GB2519344A - Compounds - Google Patents

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof: wherein A is a 5-membered heterocyclic moiety, wherein the 5-membered heterocyclic moiety is either:         substituted by a 6-membered moiety or a 6-membered heteroaryl moiety, the 6-membered aryl moiety or the 6-membered heteroaryl moiety being unsubstituted or substituted by from one to four independently seleted R5 groups; or          fused to a 6-membered aryl or heteroaryl moiety to form a 9-membered fused bicyclic ring system, the 6-membered aryl moiety or 6-membered heteroaryl moiety being unsubstituted or substituted by from one to four independently selected R5 groups;          and wherein the 5-membered heterocyclic moiety is unsubstituted or substituted; R1, R2 and R3 are each independently selected from hydrogen and a substituent; R4 is a substituent where n is 0, 1, 2, 3 or 4. These compounds are hedgehog pathway agonists. Specifically, the compounds of the invention are useful as Smoothened (SMO) agonists. The compounds are useful for treating conditions treatable by the inhibition of the Hedgehog pathway and SMO, for example cancer. Other pharmaceutical uses include the treatment of benign prostate hyperplasia (BPH) and psoriasis.

Description

Compounds [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 abnormaUties 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-i receptor. The Patched-i receptor inhibits Smo activation and upon binding of a Hedgehog protein with Patched-i Smo is activated, leading to activation of the GLI transcription factors and expression of 01W, 01i2 and 01i3 which are involved in cell fate determination and proliferation.

[0004] Aberrant activation of Smo through activating mutations in Smo, reduced function of Patched through loss-of-function mutations or increased Hh signaling have been shown in patients suffering from a range of cancers, for example Basal cell carcinoma, pancreatic cancer, medulloblastoma, small cell lung cancer and prostate cancer. Aberrant activation of Smo can result in abnormal activation of adult stem cells and transformation into cancer stem cells and this has been suggested as the cause of these cancers.

[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/i 47917 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 for further 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 thereof: L. (I) wherein A is a 5-membered helerocyclic moiety, wherein The 5-membered helerocyclic moiety is either: substituted by a 6-membereci aryl moiety or a 6-membered heteroaryl moiety, the 6-membered aryl moiety or the 6-membered heteroaryl moiety being unsubstituted or substituted by from one to four independently selected R5 groups; or fused to a 6-membered aryl or heteroaryl moiety to form a 9-membered fused bicyclic ring system, the 6-membered aryl moiety or 6-membered heteroaryl moiety being unsubstituted or substituted by from one to four independently selected R5 groups; and wherein the 5-membered heterocyclic moiety is unsubstituted or substituted; R1, R2 and R3 are independently selected from hydrogen or-S02R3, or are a substituted or unsubstituted group independently selected from: C.4 alkyl, 0.4 haloalkyl, C14 acyl, cycloalkyl, and C37 halocycloalkyl; R4 is independently selected at each occurrence from: halo, ORa, sRa, -NR°R, -CN, _NRUC(O)Rc, c(o)NRaRb, -SOR3, -S02R3, So2NR3Rb, -NRso2R alkyl, C16 haloalkyl, C37 cycloalkyl and C37 halocycloalkyl; R5 is independently selected at each occurrence from: halo, C16 alkyl, C16 haloalkyl, ORa, SRa, cRRdoRa, C26 alkenyl, C26 alkynyl, C37 cycloalkyl, C37 cycloalkenyl, NRaRh, -ON, azido, -C(O)R3, -C(O)0R3, soR, so2R, SO2NR8Rb, NR3SO2Rb, _NR3C(O)Rc, and 0(O)NR3Rb, aryl and heteroaryl; or two adjacent R5 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 R5 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; n is selected from 0, I, 2, 3 or 4; Ra and Rh are independently selected at each occurrence from: H, C14 alkyl, C14 haloalkyl, C14 acyl, C37 cycloalkyl, and C37 halocycloalkyl; R° and Rd are independently selected at each occurrence from: H, halo, Qpa, C14 alkyl, C14 haloalkyl, C14 acyl, C7 cycloalkyl, and C37 halocycloalkyl; when a group is substituted, the group contains I to 5 substituents independently selected at each occurrence from the group comprising: halo, oRa, -sRa, Npapb, NO2, =0, -CN, acyl, Cl_s alkyl, C16 haloalkyl, C7 cycloalkyl, -SO2R', and SO3R' , c(oRa)Rapb, C(O)REI, C(O)OREI and C(O)N REI R. [0009] In an embodiment the 5-membered heterocyclic moiety of A is a 5 membered heteroaryl group. All disclosures given below in relation to the 5-membered heterocyclic moiety of A extend to the embodiment where the 5-membered heterocyclic moiety of A is a S membered heteroaryl group.

[0010] In an embodiment the 5-membered heterocyclic moiety of A comprises at least one hetero atom selected from 0, S or N. In a preferred embodiment the 5-membered heterocyolic moiety of A comprises at least one nitrogen atom. In an aternative, yet equally preferred embodiment one of the at least one heteroatoms of the 5-membered heterocyclic moiety of A is an oxygen atom.

[0011] In an embodiment the 5-membered heterocyclic moiety of A comprises three hetero atoms selected from 0, S or N and is substituted by a 6-membered aryl or heteroaryl moiety. In a preferred embodiment one of the heteroatoms is oxygen or nitrogen. Alternatively, a first heteroatom is oxygen and a second heteroatom is nitrogen.

[0012] In an alternative embodiment the 5-membered heterocyclic moiety of A comprises two hetero atoms selected from 0, S or N and is fused to a 6-membered aryl or heteroaryl moiety to form a 9-membered fused bicyclic ring system. In a preferred embodiment one of the heteroatoms is oxygen or nitrogen. Alternatively, a first heteroatom is oxygen and a second heteroatom is nitrogen, or a first heteroatom is sulphur and a second heteroatom is nitrogen, or a first heteroatom is nitrogen and a second heteroatom is nitrogen.

[0013] In an embodiment the 5-membered heterocyclic moiety of A is selected from: oxadiazolyl, thiadiazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl and triazolyl. In a particular embodiment the 5-membered heterocyclic moiety of A is selected from: oxadiazolyl, thiadiazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl and triazolyl; and is substituted by a 6-membered aryl or heteroaryl moiety. In an alternative embodiment the 5-membered heterocyclic moiety of A is selected from: oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl and imidazolyl; and is fused to a 6-membered aryl or heteroaryl moiety forming a 9-membered fused bicyclic ring system.

[0014] In an embodiment the 6-membered aryl or heteroaryl moiety of A is selected from: phenyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. Preferably, the 6-membered aryl or heteroaryl moiety of A is phenyl. The 6-membered aryl or heteroaryl moiety of A may be the 6-membered moiety substituted or fused onto the 5-membered heterocyclic moiety of A. [0015] In an embodiment A is represented by: x2 -X3 wherein X1 is selected from 0, S or NRa; X2 is selected from CRC or N; and X3 is CR° or N and R6 is a 6-membered aryl or 6-membered heteroaryl moiety; or X3 is C and X3 together with R6 form a fused 6-membered aryl or 6-membered heteroaryl moiety; wherein the 6-membered aryl or 6-membered heteroaryl moiety is unsubstituted or substituted by from one to four independently selected R5 groups.

[0016] Thus, in an embodiment of the invention the compound of formula (I) is a compound according to formula (II): x2 -P1 \)-_.p6 N X1 p3 (II) [0017] In an embodiment R6 is selected from: phenyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. Preferably, R6 is phenyl. In an embodiment the fused 6-membered aryl or 6-membered heteroaryl moiety formed by X3 together with R6 is selected from: phenyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl; preferably phenyl.

x2 -X3 I! [0018] In an embodiment A or are represented by: r"x (R5)0 x2N />(R5)m X21⁄41 X1 wherein m and o are both independently selected from 0, 1, 2, 3 and 4.

[0019] Thus, in an embodiment the compound of formula (I) is a compound according to formula (III) or (IV):

-

N)»=-js (R5)m RL N (III) (l/') [0020] In an embodiment m isO, 1 or 2, optionally 1 or 2. In an embodiment o isO, 1 or 2, preferably o is 0.

[0021] In any embodiment disclosed herein X1 and X2 may be selected from the following: X1 isO and X2 is N; X1 is Sand X2 is N; and X1 is NRa and X2 is N. x2 - [0022] In an embodiment A or X are represented by: NN /(R) NK\ j j NkN 1 [0023] In an embodiment R5 is selected from: halo, 016 alkyl, C16 haloalkyl, OR', NRE1Rb, -NRt(O)Rc, and C(O)NR3Rb and -CN; or two adjacent R5 groups may form a ring with the carbon atom to which they are attached forming a fused bicyclic ring system of 10 atoms, wherein the ring formed by the two R5 groups is a heterocyclic ring with 6 atoms containing 2 oxygen atoms. In particular embodiments R5 is selected from: chloro, fluoro, trifluomethyl and -OMe.

[0024] In an embodiment m or o is 1 and R5 is selected from: halo, C.6 alkyl, C. haloalkyl, and -eN, optionally wherein R5 is selected from: chloro, fluoro, trifluomethyl, -CN and -OMe. In alternative embodiment m or o is 2 and R5 is selected from: halo, C16 alkyl, C16 haloalkyl, -OW and -CN, and two adjacent P5 groups may form a ring with the carbon atom to which they are attached forming a fused bicyclic ring system of 10 atoms, wherein the ring formed by the two R4 groups is a saturated heterocyclic ring with 6 atoms containing 2 oxygen atoms, optionally wherein R5 is selected from: chloro, fluoro, trifluomethyl, -CN and -OMe.

