BR112016012182B1 - COMPOUND AND ITS USE - Google Patents

Abstract

COMPOUND, PROCESS FOR PREPARING A COMPOUND, PHARMACEUTICAL COMPOSITION, INTERMEDIATE The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof wherein R1, R2, R3, R4 and R5 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing the same and their use in therapy. (I)

Description

[001] The present invention relates to the use of piperidine derivatives in therapy, particularly for the treatment or prevention of neurological and psychiatric conditions.

[002] Prokineticins are cysteine-rich regulatory peptides that are thought to exert signaling activity through two highly conserved G protein-coupled receptors (GPCRs), the prokineticin receptor 1 (PKR1 or PROKR1) and the prokineticin receptor 2 ( PKR2 or PROKR2), which belong to the 7-transmembrane domain, G protein-coupled receptor (GPCR) superfamily.

[003] Prokineticin Receptor 1 (also known as GPR73) shows 87% homology to Prokineticin Receptor 2 (also known as GPR73L1). Prokineticins (PK1 and PK2) contain 86 and 81 amino acids respectively, sharing 45% amino acid identity. Both prokineticins activate the two prokineticin receptors, PKR1 and PKR2, with similar potency.

[004] The PKR1 receptor couples to Gq/G11 proteins leading to activation of phospholipase C, inositol phosphate production, and calcium mobilization. In addition, activation of mitogen-activated protein kinase (MAPK) pathways has also been described.

[005] PKR1 is widely distributed in peripheral tissues, including the intestinal tract, testis, uterus, lung, mouse dorsal root ganglion, macrophage, bone, heart, rectum, white adipose tissue, and peripheral blood leukocytes.

[006] In addition, the receptor is expressed in the brain particularly in the olfactory regions, as well as in neurons of the dorsal root ganglion (DRG), mouse hippocampus, dentate gyrus, cerebellar cortex, cerebral cortex, human hippocampus, amygdala, medulla medulla and spinal cord.

[007] Prokineticins were originally identified as potent agents mediating gut motility, but were later shown to promote angiogenesis in steroidogenic glands (eg, adrenal gland), heart, and reproductive systems. They also modulate neurogenesis, circadian rhythms, nociception, hematopoiesis, as well as the immune response. Prokineticins are thought to be associated with pathologies of the reproductive and nervous systems, myocardial infarction and tumorigenesis.

[008] Consequently, antagonism of the functions of prokineticins may have utility in the treatment of disorders or diseases including gastrointestinal motility, angiogenesis, hematopoiesis, diabetes (for example, as described in International Patent Application Publication No. WO 2010/077976) and pain (for example, as described in International Patent Application Publication WO 2007/079214).

[009] Certain piperidine derivatives are known chemical library compounds with no known use that are available from commercial suppliers such as Chembridge Corporation, Asinex Limited or Aurora Fine Chemicals, in particular the following compounds having Nos. Registration in Chemical Abstracts. 1394453-66-7, 1394435-52-9, 1381674-37-8, 1381666-19-8, 1214443-17-0, 1428016-79-8, 1381044-09-2, 1380857-90-8 and 1380854- 82-9. Other piperidine derivatives which are said to be metabotropic glutamate receptor (mGluR) modulators are known from International Patent Application Publication No. WO 2008/015271.

[0010] We have now discovered a new class of compounds that are prokineticin receptor modulators that have desirable activity profiles. The compounds of this invention have beneficial potency, selectivity and/or pharmacokinetic properties.

em que R1 representa um grupo heteroaromático de 6 a 10 membros contendo de um a três heteroátomos no anel selecionados de átomos de nitrogênio, o grupo heteroaromático sendo substituído por pelo menos um substituinte selecionado de halogênio, ciano, C1-C6 alquil, C2-C6 alquenil, C2-C6 alquinil, C1-C6 haloalquil, C1-C6 hidroxialquil, C1-C6 alcoxi, C1-C6 haloalcoxi, C1-C6 alquilcarbonil, C1-C6 alquilcarboniloxi, C1-C6 alcoxicarbonil, -NR6R7, -CONR8R9, C3-C6 cicloalquil, C3-C6 cicloalquiloxi ou C3-C6 cicloalquilmetil; R2 representa um hidrogênio ou átomo de flúor ou um hidroxil ou Grupo C1-C3 alcoxi, R3 representa um átomo de hidrogênio e R4 representa um átomo de hidrogênio, ou, quando R4 representa um átomo de hidrogênio, R2 pode juntamente com R3 formar uma ligação carbono-carbono simples ou R2 e R3 pode juntamente com os átomos de carbono aos quais estão ligados formar um anel ciclopropil, ou, quando R3 representa um átomo de hidrogênio, R2 pode juntamente com R4 formar uma ligação carbono-carbono simples ou R2 e R4 pode juntamente com os átomos de carbono aos quais estão ligados formar um anel ciclopropil; R5 representa um grupo heteroaromático de 5- a 6-membros contendo de um a três heteroátomos no anel selecionados de átomos de nitrogênio, o grupo heteroaromático sendo substituído por pelo menos um substituinte selecionado de halogênio, ciano, C1-C6 alquil, C2-C6 alquenil, C2-C6 alquinil, C1-C6 haloalquil, C1-C6 hidroxialquil, C1-C6 alcoxi, C1-C6 haloalcoxi, C1-C6 alquilcarbonil, C1-C6 alquilcarboniloxi, C1-C6 alcoxicarbonil, -NR10R11, -CONR12R13, C3-C6 cicloalquil, C3-C6 cicloalquiloxi ou C3-C6 cicloalquilmetil; R6 e R7 cada um independentemente representa um átomo de hidrogênio ou um grupo C1-C6 alquil ou C3-C6 cicloalquil, ou R6 e R7podem juntamente com o átomo de nitrogênio ao qual estão ligados formar um anel heterocíclico saturado de 4 a 7 membros opcionalmente substituído por pelo menos um substituinte selecionado de flúor, hidroxil e C1-C3 alcoxi; R8 e R9 cada um independentemente representa um átomo de hidrogênio ou um grupo C1-C6 alquil, ou R8 e R9pode juntamente com o átomo de nitrogênio ao qual estão ligados formar um anel heterocíclico saturado de 4 a 7 membros; R10 e R11 cada um independentemente representa um átomo de hidrogênio ou um hidroxil, C1-C6 alquil, C1-C6 haloalquil, Grupo C1-C6 alcoxi ou C3-C6 cicloalquil, ou R10 e R11pode juntamente com o átomo de nitrogênio ao qual estão ligados formar um anel heterocíclico saturado de 4 a 7 membros opcionalmente substituído por pelo menos um substituinte selecionado de flúor, hidroxil e C1-C3 alcoxi; e R12 e R13 cada um independentemente representa um átomo de hidrogênio ou um grupo C1-C6 alquil, ou R12 e R13pode juntamente com o átomo de nitrogênio ao qual estão ligados formar um anel heterocíclico saturado de 4 a 7 membros; contanto que o composto de fórmula (I) não seja: (1)[4-[3-(7-metil-1H-1,3-benzodiazol-2-il)piperidina-1- carbonil]piridin-2-amina] (CAS N.° 1394453-66-7), (2)[N-metil-4-[3-(7-metil-1H-1,3-benzodiazol-2-il)piperidina- 1-carbonil]piridin-2-amina (CAS N.° 1394435-52-9), (3) [3-[3-[(1,1-dimetiletil)amino)imidazo[1,2-a]piridin-2-il]- 1-piperidinil](3-metil-4-piridinil)metanona (CAS N.° 1381674 37-8), (4)[3-[3-[(1,1-dimetiletil)amino)imidazo[1,2-a]piridin-2-il]- 1-piperidinil](2-metoxi-4-piridinil)metanona (CAS N.° 1381666 19-8), (5)[2-(metilamino)-4-piridinil][3-[1-(1-metiletil)-1H- benzimidazol-2-il]-1-piperidinil]metanona (CAS N.° 1214443-17 0), (6)(1,5-dimetil-1H-pirazol-4-il)[3-(6-metil-1H-benzimidazol-2- il)-1-piperidinil]metanona (CAS N.° 1428016-79-8), (7)6-{1-[(1,3-dimetil-1H-pirazol-4-il)carbonil]-3- piperidinil}-N,N-dimetilnicotinamida (CAS N.° 1381044-09-2), (8)(1-metil-1H-pirazol-4-il)[3-(5-metil-2-piridinil)-1- piperidinil]metanona (CAS N.° 1380857-90-8), ou (9)[3-[6-(metilamino)-2-piridinil]-1-piperidinil](1-metil-1H- pirazol-4-il)metanona (CAS N.° 1380854-82-9); ou um sal farmaceuticamente aceitável dos mesmos.[0011] In accordance with the present invention there is therefore provided a compound of formula

wherein R1 represents a 6- to 10-membered heteroaromatic group containing from one to three ring heteroatoms selected from nitrogen atoms, the heteroaromatic group being replaced by at least one substituent selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkoxycarbonyl, -NR6R7, -CONR8R9, C3- C6 cycloalkyl, C3-C6 cycloalkyloxy or C3-C6 cycloalkylmethyl; R2 represents a hydrogen or fluorine atom or a hydroxyl or C1-C3 alkoxy Group, R3 represents a hydrogen atom and R4 represents a hydrogen atom, or, when R4 represents a hydrogen atom, R2 may together with R3 form a bond single carbon-carbon or R2 and R3 can together with the carbon atoms to which they are attached form a cyclopropyl ring, or, when R3 represents a hydrogen atom, R2 can together with R4 form a single carbon-carbon bond or R2 and R4 can together with the carbon atoms to which they are attached form a cyclopropyl ring; R5 represents a 5- to 6-membered heteroaromatic group containing from one to three ring heteroatoms selected from nitrogen atoms, the heteroaromatic group being substituted by at least one substituent selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkoxycarbonyl, -NR10R11, -CONR12R13, C3- C6 cycloalkyl, C3-C6 cycloalkyloxy or C3-C6 cycloalkylmethyl; R6 and R7 each independently represent a hydrogen atom or a C1-C6 alkyl or C3-C6 cycloalkyl group, or R6 and R7 may together with the nitrogen atom to which they are attached form an optionally substituted 4- to 7-membered saturated heterocyclic ring by at least one substituent selected from fluorine, hydroxyl and C1-C3 alkoxy; R8 and R9 each independently represent a hydrogen atom or a C1-C6 alkyl group, or R8 and R9 can together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R10 and R11 each independently represents a hydrogen atom or a hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl group, or R10 and R11 can together with the nitrogen atom to which they are attached forming a 4- to 7-membered saturated heterocyclic ring optionally substituted with at least one substituent selected from fluoro, hydroxyl and C1-C3 alkoxy; and R12 and R13 each independently represents a hydrogen atom or a C1-C6 alkyl group, or R12 and R13 can together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; provided that the compound of formula (I) is not: (1)[4-[3-(7-methyl-1H-1,3-benzodiazol-2-yl)piperidine-1-carbonyl]pyridin-2-amine] (CAS No. 1394453-66-7), (2)[N-methyl-4-[3-(7-methyl-1H-1,3-benzodiazol-2-yl)piperidine-1-carbonyl]pyridin- 2-amine (CAS No. 1394435-52-9), (3) [3-[3-[(1,1-dimethylethyl)amino)imidazo[1,2-a]pyridin-2-yl]-1 -piperidinyl](3-methyl-4-pyridinyl)methanone (CAS No. 1381674 37-8), (4)[3-[3-[(1,1-dimethylethyl)amino)imidazo[1,2-a ]pyridin-2-yl]-1-piperidinyl](2-methoxy-4-pyridinyl)methanone (CAS No. 1381666 19-8), (5)[2-(methylamino)-4-pyridinyl][3- [1-(1-methylethyl)-1H-benzimidazol-2-yl]-1-piperidinyl]methanone (CAS No. 1214443-170), (6)(1,5-dimethyl-1H-pyrazol-4- yl)[3-(6-methyl-1H-benzimidazol-2-yl)-1-piperidinyl]methanone (CAS No. 1428016-79-8), (7)6-{1-[(1,3- dimethyl-1H-pyrazol-4-yl)carbonyl]-3-piperidinyl}-N,N-dimethylnicotinamide (CAS No. 1381044-09-2), (8)(1-methyl-1H-pyrazol-4-yl) )[3-(5-methyl-2-pyridinyl)-1-piperidinyl]methanone (CAS No. 1380857-90-8), or (9)[3-[6-(methylamino)-2-pyridinyl]- 1-piperidinyl](1-methyl-1H-pyrazol-4-yl)methanone (CAS No. 1380854-82-9); or a pharmaceutically acceptable salt thereof.

[0012] In the context of the present specification, unless otherwise indicated, an alkyl, alkenyl or alkynyl substituent group or an alkyl, alkenyl or alkynyl moiety in a substituent group may be linear or branched. Examples of C1-C6 alkyl groups/moieties include methyl, ethyl, propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2- methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl -2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, tert-butyl , n-pentyl, isopentyl, neopentyl and n-hexyl. Examples of C2-C6 alkenyl groups/moieties include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1- hexadienyl. Examples of C2-C6 alkynyl Groups/fractions include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl and 1-hexynyl.

[0013] A C1-C6 haloalkyl or C1C6 substituent group/moiety will be composed of at least one halogen atom, for example one, two, three, four or five halogen atoms, examples of which include trifluoromethyl, trifluoromethoxy or pentafluoroethyl .

[0014] A C1-C6 hydroxyalkyl substituent group/moiety will comprise at least one hydroxyl group, for example one, two, three or four hydroxyl groups, examples of which include -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH (OH)CH2OH, -CH(CH3)OH and -CH(CH2OH)2.

[0015] The term "heteroaromatic" group, as used herein, refers to an aryl group in which 1 to 3 carbon atoms in the ring are replaced by nitrogen atoms. The heteroaromatic group can be monocyclic or polycyclic (e.g., bicyclic) in which two or more rings are fused. The heteroaromatic group may be attached to any suitable ring atom (i.e., to any carbon or nitrogen atom of the heteroaromatic ring system). Examples of heteroaromatic groups include the following:

[0016] A C3-C6 cycloalkyl group or moiety in a substituent group represents a saturated monocyclic hydrocarbon ring structure containing from three to six carbon atoms.

[0017] A 4- to 7-membered saturated heterocyclic ring will contain at least one ring nitrogen atom and may contain one or more (e.g., one or two) other ring heteroatoms independently selected from nitrogen, oxygen and sulfur atoms . It will be understood that the definition is not intended to include unstable structures or any O-O, O-S or S-S bonds and that a substituent, if present, may be attached to any atom in the ring. Examples of heterocyclic rings include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 1,4-azathianyl, azepanyl and 1,4-oxazepanyl.

[0018] When any chemical moiety or group in formula (I) is described as being optionally substituted, it will be appreciated that the moiety or group may be substituted or unsubstituted by one or more of the specified substituents. It will be appreciated that the number and nature of the substituents will be selected in order to avoid sterically undesirable combinations.

[0019] R1 represents a 6, 7 or 8 to 9 or 10 membered heteroaromatic group containing one, two or three heteroatoms selected from nitrogen atoms (e.g. pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzodiazolyl, indolyl, quinolinyl and quinazolinyl), the heteroaromatic group being substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g. fluorine, chlorine or bromine), cyano, C1-C6, or C1 -C4, or C1-C2 alkyl, C2-C6 or C2-C4 alkenyl, C2-C6 or C2-C4 alkynyl, C1-C6, or C1-C4, or C1-C2 haloalkyl, C1C6, or C1-C4, or C1-C2 hydroxyalkyl, C1-C6, or C1-C4, or C1-C2 alkoxy, C1-C6, or C1-C4, or C1-C2 haloalkoxy, C1-C6, or C1-C4, or C1-C2 alkylcarbonyl, C1-C6, or C1-C4, or C1-C2 alkylcarbonyloxy, C1-C6, or C1-C4, or C1-C2 alkoxycarbonyl, -NR6R7, -CONR8R9, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, or C3-C6 cycloalkylmethyl .

[0020] In one embodiment of the invention, R1 represents a 6- to 7-, 8- or 9-membered heteroaromatic group containing one, two or three heteroatoms selected from nitrogen atoms, the heteroaromatic group being replaced by at least one substituent (e.g., one, two, three or four substituents independently) selected from halogen (e.g. fluorine, chlorine or bromine), cyano, C1-C4, or C1-C3, or C1-C2 alkyl, C2-C4 alkenyl, C2-C4 alkynyl , C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, C1-C2 alkylcarbonyl, C1-C2 alkylcarbonyloxy, C1-C2 alkoxycarbonyl, -NR6R7, -CONR8R9, C3-C6 or C3-C5 or C5-C6 cycloalkyl, C3-C6 or C3-C5 or C5-C6 cycloalkyloxy or C3-C6 or C3-C5 or C5-C6 cycloalkylmethyl.

[0021] In another embodiment of the invention, R1 represents a 6- to 7-, 8- or 9-membered heteroaromatic group containing one or two heteroatoms in the ring selected from nitrogen atoms (such as pyridinyl, benzodiazolyl or indolyl), the heteroaromatic group being replaced by one or two substituents independently selected from halogen (eg fluorine, chlorine or bromine, particularly chlorine), C1-C3 alkyl (eg methyl, ethyl or isopropyl) and C1-C2 haloalkyl (eg trifluoromethyl).

[0022] In a preferred embodiment, R1 represents any one of the following moieties or is selected from a group containing two or more such moieties in any combination: (i)methyl-1,3-benzodiazolyl (for example, 1-( methyl)-1,3-benzodiazol-2-yl), (ii)isopropyl-1,3-benzodiazolyl (e.g. 1-(isopropyl)-1,3-benzodiazol-2-yl), (iii)methyl- indolyl (e.g. 1-(methyl)indol-2-yl), (iv)ethylindolyl (e.g. 1-(ethyl)indol-2-yl), (v)isopropylindolyl (e.g. , 1-(isopropyl)-indol-2-yl), (vi)indolyl di-alkyl substituted (e.g., (1-ethyl-5-methyl)-indol-2-yl or (1-ethyl-3-methyl )-indol-2-yl), (vii)(1-ethyl-5-chloro)-indol-2-yl, (viii)(3-methyl-5-chloro)-pyridin-2-yl, and (ix )(3-Trifluoromethyl-5-chloro)-pyridin-2-yl.

[0023] In one embodiment of the invention, R2 represents a hydrogen atom, R3 represents a hydrogen atom and R4 represents a hydrogen atom.

[0024] In another embodiment, R2 represents a fluorine atom, R3 represents a hydrogen atom and R4 represents a hydrogen atom.

[0025] In yet another embodiment, R2 represents a hydroxyl group, R3 represents a hydrogen atom, and R4 represents a hydrogen atom.

[0026] In another embodiment, R2 represents a C1-C3 alkoxy group (particularly methoxy), R3 represents a hydrogen atom, and R4 represents a hydrogen atom.

