WO2015001348A1

WO2015001348A1 - Pyridazine derivatives as hedgehog pathway inhibitors

Info

Publication number: WO2015001348A1
Application number: PCT/GB2014/052029
Authority: WO
Inventors: Richard Armer; Matilda Bingham; Inder Bhamra; Andrew TUFFNELL
Original assignee: Redx Pharma Ltd
Current assignee: Redx Pharma Ltd
Priority date: 2013-07-03
Filing date: 2014-07-03
Publication date: 2015-01-08
Anticipated expiration: 2016-01-03
Also published as: GB201311953D0

Abstract

This invention relates to novel compounds. The compounds of the invention are hedgehog pathway agonists. Specifically, the compounds of the invention are useful as Smoothened (SMO) agonists. 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.

Description

PYRIDAZINE DERIVATIVES AS HEDGEHOG PATHWAY INHIBITORS

[0001] This invention relates to compounds. More specifically, the invention relates to compounds useful as inhibitors of the Hedgehog signalling pathway. Specifically, inhibitors of Smoothened (Smo) are contemplated by the invention. In addition the invention contemplates processes to prepare the compounds and uses of the compounds.

[0002] The Hedgehog signalling pathway plays a key role in embryonic cells and is one of the key regulators of animal development. Malfunction of the Hedgehog signalling pathway during embryonic development can lead to abnormalities in the structure of bodily organs and the structure of the skeleton. Later in life, the Hedgehog signalling pathway has a role in regulating adult stem cells in the maintenance and the regeneration of tissue by directing cell differentiation and proliferation. Abnormalities in the Hedgehog signalling pathway have been shown to result in certain conditions, for example cancer.

[0003] There are three Hedgehog proteins (Hh) associated with the Hedgehog signalling pathway, Sonic Hedgehog (Shh), Indian Hedgehog (Ihh) and Desert Hedgehog (Dhh). The

Hedgehog proteins bind to the Patched-1 receptor. The Patched-1 receptor inhibits Smo activity and upon binding of a Hedgehog protein with Patched-1 this inhibition is alleviated, leading to activation of the GLI transcription factors Gli1 , Gli2 and Gli3 which are involved in cell fate determination and proliferation.

[0004] Aberrant activation of the hedgehog pathway has been implicated in patients suffering from a range of cancers, for example Basal cell carcinoma, pancreatic cancer, medulloblastoma, small cell lung cancer and prostate cancer. Moreover, it has been suggested that aberrant hedgehog signalling may contribute to the regulation of cancer stem cells.

[0005] In January 2012 Genentech was given FDA approval for Vismodegib for the treatment of basal-cell carcinoma. This was approval of the first Hedgehog signalling pathway inhibitor.

Vismodegib is being studied in the clinic for the treatment of a range of other cancers including colorectal cancer, small-cell lung cancer, stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma. Recently, WO 2010/147917 disclosed Hedgehog pathway inhibitors for the treatment of various cancers. In addition Novartis Oncology have completed Phase II clinical trials for the treatment of Basal Cell Carcinomas on LDE225, a Smo receptor inhibitor. Thus, it is clear that inhibition of aberrant Hedgehog pathway signalling and Smo activation has emerged as an attractive target for anticancer therapy.

[0006] Inhibiting the Hedgehog signalling pathway with small molecules has become an important target for clinicians to treat clinically significant cancers, such as solid tumours, through the reversal or control of aberrant cell growth. However, there is still a need to possess effective Hedgehog signalling pathway inhibitors and Smo inhibitors as effective treatments for various cancer types. [0007] In accordance with the present invention there is provided compounds as disclosed below. Furthermore, the invention provides compounds capable of inhibiting the Hedgehog signalling pathway, specifically Smoothened (Smo) and the use of these compounds in inhibiting the Hedgehog signalling pathway and Smo. In accordance with the invention there is provided a method of treating conditions modulated by the Hedgehog signalling pathway, specifically Smo. The invention provides compounds for use in treating a condition which is modulated by the Hedgehog signalling pathway, specifically Smo.

[0008] According to the invention there is provided a compound according to formula (I) and pharmaceutically acceptable salts and solvates thereof:

"het" is selected from substituted or unsubstituted: pyrolidinylene, piperidinylene and azepanylene; or "het" represents a substituted or unsubstituted heteroalkylene chain in which the heteroatom present in a C1-6 alkylene chain is nitrogen and wherein the nitrogen atom is substituted by hydrogen or Ci-4 alkyl;

at least one of A¹ , A², A³ and A⁴ is N and the remaining A¹ , A², A³ and A⁴ are each independently selected from CR⁴ or N;

wherein R⁴ is selected from H, halo, Ci-e alkyl, Ci-e haloalkyl, -OR^a, -CR^cR^dOR^a, C₂-e alkenyl, C₂-e alkynyl, C₃-₈ cycloalkyl, C₃-₈ cycloalkenyl, -NR^aR^b, -CN, -C(0)R^a, -C(0)OR^a and -C(0)NR^aR^b, and two adjacent R⁴ groups may form a ring with the carbon atom to which they are attached forming a fused bicyclic ring system of 8 to 12 atoms, wherein the ring formed by the two R⁴ 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 containing 1 , 2 or 3 heteroatoms;

L is selected from either a substituted or unsubstituted C1-3 alkylene chain which is saturated or unsaturated and which may also optionally contain, where chemically possible, 1 N, O, or S atoms in the chain which are independently chosen at each occurrence;

or L is selected from a bond, -C(O)-, -C(NR^a)-, -C(0)0-, -C(0)NR^a-, -C(NR^a)NR^a-, and -SO2-;

R¹ is selected from substituted or unsubstituted: heterocycloalkyl, -O-heterocycloalkyl,

-NR^a-heterocycloalkyl, -CR^cR^d-heterocycloalkyl, heterocycloalkenyl, -O-heterocycloalkenyl, -NR^a-heterocycloalkenyl, -CR^cR^d-heterocycloalkenyl, aryl, -O-aryl, -NR^a-aryl, -CR^cR^d-aryl, heteroaryl, -O-heteroaryl, -NR^a-heteroaryl, and -CR^cR^d-heteroaryl; R² is represented by -CR⁵R⁶R⁷, wherein R⁵, R⁶ and R⁷ are independently selected at each occurrence from H and substituted or unsubstituted: C1 -14 alkyl, C1-14 haloalkyl, carbocyclic, and heterocyclic,

or R² is selected from substituted or unsubstituted: C1-14 alkyl, C1-14 haloalkyl, carbocyclic, and heterocyclic;

R³ is selected from H, substituted or unsubstituted C1-4 alkyl, C1 -4 haloalkyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic;

R^a and R^b are independently selected at each occurrence from : H, C1-4 alkyl, C1-4 haloalkyl, C1-4 acyl, C3-7 cycloalkyl, and C3-7 halocycloalkyl ;

R^c and R^d are independently selected from H, halo, -OR^a, C1-4 alkyl, C1-4 haloalkyl, C1-4 acyl, C3-7 cycloalkyl, and C3-7 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 comprising: halo, -OR^a, - SR^a, -NR^aR^b, NO2, =0, -CN, acyl, C1-6 alkyl, C1-6 haloalkyl, C₃-₈ cycloalkyl, -S0₂R^a, and S0₃R^a , -C(OR^a)R^aR^b, -C(0)R^a, -C(0)OR^a and

-C(0)NR^aR^b.

[0009] In certain embodiments of the invention there is provided a compound according to formula (I) and pharmaceutically acceptable salts and solvates thereof:

"het" is selected from substituted or unsubstituted: pyrolidinylene, piperidinylene and azepanylene; or "het" represents a substituted or unsubstituted heteroalkylene chain in which the heteroatom present in a C1-6 alkylene chain is nitrogen and wherein the nitrogen atom is substituted by hydrogen or C1-4 alkyl;

wherein R⁴ is selected from H, halo, C1-6 alkyl, C1 -6 haloalkyl, -OR^a, -CR^cR^dOR^a, C2-6 alkenyl, C2-6 alkynyl, C₃-₈ cycloalkyl, C₃-₈ cycloalkenyl, -NR^aR^b, -CN, -C(0)R^a, -C(0)OR^a and -C(0)NR^aR , and two adjacent R⁴ groups may form a ring with the carbon atom to which they are attached forming a fused bicyclic ring system of 8 to 12 atoms, wherein the ring formed by the two R⁴ 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 containing 1 , 2 or 3 heteroatoms;

-NR^a-heterocycloalkyl, -CR^cR^d-heterocycloalkyl, heterocycloalkenyl, -O-heterocycloalkenyl, -NR^a-heterocycloalkenyl, -CR^cR^d-heterocycloalkenyl, aryl, -O-aryl, -NR^a-aryl, -CR^cR^d-aryl, heteroaryl, -O-heteroaryl, -NR^a-heteroaryl, and -CR^cR^d-heteroaryl;

R² is represented by -CR⁵R⁶R⁷, wherein R⁵, R⁶ and R⁷ are independently selected at each occurrence from H and substituted or unsubstituted: C1 -14 alkyl, C1-14 haloalkyl, carbocyclic, and heterocyclic,

R³ is selected from substituted or unsubstituted C1 -14 alkyl, C1-14 haloalkyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic;

R^a and R^b are independently selected at each occurrence from : H, C1-4 alkyl, C1-4 haloalkyl, C1-4 acyl, C3-7 cycloalkyl, and C3-7 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 comprising: halo, -OR^a, - SR^a, -NR^aR^b, NO2, =0, -CN, acyl, C1-6 alkyl, Ci- 6 haloalkyl, C₃-₈ cycloalkyl, -S0₂R^a, -S0₃R^a , -C(OR^a)R^aR^b, -C(0)R^a, -C(0)OR^a and C(0)NR^aR^b.

[0010] In certain embodiments, the compounds of formula (I) are as described above in paragraph [0008] or [0009] with the proviso that when:

two adjacent R⁴ groups form a ring with the carbon atom to which they are attached and the ring formed by the two R⁴ groups and those carbon atoms is a benzene ring; and

L is C1-3 alkylene chain which is saturated or unsaturated;

then R¹ is selected from substituted or unsubstituted: aryl or heteroaryl, preferably substituted or unsubstituted heteroaryl (and optionally R¹ is selected from substituted or unsubstituted: pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl; preferably substituted or unsubstituted pyrazolyl). [001 1 ] In certain embodiments, the compounds of formula (I) are as described above in paragraph [0008] or [0009] with the proviso that when:

two adjacent R⁴ groups form a ring with the carbon atom to which they are attached and the ring formed by the two R⁴ groups and those carbon atoms is a benzene ring;

then R¹ is selected from substituted or unsubstituted: aryl or heteroaryl, preferably substituted or unsubstituted heteroaryl (and optionally R¹ is selected from substituted or unsubstituted: pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl; preferably substituted or unsubstituted pyrazolyl).

[0012] In certain embodiments, the compounds of formula (I) are as described above in paragraph [0008] or [0009] with the proviso that R¹ is aryl and heteroaryl (optionally R¹ is selected from substituted or unsubstituted: pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl) when L is selected from either a substituted or unsubstituted C1 -3 alkylene chain. Thus, in these embodiments, R¹ is not selected from substituted or unsubstituted: heterocycloalkyl,

-O-heterocycloalkyl, -NR^a-heterocycloalkyl, -CR^cR^d-heterocycloalkyl, heterocycloalkenyl,

-O-heterocycloalkenyl, -NR^a-heterocycloalkenyl, -CR^cR^d-heterocycloalkenyl, -O-aryl, -NR^a-aryl, - CR^cR^d-aryl, -O-heteroaryl, -NR^a-heteroaryl, and -CR^cR^d-heteroaryl, when L is selected from either a substituted or unsubstituted C1-3 alkylene chain.

[0013] In certain embodiments of the compounds of Formula (I) as described in any of the preceding paragraphs, R⁴ is selected from halo, C1-6 alkyl, C1 -6 haloalkyl, -OR^a, -CR^cR^dOR^a, C2-6 alkenyl, C2-6 alkynyl, C₃-₈ cycloalkyl, C₃-₈ cycloalkenyl, -NR^aR^b, -CN, -C(0)R^a, -C(0)OR^a and - C(0)NR^aR^b, and two adjacent R⁴ groups may form a ring with the carbon atom to which they are attached forming a fused bicyclic ring system of 8 to 12 atoms, wherein the ring formed by the two R⁴ 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 containing 1 , 2 or 3 heteroatoms;

L is an unsubstituted C1-3 alkylene chain which is saturated or unsaturated;

R¹ is selected from substituted or unsubstituted: aryl and heteroaryl (optionally R¹ is selected from substituted or unsubstituted: pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl); and m is 0 or 1 .

[0014] In all embodiments "het" may be selected from substituted or unsubstituted pyrolidinylene, substituted or unsubstituted piperidinylene, and substituted or unsubstituted azepanylene. [0015] In an embodiment "het" is selected from substituted or unsubstituted: pyrolidinylene, piperidinylene and azepanylene. In an alternative embodiment "het" represents a substituted or unsubstituted heteroalkylene chain in which the heteroatom present in a C1-6 alkylene chain is nitrogen and wherein the nitrogen atom is substituted by hydrogen or Ci-4 alkyl.