[0025] In particular embodiments: m is 1 and R5 is fluoro; m is 1 and R5 is trifluoromethyl; m is 1 and R5 is -OMe; m is I and R5 is -CN; m is I and R5 is chloro; m is 2 and R5 is fluoro; and m is 2 and P5 is fluoro and trifluoromethyl.

x2 -X3 [0026] In particular embodiments A and X are represented by: )i>-O -Q-CI Q-F Q-CN )J4DCFS L>Q Q-OMe 1 _9F _9-F [0027] In an embodiment R1, P2 and P3 are independently selected from hydrogen orSO2Ra, or substituted or unsubstituted: C14 alkyl, C14 haloalkyl or C14 acyl. In a particular embodiment R1, R2 and R3 are independently selected from hydrogen or unsubstituted C1 alkyl, for example, methyl, ethyl, propy, isopropyl, butyl and tert-butyl. Preferably, R1 is hydrogen, R2 is C14 alkyl, preferably methyl, and R3 is hydrogen.

[0028] In an embodiment R4 is independently selected at each occurrence from: halo, QRa, NR0Rb, -CN, _NRt(O)Rc, sO2Ra, So2NRE1Rb, NRE1SO2Rb, C1 alkyl and °16 haloalkyl. In an embodiment R4 is independently selected at each occurrence from: halo, NR3Rb, -NRt(O)Rc, and C(O)NR3Rb, C19 alkyl and C1.6 haloalkyl, wherein Ra, Rb and R are selected from hydrogen and G14 alkyl, for example methyl or ethyl.

[0029] In an embodiment n is selected from 0 or 1. In particular embodiments n is 0.

[0030] In an embodiment Ra, Rh, R° and Rd are independently selected from: H and 014 alkyl, preferably H and methyl.

[0031] In an embodiment the groups attached to the carbon atoms marked with an asterisk, see below, on the piperidine ring of formula (I) are oriented to be trans to one another. In an alternative embodiment the groups at the carbons marked with an asterisk are oriented cis to one another. The stereochemistry at the carbons indicated with an asterisk may be such that the compounds of formula (I) are a mixture of enantiomers with a trans relationship between the two indicated carbon atoms. Alternatively the stereochemistry of the carbon atoms indicated with an asterisk may be such that the groups attached to the carbon atoms are trans to one another and the compounds are single enantiomers. This is applicable to all embodiments of the invention.

[0032] For example, the compounds of formula (I) may be the individual enantiomers (Ia) or (Ib), shown below, or they may be an enantiomeric mixture of the two enantiomers (Ia) or (Ib).

A A a

R2 L(R)n R2 (Ia) (Ib) [0033] In embodiments where there is a single enantiomer of the compounds of the invention, the compounds of the invention may have an enantiomeric purity of at least about 90% enantiomeric excess (ee), at least about 95% enantiomeric excess (ee), at least about 98% enantiomeric excess (ee), at least about 99% enantiomeric excess (ee), or 100% enantiomeric excess (ee). In embodiments where there is a mixture of enantiomers of the compounds of the invention, the compounds of the invention may be a racemic mixture or any other mixture of enantiomers, for oxamplo the compounds of tho invontion may havo an onantiomoric purity of at loast about 50% enantiomeric excess (ee), at least about 60% enantiomeric excess (ee), at least about 70% enantiomeric excess (ee), at least about B0% enantiomeric excess (ee), at least about 90% enantiomeric excess (ee), or at least about 95% enantiomeric excess (ee).

[0034] In an embodiment the compound of the invention is a compound selected from the following compounds.

I

_zzYz _zYz o w I zi zi I I zi -z -z z z /\ i I I I -z Z zK z?O 6' ct&0c -I zi rrT' z z 0

I

__ z z -z z 0 z I' i -z z _zazz a' zi zI a, p m H N CF3 NLt [0035] In particular embodiments the compounds of the invention are those shown below. The stereochemistry shown in the compounds below is representative of the relative stereochemistry and the absolute stereochemistry. This is to say that the compounds of the invention may be an enantiomeric mixture of compounds with a trans relationship between the two groups on the piperidine ring. Equally, this is to that the compounds of the invention may be a single enantiomer with the stereochemistry as defined in the compounds below.

HVLP xP

HN N

HN aH áH

H

I I I

F

->Q-0 Me H N F HN0 HN)0>Q0 áH

I F3C

H N N -CN N - F

II II

F HN'0 HN0 H H C") H I 1)6, I g:TcNgcl r t

NN

HNOCF3 -,, N [0036] In another aspect of the invention there is provided a compound of the invention for use as a medicament.

[0037] 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.

[0038] 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.

[0039] 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, for example 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.

[0040] 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.

[0041] Conditions also treatable by the inhibition of the Hedgehog signalling pathway or Smo may be selected from benign prostatic hyperplasia, psoriasis and osteoporosis.

[0042] In an embodiment the compounds of the invention are for use in inhibiting stem cell production, inhibiting stem cell renewal and inhibiting and/or modulating stem cell differentiation. In an embodiment the stem cells are cancer stem cells which may also be referred to as tumorigenic stem cells or stem cell like tumorigenic cells.

[0043] In embodiments, a compound of the invention may be for use in the treatment of: cancer, for example 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.

[0044] A compound of the invention may be for use in the treatment of: benign prostatic hyperplasia, psoriasis and osteoporosis.

[0045] 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. In the above embodiments the stem cells may be cancer stem cells which may also be referred to as tumorigenic stem cells or stem cell like tumorigenic cells.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] The invention also provides a method of treating a condition selected from: cancer, for example 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 treatng a specific condition selected from: basal cell carcinoma, meclulloblastoma, 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, bane 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.

[0050] 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.

[0051] 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. The stem cells may be cancer stem cells which may also be referred to as tumorigenic stem cells or stem cell like tumorigenic cells.

[0052] In another aspect of the invention there is provided a pharmaceutical composition, comprising a compound of the invention and a pharmaceutically acceptable excipient. 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.

[0053] 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.

[0054] In an aspect of the invention there is provided a method of treatment of a condition selected from cancer, for example 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.

[0055] 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, for example sarcoma, carcinoma, blastoma, lymphoma and leukemia. Optionally, the condition to be treated can be selected from any of those conditions mentioned above.

[0056] 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

[0057] 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.

[0058] 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.

[0059] The term "G. 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, "C14 alkyl" refers to a linear or branched hydrocarbon chain containing 1, 2, 3 or 4 carbon atoms, "C13 alkyl" refers to a linear or branched hydrocarbon chain containing 1, 2 or 3 carbon atoms and "0114 alkyl" refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Alkylene groups may likewise be linear or branched and may have two places of attachment to the remainder of the molecule.

Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. The alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substiuents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C16 alkoxy.

[0060] 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, C1.6 alkoxy.

[0061] 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, "C14 haloalkyl" refers to a linear or branched hydrocarbon chain containing 1, 2,3 or 4 carbon atoms and "C114 haloalkyl" refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, Ii, 12, i 3 or 14 carbon atoms. The halogen atom may be present at any position on the hydrocarbon chain. For example, C1.5 haloalkyl may refer to chloromethyl, flouromethyl, trifluoromethyl, chloroethyl e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl e.g. I,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.

[0062] 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 Eor Zisomer. The double bond may be at any possible position of the hydrocarbon chain. For example, the "C25 alkenyl" may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0063] The term "C2.5 alkynyl" refers to a branched 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 "C2.5 alkynyl" may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0064] The term "C5 heteroalkyl" refers to a branched or linear hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, 0 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 C1.5 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom. For example, the "C1.5 heteroalkyl" may be C1.5 N-alkyl, C1.5 N,N-alkyl, or C16 O-alkyl.

[0065] The term "carbocyclic' refers to a saturated or unsaturated carbon containing ring system.

A "carbocyclic" system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic. A "carbocyclic" moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Carbocyclic" encompasses cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems and fused ring systems including an aromatic portion. "Carbocyclic" may be C38 cycloalkyl or C610 aryl.

[0066] The term "heterocyclic" refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, 0 or S. A "heterocyclic" system may contain 1, 2, 3014 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, 055 heteroaryl. For example, the heterocyclic group may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolicline, piperidine, morpholine, thiomarpholine, piperazine, and tetrah yd ro pyran.

[0067] The term "C314 cycloalkyl" refers to a saturated hydrocarbon ring system containing 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Similarly,"038 cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and "057 cycloalkyl" refers to a saturated hydrocarbon ring system containing 5,6or7 carbon atoms. For example, the "C30 cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "C3.7 halocycloalkyl" is a "cycloalkyl" ring having at least one halogen substituted thereon, independently selected at each occurrence. For example, the halogen may be fluorine, chlorine, bromine or iodine.

[0068] The term "033 cycloalkenyl" refers to an unsaturated hydrocarbon ring system containing 3,4, 5, 6, 7 orB carbon atoms. The ring may contain more than one double bond. For example, the "033 cyoloalkyl" may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[0069] The term "03-14 heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3,4,5,6,7,8,9, 10, 11, 12, 13 or 14 carbon atoms and at least one heteroatom within the ring selected from N, 0 and S. For example there may be 1, 2 or 3 heteroatoms, optionally 1 or 2.

Similarly,"C33 heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and "C57 heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 5, 6 or 7 carbon atoms. The CS.S beterocycloalkyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "C3 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 "C38 heterocycloalkyl" may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrah yd ro pyran.

[0070] The term "C314 heterocycloalkyl" refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms and at least one heteroatom within the ring selected from N, 0 and S. For example there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. Similarly,"C3.3 heterocycloalkyl" refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and "CJ heterocycloalkyl" refers to an unsaturated hydrocarbon ring system containing 5,6 or 7 carbon atoms. The "03.8 heterocycloalkenyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "03.8 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 beterocycloalkyl" may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.