[0027] Alternatively, when R4 represents a hydrogen atom, R2 can together with R3 form a single carbon-carbon bond, thus resulting in the formation of a double bond between the carbon atoms to which R2 and R3 are bonded, as illustrated below:

[0028] Likewise, when R3 represents a hydrogen atom, R2 can together with R4 form a single carbon-carbon bond, thus resulting in the formation of a double bond between the carbon atoms to which R2 and R4 are bonded , as illustrated below:

[0029] R5 represents a 5- to 6-membered heteroaromatic group containing from one to three ring heteroatoms selected from nitrogen atoms, the heteroaromatic group being replaced by at least one substituent (e.g., one, two, three or four substituents independently) selected from halogen (e.g., fluorine, chlorine, or bromine), cyano, C1-C6, or C1-C4, or C1-C2 alkyl, C2-C6, or C2-C4 alkenyl, C2-C6, or C2-C4 alkynyl, C1-C6, or C1-C4, or C1-C2 haloalkyl, C1-C6, or C1-C4, or C1-C2 hydroxyalkyl, C1-C6, or C1-C4, or C1-C2 alkoxy, C1-C6 , or C1-C4, or C1-C2 haloalkoxy, C1-C6, or C1-C4, or C1-C2 alkylcarbonyl, C1-C6, or C1C4, or C1-C2 alkylcarbonyloxy, C1-C6, or C1-C4, or C1-C2 alkoxycarbonyl, -NR10R11, -CONR12R13, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy or C3-C6 cycloalkylmethyl.

[0030] Examples of 5- to 6-membered heteroaromatic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl. Preferred groups include pyridinyl, pyridazinyl and pyrazolyl, especially 4-pyridinyl, 4-pyridazinyl, 5-pyridazinyl and 4-pyrazolyl.

[0031] In one embodiment, R5 represents a 5- and/or 6-membered heteroaromatic group containing one, two or three heteroatoms selected from nitrogen atoms, the heteroaromatic group being replaced by at least one substituent (e.g., one, two, three or four substituents independently) selected from halogen (e.g. fluorine, chlorine or bromine), cyano, C1-C4, or C1-C3, or C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C1 -C4, or C1-C3, or C1-C2 alkoxy, C1-C2 haloalkoxy, C1-C2 alkylcarbonyl, C1-C2 alkylcarbonyloxy, C1-C2 alkoxycarbonyl, -NR10R11, -CONR12R13, C3-C6 or C3-C5 or C5- C6 cycloalkyl, C3-C6 or C3-C5 or C5-C6 cycloalkyloxy or C3-C6 or C3C5 or C5-C6 cycloalkylmethyl.

[0032] In another embodiment, R5 represents a 5- and/or 6-membered heteroaromatic group containing one, two or three heteroatoms selected from nitrogen atoms, the heteroaromatic group being replaced by at least one substituent (e.g., one, two, three or four substituents independently) selected from halogen (e.g. fluorine, chlorine or bromine), C1-C4, or C1-C3, or C1-C2 alkyl, or -NR10R11.

[0033] In yet another embodiment, R5 represents a 5- and/or 6-membered heteroaromatic group containing one or two ring heteroatoms selected from nitrogen atoms such as pyridinyl (particularly 4-pyridinyl), pyridazinyl (particularly 4-pyridazinyl or 5-pyridazinyl) or pyrazolyl (particularly 4-pyrazolyl), the heteroaromatic group being replaced by one or two substituents independently selected from halogen (particularly chlorine), C1-C2 alkyl, and -NR10R11.

[0034] In a preferred embodiment, R5 represents any of the following moieties or is selected from a group containing two or more of these moieties in any combination: (i)2-(methylamino)-pyridin-4-yl, (ii) )2-(dimethylamino)-pyridin-4-yl, (iii)6-chloro-pyridazin-4-yl, (iv)3-(methylamino)-pyridazin-5-yl, (v)3-(dimethylamino)pyridazin -5-yl, (vi) 1-(ethyl)-pyrazol-4-yl, and (vii)(1-methyl-3-amino)-pyrazol-4-yl.

[0035] R6 and R7 each independently represents a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl, or C3-C6, or C3-C5, or C5-C6 cycloalkyl group, or R6 and R7 can together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered saturated heterocyclic ring optionally substituted by at least one substituent (e.g., one or two substituents independently) selected from fluorine, hydroxyl, and C1-C3 alkoxy .

[0036] In one aspect, the saturated heterocyclic ring may contain a single-ring heteroatom (being the nitrogen atom to which R6 and R7 are attached). In an alternative aspect, the saturated heterocyclic ring may contain a second ring heteroatom selected from a nitrogen or oxygen atom.

[0037] In a first embodiment, R6 and R7 each independently represents a hydrogen atom or a C1-C4, or C1-C3, or C1-C2 alkyl or C3-C6 group, particularly cyclopropyl, or R6 and R7 may together with the nitrogen atom to which they are attached forms a 4- or 5-membered saturated heterocyclic ring (azetidinyl or pyrrolidinyl) optionally substituted by one or two substituents independently selected from fluorine, hydroxyl and C1-C3 alkoxy.

[0038] In a second embodiment, R6 and R7 each represent a hydrogen atom.

[0039] In a third embodiment, R6 and R7 each represent a C1-C3 alkyl group.

[0040] In a fourth embodiment, one of R6 and R7 represents a hydrogen atom and the other of R6 and R7 represents a C1-C3 alkyl group.

[0041] In a fifth embodiment, one of R6 and R7 represents a cyclopropyl group and the other of R6 and R7 represents a C1-C3 alkyl group.

[0042] In a sixth embodiment, R6 and R7 together with the nitrogen atom to which they are attached form an azetidinyl or pyrrolidinyl ring optionally substituted by one or two substituents independently selected from fluorine and hydroxyl.

[0043] In a seventh embodiment, R6 and R7 together with the nitrogen atom to which they are attached form an unsubstituted azetidinyl or pyrrolidinyl ring.

[0044] R8 and R9 each independently represent a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl group, or R8 and R9 may together with the nitrogen atom to which they are attached form a heterocyclic ring saturated from 4 to 7 members.

[0045] In one embodiment of the invention, R8 and R9 each independently represent a hydrogen atom or a methyl group.

[0046] R10 and R11 each independently represent a hydrogen atom or a hydroxyl, C1-C6, or C1-C4, or C1-C2 alkyl, C1-C6, or C1-C4, or C1-C2 haloalkyl, C1 group -C6, or C1-C4, or C1-C2 alkoxy, or C3-C6, or C3-C5, or C5-C6 cycloalkyl, or R10 and R11can together with the nitrogen atom to which they are attached form a saturated heterocyclic ring of 4, 5 , 6- or 7-membered optionally substituted with at least one substituent (e.g., one or two substituents independently) selected from fluoro, hydroxyl and C1-C3 alkoxy.

[0047] In one aspect, the saturated heterocyclic ring may contain a single-ring heteroatom (being the nitrogen atom to which R10 and R11 are attached). In an alternative aspect, the saturated heterocyclic ring may contain a second ring heteroatom selected from a nitrogen or oxygen atom.

[0048] In a first embodiment, R10 and R11 each independently represents a hydrogen atom or a hydroxyl, C1-C4, or C1-C3, or C1-C2 alkyl, C1-C4, or C1-C3, or C1 group -C2 haloalkyl, C1-C4, or C1-C3, or C1-C2 or C3-C6 alkoxy, particularly cyclopropyl, or R10 and R11 can together with the nitrogen atom to which they are attached form a saturated heterocyclic ring of 4 or 5 members (azetidinyl or pyrrolidinyl) optionally substituted by one or two substituents independently selected from fluorine, hydroxyl and C1-C3 alkoxy.

[0049] In a second embodiment, R10 and R11 each represent a hydrogen atom.

[0050] In a third embodiment, R10 and R11 each represent a C1-C3 alkyl group.

[0051] In a fourth embodiment, one of R10 and R11 represents a hydrogen atom and the other of R10 and R11 represents a C1-C3 alkyl group.

[0052] In a fifth embodiment, one of R10 and R11 represents a cyclopropyl group and the other of R10 and R11 represents a C1-C3 alkyl group.

[0053] In a sixth embodiment, R10 and R11 together with the nitrogen atom to which they are attached form an azetidinyl or pyrrolidinyl ring optionally substituted by one or two substituents independently selected from fluorine and hydroxyl.

[0054] In a seventh embodiment, R10 and R11 together with the nitrogen atom to which they are attached form an unsubstituted azetidinyl or pyrrolidinyl ring.

[0055] In an eighth embodiment, one of R10 and R11 represents a hydrogen atom or a methyl group and the other of R10 and R11 represents a hydroxyl, methoxy or C1-C2 haloalkyl group.

[0056] R12 and R13 each independently represent a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl group, or R12 and R13 may together with the nitrogen atom to which they are attached form a heterocyclic ring saturated from 4 to 7 members.

[0057] In one embodiment of the invention, R12 and R13 each independently represent a hydrogen atom or a methyl group.

[0058] Subject to the above conditions, preferred compounds of formula (I) are those in which:

[0059] R1 represents a 6- to 9-membered heteroaromatic group containing one or two heteroatoms in the ring selected from nitrogen atoms, the heteroaromatic group being replaced by one or two substituents independently selected from halogen, C1-C3 alkyl and C1-C2 haloalkyl ;

[0060] R2 represents a hydrogen or fluorine atom or a methoxy group;

[0061] R3 represents a hydrogen atom;

[0062] R4 represents a hydrogen atom;

[0063] R5 represents a 5- to 6-membered heteroaromatic group containing one or two heteroatoms in the ring selected from nitrogen atoms, the heteroaromatic group being replaced by one or two substituents independently selected from halogen, C1-C2 alkyl and -NR10R11 ; It is

[0064] R10 and R11 each independently represent a hydrogen atom or a C1-C6 alkyl group.

[0065] Examples of preferred compounds of formula (I) according to the invention include: N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2 -yl]piperidin-1-carbonyl}pyridin-2-amine, N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine -1-carbonyl}pyridin-2-amine (Enantiomer 1 substantially as described above and with reference to Example 2), N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1 ,3-benzodiazol-2-yl]piperidine-1-carbonyl}pyridin-2-amine (Enantiomer 2 substantially as described above and with reference to Example 3), N,N-Dimethyl-4-[3-(1-methyl -1H-1,3-benzodiazol-2-yl)piperidine-1-carbonyl]pyridin-2-amine, 2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-(propan -2-yl)-1H-1,3-benzodiazol, N-Methyl-5-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1- carbonyl}pyridazin-3-amine, 2-[1-(1-Ethyl-1H-pyrazole-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-1,3-benzodiazole , N,N-Dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-amine, N-Methyl-5-[3-(1-methyl) -1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine, 4-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N- dimethylpyridin-2-amine, 5-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine, 5-[3-(1-Ethyl -1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyridazin-3-amine, N,N-Dimethyl-5-{3-[1-(propan-2-yl)-1H-indol- 2-yl]piperidine-1-carbonyl}pyridazin-3-amine, N-Methyl-5-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbonyl} pyridazin-3-amine, 2-{1-[(1-Ethyl-1H-pyrazol-4-yl)carbonyl]piperidin-3-yl}-1-(propan-2-yl)-1H-indole, 1- Methyl-4-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidinecarbonyl}-1H-pyrazol-3-amine, 1-Ethyl-2-{1-[( 1-Ethyl-1H-pyrazol-4-yl)carbonyl]piperidin-3-yl}-5-methyl-1H-indole, 5-[3-(1-Ethyl-3-methyl-1H-indol-2-yl) )piperidine-1-carbonyl]-N-methylpyridazin-3-amine, 5-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyridazin-3 -amine, 5-[3-(5-chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyridazin-3-amine, 5-[3-(1-Ethyl- 5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine, 5-[3-(5-chloro-1-ethyl-1H-indol-2-yl) )piperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine, N-Methyl-5-[3-(3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3- amine, N,N-Dimethyl-5-[3-(3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine, 4-[3-(1-Ethyl-3- methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine, 4-[3-(1-Ethyl-5-methyl-1H-indol-2-yl) )piperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine, 4-[3-(5-chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-1 -methyl-1H-pyrazol-3-amine, 5-[3-(5-chloro-3-methylpyridin-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine, 4-{3 -[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carbonyl}-N-methylpyridin-2-amine, 5-({3-[5-chloro-3-(trifluoromethyl )pyridin-2-yl]-3-methoxypiperidin-1-yl}carbonyl)-N-methylpyridazin-3-amine, 5-{3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3 - methoxypiperidine-1-carbonyl}-N,N-dimethylpyridazin-3-amine, 5-chloro-2-[1-(1-ethyl-1H-pyrazol-4-carbonyl)-3-methoxypiperidin-3-yl]- 3-(trifluoromethyl)pyridine, 4-{3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carbonyl}-N,N-dimethylpyridin-2-amine, 4- [3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N-methylpyridin-2-amine, 4-[3-(5-chloro-3-methylpyridin-2- yl)-3-fluoropiperidine-1-carbonyl]-N-methylpyridin-2-amine, 5-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N- methylpyridazin-3-amine, 5-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine, 5-[3-( 5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N-methylpyridazin-3-amine, 5-[3-(5-chloro-3-methylpyridin-2-yl)-3 -fluoropiperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine, 5-chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-3-methoxypiperidin-3-yl]- 3-methylpyridine, 5-chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-3-fluoropiperidin-3-yl]-3-methylpyridine, 4-[3-(5-chloro- 3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine, 4-[3-(5-chloro-3-methylpyridin-2-yl)-3 -fluoropiperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine, and pharmaceutically acceptable salts of any thereof.

[0066] It should be noted that each of the chemical compounds listed above represents a particular and independent aspect of the invention.

em que R1, R2, R3 e R4 são definidos na fórmula (I) ou um sal dos mesmos (por exemplo, um sal cloridrato), com um composto de formula

em que R5 é conforme definido na fórmula (I); e opcionalmente posteriormente realizar um ou mais dos seguintes procedimentos: • remoção quaisquer grupos de proteção •converter um composto de fórmula (I) em outro composto de fórmula (I) • formar um sal farmaceuticamente aceitável.[0067] Compounds of formula (I) and pharmaceutically acceptable salts thereof as defined above may be prepared by a process comprising reacting a compound of formula

wherein R1, R2, R3 and R4 are defined in formula (I) or a salt thereof (e.g. a hydrochloride salt), with a compound of formula

wherein R5 is as defined in formula (I); and optionally further carrying out one or more of the following procedures: • removing any protecting groups • converting a compound of formula (I) into another compound of formula (I) • forming a pharmaceutically acceptable salt.

[0068] The reaction conditions for the above process will normally require activation of the carboxylic acid of formula (III) which can be achieved by many of the widely known 'amide coupling' agents such as 1-ethyl-3-(3-dimethylaminopropyl )carbodiimide (EDC) or propylphosphonic anhydride (commercially available under the brand name “T3P”). This can be carried out in a suitable solvent such as dichloromethane, in the presence of a base such as triethylamine. The compound of formula (II), or salt thereof, may be present during the activation of the carboxylic acid of formula (III), or may be added shortly afterwards. The reactions will normally take place at room temperature (20 to 25oC). As an alternative to performing in situ activation, 'pre-activated' variants of the compound of formula (III) such as acid halides, acid anhydrides and esters (e.g. pentafluorophenyl esters) thereof can be used to react with the amine of formula (II) to form compounds of formula (I) under appropriate conditions which will be known to a person skilled in the art.

[0069] Compounds of formula (II) in which R2 is hydrogen, R3 is hydrogen and R4 is hydrogen can be prepared by reacting a compound of formula (IV), R1-B(OR20)2, where R20 represents a hydrogen atom, an alkyl group, or both OR20 groups together with the boron atom to which they are attached form a dioxoborolane ring (such as a pinacol borane) or a boronate ester of N-methyliminodiacetic acid (MIDA boronate ester), and R1 is as defined in formula (II), with 3-iodopyridine or 3-bromopyridine in the presence of a palladium catalyst according to the Suzuki-Miyaura reaction (see, for example, the following references: 1. Miyaura, Norio; Yamada, Kinji; Suzuki, Akira (1979). “A new stereospecific cross-coupling by the paladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynyl halides.” Tetrahedron Letters 20 (36): 3437-3440. 2. Miyaura, Norio; Suzuki, Akira (1979). “Stereoselective synthesis of arylated (E)-alkenes by a reaction of alk-1-enylboranes with aryl halides in the presence of paladium catalyst”. chem. Comm. (19): 866-867. 3. Miyaura, Norio; Suzuki, Akira (1995). “Paladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds”. Chemical Reviews 95 (7): 2457-2483. followed by a reduction step using hydrogen gas and a platinum(IV) oxide catalyst. In some cases, removal of a protecting group, if present, can be performed prior to the reduction step. In other cases, removal of a protecting group, if present, and alkylation of the unprotected atom can be performed prior to the reduction step.

[0070] Alternatively, compounds of formula (II) in which R2 is hydrogen, R3 is hydrogen and R4 is hydrogen can be prepared as illustrated in Scheme 1 below: Scheme 1

[0071] In Scheme 1, 'PG' denotes a nitrogen protecting group. Step 1 is performed in the presence of lithium bis(trimethylsilyl)amide and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride. The reaction product obtained may be a mixture of enol nonaflate isomers which, individually or taken as a mixture, are then reacted in step 2 with a compound of formula (IV) as described above under Suzuki-Miyaura reaction conditions. The product of step 2 is hydrogenated in step 3 using, for example, transition metal catalyzed hydrogenation (e.g. palladium on carbon, Pd(OH)2 on carbon, or platinum(IV) oxide) and finally the protecting group is removed in step 4, for example using trifluoroacetic acid or hydrochloric acid in dichloromethane, when PG is tert--butoxycarbonyl (Boc) to give a compound of formula (II). Alternatively, where PG is benzyl or 4-methoxy benzyl, deprotection may occur concurrently with hydrogenation, or may proceed step by step, normally effected by raising the hydrogenation temperature and/or pressure and/or extending the hydrogenation reaction time of so that hydrogenolysis of the PG also occurs. Alternatively, where PG is benzyl or 4-methoxy benzyl, deprotection can be carried out by treatment with α-chloroethyl chloroformate (ACE-Cl) in a suitable solvent such as dichloromethane or dichloroethane followed by a methanol treatment according to the protocol for Olofson as described in the following reference: Olofson, Martz (1984). “A New Reagent for the Selective, High-Yield N-Dealkylation of Tertiary Amines: Improved Syntheses of Naltrexone and nalbuphine”. J.Org.Org. chem. 49: 2081-2082.

[0072] Compounds of formula (II) in which R2 is other than hydrogen can be prepared as illustrated in Scheme 2 below: Scheme 2

[0073] In Scheme 2, 'PG' denotes a nitrogen-protecting group, R22 denotes a C1-C3 alkyl group and 'R1' has the same meaning as in formula (I). Step 1 is carried out in the presence of an organometallic reagent (e.g. aryl Grignard, R1-MgX) and then the protecting group is removed in step 2, e.g. using trifluoroacetic acid or hydrochloric acid in dichloromethane when PG is tert --butoxycarbonyl (Boc) to generate a compound of formula (II) wherein R2 represents hydroxyl. Alternatively, the product from step 1 (Intermediate A) can be alkylated (e.g. using a C1-C3 alkyl halide and a strong base e.g. sodium hydride) (step 3) and the protecting group removed in step 4 by a procedure analogous to that of step 2 to generate compounds of formula (II) in which R2 represents C1-C3 alkoxy. Intermediate A can also be treated with a fluorinating agent (e.g. diethylaminosulfur trifluoride) (step 5) followed by removal of the protecting group in step 6 using an analogous procedure to step 2 to generate a compound of formula (II ) where R2 represents fluorine.