[0016] In an embodiment "het" is represented by groups selected from substituted or unsubstituted:

[0017] In an alternative embodiment "het" is selected from substituted or unsubstituted:

[0018] In embodiments "het" and -(CR^cR^d)_m- are attached to each other via a carbon atom of "het". In embodiments "het" and L are attached to each other via a nitrogen atom of "het". In embodiments "het" and -(CR^cR^d)_m- are attached to each other via a carbon atom of "het" and "het" and L are attached to each other via a nitrogen atom of "het". When m = 0 and there is no

-(CR^cR^d)m- then "het" is bonded to -N(R³)-, instead of -(CR^cR^d)_m-, via a carbon atom of "het".

[0019] In embodiments "het" is selected from substituted or unsubstituted:

[0020] In an embodiment "het" is selected from substituted or unsubstituted:

[0021 ] Preferably "het" is substituted or unsubstituted:

[0022] In embodiments "het" is unsubstituted. In alternative embodiments "het" is substituted with 1 to 5 substituents independently selected at each occurrence from the group comprising: halo, -OR^a, - SR^a, -NR^aR^b, N0₂, =0, -CN, acyl, C1-6 alkyl, C1-6 haloalkyl, C₃-₈ cycloalkyl, -S0₂R^a, and S0₃R^a , -C(0)R^a and C(0)OR^a. [0023] In an embodiment the compound of formula (I) is a compound according to formula (II):

(II)

[0024] In embodiments one of A¹ , A², A³ and A⁴ is N and the remaining A¹ , A², A³ and A⁴ are each independently selected from N or CR⁴. Optionally, one of A¹ , A², A³ and A⁴ is N, two of the remaining A¹ , A², A³ and A⁴ are each CR⁴ and the remaining A¹ , A², A³ and A⁴ is selected from N or CR⁴. In embodiments at least two of A¹ , A², A³ and A⁴ are N and the remaining A¹ , A², A³ and A⁴ are each independently selected from N or CR⁴. Optionally, two of A¹ , A², A³ and A⁴ are N and two of A¹ , A², A³ and A⁴ are CR⁴.

[0025]

A¹=A²

[0026] In embodiments A A° j_s selected from

[0027

In an embodiment j_s:

[0028] In an embodiment the compound of formula (I) is a compound according to formula

<■")

[0029] In an embodiment the compound of formula (I) is a compound according to formula (III): wherein R⁴ is selected from halo, Ci-e alkyl, Ci-e haloalkyl, -OR^a, -CR^cR^dOR^a, C₂-₆ alkenyl, C₂-₆ alkynyl, C₃-₈ cycloalkyl, C₃-₈ cycloalkenyl, -NR^aR^b, -CN, -C(0)R^a, -C(0)OR^a and -C(0)NR^aR^b, and two adjacent R⁴ groups may form a ring with the carbon atom to which they are attached forming a fused bicyclic ring system of 8 to 12 atoms, wherein the ring formed by the two R⁴ 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 containing 1 , 2 or 3 heteroatoms.

[0030] In an embodiment the compound of formula (I) is a compound according to formula (III): wherein R⁴ is selected from halo, Ci-e alkyl, Ci-e haloalkyl, -OR^a, -CR^cR^dOR^a, C₂-e alkenyl, C₂-e alkynyl, C₃-₈ cycloalkyl, C₃-₈ cycloalkenyl, -NR^aR^b, -CN, -C(0)R^a, -C(0)OR^a and -C(0)NR^aR^b, and two adjacent R⁴ groups may form a ring with the carbon atom to which they are attached forming a fused bicyclic ring system of 8 to 12 atoms, wherein the ring formed by the two R⁴ 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 containing 1 , 2 or 3 heteroatoms; and m is 0 or 1 .

[0031 ] In an embodiment the compound of formula (I) is a compound according to formula (III): wherein R⁴ is selected from halo, Ci-e alkyl, Ci-e haloalkyl, -OR^a, -CR^cR^dOR^a, C₂-e alkenyl, C₂-e alkynyl, C₃-₈ cycloalkyl, C₃-₈ cycloalkenyl, -NR^aR^b, -CN, -C(0)R^a, -C(0)OR^a and -C(0)NR^aR^b, and two adjacent R⁴ groups may form a ring with the carbon atoms to which they are attached the ring being 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 containing 1 , 2 or 3 heteroatoms; and m is 0 or 1 ;

with the proviso that when:

two adjacent R⁴ groups form a ring with the carbon atom to which they are attached and the ring formed by the two R⁴ groups and those carbon atoms is a benzene ring, and

L is Ci-₃ alkylene chain which is saturated or unsaturated

[0032] In an embodiment the compound of formula (I) is a compound according to formula (III): wherein R⁴ is selected from halo, Ci-₆ alkyl, Ci-e haloalkyl, -OR^a, -CR^cR^dOR^a, C₂-₆ alkenyl, C₂-₆ alkynyl, C₃-₈ cycloalkyl, C₃-₈ cycloalkenyl, -NR^aR^b, -CN, -C(0)R^a, -C(0)OR^a and -C(0)NR^aR , and two adjacent R⁴ groups may form a ring with the carbon atoms to which they are attached the ring being 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 containing 1 , 2 or 3 heteroatoms; and m is 0 or 1 ; with the proviso that when two adjacent R⁴ groups form a ring with the carbon atom to which they are attached and the ring formed by the two R⁴ groups and those carbon atoms is a benzene ring, then R¹ is selected from substituted or unsubstituted: aryl or heteroaryl, preferably substituted or unsubstituted heteroaryl (and optionally R¹ is selected from substituted or unsubstituted: pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl; preferably substituted or unsubstituted pyrazolyl).

[0033] In an embodiment the compound of formula (I) is a compound according to formula (III): wherein R⁴ is selected from halo, Ci-e alkyl, Ci-e haloalkyl, -OR^a, -CR^cR^dOR^a, C₂-₆ alkenyl, C₂-₆ alkynyl, C₃-₈ cycloalkyl, C₃-₈ cycloalkenyl, -NR^aR^b, -CN, -C(0)R^a, -C(0)OR^a and -C(0)NR^aR^b, and two adjacent R⁴ groups may form a ring with the carbon atoms to which they are attached the ring being 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 containing 1 , 2 or 3 heteroatoms; and m is 0 or 1 ;

with the proviso that when two adjacent R⁴ groups form a ring with the carbon atom to which they are attached and the ring formed by the two R⁴ groups and those carbon atoms is a benzene ring, then L is not C1-3 alkylene chain which is saturated or unsaturated.

[0034] In an embodiment the compound of formula (I) is a compound according to formula (III): wherein R⁴ is selected from halo, C1-6 alkyl, C1-6 haloalkyl, -OR^a, -CR^cR^dOR^a, C2-6 alkenyl, C2-6 alkynyl, C₃-₈ cycloalkyl, C₃-₈ cycloalkenyl, -NR^aR^b, -CN, -C(0)R^a, -C(0)OR^a and -C(0)NR^aR^b, and two adjacent R⁴ groups may form a ring with the carbon atoms to which they are attached the ring being 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 containing 1 , 2 or 3 heteroatoms; and m is 0 or 1 ;

with the proviso that when L is selected from either a substituted or unsubstituted C1-3 alkylene chain, then R¹ is selected from substituted or unsubstituted: aryl or heteroaryl, preferably substituted or unsubstituted heteroaryl (and optionally R¹ is selected from substituted or unsubstituted: pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl; preferably substituted or unsubstituted pyrazolyl).

[0035] In an embodiment the compound of formula (I) is a compound according to formula (III): wherein R⁴ is selected from halo, C1-6 alkyl, C1-6 haloalkyl, -OR^a, -CR^cR^dOR^a, C2-6 alkenyl, C2-6 alkynyl, C₃-₈ cycloalkyl, C₃-₈ cycloalkenyl, -NR^aR^b, -CN, -C(0)R^a, -C(0)OR^a and -C(0)NR^aR , and two adjacent R⁴ groups may form a ring with the carbon atoms to which they are attached the ring being 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 containing 1 , 2 or 3 heteroatoms; R¹ is selected from substituted or unsubstituted: aryl or heteroaryl, preferably substituted or unsubstituted heteroaryl (and optionally R¹ is selected from substituted or unsubstituted: pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl; preferably substituted or unsubstituted pyrazolyl); and

m is 0 or 1 .

[0036] Preferably, the R⁴ groups of compounds of formula (III) are both C1-6 alkyl or both form a ring with the atom to which the R⁴ groups are attached forming a fused bicyclic ring system of 8 to 12 atoms, (preferably 9 or 10 atoms) wherein the ring formed by the two R⁴ groups is a saturated or unsaturated carbocyclic ring with 4, 5, 6, 7 or 8 carbon atoms (preferably 5 or 6 atoms) or a saturated or unsaturated heterocyclic ring with 4, 5, 6, 7 or 8 atoms (preferably 5 or 6 atoms) containing 1 , 2 or 3 heteroatoms (e.g. 1 or 2 heteroatoms). Preferably, the heteroatom may be nitrogen.

[0037] In an embodiment the compound of formula (I) is a compound according to formula (IV) :

(IV)

[0038] In embodiments R⁴ is selected from: Ci-e alkyl, Ci-e haloalkyl, -CR^cR^dOR^a, C₃-₈ cycloalkyl, C₃-8 cycloalkenyl, -NR^aR^b, -CN, -C(0)R^a, -C(0)OR^a and -C(0)NR^aR^b, and two adjacent R⁴ groups may form a ring with the atom to which the R⁴ groups are attached forming a fused bicyclic ring system of 8 to 12 atoms, wherein the ring formed by the two R⁴ 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 containing 1 , 2 or 3 heteroatoms (e.g. 1 or 2 heteroatoms).

[0039] In embodiments two adjacent R⁴ groups are both C1-6 alkyl or both form a ring with the atom to which the R⁴ groups are attached forming a fused bicyclic ring system of 8 to 12 atoms, wherein the ring formed by the two R⁴ 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 containing 1 , 2 or 3 heteroatoms (e.g. 1 or 2 heteroatoms).

[0040] In embodiments two adjacent R⁴ groups are both methyl or both form a ring with the atom to which the R⁴ groups are attached forming a fused bicyclic ring system of 9 or 10 atoms, wherein the ring formed by the two R⁴ groups is a saturated or unsaturated carbocyclic ring with 5 or 6 carbon atoms or a saturated or unsaturated heterocyclic ring with 6 atoms containing 1 or 2 heteroatoms.

In embodiments is selected from:

In an embodiment is selected from :

A¹zA²

[0044] In an embodiment A⁴ A H^" is

[0045] In an embodiment the compound of formula (I) is a compound according to formula (Va), formula (Vb) or formula (Vc): R^cR^d)_m— het— LR² b)

(Vc) [0046] In addition the compound of formula (I) may be a compound according to formula (Vd):

[0047] In an embodiment the compound of formula (I) is a compound according to formula (Via), formula (Vlb) or formula (Vic):

(Vic)

[0048] In addition the compound of formula (I) may be a compound according to formula (VId):

[0049] In embodiments L is selected from a substituted or unsubstituted saturated C1-3 alkylene chain which may also contain where chemically possible 1 N, O or S atoms in the chain which are independently chosen at each occurrence, or L is selected from a bond, -C(O)-, -C(NR^a)-, -C(0)0-, -C(0)NR^a-, C(NR^a)NR^a- and -SO2-.

[0050] There are provided compounds where L is selected from a bond, -C(O)-, -C(NR^a)-, - C(0)0-, -C(0)NR^a-, -C(NR^a)NR^a-, and -SO2-.

[0051] In embodiments L is selected from a bond, -CR^cR^d-, -CR^cR^dCR^cR^d-, -C(O)-, -C(0)NR^a- and -SO2-. Optionally, R^c and R^d are independently selected at each occurrence from H and C1-4 alkyl and R³ is selected from H and C1-4 alkyl. In an alternative embodiment L is selected from a bond, -C(O)-, -C(0)NR^a- and -SO2-. [0052] In embodiments L is selected from a bond, -CH₂-, -CH2CH2-, -CH(CH₃)-, -C(NH)-, -C(0)NH-, -C(0)N(CH₃)- and -SO2-. In an embodiment L is -CH₂- or -C(0)NH-. In an alternative embodiment, L is selected from a bond, -C(O)-, -C(NH)-, -C(0)NH-, -C(0)N(CH₃)- and -SO2-.