[0071] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated ii system within a ring where all atoms contributing to the conjugated ii system are in the same plane. The aryl group may be C614 aryl, optionally C610 aryl or 06 aryl, wherein a C614 aryl is a ring system with 6, 7, 8, 9, 10, II, 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.

[0072] 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 0, N and S. The heteroaryl group may be C5.14 heteroaryl, optionally heteroaryl or C5.6 heteroaryl, wherein a C514 heteroaryl is a ring system with 5, 6, 7, 8, 9, 10, Ii 12, 13 or 14 ring atoms with at least one heteroatom within a single ring or within a fused ring system, selected from 0, N and 5, 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 u system where all atoms contributing to the conjugated ii system are in the same plane. For example, the "heteroaryl" may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

[0073] The term alkaryl" refers to an aryl group, as defined above, bonded to a 014 alkyl, where the C14 alkyl group provides attachment to the remainder of the molecule.

[0074] The term alkheteroaryl" refers to a heteroaryl group, as defined above, bonded to a 014 alkyl, where the alkyl group provides attachment to the remainder of the molecule.

[0075] The term halogen" herein includes reference to F, Cl, Br and I. Halogen may be Cl.

Halogen may be F. [0076] A bond terminating in a" " represents that the bond is connected to another atom that is riot shown. A bond terminating inside a cycUc 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.

[0077] 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, NHR3, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(O)H, acyl, acyloxy, carboxy, sulfa, sulfamoyl, carbamoyl, cyano, azo, nitro, halo, Cl_U alkyl, C16 alkoxy, G15 haloalkyl, C38 cycloalkyl, C26 alkenyl, C26 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 C48 ring along with the atoms of the moiety on which the substituents are substituted, wherein the C48 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 I, 2 or 3 heteroatoms.

[0078] 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 undue effort which substitutions are chemically possible and which are not.

[0079] 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, C16 alkyl, C3 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C13 alkyl. In one embodiment acyl is alkyl-carbonyl. Examples of acyl groups include, but are not limited to, formyl, acetyl, proponyl and butyryl. A particular acyl group is acetyl.

[0080] AH stereoisomers of the compounds of the invention are contemplated. The compounds of the invention may be present as a single stercoisomer or may be mixtures of stereoisomers, for example racemic mixtures, and other enantiomeric mixtures, and diastereomeric mixtures. Where the mixture is a mixture of enantiomers the enantiomeric excess may be any of those disclosed above. Where the compound is a single stereoisomer the compound may still contain other diastereoisomers or enantiomers as impurities. Hence a single stereoisomer does not necessarily have an enantiomeric excess (e.e.) or diastereomeric excess (d.e.) of 1 W0k but could have an e.e.

or d.e. of about at least 85%.

[0081] The invention contemplates pharmaceutically acceptable salts of the compounds of formula (I). These may include the acid addition and base salts of the compounds. In addition the invention contemplates solvates of the compounds. These may be hydrates or other solvated forms of the compound.

[0082] 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, hydroiodicle/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 1 5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

[0083] 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).

[0084] Preferably the salt is an acid addition salt. The salts may be formate or hydrochloride.

[0085] For example, pharmaceutically acceptable salts of compounds of formula (I) may be prepared: (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 (Hi) 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.

[0086] AH 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.

[0087] The compounds of the invention may exist in both unsolvated and solvated forms. The term solvate' is used herein to describe a moecular 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.

[0088] 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).

[0089] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[0090] The compounds of the invention incude 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.

[0091] 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.

[0092] 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 protectng 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-lnterscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used. All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.

[0093] 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.

[0094] The method of treatment or the compound of the invention 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.

[0095] The method of treatment or the compound tor use in the treatment of cancer, for example 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.

[0096] The method of treatment or the compound for use in the treatment of cancer, for example 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, mtobronitol, carboquone, thiotepa, ranimustine, nimustine, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, carmustine, estramustine, lotemustine, gulfosfamide, KW-21 70, 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 arabinosde, 6-mercaptopurine riboside, leucovarin, UFT, doxifluridine, carmoflur, cytarabine, enocitabine S-i, 5-azacitidine, cepecitabine, clofarabine, decitabine, eflornithine, ethynlcytidine, IS-i, 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, parubicin, rebeccamycin, stimalamer, streptozocin, valrubicin and zinostatin); antimitotic agents (for example ymca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol, docetaxol (Taxotere), and pacltaxel 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, 1 0-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; (H) 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 5ct-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 [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbBi antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy) -quinazolin-4-amine (Cl 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 (AMNI 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 AKI knases, c-kit inhibitors, abl kinase inhibitors, P13 kinase inhibitors, P1t3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitors and cycliri 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 (AvastinTM); COXII inhibitors (for example Arcoxia (etoricoxib), Bextra (valdecoxib), Celebrex (celecoxib), Paracoxib Vioxx (rofecoxibfl; 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-541 6, 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; (vU) immunotherapy approaches, including for example antibody therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons such as interferon a; 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-la, and interferon gamma-n; PF351 2676; Filgrastim (Neupogen); lentinan; sizofilan; Theracys; ubenimex; WF-1O; BAM-002; dacarbazine; daclizumab; denileukin; gemluzumab; ozogamcin; 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 (vhi) cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (NipentTM), edotecarin, SU-1 1248, paclitaxel, Erbitux, and irinotecan; (ix) steroids such as corticosteroids, incuding glucocorticoids and mineraocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, ameinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, olobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, fumethasone, 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, methyiprednisolone, 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 PISKd 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, FHgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi and Emend), biological response modifiers (e.g. Krestin, lentinan, sizofiran, picibanil and ubenimex), alitretinoin, ampligen, atrasenten, bexarotene, bosentan, calcitriol, exisulind, fotemustine, ibandronic acid, miltefosine, 1-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, tazarotne, TLK-286, Velcade, Tarceva, tretinoin.

[0097] 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.

[0098] 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.

[0099] 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.

[00100] 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.

[00101] In an embodiment the condition is a condition modulated by Smo.

[00102] 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.

[00103] 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.

[00104] 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.

[00105] The condition modulated by the Hedgehog signalling pathway or Sma described above may be cancer, for example sarcoma, carcinoma, blastoma, lymphoma and leukemia. More specifically the condition modulated by 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.

[00106] Conditions also treatable by the inhibition of the Hedgehog signalling pathway or Smo may be selected benign prostatic hyperplasia, psoriasis and osteoporosis.

[00107] The condition modulated by the Hedgehog signalling pathway or Sma described above may be modulated by inhibiting stem cell production, inhibiting stem cell renewal, and/or modulating stem cell differentiation. In the above embodiments the stem cells may be cancer stem cells which may also be referred to as tumorigenic stem cells or stem cell like tumorigenic cells.

[00108] Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous. Thus, compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

[00109] For the above-mentioned compounds of the invention the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (pg/kg) to 100 milligrams per kilogram body weight (mg/kg).

[00110] A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation a! suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals -The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

[00111] Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.

[00112] The pharmaceutical compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.

[00113] For oral administration the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saceharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.

Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[00114] For the preparation of soft gelatine capsules, the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thckening agent or other excipients known to those skilled in art.

[00115] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

[00116] The size of the dose for therapeutic purposes of compounds of the invention will naturally vary accordng to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

[00117] Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient. The standard duration of treatment with compounds of the invention is expected to vary between one and seven days for mast clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.

EXAMPLES AND SYNTHESIS

[00118] As used herein the following terms have the meanings given: "Boc" refers to tert-butoxycarbonyl; :BOP refers to benzotriazole-1 -yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate; "t-Bu" refers to tert-butyl; "Bz" refers to benzyl; "DOM" refers to dichloromethane; "DIPEA" refers to N,N-Dhsopropylethylamine; "LCMS" refers to liquid chromatography/mass spectrometry; "MIM" refers to monoisotopic mass; Thin refers to minutes; Ms' refers to mesyl which is -SQ2CH3; "NMP" refers to N-methylpyrrolidinone; "TLC" refers to thin layer chromatography; "Pf" refers to Retentian factor; "PT' refers to retention time; "SCX" refers to strong cation exchange; STAB" refers to sodum triacetoxyborohydride; "TFA" refers to trifluoroacetic acid; THE' refers to tetrahydrofuran; and TBME refers to tert-butyl methyl ether.

[00119] The following reaction route, Scheme 1, shows a process for obtaining a late stage intermediate in the synthesis of compounds of the invention. The late stage intermediate can be converted into compaunds of the inventian by further chemical reactions described below. The reaction scheme defines the chemicals with specific stereochemistry; it will be apparent to the person skilled in the art that different stereochemistry can be tolerated within the synthesis and the route is in no way limited to the compounds with the disclosed stereochemistry.

Scheme 1

OH OH OH

(Boo)20 10% Pd-C, H2 Et3N, DMAP MsCI, pyridine N "p MeOH N DCM N DCM

I I I-I I I

Bz OMe OMe Boo OMe OMs N3 N3 1,2-diaminobenzene NaN3 LiOH BOP, DIPEA LN),O DMF N THF,MeOH N DMF I I I I H2O I I Boo OMe Boo OMe Boo OH N3 N3 N3 AoOH 1.TFA L. )..,,,,M L _J..,, 2.CH2O,STAB L J. Boo HN5 L DCM j cc NH2 10% Pd-C, H2

H

MeOH,, N [00120] 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#LCAOB1). The diode array detector wavelength was 254nM and the MS was in positive and negative electrospray mode (m/z: 150-800). A 2pL aliquot was injected onto a guard column (0.2pm x 2mm filters) and UPLC column (C18, 50 x 2.1 mm, cz2Fim) in sequence maintained at 40°C. The samples were eluted at a flow rate of 0.6mLlmin 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.

