin-3-yl]piperidin-4-amine 50 4-fluoro-N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-4-piperidyl]-2- 1.79 (trifluoromethyl)benzenesulfonamide 79 N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-[4-(2-methylpyrazol- 7.85 3-yl)phthalazin-1-yl]piperidin-4-amine 112 3-[4-fluoro-2-(trifluoromethyl)phenyl]-1-methyl-1-[1-[1-(2- 1.26 methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]-4-piperidyl]urea 151 1-[1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4- 5.12 piperidyl]-3-[4-fluoro-2-(trifluoromethyl)phenyl]-1-methyl-urea
Thermodynamic Solubility with Filtration

(341) 0.5 mg is weighed into a Mini Uniprep filter vial (Whatman, PVDF, 0.2 m). 0.5 mL of pH 7.4 phosphate buffer (0.1 M) is dispensed and the vial is shaken at 600 rpm for 24 h at room temperature. At the end of this period, the solution is then filtered and an aliquot of the filtrate is used to create a tenfold dilution. Standards are prepared by serially diluting a 1250 g/mL DMSO stock solution of the compound to 125 and 2.5 g/mL, in Acetonitrile/Water (50:50, v/v). The concentration of the filtrate and tenfold dilution is measured by detection against the two calibration standards. Representative data for examples of the invention are given in Table 15.

(342) TABLE-US-00016 TABLE 15 Solubility ID STRUCTURE_NAME mg/L 97 1-[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3- 1009 yl]-N-methyl-N-[[2-methyl-5-(trifluoromethyl)oxazol- 4-yl]methyl]piperidin-4-amine 98 N-methyl-1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]- 106 N-[[2-methyl-5-(trifluoromethyl)oxazol-4- yl]methyl]piperidin-4-amine 112 3-[4-fluoro-2-(trifluoromethyl)phenyl]-1-methyl-1-[1- 399 [1-(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]- 4-piperidyl]urea 116 1-tert-butyl-3-[1-[4,5-dimethyl-6-(2-methylpyrazol-3- 1262 yl)pyridazin-3-yl]-4-piperidyl]urea 156 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-[[4- 321 (trifluoromethyl)-3-pyridyl]methyl]piperidin-4-amine 170 1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]-N-(o- 1193 tolylmethyl)piperidin-4-amine

(343) It can be seen from the above data that in addition to good IC50 values the compounds of the invention also possess good thermodynamic solubility. This provides a further potential benefit when the compounds are used in therapy.

(344) Throughout the description and claims of this specification, the words comprise and contain and variations of them mean including but not limited to, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

(345) Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

(346) The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.