[0053] In an embodiment R¹ is selected from unsubstituted heterocycloalkyi, unsubstituted heterocycloalkenyl, and the following substituted or unsubstituted groups: -O-heterocycloalkyl, -NR^a-heterocycloalkyl, -CR^cR^d-heterocycloalkyl, -O-heterocycloalkenyl , -NR^a-heterocycloalkenyl , -CR^cR^d-heterocycloalkenyl , aryl, -O-aryl, -NR^a-aryl, -CR^cR^d-aryl, heteroaryl, -O-heteroaryl ,

-NR^a-heteroaryl , and -CR^cR^d-heteroaryl. Optionally, heterocycloalkyi is C3-14 heterocycloalkyi (e.g. C3-8 heterocycloalkyi or C5-7 heterocycloalkyi), heterocycloalkenyl is C3-14 heterocycloalkenyl (e.g. C3-8 heterocycloalkenyl or C5-7 heterocycloalkenyl), aryl is Ce-14 aryl (e.g. Ce-ιο aryl or Ce aryl) and heteroaryl is C5-14 heteroaryl (e.g. C5-10 heteroaryl or C5-6 heteroaryl).

[0054] In certain embodiments R¹ is not heterocycloalkyi or heterocycloalkenyl .

[0055] In an embodiment R¹ is selected from substituted or unsubstituted: -O-heterocycloalkyl, -NR^a-heterocycloalkyl, -CR^cR^d-heterocycloalkyl, -O-heterocycloalkenyl , -NR^a-heterocycloalkenyl , -CR^cR^d-heterocycloalkenyl , aryl, -O-aryl, -NR^a-aryl, -CR^cR^d-aryl, heteroaryl, -O-heteroaryl ,

-NR^a-heteroaryl , and -CR^cR^d-heteroaryl.

[0056] In an embodiment the heterocycloalkyi group and the heterocycloalkenyl group of R¹ is not a group where the only heteroatoms are 1 or 2 nitrogen atoms. For example, in this embodiment the heterocycloalkyi group and the heterocycloalkenyl group of R¹ still encompass groups where both N and O heteroatoms are present but not groups where only N is present. In an embodiment the heterocycloalkyi group of R¹ is not piperidine, piperazine, piperidinone, or piperazinone. In an embodiment the heterocycloalkenyl group of R¹ is not tetrahydropyridine.

[0057] In embodiments R¹ is selected from unsubstituted heterocycloalkyi, unsubstituted heterocycloalkenyl and substituted or unsubstituted: -O-heterocycloalkyl, -NR^a-heterocycloalkyl, -CR^cR^d-heterocycloalkyl, -O-heterocycloalkenyl, -NR^a-heterocycloalkenyl ,

-CR^cR^d-heterocycloalkenyl , aryl, -O-aryl, -NR^a-aryl, -CR^cR^d-aryl, heteroaryl, -O-heteroaryl ,

-NR^a-heteroaryl , and -CR^cR^d-heteroaryl. Optionally, heterocycloalkyi is C3-14 heterocycloalkyi (e.g. C3-8 heterocycloalkyi or C5-7 heterocycloalkyi), heterocycloalkenyl is C3-14 heterocycloalkenyl (e.g. C3-8 heterocycloalkenyl or C5-7 heterocycloalkenyl), aryl is Ce-14 aryl (e.g. Ce-ιο aryl or C6 aryl) and heteroaryl is C5-14 heteroaryl (e.g. C5-10 heteroaryl or C5-6 heteroaryl).

[0058] In embodiments R¹ is selected from substituted or unsubstituted : heteroaryl,

-O-heteroaryl , -NR^a-heteroaryl, and -CR^cR^d-heteroaryl . Optionally, heteroaryl is C5-14 heteroaryl (e.g. C5-10 heteroaryl or C5-6 heteroaryl). Optionally heteroaryl is selected from : pyrrolyl , imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl , tetrazolyl, thiazolyl, isothiazolyl, furanyl , pyridinyl , pyridazinyl , pyrazinyl and pyrimidinyl .

[0059] In an embodiment R¹ is substituted or unsubstituted heteroaryl . Preferably, R¹ is substituted or unsubstituted C5-14 heteroaryl (e.g. C5-10 heteroaryl or C5-6 heteroaryl). Optionally, the heteroatom is nitrogen. [0060] In an embodiment R¹ is selected from substituted or unsubstituted: pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl. In an embodiment the substituted or unsubstituted C5-6 heteroaryl of R¹ may be substituted or unsubstituted: pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl or tetrazolyl. Preferably, R¹ is substituted or unsubstituted pyrimidinyl, pyrazolyl, isoxazolyl and triazolyl. Preferably, R¹ is substituted or unsubstituted pyrazolyl.

[0061 ] R¹ may be selected from :

[0062] In an embodiment R¹ is:

[0063] In an embodiment A¹ , A², A³, A⁴ and R¹ are each as defined above with the exception that

, R¹ is substituted or unsubstituted aryl or heteroaryl. Preferably, R¹ is substituted or unsubstituted C5-14 heteroaryl (e.g. C5-10 heteroaryl or C5-6 heteroaryl). Optionally, the heteroatom is nitrogen. Heteroaryl may be selected from substituted or unsubstituted: pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl. Heteroaryl may be substituted or unsubstituted: pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl or tetrazolyl. Preferably, heteroaryl may be substituted or unsubstituted pyrimidinyl, pyrazolyl, isoxazolyl and triazolyl. Preferably, heteroaryl may be substituted or unsubstituted pyrazolyl.

[0064] In an embodiment A¹ , A², A³, A⁴ and R¹ are each as defined above with the exception that

, R¹ is substituted or unsubstituted pyrazolyl. [0065] In an embodiment R² is represented by -CR⁵R⁶R⁷, wherein R⁵, R⁶ and R⁷ are

independently selected at each occurrence from H and substituted or unsubstituted: C1-14 alkyl, C1-14 haloalkyi, carbocyclic, and heterocyclic. The carbocyclic and heterocyclic moieties may be monocyclic or fused polycyclic ring systems, for example bicyclic fused ring systems. Optionally, carbocyclic may be cycloalkyl and aryl and heterocyclic may be heterocycloalkyl and heteroaryl. Further optionally carbocyclic may be C3-14 cycloalkyl (e.g. C3-8 cycloalkyl or C5-7 cycloalkyl) and Ce- 14 aryl (e.g. Ce-ι ο aryl or Ce aryl) and heterocyclic may be C3-14 heterocycloalkyl (e.g. C3-8 heterocycloalkyl or C5-7 heterocycloalkyl) and C5-14 heteroaryl (e.g. C5-10 heteroaryl or C5-6 heteroaryl) .

[0066] In an embodiment R² is represented by -CR⁵R⁶R⁷, wherein R⁵, R⁶ and R⁷ are

independently selected at each occurrence from H and substituted or unsubstituted: C1-14 alkyl (optionally C1-6 alkyl) , C1-14 haloalkyi (optionally C1-6 haloalkyi), cyclobutyl, cyclopentyl , cyclohexyl, cycloheptyl, oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, phenyl, toluenyl , pyridinyl, pyridazinyl , pyrimidinyl , pyrazinyl, pyrrolyl, pyrazolyl, triazolyl , tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, and isothiazolyl .

[0067] In an embodiment two of R⁵, R⁶ and R⁷ are the same and the third is selected

independently. In an alternative embodiment R⁵, R⁶ and R⁷ are all the same.

[0068] In an embodiment R⁵, R⁶ and R⁷ are all one of the groups selected from : methyl, trifluoromethyl, cyclohexanyl and phenyl.

[0069] In an embodiment R² is selected from substituted or unsubstituted: C1-14 alkyl, C1-14 haloalkyi, carbocyclic, and heterocyclic. In a preferred embodiment R² is selected from substituted or unsubstituted: carbocyclic, and heterocyclic. The carbocyclic and heterocyclic moieties may be monocyclic or fused polycyclic ring systems, for example bicyclic fused ring systems. Optionally, carbocyclic may be cycloalkyl and aryl and heterocyclic may be heterocycloalkyl and heteroaryl. Further optionally carbocyclic may be C3-14 cycloalkyl (e.g. C3-8 cycloalkyl or C5-7 cycloalkyl) and Ce- 14 aryl (e.g. Ce-ι ο aryl or Ce aryl) and heterocyclic may be C3-14 heterocycloalkyl (e.g. C3-8 heterocycloalkyl or C5-7 heterocycloalkyl) and C5-14 heteroaryl (e.g. C5-10 heteroaryl or C5-6 heteroaryl) .

[0070] In an embodiment R² is selected from substituted or unsubstituted: C1-14 alkyl (optionally C1-6 alkyl), C1-14 haloalkyi (optionally C1-6 haloalkyi), cyclobutyl, cyclopentyl , cyclohexyl, cycloheptyl, oxirane, aziridine, azetidine, oxetane, tetrahydrofuran , pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, phenyl, toluenyl, pyridinyl , pyridazinyl , pyrimidinyl , pyrazinyl, pyrrolyl , pyrazolyl , triazolyl, tetrazolyl, oxazolyl , isoxazolyl , oxadiazolyl, thiazolyl, and isothiazolyl. [0071 ] In an embodiment R² may be selected from substituted or unsubstituted: phenyl, toluenyl, pyridinyl , pyridazinyl , pyrimidinyl , pyrazinyl, pyrrolyl, pyrazolyl, triazolyl , tetrazolyl , oxazolyl, isoxazolyl, oxadiazolyl , thiazolyl , and isothiazolyl . Preferably, R² is substituted or unsubstituted phenyl, toluenyl or pyridinyl .

[0072] In an embodiment R² may be selected from substituted or unsubstituted: ferf-butyl, isopropyl, cyclopentyl, phenyl, toluenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, triazolyl , tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, and isothiazolyl. Preferably, R² may be selected from substituted or unsubstituted: phenyl , toluenyl, pyridinyl, pyridazinyl , oxazolyl, ferf-butyl, isopropyl, and cyclopentyl .

[0073] In embodiments where R² is substituted, R² may be substituted by 1 to 5 substituents, optionally 1 , 2 or 3 substituents, independently selected at each occurrence from the group comprising halo, -OR^a, -NO2, C1-6 alkyl, C1-6 haloalkyl, -C(OR^a)R^aR^b, -SC1-4 alkyl, -C(0)R_aRb, -N(CO)R_a, and -CN . In embodiments where R² is a cyclic group, for example a cycloalkyl, heterocycloalkyi, aryl or heteroaryl group, the group may be substituted at the ortho position, meta position, para position or a combination of these positions. In embodiments where R² is a cyclic group the ring may be ortho substituted. In embodiments where R² is a cyclic group the ring may be meta substituted. In embodiments where R² is a cyclic group the ring may be para substituted. In embodiments where R² is a cyclic group the ring may be ortho and para substituted. In

embodiments where R² is a cyclic group the ring may be di-meta substituted.

[0074] In embodiments where R² is substituted, R² may be substituted by 1 or 2 substituents independently selected at each occurrence from the group comprising halo, -NO2, -OC1-4 haloalkyl , C1-6 alkyl, C1-6 haloalkyl, -C(OH)( C1-6 alkyl)Ci-e alkyl, -SC1-4 alkyl and -CN. For example, the substituents may be selected from fluoro, chloro, -NO2, -OCF3, -OCF2H, -OMe, -OEt, -SMe, -SEt, methyl, ethyl , trifluoromethyl, -C(OH)(CH₃)CH₃, -C(OH)(CH₃)CH2CH₃ and -CN.

[0075] In an embodiment R² is substituted by trifluoromethyl. In an alternative embodiment R² is substituted by -OCF₃. In an embodiment R² is substituted by -C(OH)(CH₃)CH₃. In an embodiment R² is substituted by methyl. In an embodiment R² is substituted by fluoro. In an embodiment R² is substituted by chloro. In an embodiment R² is substituted by -CN. In an embodiment R² is substituted by fluoro and trifluoromethyl. In an embodiment R² is substituted by fluoro and -OCF₃. In an embodiment R² is substituted by fluoro and methyl.

[0076] R² may be represented by:

[0077] R² may be represented by:



[0081] R³ may be selected from : H, substituted or unsubstituted Ci-4 alkyl, Ci-4 haloalkyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic.

[0082] R³ may be selected from : substituted or unsubstituted C1-4 alkyl, C1-4 haloalkyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic.

[0083] In an embodiment R³ is H, substituted or unsubstituted C1-4 alkyl or substituted or unsubstituted C1-4 haloalkyl. Preferably, R³ is H methyl, ethyl or -C(0)CF₃.

[0084] In an embodiment R³ is substituted or unsubstituted C1-4 alkyl or substituted or unsubstituted C1-4 haloalkyl. Preferably, R³ is methyl, ethyl or -C(0)CF₃.

[0085] In an embodiment R³ and L are as described herein except that when R³ is H, L is selected from a bond, -C(O)-, -C(NR^a)-, -C(0)0-, -C(0)NR^a-, -C(NR^a)NR^a-, and -SO2-. Thus, when R³ is H, L is not selected from either a substituted or unsubstituted C1-3 alkylene chain which is saturated or unsaturated and which may also optionally contain, where chemically possible, 1 N, O, or S atoms in the chain which are independently chosen at each occurrence. In particular, when R³ is H, L is not an unsubstituted C1-3 alkylene chain which is saturated or unsaturated.

