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WO2021145401A1 - Spiroheterocyclic derivatives as crhr2 antagonist - Google Patents

Spiroheterocyclic derivatives as crhr2 antagonist Download PDF

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Publication number
WO2021145401A1
WO2021145401A1 PCT/JP2021/001150 JP2021001150W WO2021145401A1 WO 2021145401 A1 WO2021145401 A1 WO 2021145401A1 JP 2021001150 W JP2021001150 W JP 2021001150W WO 2021145401 A1 WO2021145401 A1 WO 2021145401A1
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Prior art keywords
methyl
cyclohexyl
chloro
azetidine
difluoromethyl
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PCT/JP2021/001150
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French (fr)
Inventor
Masashi Ohmi
Tatsuya Yamagishi
Ryuichi Yamaguchi
Yutaka Fukumoto
Kazuo Ando
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Raqualia Pharma Inc.
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Publication of WO2021145401A1 publication Critical patent/WO2021145401A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • Compounds of the invention are also in particular useful for the treatment or prevention of major depressive disorders including bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, the treatment of anxiety and the treatment of panic disorders.
  • Compounds of the invention are useful as analgesics.
  • they are useful in the treatment of traumatic pain such as postoperative pain; traumatic avulsion pain such as brachial plexus; chronic pain such as arthritic pain such as occurring in osteo-, rheumatoid or psoriatic arthritis; neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS related neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom limb pain; various forms of headache such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain, cluster headache; odontalgia; cancer pain; pain of visceral origin; gastrointestinal pain; nerve entrapment
  • Emesis i.e. nausea, retching and vomiting.
  • Emesis includes acute emesis, delayed emesis and anticipatory emesis.
  • the compounds of the invention are useful in the treatment of emesis however induced.
  • emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g.
  • Compounds of the invention are useful for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, hypoxia, anoxia, perinatal asphyxia, and cardiac arrest.
  • prodrugs of the compounds of formulae (I), (II), and (III).
  • certain derivatives of compounds of formulae (I), (II), and (III) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formulae (I), (II), and (III) having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as "prodrugs”.
  • Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
  • HPLC Apparatus: Waters MS-trigger AutoPurification (registered trademark) system
  • Column Waters XBridge C8, 19 mm x 50 mm, 5 micrometer particle or Waters XBridge C18, 19 mm x 50 mm, 5 micrometer particle
  • Mobile phase 1 (A) 0.05%(v/v) ammonia aqueous solution
  • MeOH or MeCN Mobile phase 2: (A) 0.05%(v/v) formic acid aqueous solution
  • Mobile phase 3 (A) 10 mM ammonium formate aqueous solution
  • MeCN/water 90/10(v/v)
  • Flow rate 20 mL/min Gradient: A/B (95/5) to A/B (5/95) in 5 or 7 or 10 min
  • Step-1 of Scheme 6 a compound of formula (XXIV) can be prepared from a compound of formula (XXIII) and a compound of formula (V) by the similar general protocol in Scheme 1.
  • the title compound is prepared in 27% yield (4.3 mg) by the similar manner to Step-3 of Example 180 using 2 M methylamine in THF (0.073 mL, 0.15 mmol) in place of ammonium chloride.
  • Step-2> 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
  • the title compound is prepared in 54% yield (22 mg, brown solid) by the similar manner to Step-1 of Example 201 using 2-bromo-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (36 mg, 0.12 mmol, Step-1 of Example 215) in place of 2-bromo-6-((methoxymethoxy)methyl)pyridine.
  • NADPH generation system is also used instead of NADPH.
  • An aliquot of samples of P450 group is collected at 0, 10, 30, and 60 min time point, where 0 min time point indicates the time when NADPH is added into the reaction mixture of P450 group.
  • An aliquot of samples of non-P450 group is collected at -10 min and 65 min time point. Collected aliquots are extracted with acetonitrile solution containing an internal standard. The precipitated protein is spun down in centrifuge (2000 rpm, 15 min). The compound concentration in supernatant is measured by LC/MS/MS system.

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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Heart & Thoracic Surgery (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention relates to spiroheterocyclic derivatives which have antagonistic activities against CRHR2, and which are useful in the treatment or prevention of disorders and diseases in which CRHR2 is involved. The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CRHR2 is involved.

Description

SPIROHETEROCYCLIC DERIVATIVES AS CRHR2 ANTAGONIST
　 The present invention relates to spiroheterocyclic derivatives which have antagonistic activities against corticotropin releasing hormone receptor 2 (CRHR2), and which is useful in the treatment or prevention of disorders and diseases in which CRHR2 is involved. The invention also relates to their preparation, pharmaceutical compositions comprising these compounds, and the use of these compounds and compositions in the prevention or treatment of such diseases in which CRHR2 is involved.
　 Corticotropin-releasing hormone receptors (CRHRs), also known as corticotropin-releasing factor receptors (CRFRs), are a G protein-coupled receptor (GPCR) family that binds corticotropin-releasing hormone (CRH) (NPL 1: Hauger RL, et al., Pharmacol. Rev. 55 (1): 21-6, 2003).　There are two receptors in the family, designated as type 1 and 2, each encoded by a separate gene (CRHR1 and CRHR2 respectively). CRHRs are important mediators in the stress response. (NPL 2: Grammatopoulos DK, et al., Trends Endocrinol. Metab. 13 (10): 436-44, 2002).　Cells in the anterior lobe of the pituitary gland known as corticotropes express the receptors and will secrete adrenocorticotropic hormone (ACTH) when stimulated. This binding of corticotropin releasing-hormone (CRH) activates the hypothalamic-pituitary-adrenal (HPA) axis, one of the two parts of the fight-or-flight response to stress. (NPL 3: Aguilera G, et al., Neuroendocrinology. 43 (1): 79-88, 1986).　CRHRs are also present in other brain areas such as the amygdala, locus coeruleus and hippocampus. Chronic activation of CRHRs by CRH induced by early life stress has been shown to underlie memory deficits and learning impairments and anxiety in adulthood.
　 Recently, Tsuda T, Takefuji M, et al., reported that the GPCR corticotropin releasing hormone receptor 2 (CRHR2) is highly expressed in the heart and facilitates heart failure (NPL 4: Tsuda T, Takefuji M, et al., J. Experimental Medicine, 214, 1877-1888, 2017). The results indicate that CRHR2 may be a promising therapeutic target for chronic heart failure.
　 The spiroheterocyclic derivatives of the present invention show excellent CRHR2 antagonistic activities and have a number of therapeutic applications.
{NPL 1} Hauger RL, et al., Pharmacol. Rev. 55 (1): 21-6, 2003.
{NPL 2} Grammatopoulos DK, et al., Trends Endocrinol. Metab. 13 (10): 436-44, 2002.
{NPL 3} Aguilera G, et al., Neuroendocrinology. 43 (1): 79-88, 1986.
{NPL 4} Tsuda T, Takefuji M, et al., J. Experimental Medicine, 214, 1877-1888, 2017.
{PL 1} WO2011/092293
{PL 2} WO2011/095450
{PL 3} WO2019/198692
　 It is an objective of the invention to provide new CRHR2 antagonists that are good drug candidates.　They possess favorable pharmacokinetic properties such as absorption, distribution, metabolism, and excretion.　They are non-toxic and demonstrate few side-effects.　Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated.
　 With respect to other compounds disclosed in the art, the compounds of the present invention may show less toxicity, favorable absorption and distribution, favorable solubility, favorable plasma protein binding, less drug-drug interaction, favorable metabolic stability, reduced inhibitory activity at hERG channel, and/or reduced QT prolongation.
　 This invention provides:
[1] A compound of the following formula (I):
Figure JPOXMLDOC01-appb-C000004
 wherein:
A is aryl or heteroaryl; preferably A is phenyl, naphthyl, or 5 to 10-membered heteroaryl with 1-4 heteroatoms independently selected from O, N, and S; more preferably A is phenyl, naphthyl, benzoimidazolyl, dihydroisoquinolyl, indolyl, indazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridyl, quinolyl, isoquinolyl and thiazolyl; further more preferably A is phenyl, pyridyl, and indazolyl;
W is S or O; preferably W is O;
Ra, Rb, Rc, and Rd are independently selected from the group consisting of: (1) hydrogen and (2) C1-6 alkyl; wherein the C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl; preferably Ra, Rb, Rc, and Rd are independently selected from the group consisting of: (1) hydrogen and (2) methyl;
R1 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) C1-6 alkyl, and (4) -O-C1-6 alkyl, wherein the C1-6 alkyl or the -O-C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl; preferably R1 is independently selected from the group consisting of: chloro, methyl, difluoromethyl, trifluoromethyl, and difluoromethoxy;
p is 1, 2, or 3; preferably p is 1 or 2;
R2 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C1-6 alkyl, (5) -O-C1-6 alkyl, and (6) -CN; preferably R2 is independently selected from the group consisting of: fluoro, chloro, methyl, methoxy;
q is 1, 2, 3, or 4; preferably q is 1 or 2;
Y1, Y2, Y3, and Y4 are independently selected from the group consisting of CH, CR2, in which R2 has the same meaning as above, and N,
wherein the number of nitrogen atom(s) in the Y1, Y2, Y3, and Y4 is 0 to 2; preferably Y1, Y2, Y3, and Y4 are independently selected from the group consisting of CH and CR2;
X1, X2, and X3 are independently selected from the group consisting of a chemical bond, CH2, CH(C1-6 alkyl), and C(C1-6 alkyl)(C1-6 alkyl); preferably X1, X2, and X3 are independently a chemical bond or CH2;
R3 is selected from the group consisting of: (1) C1-6 alkyl, (2) C2-6 alkenyl, (3) C3-7 cycloalkyl, (4) C3-7 cycloalkylC1-6 alkyl, (5) heterocyclyl, wherein the C1-6 alkyl, the C2-6 alkenyl, the C3-7 cycloalkyl, the C3-7 cycloalkylC1-6 alkyl, or the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl, (6) aryl, (7) heteroaryl, (8) arylC1-6 alkyl, (9) heteroarylC1-6 alkyl, wherein the aryl, the heteroaryl, the arylC1-6 alkyl, or the heteroarylC1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, C3-7 cycloalkyl, -O-C3-7 cycloalkyl, heterocyclyl, hydroxyC1-6 alkyl, C1-6 alkoxyC1-6 alkyl, hydroxyC1-6 alkoxyl, (C=O)-R5, -CH2(C=O)C1-6 alkyl, -(C=O)-NR5R6, -CH2(C=O)-NR5R6, -NR6(C=O)R5, -NR5R6, -C1-6 alkyl-NR5R6, -C1-6 alkoxy-NR5R6, -NR6-S(O)2R5, -S(O)2-R5, and -CN, (10) -(C=O)-R4, (11) -S(O)2-R4, and (12) -CN; preferably R3 is selected from the group consisting of: (6) aryl, (7) heteroaryl, and (10) -(C=O)-R4; more preferably R3 is selected from the group consisting of: phenyl, pyrimidinyl, pyrazinyl, pyridyl, thiazolyl, and pyrazolyl, wherein the phenyl, the pyrimidinyl, the pyrazinyl, the pyridyl, the thiazolyl, and the pyrazolyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, C3-7 cycloalkyl, -O-C3-7 cycloalkyl, hydroxyC1-6 alkyl, hydroxyC1-6 alkoxyl, (C=O)-R5, -CH2(C=O)C1-6 alkyl, -(C=O)-NR5R6, -CH2(C=O)-NR5R6, -NR6(C=O)R5, -NR5R6, -C1-6 alkyl-NR5R6, -C1-6 alkoxy-NR5R6, -NR6-S(O)2R5, -S(O)2-R5, and -CN;
R4 is selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) -O-C1-6 alkyl, (4) C1-6 alkoxyC1-6 alkyl, (5) C3-7 cycloalkyl, (6) C3-7 cycloalkylC1-6 alkyl, (7) -O-C3-7 cycloalkyl, (8) C2-6 alkenyl, (9) aryl, (10) heteroaryl, (11) heterocyclyl, (12) -O-aryl, (13) -O-heteroaryl, (14) -O-heterocyclyl, and (15) -NR7R8, wherein the C1-6 alkyl, the -O-C1-6 alkyl, the C1-6 alkoxyC1-6 alky, the C3-7 cycloalkyl, the C3-7 cycloalkylC1-6 alkyl, the -O-C3-7 cycloalkyl, the C2-6 alkenyl, the heterocyclyl, or the -O-heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and -CN; wherein the aryl, the heteroaryl, the -O-aryl, or the -O-heteroaryl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NR7R8, and -CN; preferably R4 is selected from the group consisting of: (2) C1-6 alkyl, (3) -O-C1-6 alkyl, (4) C1-6 alkoxyC1-6 alkyl, (5) C3-7 cycloalkyl, (6) C3-7 cycloalkylC1-6 alkyl, (9) aryl, (10) heteroaryl, (11) heterocyclyl, and (15) -NR7R8; wherein the aryl is phenyl or naphthyl, wherein the heteroaryl is 5 to 10-membered heteroaryl with 1-4 heteroatoms independently selected from O, N, and S, wherein the heterocyclyl is 4 to 8-membered heterocyclyl with 1-4 heteroatoms independently selected from O, N, and S, in which the heterocyclyl optionally contains carbonyl;
R5 is independently selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) C3-7 cycloalkyl, (4) heterocyclyl, (5) C3-7 cycloalkylC1-6 alkyl, (6) heterocyclylC1-6 alkyl, (7) aryl, (8) arylC1-6 alkyl, (9) heteroaryl, and (10) heteroarylC1-6 alkyl, wherein the C1-6 alkyl, the C3-7 cycloalkyl, the heterocyclyl, the C3-7 cycloalkylC1-6 alkyl, the heterocyclylC1-6 alkyl, the aryl, the arylC1-6 alkyl, the heteroaryl, or the heteroarylC1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxyl, and -CN;
R6 is independently selected from the group consisting of: (1) hydrogen and (2) C1-6 alkyl;
or R5 may form a 4 to 7 membered ring with R6 which may contain N, O, S, or carbonyl; wherein the 4 to 7 membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxyl; and
R7 and R8 are independently selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) C3-7 cycloalkyl, (4) heterocyclyl, (5) C3-7 cycloalkylC1-6 alkyl, (6) heterocyclylC1-6 alkyl, (7) aryl, (8) arylC1-6 alkyl, (9) heteroaryl, and (10) heteroarylC1-6 alkyl, wherein the C1-6 alkyl, the C3-7 cycloalkyl, the heterocyclyl, the C3-7 cycloalkylC1-6 alkyl, the heterocyclylC1-6 alkyl, the aryl, the arylC1-6 alkyl, the heteroaryl, or the heteroarylC1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxyl, and -CN;
or R7 may form a 4 to 7 membered ring with R8 which may contain N, O, S, or carbonyl; wherein the 4 to 7 membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxyl; preferably R7 and R8 are independently selected from the group consisting of: (2) C1-6 alkyl, or R7 may form a 4 to 6 membered ring with R8 which may contain N, O, S, and carbonyl, more preferably R7 and R8 are independently selected from the group consisting of: methyl and ethyl;
or a pharmaceutically acceptable salt thereof or a prodrug thereof,
[2] The compound according to [1]:
wherein:
A is phenyl, naphthyl, or 5 to 10-membered heteroaryl with 1-4 heteroatoms independently selected from O, N, and S;
Y1, Y2, Y3, and Y4 are independently selected from the group consisting of CH and CR2;
or a pharmaceutically acceptable salt thereof or a prodrug thereof,
[3] The compound according to [1] or [2]
wherein:
A is selected from the group consisting of phenyl, naphthyl, benzoimidazolyl, dihydroisoquinolyl, indolyl, indazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridyl, quinolyl, isoquinolyl, and thiazolyl;
or a pharmaceutically acceptable salt thereof or a prodrug thereof,
[4] The compound according to [1], wherein the compound of the formula (I) is represented by a compound of the following formula (II):
Figure JPOXMLDOC01-appb-C000005
 wherein:
R1 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) C1-6 alkyl, and (4) -O-C1-6 alkyl, wherein the C1-6 alkyl or the -O-C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl;
p is 1, 2, or 3;
Z is selected from the group consisting of CH, CR1, in which R1 has the same meaning as above, and N, preferably Z is selected from the group consisting of CH and CR1;
R2 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C1-6 alkyl, (5) -O-C1-6 alkyl, and (6) -CN;
q is 1, 2, 3, or 4;
X1, X2, and X3 are independently selected from the group consisting of a chemical bond and CH2;
R3 is selected from the group consisting of: (1) C1-6 alkyl, (2) C2-6 alkenyl, (3) C3-7 cycloalkyl, (4) C3-7 cycloalkylC1-6 alkyl, (5) heterocyclyl, wherein the C1-6 alkyl, the C2-6 alkenyl, the C3-7 cycloalkyl, the C3-7 cycloalkylC1-6 alkyl, or the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl, (6) aryl, (7) heteroaryl, (8) arylC1-6 alkyl, (9) heteroarylC1-6 alkyl, wherein the aryl, the heteroaryl, the arylC1-6 alkyl, or the heteroarylC1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, C3-7 cycloalkyl, -O-C3-7 cycloalkyl, heterocyclyl, hydroxyC1-6 alkyl, C1-6 alkoxyC1-6 alkyl, hydroxyC1-6 alkoxyl, -(C=O)-R5, -CH2(C=O) C1-6 alkyl, -(C=O)-NR5R6, -CH2(C=O)-NR5R6, -NR6(C=O)R5, -NR5R6, -C1-6 alkyl-NR5R6, -C1-6 alkoxy-NR5R6, -NR6-S(O)2R5, -S(O)2-R5, and -CN, (10) -(C=O)-R4, (11) -S(O)2-R4, and (12) -CN;
R4 is selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) -O-C1-6 alkyl, (4) C1-6 alkoxyC1-6 alkyl (5) C3-7 cycloalkyl, (6) C3-7 cycloalkylC1-6 alkyl, (7) -O-C3-7 cycloalkyl, (8) C2-6 alkenyl, (9) aryl, (10) heteroaryl, (11) heterocyclyl, (12) -O-aryl, (13) -O-heteroaryl, (14) -O-heterocyclyl, and (15) -NR7R8, wherein the C1-6 alkyl, the -O-C1-6 alkyl, the C1-6 alkoxyC1-6 alky, the C3-7 cycloalkyl, the C3-7 cycloalkylC1-6 alkyl, the -O-C3-7 cycloalkyl, the C2-6 alkenyl, the heterocyclyl, or the -O-heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and -CN; wherein the aryl, the heteroaryl, the -O-aryl, or the -O-heteroaryl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NR7R8, and -CN;
R5 is independently selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) C3-7 cycloalkyl, (4) heterocyclyl, (5) C3-7 cycloalkylC1-6 alkyl, (6) heterocyclylC1-6 alkyl, (7) aryl, (8) arylC1-6 alkyl, (9) heteroaryl, and (10) heteroarylC1-6 alkyl, wherein the C1-6 alkyl, the C3-7 cycloalkyl, the heterocyclyl, the C3-7 cycloalkylC1-6 alkyl, the heterocyclylC1-6 alkyl, the aryl, the arylC1-6 alkyl, the heteroaryl, or the heteroarylC1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxyl, and -CN;
R6 is independently selected from the group consisting of: (1) hydrogen and (2) C1-6 alkyl;
or R5 may form a 4 to 7 membered ring with R6 which may contain N, O, S, or carbonyl; wherein the 4 to 7 membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxyl; and
R7 and R8 are independently selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) C3-7 cycloalkyl, (4) heterocyclyl, (5) C3-7 cycloalkylC1-6 alkyl, (6) heterocyclylC1-6 alkyl, (7) aryl, (8) arylC1-6 alkyl, (9) heteroaryl, and (10) heteroarylC1-6 alkyl, wherein the C1-6 alkyl, the C3-7 cycloalkyl, the heterocyclyl, the C3-7 cycloalkylC1-6 alkyl, the heterocyclylC1-6 alkyl, the aryl, the arylC1-6 alkyl, the heteroaryl, or the heteroarylC1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxyl, and -CN;
or R7 may form a 4 to 7 membered ring with R8 which may contain N, O, S, or carbonyl; wherein the 4 to 7 membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxyl;
or a pharmaceutically acceptable salt thereof or a prodrug thereof,
[5] The compound according to [1] or [4], wherein the compound of the formula (I) or (II) is represented by a compound of the following formula (III):
Figure JPOXMLDOC01-appb-C000006
 wherein:
R1 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) C1-6 alkyl, and (4) -O-C1-6 alkyl, wherein the C1-6 alkyl or the -O-C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl;
p is 1, 2, or 3;
R2 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C1-6 alkyl, (5) -O-C1-6 alkyl, and (6) -CN;
q is 1, 2, or 3;
X2 and X3 are independently selected from the group consisting of a chemical bond and CH2;
R3 is selected from the group consisting of: (6) aryl, (7) heteroaryl, (8) phenylCH2-, (9) heteroarylCH2-, wherein the aryl, the heteroaryl, the phenylCH2-, or the heteroarylCH2- is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, C3-7 cycloalkyl, heterocyclyl, hydroxyC1-6 alkyl, C1-6 alkoxyC1-6 alkyl, hydroxyC1-6 alkoxyl, -(C=O)-NR5R6, -NR6(C=O)R5, -NR5R6, and -CN, and (10) -(C=O)-R4;