_________________ Method_1 ____________ Time (mm) %A %B 0 95 5 1.1 95 5 6.1 5 95 7 5 95 7.5 95 5 8 95 5 __________________ Method_2 _____________ Time (mm) %A __________ 0 95 5 0.3 95 5 2 5 95 2.6 95 5 3 95 5

Table 1

[00121] 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 XBridgeTM prep Cl 8 5pM OBO 1 9x1 00mm 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.

Time (mm) %A %B 0 90 10 1.5 90 10 11.7 5 95 13.7 5 95 14 90 90 90 90

Table2

[00122] 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.

[00123] Preparation of intermediates useful in the synthesis of compounds of the invention.

[00124] The compounds disclosed in this section are mixtures of two enantiomers. Only one enantiomer of the mixture is shown. It would be evident to the skilled person what the other enantiomer would, the other enantiomer being a mirror image of the enantiomer shown and having the opposite stereochemistry at each sterocentre. A method for preparing enantiomerically pure intermediates for use in the invention is given in Example 11.

[00125] Preparation of cis-(+/-)-methyl-1-benzyl-4-hydroxypiperidine-2-carboxylate (1) Bz OMe The compound was prepared using the method reported in J. Org. Chem. 56(12)1991 4084-4086.

[00126] Preparation of cis-(+/-)-methyl-4-hydroxypiperid ine-2-carboxylate (2) OMe cis-(÷/-)-Methyl-1 -benzyl-4-hydroxypiperidine-2-carboxylate (5.7g, 22.86mmol) was dissolved in MeOH (50m1) and hydrogenated for 48hrs over 10% Pd-C (0.lg). The mixture was purged of H2 and filtered through celite before concentrating in vacuo to afford cis-(÷/-)-methyl-4-hydroxypiperidine-2-carboxylate (2) (3.65g, 22.8Gmmol, 1000/c) as a brown viscous oil.

1H NMR (400MHz, D6-DMSO) 6/ppm: 5.00-6.00 (2H, bs) 3.86-3.91 (1H, dd, J=2.9, 11.2Hz), 3.73 (3H, s), 3.62-3.73(1 H, m), 3.18-3.26 (IH, m), 2.74-2.84 (1H, dt, J=I.8, 12.0Hz), 2.11 -2.19 (I H, bd, J=12.8Hz), 1.79-1.88(1 H, bd, J=12.8Hz), 1.34-1.49 (2H, m).

[00127] Preparation of cis-(+I-)-1-tert-Butyl 2-metliyI-4-hydroxypiperidine-1,2-dicarboxylate (3) Boc OMe cis-(-i-/-)-Methyl-4-hydroxypiperidine-2-carboxylate (2) (2.6g, 1 6.3ammol) was suspended in DCM (3OmL) and triethylamine (4.55mL, 32.67mmoI) was added forming a pale yellow solution. 4-Dimethylamino pyridine, DMAP (0.2g, 1.6ammol) was added and the suspension was cooled to Dcc before adding di-tert-butyl dicarbonate (4.63g, 21.23mmol). The mixture was allowed to reach room temperature and stir for 3 hrs. Water (60m1) and DCM (30m1) were added and the phases separated. The organic phase was washed with brine, dried (MgSO4) and filtered and concentrated to a brown oil. Purification via flash column chromatography (Si02, loading in DCM and eluting with -80% EtOAc in heptane) afforded cis-(÷/-)-1 -tert-butyl-2-methyl-4-hydroxypiperidine-1 2-dicarboxylate (3) (3.6g, 13.8Bmmol, 85%) as a clear pale brown oil.

H NMR (400MHz,CDCI3) 6/ppm: 4.61 -4.79(1 H, bm), 4.13-4.19(1 H, m), 3.79-3.95 (1 H, bm), 3.75 (3H, s), 3.28-3.47 (1H, m), 2.39-2.49(1 H, m), 1.89-1.95 (1H, m), 1.60-1.79 (bm, 2H), 1.48 (bs, 9H) [00128] Preparation of cis-(+/-)-1-tert-Butyl-2-methyl-4-(methanesulfonyloxy)piperidine-1, 2-dicarboxylate (4) OMs Boc OMe cis-(-i-/-)-1 -tert-Butyl-2-methyl-4-hydroxypiperidine-1,2-dicarboxylate (3) (3.6g, I 3.8Bmmol) was dissolved in DCM (20mL) and pyridine (lOmL) and cooled to 0°C. Methanesulfonyl chloride (1.29mL, 16.e6mmoI) was added slowly and the mixture allowed to warm to room temperature and stir overnight. Saturated NaHCO3 (50 ml) and DCM (50m1) were added and the phases separated.

The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to a pale brown oil cis-(+/-)-l -tert-butyl-2-methyl-4-(methanesulfonyloxy)piperidine-1,2-dicarboxylate (4) (4.5g, 13.34mmol, 96% yield).

1H NMfl (400MHz,CDCI3) ö/ppm:4.71 -4.94(1 H, bm), 3.95-4.04(1 H, m), 3.79-3.95 (1 H, bm), 3.73 (3H, s), 3.25-3.40 (1H, m), 2.99 (3H, s), 2.55-2.63 (1H, m), 1.95-2.02 (2H, m), 1.66-1.70 (1H,m),1.45(9H,bs) [00129] Preparation of trans-(+I-)-1 -tert-Butyl-2-methyl-4-azidopiperidine-1,2-dicarboxylate (5) .yO Boc OMe cis-(-i-/-)-1 -tert-Butyl-2-methyl-4-(methanesulfonyloxy)piperidine-1,2-dicarboxylate (4) (4.8g, 14.23mmol) was dissolved in DMF (5OmL) before adding sodium azide (lug, 17.O7mmol) and heating to 60°C with stirring for l8hrs. Mixture was cooled to room temperature and diluted with saturated NaHCO3 (200m1) and EtOAc (200m1). Aqueous phase was further diluted with water (due to emulsion) and extracted with EtOAc (2 xl OOml). Combined organics were washed with water (150 ml) and brine (150 ml), dried (Na2SO4), filtered and concentrated to a pale brown oil trans-(÷/-)-l-tert-butyl-2-methyl-4-azidopiperidine-l,2-dicarboxylate (5) (3.3g, ii.GOmmol, 82%).

1H NMR (400MHz,CDCI3) 6/ppm: 4.81 -5.05(1 H, bm), 4.01 -4.21 (I H, m), 3.73 (3H, s), 3.39- 3.48(1 H, bm),2.98 -3.07 (IH, m), 2.41 -2.51 (IH, m), 1.95-2.01 (I H, m), 1.60-1.70 (1H, m), 1.50 (bs, I OH) [00130] Preparation of trans-(+/-)-4-Azido-1-[( tert-butoxy)carbonyl]piperidine-2-carboxylic acid (6) Boc OH trans-(+/-)-1 -tert-Butyl-2-methyl-4-azidopiperidine-1,2-dicarboxylate (5) (2.7g, 9.SOmmol) was dissolved in THF (9mL), Methanol (6mL) and Water (3mL) at room temperature. LiOH (907mg, 37.SBmmol) was added in a single portion and the mixture allowed to stir for l8hrs. The mixture was acidified (pH2-3) and extracted with EtOAc (3 x 20m1) and brine (20m1), dried (MgSO4), filtered and concentrated to a white solid trans-(+I-)-4-azido-1 -[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid (6) (2.6g, 9.5mmol, 1 OQ% yield).

1H NMR (400MHz, MeOD) 5/ppm: 4.88-4.95 (1 H, bm), 4.01 -4.11 (1 H, m), 3.39-3.49 (1 H, tt, J= 4.4, 13.4Hz), 2.93 -3.15 (1 H, m), 2.42-2.50 (1H, m), 1.93-2.04 (2H, m), 1.55-1.72 (m, 1H), 1.48 (bs, 9H rotamer a), 1.46 (bs, 9H rotamer b), 1.41 -1.45(1 H, m) [00131] Preparation of trans-(+/-)-tert-Butyl-2-[(2-ami nophenyl)carbamoyll-4-azidopiperidine- 1-carboxylate (7) N3 L N " NH2 H( trans-(+/-)-4-Azido-1 -[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid (6) (2.3g, 8.51 mmol) was dissolved in DMF (1 5mL) under an N2 atmosphere and N,N-dhsopropylethylamine (1.63mL, 9.36mm01) and (benzotriazol-l -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (4.35g, 9.79mmol) were added. The mixture was stirred for 1 Omins before adding o-phenylenediamine (1.12g, 9.36mmol) in several portions. The solution became pale yellow and was allowed to stir overnight. Reaction was diluted with EtOAC (100 ml) and water (100 ml). The phases were separated and aqueous phase, re-extracted with EtOAc (2 x 50 ml). Combined organics were washed with saturated NaHCQ3 (100 ml) and brine (100 ml), dried (MgSO4), filtered and concentrated to a brown oil. Purified by flash chromatography (8i02, loaded in DCM, eluted with 20 -50% EtOAc in heptane). trans-(+/-)-tert-Butyl-2-[(2-aminophenycarbamoyl]-4-azidopiperidine-1 -carboxylate (7) was isolated as a colourless foam (3.14g, 8.38mmol, 98%).

1H NMR (400MHz CDCIS) 5/ppm: 7.95-8.1 (I H, bs), 7.29-7.34(1 H, m), 7.10-7.15(1 H, t, J=7.3Hz) 6.78-6.82 (2H, t, J=7.BHz), 5.05-5.10 (I H, d, J=5.2Hz), 3.85-4.30 (2H, 2xbs), 3.70- 3.85 (2H, s), 2.91 -3.05 (1H, m), 2.51 -2.69(1 H, m), 1.94-2.03 (1H, m), 1.40-165(1 1H, m).