[0086] In an embodiment all occurrences of R^a and R^b are hydrogen.

[0087] In an embodiment all occurrences of R^c and R^d are hydrogen.

[0088] In an embodiment m is 0 or 1 . Preferably, m is 0.

[0089] In embodiments the compound of formula (I) is a compound according to formula (VII):

(VII}

[0090] In embodiments the compound of formula (I) is a compound according to formula (VIII):

(Vitl)

[0091] In embodiments, the compound of formula (I) is a compound according to formula (IXa), (IXb) or formula (IXc):

(IXc)

[0092] In addition the compound of formula (I) may be a compound according to formula (IXd):

[0093] In an embodiment, the compound of formula (I) is a compound according to formula (X):

(X)

[0094] In an embodiment, the compound of formula (I) is a compound according to formula

(XI)

[0095] In an embodiment, the compound of formula (I) is a compound according to formula (Xlla), formula (Xllb) or formula (Xllc):

[0096] In addition the compound of formula (I) may be a compound according to formula (Xlld):

(Xlld)

[0097] In certain embodiments of the compound according to formula (I):

"het" is selected from substituted or unsubstituted: pyrolidinylene, piperidinylene and azepanylene;

wherein two adjacent R⁴ groups are both C1-6 alkyl or both form a ring with the atom to which the R⁴ groups are attached forming a fused bicyclic ring system of 8 to 12 atoms (preferably 9 or 10 atoms), wherein the ring formed by the two R⁴ groups is a saturated or unsaturated carbocyclic ring with 4, 5, 6, 7 or 8 carbon atoms (preferably 5 to 6 carbon atoms) or a saturated or unsaturated heterocyclic ring with 4, 5, 6, 7 or 8 atoms (preferably 6 atoms) containing 1 , 2 or 3 heteroatoms (e.g. 1 or 2 heteroatoms);

L is an unsubstituted C1-3 alkylene chain which is saturated or unsaturated;

or L is selected from a bond, -C(O)-, -C(NR^a)-, -C(0)0-, -C(0)NR^a-, -C(NR^a)NR^a-, and -SO2-, with the proviso that when

, L is selected from a bond, -

C(O)-, -C(NR^a)-, -C(0)0-, -C(0)NR^a-, -C(NR^a)NR^a-, and -SO2-

R¹ is selected from substituted or unsubstituted: aryl and heteroaryl;

R² is selected from substituted or unsubstituted: carbocyclic and heterocyclic;

R³ is selected from H, substituted or unsubstituted C1-4 alkyl and C1-4 haloalkyl;

m is 0 or 1 ; and

-C(0)NR^aR^b.

[0098] In certain embodiments of the compound according to formula (I):

wherein R⁴ is selected from halo, C1-6 alkyl, C1-6 haloalkyl, -OR^a, -CR^cR^dOR^a, C2-6 alkenyl, C2-6 alkynyl, C₃-₈ cycloalkyl, C₃-₈ cycloalkenyl, -NR^aR , -CN, -C(0)R^a, -C(0)OR^a and -C(0)NR^aR , and two adjacent R⁴ groups may form a ring with the carbon atom to which they are attached forming a fused bicyclic ring system of 8 to 12 atoms, wherein the ring formed by the two R⁴ 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 containing 1 , 2 or 3 heteroatoms, optionally two adjacent R⁴ groups are both C1-6 alkyl or both form a ring with the atom to which the R⁴ groups are attached forming a fused bicyclic ring system of 8 to 12 atoms (preferably 9 or 1 0 atoms), wherein the ring formed by the two R⁴ groups is a saturated or unsaturated carbocyclic ring with 4, 5, 6, 7 or 8 carbon atoms (preferably 5 to 6 carbon atoms) or a saturated or unsaturated heterocyclic ring with 4, 5, 6, 7 or 8 atoms (preferably 6 atoms) containing 1 , 2 or 3 heteroatoms (e.g. 1 or 2 heteroatoms); L is selected from either a substituted or unsubstituted C1-3 alkylene chain which is saturated or unsaturated and which may also optionally contain, where chemically possible, 1 N, O, or S atoms in the chain which are independently chosen at each occurrence;

R¹ is selected from substituted or unsubstituted pyrazolyl ;

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 comprising: halo, -OR^a, - SR^a, -NR^aR^b, NO2, =0, -CN, acyl, C1-6 alkyl, C1-6 haloalkyl, C₃-₈ cycloalkyl, -S0₂R^a, and S0₃R^a , -C(OR^a)R^aR^b, -C(0)R^a, -C(0)OR^a and -C(0)NR^aR^b.

[0099] Compounds of formula (I) include:





[00100] Compounds also contemplated by the invention that are particularly preferred are: 

[00102] Compounds also contemplated by the invention that are preferred are:

30

[00103] In another aspect of the invention there is provided a compound of the invention for use as a medicament. [00104] In another aspect, a compound of the invention is for use in a method of treatment of a condition which is modulated by the Hedgehog signalling pathway. Usually conditions that are modulated by the Hedgehog signalling pathway are conditions that would be treated by the inhibition of the Hedgehog signalling pathway using a compound of the present invention. A compound of the invention may be for use in the treatment of a condition treatable by the inhibition of the Hedgehog signalling pathway.

[00105] In addition the compounds of the present invention are for use in a method of treatment of a condition which is modulated by Smoothened (Smo), a receptor in the Hedgehog signalling pathway. Therefore, in a related aspect a compound of formula (I) is for use in the treatment of a condition which is modulated by Smo. Usually conditions that are modulated by Smo are conditions that would be treated by the inhibition of Smo using a compound of the present invention. A compound of the invention may be for use in the treatment of a condition treatable by the inhibition of Smo.

[00106] Inhibition of the Hedgehog signalling pathway and Smo is a novel approach for treating many different human diseases associated with the inappropriate activation of the Hedgehog signalling pathway and aberrant activation of Smo, including various cancers, for example, solid tumours. In embodiments the condition treatable by the inhibition of the Hedgehog signalling pathway or Smo 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.

[00107] In embodiments the preferred condition 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, brain cancer, esophagus cancer, breast cancer, ovarian cancer, stomach cancer, colorectal cancer, liver cancer, kidney cancer, head and neck cancer, soft tissue sarcomas, bone sarcomas, testicular cancer, prostate cancer, pancreatic cancer, bone cancer, bone metastasis, acute leukemia, glioma, bladder cancer, parathyroid gland cancer, thyroid gland cancer, cervical cancer, ovarian cancer, skin cancer, renal cell carcinoma, gastric cancer and biliary tract cancer.

[00108] 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. The conditions treatable by the inhibition of the Hedgehog signalling pathway or Smo may be selected from inhibiting stem cell production, inhibiting stem cell renewal and inhibiting and/or modulating stem cell differentiation

[00109] In embodiments, a compound of the invention may be for use in the treatment of: cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia. The compound of the invention may be for use in the treatment of specific conditions 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, 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. [001 10] A compound of the invention may be for use in the treatment of: inhibiting stem cell production, inhibiting stem cell renewal, inhibiting and/or modulating stem cell differentiation, benign prostatic hyperplasia, psoriasis and osteoporosis.

[001 11 ] The compounds of the present invention may be for use in a method of treatment wherein the treatment comprises inhibiting stem cell production, inhibiting stem cell renewal and/or inhibiting and/or modulating stem cell differentiation. In an embodiment the compounds of the present invention may be for use in a method of treatment wherein the treatment comprises inhibiting stem cell renewal and/or stem cell production and the condition being treated is selected from any of the conditions mentioned above.

[001 12] In an aspect of the invention there is provided a method of treatment of a condition which is modulated by Hedgehog signalling pathway, wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof.

[001 13] In an embodiment of the invention there is provided a method of treatment of a condition which is modulated by Smo, wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof.

[001 14] The method of treatment may be a method of treating a condition treatable by the inhibition of the Hedgehog signalling pathway. Furthermore, the method of treatment may be a method of treating a condition treatable by the inhibition of Smo.

[001 15] The invention also provides a method of treating a condition selected from: cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia, wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof. The invention also provides a method of treating a specific condition 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, 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, wherein the method comprises administering a therapeutic amount of a compound of formula (I), to a patient in need thereof.

[001 16] The invention also provides a method of treating a condition selected from: inhibiting stem cell production, inhibiting stem cell renewal, inhibiting and/or modulating stem cell differentiation, benign prostatic hyperplasia, psoriasis and osteoporosis wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof. [001 17] In an aspect of the invention there is provided a method of inhibiting stem cell renewal and/or stem cell production, wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof.

[001 18] In another aspect of the invention there is provided a pharmaceutical composition, wherein the composition comprises a compound of the invention and pharmaceutically acceptable excipients. The pharmaceutical composition may be used in the treatment of the diseases mentioned above. The method of treatment mentioned above may comprise administering a pharmaceutical composition of the invention instead of the compound of the invention.

[00119] In an embodiment the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent. The additional pharmaceutically active agent may be an anti-tumor agent, as described below.

[00120] In an aspect of the invention there is provided a method of treatment of a condition selected from cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia comprising administering a therapeutically effective amount of a compound of the invention, or a

pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-tumour agent to a patient in need thereof.

[00121 ] In an aspect there is provided the use of a compound of formula (I) in the manufacture of a medicament for use in the treatment of a condition modulated by the Hedgehog pathway, for example a condition selected from cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia. Optionally, the condition to be treated can be selected from any of those conditions mentioned above.

[00122] The embodiments described above may be applied individually, or in any combination of one another, and independently, to the compounds of the invention.

DETAILED DESCRIPTION

[00123] 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.

[00124] 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.

[00125] The term "C1-6 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, "C1-4 alkyl" refers to a linear or branched hydrocarbon chain containing

1 , 2, 3 or 4 carbon atoms, "C1-3 alkyl" refers to a linear or branched hydrocarbon chain containing 1 , 2 or 3 carbon atoms and "C1-14 alkyl" refers to a linear or branched hydrocarbon chain containing 1 ,

2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 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. Substiuents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C1-6 alkoxy. [00126] The term "C1-6 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, Ci-6 alkoxy.

[00127] The term "C1-6 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, "C1-4 haloalkyl" refers to a linear or branched hydrocarbon chain containing 1 ,

2, 3 or 4 carbon atoms and "C1-14 haloalkyl" refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5, 6, 7, 8, 9, 1 0, 1 1 , 12, 13 or 14 carbon atoms. The halogen atom may be present at any position on the hydrocarbon chain. For example, C1-6 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.

[00128] The term "C2-6 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 "C2-6 alkenyl" may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[00129] The term "C2-6 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 "C2-6 alkynyl" may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[00130] The term "C1-6 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 C1-6 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom. For example, the "C1-6 heteroalkyl" may be C1-6 /V-alkyl, C1-6 Λ ,/V-alkyl, or C1-6 O-alkyl.

[00131 ] 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 cycloalkyi moieties, cycloalkenyl moieties, aryl ring systems and fused ring systems including an aromatic portion. "Carbocyclic" may be C3-8 cycloalkyi or Ce-ιο aryl.

[00132] 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 C3-8 heterocycloalkyl, C5-6 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.

[00133] The term "C3-14 cycloalkyi" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 carbon atoms. Similarly,"C3-8 cycloalkyi" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and "C5-7 cycloalkyi" refers to a saturated hydrocarbon ring system containing 5, 6 or 7 carbon atoms. For example, the "C3-8 cycloalkyi" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "C3-7 halocycloalkyl" is a "cycloalkyi" ring having at least one halogen substituted thereon, independently selected at each occurrence. For example, the halogen may be fluorine, chlorine, bromine or iodine.

[00134] The term "C3-8 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 "C3-8 cycloalkyi" may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[00135] The term "C3-14 heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 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. Similarly,"C3-8 heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and "C5-7 heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 5, 6 or 7 carbon atoms. The "C3-8 heterocycloalkyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "C3-8 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 "C3-8 heterocycloalkyl" may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran. [00136] The term "C3-14 heterocycloalkyl" refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 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. Similarly,"C3-8 heterocycloalkyl" refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and "C5-7 heterocycloalkyl" refers to an unsaturated hydrocarbon ring system containing 5, 6 or 7 carbon atoms. The "C3-8 heterocycloalkenyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "C3-8 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 "C3-8 heterocycloalkyl" may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.

[00137] 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. The aryl group may be Ce-14 aryl, optionally Ce-ι ο aryl or Ce aryl, wherein a Ce-14 aryl is a ring system with 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 ring carbons within a single ring or within a fused ring system. For example, the "aryl" may be phenyl and napthyl. The aryl system itself may be substituted with other groups.

[00138] 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 heteroaryl group may be C5-14 heteroaryl, optionally C5-10 heteroaryl or C5-6 heteroaryl, wherein a C5- 14 heteroaryl is a ring system with 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms with at least one heteroatom within a single ring or within a fused ring system, selected from O, N and S, for example there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2. 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.

[00139] The term "alkaryl" refers to an aryl group, as defined above, bonded to a C1-4 alkyl, where the C1-4 alkyl group provides attachment to the remainder of the molecule.