R4 is selected from the group consisting of: (2) C1-6 alkyl, (3) -O-C1-6 alkyl, (4) C1-6 alkoxyC1-6 alkyl, (5) C3-7 cycloalkyl, (6) C3-7 cycloalkylC1-6 alkyl, (7) -O-C3-7 cycloalkyl, (8) C2-6 alkenyl, (9) aryl, (10) heteroaryl, (11) heterocyclyl, and (15) -NR7R8, wherein the C1-6 alkyl, the -O-C1-6 alkyl, the C1-6 alkoxyC1-6 alky, the C3-7 cycloalkyl, the C3-7 cycloalkylC1-6 alkyl, the -O-C3-7 cycloalkyl, the C2-6 alkenyl, or the heterocyclyl, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and -CN; wherein the aryl or the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -NR7R8, and -CN;
R5 is independently selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) C3-7 cycloalkyl, and (5) C3-7 cycloalkylC1-6 alkyl; wherein the C1-6 alkyl, the C3-7 cycloalkyl, or the C3-7 cycloalkylC1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxyl, and -CN;
R6 is independently selected from the group consisting of: (1) hydrogen and (2) C1-6 alkyl;
or R5 may form a 4 to 7 membered ring with R6 which may contain N, O, S, or carbonyl; wherein the 4 to 7 membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxyl; and
R7 and R8 are independently selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) C3-7 cycloalkyl, and (4) heterocyclyl, wherein the C1-6 alkyl, or the C3-7 cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxyl, and -CN;
or R7 may form a 4 to 7 membered ring with R8 which may contain N, O, S, or carbonyl; wherein the 4 to 7 membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxyl;
wherein the aryl is phenyl or naphthyl;
wherein the heteroaryl is 5 to 10-membered heteroaryl with 1-4 heteroatoms independently selected from O, N, and S; and
wherein the heterocyclyl is 4 to 8-membered heterocyclyl with 1-4 heteroatoms independently selected from O, N, and S, in which the heterocyclyl optionally contains with carbonyl;
or a pharmaceutically acceptable salt thereof or a prodrug thereof,
[6] The compound according to [5],
wherein:
R3 is is selected from the group consisting of: (6) aryl, (7) heteroaryl, and (10) -(C=O)-R4; wherein the aryl or the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, C3-7 cycloalkyl, oxetanyl, hydroxyC1-6 alkyl, C1-6 alkoxyC1-6 alkyl, hydroxyC1-6 alkoxyl, -(C=O)-NR5R6, -NR6(C=O)R5, -NR5R6, and -CN;
R4 is selected from the group consisting of: (3) -O-C1-6 alkyl, (7) -O-C3-7 cycloalkyl, (9) aryl, and (10) heteroaryl, wherein the -O-C1-6 alkyl or the -O-C3-7 cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and -CN; wherein the aryl or the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, and -CN;
or a pharmaceutically acceptable salt thereof or a prodrug thereof,
[7] A compound which is selected from the group consisting of:
1-(((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl)-N,N-dimethyl-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxamide;
ethyl 1-(((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate;
5-chloro-N-((1r,4r)-4-((1'-(3-methoxyphenyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((1'-(5-chloropyridin-2-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((1'-(5-cyanopyridin-2-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2-oxo-1'-propionylspiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1'-(cyclopropanecarbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-N,N-dimethyl-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxamide;
5-chloro-N-((1r,4r)-4-((1'-(cyclobutanecarbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-N,N-diethyl-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxamide;
5-chloro-2-methyl-N-((1r,4r)-4-((1'-(1-methyl-1H-pyrazol-3-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
ethyl 1-(((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate;
5-chloro-2-methyl-N-((1r,4r)-4-((2-oxo-1'-(pyrrolidine-1-carbonyl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1'-(azetidine-1-carbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-5-chloro-2-methylnicotinamide;
N-((1r,4r)-4-((1'-acetyl-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methyl-2H-indazole-3-carboxamide;
N-((1r,4r)-4-((1'-acetyl-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(2,2,2-trifluoroethyl)-2H-indazole-3-carboxamide;
1-(((1r,4r)-4-(5-chloro-2-(trifluoromethyl)nicotinamido)cyclohexyl)methyl)-N,N-dimethyl-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxamide;
methyl 1-(((1r,4r)-4-(5-chloro-2-(trifluoromethyl)nicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate;
ethyl 1-(((1r,4r)-4-(5-chloro-2-(trifluoromethyl)nicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate;
methyl 1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate;
ethyl 1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate;
5-chloro-N-((1r,4r)-4-((1'-(cyclopropanecarbonyl)-6-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6-fluoro-N,N-dimethyl-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxamide;
methyl 1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6-fluoro-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate;
ethyl 1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6-fluoro-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate;
5-chloro-N-((1r,4r)-4-((1'-(3-cyanopyridin-2-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-methyl-N-((1r,4r)-4-((2-oxo-1'-(pyrazin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1'-(4-cyanopyridin-3-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((1'-(2-cyanopyridin-3-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-methyl-N-((1r,4r)-4-((2-oxo-1'-(pyrimidin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1'-(cyclopropanecarbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
N-((1r,4r)-4-((1'-(cyclopropanecarbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methyl-2H-indazole-3-carboxamide;
5-chloro-N-((1r,4r)-4-((1'-(cyclopropanecarbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethoxy)benzamide;
ethyl 1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-2-oxo-1'-propionylspiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-1'-(1-fluorocyclopropane-1-carbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-2-oxo-1'-(pyrrolidine-1-carbonyl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1'-(1-cyanocyclopropane-1-carbonyl)-6-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(cyclopropanecarbonyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
ethyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-2-oxo-1'-(pyrazin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1'-(2-cyanopyridin-3-yl)-6-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-2-oxo-1'-(pyrimidin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-1'-(5-fluoropyrimidin-2-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-1'-(4-methylpyrimidin-2-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2-oxo-1'-(pyrimidin-2-yl)spiro[indoline-3,3'-pyrrolidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2-oxo-1'-(pyrazin-2-yl)spiro[indoline-3,3'-pyrrolidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1'-(2-cyanopyridin-3-yl)-2-oxospiro[indoline-3,3'-pyrrolidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrimidin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrazin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-N,N-dimethyl-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxamide;
methyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
5-chloro-N-((1r,4r)-4-((1-(cyclobutanecarbonyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(1-cyanocyclopropane-1-carbonyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-propionylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(piperidine-1-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(2-cyclopropylacetyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrimidin-2-yl)-2'H-spiro[piperidine-4,3'-quinolin]-1'(4'H)-yl)methyl)cyclohexyl)nicotinamide;
1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-N,N-dimethyl-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxamide;
methyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
ethyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrimidin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-propionylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(piperidine-1-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(cyclopropanecarbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-picolinoylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrazin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazol-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiophene-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-imidazole-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazole-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
isopropyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
N-((1r,4r)-4-((1-(3-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(3-cyanopyrazin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(5-cyanopyrimidin-4-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(6-cyanopyrazin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrimidin-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(but-3-enoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
N-((1r,4r)-4-((1-acryloyl-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
N-((1r,4r)-4-((1-(3-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-(dimethylamino)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazol-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-hydroxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(3-amino-6-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-(methylamino)pyrazin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(3-amino-6-methoxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(4-fluorophenyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrimidin-5-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1,2,4-thiadiazol-5-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(4-(trifluoromethyl)thiazol-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-imidazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(5-aminopyrimidin-4-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
N-((1r,4r)-4-((1-(4-aminopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
N-((1r,4r)-4-((1-benzyl-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(tetrahydro-2H-pyran-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiophen-3-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methylpicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methylpicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(4-methylpicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-hydroxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methoxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-fluoro-3-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-methylpicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methoxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-fluoropicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(3-amino-6-methylpyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methyl-1,2,4-oxadiazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-(2-hydroxyethoxy)pyrazin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(5-cyanopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-fluoropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-methoxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(dimethylamino)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(5-acetamidopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(1-cyclobutyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-fluoro-4-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(2-methylpyrimidin-5-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-picolinoylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyridazine-3-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrazine-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyridazine-3-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrimidine-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(4-methyl-1,2,5-oxadiazole-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrimidin-5-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-fluoropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-methyl-1,2,4-oxadiazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(3-cyanopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
N-((1r,4r)-4-((1-(4-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methyl-1,3,4-oxadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(5-carbamoylpyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-(methylcarbamoyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(dimethylcarbamoyl)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(4-methylpyrimidin-5-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(4-methoxypyrimidin-5-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(6-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(isothiazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-ethyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(6-aminopyridin-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(dimethylamino)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(6-acetamidopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
N-((1r,4r)-4-((1-(2-aminopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(6-oxo-1,6-dihydropyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-benzoyl-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(5-(trifluoromethyl)picolinoyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyridin-3-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(hydroxymethyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyridin-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrimidine-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(isothiazole-5-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(6-(trifluoromethyl)picolinoyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(isoxazole-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(oxazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(isothiazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazole-5-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1,2,3-thiadiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(2-methylthiazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(hydroxymethyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
6-(1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2'-oxospiro[azetidine-3,3'-indolin]-1-yl)-N-methylpicolinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(2-hydroxyethoxy)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(2-hydroxyethoxy)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(6-aminopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyridin-3-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-fluoro-4-methoxypyrimidin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(2-methylpyrimidin-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methylcyclopropane-1-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-fluorocyclopropane-1-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1,3-dihydroisobenzofuran-5-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(1-cyanocyclopropane-1-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
N-((1r,4r)-4-((1-(6-acetamidopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methoxypyrimidin-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methylpyrimidin-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(2-cyanopyrimidin-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(6-(trifluoromethyl)pyrimidin-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-fluorobenzoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(2-fluorobenzoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-methoxybenzoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(2-methoxyisonicotinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1,3,4-thiadiazol-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(1,3,4-thiadiazol-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1H-pyrazol-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-fluoropyrimidin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-benzoyl-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrimidine-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(6-(pyrrolidin-1-yl)picolinoyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(oxazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(2-methylthiazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(isoxazole-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(1,2,3-thiadiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypyrazine-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbonyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-imidazole-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(thiazole-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(1,2,5-thiadiazole-3-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazole-5-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(oxazole-5-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carbonyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypyridazine-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(1,2,3-thiadiazole-5-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methoxypyrimidin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methylthiazole-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-fluorocyclopropane-1-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(imidazo[2,1-b]thiazole-6-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-cyano-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(cyclopropanecarbonyl)-5'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(1-fluorocyclopropane-1-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(1-cyanocyclopropane-1-carbonyl)-5'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-(thiazole-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-(1,2,3-thiadiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(oxazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(isoxazole-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-picolinoylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(6-methoxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(3-hydroxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((7'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((4'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methyl-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((7'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((4'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methyl-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((7'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((5'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((6'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((4'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((5'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-methyl-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-methyl-N-((1r,4r)-4-((2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((4'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((5'-methoxy-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((4'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((5'-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((5'-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((4'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((5'-methoxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((6'-methoxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-methyl-N-((1r,4r)-4-((6'-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methoxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-methyl-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-methyl-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide; and
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
or a pharmaceutically acceptable salt thereof or a prodrug thereof.