MS Method 2: RT: 1.66mm, m/z 383.3 [M+Na] [00132] Preparation of trans-(÷!-)-tert-Butyl-4-azido-2-(1 H-i,3-benzodiazol-2-yl)piperidine-1 -carboxylate (8) N3 aH N r Boc N /_\ trans-(+/-)-tert-Butyl-2-[(2-aminophenyl)carbamoyl]-4-azidopiperidine-1 -carboxylate (7) (I.99g, 5.S2mmol) was dissolved in acetic acid (I OmL) and heated to 80 C for 3omins.

Mixture was allowed to cool and AcOH removed in vacua to afford trans-(+/-) tert-butyl-4-azido-2- (1 H-i,3-benzodiazol-2-ypiperidine-i -carboxylate (8) (1.91 g, 5.S2mmol, 100%) as a colourless glassy solid.

H NMR (400MHz, CDCIS) 5/ppm: 7.59-7.65 (2H, my 7.25-7.31 (2H, m), 5.7i -5.76 (I H, d, J=5.9Hz), 3.89 -4.20 (1H, m), 2.68-3.03 (2H, m), 1.95-2.05 (1H, m), 1.84-i.89 (1H, dd, J=6.1, 12.0Hz), 1.79-1.84(1 H, dd J=6.1, 12.0Hz), 1.50-1.63 (1OH, m).

MS Method 2: RT: 1.46mm, m/z 343.3 [M+H] [00133] Preparation of trans-(+/-)2-[-4-Azido-i-metliylpiperidin-2-yII-i H-i,3-benzodiazole (9) N3

H

trans-(+/-)tert-Butyl-4-azido-2-(1 H-i,3-benzodiazol-2-ypiperidine-i -carboxylate (8) (2.7g, 7.B9mmol) was dissolved in TFA (6.OBmL, 78.B6mmol) and stirred at room temperature for 1 hr. The TFA was removed in vacua and the oily residue passed through an SCX cartridge eluting with MeOH (30m1) followed by 1 M NH3 in MeOH (30m1). The basic elution was concentrated to a colourless oil which was dissolved in DCM (30m1), formaldehyde solution (36.5-38%) in water (2.2mL, 79.8Smmol) was added and the solution stirred vigourously for 1 hr at room temperature.

The mixture was cooled to 0°C before adding sodium triacetoxyborohydride (4.1 6g, 1 9.61 mmol) in several portions over 10 mins. The mixture was then allowed to warm to room temperature and stir overnight.

The resulting suspension was quenched with 1 M NaOH (to pH8) and passed through a phase separator, dried (Na2SO4) and concentrated to a white solid trans-(+/-)2-[-4-azido-1 -methylpiperidin- 2-ylJ-1H-1,3-benzodiazole (9)(1.lg, 4.2gmmol, 55%).

H NMR (400MHz, CDCIS) 5/ppm: 9.45-9.59(1 H, bs), 7.73-7.78 (I H, m), 7.41 -7.46(1 H, m), 7.25-7.31 (2H, m), 4.00-4.05 (1H, m), 3.78 -3.83 (IH, dd, J=3.4, 10.6Hz), 2.82-2.89 (1H, dt, J=4.0, 12.2Hz), 2.57-2.66 (1H, dt, J=3.6, 11.0Hz), 2.23 (3H, s), 2.11 -2.18 (1H, m), 1.86-2.05 (3H, m).

MS Method 2: RT: 0.97mm, m/z 257.2 [M+H] [00134] Preparation of trans-(+/-)-2-(i H-i,3-Benzodiazol-2-yl)-i-methylpiperidin-4-amine (10) NH2 trans-(+/-)2-[-4-Azido-i -methylpiperidin-2-yl]-i H-i,3-benzodiazole (9) (1.2g, 4.6Smmol) was dissolved in methanol (2OmL) and hydrogenated with i 0% palladium on carbon (20mg) at room temperature and atmospheric pressure for 1 Bhrs. The mixture was purged of H2, filtered through celite and concentrated to a white solid trans-(+/-)-2-(i H-i,3-Benzodiazol-2-y-i -methylpiperidin-4-amine (10) (1.05g, 4.SSmmol, 97%).

1H NMR (400Mhz, ODdS) 3/ppm: 9.61 -9.85 (1 H, bs), 7.72-7.78 (1 H, m), 7.41 -7.46 (1 H, m), 7.22-7.28 (2H, my 3.90-4.06 (1 H, dd, J=3.6, 9.7Hz), 3.31 -3.37(1 H, my 2.77-2.86 (I H, dt, J=4.6, 12.0Hz), 2.69-2.73 (iH, dt, J=3.i, 10.8Hz) 2.29 (3H, s), 2.04-2.11 (I H, m), I.83-1.92 (2H, m), 1.59-1.69 (1 H, m), 1.09-1.29 (2H, bs).

MS Method 2: RT: 0.37mm, m/z 23i.2 [M+H] [00135] Compounds of the Invention [00136] General Procedure 1 described within Example 1 was used in the preparation of Examples 2 to 12. Each of examples I to ID discloses a procedure to produce a racemic mixture ot two enantiomers. One of the two enantiomers is shown [00137] Example 1: trans-(÷I-)-2-(i H-i,3-Benzodiazol-2-yI)-i -methyl-N-(5-phenyl-i,3,4-oxadiazol-2-yI)piperidin-4-amine (ii)

NN

j \\__ /\ HN "O

H

. -S.,, N P3 [00138] General Procedure 1 5-phenyl-3H-i,3,4-oxadiazol-2-one (74.99mg. 0.46mmol) was dissolved in DMF (2mL). DIPEA (0.11 mL, 0.6Smmol), BOP (21 6mg, 0.49mmo) and trans-(-i-/-)-2-(l H-i,3-benzodiazol-2-yl)-i -methylpiperdin-4-amine (10) (75mg, O.S300mmol) were added and the reaction mixture stirred at room temperature for 2 hours. LCMS analysis showed consumption of starting material and formation of product. The reaction mixture was diluted with water (50 mL). The aqueous layer was extracted with EtOAc (4 x 30 mL). The organic layers were combined, washed with brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a crude oil. The crude material was purified using mass directed preparative LCMS. Fractions containing the product were combined and concentrated under reduced pressure. The resulting white solid was dissolved in MeOH and passed through an SCX cartridge eluting with MeOH followed by 1 M NH3 in MeOH.

Fractions containing the product were combined and concentrated under reduced pressure to afford trans-(+/-)-2-(1 H-I,3-benzodiazol-2-yl)-l -methyl-N-(5-phenyl-I,3,4-axadiazol-2-yl)pipericlin-4-amine (11) as a white solid (31mg, 0.OBmmol, 26%).

1H NMR (400MHz, D6-DMSO) ö/ppm: 12.23-12.53 (1 H, bs), 7.95-7.87(1 H, m), 7.76-7.88 (2H, m), 7.37-7.66 (5H, m), 7.06-7.21 (2H, m), 4.04 -4.16 (1H, m), 3.78 -3.95 (IH, m), 2.82 -3.00 (1 H, m), 2.56-2.70 (1 H, m), 1.84-2.20 (7H, m) MS Method 1: RT: 3.09mm, m/z 375.3 [M+H] [00139] The compounds disclosed in Examples 2 to 12 were prepared using General Procedure 1, replacing 5-phenyl-3H-1,3,4-oxadiazol-2-one with the appropriate oxadiazolone.

[00140] Example 2: trans-(+I-)-2-(i H-i,3-Benzodiazol-2-yI)-N-[5-(4-fluorophenyl)-1,3, 4-oxadiazol-2-yII-1-methylpiperidin-4-amine (12)

HN

H

N

Isolated as a white solid (26mg, O.O7mmol, 16%).

1H NMR (400MHz, D4-MeOD) 6/ppm: 7.91 -8.00 (2H, m), 7.51 -7.58 (2H, m), 7.32-7.33 (4H, m), 4.06 -4.11 (1H, m), 3.71 -3.76 (1H, dd, J=3.6, 10.9Hz), 2.93-3.00(1 H, dl, J=3.9, 12.3Hz), 2.59- 2.69 (IH, td, J=3.3, 12.1Hz), 2.03-2.30 (7H, m).

MS Method 1: RT: 2.71 mm, m/z 393.2 [M÷H] [00141] Example 3: trans-(+I-)-2-(i H-i,3-Benzodiazol-2-yl)-N-{5-[4-fluoro-2- (trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-1 -methylpiperidin-4-amine (13) F3C

NN

H N L F

H

N.i#iç_N Isolated as a white solid (14mg, 0.O3mmoI, 7%).

1H NMR (400MHz, D4-MeOD) 5/ppm: 7.99-8.07 (1 H, m), 7.71 -7.75 (1 H, dd, J=2.6, 9.0Hz), 7.51 -7.62 (3H, m), 7.21 -7.27 (2H, m) 4.06-4.11 (1H, m), 3.71 -3.76 (1H, dd, J=3.6, 6.8Hz), 2.92- 2.99(1 H, dt, J=3.9, 12.2Hz), 2.59 -2.69 (1H, td, J=3.3, 12.0Hz), 2.03-2.30 (7H, m).

MS Method I: PT: 3.00mm, m/z 461.2 [M+H]t [00142] Example 4: trans-(÷I-)-3-(5-{[(-2-(i H-i,3-Benzodiazol-2-yl)-1 -methylpiperidin-4-yl]amino}-1,3,4-oxadiazol-2-yl)benzonitrile (14)

HN

H

Isolated as a white solid (11mg, 0.O3mmoI, 5%).

1H NMP (400MHz, D4-MeOD) 5/ppm: 8.24-8.26(1 H, m), 8.19-8.22 (1 H, m), 7.88-7.91 (1 H, dt, J=l.2, 7.8Hz), 7.70-7.75 (I H, dt, J=0.6, 7.8Hz), 7.52-7.57 (2H, m), 7.21 -7.27 (2H, m) 4.08- 4.14 (1 H, m), 3.69-3.78 (1H, dd, J=3.8, 10.6Hz), 2.91 -3.06 (1H, dt, J=4.3, 12.4Hz), 2.59-2.69 (1H, td, J=3.2, 12.1 Hz), 2.03-2.30 (7H, m).