[00140] The term "alkheteroaryl" refers to a heteroaryl group, as defined above, bonded to a C1-4 alkyl, where the alkyl group provides attachment to the remainder of the molecule. [00141 ] The term "halogen" herein includes reference to F, CI, Br and I. Halogen may be CI. Halogen may be F.

[00142] A bond terminating in a " " represents that the bond is connected to another atom that is not shown. 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. [00143] Throughout the specification A¹ , A², A³ and A⁴ 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 A¹ , A², A³ and A⁴ may be referred to as the "A ring".

[00144] 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 substitutuents, 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^a, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(0)H, acyl, acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, nitro, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl or alkaryl. Where the group to be substituted is an alkyl group the substituent may be =0. Where the moiety is substituted with two or more substituents and two of the substituents are adjacent the adjacent substituents may form a C4-8 ring along with the atoms of the moiety on which the substituents are substituted, wherein the C4-8 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.

[00145] 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. [00146] Ortho, meta and para substitution are well understood terms in the art. For the absence of doubt, "ortho" substitution is substitiution 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:

[00147] "Meta" substitution is substitiution 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:

[00148] "Para" substitution is substitiution 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:

[00149] 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 R-C(O)-, where R may be selected from H, Ci-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C1-3 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.

[00150] The invention contemplates pharmaceutically acceptable salts of the compounds of formula (I). These may include the acid addition and base salts of the compounds.

[00151 ] 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/di hydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

[00152] 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).

[00153] Preferably the salt is an acid addition salt. The salts may be formate or hydrochloride.

[00154] 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.

[00155] 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. [00156] 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. [00157] 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).

[00158] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[00159] 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.

[00160] 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.

[00161 ] 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. Wiley- Interscience Publication, 1 981 ) 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.

[00162] 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.

[00163] 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. Optionally, the additional active agent may be an anti-tumour agent selected from the list below.

[00164] 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:-

(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 5a-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-/V-(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 (AMN1 07); 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-1 R 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-1 1248, 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-1 a, 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-1 1248, 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, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, tazarotne, TLK-286, Velcade, Tarceva, tretinoin.

[00165] 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 may employ the compounds of this invention within a therapeutically effective dosage range and the other pharmaceutically-active agent within its approved dosage range.

[00166] 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.

[00167] 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.

[00168] 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.

[00169] In an embodiment the condition is a condition modulated by Smo.

[00170] 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. The condition may be any condition described in this specification.

[00171 ] 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.

[00172] 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.

[00173] 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. [00174] 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.

EXAMPLES AND SYNTHESIS

[00175] As used herein the following terms have the meanings given : "atm" refers to atmosphere; "Boc" refers to tert-butoxycarbonyl; "BOP" refers to (Benzotriazol-1 - yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; "DCM" refers to dichloromethane; "DIPEA" refers to Ν,Ν-Diisopropylethylamine; "DMF" refers to Ν,Ν-dimethylformamide; "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.

[00176] The compounds of the invention may be synthesised by analogy with the following reaction route.

Stank! coupling reductive

soeyanate urea

[00177] 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.

[00178] 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 254nM and the MS was in positive and negative electrospray mode (m/z: 1 50-800). A 2μΙ_ aliquot was injected onto a guard column (0.2μιτι x 2mm filters) and UPLC column (C18, 50 x 2.1 mm, < 2μιτι) in sequence maintained at 40°C. The samples were eluted at a flow rate of 0.6ml_/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.

Table 1

[00179] NMR was also used to characterise final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay with 5mm BBFO probe. Optionally, compound Rf values on silica thin layer chromatography (TLC) plates were measured.

[00180] 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 20ml_/min on a XBridge™ prep C18 5μΜ OBD 19x100mm 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.

Table 2

[00181 ] Chemical names in this document were generated using mol2nam - Structure to Name Conversion by OpenEye Scientific Software. Starting materials were purchased from commercial sources or synthesised according to literature procedures. [00182] Certain starting materials in the synthesis of compounds of formula (I) can be produced by the following procedures:

[00183] Procedure A

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

Pyridine-3,4-dicarboxylic acid (3.1 Og, 18.6mmol) and acetic anhydride (7.0ml_, 74.2mmol) were 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 concentrated in vacuo to afford crude 3,4-pyridinedicarboxylic anhydride (2.68g, 18.0mmol, 97%) as brown crystals which was taken onto the next step without further purification.

3,4-Pyridinedicarboxylic anhydride (690mg, 4.6mmol) and acetic acid (8.9ml_) were combined. To this was added hydrazine hydrate (1 .6ml_, 18.5mmol) 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 concentrated in vacuo to afford pyrido[3,4-d]pyridazine-1 ,4-diol (600mg, 3.7mmol, 80%)

¹ H NMR (400MHz, d6 DMSO) δ /ppm : 1 1 .9 (s(br), 2H), 9.34 (s(br),1 H), 9.03 (d, J 5.3Hz, 1 H), 7.90 (s(br),1 H)

MS Method 2: RT: 0.54min, ES⁺ m/z 164.0 [M+H]⁺

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

Pyrido[3,4-d]pyridazine-1 ,4-diol (1 .83g, 1 1 .2mmol) and phosphorus oxychloride (8.4ml_, 89.7mmol) were added to a round bottomed flask. To this was added DIPEA (2.0ml_, 1 1 .2mmol) slowly. The suspension was then heated for 1 hour at 1 00°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 NaHCCb solution (aq). Saturated NaHCCb 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 (500ml_). The organic layers were combined and dried (MgSCH) and then concentrated in vacuo to afford 1 ,4- dichloropyrido[3,4-d]pyridazine (1 .74g, 8.7mmol, 78%).

1 H NMR (400MHz, CDC ) δ/ppm : 9.78 (d, J 0.9Hz, 1 H), 9.27 (d, J 5.7Hz, 1 H), 8.09 (dd, J 5.7Hz, 0.9Hz, 1 H).

MS Method 2: RT: 1 .1 6min, ES⁺ m/z 209.0 [M+H]⁺ Similarly prepared were:

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

¹ H NMR (400MHz, CDCb) δ/ppm : 3.13 (t, J 7.8Hz, 2H), 2.27 (m, J 7.8Hz, 4H).

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

Gl— & V- Ql

¹ H NMR (400MHz, CDCb) δ/ppm : 2.46 (s, 6H).

[00184] Procedure B

Preparation of N-Methyl-1-(2-methylpyrazol-3-yl)-N-(4-piperidyl)-6,7-dihydro-5H- cyclopenta[d]pyridazin-4-amine and related compounds, intermediates in the synthesis of compounds of formula (I).

tert-Butyl 4-[(4-chloro-6J-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-methyl-amino]piperidine- 1-carboxylate

1 ,4-Dichloro-6,7-dihydro-5/-/-cyclopenta[d]pyridazine (2.0g, 10.6mmol) and N-Boc-4- methylaminopiperidine (2.3ml_, 10.6mmol) were placed in a microwave vial which was sealed and purged with nitrogen. Triethylamine (1 .8ml_, 12.7mmol) and anhydrous NMP (14ml_) were then added and the mixture heated using microwave irradiation at 200°C for 4 hours. The reaction mixture was diluted with EtOAc (200ml_) and water (1 OOmL) and the two phases were separated. The aqueous phase was extracted with EtOAc and the organic layers combined and washed with water (6 x 1 0OmL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica flash column chromatography eluting with 0% ethyl acetate in heptane with a gradient to 80% ethyl acetate to afford 970mg of recovered starting material and the desired product ferf-butyl 4-[(4-chloro-6,7-dihydro-5 -/-cyclopenta[d]pyridazin-1 -yl)-methyl-amino]piperidine- 1 -carboxylate (441 mg, 1 .2mmol, 1 1 %) ¹ H NMR (400MHz, CDC ) δ/ppm : 4.34-4.17 (m, 3H), 3.1 1 (t, J 7.5Hz, 2H), 2.98 (s, 3H), 2.95 (t, J 7.5Hz, 2H), 2.87-2.74 (m, 2H), 2.18-2.1 1 (m, 2H), 1 .83-1 .69 (m, 4H), 1 .49 (s, 9H).

MS Method 2: RT: 1 .78min, ES⁺ m/z 367.2 [M+H]⁺

tert-Butyl 4-[methyl-[1-(2-methylpyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-4- yl]amino]piperidine-1-carboxylate

tert-Butyl 4-[(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-1 -yl)-methyl-amino]piperidine-1 - carboxylate (627.8mg, 1 .71 mmol), 1 -methyl-1 H-pyrazole-5-boronic acid, pinacol ester (0.71 g, 3.42mmol) and potassium carbonate (0.47g, 3.42mmol) were combined in toluene (9ml_), ethanol (3ml_) and water (3ml_) and the mixture was degassed. Palladium (0) tetrakis(triphenylphosphine) (0.1 g, 0.090mmol) was quickly added and the vial capped and heated using microwave irradiation at 120°C for 1 hour. LCMS analysis showed the reaction had not gone to completion. Further 1 - methyl-1 H-pyrazole-5-boronic acid, pinacol ester (0.36g, 1 .7mmol), potassium carbonate (0.24g, 1 .7mmol) and palladium (0) tetrakis(triphenylphosphine) (0.1 g, 0.09mmol) were added and the reaction heated using microwave irradiation at 120°C for 1 hour. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water (x3), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica flash column chromatography eluting with 20% ethyl acetate in heptane with a gradient to 100% ethyl acetate to afford tert-butyl 4-[methyl-[1 -(2-methylpyrazol-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyridazin-4-yl]amino]piperidine-1 -carboxylate (545mg,1 .32mmol, 77% yield) as a yellow orange oil which was used immediately in the next step.

MS Method 2: RT: 1 .45min, ES⁺ m/z 413.3 [M+H]⁺

N-methyl-1-(2-methylpyrazol-3-yl)-N-(4-piperidyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-4- amine

A solution containing ferf-butyl 4-[methyl-[1 -(2-methylpyrazol-3-yl)-6,7-dihydro-5 -/- cyclopenta[d]pyridazin-4-yl]amino]piperidine-1 -carboxylate (544.6mg, 1 .32mmol) and trifluoroacetic acid (1 .13ml_, 15.8mmol) in DCM (4ml_) was prepared and stirred overnight. The reaction mixture was concentrated in vacuo before being loaded onto an SCX cartridge, washed with methanol and eluted using 2M ammonia in methanol. Concentration in vacuo afforded A -methyl-1 -(2- methylpyrazol-3-yl)-/V-(4-piperidyl)-6,7-dihydro-5 -/-cyclopenta[d]pyridazin-4-amine

(285mg,0.91 mmol, 69% yield) as an oil. ¹ H NMR (400MHz, MeOD) δ/ppm: 7.57 (d, J2.1 Hz, 1 H), 6.55 (d, 2.1 Hz, 1 H), 4.27-4.18 (tt, J1 1 .5Hz, 4.0Hz, 1 H), 4.01 (s, 3H), 3.21 -3.1 6 (m, 4H), 3.10 (s, 3H), 2.96 (t, J7.5Hz, 2H), 2.77-2.70 (td, J12.4HZ, 2.8Hz, 2H), 2.18-2.1 0 (m, J7.5Hz, 2H), 1 .96-1 .91 (dd, J1 1 .9Hz, 4.1 Hz, 1 H), 1 .90-1 .85 (dd, J12.2HZ, 4.1 Hz, 1 H) 1 .85-1 .78 (m, 2H).

MS Method 2: RT: 0.90min, ES⁺ m/z 313.3 [M+H]⁺

Similarly prepared were:

N-Methyl-4-(2-methylpyrazol-3-yl)-N-(4-piperidyl)phthalazin-1 -amine

¹ H NMR (CDCI3, 400 MHz) /ppm: 8.10 (d, J = 7.5 Hz, 1 H), 8.03 (d, J = 7.5 Hz, 1 H), 7.83 (m, 2H), 7.67 (d, J = 2.0 Hz, 1 H), 6.59 (d, J = 2.0 Hz, 1 H), 4.06 (m, 5H), 3.24 (m, 5H), 2.71 (m, 2H), 2.01 (m,

4H).

MS Method 2: RT: 0.93min, ES⁺ m/z 323.3 [M+H]⁺

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

1 H NMR (CDCI3, 400 MHz) /ppm:9.52 (d, J0.8Hz, 1 H), 8.91 (d, J5.7Hz, 1 H), 7.81 (dd, J5.7,0.8Hz, 1 H), 7.68 (d, J2.0Hz, 1 H), 6.59 (d, J2.0Hz, 1 H), 4.45-4.36 (m, 1 H), 4.10 (s, 3H), 3.34 (s, 3H), 3.30- 3.24 (m, 2H), 2.80-2.75 (m, 2H), 2.09-1 .97 (m, 4H).