[8] The compound according to [7], which is selected from the group consisting of:
5-chloro-2-methyl-N-((1r,4r)-4-((1'-(1-methyl-1H-pyrazol-3-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1'-(cyclopropanecarbonyl)-6-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1'-(3-cyanopyridin-2-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-methyl-N-((1r,4r)-4-((2-oxo-1'-(pyrazin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1'-(4-cyanopyridin-3-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((1'-(2-cyanopyridin-3-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-methyl-N-((1r,4r)-4-((2-oxo-1'-(pyrimidin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1'-(cyclopropanecarbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methyl-2H-indazole-3-carboxamide;
5-chloro-N-((1r,4r)-4-((1-(cyclopropanecarbonyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
ethyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-2-oxo-1'-(pyrazin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1'-(2-cyanopyridin-3-yl)-6-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-2-oxo-1'-(pyrimidin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrimidin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrazin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-N,N-dimethyl-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxamide;
methyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
methyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
ethyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-picolinoylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrazin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazol-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiophene-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-imidazole-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazole-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(3-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(3-cyanopyrazin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(5-cyanopyrimidin-4-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(6-cyanopyrazin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
N-((1r,4r)-4-((1-(3-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazol-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(3-amino-6-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
N-((1r,4r)-4-((1-(3-amino-6-methoxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrimidin-5-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1,2,4-thiadiazol-5-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiophen-3-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methylpicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(4-methylpicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methoxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-fluoropicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(3-amino-6-methylpyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methyl-1,2,4-oxadiazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(5-cyanopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-fluoropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-methoxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(dimethylamino)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(2-methylpyrimidin-5-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-picolinoylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrimidin-5-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-fluoropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-(3-cyanopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(4-methylpyrimidin-5-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(4-methoxypyrimidin-5-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(6-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(isothiazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-ethyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(6-aminopyridin-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(6-acetamidopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
N-((1r,4r)-4-((1-(2-aminopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
N-((1r,4r)-4-((1-benzoyl-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyridin-3-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(hydroxymethyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(6-(trifluoromethyl)picolinoyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(isoxazole-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1,2,3-thiadiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(2-methylthiazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(2-hydroxyethoxy)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(6-aminopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyridin-3-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-fluorocyclopropane-1-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-(6-acetamidopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(1,3,4-thiadiazol-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1H-pyrazol-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-fluoropyrimidin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
N-((1r,4r)-4-((1-benzoyl-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(oxazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(2-methylthiazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(isoxazole-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(1,2,3-thiadiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypyrazine-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbonyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-imidazole-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(thiazole-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(1,2,5-thiadiazole-3-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypyridazine-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methylthiazole-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-fluorocyclopropane-1-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(imidazo[2,1-b]thiazole-6-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((1-cyano-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-(thiazole-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-(1,2,3-thiadiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(oxazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(isoxazole-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-picolinoylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(6-methoxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(3-hydroxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((4'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((7'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((4'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((7'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((6'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((4'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((5'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-methyl-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-methyl-N-((1r,4r)-4-((2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((4'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-N-((1r,4r)-4-((6'-methoxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-methyl-N-((1r,4r)-4-((6'-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methoxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-methyl-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
5-chloro-2-methyl-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide; and
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
or a pharmaceutically acceptable salt thereof or a prodrug thereof,
[9] A use of a compound according to any one of [1] to [8] or a pharmaceutically acceptable salt, prodrug, solvate or composition thereof for the manufacture of a medicament for the treatment of a condition or disorder in which CRHR2 is involved,
[10] The use according to [9], wherein said condition or disorder is selected from the group consisting of: gastrointestinal disorders, major depressive disorders, schizophrenic disorders, neurodegenerative diseases, pain, dysfunction of appetite and food intake, sleep disorders, cognitive disorders, tolerance to and dependence on a number of substances, inflammation, fertility problems, sexual dysfunctions and pre-term birth and non-inflammatory urogenital disorders, allergic disorders, mast cell activation disorders, Cushing’s syndrome, emesis, gastrointestinal disorders, neurotoxic injury, loss of hair, heart disease, and combinations thereof,
[11] The use according to [10], wherein the heart disease is selected from the group consisting of: acute and chronic heart failure, cardiovascular disease, hyper tension, myocardial infarction, coronary artery disease, and abdominal aortic aneurysm,
[12] A method for the treatment of a condition or disorder in which CRHR2 is involved, in an animal, including a human, which comprises administering to the animal in need of such treatment a therapeutically effective amount of a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, according to any one of [1] to [8],
[13] The method according to [12], wherein said condition or disorder is selected from the group consisting of: gastrointestinal disorders, major depressive disorders, schizophrenic disorders, neurodegenerative diseases, pain, dysfunction of appetite and food intake, sleep disorders, cognitive disorders, tolerance to and dependence on a number of substances, inflammation, fertility problems, sexual dysfunctions and pre-term birth and non-inflammatory urogenital disorders, allergic disorders, mast cell activation disorders, Cushing’s syndrome, emesis, gastrointestinal disorders, neurotoxic injury, loss of hair, heart disease and combinations thereof,
[14] The method according to [13], wherein the heart disease is selected from the group consisting of: acute and chronic heart failure, cardiovascular disease, hyper tension, myocardial infarction, coronary artery disease, and abdominal aortic aneurysm,
[15] A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof or a prodrug thereof, according to any one of [1] to [8], and a pharmaceutically acceptable carrier,
[16] The pharmaceutical composition according to [15], further comprising another pharmacologically active agent,
[17] A compound according to any one of [1] to [8] or a prodrug thereof or a pharmaceutically acceptable salt for use in the treatment of a condition or disorder in which CRHR2 is involved,
[18] A process for preparing a pharmaceutical composition, wherein the process comprises mixing a compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof or a prodrug thereof and a pharmaceutically acceptable carrier or excipient.
　 The compounds showed activities against CRHR2.　In particular, the spiroheterocyclic derivatives of the present invention show excellent antagonistic activities against the CRHR2 over the compounds with close chemical structure, leading to better pharmacological profiles, favorable absorption and distribution, favorable solubility, favorable plasma protein binding, and favorable metabolic stability, leading to improvements in the side-effect profile such as reducing inhibitory activity at hERG channel and/or QT prolongation.　The spiroheterocyclic derivatives of the present invention are therefore useful in the treatment of a wide range of disorders.
　 Therefore, according to a further aspect of the invention, we provide a compound of formulae (I), (II), and (III), or a salt thereof, for the treatment or alleviation of treatment of any state with increased endogenous level of CRH and urocortins or in which the HPA (hypothalamic pituitary axis) is dysregulated, or of various diseases induced or facilitated by CRH and urocortins.
　 Compounds of the invention are in particular useful for the treatment or prevention of gastrointestinal disorders including irritable bowel syndrome with or without diarrhea, inflammatory bowel diseases, post-operative ileus, reflux disease and infectious diarrhea.
　 Compounds of the invention are also in particular useful for the treatment or prevention of major depressive disorders including bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, the treatment of anxiety and the treatment of panic disorders. Other mood disorders encompassed within the term major depressive disorders include fatigue syndrome and dysthymic disorder with early or late onset and with or without atypical features, neurotic depression, post traumatic stress disorders, post operative stress and social phobia; dementia of the Alzheimer type, with early or late onset, with depressed mood; vascular dementia with depressed mood; mood disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; schizoaffective disorder of the depressed type; and adjustment disorder with depressed mood. Major depressive disorders may also result from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc.
　 Compounds of the invention are also useful in the treatment or prevention of schizophrenic disorders including paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, residual schizophrenia.
　 Compounds of the invention are also useful in the treatment or prevention of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, senile dementia of the Alzheimer’s type, and multiinfarct dementia.
　 Compounds of the invention are useful as analgesics. In particular, they are useful in the treatment of traumatic pain such as postoperative pain; traumatic avulsion pain such as brachial plexus; chronic pain such as arthritic pain such as occurring in osteo-, rheumatoid or psoriatic arthritis; neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS related neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom limb pain; various forms of headache such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain, cluster headache; odontalgia; cancer pain; pain of visceral origin; gastrointestinal pain; nerve entrapment pain; sport’s injury pain; dysmenorrhea; menstrual pain; meningitis; arachnoiditis; musculoskeletal pain; low back pain e.g. spinal stenosis; prolapsed disc; sciatica; angina; ankylosing spondylitis; gout; burns; scar pain; itch; and thalamic pain such as post stroke thalamic pain.
　 Compounds of the invention are also useful for the treatment of dysfunction of appetite and food intake and in circumstances such as anorexia, anorexia nervosa, bulimia, obesity and metabolic syndrome.
　 Compounds of the invention are also useful in the treatment of sleep disorders including dyssomnia, insomnia, sleep apnea, narcolepsy, and circadian rhythmic disorders.
　 Compounds of the invention are also useful in the treatment or prevention of cognitive disorders. Cognitive disorders include dementia, amnestic disorders and cognitive disorders not otherwise specified.
　 Furthermore compounds of the invention are also useful as memory and/or cognition enhancers in healthy humans with no cognitive and/or memory deficit.
　 Compounds of the invention are also useful in the treatment of tolerance to and dependence on a number of substances. For example, they are useful in the treatment of dependence on nicotine, alcohol, caffeine, phencyclidine (phencyclidine like compounds), or in the treatment of tolerance to and dependence on opiates (e.g. cannabis, heroin, morphine) or benzodiazepines; in the treatment of cocaine, sedative hypnotic, amphetamine or amphetamine-related drugs (e.g. dextroamphetamine, methylamphetamine) addiction or a combination thereof.
　 Compounds of the invention are also useful as anti-inflammatory agents. In particular, they are useful in the treatment of inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis; in the treatment of inflammatory diseases of the gastrointestinal tract such as Crohn’s disease, ulcerative colitis, postoperative gastric ileus (POI), inflammatory bowel disease (IBD) and non-steroidal anti-inflammatory drug induced damage; inflammatory diseases of the skin such as herpes and eczema; inflammatory diseases of the bladder such as cystitis and urge incontinence; and eye and dental inflammation.
　 Compounds of the invention are also useful in the treatment of fertility problems, sexual dysfunctions and pre-term birth and non-inflammatory urogenital disorders such as overactive bladder and related urinary incontinence.
　 Compounds of the invention are also useful in the treatment of allergic disorders, in particular allergic disorders of the skin such as urticaria, and allergic disorders of the airways such as rhinitis.
　 Compounds of the invention are also useful in the treatment of mast cell activation disorders such as mastocytosis.
　 Compounds of the invention are also useful the treatment of Cushing’s syndrome induced by drugs such as steroids or cancer such as pituitary adenoma.
　 Compounds of the invention are also useful in the treatment of emesis, i.e. nausea, retching and vomiting. Emesis includes acute emesis, delayed emesis and anticipatory emesis. The compounds of the invention are useful in the treatment of emesis however induced. For example, emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide, vinblastine and vincristine; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiation therapy, e.g. irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, e.g. gastritis, or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as motion sickness, vertigo, dizziness and Meniere’s disease; post-operative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, e.g. myocardial infarction or peritonitis; migraine; increased intracranial pressure; decreased intracranial pressure (e.g. altitude sickness); opioid analgesics, such as morphine; and gastro-oesophageal reflux disease, acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn and dyspepsia.
　 Compounds of the invention are of particular use in the treatment of gastrointestinal disorders such as irritable bowel syndrome; skin disorders such as psoriasis, pruritus and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud’s disease; cerebral ischemia such as cerebral vasospasm following subarachnoid haemorrhage; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders related to immune enhancement or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrositis; and cough.
　 Compounds of the invention are useful for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, hypoxia, anoxia, perinatal asphyxia, and cardiac arrest.
　 Compounds of the invention are useful for hair growth.
　 Compounds of the invention are useful for heart disease including acute and chronic heart failure, cardiovascular disease, hyper tension, myocardial infarction, coronary artery disease, and abdominal aortic aneurysm.
　 The utility of the agents of the invention in the above indicated diseases can be confirmed in a range of standard tests.　Examples of such tests may include, but are not limited to, the following:
(1) The anxiolytic activity of the agents of the invention can be confirmed in the mouse elevated plus-maze [see, for example, Rodgers R. J., Behavioural Pharmacology 8:477-496 (1997) where the relevance of the elevated plus-maze is discussed on p. 486; for the method, see Rodgers R. J. et al. Ethology and Psychopharmacology (Eds SJ Cooper and CA Hendrie), pp 9-44 (1994), J. Wiley, Chichester]. (2) The analgesic activity of the agents of the invention can be confirmed in rat visceral hyperalgesia models following colorectal distension [see for example Schwetz I, Am J Physiology 286: G683-G691 (2004); for the method, see Ness T. J., Brain Research 450:153-169 (1988)]. (3) The anti-diarrheal activity of the agents of the invention can be confirmed in rat defecation models during stress or CRF challenge [see for example, Maillot C., Gastroenterology 119:1569-1579 (2002)]. (4) The hair growth activity of the agents of the invention can be confirmed in the method described in WO 2007/149938. (5) The anti-heart disease activity of the agents of the invention can be confirmed in the method described in this specification and the literature, e.g. Drug Discovery Today Volume 20, Number 7, 906-914 (2015). (6) Other activities of the agents of the invention can be confirmed in the method described in literatures known by a person skilled in the art including well-known art and commonly used art.
　 Novartis discloses structurally close arts in WO2011/092293 and WO2011/095450. Example 2.21 in WO2011/092293 is thought to be the structurally close compound which do not show any biological activity. The compounds of present invention show much better activities than those of the close arts.
　 Namely the present invention is characterized by spiroheterocyclic ring in the above formulae (I), (II), and (III). The core structure of the present invention is quite different from those of the above invention in WO2011/092293 and WO2011/095450.
　RaQualia discloses structurally close arts in WO2019/198692. The core structure of the present invention is quite different from those of the invention in WO2019/198692.
　 As appreciated by those of skill in the art, "halogen" as used herein is intended to include fluoro, chloro, bromo and iodo.　Similarly, 1-6, as in C1-6 is defined to identify the number as having 1, 2, 3, 4, 5, or 6. According to the definition, for example, C1-6, as in C1-6 alkyl is defined to identify the alkyl group as having 1, 2, 3, 4, 5, or 6 carbons. Similarly, C2-6 alkenyl is defined to identify the alkenyl group as having 2, 3, 4, 5, or 6 carbons.　A group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents.
　 The term "alkyl", as used herein, means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
The term "haloalkyl", as used herein, means a straight-chain or branched-chain alkyl which has been substituted by a halogen atom or halogen atoms. Examples of the haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, and trichloromethyl, and the like.
　 The term "alkoxy", as used herein, means an -O-alkyl such as, but not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy (including all isomeric forms), and the like.
　 The term "cycloalkyl", as used herein, means a mono- or bi-cyclic ring such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl groups, and the like. In this specification, preferable cycloalkyl is C3-7 mono cycloalkyl, more preferable cycloalkyl is C3-6 mono cycloalkyl, further more preferable cycloalkyl is C3-5 mono cycloalkyl.