[0074] Compounds of formula (II) in which R2 and R3 form a single carbon-carbon bond or R2 and R4 form a single carbon-carbon bond can be prepared by treating the product obtained from step 2 of Scheme 1 above with ACE-Cl followed by methanol (see above) to remove the protecting group.

[0075] Compounds of formula (II) in which R2 and R3 together with the carbon atoms to which they are attached form a cyclopropyl ring, or, R2 and R4 together with the carbon atoms to which they are attached form a cyclopropyl ring may be prepared by treating the product of step 2 of Scheme 1 with a Simmons-Smith cyclopropanation reagent such as an organozinc derived from diiodomethane, diethyl zinc and trifluoroacetic acid, for example as described in the reference by J. C. Lorenz, J. Long, Z. Yang , S. Xue, X. Xie, Y. Shi, “A Novel Class of Tunable Zinc Reagents (RXZnCH2Y) for Efficient Ciclopropanation of Olefins”, J. Org.Org. Chem., 2004, 69, 327-334. The reaction may be followed by a deprotection step to remove any protecting groups, for example using ACE-Cl, or catalytic transition metal (e.g. platinum(IV) oxide) hydrogenolysis, to give the compound of formula (II).

[0076] Some intermediates of formula (II) are new compounds. Therefore, the present invention also provides novel intermediate compounds of formula (II), such as compounds of formula (II) wherein R1 represents a pyridinyl group substituted by one or two independently selected halogen substituents (e.g. fluorine, chlorine or bromine , particularly chlorine), C1-C3 alkyl (e.g. methyl, ethyl or isopropyl) and C1-C2 haloalkyl (e.g. trifluoromethyl).

[0077] Compounds of formulas (III) and (V) are commercially available, are well known in the literature or can be prepared using known techniques.

[0078] It will be appreciated by those skilled in the art that in the above processes, certain functional groups such as phenol, hydroxyl or amino groups in the reagents may need to be protected by protecting groups. Thus, the preparation of compounds of formula (I) may involve, at an appropriate stage, the introduction and/or removal of one or more protecting groups.

[0079] The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1999).

[0080] The compounds of formula (I) above can be converted into a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as formate salt, hemiformate, hydrochloride, hydrobromide, benzenesulfonate (besylate), saccharin (e.g. example, monosaccharin), trifluoroacetate, sulfate, nitrate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, valerate, propanoate, butanoate, malonate, oxalate, 1-hydroxy-2-naphthoate (xinafoate), methanesulfonate or p--toluenesulfonate.

[0081] In one aspect of the invention, compounds of formula (I) defined above may bear one or more radiolabels. These radiolabels can be introduced using radiolabel-containing reagents in the synthesis of compounds of formula (I) or they can be introduced by coupling the compounds of formula (I) to chelating moieties capable of binding to a radioactive metal atom. These radiolabelled versions of the compounds can be used, for example, in diagnostic imaging studies.

[0082] Unless otherwise indicated, any atom specified herein may also be an isotope of said atom. For example, the term "hydrogen" includes 1H, 2H and 3H. Likewise, carbon atoms are to be understood to include 12C, 13C and 14C, nitrogen atoms are to be understood to include 14N and 15N, and oxygen atoms are to be understood to include 16O, 17O and 18O.

[0083] In another aspect of the invention, compounds of formula (I) may be isotopically labeled. As used herein, an "isotopically labeled" compound is one in which the abundance of a particular nuclide at a particular atomic position within the molecule is increased above the level at which it occurs in nature.

[0084] Compounds of formula (I) and their salts may be in the form of hydrates or solvates which form an aspect of the present invention. Such solvates can be formed with common organic solvents, including but not limited to alcoholic solvents, for example, methanol, ethanol or isopropanol.

[0085] Where compounds of formula (I) above are capable of existing in stereoisomeric forms, it will be understood that the invention includes the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. Enantiomerically pure forms are particularly desired.

[0086] Compounds of formula (I) and their salts may be amorphous or in a polymorphic form or a mixture of any of these, each of which forms an aspect of the present invention.

[0087] The compounds of formula (I) and their pharmaceutically acceptable salts have activity as medicaments, in particular as prokineticin receptor modulators, and can thus be used in the treatment of schizophrenia and other psychotic disorders (e.g. schizophreniform disorder, schizoaffective and psychosis); dementia (including behavioral and psychological symptoms of dementia, BPSD) and other cognitive disorders; anxiety disorders (eg, generalized anxiety disorder, post-traumatic stress disorder, and panic attack); mood disorders (eg depressive disorders, major depressive disorders, bipolar disorders including bipolar I and II, bipolar mania, bipolar depression); sleep disorders; disorders usually first diagnosed in childhood or adolescence (eg, attention deficit disorder, autism spectrum disorder, Rett syndrome, Fragile X syndrome, Asperger syndrome, and disruptive behavior disorders); pain (eg, neuropathic pain, including chemotherapy-induced pain, or visceral pain, or gastrointestinal pain); inflammatory conditions, such as inflammatory bowel disease (eg, Crohn's disease, celiac disease, ileitis, ulcerative colitis, enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis resulting after proctocolectomy and ileoanal anastomosis) , cholecystitis, cholangitis, Behcet's disease, pericolangitis, graft versus host disease, sarcoidosis, and chronic gastritis (eg, autoimmune gastritis); neurodegenerative disorders (eg, Crohn's disease, celiac disease, ileitis, ulcerative colitis, enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis resulting after proctocolectomy and ileoanal anastomosis), cholecystitis, cholangitis, Behcet, pericolangitis, graft versus host disease, sarcoidosis, and chronic gastritis (eg, autoimmune gastritis); neurodegenerative disorders (eg, Alzheimer's or Parkinson's disease or multiple sclerosis); gastrointestinal disorders (eg, irritable bowel syndrome (IBS), and functional dyspepsia); autoimmune disorders (eg, rheumatoid arthritis); and dependence (eg, drug dependence, alcohol dependence, and nicotine dependence).

[0088] Thus, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in therapy, in particular for the treatment of conditions the development or symptoms of which are linked to prokineticin receptor activity .

[0089] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for the preparation of a medicament for the treatment of conditions the development or symptoms of which are linked to receptor activity of prokineticin.

[0090] In the context of this specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutically" and "therapeutically" shall be interpreted accordingly.

[0091] Prophylaxis should be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disorder or condition in question. People at risk of developing a particular disorder or condition generally include those who have a family history of the disorder or condition or those who have been identified by genetic testing or screening as being particularly susceptible to developing the disorder or condition or those in the prodromal phase of a disorder .

[0092] In particular, the compounds of formula (I) and their pharmaceutically acceptable salts as defined above can be used in the treatment of the positive symptoms of schizophrenia, schizophreniform disorder or schizoaffective disorder (e.g. voices or hallucinations), cognitive disorders (e.g. dementia and impaired learning) pain (such as neuropathic pain), irritable bowel disease, and irritable bowel syndrome.

[0093] The invention also provides a method of treating at least one symptom or condition associated with schizophrenia and other psychotic disorders (eg, schizophreniform disorder, schizoaffective disorder, and psychosis); dementia (including behavioral and psychological symptoms of dementia, BPSD) and other cognitive disorders; anxiety disorders (eg, generalized anxiety disorder, post-traumatic stress disorder, and panic attack); mood disorders (eg depressive disorders, major depressive disorders, bipolar disorders including bipolar I and II, bipolar mania, bipolar depression); sleep disorders; disorders usually first diagnosed in childhood or adolescence (eg, attention deficit disorder, autism spectrum disorder, Rett syndrome, Fragile X syndrome, Asperger syndrome, and disruptive behavior disorders); pain (eg, neuropathic pain, including chemotherapy-induced pain, or visceral pain, or gastrointestinal pain); inflammatory conditions, such as inflammatory bowel disease (eg, Crohn's disease, celiac disease, ileitis, ulcerative colitis, enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis resulting after proctocolectomy and ileoanal anastomosis) , cholecystitis, cholangitis, Behcet's disease, pericolangitis, graft versus host disease, sarcoidosis, and chronic gastritis (eg, autoimmune gastritis); neurodegenerative disorders (eg, Crohn's disease, celiac disease, ileitis, ulcerative colitis, enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis resulting after proctocolectomy and ileoanal anastomosis), cholecystitis, cholangitis, Behcet, pericolangitis, graft versus host disease, sarcoidosis, and chronic gastritis (eg, autoimmune gastritis); neurodegenerative disorders (eg, Alzheimer's or Parkinson's disease or multiple sclerosis); gastrointestinal disorders (eg, irritable bowel syndrome (IBS), and functional dyspepsia); autoimmune disorders (eg, rheumatoid arthritis); and dependence (e.g. drug dependence, alcohol dependence and nicotine dependence) comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein .

[0094] These symptoms and conditions include, but are not limited to, anxiety, agitation, hostility, panic, an eating disorder, an affective symptom, a mood symptom, a negative and positive psychotic symptom commonly associated with psychotic disorder and neurodegenerative disorder.

[0095] For the aforementioned therapeutic uses, the dose administered will, of course, vary with the compound employed, the mode of administration, the treatment desired, and the disorder indicated. For example, the daily dose of a compound according to the invention (i.e. a compound of formula (I) or a pharmaceutically acceptable salt thereof), if inhaled, may be in the range of 0.05 micrograms per kilogram of body weight body weight (μg/kg) to 100 micrograms per kilogram of body weight (μg/kg). Alternatively, if the compound is administered orally, then the daily dose of the compound of the invention can be in the range of 0.01 micrograms per kilogram of body weight (μg/kg) to 100 milligrams per kilogram of body weight (mg/kg ).

[0096] The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own, but will generally be administered in the form of a pharmaceutical composition in which the compound/salt of formula (I) (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0097] Therefore, the present invention further provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0098] The invention further provides a process for preparing a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0099] Conventional procedures for selecting and preparing suitable pharmaceutical formulations are described in, for example, "Pharmaceutics - The Science of Dosage Form Design", M. E. Aulton, Churchill Livingstone, 1988.

[00100] Adjuvant diluents or pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the invention are those conventionally employed in the field of pharmaceutical formulation and include, among others, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminum stearate , lecithin, whey proteins such as human serum albumin, buffering substances such as phosphates, glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts and electrolytes such as protamine sulfate, hydrogen disodium, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene block polymers polyoxypropylene, polyethylene glycol and wool grease.

[00101] The pharmaceutical compositions of the present invention can be administered orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or through an implanted reservoir. Oral administration is preferred. The pharmaceutical compositions of the invention may contain any conventional pharmaceutically acceptable non-toxic adjuvants, diluents or carriers. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[00102] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. Such a suspension may be formulated according to known techniques using suitable dispersing or wetting agents (eg Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable diluents and solvents that may be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables as they are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[00103] The pharmaceutical compositions of this invention can be orally administered in any orally acceptable pharmaceutical form, including but not limited to capsules, tablets, powders, granules, and aqueous emulsions and suspensions. These dosage forms are prepared according to techniques known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers that are commonly used include lactose and cornstarch. Lubricating agents such as magnesium stearate are also usually added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

[00104] The pharmaceutical compositions of this invention can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the active ingredient. These materials include but are not limited to cocoa butter, beeswax and polyethylene glycols.

[00105] The pharmaceutical compositions of this invention can be administered by nasal spray or inhalation. Such compositions are prepared in accordance with well known techniques of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and/or other solubilizing or dissolving agents. dispersion known in the art.

[00106] Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight (percentage by weight), more preferably from 0.05 to 80% by weight, even more preferably from 0.10 to 70% by weight, and even more preferably from 0.10 to 50% by weight, of active ingredient, all percentages by weight being based on the total composition.

[00107] The compounds of formula (I) and pharmaceutically acceptable salts thereof as defined above may also be administered together with other compounds used for the treatment of the above conditions.

[00108] The invention therefore further relates to combination therapies in which a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above or a pharmaceutical composition or formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above is administered with another therapeutic agent or agents, for the treatment of one or more of the above-listed conditions. These therapeutic agents can be selected from the following: (i) antidepressants such as, for example, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, mirtazeprine, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, reboxetine, robalzotan, sertraline, sibutramine, thionisoxetine, tranylcypromine, trazodone, trimipramine, venlafaxine, and pharmaceutically active equivalents and isomers and/or metabolites thereof; (ii) atypical antipsychotics including, for example, quetiapine and pharmaceutically active isomers and/or metabolites thereof; (iii) antipsychotics, including, for example, amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutylpiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, suproclone, suiclone, thioridazine, trifluoperazine, trimethozine, valproate, valproic acid, zopiclone, zotepine, ziprasidone and pharmaceutically active equivalents and isomers and/or metabolites thereof; (iv) anxiolytics including, for example, alnespirone, azapirones, benzodiazepines, barbiturates, and pharmaceutically active equivalents and isomers and/or metabolites thereof. Exemplary anxiolytics include adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyrazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, mida zolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, and zolazepam; and pharmaceutically active equivalents and isomers and/or metabolites thereof; (v) anticonvulsants including, for example, carbamazepine, valproate, lamotrigine, and gabapentin, and pharmaceutically active equivalents and isomers and/or metabolites thereof; (vi) Alzheimer's therapies including, for example, donepezil, memantine, tacrine, and equivalents and pharmaceutically active isomers and/or metabolites thereof; (vii) Parkinson's therapies including, for example, deprenyl, L-dopa, Requip, Mirapex, monoamine oxidase type B (MAO-B) inhibitors such as selegiline and rasagiline, catechol-O-methyl-transferase (COMT) inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, and dopamine agonists and neuronal nitric oxide synthase inhibitors, and pharmaceutically active equivalents and isomers and/or metabolites thereof. (viii) migraine therapies including, for example, almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan, and zomitriptan and equivalents and isomers and /or pharmaceutically active metabolites thereof; (ix) stroke therapies including, for example, abciximab, activase, NXY-059, citicoline, crobenetin, desmoteplase, repinotan, traxoprodil and equivalents and pharmaceutically active isomers and/or metabolites thereof; (x) urinary incontinence therapies including, for example, darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, and tolterodine and pharmaceutically active equivalents and isomers and/or metabolites thereof; (xi) neuropathic pain therapies including, for example, gabapentin, lidoderm, and pregablin, and pharmaceutically active equivalents and isomers and/or metabolites thereof; (xii) nociceptive pain therapies such as, for example, celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen and paracetamol, and pharmaceutically active equivalents and isomers and/or metabolites thereof; (xiii) insomnia therapies including, for example, allobarbital, allonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, chloractate, dexclamol, etcchlorvinol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur , nisobamate, pentobarbital, phenobarbital, propofol, roletamide, triclofos, secobarbital, zaleplon, and zolpidem, and pharmaceutically active equivalents and isomers and/or metabolites thereof; (xiv) mood stabilizers including, for example, carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, and verapamil and pharmaceutically active equivalents and isomers and/or metabolites thereof; (xv) 5HT1B binders as, for example, compounds disclosed in WO 99/05134 and WO 02/08212; (xvi) mGluR2 agonists; (xvii) nicotinic Alpha 7 agonists such as, for example, compounds disclosed in WO 96/006098, WO 97/030998, WO 99/003859, WO 00/042044, WO 01/029034, WO 01/60821, WO 01/36417 , WO 02/096912, WO 03/087102, WO 03/087103, WO 03/087104, WO 2004/016617, WO 2004/016616, and WO 2004/019947; (xviii) CCR1 chemokine receptor inhibitors; and (xix) opioid delta agonists as, for example, compounds disclosed in WO 97/23466 and WO 02/094794.

[00109] These combination products employ the compound of formula (I) or a pharmaceutically acceptable salt thereof as previously defined within the dosage range described herein and the other pharmaceutically active agent within approved dosage ranges and/or the dosage as described in the publication reference.

[00110] In another aspect, the present invention provides a combination (e.g. for the treatment of schizophrenia, cognitive disorders or pain) of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein and one or more independently selected agents of carbamazepine, olanzapine, quetiapine, verapamil, lamotrigine, oxcarbazepine, risperidone, aripiprazole, ziprasidone, and lithium.

[00111] The invention also provides a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein, and a preparation of a second active ingredient which is carbamazepine, olanzapine, quetiapine, verapamil, lamotrigine, oxcarbazepine, risperidone, aripiprazole, ziprasidone or lithium, for simultaneous, sequential or separate use in therapy.

[00112] In another aspect, the invention provides a kit comprising a preparation of a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein, and a preparation of a second active ingredient which is carbamazepine, olanzapine, quetiapine, verapamil, lamotrigine, oxcarbazepine, risperidone, aripiprazole, ziprasidone or lithium, and instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.

[00113] The present invention will now be explained further with reference to the following illustrative examples, in which the raw materials and reagents used are available from commercial suppliers.

[00114] Nuclear magnetic resonance (NMR) spectra were recorded at 400MHz and 300.3 K, unless otherwise indicated; chemical shifts (□) are reported in parts per million. Spectra were recorded using a Bruker 400 Avance instrument equipped with a 5mm BBFO probe or DUL probe with instrument controlled by Bruker TopSpin 2.1 software, or by a Jeol Lambda spectrometer instrument (JN-LMA400) equipped with a 5mm Jeol TH5 probe with instrument controlled by Jeol Delta v4.3.5 software.

[00115] With regard to NMR analysis, compounds of formula (I) often show signal splitting and/or broadening due to conformationally restricted movement of the linked substituents of the N-acyl piperidine ring. These effects are temperature and solvent dependent and can complicate the assignment of signals and coupling constants. For the avoidance of doubt, these splitting or widening signals were assigned a range of chemical shifts as observed and were designated as multiplets.

[00116] Purity was assessed using one or more of the following: • UPLC with UV detection (photodiode array) over a wide range of wavelengths, typically 220-450nm, using a Waters Acquity UPLC system equipped with UPLC BEH columns or HSS C18 (2.1mm id x 50mm length) operated at 50 or 60°C. Mobile phases typically consisted of acetonitrile or methanol mixed with water containing 0.05% formic acid or 0.025% ammonia. Mass spectra were recorded with a Waters SQD single quadrupole mass spectrometer using atmospheric pressure ionization. • Perkin Elmer 200 series system equipped with an Agilent Poroshell 120 column (SB-C18, 4.6mm id x 30mm, 2.7Qm) operated at 20oC. Mobile phases consisted of acetonitrile and water, both containing 0.1% v/v formic acid. Mass spectra were recorded with a PE SCIEX API 2000 MS/MS mass spectrometer. The system was controlled by the Analyst software (version 1.5.1).

[00117] The compounds were purified using normal phase chromatography on silica, using Biotage or Isolute KP-Sil cartridges or Kinesis Telos Silica cartridges, or on basic silica, using Biotage or Isolute KP-NH cartridges, or by chromatographic methods by reverse phase, using Biotage or Isolute KP-C18-HS cartridges or by SCX-2 capture-release cartridges, or by Preparative HPLC, or by Supercritical Fluid Chromatography (SFC).