MS Method 2: RT: 0.93min, ES⁺ m/z 324.3 [M+H]⁺

4,5-dimethyl-6-(2-methylpyrazol-3-yl)-N-(4-piperidyl)pyridazin-3-amine

¹ H NMR (MeOD, 400 MHz) /ppm:7.58 (d, J2.0Hz, 1 H),6.43 (d, J2.0Hz, 1 H), 4.25 (tt, J1 1 .1 Hz, 4.0Hz, 1 H), 3.77 (s, 3H), 3.19-3.13 (m, 2H), 2.79 (td, J12.5, 2.4Hz, 2H), 2.19 (s, 3H), 2.15 (s, 3H), 2.18-2.10 (m, 2H), 1 .60 (qd, J12.1 , 4.0Hz, 2H).

MS Method 2: RT: 0.79min, ES⁺ m/z 287.3 [M+H]

4-(2-methylpyrazol-3-yl)-N-(4-piperidyl)phthalazin-1 -amine

¹ H NMR (CDC , 400 MHz) /ppm: 7.99-7.78 (m, 4H), 7.65 (d, J1 .9Hz, 1 H), 6.54 (d, J1 .9Hz, 1 H), 5.45 (d, J7.3Hz, 1 H), 4.68-4.57 (m, 1 H), 4.01 (s, 3H), 3.32-3.25 (m, 2H), 2.94 (td, J21 .5, 2.3, 2H), 2.40-2.31 (m, 2H), 1 .75-1 .63 (m, 2H).

MS Method 2: RT: 0.81 min, ES⁺ m/z 309.2 [M+H]⁺

[00185] Procedure C

[00186] Preparation of N,4,5-trimethyl-6-(2-methylpyrazol-3-yl)-N-(4-piperidyl)pyridazin-3- amine and related compounds, intermediates in the synthesis of compounds of formula (I)..

N-(1 -benzyl-4-piperidyl)-6-chloro-N,4,5-trimethyl-pyridazin-3-amine

1 -Benzyl-N-methyl-piperidin-4-amine (0.9ml_, 4.1 mmol), 3,6-dichloro-4,5-dimethyl-pyridazine (1 .g, 5.65mmol) and DIPEA (1 .08ml_, 6.21 mmol) were dissolved in NMP (2.5ml_) and heated to 150 °C under microwave irradiation for 10hrs. The resulting solution was partitioned between EtOAc (50ml_) and water (50ml_). The phases were separated and the water re-extracted with EtOAc (50ml_). The combined organics were washed with brine (3 x 50ml_), dried (Na2S04) and concentrated to afford a brown oil. Purification by silica flash chromatography eluting with 20% EtOAc in heptane with a gradient to 80% ethyl acetate afforded Λ/-(1 -benzyl-4-piperidyl)-6-chloro- A ,4,5-trimethyl-pyridazin-3-amine (1 .0g, 2.90mmol, 51 % yield) as a colourless oil which crystalised on standing at room temperature.

MS Method 2: RT: 1 .1 8min, ES⁺ m/z 345.3 [M+H]⁺

¹ H NMR (400MHz, CDCb) δ/ppm : 7.34-7.25 (m, 5H), 3.52 (s, 2H), 3.26-3.18 (tt, J 1 1 .2Hz, 3.9Hz, 1 H), 3.00-2.94 (m, 2H), 2.85 (s, 3H), 2.34 (s, 3H), 2.25 (s, 3H), 2.05-1 .87 (m, 4H), 1 .79-1 .72 (m,

2H).

N-(1 -benzyl-4-piperidyl)-N,4,5-trimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-amine

Λ/-(1 -Benzyl-4-piperidyl)-6-chloro-/V,4,5-trimethyl-pyridazin-3-amine (500mg, 1 .45mmol) and potassium carbonate (401 mg, 2.9mmol) were added to toluene (1 .5ml_), ethanol (1 mL) and water (0.50ml_) and degassed by purging with nitrogen for 1 0min. Palladium (0) tetrakis(triphenylphosphine) (252mg, 0.22mmol) and 1 -methyl-1 H-pyrazole-5-boronic acid, pinacolester (452mg, 2.17mmol) were then added, the vial sealed and heated by microwave irradiation at 150°C for 55 mins. The reaction mixture was poured into EtOAc (25ml_) and water (25ml_) and the phases were separated. The aqueous layer was re-extracted with EtOAc (2x25 mL) and the combined organic layers washed with brine, dried (Na2S04), filtered and concentrated in vacuo lo afford brown semi-solid. The residue was taken up in methanol and purified through a 5g SCX cartridge with methanol washings followed by 0.7M ammonia in methanol solution to elute the product. Concentration in vacuo afforded N-(1 -benzyl-4-piperidyl)-N,4,5-trimethyl-6-(2- methylpyrazol-3-yl)pyridazin-3-amine (500mg,1 .28mmol, 88% yield) as a pale yellow oil which was used immediately in the next step.

MS Method 2: RT: 1 .1 Omin, ES⁺ m/z 391 .3 [M+H]⁺

N,4,5-trimethyl-6-(2-methylpyrazol-3-yl)-N-(4-piperidyl)pyridazin-3-amine

Λ/-(1 -benzyl-4-piperidyl)-/V,4,5-trimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-amine (490. mg, 1 .25mmol) was dissolved in methanol (1 OmL) and hydrogenated over 10% palladium on carbon (20mg, 0.06mmol) under 1 atm hydrogen. The reaction was stirred for 72h at room temperature. The reaction was purged with nitrogen to replace the hydrogen, filtered through celite and concentrated to afford the crude as a brown oil. The residue was taken up in methanol and purified through a 5g SCX cartridge with methanol washings followed by 0.7M ammonia in methanol solution to elute the product. Concentration in vacuo afforded A ,4,5-trimethyl-6-(2-methylpyrazol-3- yl)-/V-(4-piperidyl)pyridazin-3-amine as a pale yellow oil (385mg,1 .28mmol, quantitative)

¹ H NMR (400MHz, CDC ) δ/ppm : 7.58 (d, J1 .9Hz, 1 H), 6.37 (d, J1 .9Hz, 1 H), 3.95 (s, 3H), 3.50- 3.42 (m, 1 H), 3.23-3.16 (m, 2H), 2.96 (s, 3H), 2.72-2.63 (m, 2H), 2.29 (s, 3H), 2.24 (s, 3H), 1 .89- 1 .79 (m, 4H).

MS Method 2: RT: 0.96 min, m/z 301 .3 [M+H]⁺

[00187] Compounds produced in the Procedures described above may take part in reactions to produce compounds of the invention, for example those exemplified below.

[00188] Example 1

[00189] Compounds of formula (I) can be prepared by General Method A, shown below. General Method A may be carried out using the compound prepared by Procedure B or C or another appropriate method for producing the compound.

General Method A

Aldehyde

2-fluoro-5-[[4-[methyl-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]amino]-1- piperidyl]methyl]benzonitrile

A -Methyl-4-(2-methylpyrazol-3-yl)-/V-(4-piperidyl)phthalazin-1 -amine (50.0mg, 0.1 6mmol) and 2- fluoro-5-formylbenzonitrile (27.8mg, 0.19mmol) were dissolved in DCM (10ml_) in a 100ml_ round- bottomed flask. The reaction was stirred for 15min and sodium triacetoxyborohydride (66mg, 0.31 mmol) was added and the reaction stirred overnight. LC-MS analysis indicated that the reaction was not complete. 2-fluoro-5-formylbenzonitrile (28mg, 0.19 mmol) and sodium

triacetoxyborohydride (33mg, 0.16mmol) were added to the flask and the reaction stirred overnight. LC-MS indicated that the reaction was complete. The reaction mixture diluted with saturated sodium bicarbonate solution (50mL) and extracted with DCM (3 χ 20mL). The combined organic layers were combined, dried (Na2S04), and the solvent removed in vacuo to afford the crude material which was purified by preparative LCMS to afford the formate salt of 2-fluoro-5-[[4-[methyl-[4-(2- methylpyrazol-3-yl)phthalazin-1 -yl]amino]-1 -piperidyl]methyl]benzonitrile (24.5 mg, 0.05 mmol, 35%) as a yellow solid.

¹ H NMR (CDC , 400 MHz) /ppm: 8.23 (s, 1 H), 8.10 (d, J = 7.5 Hz, 1 H), 8.03 (d, J = 7.5 Hz, 1 H), 7.88-7.80 (m, 2H), 7.69-7.61 (m, 3H), 7.22 (t, J = 8.5 Hz, 1 H), 6.59 (d, J = 2.0 Hz, 1 H), 4.1 9-4.10 (m, 1 H), 4.05 (s, 3H), 3.63 (s, 2H), 3.22 (s, 3H), 3.1 1 -3.05 (m, 3H), 2.30-2.04 (m, 6H).

MS Method 1 : RT: 2.61 min, m/z 456.4 [M+H]⁺

[00190] The compounds shown below in Table 3 were similarly prepared by varying the aldehyde shown in the reaction scheme for General Method A:

Table 3

[00191 ] Example 2

[00192] Compounds of formula (I) can be prepared by General Method B, shown below. General Method B may be carried out using the compound prepared by Procedure B or another appropriate method for producing the compound.

General Method B

Chloride N-[1 -[(5-isopropyloxazol-4-yl)methyl]-4-piperidyl]-N-methyl-4-(2-methylpyrazol-3- yl)phthalazin-1 -amine

A -Methyl-4-(2-methylpyrazol-3-yl)-N-(4-piperidyl)phthalazin-1 -amine (50mg, 0.16mmol) was dissolved in DMF (5ml_), to which was added 4-(chloromethyl)-5-isopropyl-oxazole (37mg, 0.23mmol) and sodium carbonate (33mg, 0.31 mmol). The reaction was heated at 100°C overnight before cooling to room temperature. The reaction was diluted with ethyl acetate (30ml_) and washed with water (4 x 50ml_). The aqueous layer was re-extracted with n-butanol (10ml_). The organic layers were combined, dried (Na2S04) and concentrated in vacuo, to afford 90 mg of crude product. The crude product was purified by preparative LCMS. The sample obtained was further purified by SCX with methanol washings and elution with 1 M ammonia in methanol. Further purification by silica flash chromatography with 0% methanol in DCM with a gradient to 1 0% methanol afforded a sample which was further purified by SCX with methanol washings and elution with 1 M ammonia in methanol to afford Λ/-[1 -[(5-isopropyloxazol-4-yl)methyl]-4-piperidyl]-/V-methyl-4-(2-methylpyrazol-3- yl)phthalazin-1 -amine (1 1 .2mg,0.025mmol, 16% yield).

Ή NMR (CDC , 400 MHz) /ppm: 8.1 1 -8.08 (m, 1 H), 8.03-8.00 (m, 1 H), 7.88-7.78 (m, 2H), 7.75 (s, 1 H), 7.66 (d, J2.0Hz, 1 H), 6.58 (d, J2.0Hz, 1 H), 4.05 (s, 3H), 4.07-4.04 (m(br), 1 H), 3.56 (s(br), 2H), 3.19 (s, 3H), 3.21 -3.10 (m, 3H), 2.35-1 .99 (m, 6H), 1 .28 (d, J7.0Hz, 6H).

MS Method 1 : RT: 2.60min, m/z 446.4 [M+H]⁺

Similarly prepared was:

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

¹ H NMR (400MHz, CDCb) δ/ppm : 7.99 (d, J7.9Hz, 1 H), 7.94, (d, J7.7Hz, 1 H), 7.74 (m, 2H), 7.58 (d, J1 .9Hz, 1 H), 7.50 (dd, J8.5, 5.4Hz, 1 H), 7.28 (dd, J7.9, 2.6Hz, 1 H), 7.22 (dt, J8.3, 2.9Hz, 1 H), 6.50 (d, J1 .9Hz, 1 H), 3.97 (s, 3H), 3.93 (tt, J1 1 .5, 3.8Hz, 1 H), 3.61 (s, 2H), 3.1 1 (s, 3H), 2.92 (d, J1 1 .6Hz, 2H), 2.03 (m, 6H)

MS Method 1 : RT: 2.58min, m/z 456.4 [M+H]⁺

[00193] Example 3

[00194] Compounds of formula (I) can be prepared by General Method C, shown below. General Method C may be carried out using the compound prepared by Procedure B or C or another appropriate method for producing the compound.