MS Method I: PT: 2.60mm, m/z 400.2 [M+H]t [00143] ExampleS: trans-(+/-)-2-(1 H-i,3-Benzodiazol-2-yl)-i -methyl-N-{5-[4- (trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-4-amine (15) 11 H S.. N Isolated as a white solid (22mg, 0.OSmmoI, 8%).

1H NMR (400MHz, D4-MeOD) 5/ppm: 8.06-8.14 (2H, m), 7.83-7.80 (2H, m), 7.51 -7.60 (2H, m), 7.22-7.27 (2H, m) 4.08-4.14 (1 H, m), 3.69-3.77(1 H, dd, J=3.6, 10.7Hz), 2.94-3.01 (1 H, dt, J=3.7, 12.0Hz), 2.59-2.69 (I H, td, J=2.6, 12.1 Hz), 2.03-2.30 (7H, m).

MS Method 1: RT: 3.1 0mm, m!z 443.2 [M+H] [00144] Example 6: trans-(+/-)-2-(i H-i,3-Benzodiazol-2-yl)-N-[5-(4-methoxyphenyl)-i,3,4-oxadiazol-2-ylI-i -methylpiperid in-4-amine (i 6) oOMe 11 H Isolated as a white solid (38mg, 0.O8mmol, 12%).

H NMR (400MHz, D4-MeOD) 6/ppm: 7.81 -7.87 (2H, m), 7.52-7.57 (2H, m), 7.19-7.27 (2H, m), 7.03-7.09 (2H, m) 4.04-4.09(1 H, m), 3.87 (3H, s), 3.71 -3.77 (1H, dd, J=3.5, 11.0Hz), 2.91 - 2.99(1 H, dt, J=3.B, 12.2Hz), 2.59 -2.69 (1H, td, J=3.2, 12.0Hz), 2.03-2.30 (7H, m).

MS Method I: PT: 2.68mm, m/z 405.3 [M+H]t [00145] Example 7: trans-(÷I-)-2-(i H-i,3-Benzodiazol-2-yl)-N-[5-(2,3-dihydro-i,4-benzodioxin- 6-yl)-i,3,4-oxadiazol-2-yl]-i-methylpiperidin-4-amine (i7) Isolated as a white solid (45mg, 0.lOmmol, 16%).

1H NMR (400MHz, D4-MeOD) 5/ppm: 7.51 -7.59 (2H, m), 7.37-7.41 (2H, dd, J=2.1,4.9Hz), 7.20 -7.25 (2H, m), 6.95-6.99 (1 H, d, J=8.7Hz), 4.28-4.35 (4H, m), 4.04-4.09 (1 H, m), 3.71 -3.75 (1 H, dd, J=3.6, 11.0Hz), 2.92-2.99 (1 H, dt, J=3.8, 12.2Hz), 2.59-2.67(1 H, td, J=3.3, 12.2Hz), 2.03-2.30 (7H, m).

MS Method 1: PT: 2.65mm, m/z 433.2 [M+H] [00146] Example 8: trans-(.i-!-)-2-(i H-i,3-Benzodiazol-2-yl)-N-[5-(2,4-ditluorophenyl)-i,3, 4-oxadiazol-2-ylI-i-methylpiperidin-4-amine (i8)

F

NN

H N..L 0>jj F

H

ç 2..,, N It, Isolated as a white solid (19mg, 0.OSmmoI, 7%).

1H NMR (400MHz, D4-MeOD) 5/ppm: 7.92-8.01 (1 H, m), 7.49-7.60 (2H, bs), 7.13-7.27 (4H, m), 4.07-4.12 (1H, m), 3.69-3.74(1 H, dd, J=3.6, 10.9Hz), 2.92-2.99 (1H, m), 2.59-2.67 (1H, td, J=3.4, 12.1Hz), 2.03-2.30 (7H, m).

MS Method 1: RT: 2.69mm, m/z 411.2 [M+H] [00147] Example 9: trans-(+I-)-4-(5-{[-2-(i H-i,3-Benzodiazol-2-yl)-i-methylpiperidin-4-yl]amino}-i,3, 4-oxadiazol-2-yl)benzonitrile (19)

HN

H

- N

Isolated as a white solid (2.4mg, 0.OO6mmol, 1%).

1H NMR (400MHz, D4-MeOD) 6/ppm: 8.05-8.12 (2H, d, J=8.7Hz), 7.90-7.94 (2H, d, J=8.7Hz), 7.53-7.58 (2H, m), 7.21 -7.26 (2H, m) 4.09-4.14(1 H, t, J=3.4Hz), 3.71 -3.76 (1H, dd, J=3.6, 10.4Hz), 2.91 -2.99 (1 H, dt, J=3.9, 12.1 Hz), 2.59-2.69 (1 H, Id, J=3.4, 12.5Hz), 2.03-2.30 (7H, m).

MS Method 1: RT: 2.60mm, m/z 400.3 [M+H] [00148] Example 10: trans-(+/-)-2-(1 H-i,3-Benzodiazol-2-yl)-N-[5-(4-ch lorophenyl)-i,3,4-oxadiazol-2-ylI-i-methylpiperidin-4-amine (20) H N Cl

H

-,, N i-b Isolated as a white solid (35mg, 0.OOmmol, 22%).

1H NMR (400MHz, D4-MeOD) 6/ppm: 7.86-7.90 (2H, d, J=8.2Hz), 7.55-7.71 (4H, m), 7.21 - 7.26 (2H, m) 4.09-4.14 (I H, m), 3.76-3.79(1 H, d, J=8.6Hz), 2.99-3.08 (I H, d, J=12.2Hz), 2.66 -2.75(1 H, t, J=l 0.9Hz), 2.03-2.30 (7H, m).

MS Method 2: RT: 1.25mm, m/z 409.2, 411.2 [M+H] [00149] Single enantiomers of compounds cf the invention were generally prepared via the methods described above, including the process of Scheme 1 and General Procedure I. Commercially available optically pure I -tert-butyl 2-methyl (2R,4S)-4-hydroxypiperidine-1 2-dicarboxylate (3a) was converted into intermediate (ba) by analogous steps to those shown in Scheme 1 starting from the mesylation reaction. The single enantiomers of compounds of the invention were obtained from (ba) following General Procedure 1.

OH

Boc OMe -(Sa) (ba) [00150] Example 11: (28,4F0-2-(1 H-i,3-Benzodiazol-2-yl)-N-[5-(4-chloropbenyl)-i,3, 4-oxadiazol-2-ylI-i-methylpiperidin-4-amine (21) H N Cl

H

-.. 2',, N i-b Isolated as a white solid (30mg, 0.O7mmol, 33%).

H NMR (400MHz, D4-MeOD) 6/ppm: 7.86-7.90 (2H, d, J=8.2Hz), 7.55-7.59 (4H, m), 7.24- 7.27(2H, m) 4.09 -4.14 (1H, rn) 3.76-3.79(1H, dd, J=3.5, 5.9Hz), 2.99-3.08 OH, dt, J=3.0, 12.2Hz), 2.66-2.75 (1H, td, J=3.2, 12.1 Hz), 2.03-2.30 (7H, m).

MS Method 2: RT: 1.25mm, m/z 409.2, 411.2 [M+H] [00151] Example 12: 4-(5-{[(2R,48)-2-(1 H-i,3-Benzodiazol-2-yl)-i -methylpiperidin-4-yl]amino}-1,3,4-oxadiazol-2-yl)benzonitrile (22)

OQCN 11 H

N

Isolated as a white solid (5mg, 0.01 mmol, 6%).

H NMR (400MHz, CDCI3) S/ppm: 9.85-10.29 (1 H, bs) 7.87 -7.91 (2H, d, J=8.7Hz), 7.62-7.70 (3H, m), 7.31 -7.43 (1H, bs), 7.16-7.22 (2H, m), 6.61 -6.70(1 H, bs), 4.09 -4.16 (1H, m), 3.86- 3.92 (1 H, dd, J=5.8, 8.1 Hz), 2.88-2.95 (1 H, dt, J=4.0, 12.6Hz), 2.56-2.66 (1 H, td, J=3.8, 12.5Hz), 2.25 (3H, s), 2.18-2.24 (2H, m), 2.01 -2.12 (2H, m).

MS Method 2: RT: 1.1 4mm, m/z 400.3 [M+H] [00152] Example 13: trans-(+/-)N-[2-(1 H-i,3-Benzodiazol-2-yl)-i-methylpiperidin-4-yl]-i,3-benzothiazol-2-amine (23) N \/

HN S aH

N

trans-(+/-)-2-(1 H-i,3-Benzodiazol-2-y-1 -methylpiperidmn-4-ammne (10) (100mg, 0.43mmol) and 2-chlorobenzothiazole (81 mg, 0.4Bmmol) were suspended in MeGN (2mL) and heated in a sealed vial in a microwave at 170 CC for 9 hrs. The mixture was diluted with MeOH and purified on an SCX cartridge (2g) eluting with MeOH (20m1) then 1 M NH3 in MeOH (20m1) prior to flash chromatography (5i02 loading in DCM and eluting in 0 -5% MeOH in EtOAc). Pure fractions were combined and concentrated to afford trans-(+/-)N-[2-(i H-i,3-benzodiazol-2-y-1 -methylpiperidin-4-yl]-1 3-benzothiazol-2-amine (23) (30mg, 0.OBmmol, i9.% yield) as a white solid.