[00118] Preparative HPLC was performed using one or more of the following: • Agilent Technologies 1100 series system or a Waters autopurification LC/MS system typically using Waters 19mm id x 100mm length C18 columns such as XBridge or SunFire 5μm materials in room temperature. • Gilson HPLC system using Waters XBridge Column (C18, 5_m, 19mm id x 250mm), controlled by UniPoint software (version 2.10) • Waters autopurification LC/MS system using Varian Column (C18, 5^m, 21.2mm id x 150mm), controlled by MassLynx software (version 4.0 SP4)

[00119] Mobile phases typically consisted of acetonitrile or methanol mixed with water containing 0.1% formic acid or 0.1% ammonia, unless otherwise noted.

[00120] Ambient temperature in the following examples means the temperature ranging from 20oC to 25oC.

[00121] The following abbreviations are used in the Examples: ACE-Cl α-chloroethyl chloroformate ACN acetonitrile aq. aqueous CHCl3 chloroform CV column volumes DCM dichloromethane DMAP 4-(dimethylamino)pyridine DMSO dimethyl sulfoxide DMF dimethylformamide DPPF 1,1'-bis(diphenylphosphanyl)ferrocene EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc acetate ethyl EtOH ethanol g grams HBr hydrobromic acid HCl hydrochloric acid HOAt 1-hydroxy-7-azabenzotriazole HPLC high pressure liquid chromatography LCMS mass spectrometry liquid chromatography LiHMDS lithium bis(trimethylsilyl)amide MgSO4 magnesium sulfate MeOH methanol mg milligrams mins minutes mL milliliters mmol millimoles MS mass spectrometry NaHCO3 sodium hydrogen carbonate NaOH sodium hydroxide Na2SO4 sodium sulfate NH3 ammonia NH4Cl ammonium chloride NMP 1-methyl-2-pyrrolidone NMR nuclear magnetic resonance ppm parts per million Rt retention time sat. saturated SFC supercritical fluid chromatography TFA trifluoroacetic acid THF Tetrahydrofuran

1 Intermediaries

[00122] Intermediate 1 6-chloropyridazine-4-carboxylic acid

[00123] To a stirring solution of methyl 6-chloropyridazine-4-carboxylate (CAS 1093860-48-0, 5.05 g, 29.3 mmol) in THF (10 mL)/water (20 mL) was added hydroxide of lithium (1.402 g, 58.5 mmol). After 90 minutes, the reaction mixture was acidified to pH 1-2 with conc. HCl (11.8 M, 5 mL) and concentrated in vacuo to remove THF. The resulting precipitate was stirred in the predominantly aqueous medium at room temperature for approximately 30 minutes and was then filtered through a vacuum sinter and dried in a vacuum oven to give the title compound. MS ES+: 159

[00124] Intermediate 2 1-Methyl-2-(piperidin-3-yl)-1H-indole

[00125] To a stirring solution of 2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-methyl-1H-indole (Intermediate 3; 0.217 g, 0.718 mmol) in ethanol (10 mL) was added ammonium formate (0.452 g, 7.18 mmol) and palladium hydroxide on carbon (20% by weight, 0.050 g). The reaction mixture was heated to reflux under a nitrogen atmosphere for 5.5 hours. The reaction was then removed from the heat and cooled and filtered through diatomaceous earth. The solvent was removed in vacuo and the crude product was purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia) to give the title compound. MS ES+: 215

[00126] Intermediate 3 2-(1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-methyl-1H-indole

[00127] A microwave flask was charged with 1-benzyl-1,2,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1 -sulfonate (Intermediate 4; 0.986 g, 2.093 mmol), 1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (CAS 596819- 10-2; 0.565 g, 2.197 mmol) and potassium carbonate (0.868 g, 6.28 mmol) in dioxane (15 mL)/water (3.75 mL). The stirring mixture was degassed by bubbling nitrogen through it for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.121 g, 0.105 mmol) was added and the mixture was degassed for a further minute before being sealed and irradiated in a microwave reactor at 100 °C for 20 minutes. The reaction mixture was diluted with EtOAc and washed with water then brine and the organic portion were loaded onto a pre-equilibrated cation exchange cartridge (SCX-2) and eluted with EtOAc then EtOAc/[1M NH3 in MeOH] ( 4:1) and then EtOAc/[2M NH3 in MeOH] (4:1). Fractions containing product were combined and reduced in vacuo to give the title compound. MS ES+: 303

[00128] Intermediate 4 1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate

[00129] 1-Benzylpiperidin-3-one hydrate hydrochloride (CAS 50606-58-1) was freshly converted to free base by dissolving in water/ACN (1:1, 0.1g/mL) and loading into a SCX-2 cartridge (5 g adsorbent / 1 g substrate). The cartridge was washed with water/acetonitrile (10 vols), acetonitrile (10 vols) then the free base eluted with acetonitrile/[2M NH 3 in MeOH] (4:1) (50 vols). 1-Benzylpiperidin-3-one (6.45 g, 34.1 mmol) was dissolved in anhydrous THF (100 mL) and the solution was stirred at -78 °C under a nitrogen atmosphere. To the stirring solution was added LiHMDS [1.0M in THF] (47.7 mL, 47.7 mmol) over 5 minutes. To the stirred reaction mixture was added 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (CAS 375-72-4; 9.18 ml, 51.1 mmol). After 75 minutes the reaction mixture was removed from the cold bath and warmed to room temperature. After 1 hour, the reaction was quenched with saturated aqueous NaHCO 3 , concentrated in vacuo to approximately one-third (1/3) volume, and extracted with diethyl ether. The organic phase was back-extracted with brine and dried over Na2SO4. The crude product was purified by column chromatography (silica gel) eluting with 0-20% EtOAc in 40-60 petroleum ether to give the title compound. MS ES+: 472

[00130] Intermediate 5 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole

[00131] To a stirred solution of 1-methyl-2-(piperidin-3-yl)-1H-indole (Intermediate 2; 0.083 g, 0.387 mmol) and 6-chloropyridazine-4-carboxylic acid (Intermediate 1; 0.074 g, 0.465 mmol) in dichloromethane (2 mL) was added triethylamine (0.108 mL, 0.775 mmol) and then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2,4, 6-Trioxide (50% by weight solution in EtOAc) (0.577 ml, 0.968 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction was stopped with saturated aqueous NaHCO3 and the mixture was separated using a phase separator cartridge. The aqueous was extracted with more DCM and the combined organics were eluted through a cation exchange cartridge (SCX-2, 1g). The solvent was removed in vacuo to give the title compound which was used without further purification. MS ES+: 355

[00132] Intermediate 6 1-Ethyl-2-(piperidin-3-yl)-1H-indole

[00133] A solution of 2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-ethyl-1H-indole (Intermediate 7; 0.27 g, 0.853 mmol) in MeOH ( 30 mL) was cycled through a hydrogen generation flow reactor equipped with one in a cartridge of 20% palladium(II) hydroxide on carbon catalyst at room temperature and pressure at 1.0 mL/min flow rate. After 5 hours, hydrogen generation was stopped and the eluent was purged from the reactor and the system was washed with MeOH and concentrated in vacuo to give the title compound. MS ES+: 229

[00134] Intermediate 7 2-(1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-ethyl-1H-indole

[00135] To a stirring solution of 2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole (Intermediate 8; 0.5 g, 1.734 mmol) in DMF (5 mL) was added sodium hydride (60% by weight in mineral oil) (0.083 g, 2.081 mmol). After 20 minutes, iodoethane (0.209 ml, 2.60 mmol) was added. The flask was purged with nitrogen, sealed and shaken at room temperature. After 16.5 hours, the reaction was stopped with saturated aqueous NH4Cl. The mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 , the aqueous layer was removed and the organic phase was washed with water then brine. The crude product was purified by column chromatography (silica gel) eluting with 0-25% ethyl acetate/petroleum to give the title compound. MS ES+: 317

[00136] Intermediate 8 2-(1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole

[00137] To a stirred solution of tert-butyl 2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-1-carboxylate (Intermediate 9; 3.44 g, 8.85 mmol) in DCM (45 mL) was added TFA (5 mL). The reaction was stirred at room temperature. After 18 hours, the reaction mixture was concentrated in vacuo, azeotroped with DCM and the residue was neutralized by addition of 2M ammonia in methanol and concentrated in vacuo. After 18 hours, the reaction mixture was concentrated in vacuo, azeotroped with DCM and the residue was neutralized by addition of 2M ammonia in methanol and concentrated in vacuo. The crude product was dissolved in DCM and loaded onto a pre-equilibrated cation exchange cartridge (SCX-2, 50g). This was washed with DCM then eluted with DCM/[2M NH3 in MeOH]. The crude product was purified by column chromatography (silica gel) eluting with 0-15% {EtOAc / [2M NH 3 in MeOH (9:1)} / petroleum ether 40-60 to give the title compound. MS ES+: 289

[00138] Intermediate 9 tert-Butyl 2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-1-carboxylate

[00139] Prepared as described for 2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-methyl-1H-indole (Intermediate 3) from 1-benzyl-1,2 ,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Intermediate 4; 5.62 g, 11.92 mmol) and acid ( 1-[(tert-butoxy)carbonyl]-1H-indol-2-yl}boronic acid (CAS 213318-44-6; 3.11 g, 11.92 mmol) using tetrakis(triphenylphosphine)palladium(0) (0.689 g , 0.596 mmol) and potassium carbonate (4.94 g, 35.8 mmol) in water (8 mL) and 1,4-dioxane (32 mL) and irradiated in a microwave at 100 °C for 20 minutes to generate the title compound. MS ES+: 389

[00140] Intermediate 10 2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-1H-indole

[00141] Prepared as described for Intermediate 5, from 6-chloropyridazine-4-carboxylic acid (Intermediate 1; 65.8 mg, 0.415 mmol) and 1-ethyl-2-(piperidin-3-yl)-1H- indole (Intermediate 6; 79 mg, 0.346 mmol) to give the title compound. MS ES+: 369

[00142] Intermediate 11 2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-indole

[00143] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 6-chloropyridazine-4-carboxylic acid (Intermediate 1; 0.076 g, 0.480 mmol) and 2-(piperidin-3-yl)-1-(propan-2-yl)-1H-indole (Intermediate 12; 0.097 g, 0.400 mmol) to give the title compound . MS ES+: 383

[00144] Intermediate 12 2-(Piperidin-3-yl)-1-(propan-2-yl)-1H-indole

[00145] Prepared as described for 1-ethyl-2-(piperidin-3-yl)-1H-indole (Intermediate 6) from 2-(1-benzyl-1,2,5,6-tetrahydropyridin-3- yl)-1-(propan-2-yl)-1H-indole (Intermediate 13; 0.3 g, 0.908 mmol), except that the reaction cycle time was 2.5 hours, to give the title compound. MS ES+: 243

[00146] Intermediate 13 2-(1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-(propan-2-yl)-1H-indole

[00147] To a stirring solution of palladium(II) acetate (5.88 mg, 0.026 mmol) and 1,3-bis-(2,6-diisopropylphenyl)imidazolium chloride (0.011 g, 0.026 mmol) in toluene (1.0 mL) was added potassium 2-methylpropan-2-olate (0.117 g, 1.047 mmol). The reaction mixture was stirred at room temperature in a sealed tube under a nitrogen atmosphere for 10 minutes, after which time a solution of 2-[2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl )ethynyl]-N-(propan-2-yl)aniline (Intermediate 14; 0.173g, 0.524mmol) in toluene (1ml) was added. The reaction mixture was heated to 80 °C for 50 minutes and then cooled to room temperature before being diluted with EtOAc and washed with saturated aqueous NaHCO 3 and then brine. The combined organics were dried over MgSO4 and purified by column chromatography (silica gel) eluting with 0-25% ethyl acetate/petroleum 40-60 to give the title compound. MS ES+: 331

[00148] Intermediate 14 2-[2-(1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)ethynyl]-N-(propan-2-yl)aniline

[00149] To a stirring solution of 2-ethynyl-N-(propan-2-yl)aniline (Intermediate 15; 0.242 g, 1.520 mmol) and 1-benzyl-1,2,5,6-tetrahydropyridin-3- yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Intermediate 4; 0.716 g, 1.520 mmol) in DMF (7.5 ml) was added triethylamine (0.636 ml, 4 .56 mmol), palladium(II) acetate (0.014 g, 0.061 mmol), copper(I) iodide (0.014 g, 0.076 mmol) and DPPF (0.051 g, 0.091 mmol). A reaction flask was purged with nitrogen and heated to 70 °C under nitrogen. After 2 hours, the reaction was cooled, diluted with EtOAc, washed with water then brine. The crude product was purified by column chromatography (silica gel) eluting with 0-25% EtOAc / 40-60 petroleum ether to give the title compound. MS ES+: 331

[00150] Intermediate 15 2-Ethynyl-N-(propan-2-yl)aniline

[00151] To a stirring solution of 2-ethynylaniline (CAS 5267038-9; 1 g, 8.54 mmol) in dichloromethane (25 mL) was added acetic acid (1.955 mL, 34.1 mmol), 2-methoxyprop- 1-ene (CAS 116-11-0; 3.27 ml, 34.1 mmol) and then sodium triacetoxyborohydride (2.71 g, 12.80 mmol). The reaction was stirred at room temperature for 20 hours and then quenched with saturated aqueous NaHCO3. The organic phase was separated and the aqueous was extracted with DCM. The crude product was purified by column chromatography (silica gel) eluted with 0-10% ethyl acetate/petroleum ether 40-60 to give the title compound. 1H NMR (400 MHz, CDCl3) □ ppm 1.28 (d, J=6.32 Hz, 6H) 3.42 (s, 1H) 3.59 - 3.80 (m, 1H) 6, 55 - 6.69 (m, 2H) 7.14 - 7.27 (m, 1H) 7.35 (dd, J=7.58, 1.52 Hz, 1H)

[00152] Intermediate 16 tert-Butyl N-(1-methyl-4-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbonyl}-1H-pyrazole- 3-yl)carbamate

[00153] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 2-(piperidin-3-yl) )-1-(propan-2-yl)-1H-indole (Intermediate 12; 0.048 g, 0.198 mmol) and 3-{[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4 acid -carboxylic acid (Intermediate 17; 0.057 g, 0.238 mmol) in dichloromethane (1 mL), except that purification was carried out as follows:

[00154] The reaction mixture was stopped by addition of saturated aqueous NaHCO 3 and then diluted in EtOAc and washed first with saturated aqueous NaHCO 3 and then dilute aqueous HCl (3%) and then brine. The solvent was removed in vacuo to give the title compound which was used without further purification. MS ES+: 466

[00155] Intermediate 17 3-{[(tert-Butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylic acid

[00156] To a stirred suspension of ethyl 3-{bis[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylate (Intermediate 18; 2.18g, 5.90 mmol) in EtOH (30 mL) was added sodium hydroxide solution (2M, 5.90 mL, 11.80 mmol) under nitrogen atmosphere. The reaction was heated to reflux for 4 hours. Additional sodium hydroxide (2M, 5.90 mL, 11.80 mmol) was added and the reaction was heated to reflux for an additional 2 hours. The reaction mixture was concentrated in vacuo and acidified with aqueous hydrogen chloride (2M) then partitioned between ethyl acetate and water. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined organics were dried (MgSO4) and concentrated in vacuo to give the compound which was used without purification. MS ES-: 240

[00157] Intermediate 18 Ethyl 3-{bis[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylate

[00158] To a mixture of ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate (CAS 21230-43-3; 1 g, 5.91 mmol), triethylamine (2.472 mL, 17.73 mmol) and DMAP (0.01 g, 0.082 mmol) in THF (30 mL) was added di-tert-butyl dicarbonate (3.23 g, 14.78 mmol). The reaction was heated to reflux for 48 hours. Additional di-tert-butyl dicarbonate (3.23 g, 14.78 mmol) was added and the solution heated to reflux overnight. The mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous extracted with ethyl acetate. The combined organics were washed with brine, passed through a phase separator cartridge to remove the aqueous phase and concentrated in vacuo to give the title compound, used in the next step without further purification. MS ES+: 370

[00159] Intermediate 19 1-Ethyl-5-methyl-2-(piperidin-3-yl)-1H-indole hemi-formate

[00160] To a solution of 1-ethyl-5-methyl-2-(pyridin-3-yl)-1H-indole (Intermediate 20; 0.75 g, 3.17 mmol) and HCl (32%, 0. 27 mL, 3.17 mmol) in EtOH (30 mL) under a nitrogen atmosphere was added platinum(IV) oxide (0.072 g, 0.317 mmol). A reaction flask was evacuated and refilled with hydrogen gas and the reaction stirred at room temperature for 2 days during which time the hydrogen atmosphere was renewed three times. The reaction mixture was filtered through diatomaceous earth, concentrated in vacuo and purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% formic acid) to give the title compound. MS ES+: 243

[00161] Intermediate 20 1-Ethyl-5-methyl-2-(pyridin-3-yl)-1H-indole

[00162] To a stirring suspension of sodium hydride (60% in mineral oil, 0.428 g, 10.69 mmol) in DMF (70 mL) at 0 oC was added a solution of 5-methyl-2-(pyridin- 3-yl)-1H-indole (Intermediate 21; 1.485 g, 7.13 mmol) in DMF (15 mL) dropwise over 20 minutes. Iodoethane (2.22 g, 14.26 mmol) was added and the reaction mixture was stirred at 0 °C for 1 hour, then warmed to room temperature and stirred for a further 3 hours. The reaction mixture was poured into ice/water and extracted with DCM. The combined organics were dried (Na2SO4) and the crude product was purified by column chromatography (silica gel) eluted with 12% EtOAc in petroleum ether to give the title compound. MS ES+: 237

[00163] Intermediate 21 5-Methyl-2-(pyridin-3-yl)-1H-indole

[00164] To a stirring solution of tert-butyl 5-methyl-2-(pyridin-3-yl)-1H-indole-1-carboxylate (Intermediate 22, 3.37 g, 10.93 mmol) in DCM ( 33.7 mL) was added anisole (16.85 mL) and TFA (33.7 mL). The reaction mixture was stirred at room temperature overnight and was then concentrated in vacuo, quenched with saturated aqueous NaHCO 3 and extracted with DCM. The organic phase was treated further with saturated aqueous NaHCO 3 , dried (Na 2 SO 4 ), concentrated in vacuo and triturated with diethyl ether to give the title compound. MS ES+: 209

[00165] Intermediate 22 tert-Butyl 5-methyl-2-(pyridin-3-yl)-1H-indole-1-carboxylate

[00166] To a stirring mixture of 3-iodopyridine (CAS 112090-7; 2.03 g, 9.91 mmol) and {1-[(tert-butoxy)carbonyl]-5-methyl-1H-indole- 2-yl}boronic acid (CAS 475102-14-8, 3.0 g, 10.91 mmol) in toluene (50 mL) and EtOH (12.2 mL) was added aqueous sodium carbonate solution (2.0M, 14.72 mL, 29.73 mmol). The reaction mixture was degassed with nitrogen and tetrakis(triphenylphosphine)palladium(0) (0.389 g, 0.33 mmol) was added. The reaction mixture was heated at 90°C for 16 hours then cooled and diluted with EtOAc, washed with water and brine. The organics were dried (Na2SO4) and the crude product was purified by column chromatography (silica gel) eluted with 20% EtOAc in 40-60 petroleum ether to give the title compound. MS ES+: 309