　 The term "aryl", as used herein, means unsaturated or partially saturated mono- or bi-cyclic 5-15 membered ring which consists of carbon atoms. Examples of such aryl include, but are not limited to, phenyl, naphthyl, indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, 2,3-dihydro-1H-indenyl, cyclohexenyl, cyclopentenyl, (1S,4S)-bicyclo[2.2.2]oct-2-enyl, and (1R,4S)-bicyclo[2.2.1]hept-2-enyl and the like. In this specification, preferable aryl is 6-10 membered unsaturated aryl, more preferable aryl is phenyl or naphthyl.
　 The term "heteroaryl" as used herein, means unsaturated or partially saturated mono- or bi-cyclic 5-15 membered ring with 1-4 heteroatoms independently selected from O, N, S, and carbonyl, preferably unsaturated or partially saturated mono- or bi-cyclic 5-10 membered ring with 1-4 heteroatoms independently selected from O, N, S, and carbonyl, more preferably unsaturated 5-6 membered ring with 1-4 heteroatoms independently selected from O, N, and S, or unsaturated or partially saturated 9-10 membered ring with 1-4 heteroatoms independently selected from O, N, S, and carbonyl.
　 Examples of such heteroaryl include, but are not limited to, thiophenyl, thiazolyl, isoxazolyl, pyrazolyl, pyrazyl, tetrazolyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyranyl, triazinyl, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridyl, benzofuranyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, indolyl, indazolyl, benzoimidazolyl, pyrrolopyridyl, 2,3-dihydro-pyrrolo[2,3-b]pyridyl, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl, pyrrolopyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, imidazopyridinyl, furopyridyl, benzoisoxazolyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyrimidinyl, quinolyl, isoquinolyl, quinoxalyl, quinazolinyl, phthalazinyl, quinoxalinyl, naphthyridinyl, pyridopyrimidinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridyl, 2,3-dihydro-[1,4]dioxino[2,3-c]pyridyl, 1H-indolyl, 1H-pyrrolo[2,3-b]pyridyl, 1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolo[3,2-c]pyridyl, 1H-pyrrolo[3,2-b]pyridyl, 7H-pyrrolo[2,3-d]pyrimidyl, 7H-pyrrolo[2,3-c]pyridazinyl, 1H-indazolyl, 2H-indazolyl, 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[3,4-c]pyridyl, 1H-pyrazolo[4,3-c]pyridyl, 1H-pyrazolo[4,3-b]pyridyl, 1H-pyrazolo[3,4-d]pyrimidyl, 1H-benzo[d]imidazolyl, 3H-imidazo[4,5-b]pyridyl, 1H-imidazo[4,5-b]pyridyl, 9H-purinyl, 1H-imidazo[4,5-d]pyridazinyl, 1H-imidazo[4,5-b]pyrazinyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidyl, furo[3,2-c]pyridyl, benzo[d]isoxazolyl, 2,3-dihydro-1H-indenyl, indolinyl, isoindolinyl, indolin-2-one-yl, isoindolin-1-one-yl, 1H-benzo[d]imidazol-2(3H)-one-yl, benzo[d]oxazol-2(3H)-one-yl, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one-yl, 1H-imidazo[4,5-b]pyridin-2(3H)-one-yl, quinolyl, isoquinolyl, quinazolinyl, phthalazinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, quinoxalinyl, pyrido[3,4-d]pyrimidyl, pyrido[2,3-d]pyrimidyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridyl, 3,4-dihydroquinolin-2(1H)-one-yl, 2H-benzo[b][1,4]oxazin-3(4H)-one-yl, quinolin-2(1H)-one-yl, or 4,5-dihydro-1H-benzo[b]azepin-2(3H)-one-yl, and N-oxides thereof and S-oxides thereof and the like.
Examples of such heteroaryl also include the following rings.
Figure JPOXMLDOC01-appb-C000007
　 In this specification, preferable heteroaryl is 5 to 6-membered heteroaromatic ring with 1-4 heteroatoms independently selected from O, N, and S, or 9 to 10-membered heteroaromatic ring with 1-4 heteroatoms independently selected from O, N, and S , more preferable heteroaryl is 5-6 membered N-containing heteroaromatic ring, further more preferable heteroaryl is benzoimidazolyl, dihydroisoquinolyl, indolyl, indazolyl, pyrazolyl, pyrazinyl, pyridazinyl, thiadiazolyl, pyridyl, quinolyl, isoquinolyl and thiazolyl.
　 The term "heterocyclyl" as used herein includes both unsaturated and saturated heterocyclic moieties, wherein the unsaturated heterocyclic moieties (i.e. "heteroaryl") include, but not limited to, benzofuranyl, benzofurazanyl, benzimidazolonyl, benzoimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzothiadiazolyl, benzothiazolyl, benzoxadiazolyl, benzoxazolonyl, benzoxazolyl, benzothiophenyl, benzotriazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, 2,3-dioxoindolyl, furanyl, furazanyl, furopyridyl, furopyrrolyl, imidazolyl, imidazopyrazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiazolyl, indazolyl, indolazinyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolyl, isoquinolyl, isoxazolopyridyl, isoxazolinyl, isoxazolyl, isothiazolyl, naphthyridinyl, oxazolinyl, oxadiazolyl, oxazolyl, oxetanyl, 2-oxoindolyl, oxoisoindolyl, phthalazyl, pyrazolyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, pyridopyrimidinyl, pyrrolopyridyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolopyridyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, thienopyrazinyl, thienopyrazolyl, thienopyridyl, thienopyrrolyl, triazolopyrimidinyl, triazolyl, 5,6-dihydropyridin-2(1H)-one-ly, 4-oxo-1,4-dihydroquinolyl, 2-oxo-1,2-dihydropyridyl, 4-oxo-1,4-dihydropyrimidyl, 2-oxo-1,2-dihydroquinolyl, 4-oxo-4H-pyrido[1,2-a]pyrimidyl, 4-oxo-1,4-dihydro-1,8-naphthyridyl, 3,6-dihydro-2H-pyranyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-thiopyran 1,1-dioxide, and N-oxides thereof, and wherein the saturated heterocyclic moieties include, but not limited to, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, triazolopyrimidyl, tetrahydrothienyl, pyrrolidinonyl, azetidin-2-one-ly, pyrrolidin-2-one-ly, piperidin-2-one-ly, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2-oxo-2,5,6,7-tetrahydro-1H-cyclopentapyridyl, 4,5,6,7-tetrahydro-indazolyl, 5,6,7,8-tetrahydro-1,6-naphthyridyl, 1,4-oxazepanyl, and N-oxides thereof and S-oxides thereof. In this specification, preferable heterocyclyl is 3 to 8-membered heterocyclyl with 1-4 heteroatoms independently selected from O, N, and S, in which the heterocyclyl optionally contains carbonyl, more preferable heterocyclyl is 4-6 membered saturated mono heterocyclyl with 1-4 heteroatoms selected from O, N, and S, in which the heterocyclyl optionally contains carbonyl, further more preferable heterocyclyl is 5-6 membered saturated mono heterocyclyl with 1-3 heteroatoms selected from O, N, and S, in which the heterocyclyl optionally contains carbonyl.
　 The term "protecting group", as used herein, means a hydroxy or amino protecting group which is selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 2007).
　 The term "treating" or "treatment", as used herein, includes prohibiting, restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.　As used herein, the term "preventing" or "to prevent" includes prohibiting, restraining, or inhibiting the incidence or occurrence of a symptom or disorder.
　 As used herein, the article "a" or "an" refers to both the singular and plural form of the object to which it refers unless indicated otherwise.
　 Included within the scope of the "compounds of the invention" are all salts, solvates, hydrates, complexes, polymorphs, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of formulae (I), (II), and (III).
　 Compounds of formulae (I), (II), and (III) can form acid addition salts thereof.　It will be appreciated that for use in medicine the salts of the compounds of formulae (I), (II), and (III) should be pharmaceutically acceptable.　Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci, 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g., but not limited to, hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g., but not limited to, succinic, maleic, formic, acetic, trifluoroacetic, propionic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.　Certain of the compounds of formulae (I), (II), and (III) may form acid addition salts with one or more equivalents of the acid.　The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.　In addition, certain compounds containing an acidic function group such as a carboxyl group can be isolated in the form of their inorganic salt in which the counter ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases such as choline, arginine, benzathine, diethylamine, glycine, lysine, meglumine, olamine, 2-amino-2-methylpropan-1-ol, benethamine, tert-butylamine, epolamine, ethylenediamine, hydrabamine, morpholine, piperazine, procaine, triethanolamine, diethanolamine, monoethanolamine, triisopropanolamine, and tromethamine.
　 Also within the scope of the invention are so-called "prodrugs" of the compounds of formulae (I), (II), and (III).　Thus certain derivatives of compounds of formulae (I), (II), and (III) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formulae (I), (II), and (III) having the desired activity, for example, by hydrolytic cleavage.　Such derivatives are referred to as "prodrugs".　Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
　 The term "animal," as used herein, includes a mammalian subject or a non-mammalian subject.　Examples of suitable mammalian subject may include, without limit, human, rodents, companion animals, livestock, and primates.　Suitable rodents may include, but are not limited to, mice, rats, hamsters, gerbils, and guinea pigs.　Suitable companion animals may include, but are not limited to, cats, dogs, rabbits, and ferrets.　Suitable livestock may include, but are not limited to, horses, goats, sheep, swine, cattle, llamas, and alpacas.　Suitable primates may include, but are not limited to, chimpanzees, lemurs, macaques, marmosets, spider monkeys, squirrel monkeys, and vervet monkeys.　Examples of suitable non-mammalian subject may include, without limit, birds, reptiles, amphibians, and fish.　Non-limiting examples of birds include chickens, turkeys, ducks, and geese.　The preferred mammalian subject is a human.
　 The term "CRHR2 agonist", as used herein, includes but are not limited to, urocortin 2, urocortin 1, urocortin 3, sauvagine, CRF, and CRF peptide family containing CRF analogs.
　 Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formulae (I), (II), and (III) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H Bundgaard (Elsevier, 1985).　Some examples of prodrugs in accordance with the invention include:
(i) where the compound of formulae (I), (II), and (III) contains an alcohol functionality (-OH), compounds wherein the hydroxy group is replaced with a moiety convertible in vivo into the hydroxy group.　Said moiety convertible in vivo into the hydroxy group means a moiety transformable in vivo into a hydroxyl group by e.g. hydrolysis and/or by an enzyme, e.g. an esterase.　Examples of said moiety include, but are not limited to, ester and ether groups which may be hydrolyzed easily in vivo.　Preferred are the moieties replaced the hydrogen of hydroxy group with acyloxyalkyl, 1-(alkoxycarbonyloxy)alkyl, phthalidyl and acyloxyalkyloxycarbonyl such as pivaloyloxymethyloxycarbonyl; and
(ii) where the compound of the formulae (I), (II), and (III) contains an amino group, a spiroheterocyclic derivative prepared by reacting with a suitable acid halide or a suitable acid anhydride is exemplified as a prodrug.　A particularly preferred spiroheterocyclic derivative as a prodrug is -NHCO(CH2)2OCH3, -NHCOCH(NH2)CH3 or the like.
　 Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.
　 Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formulae (I), (II), and (III) and their pharmaceutically acceptable salts.
　 Compounds of formulae (I), (II), and (III) may have polymorphs in crystalline form, which are within the scope of the present invention.
　 Additionally, compounds of formulae (I), (II), and (III) may be administered as prodrugs.　As used herein, a "prodrug" of a compound of formulae (I), (II), and (III) is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of formulae (I), (II), and (III) in vivo.　Administration of a compound of formulae (I), (II), and (III) as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of action of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound.　Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo.　Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
　 In certain of the compounds of formulae (I), (II), and (III), there may be one or more chiral carbon atoms.　In such cases, compounds of formulae (I), (II), and (III) exist as stereoisomers.　The invention extends to all optical isomers such as stereoisomeric forms of the compounds of formulae (I), (II), and (III) including enantiomers, diastereoisomers and mixtures thereof, such as racemates.　The different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereoselective or asymmetric syntheses.
　 Certain of the compounds herein can exist in various tautomeric forms and it is to be understood that the invention encompasses all such tautomeric forms.
　 The invention also includes isotopically-labeled compounds, which are identical to those described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.　Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 18F, 123I and 125I.　Compounds of the invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention.　Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays.　Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability.　11C and 18F isotopes are particularly useful in PET (positron emission tomography), and 123I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging.　Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.　Isotopically labeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, then substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
　 With respect to other compounds disclosed in the art, certain compounds exhibit unexpected properties, such as with respect to duration of action and/or metabolism, such as favorable metabolic stability, favorable oral bioavailability or absorption, and/or decreased drug-drug interactions.
　 A skilled physician will be able to determine the appropriate situation in which subjects are susceptible to or at risk of, for example, stroke as well as suffering from stroke for administration by methods of the present invention.
　 CRHR2 have been implicated in a wide range of biological functions.　This has suggested a potential role for these receptors in a variety of disease processes in humans or other species.　The compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders associated with CRHR2, including one or more of the following conditions or diseases: gastrointestinal disorders, major depressive disorders, schizophrenic disorders, neurodegenerative diseases, pain, dysfunction of appetite and food intake, sleep disorders, cognitive disorders, tolerance to and dependence on a number of substances, inflammation, fertility problems, sexual dysfunctions and pre-term birth and non-inflammatory urogenital disorders, allergic disorders, mast cell activation disorders, Cushing’s syndrome, emesis, gastrointestinal disorders, neurotoxic injury, loss of hair, heart failure, and the like.
　 The dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.　The active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
　 The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.　The dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize.
　 For administration to human patients, the total daily dose of the compounds of the invention is typically in the range of 0.1 mg to 1000 mg depending, of course, on the mode of administration.　For example, oral administration may require a total daily dose of from 1 mg to 1000 mg, while an intravenous dose may only require from 0.1 mg to 100 mg.　The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
　 These dosages are based on an average human subject having a weight of about 60 kg to 70 kg.　The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
　 In one embodiment, the dosage range will be about 0.5 mg to 500 mg per patient per day; in another embodiment about 0.5 mg to 200 mg per patient per day; in another embodiment about 1 mg to 100 mg per patient per day; and in another embodiment about 5 mg to 50 mg per patient per day; in yet another embodiment about 1 mg to 30 mg per patient per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient.　The pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient.　For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.　The compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day.