1H NMR (400MHz, ODd3) 5/ppm: 9.52-9.78 (1 H, bs), 7.69-7.78 (1 H, bs), 7.53-7.63 (2H, m), 7.42-7.51 (1H, bs), 7.24-7.35 (m, 3H), 7.09-7.15(1 H, t, J=7.8Hz), 5.47-5.53 (1H, bs), 4.21 - 4.27(1 H, m), 3.79-3.85 (I H, dd, J=3.5, 10.6Hz), 2.94-3.01 (I H, dt, J=4.0, 12.3Hz), 2.56-2.64 (IH, m), 2.31 -2.38 (IH, m), 2.17-2.28 (4H, m), 2.07-2.15 (2H, m) MS Method 2: RT: 1.20mm, m/z 364.2 [M+H] [00153] Example 14: trans-(+I-)N-[-2-(l H-1,3-Benzodiazol-2-yl)-1-methylpiperidin-4-ylI-1,3- benzoxazol-2-amine (25) and trans-(+/-)-N-I-1 -Methyl-2-(i-methyl-i H-i,3-benzodiazol-2-yl)piperidin-4-ylI-1,3-benzoxazol-2-amine (26)

HNP

H

trans-(+/-)-2-(i H-i,3-Benzodiazol-2-y-i -methylpiperidin-4-amine (10) (100mg, 0.43mmol) and 2-chlorobenzoxazole (73mg, 0.48mmol) were suspended in MeGN (2mL) and heated in a sealed vial in a microwave at 170 0C for 9 hrs. The mixture was diluted with MeOH and purified on an SCX cartridge (2g) eluting with MeOH (20m1) then 1 M NH3 in MeOH (20m1) prior to flash chromatography (Si02 loading in 0CM and eluting in 0 -5% MeOH in EtOAc). Pure fractions were combined and concentrated to afford trans-(+/-)N-[2-(i H-i,3-benzodiazol-2-y-1 -methylpiperidin-4-yl]-i 3-benzothiazol-2-amine (23) (25mg, 0.O6mmol, 13% yield) as a white solid.

1H NMR (400MHz, D4-MeOD) 5/ppm: 8.53-8.61 (1 H bs) 7.52-7.59 (2H, m), 7.20-7.29 (4H, m), 7.12-7.19 (1H, t, J=7.6Hz), 7.00-7.06 (1H, t, J=7.6Hz), 3.79-3.82(1 H, m), 3.49-3.54 (1H, dd, J=2.8, 11.6Hz), 3.13-3.19 (1H, m), 2.45-2.49 (1H, td, J=2.4, 12.2Hz), 2.29 -2.36 (1H, m), 2.18- 2.25 (IH, m), 2.13 (3H, s), 1.79-2.00 (2H, m) MS Method 2: RT: 1.1 6mm, m/z 348.2 [M+H] trans-(+/-)-N-[-i -Methyl-2-(l -methyl-I H-i,3-benzodiazol-2-yl)piperidin-4-yl]-I,3-benzoxazol-2-amine (26) was isolated as an impurity from the reaction of trans-(-i-/-)-2-(i H-i,3-benzodiazol-2-y-1 -methylpiperdin-4-amine (10) and 2-chlorobenzoxazole (15mg, 0.O4mmol, 9%). N \/ HN 0 a'

H NMP (400MHz, CDCI3) 5/ppm: 9.96-10.37 (I H bs) 7.59-7.70 (I H, bs), 7.34-7.43 (I H, bs), 7.25-7.36 (1H, dd, J=0.6, 7.9Hz), 7.15-7.22 (4H, m), 7.05-7.11 (1H, td, J=1.1, 7.6Hz)7.00 - 7.06 (1 H, td, J=1.1, 7.6Hz), 4.25-4.34 (1 H, m), 3.64-3.69 (1 H, dd, J=4.3, 10.6Hz), 3.42 (3H, s), 3.11 -3.17 (1H, dt, J=3.8, 11.8Hz), 2.39-2.54(1 H, m), 2.01 -2.26 (6H, m), 1.85-1.91 (1 H, m) MS Method 2: PT: 1.21 mm, m/z 362.2 [M+H]t [00154] Example 15: trans-(+/-)-N-[-2-(i H-i,3-Benzodiazol-2-yl)-1-methylpiperidin-4-ylI-1H- 1,3-benzodiazol-2-amine (24) i-p trans-(+/-)-2-(1 H-i,3-Benzodiazol-2-y-1 -methylpiperidin-4-amine (10) (100mg, 0.43mmol) was dissolved in a biphasic mixture of DCM (SmL) and saturated aqueous NaHCO3 (5 ml) and stirred vigorously before adding thiophosgene (0.O4rnL, 0.48mmol), the resulting mixture was left to stir for 1 hr. The mixture was added to a phase separator and the DCM concentrated to a brown foam which was dissolved in DMF (5mL) before adding (benzotriazol-1 - yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (289mg, 0.6Smmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (132.2mg, 0.B700mmol) and o-phenylenediamine (51.65mg, 0.4800mmol). The mixture was transferred to a microwave vial and heated to 150 C for 1 hr. The solvent was removed in vacuo and the mixture passed through an SCX cartridge (eluting with MeOH, then I M NH3 in MeOH) before purification by flash column chromatography, (loading in DOM and eluting with 5-20% MeOH in EtOAc). The product trans-(+/-)-N-[-2-(i H-i,3-benzodiazol-2-yD-1 -methylpiperidin-4-yl]-i H-i,3-benzodiazoH2-amine (24) was isolated as a white solid (30mg, 0.09, 20%).

H NMP (400MHz, D4-MeOD) 5/ppm: 7.51 -7.57 (2H, m), 7.19-7.27 (4H, m), 6.97-7.03 (2H, m), 5.47-5.53 (iH, bs), 4.17-4.23 (m, 1H), 3.72-3.77(1 H, dd, J=4.1, 10.3Hz), 2.94 -3.01 (iH, dt, J=4.0, 12.3Hz), 2.61 -2.69 (I H, td, J=3.0, I 2.2Hz), 2.31 -2.38 (I H, m), 2.11 -2.26 (6H, m), 2.07- 2.15 (IH, m) MS Method 2: PT: 0.97mm, m/z 347.3 [M+H]t [00155] 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 1C50 values.

[00156] The Oh-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.

[00157] Oh-reporter NIH-3T3 cells were seeded at 20,000 cells/well into 96 well, poly-D-lysine coated white clear bottomed full area TC plates in growth media (without geneticin). Three wells were left with just media as cell free controls. Cells were then incubated for 24 hours at 37°C in a 5% CO2.

[00158] Serial dilutions of the test compounds were prepared in 1 00% DMSO. 1 Op1 of compound or DM50 from each well was pipetted into a sterile, 0.5m1 deep well conical bottomed 96 well plate (intermediate plate). 1 90pl of warmed assay media (Opti-MEM supplemented with 0.5% calf serum, 1% non-essential amino acids, 1mM sodium pyruvate, 10mM HEPES, 1% penicillin/Streptomycin) was then added to each well and mixed five times at 1 80p1 by electronic pipette to ensure homogeneity of the compound solution. This 1:20 dilution gives a top concentration of 5OpM in 5% OMSO, 95% assay media. 1 Op1 was pipetted from each well of the intermediate plate into a second deep well sterile plate. 490p1 of warm assay media was then added to each well and mixed five times at 300p1. This gives a final top concentration of 1 pM in 0.1% DM50.

[00159] After the 24 hour incubation, media was carefully removed by pipette and replaced with 45pl of compound dilutions in triplicate. This was incubated for one hour at 37°C in a 5% CO2. After an hour, 5p1 1 Opg/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.

[00160] After 24 hours, plates were removed from the incubator and left to acclimatise to room temperature for 20 minutes. SOp1 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).

[00161] 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 1C50 value of the compound as "+", "++" and "-i-+-i-". The category "+" refers to compounds with an 1C50 of IOU nM to 1 pM. The category "++" refers to compounds with an 1C50 of 25 nM to 100 nM. The category ÷÷÷" refers to compounds with an 1C50 of <25 nM.

Table 3

Compound Category 1 trans-(-i-I-)-N-[-i -Methyl-2-(i -methyl-i H-i,3-benzodiazol-2-ypiperidin-4-yl]-i 3-benzoxazol-2-amine + 2 trans-(+I-)N-[-2-(i H-i 3-Benzodiazol-2-yl)-i -methylpiperidin-4-yl]- 1,3-benzoxazol-2-amine trans-(-i-I-)-N-[-2-(1 H-i,3-Benzodiazok2-y-i -methylpiperidin-4-yl]-i H-i 3-benzodiazol-2-amine + 4 trans-(+I-)N-[2-(i H-i 3-Benzodiazol-2-y-i -methylpiperidin-4-yl]-i,3-benzothiazol-2-amine + trans-(+/-)-2-(i H-i,3-Benzodiazol-2-y-i -methyl-N-(5-phenyl-i 3,4-oxadiazol-2-ypiperdin-4-amine ++ 6 trans-(+I-)-2-(i H-i,3-Benzodiazol-2-y)-N-[5-(4-chlorophenyl)-i 3,4-oxadiazol-2-yl]-i -methylpiperidin-4-amine ++ 7 (2R,4R)-2-(i H-i,3-Benzodiazol-2-y-N-[5-(4-chloropheny-i 3,4-oxacliazol-2-yl]-i -methylpiperidin-4-amine 8 trans-(÷/-)-2-(i H-i,3-Benzocliazol-2-y-N-[5-(4-fluorophenyl)-i 3,4-oxadiazol-2-yl]-i -methylpiperidin-4-amine ++ trans-(+I-)-2-(i H-i,3-Benzodiazol-2-yl)-N-{5-[4-fluoro-2- 9 (trifluoromethyphenyl]-i,3,4-oxadiazol-2-yl}-1 -methylpiperidin-4-++ ____ amine __________ trans-(+/-)-3-(5-{[(-2-(i H-i,3-Benzodiazol-2-y-i -methylpiperidin-4-++ yl]amino}-i,3,4-oxadiazol-2-ybenzonitrile trans-(+/-)-2-(i H-i,3-Benzodiazol-2-y-i -methyl-N-{5-[4- (trifluoromethyl)phenyl]-i,3,4-oxactazol-2-yl}piperidin-4-amine i 2 trans-(+/-)-2-(i H-i,3-Benzodiazol-2-y-N-[5-(4-methoxypheny-i,3,4-oxadiazol-2-yl]-i -methylpiperidin-4-amine -f i 3 trans-(+/-)-2-(i H-i,3-Benzodiazol-2-y-N-[5-(2,3-dihydro-i 4-benzodioxin-6-y-i,3,4-oxadiazol-2-yl]-i -methylpiperidin-4-amine + i 4 trans-(+/-)-2-(i H-i,3-Benzodiazol-2-yl)-N-[5-(2,4-difluoropheny-i,3,4-oxadiazol-2-yl]-i -methylpiperidin-4-amine + i 5 trans-(+/-)-4-(5-{[-2-(i H-i,3-Benzodiazol-2-y-i -methylpiperidin-4-++ yl]amino}-i,3,4-oxadiazol-2-ybenzonitrile i 6 4-(5-{[(2R,4R)-2-(i H-i,3-Benzodiazol-2-yl)-i -methylpiperidin-4-yl]amino}-i,3,4-oxadiazol-2-ybenzonitrile [00162] Examples of compounds of the invention with values for their 1C50 are given in the table below.