General Method C

Sulphonyl chloride

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

A -Methyl-4-(2-methylpyrazol-3-yl)-/V-(4-piperidyl)phthalazin-1 -amine (43mg, 0.13mmol) and pyridine (0.3ml_, 3.71 mmol) were taken up in DCM and cooled to 0°C then 4-fluoro-2- (trifluoromethyl)benzenesulfonyl chloride (132mg, 0.50mmol) was added. The mixture was slowly allowed to warm to room temperature then stirred at this temperature for 7 hours. LCMS analysis indicated no product was present. The reaction mixture was left to stand overnight. 4-fluoro-2- (trifluoromethyl)benzenesulfonyl chloride (100mg, 0.38mmol) and pyridine (0.2 mL) were added and the mixture was heated to 40°C for 6 hours. The reaction was cooled to room temperature and the reaction mixture was washed with water (1 OmL) and brine (1 0 mL). The organics were collected, dried (Na2S04) and concentrated in vacuo to afford a brown oil. The crude material was purified by preparative LCMS to afford Λ/-[1 -[4-fluoro-2-(trifluoromethyl)phenyl]sulfonyl-4-piperidyl]-/V-methyl-4- (2-methylpyrazol-3-yl)phthalazin-1 -amine (4.7mg, 8.6μΐηοΙ, 6.4% yield)

¹ H NMR (CDC , 400 MHz) /ppm: 8.24-8.20 (dd, J8.9Jz, 5.2Hz, 1 H), 8.10-8.08 (m, 1 H), 8.05-8.02 (m, 1 H), 7.88-7.80 (m, 2H), 7.67 (d, J1 .9Hz, 1 H), 7.63 (dd, J 8.9Hz, 2.8Hz, 1 H), 7.44-7.39 (m, 1 H), 6.58 (d, J1 .9Hz, 1 H), 4.29-4.21 (m, 1 H), 4.05 (s, 3H), 4.01 -3.95 (m, 2H), 3.20 (s, 3H), 2.93-2.84 (td, J12.4Hz, 2.7Hz, 2H), 2.20-2.04 (m, 4H)

MS Method 1 : RT: 3.82 min, m/z 549.2 [M+H]⁺

[00195] The compounds shown below in Table 4 were similarly prepared by varying the sulphonyl chloride shown in the reaction scheme for General Method C:

Table 4

LCMS RT m/z

Structure Compound Name

MIM

[00196] Example 4

[00197] Compounds of formula (I) can be prepared by General Method D, shown below. General Method D may be carried out using the compound prepared by Procedure B or C or another appropriate method for producing the compound.

General Method D

IsQcyanate

N-tert-butyl-4-[[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-methyl-amino]piperidine- 1-carboxamide

A ,4,5-Trimethyl-6-(2-methylpyrazol-3-yl)-A -(4-piperidyl)pyridazin-3-amine (100mg, 0.33mmol) was dissolved in DCM (2ml_) and DIPEA (0.12ml_, 0.67mmol). The reaction was stirred at room temperature under nitrogen, ferf-butyl isocyanate (0.04ml_, 0.33mmol) was added in one portion and the reaction was stirred overnight. Water (20ml_) and DCM (20ml_) were added and the aqueous and organic layers were separated through a phase separator. Concentration in vacuo afforded a crude oil which was purified by flash column chromatography using 5% methanol in ethyl acetate with a gradient increasing to 30% MeOH to afford N-tert-butyl-4-[[4,5-dimethyl-6-(2- methylpyrazol-3-yl)pyridazin-3-yl]-methyl-amino]piperidine-1 -carboxamide (95mg,0.21 mmol, 64% yield).

¹ H NMR (CDC , 400 MHz) /ppm: 7.58 (d, J1 .9Hz, 1 H), 6.37 (d, J1 .9Hz, 1 H), 4.36 (s, 1 H), 4.02- 3.95 (m, 2H), 3.94 (s, 3H), 3.68-3.59 (tt, J1 1 .3Hz, 3.9Hz, 1 H), 2.89 (s, 3H), 2.86-2.78 (m, 2H), 2.29 (s, 3H), 2.24 (s, 3H), 1 .95-1 .88 (m, 2H), 1 .88-1 .76 (qd, J12.1 Hz, 4.0Hz, 2H), 1 .38 (s, 9H).

MS Method 1 : RT: 3.12min, m/z 400.4 [M+H]⁺

[00198] The compounds shown below in Table 5 were similarly prepared by varying the sulphonyl chloride shown in the reaction scheme for General Method C:

Table 5

[00199] Example 5

[00200] Compounds of formula (I) can be prepared by General Method E, shown below. General Method E may be carried out using the compound prepared by Procedure B or another appropriate method for producing the compound.

General Method E

Acid chloride

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

To a solution of /V-methyl-4-(2-methylpyrazol-3-yl)-N-(4-piperidyl)phthalazin-1 -amine (477 mg, 1 .48 mmol) in DCM (8ml_) was added triethylamine (0.41 mL, 2.96mmol). The solution was cooled to 0°C before 4-fluoro-2-(trifluoromethyl)benzoyl chloride (0.25ml_, 1 .63mmol) was slowly added dropwise. The solution was stirred for 5min before allowing to warm to room temperature and left to stir for 2 hours. LCMS indicated that the starting material had been consumed so the solution was diluted with DCM (15ml_) and partitioned with water (20ml_) before being passed through a phase separator. The organic layer was concentrated in vacuo and the resulting oil was purified using silica flash column chromatography using 0% methanol in DCM with a gradient to 5% methanol to afford the crude product. 1 0Omg of this material was further purified by preparative LCMS to afford [4-fluoro-2-(trifluoromethyl)phenyl]-[4-[methyl-[4-(2-methylpyrazol-3-yl)phthalazin-1 -yl]amino]-1 - piperidyl]methanone (10.2mg, 0.020mmol, 1 .3%)

MS Method 2: RT: 1 .49 min, m/z 513.5 [M+H]⁺

¹ H NMR (400 MHz, MeOD) /ppm : 8.30-8.26 (d(br), J8.2Hz, 1 H), 8.03-7.93 (m, 3H), 7.71 (d, J2.0Hz, 1 H), 7.71 -7.49 (m, 3H), 6.68 (d, J2.0Hz, 1 H), 4.86-4.79 (m, 1 H), 4.40-4.29 (m, 1 H), 3.50 (s, 3H), 3.46-3.39 (m, 1 H), 3.29-3.12 (m, 1 H), 3.24 (s, 1 .5H, rotamer), 3.19 (s, 1 .5H, rotamer), 2.95- 2.85 (m, 1 H), 2.24-1 .86 (m, 4H).

Table 6

LCMS RT m/z

Structure Compound Name

MIM

n I j o [4-fluoro-2-(trifluoromethyl)phenyl]-[4- [methyl-[1 -(2-methylpyrazol-3-yl)-6,7- 3.35min 503.4 dihydro-5 -/-cyclopenta[d]pyridazin-4- (Method 1 ) [M+H]⁺ yl]amino]-1 -piperidyljmethanone

^Ν_ίί I / [4-[[4,5-dimethyl-6-(2-methylpyrazol- 3-yl)pyridazin-3-yl]-methyl-amino]-1 - 3.63min 491 .4 piperidyl]-[4-fluoro-2- (Method 1 ) [M+H]⁺ (trifluoromethyl)phenyl]methanone

1 -[4-[[4,5-dimethyl-6-(2- methylpyrazol-3-yl)pyridazin-3-yl]- 3.23min 385.4 methyl-amino]-1 -piperidyl]-2,2- (Method 1 ) [M+H]⁺

dimethyl-propan-1 -one I v C 2,2-dimethyl-1 -[4-[methyl-[1 -(2- methylpyrazol-3-yl)-6,7-dihydro-5 -/- 2.90min 397.4 cyclopenta[c/|pyridazin-4-yl]amino]-1 - (Method 1 ) [M+H]⁺ piperidyl]propan-1 -one

[4-fluoro-2-(trifluoromethyl)phenyl]-[4-

[methyl-[1 -(2-methylpyrazol-3- 1 .48min 514.3 yl)pyrido[3,4-d]pyridazin-4-yl]amino]- (Method 2) [M+H]⁺

1 -piperidyljmethanone

[00201] Example 6

[00202] Compounds of formula (I) can be prepared by General Method F, shown below. General Method F may be carried out using the compound prepared by Procedure B or another appropriate method for producing the compound.

General Method F

Acid

Acid

[4-[[4,5-Dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-methyl-amino]-1-piperidyl]-[2-methyl- 5-(trifluoromethyl)oxazol-4-yl]methanone

To a round bottomed flask were added A ,4,5-trimethyl-6-(2-methylpyrazol-3-yl)-/V-(4- piperidyl)pyridazin-3-amine (130mg, 0.43mmol), BOP (210mg, 0.48mmol), 2-methyl-5- (trifluoromethyl)oxazole-4-carboxylic acid (93mg, 0.48mmol) and triethylamine (88mg, 0.87mmol) in DCM. The reaction was stirred at RT overnight. The reaction was then partitioned between water and DCM. The organic layer was obtained through a phase separator. The aqueous layer was extracted with DCM (3x1 OmL). The organic layers were combined and concentrated in vacuo. The resulting residue purified by flash silica chromatography using 0-20% MeOH in EtOAc Further purification was performed by preparative LCMS to afford .[4-[[4,5-dimethyl-6-(2-methylpyrazol-3- yl)pyridazin-3-yl]-methyl-amino]-1 -piperidyl]-[2-methyl-5-(trifluoromethyl)oxazol-4-yl]methanone (6mg,0.013mmol, 2.9% yield).

MS Method 2: RT: 1 .47 min, m/z 478.4 [M+H]⁺ ¹ H NMR (400 MHz, MeOD) /ppm: 7.61 (d, J2.0Hz, 1 H), 6.50 (d, J2.0Hz, 1 H),4.72-4.64 (m, 1 H), 3.92-3.77 (m, 2H), 3.80 (s, 3H), 3.29-3.20 (m, 1 H), 2.98 (td, J12.8, 3.0Hz, 1 H),2.93 (s, 3H), 2.59 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H), 2.07-2.00 (m, 1 H), 1 .97-1 .84 (m, 3H).

Table 7

[00203] Example 7

[00204] 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 reported as IC50 values.

[00205] 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% CO2. 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.

[00206] 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 [00207] Serial dilutions of the test compounds were prepared in 100% DMSO. 10 I of compound or DMSO from each well was pipetted into a sterile, 0.5ml deep well conical bottomed 96 well plate (intermediate plate). 190 I of warmed assay media (Opti-MEM supplemented with 0.5% calf serum, 1 % non-essential amino acids, 1 mM sodium pyruvate, 10mM HEPES, 1 % penicillin/Streptomycin) was then added to each well and mixed five times at 180 I 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 I was pipetted from each well of the intermediate plate into a second deep well sterile plate. 490 I of warm assay media was then added to each well and mixed five times at 300 I. This gives a final top concentration of 1 M in 0.1 % DMSO.

[00208] After the 24 hour incubation, media was carefully removed by pipette and replaced with 45 I of compound dilutions in triplicate. This was incubated for one hour at 37°C in a 5% CO2. After an hour, 5 1 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% CO2.

[00209] After 24 hours, plates were removed from the incubator and left to acclimatise to room temperature for 20 minutes. 50 I 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).

[00210] The results of the in vitro biological data for certain compounds of the invention are given in the table 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 75 nM to 1500 nM. The category "++" refers to compounds with an IC50 of 15 nM to 75 nM. The category "+++" refers to compounds with an IC50 of <15 nM. The category "-" refers to a compound with a IC50 value of >6uM.

ID

Compound Category

No.

N-tert-butyl-4-[methyl-[4-(2-methylpyrazol-3-yl)phthalazin-1 -

1 ++

yl]amino]piperidine-1 -carboxamide

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

2 +

piperidyl]methyl]benzonitrile

N-(4-fluorophenyl)-4-[methyl-[4-(2-methylpyrazol-3-yl)phthalazin-

3 +

1 -yl]amino]piperidine-1 -carboxamide

N-(2,4-difluorophenyl)-4-[methyl-[4-(2-methylpyrazol-3-

4 ++

yl)phthalazin-1 -yl]amino]piperidine-1 -carboxamide

N-[1 -[4-fluoro-2-(trifluoromethyl)phenyl]sulfonyl-4-piperidyl]-N-

5 +++

methyl-4-(2-methylpyrazol-3-yl)phthalazin-1 -amine

[4-fluoro-2-(trifluoromethyl)phenyl]-[4-[methyl-[4-(2-methylpyrazol-

6 +++

3-yl)phthalazin-1 -yl]amino]-1 -piperidyl]methanone

N-[1 -[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-N-

7 +++

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

++ piperidyl]-[5-(trifluoromethyl)pyridazin-4-yl]methanone

N-[4-fluoro-2-(trifluoromethyl)phenyl]-4-[methyl-[1 -(2- methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-yl]amino]piperidine-1 - +++ carboxamide

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

++ amino]-1 -piperidyl]-[3-(trifluoromethyl)pyridazin-4-yl]methanone

[4-[[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-methyl- amino]-1 -piperidyl]-[2-methyl-5-(trifluoromethyl)oxazol-4- + yl]methanone

N-[1 -[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-N- methyl-1 -(2-methylpyrazol-3-yl)-6,7-dihydro-5H- + cyclopenta[d]pyridazin-4-amine

N-[1 -[4-fluoro-2-(trifluoromethyl)phenyl]sulfonyl-4-piperidyl]-N-

+++ methyl-1 -(2-methylpyrazol-3-yl)pyrido[3,4-d]pyridazin-4-amine

2,2-dimethyl-1 -[4-[methyl-[1 -(2-methylpyrazol-3-yl)-6,7-dihydro-

+ 5H-cyclopenta[d]pyridazin-4-yl]amino]-1 -piperidyl]propan-1 -one

N-[1 -[4-fluoro-2-(trifluoromethyl)phenyl]sulfonyl-4-piperidyl]-N- methyl-1 -(2-methylpyrazol-3-yl)-6,7-dihydro-5H- +++ cyclopenta[d]pyridazin-4-amine