　 Compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.　Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.　When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is envisioned.　However, the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
　 Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention.　The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
　 Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful.　Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.　When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is envisioned.　Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
　 The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.　Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, including about 200: 1 to about 1:200.　Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.　In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction.　In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
　 A CRHR2 antagonist may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of inflammatory, pain and urological diseases or disorders.　For example, a CRHR2 antagonist, particularly a compound of formulae (I) and (II), or a prodrug thereof or a pharmaceutically acceptable salt or solvate thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from:
　- an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, or pentazocine;
　- a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac;
　- a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, or thiopental;
　- a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam;
　- an H1 antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclizine;
　- a sedative such as glutethimide, meprobamate, methaqualone, or dichloralphenazone;
　- a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine;
　- an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinone, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex (registered trademark), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;
　- an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline;
　- a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline, or nortriptyline;
　- an anticonvulsant, e.g. carbamazepine, lamotrigine, topiramate, or valproate;
　- a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6, 13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);
　- a muscarinic antagonist, e.g. oxybutynin, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, temiverine, or ipratropium;
　- a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;
　- a coal-tar analgesic, e.g. paracetamol;
　- a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion (registered trademark), or sarizotan;
　- a vanilloid receptor agonist (e.g. resiniferatoxin) or antagonist (e.g. capsazepine);
　- a transient receptor potential cation channel subtype (V1, V2, V3, V4, M8, M2, A1) agonist or antagonist;
　- a beta-adrenergic such as propranolol;
　- a local anaesthetic such as mexiletine;
　- a corticosteroid such as dexamethasone;
　- a 5-HT receptor agonist or antagonist, particularly a 5-HT1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan;
　- a 5-HT2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
　- a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine;
　- Tramadol (registered trademark);
　- a PDEV inhibitor, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, or 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;
　- an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, (3-(aminomethyl)bicyclo[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-(aminomethyl)-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-((1-(aminomethyl)cyclohexyl)methyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-((1H-tetrazol-5-yl)methyl)cycloheptyl]methylamine, (3S,4S)-(1-(aminomethyl)-3,4-dimethylcyclopentyl)acetic acid, (3S,5R)-3-(aminomethyl)-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (3R,4R,5R)-3-amino-4,5-dimethylheptanoic acid, or (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid;
　- a cannabinoid;
　- a metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;
　- a serotonin reuptake inhibitor such as sertraline, sertraline metabolite desmethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine, or trazodone;
　- a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine, or viloxazine (Vivalan (registered trademark)), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;
　- a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran, or imipramine;
　- an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile; 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, or guanidinoethyldisulfide;
　- an acetylcholinesterase inhibitor such as donepezil;
　- a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide, or 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;
　- a leukotriene B4 antagonist; such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057), or DPC-11870,
　- a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504);
　- a sodium channel blocker, such as lidocaine;
　- a calcium channel blocker, such as ziconotide, zonisamide, or mibefradil;
　- a 5-HT3 antagonist, such as ondansetron;
　- a chemotherapy drug such as oxaliplatin, 5-fluorouracil, leucovorin, or paclitaxel;
　- a calcitonin gene related peptide (CGRP) antagonist;
　- a bradykinin (BK1 and BK2) antagonist;
　- a voltage gated sodium dependent channel blocker (Nav1.7, Nav1.8);
　- a voltage dependent calcium channel blocker (N-type, T-type);
　- a P2X (ion channel type ATP receptor) antagonist;
　- an acid-sensing ion channel (ASIC1a, ASIC3) antagonist;
　- an angiotensin-converting enzyme (ACE) inhibitors, such as AT2 antagonist;
　- an Angiotensin receptor blockers (ARBs);
　- a direct renin inhibitors (DRIs);
　- mineralocorticoid receptor antagonists (MRAs);
　- funny channel (If channel) inhibitor, such as ivabradine;
　- a Chemokine CCR2B receptor antagonist;
　- a Cathepsin (B, S, K) inhibitor;
　- a sigma1 receptor agonist or antagonist;
　- cardiac sarcomere modulators, such as omecamtiv mecarbil (OM), or MYK-491, Mavacamten,
　- soluble guanylate cyclase (sGC) stimulators, such as vericiguat,
　- apelin receptor agonists,
　-a drugs for heart failure, such as Entresto (registered trademark) which is a combination of sacubitril and valsartan,
　 or the pharmaceutically acceptable salts, or the solvates thereof.
　 Such combinations offer significant advantages, including synergistic activity, in therapy.
　 A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories.　Orally administrated compositions are generally preferred.　Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); tabletting lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); and acceptable wetting agents (e.g. sodium lauryl sulphate).　The tablets may be coated according to methods well known in normal pharmaceutical practice.
　 Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.　Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (which may include edible oils e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid), and, if desired, conventional flavourings or colorants, buffer salts and sweetening agents as appropriate.　Preparations for oral administration may be suitably formulated to give controlled release of the active compound or pharmaceutically acceptable salt thereof.
　 For parenteral administration, fluid unit dosage forms are prepared utilising a compound of formulae (I), (II), and (III) or pharmaceutically acceptable salt thereof and a sterile vehicle.　Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose, utilising a compound of formulae (I), (II), and (III) or pharmaceutically acceptable salt thereof and a sterile vehicle, optionally with an added preservative.　The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.　Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.　The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.　In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.　Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.　To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.　Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.　The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.　Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
　 Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.　Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents.　They may also contain a preservative.
　 Compounds of formulae (I), (II), and (III) or pharmaceutically acceptable salts thereof may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
　 Compounds of formulae (I), (II), and (III) or pharmaceutically acceptable salts may also be formulated as depot preparations.　Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.　Thus, for example, the compounds of formulae (I), (II), and (III) or pharmaceutically acceptable salts may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
　 For intranasal administration, compounds formulae (I), (II), and (III) or pharmaceutically acceptable salts thereof may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.　Thus compounds of formulae (I), (II), and (III) or pharmaceutically acceptable salts thereof may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).　The compounds of formulae (I), (II), and (III) and pharmaceutically acceptable salts thereof may be formulated for topical administration in the form of ointments, creams, gels, lotions, pack, tape, pessaries, aerosols or drops (e.g. eye, ear or nose drops).　Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilized components.
General Synthesis
　 Throughout the instant application, the following abbreviations are used with the following meanings:
AcOH　 Acetic acid
BINAP　2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl
Boc　　tert-Butoxycarbonyl
JohnPhos　 2-(Di-tert-butylphosphino)biphenyl
CDI　　1,1'-Carbonyldiimidazole
CyJohnPhos　2-(Dichlorohexylphosphino)biphenyl
DABCO　1,4-Diazabicyclo[2.2.2]octane
DavePhos　　2-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenyl
dba　　 Dibenzylidenacetone
DBN　　1,5-Diazabicyclo[4.3.0]non-5-ene
DBU　　1,8-Diazabicyclo[5.4.0]undec-7-ene
DCM　　Dichloromethane
DIEA　　N,N-Diisopropylethylamine
DME　　1,2-Dimethoxyethane
DMEDA　N,N'-Dimethylethylenediamine
DMF　　N,N-Dimethylformamide
DMA　　N,N-Dimethylacetamide
DMAP　　N,N-Dimethyl-4-aminopyridine
DMSO　Dimethyl sulfoxide
EDC　　1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride
ESI　　 Electrospray ionization
EtOAc　Ethyl acetate
EtOH　 Ethanol
Ex　　 Example
HOBT　1-Hydroxybenzotriazole
HATU　O-(7-Aza-1H-benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate
HBTU　O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HPLC　High-Performance liquid chromatography
IPE　　Diisopropyl ether
LC　　 Liquid chromatography
LG　　 Leaving group
tR　　　Retention time
MeCN　Acetonitrile
MeOH　Methanol
MHz　　Megahertz
Ms　　Methanesulfonyl
MS　　 Mass spectrometry
MS 4A　 Molecular sieves 4 angstrom
NMP　 N-methylpyrrolidone
NMR　 Nuclear magnetic resonance
Pd(dppf)Cl2　 [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
Pd(PPh3)4　 Tetrakis(triphenylphospine)palladium(0)
PEPPSI (registered trademark)-IPr　 [1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride
Xphos Pd G3　 (2-Dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate
rt　　　 Room temperature
SFC　 Supercritical fluid chromatography
SPhos　 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl
tBuXPhos　2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl
T3P (trademark)　Propylphosphonic acid anhydride (Cyclic Trimer)
TEA　　Triethylamine
TFA　　Trifluoroacetic Acid
TfOH　 Trifluoromethanesulfonic acid
THF　　Tetrahydrofuran
THP　　Tetrahydropyranyl
TLC　　Thin layer chromatography
TMEDA　N,N,N’,N’-tetramethylethylenediamine
TosMIC　p-Toluenesulfonylmethyl isocianide
UV　　 Ultraviolet
XPhos　 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl
Xantphos　 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
　 The term of "base" is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here.　Examples of such bases include, but not limited to: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium phosphate, and barium hydroxide; alkali metal hydrides, such as lithium hydride, sodium hydride, and potassium hydride; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal hydrogencarbonates, such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, N,N-dimethyl-4-aminopyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lutidine, and colidine; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropyl amide, potassium diisopropyl amide, sodium diisopropyl amide, lithium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide.　Of these, triethylamine, diisopropylethylamine, DMAP, DBU, DBN, DABCO, pyridine, lutidine, colidine, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium carbonate, potassium hydrogencarbonate, potassium hydroxide, potassium phosphate, barium hydroxide, and cesium carbonate are preferred.
　 The reactions are normally and preferably effected in the presence of inert solvent.　There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include, but not limited to: halogenated hydrocarbons, such as DCM, chloroform, carbon tetrachloride, and dichloroethane; ethers, such as diethyl ether, diisopropyl ether, THF, and 1,4-dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as, DMF, DMA, and hexamethylphosphoric triamide; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, N,N-dimethylaniline, and N,N-diethylaniline; alcohols, such as methanol, ethanol, propanol, isopropanol, and butanol; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO) and sulfolane; ketones, such as acetone and diethylketone. Of these solvents, including but not limited to DMF, DMA, DMSO, THF, diethylether, diisopropylether, dimethoxyethane, acetonitrile, DCM, dichloroethane and chloroform are preferred.
　 The invention is illustrated in the following non-limiting examples in which, unless stated otherwise: all reagents are commercially available, all operations are carried out at room or ambient temperature, that is, in the range of about 18-25 oC; microwave reactions are carried out using Biotage Initiator or Biotage Initiator+; evaporation of solvent is carried out using a rotary evaporator under reduced pressure with a bath temperature of up to about 60 oC; reactions are monitored by thin layer chromatography (TLC) and reaction times are given for illustration only; the structure and purity of all isolated compounds are assured by at least one of the following techniques: TLC (Merck silica gel 60 F254 precoated TLC plates or Merck NH2 F254 precoated HPTLC plates), mass spectrometry or NMR. Yields are given for illustrative purposes only. Flash column chromatography is carried out using Biotage SNAP KP-Sil, Biotage SNAP Isolute NH2, Merck silica gel 60 (230-400 mesh ASTM), Fuji Silysia Chromatorex (registered trademark) NH-DM1020 and NH-DM2035. The pre-purification for the HPLC (preparative LC-MS) is carried out using a strong cation exchange cartridge (ISOLUTE (registered trademark) SCX-2, 1 g/6 mL, Biotage), or strong anion exchange cartridge (ISOLUTE (registered trademark) PE-AX, 1 g/6 mL, Biotage). The purification of compounds using HPLC (preparative LC-MS) or SFC (preparative SFC-MS) is performed by the following apparatus and conditions.
HPLC:
Apparatus: Waters MS-trigger AutoPurification (registered trademark) system
Column: Waters XBridge C8, 19 mm x 50 mm, 5 micrometer particle or Waters XBridge C18, 19 mm x 50 mm, 5 micrometer particle
Mobile phase 1: (A) 0.05%(v/v) ammonia aqueous solution, (B) MeOH or MeCN
Mobile phase 2: (A) 0.05%(v/v) formic acid aqueous solution, (B) MeOH or MeCN
Mobile phase 3: (A) 10 mM ammonium formate aqueous solution, (B) MeCN/water = 90/10(v/v)
Flow rate: 20 mL/min
Gradient: A/B (95/5) to A/B (5/95) in 5 or 7 or 10 min
SFC:
Apparatus: Waters Prep15 SFC system with ACQUITY QDa Detector
Column: Waters Torus 2-PIC, 10 mm x 150 mm, 5 micrometer particle; Waters Torus DEA, 10 mm x 150 mm, 5 micrometer particle; Waters Torus DIOL, 10 mm x 150 mm, 5 micrometer particle; Waters Torus 1-AA, 10 mm x 150 mm, 5 micrometer particle
Mobile phase: (A) Carbon dioxide (CO2), (B) MeOH or 10 mM ammonia in MeOH
Flow rate: 15 mL/min
Gradient: A/B (95/5) to A/B (60/40) in 7 or 10 min
Temperature: 40 oC
Pressure: 120 bar (1740 psi)
Mass spectral data (ESI) are obtained by Waters Alliance HPLC system with ZQ mass spectrometer and UV detector. NMR data are determined by 400 MHz (JEOL JNM-ECZ400S) using deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent unless indicated otherwise, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); conventional abbreviations used are: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, etc. Chemical symbols have their usual meanings; M (mol(s) per liter), L (liter(s)), mL (milliliter(s)), g (gram(s)), mg (milligram(s)), mol (moles), mmol (millimoles).
Each prepared compound is generally named by ChemDraw (version 18.1, PerkinElmer Informatics).
Conditions for determining HPLC retention time:
QC Method:
Apparatus: Waters Acquity Ultra Performance LC with PDA Detector and ZQ mass spectrometer
Column: YMC Triart C18, 2.1 x 100 mm, 1.9 micrometer particle
Column Temperature: 60 oC
PDA detection: 200 - 400 nm scan
MS detection: ESI positive/negative mode
Mobile phase:
A: 10 mM ammonium acetate aqueous solution
B: acetonitrile
Figure JPOXMLDOC01-appb-I000008
　 All of the compounds of the formulae (I), (II), and (III) can be prepared by the procedures described in the general methods presented below or by the specific methods described in the Example synthesis part and Intermediate synthesis part, or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the compound of formulae (I), (II), and (III), in addition to any novel intermediates used therein.
　 In the following general methods, descriptors (R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, Rc, Rd, A, B, W, X1, X2, X3, p, q, Y1, Y2, Y3, Y4, and Z) are as previously defined for the compound of the formulae (I), (II), and (III) unless otherwise stated. All starting materials in the following general syntheses may be commercially available or obtained by the conventional methods known to those skilled in the art, otherwise noted in the Intermediate synthesis part.
<Scheme 1>
Figure JPOXMLDOC01-appb-C000009
　 In Scheme 1, a compound of formula (VI) can be prepared by the substitution reaction of a compound of formula (IV) with a compound of formula (V) in the presence of a suitable base in an inert solvent. LG is a suitable leaving group such as O-trifluoromethanesulfonate, O-tosylate, O-mesylate, iodide, bromide, chloride, fluoride. Examples of a suitable base include, but not limited to, such as sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethyl amine, pyridine, and N,N-diisopropylethylamine. Examples of a suitable organic solvent include such as THF, 1,4-dioxane, DMF, DMSO, MeCN, DMA, NMP, toluene. The reaction can be carried out at a temperature from about -20 to 200 oC, more preferably from about 0 to 100 oC. Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 1 hour to 24 hours.
<Scheme 2>
Figure JPOXMLDOC01-appb-C000010
　 In Step-1 of Scheme 2, a compound of formula (VIII) can be prepared a compound of formula (IV) and a compound of formula (VII) in the substitution reaction conditions by the similar general protocol in Scheme 1.
　 In Step-2 of Scheme 2, deprotection of Boc group by usual acidic treatment (for example, hydrogen chloride in 1,4-dioxane, TFA-DCM) to afford a compound of formula (IX).
　 In Step-3 of Scheme 2, a compound of a compound of formula (VI) can be prepared from a compound of formula (IX) and a compound of formula (X) or (XI) in the presence of a suitable base in an inert solvent. Examples of a suitable base include such as triethylamine, N,N-diisopropylethylamine, DMAP, DABCO, and DBU. Examples of a suitable solvent include such as THF, DME, 1,4-dioxane, DMF, DMA, and DCM. This reaction can be carried out at a temperature in the range from about -20 to 80 oC. Reaction times are, in general, from about 1 hour to 48 hours.
　 In Step-4 of Scheme 2, a compound of formula (VI) can be prepared from a compound of formula (IX) by the condensation with a compound of formula (XII) using a suitable condensation reagent such as HBTU, HATU, T3P (registered trademark), EDC, and EDC-HOBT, preferably under the presence of a base such as triethylamine, N,N-diisopropylethylamine, DMAP, DABCO, and DBU in a suitable solvent such as THF, DME, 1,4-dioxane, DMF, DMA, and DCM. This reaction can be carried out at a temperature in the range from about 5 to 60 oC. Reaction times are, in general, from about 1 hour to 48 hours.