[00167] Intermediate 23 2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-3-methyl-1H-indole

[00168] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 6-chloropyridazine-4-carboxylic acid (Intermediate 1; 88 mg, 0.552 mmol) and 1-ethyl-3-methyl-2-(piperidin-3-yl)-1H-indole hemiformate salt (Intermediate 24; 132 mg, 0.502 mmol) except that Column chromatography (silica gel) using 0100% EtOAc in 40-60 petroleum ether was used in place of solid phase extraction to give the title compound. MS ES+: 383

[00169] Intermediate 24 1-Ethyl-3-methyl-2-(piperidin-3-yl)-1H-indole hemiformate salt

[00170] Prepared as described for 1-ethyl-5-methyl-2-(piperidin-3-yl)-1H-indole hemiformate (Intermediate 19) from 1-ethyl-3-methyl-2-(pyridin -3-yl)-1H-indole (Intermediate 25; 1.3 g, 5.51 mmol), except that a solution of HCl in 1,4-dioxane (4M, 1.37 mL, 5.48 mmol) was used. The crude product was purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% formic acid) to give the title compound. MS ES+: 243

[00171] Intermediate 25 1-Ethyl-3-methyl-2-(pyridin-3-yl)-1H-indole

[00172] Prepared as described for 1-ethyl-5-methyl-2-(pyridin-3-yl)-1H-indole (Intermediate 20) from 3-methyl-2-(pyridin-3-yl)-1H -indole (Intermediate 26, free base; 4g, 19mmol) and iodoethane (6g, 38mmol) except that the reaction was kept at 0°C for 1 hour before being poured into ice/water and extracted into DCM. The combined organics were washed with water and brine and concentrated in vacuo and the residue was then partitioned between diethyl ether and brine then water and was then purified by column chromatography (silica gel) eluted with DCM to give the title compound. MS ES+: 237

[00173] Intermediate 26 3-Methyl-2-(pyridin-3-yl)-1H-indole hydrochloride

[00174] To a stirring solution of crude 3-[1-(2-phenylhydrazin-1-ylidene)propyl]pyridine (Intermediate 27, not isolated) in EtOH (100 mL) was added a solution of HCl in 1.4 -dioxane (4.0M, 37.1 mL, 148.4 mmol) and the reaction mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and poured onto ice. The resulting precipitate was collected by filtration, washed with THF and air dried to give the title compound used in the next step without further purification. MS ES+: 209

[00175] Intermediate 27 3-[1-(2-Phenylhydrazin-1-ylidene)propyl]pyridine

[00176] A stirred solution of 1-(pyridin-3-yl)propan-1-one (CAS 1570-48-5; 5.08 g, 37.6 mmol) and phenyl hydrazine hydrochloride (5.44 g , 37.6 mmol) in EtOH (100 mL) was heated at reflux for 1 hour to give the title compound which was used in the next step without further isolation or purification. MS ES+: 226

[00177] Intermediate 28 2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-5-methyl-1H-indole

[00178] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 6-chloropyridazine-4-carboxylic acid (Intermediate 1; 104 mg, 0.655 mmol) and 1-ethyl-5-methyl-2-(piperidin-3-yl)-1H-indole hemiformate salt (Intermediate 19; 156 mg, 0.596 mmol) with the exception that purification was by column chromatography (silica gel) eluted with 0-100% EtOAc in petroleum ether 40-60 was used in place of solid phase extraction to give the title compound. MS ES+: 383

[00179] Intermediate 29 5-Chloro-2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-1H-indole

[00180] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 6-chloropyridazine-4-carboxylic acid (Intermediate 1; 93 mg, 0.585 mmol) and 5-chloro-1-ethyl-2-(piperidin-3-yl)-1H-indole hemiformate salt (Intermediate 30; 150 mg, 0.532 mmol) with the exception that column chromatography (silica gel) eluted with 0-100% EtOAc in 40-60 petroleum ether was used in place of solid phase extraction to generate the title compound. MS ES+: 403

[00181] Intermediate 30 5-chloro-1-ethyl-2-(piperidin-3-yl)-1H-indole hemi-formate

[00182] To a stirring solution of 5-chloro-1-ethyl-2-(pyridin-3-yl)-1H-indole (Intermediate 31; 500 mg, 1.95 mmol) in absolute EtOH (25 mL) was HCl (37%, 0.16 mL, 1.95 mmol) is added. A reaction flask was evacuated and refilled with nitrogen gas then platinum(IV) oxide (44 mg, 0.195 mmol) was added and the reaction flask was evacuated and refilled with hydrogen gas. The reaction mixture was stirred at room temperature under a hydrogen atmosphere overnight. The reaction mixture was filtered through diatomaceous earth and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% formic acid) to give the title compound. MS ES+: 263

[00183] Intermediate 31 5-Chloro-1-ethyl-2-(pyridin-3-yl)-1H-indole

[00184] To a stirring suspension of sodium hydride (60% dispersion in mineral oil, 490 mg, 12.73 mmol) in DMF (30 mL) at 0 oC was added a solution of 5-chloro-2-(pyridin -3-yl)-1H-indole (Intermediate 32; 1.94g, 8.84mmol) in DMF (20ml) for 20 minutes. To the stirring mixture was added iodoethane (1.37 mL, 16.97 mmol). After 90 minutes the reaction mixture warmed to room temperature and was stirred for a further 3 hours. The reaction mixture was carefully poured into ice/water and extracted into DCM. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound which was used in the next step without further purification. MS ES+: 257

[00185] Intermediate 32 5-Chloro-2-(pyridin-3-yl)-1H-indole

[00186] To a stirring solution of tert-butyl 5-chloro-2-(pyridin-3-yl)-1H-indole-1-carboxylate (Intermediate 33; 2.5 g, 7.604 mmol) and anisole (10 mL , 92.01 mmol) in DCM (75 mL) was added trifluoroacetic acid (15 mL, 196 mmol) and the reaction was stirred at room temperature under a nitrogen atmosphere overnight. The reaction mixture was concentrated in vacuo and the crude product was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo and triturated with DCM to give the title compound which was used in the next step without further purification. MS ES+: 229

[00187] Intermediate 33 tert-Butyl 5-chloro-2-(pyridin-3-yl)-1H-indole-1-carboxylate

[00188] To a stirring solution of 3-iodopyridine (3.15 g, 15.37 mmol) and {1-[(tert-butoxy)carbonyl]-5-chloro-1H-indol-2-yl}boronic acid (5.0 g, 16.92 mmol) in toluene (80 mL) and absolute EtOH (19 mL) under a nitrogen atmosphere was added to the solution and sodium carbonate (2M, 23 mL, 46 mmol). The reaction mixture was degassed by bubbling nitrogen through it for 10 minutes then tetrakis(triphenylphosphine)palladium(0) (665mg, 0.575 mmol) was added and the reaction mixture was heated at 90°C for 3.5 hours. The reaction was cooled to room temperature and diluted in EtOAc and water. The organic phase was separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo and purified by column chromatography (silica gel) eluting with 5-25% EtOAc in petroleum ether to give the title compound. MS ES+: 329

[00189] Intermediate 34 2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-3-methyl-1H-indole

[00190] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 6-chloropyridazine-4-carboxylic acid (Intermediate 1; 111 mg, 0.700 mmol) and 3-methyl-2-(piperidin-3-yl)-1H-indole (Intermediate 35; 150 mg, 0.700 mmol) with the exception that preparative reverse phase HPLC eluted with acetonitrile / water (with 0.1% ammonia) was used in place of solid phase extraction to generate the title compound. MS ES+: 355

[00191] Intermediate 35 3-Methyl-2-(piperidin-3-yl)-1H-indole

[00192] Prepared as described for 1-ethyl-5-methyl-2-(piperidin-3-yl)-1H-indole hemiformate (Intermediate 19) from 3-methyl-2-(pyridin-3 hydrochloride) -yl)-1H-indole (Intermediate 26, 2 g, 8.2 mmol) and platinum(IV) oxide (0.4 g, 1.76 mmol) except that no HCl was added and the title compound was isolated by filtration and used without further purification. MS ES+: 215

[00193] Intermediate 36 tert-Butyl N-{4-[3-(1-ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-pyrazole-3- yl)carbamate

[00194] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 1-ethyl-3- methyl-2-(piperidin-3-yl)-1H-indole hemiformate (Intermediate 24; 132 mg, 0.502 mmol) and 3-{[(tert-butoxy)carbonyl]amino}-1-methyl-1H- pyrazole-4-carboxylic acid (Intermediate 17; 0.133 g, 0.552 mmol) in dichloromethane (2 mL), except that purification was carried out as follows:

[00195] The reaction mixture was stopped by addition of saturated aqueous NaHCO 3 and the organic phase was separated using a phase separator cartridge. The aqueous phase was extracted with DCM and the combined organics were concentrated in vacuo to give the title compound which was used without further purification. MS ES+: 466

[00196] Intermediate 37 tert-Butyl N-{4-[3-(1-ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-pyrazole-3- yl}carbamate

[00197] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 1-ethyl-5-methyl- 2-(piperidin-3-yl)-1H-indole hemiformate (Intermediate 19; 156 mg, 0.596 mmol) and 3-{[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole- 4-carboxylic acid (Intermediate 17; 0.158g, 0.655mmol) in dichloromethane (2ml), except that purification was carried out as follows:

[00198] The reaction mixture was stopped by adding saturated aqueous NaHCO3 and the organic phase was separated using a phase separator cartridge. The aqueous phase was extracted with DCM and the combined organics were concentrated in vacuo to give the title compound which was used without further purification. MS ES+: 466

[00199] Intermediate 38 tert-Butyl N-{4-[3-(5-chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-pyrazole-3- yl)carbamate

[00200] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 5-chloro-1-ethyl- 2-(piperidin-3-yl)-1H-indole hemiformate (Intermediate 30; 150 mg, 0.532 mmol) and 3-{[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole- 4-carboxylic acid (Intermediate 17; 0.141 g, 0.585 mmol) in dichloromethane (2 mL), except that purification was carried out as follows:

[00201] The reaction mixture was stopped by adding saturated aqueous NaHCO3 and the organic phase was separated using a phase separator cartridge. The aqueous phase was extracted with DCM and the combined organics were concentrated in vacuo to give the title compound which was used without further purification. MS ES+: 486

[00202] Intermediate 39 3-chloro-5-[3-(5-chloro-3-methylpyridin-2-yl)piperidine-1-carbonyl]pyridazine

[00203] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 5-chloro-3-methyl- 2-(piperidin-3-yl)pyridine (Intermediate 40; 0.09g, 0.427 mmol) and 6-chloropyridazine-4-carboxylic acid (Intermediate 1; 74 mg, 0.470 mmol) in DCM (2 mL), except that the purification was carried out as follows:

[00204] The reaction mixture was diluted in DCM, washed with saturated aqueous NaHCO 3 and the organic phase was separated using a phase separator cartridge and concentrated in vacuo and purified by column chromatography (silica gel) eluted with 0-50% EtOAc in 40-60 petroleum ether to give the title compound. MS ES+: 351

[00205] Intermediate 40 5-chloro—3-methyl-2-(piperidin-3-yl)pyridine

[00206] To a stirring solution of 2-(1-benzylpiperidin-3-yl)-5-chloro-3-methylpyridine (Intermediate 41; 0.14 g, 0.465 mmol) and triethylamine (0.097 ml, 0.698 mmol) in Dichloromethane (3 mL) was added ACE-Cl (0.066 mL, 0.605 mmol) under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 hour and was then concentrated in vacuo and the residue taken up in methanol and stirred for 1.5 hours then concentrated. The crude product was purified by column chromatography (basic silica) eluted with 0-10% ethyl acetate/methanol to give the title compound. MS ES+: 211

[00207] Intermediate 41 2-(1-Benzylpiperidin-3-yl)-5-chloro-3-methylpyridine

[00208] A flask charged with platinum(IV) oxide (0.016 g, 0.072 mmol) and 2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-5-chloro-3-methylpyridine (Intermediate 42; 0.215 g, 0.720 mmol) was evacuated and purged with nitrogen three times. Ethanol (2 mL) and ethyl acetate (2 mL) were added under reduced pressure and hydrogen was introduced into the reaction flask. The suspension was stirred under a hydrogen atmosphere for 7 hours. The suspension was filtered through diatomaceous earth and the filtrate concentrated in vacuo to give the title compound which was used without further purification. MS ES+: 301

[00209] Intermediate 42 2-(1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)-5-chloro-3-methylpyridine

[00210] Prepared as described for 2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-methyl-1H-indole (Intermediate 3) from 1-benzyl-5-( tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (CAS 1313738-80-5; 0.5 g, 1.671 mmol), 2-bromo-5-chloro-3 -methylpyridine (CAS 65550-77-8; 0.380 g, 1.838 mmol), tetrakis(triphenylphosphine)palladium(0) (0.097 g, 0.084 mmol) and potassium carbonate (0.693 g, 5.01 mmol) in 1,4- dioxane (10 mL) and water (2.5 mL) and microwave irradiation at 110 °C for 30 minutes. Purification was accomplished by dilution with ethyl acetate, washing with 2 M NaOH then saturated brine and purification by column chromatography (basic silica) eluted with 0-20% ethyl acetate/petroleum ether 40-60 to give the compound of the title. MS ES+: 299

[00211] Intermediate 43 5-chloro-2-(3-methoxypiperidin-3-yl)-3-(trifluoromethyl)pyridine hydrochloride

[00212] To a stirred solution of tert-butyl 3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carboxylate (Intermediate 44; 0.1 g, 0.25 mmol) in 1,4-dioxane (1 mL) at 0 °C a solution of HCl in 1,4-dioxane (4.0 M, 1 mL, 4 mmol) was added dropwise. After 10 minutes the reaction mixture warmed up and was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and triturated with diethyl ether to give the title compound which was used in the next step without further purification. MS ES+: 295

[00213] Intermediate 44 tert-Butyl 3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carboxylate

[00214] To a stirred solution of tert-butyl 3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-hydroxypiperidine-1-carboxylate (Intermediate 45; 1.4 g, 3.68 mmol) in THF (20 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil, 0.22 g, 3.5 mmol) in portions over 15 minutes. To the reaction mixture was added iodomethane (0.78g, 5.5 mmol) and the reaction mixture was warmed to room temperature and stirred overnight. The reaction was diluted with water and extracted into EtOAc, dried (Na2SO4), filtered and concentrated in vacuo and purified by column chromatography (silica gel) eluting with 20% EtOAc in hexane to give the title compound. MS ES+: 339 [M - butyl]H+

[00215] Intermediate 45 tert-Butyl 3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-hydroxypiperidine-1-carboxylate

[00216] To a stirring solution of 2-bromo-5-chloro-3-(trifluoromethyl)pyridine (Intermediate 46; 11.4 g, 43.8 mmol) in toluene (230 mL) at -78 oC under an atmosphere of Nitrogen was added n-butyllithium in hexanes solution (2.5M, 19.3 mL, 48.2 mmol) dropwise over 20 minutes. After 15-20 min., a solution of tert-butyl 3-oxopiperidine-1-carboxylate (CAS 98977-36-7, 9.6 g, 48.1 mmol) in toluene (50 mL) was added over 5 min. The solution was stirred at -78°C for 45 minutes and then warmed to room temperature for 1 hour. The solvent was removed in vacuo and the crude product was taken up in EtOAc and water. The organic phase was removed and the aqueous phase was extracted with EtOAc and the combined organics were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo and purified by column chromatography (silica gel) eluted with 0.2% MeOH/DCM to give the title compound after trituration with hexanes. MS ES+: 325 [M - butyl]H+

[00217] Intermediate 46 2-Bromo-5-chloro-3-(trifluoromethyl)pyridine

[00218] To a stirring solution of 5-chloro-3-(trifluoromethyl)pyridin-2-amine (Intermediate 47; CAS 79456-33-0, 10 g, 50.9 mmol) in aqueous HBr (48%, 56 .7 g, 336 mmol) at -10 °C bromine (23.6 g, 147.5 mmol) was added dropwise over 20 minutes, followed by sodium nitrite solution (10.2 g, 147.8 mmol ) in water (18 mL). The reaction was stirred at room temperature for 2 hours and basified (pH 9-10) and extracted with diethyl ether. The organic was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound without further purification. MS ES+: 262

[00219] Intermediate 47 5-chloro-3-(trifluoromethyl)pyridin-2-amine

[00220] To a stirring solution of 3-(trifluoromethyl)pyridin-2-amine (CAS 183610-70-0, 25 g, 154 mmol) in DMF (200 mL) under nitrogen atmosphere was added N-chlorosuccinimide (21 .63 g, 162 mmol) in portions. The reaction mixture was heated to 60°C for 1 hour. The reaction was cooled to room temperature and concentrated in vacuo, redissolved in DCM and passed over a silica gel pad. The DCM was removed in vacuo and the crude product was taken up in diethyl ether, washed with water then brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give the title compound without further purification. MS ES+: 197

[00221] Intermediate 48 3-chloro-5-{3-[5-chloro—3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carbonyl}pyridazine

[00222] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 5-chloro-2-hydrochloride (3-methoxypiperidin-3-yl)-3-(trifluoromethyl)pyridine (Intermediate 43; 132 mg, 0.400 mmol) and 6-chloropyridazine-4-carboxylic acid (Intermediate 1; 76 mg, 0.480 mmol) in dichloromethane (1, 5 mL), except that the purification was performed as follows:

[00223] The reaction mixture was stopped by addition of saturated aqueous NaHCO 3 and the aqueous was extracted in DCM. The combined organics were concentrated in vacuo to give the title compound which was used without further purification. MS ES+: 435

[00224] Intermediate 49 5-chloro-2-(3-methoxypiperidin-3-yl)-3-methylpyridine hydrochloride

[00225] Prepared as described for 5-chloro-2-(3-methoxypiperidin-3-yl)-3-(trifluoromethyl)pyridine hydrochloride (Intermediate 43) from tert-butyl 3-(5-chloro-3- methylpyridin-2-yl)-3-methoxypiperidine-1-carboxylate (Intermediate 50; 820 mg, 2.41 mmol) in 1,4-dioxane (25 mL) using HCl in 1,4-dioxane solution (4.0 M, 35 mL, 337.4 mmol) to give the title compound. MS ES+: 241

[00226] Intermediate 50 tert-Butyl 3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carboxylate

[00227] Prepared as described for tert-butyl 3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carboxylate (Intermediate 44) from tert-butyl 3-(5) -chloro-3-methylpyridin-2-yl)-3-hydroxypiperidine-1-carboxylate (Intermediate 51; 2.0 g, 6.132 mmol) in THF (140 mL) using sodium hydride (60% dispersion in mineral oil, 1 .1 g, 27.6 mmol) and iodomethane (1.7 mL, 27.6 mmol). The crude product was purified by column chromatography (silica gel) eluting with 2-5% EtOAc/petroleum ether to give the title compound. MS ES+: 341