N-tert-butyl-4-[methyl-[1 -(2-methylpyrazol-3-yl)-6,7-dihydro-5H-

++ cyclopenta[d]pyridazin-4-yl]amino]piperidine-1 -carboxamide

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

++ amino]-1 -piperidyl]-[4-fluoro-2-(trifluoromethyl)phenyl]methanone

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

+ amino]-1 -piperidyl]-2,2-dimethyl-propan-1 -one

[4-fluoro-2-(trifluoromethyl)phenyl]-[4-[methyl-[1 -(2-methylpyrazol- 3-yl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-4-yl]amino]-1 - +++ piperidyl]methanone

[4-fluoro-2-(trifluoromethyl)phenyl]-[4-[methyl-[1 -(2-methylpyrazol-

++ 3-yl)pyrido[3,4-d]pyridazin-4-yl]amino]-1 -piperidyl]methanone

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

++ amino]-1 -piperidyl]-[5-(trifluoromethyl)pyridazin-4-yl]methanone

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

+ piperidyl]-[2-methyl-5-(trifluoromethyl)oxazol-4-yl]methanone

N-(1 -cyclopentylsulfonyl-4-piperidyl)-N-methyl-4-(2-

+++ methylpyrazol-3-yl)phthalazin-1 -amine

N-(1 -isopropylsulfonyl-4-piperidyl)-N-methyl-4-(2-methylpyrazol-3-

++ yl)phthalazin-1 -amine

5-fluoro-2-[[4-[methyl-[4-(2-methylpyrazol-3-yl)phthalazin-1 -

++ yl]amino]-1 -piperidyl]methyl]benzonitrile N-[1 -(2,4-difluorophenyl)sulfonyl-4-piperidyl]-N-methyl-4-(2-

26 ++

methylpyrazol-3-yl)phthalazin-1 -amine

N-[1 -[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-N,4,5-

27 +

trimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-amine

N-[1 -[4-fluoro-2-(trifluoromethyl)phenyl]sulfonyl-4-piperidyl]-4,5-

28 +++

dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-amine

N-tert-butyl-4-[[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-

29 +

yl]amino]piperidine-1 -carboxamide

[4-[[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]amino]-1 -

30 +

piperidyl]-[4-fluoro-2-(trifluoromethyl)phenyl]methanone

N-[1 -[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-4,5-

31 ++

dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-amine

[4-fluoro-2-(trifluoromethyl)phenyl]-[4-[[4-(2-methylpyrazol-3-

32 +

yl)phthalazin-1 -yl]amino]-1 -piperidyl]methanone

N-[1 -[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-4-(2-

33 +

methylpyrazol-3-yl)phthalazin-1 -amine

3-[[4-[[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]amino]-

34 - 1 -piperidyl]methyl]benzonitrile

[00211 ] Examples of compounds of the invention with values for their IC50 are given in the table below.

[00212] 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.

[00213] 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.

[00214] 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.

Claims

1 . A compound according to formula (I) and pharmaceutically acceptable salts and solvates thereof:

0

R² is represented by -CR⁵R⁶R⁷, wherein R⁵, R⁶ and R⁷ are independently selected at each occurrence from H and substituted or unsubstituted: C1 -14 alkyl, C1-14 haloalkyl, carbocyclic, and heterocyclic, or R² is selected from substituted or unsubstituted: C1-14 alkyl, C1-14 haloalkyl, carbocyclic, and heterocyclic;

m is 0, 1 or 2; and

2. The compound of claim 1 , wherein R³ is selected from substituted or unsubstituted C1-14 alkyl, C1-14 haloalkyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic.

3. The compound of claim 1 or claim 2, provided that when :

L is C1-3 alkylene chain which is saturated or unsaturated;

then R¹ is selected from substituted or unsubstituted: aryl or heteroaryl, optionally wherein R¹ is selected from substituted or unsubstituted: pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl ; preferably substituted or unsubstituted pyrazolyl.

4. The compound of any preceding claim, wherein "het" is represented by groups selected from substituted or unsubstituted:

5. The compound of any preceding claim, wherein "het" is selected from substituted or unsubstituted:

The compound of claim 5, wherein "het" is substituted or unsubstituted:

7. The compound of any preceding claim, wherein one of A¹ , A², A³ and A⁴ is N and the remaining A¹ , A², A³ and A⁴ are each independently selected from N or CR⁴.

The compound of any preceding claim, wherein

is selected from:

10. The compound of any preceding claim, wherein the compound of formula (I) is a according to formula (III):

(III)

1 1 . The compound of any preceding claim, wherein R⁴ is selected from : C1-6 alkyl, C1-6 haloalkyl, -CR^cR^dOR^a, C₃-₈ cycloalkyl, C₃-₈ cycloalkenyl, -NR^aR^b, -CN, -C(0)R^a, -C(0)OR^a and - C(0)NR^aR^b, and two adjacent R⁴ groups may form a ring with the atom to which the R⁴ groups are attached forming a fused bicyclic ring system of 8 to 12 atoms, wherein the ring formed by the two R⁴ 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 containing 1 , 2 or 3

heteroatoms.

12. The compound of claim 1 1 , wherein the two adjacent R⁴ groups are both C1-6 alkyl or both form a ring with the atom to which the R⁴ groups are attached forming a fused bicyclic ring system of 8 to 12 atoms, wherein the ring formed by the two R⁴ 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.

13. The compound of claim 10, wherein R⁴ is selected from halo, C1-6 alkyl, C1-6 haloalkyl, -OR^a, -CR^cR^dOR^a, C2-6 alkenyl, C2-6 alkynyl, C₃-₈ cycloalkyl, C₃-₈ cycloalkenyl, -NR^aR^b, -CN, -C(0)R^a, -

C(0)OR^a and -C(0)NR^aR^b, and two adjacent R⁴ groups may form a ring with the carbon atoms to which they are attached the ring being 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 containing 1 , 2 or 3 heteroatoms;

R¹ is selected from substituted or unsubstituted: aryl or heteroaryl, preferably substituted or unsubstituted heteroaryl (and optionally R¹ is selected from substituted or unsubstituted: pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl; preferably substituted or unsubstituted pyrazolyl); and

m is 0 or 1 .

14. The compound of claim 9,

selected from :

N = N N = N N = N N=N

. The compound of claim 14, wherein i_S

16. The compound of any preceding claim, wherein L is selected from a bond, -CR^cR^d-, - CR^cR^dCR^cR^d-, -C(O)-, -C(0)NR^a- and -SO2-.

17. The compound of claim 16, wherein L is selected from a bond, -CH2-, -CH2CH2-, -CH(CH3)-, -C(NH)-, -C(0)NH-, -C(0)N(CH₃)- and -SO2-.

18. The compound of any of claims 1 to 12 and 14 to 1 7, wherein R¹ is selected from unsubstituted heterocycloalkyi, unsubstituted heterocycloalkenyl and substituted or unsubstituted: -O-heterocycloalkyl, -NR^a-heterocycloalkyl, -CR^cR^d-heterocycloalkyl, -O-heterocycloalkenyl, -NR^a-heterocycloalkenyl, -CR^cR^d-heterocycloalkenyl, aryl, -O-aryl, -NR^a-aryl, -CR^cR^d-aryl, heteroaryl, -O-heteroaryl, -NR^a-heteroaryl, and -CR^cR^d-heteroaryl.

19. The compound of any preceding claim wherein R¹ is not heterocycloalkyi or

heterocycloalkenyl.

20. The compound of any of claims 1 to 12 and 14 to 1 9, wherein R¹ is selected from substituted or unsubstituted: Ce aryl, -O-Ce aryl, -NR -i 4 aryl, -CR^cR -i 4 aryl, -14 heteroaryl, -O 4 heteroaryl, -NR^a-Cs-i 4 heteroaryl, and -CR^cR^d-Cs-i 4 heteroaryl.

21 . The compound of any of claims 1 to 12 and 14 to 1 9, wherein R¹ is selected from substituted or unsubstituted: heteroaryl, -O-heteroaryl, -NR^a-heteroaryl, and -CR^cR^d-heteroaryl.

22. The compound of claim 21 , wherein heteroaryl is selected from : pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl.

23. The compound of any of claims 1 to 12 and 14 to 21 , wherein R¹ is selected from substituted or unsubstituted: pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidi

24. The compound of any preceding claim wherein R¹ is:

25. The compound of any preceding claim, wherein R² is represented by -CR⁵R⁶R⁷, wherein R⁵, R⁶ and R⁷ are independently selected at each occurrence from H and substituted or unsubstituted: C1-14 alkyl, C1-14 haloalkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl or R² is selected from substituted or unsubstituted: C1-14 alkyl, C1-14 haloalkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl.

26. The compound of any preceding claim, wherein R² is represented by -CR⁵R⁶R⁷, wherein R⁵, R⁶ and R⁷ are independently selected at each occurrence from H and substituted or unsubstituted: C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, Ce-ιο aryl, C3-8 heterocycloalkyl and C5-10 heteroaryl

or R² is selected from substituted or unsubstituted: C1-6 alkyl, C1 -6 haloalkyl, C3-8 cycloalkyl, Ce-ιο aryl, C3-8 heterocycloalkyl and C5-10 heteroaryl.

27. The compound of any preceding claim, wherein R⁵, R⁶ and R⁷ are independently selected at each occurrence from H and substituted or unsubstituted: methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, phenyl, toluenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, and isothiazolyl.

28. The compound of claim 27, wherein R⁵, R⁶ and R⁷ are all one of the groups selected from: methyl, trifluoromethyl, cyclohexanyl and phenyl

29. The compound of any of claims 1 to 25 wherein R² is selected from substituted or unsubstituted: methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, phenyl, toluenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, and isothiazolyl.

30. The compound of claim 29, wherein R² is substituted or unsubstituted: phenyl, toluenyl, pyridinyl, pyridazinyl, oxazolyl, ferf-butyl, isopropyl, and cyclopentyl.

31 . The compound of claim 30, wherein R² is represented by:

The compound of claim 31 wherein, R² i

33. The compound of any preceding claim, wherein R³ is H, substituted or unsubstituted Ci-4 alkyl or substituted or unsubstituted Ci-4 haloalkyl.

34. The compound of claim 33, wherein R³ is methyl, ethyl or -C(0)CF3.

35. The compound of any preceding claim, wherein R^a and R^b are hydrogen.

36. The compound of any preceding claim, wherein R^c and R^d are hydrogen.

37. The compound of any preceding claim, wherein m is 0 or 1 .

38. The compound of claim 33 wherein m is 0.

39. The compound of claim 1 , wherein the compound of formula (I) is selected from:

75

76

40. A compound of any preceding claim for use as a medicament.

41 . A compound of any of claims 1 to 39 for use in a method of treatment of a condition which is modulated by the Hedgehog signalling pathway.

42. A compound of claim 41 , wherein the condition which is modulated by the Hedgehog signalling pathway is cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia.

43. A compound of claim 41 or claim 42, wherein the condition which is modulated by the Hedgehog signalling pathway is 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.

44. A compound of any of claims 1 to 39 for use in a method of treatment wherein the treatment comprises inhibiting stem cell production, inhibiting stem cell renewal, and/or inhibiting and/or modulating stem cell differentiation.

45. A compound of any of claims 1 to 39 for use simultaneously, sequentially or separately with an additional anti-tumour agent, in a method of treatment of cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia.

46. A compound of claim 45 wherein the treatment may be of conditions treatable by the inhibition of the Hedgehog signalling pathway 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.

47. A pharmaceutical composition, wherein the composition comprises a compound of any of claims 1 to 39 and pharmaceutically acceptable excipients.

48. A pharmaceutical composition of claim 47 wherein the composition is a combination product and comprises an additional pharmaceutically active agent.

49. A method of treatment of a condition which is modulated by Hedgehog signalling pathway, wherein the method comprises administering a therapeutic amount of a compound of any of claims 1 to 39, to a patient in need thereof.

50. A method of treatment of claim 49 wherein the condition which is modulated by the Hedgehog pathway is selected from : cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia, wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof.

51 . A method of treatment of claim 49 or claim 50 wherein the condition is 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.

52. 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 any of claims 1 to 39, to a patient in need thereof.

53. A method of treatment of a condition selected from cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia comprising administering a therapeutically effective amount of a compound of any of claims 1 to 39, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-tumour agent to a patient in need thereof.

54. A method of providing a combination product, wherein the method comprises providing a compound of any of claims 1 to 39 simultaneously, sequentially or separately with an anti-tumour agent.

55. Use of a compound of any of claims 1 to 39 in combination with an anti-tumour agent.

56. Use of a compound of any of claims 1 to 39 in the manufacture of a medicament for use in the treatment of a condition modulated by the Hedgehog pathway.