In Step-5 of Scheme 2, a compound of a compound of formula (VI) can be prepared from a compound of formula (IX), a compound of formula (XIII) or (XIV), and a compound of formula (XV) in the presence of a suitable base in an inert solvent. Examples of a suitable base include such as triethylamine, N,N-diisopropylethylamine, DMAP, DABCO, and DBU. Examples of a suitable solvent include such as THF, DME, 1,4-dioxane, DMF, DMA, and DCM. This reaction can be carried out at a temperature in the range from about -20 to 80 oC. Reaction times are, in general, from about 1 hour to 48 hours. Optionally, reacting a compound of formula (IX) or (XV) with a compound of (XIII) or (XIV) in the presence of suitable base to form an active carbamate, before the treatment with a compound of (XV) or (IX).
<Scheme 3>
Figure JPOXMLDOC01-appb-C000011
　 In Step-1 of Scheme 3, a compound of formula (VI) can be prepared from a compound of formula (IX) and a suitable boronic acid or borate of formula (XVI) and a suitable copper salt and in the presence or absence of a base and in the presence or absence of a dehydrating reagent in an inert solvent. In a representation of BR’s, R’ means OH, O-low alkyl or fluorine, and s is 2 or 3, B is boron atom. As the concrete representation of substituent, B(OH)2, B(O-lower alkyl)2, B(lower alkyl)2, potassium trifluoroborate (BF3 -)(BF3K) are described, but when B(O-lower alkyl)2 may form the cyclic ring between the lower alkyl groups. Example of a suitable copper salt include, copper(0), copper(l) acetate, copper(l) bromide, copper(l) chloride, copper(l) iodide, copper(l) oxide, copper(l) trifluoromethanesulfonate, copper(ll) acetate, copper(ll) bromide, copper(ll) chloride, copper(ll) iodide, copper(ll) oxide, copper(ll) trifluoromethanesulfonate. Examples of a suitable base include, but not limited to, such as triethyl amine, pyridine, and N,N-diisopropylethylamine. Examples of suitable organic solvent include such as DCM, dichloroethane, MeOH, EtOH, THF, 1,4-dioxane, DMF, MeCN, DMA, toluene. Examples of a suitable dehydrating agent include, but not limited to, such as MS 4A, magnesium sulfate, sodium sulfate. The reaction can be carried out at a temperature from about -20 to 150 oC, more preferably from about 0 to 100 oC. Reaction times are, in general, from about 30 minutes to 7 days, more preferably from about 1 hour to 24 hours.
　 In Step-2 of Scheme 3, a compound of formula (VI) can be prepared from a compound of formula (IX) and a compound of formula (XVII) by the similar general protocol in Scheme 1.
　 Alternatively, in Step-2 of Scheme 3, a compound of formula (VI) can be prepared by cross coupling reaction of a compound of formula (IX) with a compound of formula (XVII) under coupling conditions in suitable organic solvents in the presence of a suitable transition metal catalyst and in the presence or absence of a base. Examples of suitable transition metal catalysts include: tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(ll) chloride, copper(0), copper(l) acetate, copper(l) bromide, copper(l) chloride, copper(l) iodide, copper(l) oxide, copper(ll) trifluoromethanesulfonate, copper(ll) acetate, copper(ll) bromide, copper(ll) chloride, copper(ll) iodide, copper(ll) oxide, palladium(ll) acetate, palladium(ll) chloride, bis(acetonitrile)dichloropalladium(II), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), [1,1'-bis(diphenylphosphino)ferrocene] palladium(ll) dichloride and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II). Preferred catalysts are tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(ll) chloride, palladium(ll) acetate, palladium(ll) chloride, bis(acetonitrile)dichloropalladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), [1,1’-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II). Examples of suitable organic solvent include: THF; 1,4-dioxane; DMF; MeCN; DMSO; DMA; alcohols, such as methanol or ethanol; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform or carbon tetrachloride; and diethylether. Example of suitable base include: tripotassium phosphate, sodium bicarbonate, sodium carbonate, cesium carbonate and potassium carbonate. This reaction can be carried out in the presence of a suitable additive agent. Examples of such additive agents include: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), triphenylphosphine, tri-tert-butylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, tri-2-furylphosphine, tri-o-tolylphosphine, triphenylarsine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 2-(dichlorohexylphosphino)biphenyl (CyJohnPhos), 2-(dicyclohexylphosphino)-2'-(dimethylamino)biphenyl (DavePhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tBuXPhos), 2-(di-tert-butylphosphino)biphenyl (JohnPhos), N,N’-dimethylethylenediamine (DMEDA), N,N,N’,N’-tetramethylethylenediamine (TMEDA), 2,2’-bipyridine, 1,10-phenanthroline. The reaction can be carried out at a temperature from about 50 to 200 oC, more preferably from about 80 to 150 oC. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours. In an alternative case, the reaction can be carried out with microwave system. The reaction can be carried out at a temperature in the range from about 100 to 200 oC, preferably in the range from about 120 to 160 oC. Reaction times are, in general, from about 10 minutes to 3 hours, preferably from about 15 minutes to 1 hour.
<Scheme 4>
Figure JPOXMLDOC01-appb-C000012
　 In Step-1 of Scheme 4, a compound of formula (XX) can be prepared from a compound of formula (XVIII) and a compound of formula (XIX) by the similar general protocol in Step 4 of Scheme 2.
　 In Step-2 of Scheme 4, a compound of formula (XXI) can be prepared by the reduction of a compound of formula (XX). In a typical procedure, the reduction is conducted by using a reducing agent such as lithium aluminum hydride, borane, lithium borohydride, or sodium borohydride in an inert solvent. Suitable solvents include, such as THF, DME, and 1,4-dioxane. This reaction can be carried out at a temperature in the range of from about -80 to 100 oC. Reaction times are, in general, from about 5 minutes to 24 hours.
　 In Step-3 of Scheme 4, when LG is O-mesylate, a compound of formula (IV) can be prepared by mesylation of a compound of formula (XXI) with Ms2O or MsCl in suitable organic solvents in the presence of a base. Examples of a suitable base include, but not limited to, such as sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethyl amine, pyridine, and N,N-diisopropylethylamine. Examples of suitable organic solvents include such as DCM, THF, 1,4-dioxane, DMF, DMSO, MeCN, DMA, toluene. The reaction can be carried out at a temperature from about -20 to 100 oC, more preferably from about 0 to 50 oC. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 1 hour to 24 hours.
<Scheme 5>
Figure JPOXMLDOC01-appb-C000013
　 In Scheme 5, a compound of formula (XXI) can be prepared from a compound of formula (XVIII) and a compound of formula (XXII) by the similar general protocol in Step-4 of Scheme 2.
<Scheme 6>
Figure JPOXMLDOC01-appb-C000014
　 In Step-1 of Scheme 6, a compound of formula (XXIV) can be prepared from a compound of formula (XXIII) and a compound of formula (V) by the similar general protocol in Scheme 1.
　 In Step-2 of Scheme 6, deprotection of Boc group by usual acidic treatment (for example, hydrogen chloride in 1,4-dioxane, TFA-DCM) to afford a compound of formula (XXV).
　 In Step-3 of Scheme 6, a compound of formula (VI) can be prepared from a compound of formula (XXV) and a compound of formula (XVIII) by the similar general protocol in Step-4 of Scheme 2.
<Scheme 7>
Figure JPOXMLDOC01-appb-C000015
　 In Scheme 7, a compound of formula (XXVI) can be prepared by the substitution reaction of a compound of formula (VI) with a Lawesson’s reagent in an inert solvent. Examples of a suitable organic solvent include such as THF, 1, 4-dioxane, DMF, DMSO, MeCN, DMA, NMP, toluene. The reaction can be carried out at a temperature from about -20 to 200 oC, more preferably from about 0 to 100 oC. Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 1 hour to 24 hours.
<Scheme 8>
Figure JPOXMLDOC01-appb-C000016
　 In Step-1 of Scheme 8, a compound of formula (XXIX) can be prepared from a compound of formula (XXVII) and a compound of formula (XXVIII) by the similar general protocol in Step-4 of Scheme 2.
　 In Step-2 of Scheme 8, a compound of formula (XXIX) can be converted to a compound of formula (XXX) by a usual protection manner described in Protecting Groups in Organic Synthesis Forth Edition (John Wiley & Sons, 2007).
　 In Step-3 of Scheme 8, a compound of formula (XXXI) can be prepared from a compound of formula (XXX) by the similar protocol in Step-2 of Scheme 3.
　 In Step-4 of Scheme 8, a compound of formula (XXXI) can be converted to a compound of formula (V) by a usual deprotection manner described in Protecting Groups in Organic Synthesis Forth Edition (John Wiley & Sons, 2007).
Intermediate synthesis part
Each chemical structure of Intermediate synthesis part is described as a free-base.
Intermediate-A:
((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl methanesulfonate
Figure JPOXMLDOC01-appb-C000017
<Step-1>: (1r,4r)-methyl 4-(5-chloro-2-methylnicotinamido)cyclohexanecarboxylate
　 A mixture of 5-chloro-2-methylnicotinic acid (5.23 g, 30.5 mmol), (1r,4r)-methyl 4-aminocyclohexanecarboxylate hydrochloride (5.90 g, 30.5 mmol), HOBt (9.34 g, 61.0 mmol) , EDC (11.7 g, 61.0 mmol), and TEA (17 mL, 122 mmol) in DCM (200 mL) is stirred at room temperature overnight. To the mixture is added saturated aqueous sodium bicarbonate. The resultant mixture is extracted with EtOAc. The organic phase is washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resultant residue is purified by column chromatography on silica-gel eluting with 0-70% EtOAc in n-hexane to give 8.55 g (90% yield) of the title compound as a white solid.
1H-NMR (400 MHz, CDCl3) delta 8.50 (1H, d, J = 2.3 Hz), 7.62 (1H, d, J = 2.7 Hz), 5.57 (1H, d, J = 8.2 Hz), 4.00-3.91 (1H, m), 3.69 (3H, s), 2.62 (3H, s), 2.29 (1H, tt, J = 12.3, 3.6 Hz), 2.21-2.18 (2H, m), 2.11-2.07 (2H, m), 1.68-1.56 (2H, m), 1.28-1.22 (2H, m). MS (ESI) m/z: 311.2 (M+H)+.
<Step-2>: 5-chloro-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-2-methylnicotinamide
　To a solution of (1r,4r)-methyl 4-(5-chloro-2-methylnicotinamido)cyclohexanecarboxylate (8.55 g, 27.5 mmol, Step-1 of Intermediate-A) in THF (180 mL) is added lithium aluminum hydride (1.57 g, 41.3 mmol) portion wise at 0 oC. The reaction mixture is stirred at 0 oC. After 1 hr the reaction is quenched with water (150 mL) and Rochelle salt (75 g). The resultant mixture is stirred at room temperature for 1 day. The resultant mixture is extracted with EtOAc, dried over MgSO4, filtered and concentrated in vacuo to give 7.49 g (96% yield) of the title compound as a white solid.
1H-NMR (400 MHz, CDCl3) delta 8.50 (1H, d, J = 2.3 Hz), 7.62 (1H, d, J = 2.3 Hz), 5.58 (1H, d, J = 7.8 Hz), 4.03-3.85 (1H, m), 3.54-3.46 (2H, m), 2.62 (3H, s), 2.22-2.11 (2H, m), 1.96-1.86 (2H, m), 1.60-1.44 (1H, m), 1.35 (1H, br s), 1.31-1.08 (4H, m). MS (ESI) m/z: 283.2 (M+H)+.
<Step-3>: ((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl methanesulfonate
　 To a mixture of 5-chloro-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-2-methylnicotinamide (10.2 g, 35.9 mmol, Step-2 of Intermediate-A) and TEA (15 mL) in DCM (120 mL) / THF (60 mL) is added portionwise methanesulfonic anhydride (14.1 g, 81 mmol) at room temperature. The mixture is stirred at room temperature for 18 hrs. To the resultant mixture is added methanesulfonic anhydride (3.13 g, 18.0 mmol) and stirred at room temperature. After 1 hr, to the mixture is added methanesulfonic anhydride (3.13 g, 18.0 mmol) and stirred at room temperature. After 1.5 hrs, the reaction is quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (3 x 150 mL). The combined organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. The residual solid is purified by column chromatography on silica-gel eluting with 0-100% EtOAc in DCM to give 10.5 g (81% yield) of the title compound as a white solid.
1H-NMR (400 MHz, CDCl3) delta 8.50 (1H, d, J = 2.3 Hz), 7.62 (1H, d, J = 2.3 Hz), 5.61 (1H, d, J = 7.8 Hz), 4.07 (2H, d, J = 6.6 Hz), 4.01-3.85 (1H, m), 3.02 (3H, s), 2.62 (3H, s), 2.24-2.15 (2H, m), 1.98-1.89 (2H, m), 1.85-1.71 (1H, m), 1.32-1.18 (4H, m). MS (ESI) m/z: 361.1 (M+H)+.
Intermediate-B:
((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl methanesulfonate
Figure JPOXMLDOC01-appb-C000018
<Step-1>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)nicotinamide
A mixture of 5-chloro-2-(difluoromethyl)nicotinic acid (500 mg, 2.41 mmol), ((1r,4r)-4-aminocyclohexyl)methanol hydrochloride (599 mg, 3.61 mmol), HBTU (1.37 g, 3.61 mmol), and TEA (1.68 mL, 12.0 mmol) in DCM (10 mL) is stirred at room temperature overnight. To the mixture is added saturated aqueous sodium bicarbonate. The resultant mixture is extracted with EtOAc. The organic layer is dried over sodium sulfate, filtered and concentrated. The resultant residue is purified by column chromatography on silica-gel eluting with 0-70% EtOAc in n-hexane to give 768 mg (quantitative yield) of the title compound as a pale yellow solid.
1H-NMR (400 MHz, DMSO-d6) delta 8.83 (1H, d, J = 2.3 Hz), 8.64 (1H, d, J = 7.8 Hz), 8.15 (1H, d, J = 2.3Hz), 7.15 (1H, t, J = 54.0 Hz), 4.40 (1H, t, J = 5.5 Hz), 3.70-3.60 (1H, m), 3.22 (2H, t, J = 5.5 Hz), 1.99-1.88 (2H, m), 1.82-1.72 (2H, m), 1.40-1.13 (3H, m), 1.17-0.90 (2H, m).
MS (ESI) m/z: 319.3 (M+H)+.
<Step-2>: ((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl methanesulfonate
To a mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)nicotinamide (768 mg, 2.41 mmol, Step-1 of Intermediate-B) and TEA (1.00 mL, 7.23 mmol) in DCM (4 mL) / THF (4 mL) is added portionwise methanesulfonic anhydride (630 mg, 3.61 mmol) at 0 oC. The mixture is stirred at room temperature for 1 hr. The mixture is quenched with saturated aqueous sodium bicarbonate and extracted with DCM. The organic layer is dried over sodium sulfate, filtered and concentrated. The residual solid is purified by column chromatography on silica-gel eluting with 0-60% EtOAc in n-hexane to give 777 mg (81% yield) of the title compound as a pale yellow solid.
1H-NMR (400 MHz, DMSO-d6) delta 8.84 (1H, d, J = 2.3 Hz), 8.67 (1H, d, J = 7.8 Hz), 8.16 (1H, d, J = 2.3 Hz), 7.15 (1H, t, J = 54.0 Hz), 4.04 (2H, d, J = 6.4 Hz), 3.75-3.62 (1H, m), 3.17 (3H, s), 1.95 (2H, br d, J = 11.4 Hz), 1.80 (2H, br d, J = 11.4 Hz), 1.72-1.61 (1H, m), 1.36-1.22 (2H, m), 1.18-1.14 (2H, m).
MS (ESI) m/z: 397.2 (M+H)+.