[00228] Intermediate 51 tert-Butyl 3-(5-chloro-3-methylpyridin-2-yl)-3-hydroxypiperidine-1-carboxylate

[00229] To a stirring solution of 2-bromo-5-chloro-3-methylpyridine (CAS 65550-77-8, 19.0 g, 92.0 mmol) in diethyl ether (350 mL) at -70 oC under nitrogen atmosphere was added n-butyllithium in hexanes solution (2.5M, 40.5 mL, 101.2 mmol) dropwise over 20 minutes. After 90 minutes a solution of tert-butyl 3-oxopiperidine-1-carboxylate (CAS 9897736-7, 20.2g, 101.2 mmol) in diethyl ether (100 mL) was added dropwise over 25 minutes. The solution was stirred at -70 °C for 2 hours and then warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with diethyl ether. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo and purified by column chromatography (silica gel) eluting with 2-8% EtOAc/toluene to give the title compound. MS ES+: 327

[00230] Intermediate 52 5-chloro-2-(3-fluoropiperidin-3-yl)-3-methylpyridine hydrochloride

[00231] Prepared as described for 5-chloro-2-(3-methoxypiperidin-3-yl)-3-(trifluoromethyl)pyridine hydrochloride (Intermediate 43) from tert-butyl 3-(5-chloro-3- methylpyridin-2-yl)-3-fluoropiperidine-1-carboxylate (Intermediate 53; 620 mg, 1.89 mmol) in 1,4-dioxane (25 mL) using HCl in 1,4-dioxane solution (4.0 M, 35 mL, 337.4 mmol) to give the title compound. MS ES+: 229

[00232] Intermediate 53 tert-Butyl 3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carboxylate

[00233] To a stirred solution of tert-butyl 3-(5-chloro-3-methylpyridin-2-yl)-3-hydroxypiperidine-1-carboxylate (Intermediate 51; 5.0 g, 15.33 mmol) in DCM (250 mL) at -78 °C under nitrogen atmosphere was added N,N-diethylaminosulfur trifluoride (6.1 mL, 45.99 mmol) dropwise. The temperature was kept at -70°C for 5.5 hours and the reaction was stopped with MeOH and water. The organic phase was separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo then purified by column chromatography (silica gel) eluting with 5% EtOAc/toluene to give the title compound. MS ES+: 273 [M - butyl]H+

[00234] Intermediate 54 3-chloro-5-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]pyridazine

[00235] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 5-chloro-2-hydrochloride (3-methoxypiperidin-3-yl)-3-methylpyridine (Intermediate 49; 100 mg, 0.361 mmol) and 6-chloropyridazine-4-carboxylic acid (Intermediate 1; 86 mg, 0.541 mmol) in dichloromethane (2 mL), except that the purification was carried out as follows:

[00236] The reaction mixture was stopped by addition of saturated aqueous NaHCO 3 and the aqueous was extracted in DCM. The combined organics were concentrated in vacuo to give the title compound which was used without further purification. MS ES+: 381

[00237] Intermediate 55 3-chloro-5-{[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidin-1-yl]carbonyl}pyridazine

[00238] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 5-chloro-2-hydrochloride (3-fluoropiperidin-3-yl)-3-methylpyridine (Intermediate 52; 100 mg, 0.377 mmol) and 6-chloropyridazine-4-carboxylic acid (Intermediate 1; 90 mg, 0.566 mmol) in dichloromethane (2 mL), except that the purification was carried out as follows:

[00239] The reaction mixture was stopped by addition of saturated aqueous NaHCO 3 and the aqueous was extracted in DCM. The combined organics were concentrated in vacuo to give the title compound which was used without further purification. MS ES+: 369

[00240] Intermediate 56 tert-Butyl N-{4-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-yl }carbamate

[00241] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 5-chloro-2-hydrochloride (3-methoxypiperidin-3-yl)-3-methylpyridine (Intermediate 49; 50 mg, 0.180 mmol) and 3-{[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylic acid (Intermediate 17; 0.057 g, 0.234 mmol) in dichloromethane (1 mL), except that purification was carried out as follows:

[00242] The reaction mixture was stopped by addition of saturated aqueous NaHCO 3 and the aqueous was extracted in DCM. The combined organics were concentrated in vacuo to give the title compound which was used without further purification. MS ES+: 464

[00243] Intermediate 57 tert-Butyl N-{4-[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-yl }carbamate

[00244] Prepared as described for 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5) from 5-chloro-2-hydrochloride (3-fluoropiperidin-3-yl)-3-methylpyridine (Intermediate 52; 50 mg, 0.189 mmol) and 3-{[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylic acid (Intermediate 17; 0.059g, 0.245mmol) in dichloromethane (1ml), except that purification was carried out as follows:

[00245] The reaction mixture was stopped by addition of saturated aqueous NaHCO 3 and the aqueous was extracted in DCM. The combined organics were concentrated in vacuo to give the title compound which was used without further purification. MS ES+: 452

2.Examples Example 1

[00246] N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidin-1-carbonyl}pyridin-2-amine (racemic )

[00247] To a stirring suspension of 2-(dimethylamino)pyridine-4-carboxylic acid (100 mg, 0.602 mmol), 2-(piperidin-3-yl)-1-(propan-2-yl)- hydrochloride 1H-1,3-benzodiazole (CAS 1185300-76-8, 190 mg, 0.602 mmol) and triethylamine (0.335 ml, 2.407 mmol) in DCM (6 ml) was added 2,4,6-tripropyl-1,3, 5,2,4,6-trioxatriphosphinan 2,4,6-trioxide (50% by weight solution in EtOAc) (0.791 ml, 0.903 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed with water and the solvent removed in vacuo. The crude product was purified by column chromatography (silica gel) eluted with 0-100% ethyl acetate in 40-60 petroleum ether to give the title compound. 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.11 - 1.56 (m, 3H) 1.57 - 2.18 (m, 7H) 2.82 - 3.31 (m, 9 H) 3.46 - 3.68 (m, 1H) 4.34 - 5.00 (m, 2H) 6.40 - 6.67 (m, 2H) 7.04 - 7.25 (m , 2H) 7.46 - 7.76 (m, 2H) 8.03 - 8.24 (m, 1H) MS ES+: 392

Example 2

[00248] N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1-carbonyl}pyridin-2-amine (enantiomer 1)

[00249] Chiral separation of N,N-dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidin-1carbonyl}pyridin-2-amine ( racemic) (Example 1) was performed using chiral SCF (Waters system equipped with Chiralpak AD-H column (10 x 250 mm, 5 Dm Daicel); 100mbar CO2 with 26% EtOH; 40 oC) to generate the title compound as the first eluting compound. MS ES+: 392

[00250] Chiral SFC (Jasco system equipped with Chiralpak AD-H (4.6 x 100mm, 5'm Daicel); 100mbar CO2 with 26% EtOH; 40 oC) Rt = 2.6 min.

Example 3

[00251] N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1-carbonyl}pyridin-2-amine (enantiomer two)

[00252] Chiral separation of N,N-dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidin-1carbonyl}pyridin-2-amine ( racemic) (Example 1) was carried out using chiral SCF (Waters system equipped with Chiralpak AD-H column (10 x 250mm, 5_m Daicel); 100mbar CO2 with 26% EtOH; 40 oC) to generate the title compound as the second compound eluting. MS ES+: 392

[00253] Chiral SFC (Jasco system equipped with Chiralpak AD-H (4.6 x 100mm, 5üm Daicel); 100mbar CO2 with 26% EtOH; 40oC) Rt = 6.75 min.

Example 4

[00254] N,N-Dimethyl-4-[3-(1-methyl-1H-1,3-benzodiazol-2-yl)piperidine-1-carbonyl]pyridin-2-amine

[00255] To a stirring solution of 1-methyl-2-(piperidin-3-yl)-1H-1,3-benzodiazole (CAS 013-81-2, 50 mg, 0.232 mmol) dissolved in DCM (10 mL ) was added 2-(dimethylamino)pyridine-4-carboxylic acid (CAS 77314-81-9, 38.6 mg, 0.232 mmol) followed by HOAt (37.9 mg, 0.279 mmol), EDC (53.4 mg, 0.279 mmol) and triethylamine (0.162 ml, 1.161 mmol). The reaction mixture was stirred at room temperature for 17 hours. Saturated sodium bicarbonate solution (10 mL) was added and the mixture stirred for 30 minutes at which time the phases were separated using a phase separator cartridge. The organics were concentrated in vacuo and the residue was dissolved in DMSO and purified by preparative HPLC to give the title compound. MS ES+: 364

Example 5

[00256] 2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-1,3-benzodiazole

[00257] Prepared as described for N,N-dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidin-1-carbonyl}pyridin-2 -amine (Example 1) from 2-(piperidin-3-yl)-1-(propan-2-yl)-1H-1,3-benzodiazole hydrochloride (CAS 1185300-76-8, 229 mg, 0.724 mmol) and 6-chloropyridazine-4-carboxylic acid (Intermediate 1; 130 mg, 0.820 mmol) and the reaction was quenched with saturated aqueous NaHCO 3 and the organic layer was filtered through a phase separation cartridge and evaporated to dryness. The crude product was purified using column chromatography (silica gel) eluted with 20-100% ethyl acetate in 40-60 petroleum ether then 0-20% methanol in ethyl acetate to give the title compound. 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.11 - 2.17 (m, 10 H) 3.03 - 3.62 (blurred m, 3 H) 4.03 (m, 1 H) 4 .21 - 4.93 (m, 2H) 7.03 - 7.26 (m, 2H) 7.51 - 7.76 (m, 2H) 8.01 - 8.18 (m, 1H ) 9.29 - 9.44 (m, 1 H) MS ES+: 384

Example 6

[00258] N-Methyl-5-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1-carbonyl}pyridazin-3-amine

[00259] 2-[1-(6-chloropyridazine-4carbonyl)piperidin-3-yl}-1-(propan-2-yl)-1H-1,3-benzodiazole (Example 5) (161 mg, 0.419 mmol) was dissolved in matanamine solution (33% in ethanol, 1.97 g, 20.97 mmol) and irradiated in a microwave reactor at 150 oC for 1 hour. The volatile components were removed in vacuo and the crude product was purified using column chromatography (silica gel) eluted with 20-100% ethyl acetate in 40-60 petroleum ether then 0-40% methanol in ethyl acetate to give the title composite. 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.26 - 2.17 (m, 10 H) 2.70 - 2.93 (m, 3 H) 2.94 - 3.66 (blurred m, 3H) 4.02 - 4.14 (m, 1H) 4.33 - 4.98 (m, 2H) 6.79 (br.s., 1H) 6.91 - 7.23 (m , 3H) 7.50 - 7.76 (m, 2H) 8.38 - 8.77 (m, 1H) MS ES+: 379

Example 7

[00260] 2-[1-(1-Ethyl-1H-pyrazole-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-1,3-benzodiazole

[00261] Prepared as described for N,N-dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidin-1-carbonyl}pyridin-2 -amine (Example 1) from 2-(piperidin-3-yl)-1-(propan-2-yl)-1H-1,3-benzodiazole hydrochloride (CAS 1185300-76-8, 0.15 g , 0.474 mmol) and 1-ethyl-1H-pyrazole-4-carboxylic acid (CAS 400858-54-0, 0.073 g, 0.522 mmol). The reaction was diluted with DCM and quenched with saturated aqueous NaHCO 3 and the organic layer was filtered through a phase separation cartridge and evaporated to dryness. The crude product was purified by column chromatography (silica gel) eluted with 0-10% methanol in DCM to give the title compound. 1H NMR (400 MHz, DMSO-d6) □ ppm 1.38 (t, J=7.33 Hz, 3H) 1.47 - 1.75 (m, 7H) 1.79 - 2.16 (m , 3H) 2.86 - 3.19 (blurred m, 3H) 4.15 (q, J=7.07 Hz, 2H) 4.21 - 4.62 (m, 2H) 4.82 (br.s., 1H) 7.09 - 7.22 (m, 2H) 7.53 - 7.61 (m, 1H) 7.63 - 7.72 (m, 2H) 8. 05 (s, 1 H) MS ES+: 366

Example 8

[00262] N,N-Dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-amine

[00263] To a stirring solution of 1-methyl-2-(piperidin-3-yl)-1H-indole (Intermediate 2; 0.02 g, 0.093 mmol) and 2-(dimethylamino)pyridine-4 acid hydrochloride -carboxylic acid (0.023 g, 0.112 mmol) in DCM (1 mL) was added triethylamine (0.026 mL, 0.187 mmol) and then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2, 4,6-Trioxide (50% by weight solution in EtOAc) (0.139 ml, 0.233 mmol). The reaction mixture was stirred at room temperature. After 80 min. the reaction was stopped with saturated aqueous NaHCO3 and extracted into DCM. The crude product was purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia) to give the title compound. 1H NMR (400 MHz, CD3CN) □ ppm 1.52 - 2.00 (m, 4H) 2.75 - 3.22 (m, 9H) 3.37 - 3.88 (m, 4H) 4 .46 - 4.85 (m, 1H) 6.21 - 6.65 (m, 3H) 6.94 - 7.61 (m, 4H) 8.06 - 8.24 (m, 1H) ) MS ES+: 363

Example 9

[00264] N-Methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine

[00265] To a microwave flask loaded with 2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole (Intermediate 5; 0.037 g, 0.104 mmol) in 1,4-dioxane (2 mL) was added methanamine [2M solution in THF] (1.043 mL, 2.085 mmol). The flask was sealed and irradiated in the microwave at 140°C for 5 hours and 20 minutes. Additional methanamine [2M solution in THF] (1.043 mL, 2.085 mmol) and nMP (1 mL) [to aid microwave absorption] were added and the reaction microwaved at 160°C for 1 hour. The volatile components were removed in vacuo and the crude product was purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia) to give the title compound. 1H NMR (400 MHz, CD3CN) □ ppm 1.53 - 1.93 (m, 4H) 2.79 - 3.32 (m, 6H) 3.45 - 3.86 (m, 4H) 4 .42 - 4.80 (m, 1H) 5.43 - 5.59 (m, 1H) 6.28 - 6.36 (m, 1H) 6.60 - 6.73 (m, 1H) ) 6.94 - 7.11 (m, 1H) 7.11 - 7.24 (m, 1H) 7.25 - 7.43 (m, 1H) 7.45 - 7.60 (m, 1H) 1H) 8.44 - 8.49 (m, 1H) MS ES+: 350

Example 10

[00266] 4-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridin-2-amine

[00267] Prepared as described for N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-amine (Example 8) from hydrochloride of 2-(dimethylamino)pyridine-4-carboxylic acid (0.040 g, 0.197 mmol) and 1-ethyl-2-(piperidin-3-yl)-1H-indole (Intermediate 6; 0.045 g, 0.197 mmol). The reaction was stopped by addition of saturated aqueous NaHCO 3 , extracted with EtOAc and washed with saturated aqueous NaHCO 3 then brine. The crude product was purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia) to give the title compound. 1H NMR (400 MHz, CDCl3) □ ppm 1.07 - 1.51 (m, 3H) 1.55 - 1.98 (m, 3H) 2.07 - 2.31 (m, 1H) 2 .66 - 3.20 (m, 9H) 3.72 - 4.04 (m, 2H) 4.25 - 4.42 (m, 1H) 4.65 - 5.01 (m, 1H) ) 6.21 - 6.38 (m, 1H) 6.41 - 6.62 (m, 2H) 6.95 - 7.42 (m, 3H) 7.47 - 7.68 (m, 2H) 1H) 8.22 (dd, J=19.71, 4.80 Hz, 1H) MS ES+: 377

Example 11

[00268] 5-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine

[00269] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 2-[ 1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-1H-indole (Intermediate 10; 0.042 g, 0.114 mmol) and dimethylamine [2.0M solution in THF] (1.139 ml, 2.277 mmol) using NMP (1 mL) as the solvent. The reaction mixture was irradiated in the microwave at 140 °C for 20 minutes to give the title compound after purification by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia). 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 0.87 - 1.40 (m, 3H) 1.59 - 1.96 (m, 3H) 2.04 - 2.15 (m, 1 H) 2.75 - 2.97 (m, 1H) 2.99 - 3.25 (m, 8H) 3.51 (m, 1H) 3.90 - 4.09 (m, 1H) 4.27 (m, 1H) 4.42 - 4.72 (m, 1H) 6.17 - 6.39 (m, 1H) 6.86 - 7.16 (m, 3H) 7. 29 - 7.54 (m, 2H) 8.54 (s, 1H) MS ES+: m/z 378

Example 12

[00270] 5-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyridazin-3-amine

[00271] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 2-[ 1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-1H-indole (Intermediate 10; 0.042 g, 0.114 mmol) and methanamine [2M solution in THF] (2.278 ml, 4.556 mmol) using NMP (1 mL) as the solvent and irradiated in the microwave at 140 °C for 2 hours 20 minutes to give the title compound after purification by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia ). 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 0.91 - 1.39 (m, 3H) 1.56 - 1.95 (m, 3H) 1.99 - 2.18 (m, 1 H) 2.74 - 2.93 (m, 4H) 2.97 - 3.12 (m, 1H) 3.12 - 3.26 (m, 1H) 3.46 - 3.61 (m , 1H) 3.91 - 4.10 (m, 1H) 4.16 - 4.33 (m, 1H) 4.43 - 4.69 (m, 1H) 6.17 - 6.38 (m, 1H) 6.69 - 6.83 (m, 1H) 6.90 - 7.17 (m, 3H) 7.28 - 7.56 (m, 2H) 8.49 (d , J=7.07 Hz, 1 H) MS ES+: 364

Example 13

[00272] N,N-Dimethyl-5-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbonyl}pyridazin-3-amine

[00273] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 2-[ 1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-indole (Intermediate 11; 0.065 g, 0.170 mmol) and dimethylamine [2.0M solution in THF ] (1.698 ml, 3.40 mmol) using NMP (1 ml) as the solvent. The reaction mixture was irradiated in the microwave at 140 °C for 20 minutes to give the title compound after purification by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia). 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.02 - 1.50 (m, 3H) 1.54 - 1.96 (m, 6H) 2.02 - 2.19 (m, 1 H) 2.76 - 2.95 (m, 1H) 3.03 - 3.22 (m, 8H) 3.38 - 3.62 (m, 1H) 4.18 - 4.91 (m , 2H) 6.11 - 6.34 (m, 1H) 6.86 - 7.17 (m, 3H) 7.35 - 7.66 (m, 2H) 8.54 (d, J =1.01 Hz, 1 H) MS ES+: 392

Example 14

[00274] N-Methyl-5-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbonyl}pyridazin-3-amine