Table 4

Compound 1C50 (nM) 7 (2R,4R)-2-(i H-i,3-Benzodiazol-2-yl)-N-[5-(4-chlorophenyl)-i -2i oxadiazol-2-yl]-i -methylpiperidin-4-amine trans-(+/-)-2-(i H-i,3-Benzodiazol-2-y-i -methyl-N-{5-[4-22 42 (trifluoromethyl)phenyl]-i,3,4-oxadazol-2-yl}piperidin-4-amine [00163] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of them mean "includng 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.

[00164] 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.

[00165] The readers attention is directed to all papers and documents which are filed concurrently with or prevous 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 (34)

1. CLAIMS1. A compound according to formula (I) and pharmaceutically acceptable salts thereof: (I) wherein A is a 5-membered heterocyclic moiety, wherein the 5-membered heterocyclic moiety is either: substituted by a 6-membered aryl moiety or a 6-membered heteroaryl moiety, the 6-membered aryl moiety or the 6-membered heteroaryl moiety being unsubstituted or substituted by from one to four independently selected R5 groups; or fused to a 6-membered aryl or heteroaryl moiety to form a 9-membered fused bicyclic ring system, the 6-membered aryl moiety or 6-membered heteroaryl moiety being unsubstituted or substituted by from one to four independently selected R5 groups; and wherein the 5-membered heterocyclic moiety is unsubstituted or substituted; R, R2 and R3 are independently selected from hydrogen or-S02R3, or are a substituted or unsubstituted group independently selected from: C4 alkyl, 04 haloalkyl, 014 acyl, cycloalkyl, and 03-7 halocycloalkyl; P4 is independently selected at each occurrence from: halo, Qpa, spa, Npapb, -ON, _NRac(o)po, C(O)NWRb, soRa, so2RE, SO2NFrRb, NRaSo2Rb 0 alkyl, C16 haloalkyl, 037 cycloalkyl and halocycloalkyl; R5 is independently selected at each occurrence from: halo, C16 alkyl, C16 haloalkyl, Qpa, sRa, oRrndORa, C26 alkenyl, 026 alkynyl, 037 cycloalkyl, 037 cycloalkenyl, NRaRb, -CN, azido, -0(O)R3, -O(O)0R3, soR, SO2R, -SO2NRR, NR3SO2Rb, _NR3C(O)Rc, and 0(O)NR3Rb, aryl and heteroaryl; or two adjacent P5 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 P5 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; n is selected from 0, I, 2, 3 or 4; Ra and pb are independently selected at each occurrence from: H, 01-4 alkyl, 01-4 haloalkyl, 01-4 acyl, 03.7 cycloalkyl, and C37 halocycloalkyl; RC and Rd are independently selected at each occurrence from: H, halo, 01-4 alkyl, 01-4 haloalkyl, C14 acyl, C7 cycloalkyl, and C37 halocycloalkyl; when a group is substituted, the group contains 1 to 5 substituents independently selected at each occurrence from the group comprising: halo, 0Ra, -SRS, NRaRb, NO2, =0, -ON, acyl, C16 alkyl, C16 haloalkyl, C7 cycloalkyl, SO2Ra, and SO3Ra, C(0Ra)RaRb, C(O)Ra C(0)0Ra and c(o)NRaRb.
2. 2. The compound of claim 1, wherein the 5-membered heterocyclic moiety of A comprises three hetero atoms selected from 0, S or N and is substituted by a 6-membered aryl or heteroaryl moiety.
3. 3. The compound of claim 1, wherein the 5-membered heterocyclic moiety of A comprises two hetero atoms selected from 0, S or N and is fused to a 6-membered aryl or heteroaryl moiety to form a 9-membered fused bicyclic ring system.
4. 4. The compound of any preceding claim, wherein the 5-membered heterocyclic moiety of A is a 5 membered heteroaryl group.
5. 5. The compound of claim 1, wherein the 5-membered heterocyclic moiety of A is selected from: oxadiazolyl, thiadiazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl and triazolyl.
6. 6. The compound of any preceding claim, wherein the 6-membered aryl or heteroaryl moiety of A is selected from: phenyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, optionally phenyl.
7. 7. The compound of claim 1, wherein A is represented by: X2X3 wherein Xis selected from 0, S or NRa; X2 is selected from CRC or N; and X3 is CRC or N and R6 is a 6-membered aryl or 6-membered heteroaryl moiety; or X3 isO and X3 together with R6 form a fused 6-membered aryl or 6-membered heteroaryl moiety; wherein the 6-membered aryl or 6-membered heteroaryl moiety is unsubstituted or substituted by from one to four independently selected R5 groups.
8. 8. The compound of claim 7, wherein P6 is selected from: phenyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, or the fused 6-membereci aryl or 6-membered heteroaryl moiety formed by X3 together with R6 is selected from: phenyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.x2 -X3 ii
9. 9. The compound of any preceding claim, wherein A or are represented by.

   X2 /=\(R)m x2 Xl wherein m and o are both independently selected from 0, 1, 2, 3 and 4. x2 -
10. 10. A compound of any preceding claim wherein, A or are represented by.

    NN />(R5)m I Nk,
11. I I II. The compound of any preceding claim, wherein P5 is selected from: halo, C16 alkyl, C16 haloalkyl, QRa and -CN; or two adjacent P5 groups may form a ring with the carbon atom to which they are attached forming a fused bicyclic ring system of 10 atoms, wherein the ring formed by the two R5 groups is a heterocyclic ring with 6 atoms.
12. 12. The compound of any preceding claim, wherein A1, R2 and R3 are independently selected from hydrogen or SO2Ra, or substituted or unsubstituted: C14 alkyl, C14 haloalkyl or C14 acyl.
13. 13. The compound of any preceding claim, wherein P1 is hydrogen, P2 is C14 alkyl, preferably methyl, and P3 is hydrogen.
14. 14. The compound of claim 1, wherein the compound of formula (I) is selected from.HN)9 HN)PFNNNNH N H N 0 Me H N F La F3CHNXOF CN NH N H NH NLtNNNH N OQ H NCN HNOHcYc:1Tb H N CF3NLO
15. 15. A compound of any preceding claim for use as a medicament.
16. 16. A compound of any of claims 1 to 14 for use in a method of treatment of a condition which is modulated by the Hedgehog signalling pathway.
17. 17. A compound of claim 16, wherein the condition which is modulated by the Hedgehog signalling pathway is cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia.
18. 18. A compound of claim 16 or claim 17, 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.
19. 19. A compound of claim 16, wherein the condition is selected from: benign prostatic hyperplasia, psoriasis and osteoporosis.
20. 20. A compound of any of claim ito 14 for use in inhibiting stem cell production, inhibiting stem cell renewal and inhibiting and/or modulating stem cell differentiation.
21. 21. A compound of any of claims 1 to 14 for use simultaneously, sequentiaNy or separately with an additional anti-tumour agent.
22. 22. The compound of claim 21 for use in a method of treatment of cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia.
23. 23. A compound of claim 21 for use in a method of treatment 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, multple 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.
24. 24. A pharmaceutical composition, wherein the composition comprises a compound of any of claims Ito 14 and a pharmaceutically acceptable excipient.
25. 25. A pharmaceutical composition of claim 24 wherein the composition is a combination product and comprises an additional pharmaceutically active agent.
26. 26. 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 ito 14, to a patient in need thereof.
27. 27. A method of treatment of claim 26 wherein the condition which is modulated by the Hedgehog pathway is selected from: cancer, sarcoma, carcinoma, blastoma, lymphoma and leukemia.
28. 28. A method of treatment of claim 26 or claim 27 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, parathyroici 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.
29. 29. 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 14, to a patient in need thereof.
30. 30. 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 14, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-tumour agent to a patient in need thereof.
31. 31. The method of treatment of claim 30, 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.
32. 32. A method of providing a combination product, wherein the method comprises providing a compound of any of claims 1 to 14 simultaneously, sequentially or separately with an anti-tumour agent.
33. 33. Use of a compound of any of claims 1 to 14 in combination with an anti-tumour agent.
34. 34. Use of a compound of any of claims 1 to 14 in the manufacture of a medicament for use in the treatment of a condition modulated by the Hedgehog pathway.