Intermediate-C:
((1r,4r)-4-(5-chloro-2-(trifluoromethyl)nicotinamido)cyclohexyl)methyl methanesulfonate
Figure JPOXMLDOC01-appb-C000019
<Step-1>: 5-chloro-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-2-(trifluoromethyl)nicotinamide
A mixture of 5-chloro-2-(trifluoromethyl)nicotinic acid (2.28 g, 6.84 mmol), ((1r,4r)-4-aminocyclohexyl)methanol hydrochloride (1.47 g, 8.89 mmol), HBTU (3.89 g, 10.3 mmol), and TEA (3.81 mL, 27.4 mmol) in DMF (35 mL) is stirred at room temperature overnight. To the mixture is added water. The resultant mixture is extracted with EtOAc (x2). The organic phase is washed with 0.5 M HCl, water, then saturated aqueous sodium bicarbonate. The organic layer is dried over MgSO4, filtered and concentrated. The resultant residue is purified by column chromatography on silica-gel eluting with 30-75% EtOAc in n-hexane to give 1.62 g (70% yield) of the title compound as a pale yellow solid.
1H-NMR (400 MHz, DMSO-d6) delta 8.87 (1H, d, J = 2.3 Hz), 8.57 (1H, d, J = 7.8 Hz), 8.22 (1H, d, J = 2.3 Hz), 4.40 (1H, t, J = 5.5 Hz), 3.69-3.57 (1H, m), 3.22 (2H, t, J = 5.5 Hz), 1.91 (2H, br d, J = 11.9 Hz), 1.77 (2H, br d, J = 11.9 Hz), 1.38-1.26 (1H, m), 1.29-1.14 (2H, m), 1.03-0.99 (2H, m).
MS (ESI) m/z: 337.4 (M+H)+.
<Step-2>: ((1r,4r)-4-(5-chloro-2-(trifluoromethyl)nicotinamido)cyclohexyl)methyl methanesulfonate
To a mixture of 5-chloro-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-2-(trifluoromethyl)nicotinamide (1.62 g, 4.81 mmol, Step-1 of Intermediate-C) and TEA (2.34 mL, 16.9 mmol) in DCM (10 mL) / THF (20 mL) is added portionwise methanesulfonic anhydride (1.26 g, 7.22 mmol) at 0 oC. The mixture is stirred at room temperature for 1.5 hrs. The mixture is quenched with saturated aqueous sodium bicarbonate and extracted with DCM (x2). The combined organic phase is dried over MgSO4, filtered and concentrated. The residual solid is purified by column chromatography on silica-gel eluting with 10-80% EtOAc in n-hexane to give 1.89 g (95% yield) of the title compound as an off-white solid.
1H-NMR (400 MHz, CDCl3) delta 8.69 (1H, d, J = 2.3 Hz), 7.89 (1H, d, J = 2.3 Hz), 5.64 (1H, d, J = 7.8 Hz), 4.07 (2H, d, J = 6.4 Hz), 4.00-3.89 (1H, m), 3.02 (3H, s), 2.23-2.14 (2H, m), 1.99-1.88 (2H, m), 1.85-1.68 (1H, m), 1.33-1.15 (4H, m).
MS (ESI) m/z: 415.4 (M+H)+.
Intermediate-1:
5-chloro-2-methyl-N-((1r,4r)-4-((2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide dihydrochloride
Figure JPOXMLDOC01-appb-C000020
<Step-1>: tert-butyl 1-(((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate
Figure JPOXMLDOC01-appb-C000021
A mixture of ((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl methanesulfonate (358 mg, 0.99 mmol, Intermediate-A), tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate (300 mg, 0.99 mmol), and cesium carbonate (970 mg, 2.98 mmol) in DMSO (6 mL) is stirred at 90 oC for 8 hrs. After cooling to room temperature, the mixture is diluted with EtOAc, and washed with water (x2). The organic layer is dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography on silica-gel eluting with 50-80% EtOAc in n-hexane to give 450 mg (80% yield) of the title compound as a colorless oil.
1H-NMR (400 MHz, CDCl3) delta 8.50 (1H, d, J = 2.7 Hz), 7.62 (1H, d, J = 2.3 Hz), 7.34-7.28 (2H, m), 7.09 (1H, t, J = 7.8 Hz), 6.88 (1H, d, J = 7.8 Hz), 5.63 (1H, d, J = 8.2 Hz), 4.00-3.74 (5H, m), 3.60 (2H, d, J = 6.9 Hz), 2.62 (3H, s), 2.19-2.12 (2H, m), 1.90-1.73 (7H, m), 1.53 (9H, s), 1.36-1.14 (4H, m).
MS (ESI) m/z: 567.3 (M+H)+.
<Step-2>: 5-chloro-2-methyl-N-((1r,4r)-4-((2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide dihydrochloride
A mixture of tert-butyl 1-(((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate (440 mg, 0.78 mmol, Step-1 of Intermediate-1) and 4 M HCl in 1,4-dioxane (15 mL) is stirred at room temperature for 2 hrs. The mixture is concentrated to give 419 mg (quantitative yield) of the title compound as a white solid.
MS (ESI) m/z: 467.2 (M+H)+.
Intermediate-2:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide hydrochloride
Figure JPOXMLDOC01-appb-C000022
　 The title compound is prepared in quantitative yield by the similar manner to Step-1 and Step-2 of Intermediate-1 using ((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl methanesulfonate (150 mg, 0.38 mmol, Intermediate-B) in place of Intermediate-A.
MS (ESI) m/z: 503.0 (M+H)+.
Intermediate-3:
5-chloro-N-((1r,4r)-4-((5-chloro-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide dihydrochloride
Figure JPOXMLDOC01-appb-C000023
　 The title compound is prepared in 84% yield by the similar manner to Step-1 and Step-2 of Intermediate-1 using tert-butyl 5-chloro-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate (330 mg, 0.98 mmol) in place of tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
MS (ESI) m/z: 501.2 (M+H)+.
Intermediate-4:
5-chloro-N-((1r,4r)-4-((5-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide
Figure JPOXMLDOC01-appb-C000024
　 The title compound is prepared in 93% yield by the similar manner to Step-1 and Step-2 of Intermediate-1 using tert-butyl 5-fluoro-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate (104 mg, 0.33 mmol) in place of tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
MS (ESI) m/z: 485.4 (M+H)+.
Intermediate-5:
5-chloro-2-methyl-N-((1r,4r)-4-((2-oxospiro[indoline-3,3'-pyrrolidin]-1-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000025
　 The title compound is prepared in quantitative yield by the similar manner to Step-1 and Step-2 of Intermediate-1 using tert-butyl 2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (120 mg, 0.42 mmol) in place of tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
MS (ESI) m/z: 453.5 (M+H)+.
Intermediate-6:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1'(2'H)-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000026
　 The title compound is prepared in 57% yield by the similar manner to Step-1 and Step-2 of Intermediate-1 using Intermediate-B (177 mg, 0.45 mmol) and tert-butyl 2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1-carboxylate (149 mg, 0.49 mmol) in place of Intermediate-A and tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
MS (ESI) m/z: 504.5 (M+H)+.
Intermediate-7:
1'-acetyl-1-(((1r,4r)-4-aminocyclohexyl)methyl)spiro[indoline-3,4'-piperidin]-2-one hydrochloride
Figure JPOXMLDOC01-appb-C000027
<Step-1>: tert-butyl ((1r,4r)-4-((1'-acetyl-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)carbamate
The title compound is prepared in 91% yield by the similar manner to Step-1 of Intermediate-1 using ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl methanesulfonate (423 mg, 1.38 mmol) and 1'-acetylspiro[indoline-3,4'-piperidin]-2-one (370 mg, 1.52 mmol) in place of Intermediate-A and tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
1H-NMR (400 MHz, CDCl3) delta 7.30-7.23 (2H, m), 7.07 (1H, t, J = 7.3 Hz), 6.85 (1H, d, J = 7.8 Hz), 4.34 (1H, br s), 4.24-4.18 (1H, m), 4.07-3.99 (1H, m), 3.88-3.78 (1H, m), 3.74-3.67 (1H, m), 3.58-3.49 (2H, m), 3.38 (1H, br s), 2.17 (3H, s), 2.06-1.98 (2H, m), 1.90-1.70 (7H, m), 1.43 (9H, s), 1.25-1.11 (2H, m), 1.10-0.98 (2H, m).
MS (ESI) m/z: 456.5 (M+H)+.
<Step-2>: 1'-acetyl-1-(((1r,4r)-4-aminocyclohexyl)methyl)spiro[indoline-3,4'-piperidin]-2-one hydrochloride
The title compound is prepared in quantitative yield by the similar manner to Step-2 of Intermediate-1 using tert-butyl ((1r,4r)-4-((1'-acetyl-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)carbamate (561 mg, 1.23 mmol, Step-1 of Intermediate-7).
MS (ESI) m/z: 356.4 (M+H)+.
Intermediate-8:
5-chloro-N-((1r,4r)-4-((2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(trifluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000028
　 The title compound is prepared in 65% yield by the similar manner to Step-1 and Step-2 of Intermediate-1 using Intermediate-C (125 mg, 0.30 mmol) and in place of Intermediate-A.
MS (ESI) m/z: 521.5 (M+H)+.
Intermediate-9:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000029
　 The title compound is prepared in 81% yield by the similar manner to Step-1 and Step-2 of Intermediate-1 using Intermediate-B (170 mg, 0.43 mmol) and tert-butyl 6-fluoro-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate (165 mg, 0.52 mmol) in place of Intermediate-A and tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
MS (ESI) m/z: 521.5 (M+H)+.
Intermediate-10:
1-(((1r,4r)-4-aminocyclohexyl)methyl)-1'-(cyclopropanecarbonyl)spiro[indoline-3,4'-piperidin]-2-one hydrochloride
Figure JPOXMLDOC01-appb-C000030
<Step-1>: 1'-(cyclopropanecarbonyl)spiro[indoline-3,4'-piperidin]-2-one
To a stirred solution of spiro[indoline-3,4'-piperidin]-2-one (200 mg, 0.99 mmol) and triethylamine (0.83 mL, 5.93 mmol) in dichloromethane (4 mL) is added cyclopropanecarbonyl chloride (103 mg, 0.99 mmol) at room temperature. The mixture is stirred at room temperature for 2 hrs. The mixture is diluted with dichloromethane (30 mL) and washed with water (20 mLx2). The organic fraction is filtered through column chromatography on amino-functional silica gel eluting with EtOAc, and the filtrate is concentrated to give 264 mg (99% yield) of the title compound as a white solid.
1H-NMR (400 MHz, CDCl3) delta 7.81 (1H, s), 7.35-7.30 (2H, m), 7.14 (1H, t, J = 7.8 Hz), 6.99 (1H, d, J = 7.8 Hz), 4.31-4.20 (2H, m), 4.17-4.07 (1H, m), 4.02-3.91 (1H, m), 2.11-1.88 (4H, m), 1.16-1.12 (2H, m), 0.91-0.86 (2H, m).
MS (ESI) m/z: 271.4 (M+H)+.
<Step-2>: 1-(((1r,4r)-4-aminocyclohexyl)methyl)-1'-(cyclopropanecarbonyl)spiro[indoline-3,4'-piperidin]-2-one hydrochloride
The title compound is prepared in 68% yield by the similar manner to Step-1 and Step-2 of Intermediate-7 using 1'-(cyclopropanecarbonyl)spiro[indoline-3,4'-piperidin]-2-one (Step-1 of Interemediate-10) in place of 1'-acetylspiro[indoline-3,4'-piperidin]-2-one.
MS (ESI) m/z: 382.5 (M+H)+.
Intermediate-11:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2-oxospiro[indoline-3,3'-pyrrolidin]-1-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000031
　 The title compound is prepared in 80% yield by the similar manner to Step-1 and Step-2 of Intermediate-1 using Intermediate-B (150 mg, 0.38 mmol) and tert-butyl 2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (120 mg, 0.42 mmol) in place of Intermediate-A and tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
MS (ESI) m/z: 489.3 (M+H)+.
Intermediate-12:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide hydrochloride
Figure JPOXMLDOC01-appb-C000032
　 The title compound is prepared in 59% yield by the similar manner to Step-1 and Step-2 of Intermediate-1 using Intermediate-B (150 mg, 0.38 mmol) and tert-butyl 6'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (122 mg, 0.42 mmol) in place of Intermediate-A and tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
1H-NMR (400 MHz, DMSO-d6) delta 10.05 (1H, br), 9.26 (1H, br), 8.83 (1H, d, J = 2.3 Hz), 8.66 (1H, d, J = 7.8 Hz), 8.15 (1H, d, J = 2.3 Hz), 8.01 (1H, dd, J = 8.2, 5.5 Hz), 7.14 (1H, t, J = 54 Hz), 7.12 (1H, dd, J = 9.6, 2.0 Hz), 6.99 (1H, td, J = 8.4, 2.4 Hz), 4.28-4.18 (2H, m), 4.17-4.07 (2H, m), 3.77-3.62 (1H, m), 3.51 (2H, d, J = 6.9 Hz), 1.90 (2H, br d, J = 10.1 Hz), 1.81-1.60 (3H, m), 1.29-1.03 (4H, m).
MS (ESI) m/z: 493.0 (M+H)+.
Intermediate-13:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-2'H-spiro[piperidine-4,3'-quinolin]-1'(4'H)-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000033
　 The title compound is prepared in 61% yield by the similar manner to Step-1 and Step-2 of Intermediate-1 using Intermediate-B (80 mg, 0.20 mmol) and tert-butyl 2'-oxo-1',4'-dihydro-2'H-spiro[piperidine-4,3'-quinoline]-1-carboxylate (64 mg, 0.20 mmol) in place of Intermediate-A and tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
MS (ESI) m/z: 517.3 (M+H)+.
Intermediate-14:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide hydrochloride
Figure JPOXMLDOC01-appb-C000034
　 The title compound is prepared in 74% yield by the similar manner to Step-1 and Step-2 of Intermediate-1 using Intermediate-B (200 mg, 0.50 mmol) and tert-butyl 2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (180 mg, 0.66 mmol) in place of Intermediate-A and tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
1H-NMR (400 MHz, DMSO-d6) delta 8.83 (1H, d, J = 2.3 Hz), 8.64 (1H, d, J = 7.8 Hz), 8.13 (1H, d, J = 2.3 Hz), 7.77 (1H, d, J = 6.9 Hz), 7.32 (1H, td, J = 7.6, 1.2 Hz), 7.14 (1H, t, J = 54 Hz), 7.13 (1H, t, J = 7.2 Hz), 7.06 (1H, d, J = 7.6 Hz), 4.00 (2H, d, J = 7.8 Hz), 3.76-3.60 (3H, m), 3.51 (2H, d, J = 6.9 Hz), 1.90 (2H, br d, J = 10.5 Hz), 1.80-1.61 (3H, m), 1.28-1.05 (4H, m). A signal due to NH is not observed.
MS (ESI) m/z: 475.0 (M+H)+.
Intermediate-15:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide hydrochloride
Figure JPOXMLDOC01-appb-C000035
<Step-1>: tert-butyl 3-((2-bromo-4-fluorophenyl)carbamoyl)azetidine-1-carboxylate
To a solution of 2-bromo-4-fluoroaniline (1.50 g, 7.89 mmol), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (1.59 g, 7.89 mmol), and TEA (3.30 mL, 23.7 mmol) in DCM (20 mL) is added propylphosphonic anhydride solution 50% in EtOAc (9.29 mL, 15.8 mmol) at 0 oC. The mixture is stirred at rt for 30 min. The reaction mixture is diluted with saturated aqueous sodium bicarbonate, followed by extraction with DCM. The organic layer is dried over Na2SO4, filtered and concentrated to give 2.92 g (99% yield) of the title compound as a pale orange solid.