[00275] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 2-[ 1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-indole (Intermediate 11; 0.065 g, 0.170 mmol) and methanamine [2M solution in THF] ( 1.698 ml, 3.40 mmol) using NMP (1 ml) as the solvent and irradiated in the microwave at 140 °C for 2 hours and 20 minutes. Additional methanamine [2M solution in THF] (1.698 ml, 3.40 mmol) was added and the reaction mixture was irradiated at 140 °C for a further 1 h to give the title compound after purification by preparative reverse phase HPLC eluted with acetonitrile / water (with 0.1% ammonia). 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.07 - 1.51 (m, 3H) 1.54 - 1.95 (m, 6H) 2.02 - 2.20 (m, 1 H) 2.75 - 2.97 (m, 4H) 2.98 - 3.24 (m, 2H) 3.44 - 3.63 (m, 1H) 4.22 - 4.91 (m , 2H) 6.14 - 6.33 (m, 1H) 6.72 - 6.86 (m, 1H) 6.86 - 7.14 (m, 3H) 7.36 - 7.67 (m, 2H) 8.40 - 8.52 (m, 1H) MS ES+: 378

Example 15

[00276] 2-{1-[(1-Ethyl-1H-pyrazol-4-yl)carbonyl]piperidin-3-yl}-1-(propan-2-yl)-1H-indole

[00277] Prepared as described for N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-amine (Example 8) from acid 1-Ethyl-1H-pyrazole-4-carboxylic acid (CAS 40085854-0, 0.033 g, 0.238 mmol) and 2-(piperidin-3-yl)-1-(propan-2-yl)-1H-indole (Intermediate 12 ;0.048 g, 0.198 mmol). The crude reaction mixture was extracted into EtOAc and purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia) to give the title compound. 1H NMR (400 MHz, DMSO-d6) □ ppm 1.26 - 1.91 (m, 12H) 2.01 - 2.18 (m, 1H) 2.5 - 3.4 (br., 3 H) 4.05 - 4.20 (m, 2H) 4.21 - 4.99 (br., 3H) 6.26 (s, 1H) 6.85 - 7.00 (m, 1H) ) 7.01 - 7.08 (m, 1H) 7.47 (d, J=7.58 Hz, 1H) 7.57 (d, J=8.08 Hz, 1H) 7.70 ( s, 1H) 8.11 (br. s., 1H) 1H NMR (300 MHz, 90oC, DMSO-d6) □ ppm 1.41 (t, J=7.27 Hz, 3H) 1.55 (d + d, J=6.89, 6H) 1.59 - 1.94 (m, 3H) 2.07 - 2.21 (m, 1H) 2.9 - 3.2 (m, 3H) 3H) 4.16 (q, J=7.18 Hz, 2H) 4.23 - 4.53 (m, 2H) 4.65 - 4.82 (m, 1H) 6.28 (s , 1H) 6.92 - 7.00 (m, 1H) 7.01 - 7.10 (m, 1H) 7.47 (d, J=7.74 Hz, 1H) 7.54 ( d, J=8.31 Hz, 1H) 7.65 (s, 1H) 8.00 (s, 1H) MS ES+: 365

Example 16

[00278] 1-Methyl-4-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidinecarbonyl}-1H-pyrazol-3-amine

[00279] To a stirred suspension of tert-butyl N-(1-methyl-4-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbonyl}- 1H-pyrazol-3-yl)carbamate (Intermediate 16; 0.072g, 0.155mmol) in methanol (1ml) was added HCl [4.0M in dioxane] (0.116ml, 0.464mmol). The reaction mixture was stirred at room temperature overnight. LCMS analysis showed that the reaction was not complete so the reaction mixture was concentrated in vacuo and redissolved in methanol (1 mL) and more HCl [4.0 M in dioxane] (0.116 mL, 0.464 mmol) was added. The reaction mixture was stirred at room temperature overnight. This process was repeated one more time until the reaction was complete. Volatile components were removed in vacuo and partitioned between DCM and saturated aqueous NaHCO3. The organic phase was removed using a phase separator cartridge and the aqueous phase was extracted with more DCM. The organics were combined and the crude product was purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia) to give the title compound. 1H NMR (400 MHz, DMSO-d 6 ) □ ppm 1.55 (m, 6 H) 1.60 - 1.86 (m, 3 H) 2.04 - 2.15 (m, 1 H) 2. 75 - 3.14 (m, 3H) 3.26 - 3.58 (m, 3H) 4.27 (m, 1H) 4.45 (m, 1H) 4.73 (m, 1H ) 5.15 (s, 2H) 6.26 (s, 1H) 6.91 - 7.00 (m, 1H) 7.01 - 7.09 (m, 1H) 7.47 (d , J=7.83 Hz, 1H) 7.58 (d, J=8.08 Hz, 1H) 7.76 (s, 1H) MS ES+: 366

Example 17

[00280] 1-Ethyl-2-{1-[(1-ethyl-1H-pyrazol-4-yl)carbonyl]piperidin-3-yl}-5-methyl-1H-indole

[00281] Prepared as described for N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-amine (Example 8) from 1 -ethyl-5-methyl-2-(piperidin-3-yl)-1H-indole hemiformate (Intermediate 19; 0.0782 g, 0.298 mmol) and 1-ethyl-1H-pyrazole-4-carboxylic acid (CAS 400858-54-0, 0.046 g, 0.328 mmol) in DCM (1 mL) with an additional step, whereby the crude product after purification was passed through a pre-equilibrated SCX-2 cartridge (1g) and washed with DCM before being purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia) to give the title compound. 1H NMR (300 MHz, CD3CN) □ ppm 1.26 (br. m, 3H) 1.44 (t, J=7.27 Hz, 3H) 1.56 - 1.92 (m, 3H) 2.17 (blurred, s, 1H) 2.41 (s, 3H) 2.51 - 3.51 (br. m, 3H) 4.16 (q, J=7.11 Hz, 4H ) 4.35 (br. m, 2 H) 6.23 (s, 1 H) 6.98 (d, J=8.31 Hz, 1 H) 7.17 - 7.37 (m, 2 H) 7.65 (s, 1H) 7.80 (br.s, 1H) MS ES+: 365

Example 18

[00282] 5-[3-(1-Ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyridazin-3-amine

[00283] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 2-[ 1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-3-methyl-1H-indole (Intermediate 23; 0.075 g, 0.196 mmol) and methanamine [2M solution in THF] (3 .92 ml, 7.84 mmol) using NMP (1 ml) as the solvent and irradiated in the microwave at 140 °C for 4 hours to give the title compound after purification by preparative reverse phase HPLC eluted with acetonitrile / water (with 0.1% ammonia). 1H NMR (400 MHz, CD3CN) □ ppm 1.03 - 1.41 (m, 3H) 1.59 - 1.85 (m, 1H) 1.90 - 2.30 (blurred, m, 3H ) 2.31 - 2.48 (m, 3H) 2.80 - 3.77 (m, 7H) 4.00 - 4.35 (m, 2H) 4.54 - 4.79 (m, 7H) 1H) 5.46 - 5.63 (m, 1H) 6.61 - 6.78 (m, 1H) 6.88 - 7.59 (m, 4H) 8.40 - 8.55 ( m, 1H) MS ES+: 378

Example 19

[00284] 5-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyridazin-3-amine

[00285] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 2-[ 1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-5-methyl-1H-indole (Intermediate 28; 0.0575 g, 0.150 mmol) and methanamine [2M solution in THF] ( 3.00 mL, 6.01 mmol) using NMP (1 mL) as the solvent and irradiated in the microwave at 140 °C for 4 hours to give the title compound after purification by preparative reverse phase HPLC eluted with acetonitrile / water (with 0.1% ammonia). 1H NMR (400 MHz, CD3CN) □ ppm 0.95 - 1.45 (m, 3H) 1.56 - 1.95 (m, 4H) 2.31 - 2.46 (m, 3H) 2 .75 - 3.26 (m, 6H) 3.57 - 3.76 (m, 1H) 3.86 - 4.34 (m, 2H) 4.50 - 4.75 (m, 1H) ) 4.80 - 5.60 (m, 1H) 6.12 - 6.31 (m, 1H) 6.55 - 6.77 (m, 1H) 6.86 - 7.06 (m, 1H) 1H) 7.12 - 7.37 (m, 2H) 8.36 - 8.53 (m, 1H) MS ES+: 378

Example 20

[00286] 5-[3-(5-chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyridazin-3-amine

[00287] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 5-chloro -2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-1H-indole (Intermediate 29; 0.062 g, 0.154 mmol) and methanamine [2M solution in THF] (3, 07 mL, 6.15 mmol) using NMP (1 mL) as the solvent and irradiated in the microwave at 140 °C for 4 hours to give the title compound after purification by preparative reverse phase HPLC eluted with acetonitrile / water ( with 0.1% ammonia). 1H NMR (400 MHz, CD3CN) □ ppm 1.02 - 1.41 (m, 3H) 1.52 - 1.90 (m, 3H) 2.11 - 2.17 (blurred m, 1H) 2.74 - 3.28 (m, 6H) 3.67 (m, 1H) 3.86 - 4.39 (m, 2H) 4.48 - 4.78 (m, 1H) 5. 45 - 5.66 (m, 1H) 6.19 - 6.39 (m, 1H) 6.58 - 6.80 (m, 1H) 6.96 - 7.20 (m, 1H) 7.24 - 7.43 (m, 1H) 7.43 - 7.62 (m, 1H) 8.31 - 8.57 (m, 1H) MS ES+: 398

Example 21

[00288] 5-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine

[00289] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 2-[ 1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-5-methyl-1H-indole (Intermediate 28; 0.0575 g, 0.150 mmol) and dimethylamine [2.0M in THF] (1.502 ml, 3.00 mmol) using NMP (1 ml) as the solvent and irradiated in the microwave at 140 °C for 30 minutes. Purification by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia) gave the title compound. 1H NMR (400 MHz, CD3CN) □ ppm 0.96 - 1.45 (m, 3H) 1.53 - 1.95 (m, 3H) 2.08 - 2.22 (blurred m, 1H) 2.32 - 2.46 (m, 3H) 2.75 - 3.28 (m, 9H) 3.51 - 3.72 (m, 1H) 3.79 - 4.34 (m, 2 H) 4.46 - 4.80 (m, 1H) 6.10 - 6.33 (m, 1H) 6.76 - 7.04 (m, 2H) 7.11 - 7.38 (m , 2H) 8.37 - 8.54 (m, 1H) MS ES+: 392

Example 22

[00290] 5-[3-(5-chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine

[00291] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 5-chloro -2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-1H-indole (Intermediate 29; 0.031 g, 0.077 mmol) and dimethylamine [2.0M in THF] (0.769 ml, 1.537 mmol) using NMP (1 ml) as the solvent and irradiated in the microwave at 140 °C for 1 hour to give the title compound after purification by preparative reverse phase HPLC eluted with acetonitrile / water (with 0. 1% ammonia). 1H NMR (400 MHz, CD3CN) □ ppm 1.00 - 1.47 (m, 3H) 1.57 - 1.94 (m, 3H) 2.18 (blurred m, 1H) 2.76 - 3.27 (m, 9H) 3.54 - 3.75 (m, 1H) 3.84 - 4.37 (m, 2H) 4.48 - 4.80 (m, 1H) 6. 19 - 6.40 (m, 1H) 6.74 - 6.96 (m, 1H) 7.12 (m, 1H) 7.24 - 7.43 (m, 1H) 7.44 - 7.59 (m, 1H) 8.39 - 8.55 (m, 1H) MS ES+: 412

Example 23

[00292] N-Methyl-5-[3-(3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine

[00293] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 2-[ 1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-3-methyl-1H-indole (Intermediate 34; 0.034 g, 0.096 mmol) and methanamine [2M solution in THF] (1.916 ml, 3.83 mmol) using NMP (1 mL) as the solvent and irradiated in a microwave at 140°C for 1 hour. Additional methanamine [2M solution in THF] (1.916 mL, 3.83 mmol) was added and the reaction was irradiated in the microwave at 140°C for a further 5 hours to give the title compound after purification by preparative reverse phase HPLC eluted with acetonitrile / water (with 0.1% ammonia). 1H NMR (400 MHz, CD3CN) □ ppm 1.77 (m, 2H) 2.15 - 2.36 (blurred m, 5H) 2.74 - 3.06 (m, 4H) 3.08 - 3.28 (m, 2H) 3.52 - 3.74 (m, 1H) 4.51 - 4.70 (m, 1H) 5.35 - 5.62 (m, 1H) 6. 59 - 6.79 (m, 1H) 6.89 - 7.17 (m, 2H) 7.20 - 7.55 (m, 2H) 8.39 - 8.54 (m, 1H) 8.89 - 9.16 (m, 1 H) MS ES+: 350

Example 24

[00294] N,N-Dimethyl-5-[3-(3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine

[00295] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 2-[ 1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-3-methyl-1H-indole (Intermediate 34; 0.034 g, 0.096 mmol) and dimethylamine [2M solution in THF] (1.916 ml, 3.83 mmol) using NMP (1 mL) as the solvent and irradiated in a microwave at 140 °C for 30 minutes to give the title compound after purification using preparative reverse phase HPLC eluted with acetonitrile / water (with 0.1 % ammonia) followed by a second purification using reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% formic acid). MS ES+: 364

Example 25

[00296] 4-[3-(1-Ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine

[00297] To a stirred solution of tert-butyl N-{4-[3-(1-ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H- pyrazol-3-yl)carbamate (Intermediate 36; 234mg, loaded from previous step without purification) in DCM (1ml) was added TFA (0.1ml, 1.298mmol). The reaction mixture was stirred at room temperature for 90 hours. The volatile components were removed in vacuo and the crude product was purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia) to give the title compound. 1H NMR (400 MHz, CD3CN) □ ppm 0.94 - 1.31 (m, 3H) 1.53 - 1.91 (shaded m, 2H) 2.01 - 2.47 (shaded m, 5H ) 3.01 - 3.15 (m, 2H) 3.25 - 3.41 (m, 1H) 3.63 (s, 3H) 4.22 (q, J=7.16 Hz, 2 H) 4.36 - 4.51 (m, 2H) 4.75 (br.s., 2H) 6.96 - 7.08 (m, 1H) 7.15 (t, J=7, 20 Hz, 1 H) 7.33 (d, J=8.08 Hz, 1 H) 7.42 - 7.54 (m, 2 H) MS ES+: 366

Example 26

[00298] 4-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine

[00299] Prepared as described for 4-[3-(1-ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine (Example 25 ) from tert-butyl N-{4-[3-(1-ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-yl }carbamate (Intermediate 37; 277 mg, loaded from previous step without purification) to give the title compound. 1H NMR (400 MHz, CD3CN) □ ppm 1.22 - 1.47 (m, 3H) 1.55 - 1.91 (m, 3H) 2.04 - 2.13 (m, 1H) 2 .37 - 2.57 (m, 3H) 2.87 - 3.20 (m, 3H) 3.64 (s, 3H) 4.20 (q, J=7.07 Hz, 2H) 4.30 - 4.41 (m, 1H) 4.45 - 4.59 (m, 1H) 4.74 (br.s., 2H) 6.23 (s, 1H) 6.98 (d, J=8.34 Hz, 1 H) 7.20 - 7.35 (m, 2 H) 7.48 (s, 1 H) MS ES+: 366

Example 27

[00300] 4-[3-(5-chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine

[00301] Prepared as described for 4-[3-(1-ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine (Example 25 ) from tert-butyl N-{4-[3-(5-chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-yl )carbamate (Intermediate 38; 259 mg, loaded from previous step without purification) to give the title compound. 1H NMR (400 MHz, CD3CN) □ ppm 1.31 (t, J=7.20 Hz, 3H) 1.60 - 1.93 (m, 3H) 2.08 - 2.13 (blurred m, 1H) 2.87 - 3.19 (m, 3H) 3.64 (s, 3H) 4.23 (q, J=7.07 Hz, 2H) 4.28 - 4.39 (m , 1H) 4.46 - 4.58 (m, 1H) 4.75 (br.s., 2H) 6.32 (s, 1H) 7.13 (dd, J=8.72, 1.89 Hz, 1 H) 7.38 (d, J=8.84 Hz, 1 H) 7.49 (s, 1 H) 7.53 (d, J=2.02 Hz, 1 H) MS ES+: 386

Example 28

[00302] 5-[3-(5-chloro-3-methylpyridin-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine

[00303] A solution of 3-chloro-5-[3-(5-chloro-3-methylpyridin-2-yl)piperidine-1-carbonyl]pyridazine (Intermediate 39; 0.063 g, 0.179 mmol) and dimethylamine (2 M in THF) (1.794 mL, 3.59 mmol) in butan-1-ol (2 mL) was heated in a sealed tube to 135°C for 2 hours. The solution was concentrated in vacuo and the crude product was purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia) to give the title compound. 1H NMR (400 MHz, DMSO-d6) □ ppm 1.56 - 1.97 (m, 4H) 2.17 - 2.42 (m, 3H) 2.78 - 3.19 (m, 8H ) 3.33 - 3.56 (m, 2H) 4.43 - 4.56 (m, 1H) 7.03 - 7.09 (m, 1H) 7.61 - 7.81 (m, 1H) 1H) 8.30 - 8.54 (m, 2H) MS ES+: 360

Example 29

[00304] 4-{3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carbonyl}-N-methylpyridin-2-amine formate

[00305] Prepared as described for N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-amine (Example 8) from 5 -chloro-2-(3-methoxypiperidin-3-yl)-3-(trifluoromethyl)pyridine (Intermediate 43 (free base); 0.010 g, 0.026 mmol) and 2-(methylamino)pyridine-4-carboxylic acid hydrochloride hemi hydrate (CAS 876717-53-2, 7.75 mg, 0.039 mmol) in DCM (0.5 mL), except that the reaction was stopped by dilution in MeOH (3 mL) and stirred for 1 hour. The crude product was purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% formic acid) to give the title compound. 1H NMR (400 MHz, Methanol-d 4 ) □ ppm 1.78 - 2.11 (m, 3H) 2.22 - 2.46 (m, 1H) 2.87 - 3.24 (m, 7 H) 3.40 - 4.95 (blurred m, 3H) 6.47 - 6.68 (m, 2H) 7.84 - 8.35 (m, 3H) 8.81 (dd, J= 13.77, 1.89 Hz, 1 H) MS ES+: 429

Example 30

[00306] 5-({3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidin-1-yl}carbonyl)-N-methylpyridazin-3-amine

[00307] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 3-chloro -5-{3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carbonyl}pyridazine (Intermediate 48; 0.08 g, 0.184 mmol) and methanamine [2 M solution in THF] (3.68 ml, 7.35 mmol) using NMP (1 ml) as the solvent and irradiated in the microwave at 140°C for 2.5 hours to give the title compound after purification by preparative HPLC of reverse phase eluted with acetonitrile / water (with 0.1% ammonia). 1H NMR (400 MHz, CD3CN) □ ppm 1.48 - 2.34 (blurred m, 4H) 2.83 - 3.13 (m, 7H) 3.20 - 4.88 (m, 3H) 5.36 - 5.54 (m, 1H) 6.53 - 6.65 (m, 1H) 8.04 - 8.24 (m, 1H) 8.28 - 8.41 (m, 1 H) 8.65 - 8.76 (m, 1H) MS ES+: 430

Example 31

[00308] 5-{3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carbonyl}-N,N-dimethylpyridazin-3-amine

[00309] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 3-chloro -5-{3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carbonyl}pyridazine (Intermediate 48; 0.08 g, 0.184 mmol) and dimethylamine [2 M solution in THF] (3.68 ml, 7.35 mmol) using NMP (1 ml) as the solvent and irradiated in the microwave at 140 °C for 1 hour to give the title compound after purification by preparative reverse-phase HPLC eluted with acetonitrile / water (with 0.1% ammonia). 1H NMR (300 MHz, CD3CN) □ ppm 1.52 - 2.44 (blurred m, 4H) 2.84 - 3.23 (m, 10H) 3.23 - 4.97 (m, 3H) 6.77 - 6.90 (m, 1H) 8.05 - 8.31 (m, 1H) 8.34 - 8.48 (m, 1H) 8.69 - 8.85 (m, 1 H) MS ES+: 444

Example 32

[00310] 5-chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-3-methoxypiperidin-3-yl]-3-(trifluoromethyl)pyridine

[00311] Prepared as described for N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-amine (Example 8) from hydrochloride of 5-chloro-2-(3-methoxypiperidin-3-yl)-3-(trifluoromethyl)pyridine (Intermediate 43; 66.2 mg, 0.2 mmol) and 1-ethyl-1H-pyrazole-4-carboxylic acid (CAS 400858-54-0, 0.031 g, 0.220 mmol) in DCM (0.5 mL) to give the title compound after purification by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia). 1H NMR (400 MHz, CD3CN) □ ppm 1.44 (t, J=7.20 Hz, 3H) 1.69 - 2.71 (broken m, 4H) 2.84 - 3.64 ( br. m, 5 H) 4.03 - 5.04 (br. m + q, 4 H) 7.62 (br. s., 1 H) 7.79 (br. s., 1 H) 8. 22 (br.s., 1H) 8.77 (m, 1H) MS ES+: 417

Example 33

[00312] 4-{3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carbonyl}-N,N-dimethylpyridin-2-amine

[00313] Prepared as described for N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-amine (Example 8) from hydrochloride of 5-chloro-2-(3-methoxypiperidin-3-yl)-3-(trifluoromethyl)pyridine (Intermediate 43; 0.050 g, 0.151 mmol) and 2-(dimethylamino)pyridine-4-carboxylic acid hydrochloride (0.046 g , 0.226 mmol) in DCM (1 mL) except purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% formic acid) to give the title compound. 1H NMR (400 MHz, CD3CN) □ ppm 1.48 - 2.67 (blurred m, 4H) 2.90 - 3.16 (m, 9H) 3.19 - 4.96 (m, 4H) 6.35 - 6.59 (m, 2H) 8.00 - 8.32 (m, 2H) 8.68 - 8.83 (m, 1H) MS ES+: 443

Example 34

[00314] 4-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N-methylpyridin-2-amine

[00315] Prepared as described for N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-amine (Example 8) from hydrochloride of 5-chloro-2-(3-methoxypiperidin-3-yl)-3-methylpyridine (Intermediate 49; 0.050 g, 0.180 mmol) and 2-(methylamino)pyridine-4-carboxylic acid hemihydrate hydrochloride (CAS 876717- 53-2, 0.053 g, 0.271 mmol) in DCM (1 mL) to give the title compound. 1H NMR (400 MHz, CD3CN) □ ppm 1.37 - 1.90 (shaded m, 2H) 1.96 - 2.28 (shaded m, 2H) 2.35 - 2.52 (shaded m, 3H ) 2.69 - 3.03 (m, 6H) 3.13 - 3.40 (m, 2H) 3.44 - 4.83 (m, 2H) 5.04 - 5.24 (m, 2H) 1H) 6.16 - 6.43 (m, 2H) 7.34 - 7.60 (m, 1H) 7.96 (m, 1H) 8.17 - 8.33 (m, 1H) ) MS ES+: 375

Example 35

[00316] 4-[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N-methylpyridin-2-amine

[00317] Prepared as described for N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-amine (Example 8) from hydrochloride of 5-chloro-2-(3-fluoropiperidin-3-yl)-3-methylpyridine (Intermediate 52; 0.050 g, 0.189 mmol) and 2-(methylamino)pyridine-4-carboxylic acid hemihydrate hydrochloride (CAS 876717- 53-2, 0.056 g, 0.283 mmol) in DCM (1 mL) to give the title compound after purification by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% formic acid). 1H NMR (400 MHz, CD3CN) □ ppm 1.59 - 1.97 (shaded m, 3H) 2.13 - 2.29 (shaded m, 1H) 2.43 - 2.59 (shaded m, 3H ) 2.77 - 4.94 (m, 7H) 5.17 - 5.39 (m, 1H) 6.31 - 6.41 (m, 1H) 6.44 - 6.56 (m, 1H) 1H) 7.53 - 7.75 (m, 1H) 7.94 - 8.15 (m, 1H) 8.25 - 8.45 (m, 1H) MS ES+: 363

Example 36

[00318] 5-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N-methylpyridazin-3-amine

[00319] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 3-chloro -5-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]pyridazine (Intermediate 54; 0.057 g, 0.150 mmol) and methanamine [2M solution in THF] (4 .50 mL, 9.00 mmol) using NMP (1.5 mL) as the solvent and irradiated in the microwave at 140 °C for 3 hours to give the title compound after purification by preparative reverse phase HPLC eluted with acetonitrile / water (with 0.1% ammonia). 1H NMR (400 MHz, Methanol-d 4 ) □ ppm 1.55 - 2.06 (m, 3H) 2.14 - 2.67 (m, 4H) 2.89 - 3.28 (m, 7 H) 3.38 - 4.97 (m, 3H) 6.76 - 6.92 (m, 1H) 7.48 - 7.73 (m, 1H) 8.30 - 8.45 (m , 2H). MS ES+: 376

Example 37

[00320] 5-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine

[00321] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 3-chloro -5-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]pyridazine (Intermediate 54; 0.057 g, 0.150 mmol) and dimethylamine [2M solution in THF] (6 .3 ml, 12.6 mmol) using NMP (1.5 ml) as the solvent and irradiated in the microwave at 140 °C for 90 minutes to give the title compound after purification by preparative reverse phase HPLC eluted with acetonitrile / water (with 0.1% ammonia). 1H NMR (400 MHz, CD3CN) □ ppm 1.51 - 2.64 (blurred m, 7H) 2.87 - 4.97 (m, 13H) 6.75 - 6.90 (m, 1H) 7.46 - 7.69 (m, 1H) 8.30 - 8.48 (m, 2H) MS ES+: 390

Example 38

[00322] 5-[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N-methylpyridazin-3-amine

[00323] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 3-chloro -5-{[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidin-1-yl]carbonyl}pyridazine (Intermediate 55; 0.087 g, 0.236 mmol) and methanamine [2M solution in THF ] (4.71 ml, 9.43 mmol) using NMP (1 ml) as the solvent and irradiated in the microwave at 140 °C for 2.5 hours to give the title compound after purification by preparative reverse phase HPLC eluted with acetonitrile / water (with 0.1% ammonia). 1H NMR (400 MHz, CD3CN) □ ppm 1.63 - 2.57 (blurred m, 7H) 2.88 - 4.93 (m, 7H) 5.49 - 5.65 (m, 1H) 6.69 (m, 1H) 7.55 - 7.73 (m, 1H) 8.25 - 8.49 (m, 2H) MS ES+: 364

Example 39

[00324] 5-[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine

[00325] Prepared as described for N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine (Example 9) from 3-chloro -5-{[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidin-1-yl]carbonyl}pyridazine (Intermediate 55; 0.087 g, 0.236 mmol) and dimethylamine [2M solution in THF ] (4.7 ml, 9.4 mmol) using NMP (1 ml) as the solvent and irradiated in the microwave at 140 °C for 1 hour to give the title compound after purification by preparative reverse phase HPLC eluted with acetonitrile / water (with 0.1% ammonia). 1H NMR (400 MHz, CD3CN) □ ppm 1.62 - 2.59 (blurred m, 7H) 2.90 - 4.97 (m, 10H) 6.77 - 6.90 (m, 1H) 7.55 - 7.73 (m, 1H) 8.26 - 8.48 (m, 2H) MS ES+: 378

Example 40

[00326] 5-Chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-3-methoxypiperidin-3-yl]-3-methylpyridine

[00327] Prepared as described for N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-amine (Example 8) from hydrochloride of 5-chloro-2-(3-methoxypiperidin-3-yl)-3-methylpyridine (Intermediate 49; 0.050 g, 0.180 mmol) and 1-ethyl-1H-pyrazole-4-carboxylic acid (CAS 400858-54-0 , 0.033 g, 0.234 mmol) in DCM (1 mL) to give the title compound. 1H NMR (400 MHz, CD3CN) □ ppm 1.45 (t, J=7.33 Hz, 3H) 1.61 - 2.69 (dark white m, 7H) 2.75 - 3.68 ( br.m, 5H) 4.04 - 5.02 (br.m + q, 4H) 7.44 - 7.68 (m, 2H) 7.79 (s, 1H) 8.29 - 8.44 (m, 1H) MS ES+: 363

Example 41

[00328] 5-chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-3-fluoropiperidin-3-yl]-3-methylpyridine

[00329] Prepared as described for N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-amine (Example 8) from hydrochloride of 5-chloro-2-(3-fluoropiperidin-3-yl)-3-methylpyridine (Intermediate 52; 0.050 g, 0.189 mmol) and 1-ethyl-1H-pyrazole-4-carboxylic acid (CAS 400858-54-0 , 0.034 g, 0.245 mmol) in DCM (1 mL) to give the title compound. 1H NMR (400 MHz, CD3CN) □ ppm 1.43 (t, J=7.07 Hz, 3H) 1.66 - 2.02 (blurred m, 2H) 2.23 - 2.62 (m, 5 H) 2.68 - 4.05 (br. m, 2 H) 4.16 (q, J=6.82 Hz, 2 H) 4.24 - 5.16 (br. m, 2 H) 7 .54 - 7.70 (m, 2H) 7.80 (br.s., 1H) 8.37 (s, 1H) MS ES+: 351

Example 42

[00330] 4-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine

[00331] To a stirred solution of tert-butyl N-{4-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-1-methyl-1H-pyrazole -3-yl}carbamate (Intermediate 56; 84 mg, 0.18 mmol) in DCM (1 mL) was added TFA (0.25 mL, 3.24 mmol). The reaction was stirred at room temperature for 140 minutes and then quenched with saturated aqueous NaHCO3. The resulting mixture was extracted into DCM, then loaded onto a strong cation exchange cartridge (SCX-2, 1g), washed with DCM/MeOH (4:1) and eluted with DCM/[2M NH3 in MeOH] (4: 1). The crude product was purified by reverse phase preparative HPLC eluted with acetonitrile / water (with 0.1% ammonia) to give the title compound. 1H NMR (400 MHz, CD3CN) □ ppm 1.56 - 2.37 (blurred m, 4H) 2.51 (s, 3H) 2.95 (s, 3H) 3.02 - 3.17 ( m, 1H) 3.37 - 3.53 (m, 1H) 3.65 (s, 3H) 4.12 - 4.27 (m, 1H) 4.58 - 4.84 (m, 3H) 3H) 7.50 (s, 1H) 7.62 (d, J=2.02 Hz, 1H) 8.39 (d, J=2.02 Hz, 1H) MS ES+: 364

Example 43

[00332] 4-[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine

[00333] Prepared as described for 4-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine (Example 42) from tert-butyl N-(4-{[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidin-1-yl]carbonyl}-1-methyl-1H-pyrazol-3- yl)carbamate (Intermediate 57; 0.076g, 0.168mmol) using TFA (0.25ml, 3.24mmol) in DCM (1ml) to give the title compound. 1H NMR (400 MHz, CD3CN) □ ppm 1.68 - 2.03 (blurred m, 3H) 2.25 - 2.34 (m, 1H) 2.40 - 2.53 (m, 3H) 3.04 (br.s., 1H) 3.63 (s, 4H) 4.33 - 4.83 (m, 4H) 7.47 (s, 1H) 7.67 (s, 1 H) 8.38 (s, 1H) MS ES+: 352

3. Biological Assay

[00334] Prokineticin 1 (PKR1) receptor antagonists may be functionally evaluated by measuring the change in intracellular calcium levels induced by the Gq-mediated increase in inositol triphosphate (IP3) levels. The ability of a compound to block PK1-mediated intracellular calcium release in RBL2H3 cells expressing human PKR1 receptors is determined as a measure of the compound's antagonistic activity in vitro.

[00335] Approximately 10,000 cells per assay well are propagated in normal culture medium in a 384-well plate (Corning). Twenty-four hours after propagation, cells are loaded with a calcium-sensitive fluorescent dye by replacing the culture medium with assay buffer (1x Hanks Buffered Saline, 25mM HEPES, 0.1% w/v free fatty acid BSA ( bovine serum albumin), pH 7.4) containing 1mM probenecid and 1x Calcium 5 Reagent (Molecular Devices). Cells are incubated at 37oC for 1 hour to allow dye uptake.

[00336] To test antagonist activity, test compounds at a final concentration range between 0.32nM - 10μM (diluted in assay buffer) are added to assay wells in duplicate and incubated for 10 minutes before stimulation with PK1 . After incubation with test compounds, the assay plate is placed in a FLIPR Tetra (Molecular Devices) and PK1 (diluted in assay buffer) is added at the determined EC80 concentration (final). Ligand-dependent changes in intracellular calcium levels are determined by measuring changes in dye fluorescence at 525nM after excitation at 485nM. Readings from wells that do not contain antagonist allow percent inhibition curves to be plotted using a 4-parameter fit algorithm and IC50 values are calculated for each test compound. A minimum of two IC50 values determined from independent assays are generated for each compound.

[00337] Results

[337] Generally, the compounds tested above have IC50 values less than 10 DM, with the most potent compounds showing antagonistic activity at the prokineticin receptor with IC50 values < 1 µM. Accordingly, compounds of the invention are expected to be useful in the prevention or treatment of conditions in which modulation of prokineticin receptors is implicated.

Claims (11)

1. Compound characterized in that it is selected from: N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidin-1- carbonyl}pyridin-2-amine, (R)-N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1- carbonyl}pyridin-2-amine, (S)-N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1- carbonyl}pyridin-2-amine, N,N-Dimethyl-4-[3-(1-methyl-1H-1,3-benzodiazol-2-yl)piperidine-1-carbonyl]pyridin-2-amine, 2- [1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-1,3-benzodiazole, N-Methyl-5-{3-[1-( propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1-carbonyl}pyridazin-3-amine, 2-[1-(1-Ethyl-1H-pyrazole-4-carbonyl)piperidin -3-yl]-1-(propan-2-yl)-1H-1,3-benzodiazole, N,N-Dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidin- 1-carbonyl]pyridin-2-amine, N-Methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine, 4-[3-( 1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridin-2-amine, 5-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1 -carbonyl]-N,N-dimethylpyridazin-3-amine, 5-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyridazin-3-amine, N,N -Dimethyl-5-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbonyl}pyridazin-3-amine, N-Methyl-5-{3-[1 -(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbonyl}pyridazin-3-amine, 2-{1-[(1-Ethyl-1H-pyrazol-4-yl)carbonyl] piperidin-3-yl}-1-(propan-2-yl)-1H-indol, 1-Methyl-4-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine -carbonyl}-1H-pyrazol-3-amine, 1-Ethyl-2-{1-[(1-ethyl-1H-pyrazol-4-yl)carbonyl]piperidin-3-yl}-5-methyl-1H- indole, 5-[3-(1-Ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyridazin-3-amine, 5-[3-(1-Ethyl-5 -methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyridazin-3-amine, 5-[3-(5-chloro-1-ethyl-1H-indol-2-yl)piperidin- 1-carbonyl]-N-methylpyridazin-3-amine, 5-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridazin-3- amine, 5-[3-(5-chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine, N-Methyl-5-[3- (3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-amine, N,N-Dimethyl-5-[3-(3-methyl-1H-indol-2-yl)piperidine -1-carbonyl]pyridazin-3-amine, 4-[3-(1-Ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-pyrazole-3- amine, 4-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine, 4-[3-(5 -chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine, 5-[3-(5-chloro-3-methylpyridin-2- yl)piperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine, 4-{3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carbonyl}- N-methylpyridin-2-amine, 5-({3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidin-1-yl}carbonyl)-N-methylpyridazin-3-amine, 5-{3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carbonyl}-N,N-dimethylpyridazin-3-amine, 5-chloro-2-[1- (1-Ethyl-1H-pyrazole-4-carbonyl)-3-methoxypiperidin-3-yl]-3-(trifluoromethyl)pyridine, 4-{3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl ]-3-methoxypiperidine-1-carbonyl}-N,N-dimethylpyridin-2-amine, 4-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N -methylpyridin-2-amine, 4-[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N-methylpyridin-2-amine, 5-[3-(5 -chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N-methylpyridazin-3-amine, 5-[3-(5-chloro-3-methylpyridin-2-yl)-3- methoxypiperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine, 5-[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N-methylpyridazin-3 -amine, 5-[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N,N-dimethylpyridazin-3-amine, 5-chloro-2-[1- (1-Ethyl-1H-pyrazole-4-carbonyl)-3-methoxypiperidin-3-yl]-3-methylpyridine, 5-chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)- 3-fluoropiperidin-3-yl]-3-methylpyridine, 4-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-1-methyl-1H-pyrazol-3 -amine, 4-[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-1-methyl-1H-pyrazol-3-amine, and pharmaceutically acceptable salts thereof. 2. Compound according to claim 1, characterized in that the compound is a racemic mixture of the R and S enantiomers of N,N-Dimethyl-4-{3-[1-(propan-2-yl)- 1H-1,3-benzodiazol-2-yl]piperidin-1-carbonyl}pyridin-2-amine or its pharmaceutically acceptable salt. 3. Compound according to claim 1, characterized in that the compound is a racemic mixture of the R and S enantiomers of N,N-Dimethyl-4-{3-[1-(propan-2-yl)- 1H-1,3-benzodiazol-2-yl]piperidin-1-carbonyl}pyridin-2-amine. 4. Compound according to claim 1, characterized in that the compound is the R enantiomer of N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3 -benzodiazol-2-yl]piperidin-1-carbonyl}pyridin-2-amine or its pharmaceutically acceptable salt. 5. Compound according to claim 1, characterized in that the compound is the S enantiomer of N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3 -benzodiazol-2-yl]piperidin-1-carbonyl}pyridin-2-amine or its pharmaceutically acceptable salt. 6. Compound according to claim 1, characterized in that the compound is N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2 -yl]piperidin-1-carbonyl}pyridin-2-amine or its pharmaceutically acceptable salt. 7. Compound according to claim 1, characterized in that the compound is 2-[1-(1-Ethyl-1H-pyrazol-4-carbonyl)piperidin-3-yl]-1-(propan-2 -yl)-1H-1,3-benzodiazole or its pharmaceutically acceptable salt. 8. Compound according to claim 1, characterized in that the compound is 4-[3-(5-chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-1- methyl-1H-pyrazol-3-amine or its pharmaceutically acceptable salt. 9. Pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 10. Use of the compound as defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, characterized in that it is for the preparation of medicine for the treatment of an inflammatory bowel disease or irritable bowel syndrome. 11. Use of the compound as defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, characterized in that it is for the preparation of medicine for the treatment of schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive disorders or pain .