1H-NMR (400 MHz, CDCl3) delta 8.26 (1H, dd, J = 8.7, 5.9 Hz), 7.53 (1H, br s), 7.31 (1H, dd, J = 7.8, 2.7 Hz), 7.11-7.03 (1H, m), 4.28-4.13 (4H, m), 3.45-3.33 (1H, m), 1.45 (9H, s).
MS (ESI) m/z: 372.9 (M+H)+.
<Step-2>: tert-butyl 3-((2-bromo-4-fluorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate
A mixture of tert-butyl 3-((2-bromo-4-fluorophenyl)carbamoyl)azetidine-1-carboxylate (2.92 g, 7.82 mmol, Step-1 of Intermediate-15), 1-(chloromethyl)-4-methoxybenzene (2.45 g, 15.7 mmol), and cesium carbonate (5.10 g, 15.7 mmol) in DMSO (20 mL) is stirred at rt for 1 day. Then, the mixture is stirred at 80 oC for 6 hrs. The reaction mixture is diluted with water, followed by extraction with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography on silica-gel eluting with 0-50% EtOAc in n-hexane to give 3.86 g (quantitative yield) of the title compound as a yellow gum.
1H-NMR (400 MHz, CDCl3) delta 7.43 (1H, dd, J = 7.8, 3.2 Hz), 7.07 (2H, d, J = 8.7 Hz), 7.94-7.88 (1H, m), 6.79 (2H, d, J = 8.7 Hz), 6.59 (1H, dd, J = 8.7, 5.5 Hz), 5.56 (1H, d, J = 14.2 Hz), 4.35-4.22 (1H, m), 4.05-3.90 (1H, m), 3.94 (1H, d, J = 14.2 Hz), 3.79 (3H, s), 3.78-3.70 (1H, m), 3.62-3.52 (1H, m), 3.09-2.99 (1H, m), 1.41 (9H, s).
MS (ESI) m/z: 492.9 (M+H)+.
<Step-3>: tert-butyl 5'-fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate
A mixture of tert-butyl 3-((2-bromo-4-fluorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate (4.45 g, 9.02 mmol, Step-2 of Intermediate-15), PEPPSI (registered trademark)-IPr (306 mg, 0.451 mmol), and sodium tert-butoxide (1.73 g, 18.0 mmol) in toluene (50 mL) is stirred at 80 oC for 1 hr. The mixture is diluted with saturated aqueous ammonium chloride, followed by extraction with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography on silica-gel eluting with 0-35% EtOAc in n-hexane to give 862 mg (23% yield) of the title compound as a pale yellow gum.
1H-NMR (400 MHz, CDCl3) delta 7.30 (1H, dd, J = 7.8, 2.7 Hz), 7.20 (2H, d, J = 8.7 Hz), 6.91 (1H, td, J = 8.7, 2.7 Hz), 6.85 (2H, d, J = 8.7 Hz), 6.66 (1H, dd, J = 8.2, 4.1 Hz), 4.82 (2H, br s), 4.44 (2H, d, J = 8.2 Hz), 4.06 (2H, d, J = 8.2 Hz), 3.78 (3H, s), 1.50 (9H, s).
MS (ESI) m/z: 413.0 (M+H)+.
<Step-4>: tert-butyl 5'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate
A mixture of tert-butyl 5'-fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (862 mg, 2.09 mmol, Step-3 of Intermediate-15) and TfOH (0.74 mL, 8.36 mmol) in DCM (10 mL) is stirred at rt for 2 hrs. Then, to the reaction mixture is added TEA (2.33 mL, 16.7 mmol) and Boc2O (0.58 mL, 2.51 mmol) at 0 oC. The mixture is stirred at rt for 30 min. The mixture is diluted with saturated aqueous sodium bicarbonate, followed by extraction with DCM. The organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography on silica-gel eluting with 0-50% EtOAc in n-hexane to give 562 mg (92% yield) of the title compound as a yellow gum.
1H-NMR (400 MHz, CDCl3) delta 8.38 (1H, br s), 7.29 (1H, dd, J = 7.8, 2.7 Hz), 6.98 (1H, td, J = 9.1, 2.7 Hz), 6.85 (1H, dd, J = 8.7, 4.1 Hz), 4.39 (2H, d, J = 8.6 Hz), 4.06 (2H, d, J = 8.6 Hz), 1.50 (9H, s).
MS (ESI) m/z: 293.1 (M+H)+.
<Step-5>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide hydrochloride
The title compound is prepared in 90% yield (415 mg, pale orange solid) by the similar manner to Step-1 and Step-2 of Intermediate-1 using Intermediate-B (339 mg, 0.86 mmol) and tert-butyl 5'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (250 mg, 0.86 mmol, Step-4 of Intermediate-15) in place of Intermediate-A and tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
MS (ESI) m/z: 493.0 (M+H)+.
Intermediate-16:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((7'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide hydrochloride
Figure JPOXMLDOC01-appb-C000036
<Step-1>: tert-butyl 3-((2-bromo-6-fluorophenyl)carbamoyl)azetidine-1-carboxylate
The title compound is prepared in quantitative yield by the similar manner to Step-1 of Intermediate-15 using 2-bromo-6-fluoroaniline (1.00 g, 5.26 mmol) in place of 2-bromo-4-fluoroaniline.
MS (ESI) m/z: 373.0 (M+H)+.
<Step-2>: tert-butyl 3-((2-bromo-6-fluorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate
A mixture of tert-butyl 3-((2-bromo-6-fluorophenyl)carbamoyl)azetidine-1-carboxylate (1.96 g, 5.26 mmol, Step-1 of Intermediate-16), 1-(chloromethyl)-4-methoxybenzene (1.24 g, 7.89 mmol), and potassium carbonate (1.45 g, 10.52 mmol) in acetonitrile (5 mL) is stirred at 90 oC for 1 day. The reaction mixture is concentrated. The residue is diluted with water, followed by extraction with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography on silica-gel eluting with 0-25% EtOAc in n-hexane to give 520 mg (20% yield) of the title compound as a yellow gum.
MS (ESI) m/z: 493.0 (M+H)+.
<Step-3>: tert-butyl 7'-fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate
A mixture of tert-butyl 3-((2-bromo-6-fluorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate (520 mg, 1.05 mmol, Step-2 of Intermediate-16), PEPPSI (registered trademark)-IPr (36 mg, 0.053 mmol), and sodium tert-butoxide (203 mg, 2.11 mmol) in toluene (15 mL) is irradiated with microwave at 130 oC for 30 min. The mixture is diluted with saturated aqueous ammonium chloride, followed by extraction with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography on silica-gel eluting with 0-25% EtOAc in n-hexane to give 205 mg (47% yield) of the title compound as a pale yellow gum.
1H-NMR (400 MHz, CDCl3) delta 7.34 (1H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.7 Hz), 7.09-6.95 (2H, m), 6.84 (2H, d, J = 8.7 Hz), 4.97 (2H, s), 4.41 (2H, d, J = 8.2 Hz), 4.04 (2H, d, J = 8.2 Hz), 3.77 (3H, s), 1.49 (9H, s).
MS (ESI) m/z: 413.2 (M+H)+.
<Step-4>: tert-butyl 7'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate
The title compound is prepared in 86% yield by the similar manner to Step-4 of Intermediate-15 using tert-butyl 7'-fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (205 mg, 0.497 mmol, Step-3 of Intermediate-16) in place of tert-butyl 5'-fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate.
1H-NMR (400 MHz, CDCl3) delta 7.70 (1H, br s), 7.35 (1H, dd, J = 6.9, 1.4 Hz), 7.12-7.02 (2H, m), 4.40 (2H, d, J = 8.7 Hz), 4.07 (2H, d, J = 8.7 HZ), 1.49 (9H, s).
MS (ESI) m/z: 293.4 (M+H)+.
<Step-5>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((7'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide hydrochloride
The title compound is prepared in 74% (201 mg, pale orange gum) yield by the similar manner to Step-1 and Step-2 of Intermediate-1 using Intermediate-B (170 mg, 0.43 mmol) and tert-butyl 7'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (125 mg, 0.43 mmol, Step-4 of Intermediate-16) in place of Intermediate-A and tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
MS (ESI) m/z: 493.4 (M+H)+.
Intermediate-17:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((4'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide hydrochloride
Figure JPOXMLDOC01-appb-C000037
<Step-1>: tert-butyl 3-((2-bromo-3-fluorophenyl)carbamoyl)azetidine-1-carboxylate
To a solution of 2-bromo-3-fluoroaniline (1.00 g, 5.26 mmol), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (1.06 g, 5.26 mmol), and TEA (2.20 mL, 15.8 mmol) in DCM (20 mL) is added propylphosphonic anhydride solution 50% in EtOAc (6.19 mL, 10.5 mmol) at 0 oC. The mixture is stirred at rt for 30 min. The reaction mixture is diluted with saturated aqueous sodium bicarbonate, followed by extraction with DCM. The organic layer is dried over Na2SO4, filtered and concentrated to give 1.96 g (quantitative yield) of the title compound as a pale orange gum.
MS (ESI) m/z: 373.2 (M+H)+.
<Step-2>: tert-butyl 3-((2-bromo-3-fluorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate
A mixture of tert-butyl 3-((2-bromo-3-fluorophenyl)carbamoyl)azetidine-1-carboxylate (1.96 g, 5.26 mmol, Step-1 of Intermediate-17), 1-(chloromethyl)-4-methoxybenzene (989 mg, 6.31 mmol), and cesium carbonate (3.43 g, 10.5 mmol) in DMSO (10 mL) is stirred at rt for 5 hrs. The residue is diluted with water, followed by extraction with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography on silica-gel eluting with 0-25% EtOAc in n-hexane to give 1.92 g (74% yield) of the title compound as a pale orange gum.
1H-NMR (400 MHz, CDCl3) delta 7.21-7.10 (2H, m), 7.09 (2H, d, J = 8.7 Hz), 6.79 (2H, d, J = 8.7 Hz), 6.50-6.45 (1H, m), 5.54 (1H, d, J = 14.2 Hz), 4.35-4.23 (1H, m), 4.05-3.93 (1H, m), 4.00 (1H, d, J = 14.2 Hz), 3.78 (3H, s), 3.80-3.70 (1H, m), 3.63-3.52 (1H, m), 3.09-2.99 (1H, m), 1.40 (9H, s).
MS (ESI) m/z: 493.0 (M+H)+.
<Step-3>: tert-butyl 4'-fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate
A mixture of tert-butyl 3-((2-bromo-3-fluorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate (1.92 g, 3.89 mmol, Step-2 of Intermediate-17), PEPPSI (registered trademark)-IPr (132 mg, 0.195 mmol), and sodium tert-butoxide (748 mg, 7.78 mmol) in toluene (15 mL) is irradiated with microwave at 130 oC for 30 min. The mixture is diluted with saturated aqueous ammonium chloride, followed by extraction with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography on silica-gel eluting with 0-25% EtOAc in n-hexane to give 904 mg (56% yield) of the title compound as a pale yellow solid.
1H-NMR (400 MHz, CDCl3) delta 7.22 (2H, d, J = 8.7 Hz), 7.17 (1H, dd, J = 8.2, 5.5 Hz), 6.85 (2H, d, J = 8.7 Hz), 6.77 (1H, t, J = 8.7 Hz), 6.58 (1H, d, J = 7.8 Hz), 4.82 (2H, s), 4.36 (4H, s), 3.77 (3H, s), 1.49 (9H, s).
MS (ESI) m/z: 413.0 (M+H)+.
<Step-4>: tert-butyl 4'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate
A mixture of tert-butyl 4'-fluoro-1'-(4-methoxybenzyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (904 mg, 2.19 mmol, Step-3 of Intermediate-17) and TfOH (0.78 mL, 8.77 mmol) in DCM (20 mL) is stirred at rt for 2 hrs. Then, to the reaction mixture is added TEA (2.44 mL, 17.5 mmol) and Boc2O (0.61 mL, 2.63 mmol) at 0 oC. The mixture is stirred at rt for 30 min. The mixture is diluted with saturated aqueous sodium bicarbonate, followed by extraction with DCM. The organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography on silica-gel eluting with 0-50% EtOAc in n-hexane to give 599 mg (93% yield) of the title compound as a yellow gum.
1H-NMR (400 MHz, CDCl3) delta 8.24 (1H, br s), 7.27-7.21 (1H, m), 6.80 (1H, t, J = 8.7 Hz), 6.72 (1H, d, J = 7.8 Hz), 4.35 (2H, d, J = 8.2 Hz), 4.32 (2H, d, J = 8.2 Hz), 1.49 (9H,s).
MS (ESI) m/z: 293.4 (M+H)+.
<Step-5>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((4'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide hydrochloride
The title compound is prepared in quantitative yield (348 mg, pale orange gum) by the similar manner to Step-1 and Step-2 of Intermediate-1 using Intermediate-B (250 mg, 0.63 mmol) and tert-butyl 4'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (184 mg, 0.63 mmol, Step-4 of Intermediate-17) in place of Intermediate-A and tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
MS (ESI) m/z: 493.4 (M+H)+.
Intermediate-18:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide hydrochloride
Figure JPOXMLDOC01-appb-C000038
<Step-1>: tert-butyl 5'-methoxy-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate
The title compound is prepared in 43% yield (681 mg, pale yellow gum) by the similar manner to Step-1, Step-2, Step-3, and Step-4 of Intermediate-17 using 2-bromo-4-methoxyaniline (1.06 g, 5.26 mmol) in place of 2-bromo-3-fluoroaniline.
1H-NMR (400 MHz, CDCl3) delta 7.85 (1H, br s), 7.13 (1H, br s), 6.80-6.79 (2H, m), 4.39 (2H, d, J = 8.7 Hz), 4.06 (2H, d, J = 8.7 Hz), 3.83 (3H, s), 1.50 (9H, s).
MS (ESI) m/z: 305.4 (M+H)+.
<Step-2>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide hydrochloride
The title compound is prepared in quantitative yield (384 mg, pale orange gum) by the similar manner to Step-1 and Step-2 of Intermediate-1 using Intermediate-B (250 mg, 0.63 mmol) and tert-butyl 5'-methoxy-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (192 mg, 0.63 mmol, Step-1 of Intermediate-18) in place of Intermediate-A and tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
MS (ESI) m/z: 505.4 (M+H)+.
Intermediate-19:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methyl-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide hydrochloride
Figure JPOXMLDOC01-appb-C000039
<Step-1>: tert-butyl 5'-methyl-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate
The title compound is prepared in 58% yield (883 mg, pale yellow gum) by the similar manner to Step-1, Step-2, Step-3, and Step-4 of Intermediate-17 using 2-bromo-4-methylaniline (979 mg, 5.26 mmol) in place of 2-bromo-3-fluoroaniline.
1H-NMR (400 MHz, CDCl3) delta 7.95 (1H, br s), 7.36 (1H, br s), 7.07 (1H, br d, J = 7.8 Hz), 6.79 (1H, d, J = 7.8 Hz), 4.38 (2H, d, J = 8.7 Hz), 4.06 (2H, d, J = 8.7 Hz), 2.37 (3H, s), 1.50 (9H, s).
MS (ESI) m/z: 289.6 (M+H)+.
<Step-2>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methyl-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide hydrochloride
The title compound is prepared in 88% yield (292 mg, pale orange gum) by the similar manner to Step-1 and Step-2 of Intermediate-1 using Intermediate-B (250 mg, 0.63 mmol) and tert-butyl 5'-methyl-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (182 mg, 0.63 mmol, Step-1 of Intermediate-19) in place of Intermediate-A and tert-butyl 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.
MS (ESI) m/z: 489.4 (M+H)+.
Intermediate-20:
5-chloro-N-((1r,4r)-4-((5'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide
Figure JPOXMLDOC01-appb-C000040
<Step-1>: tert-butyl 1'-(((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl)-5'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate
A mixture of ((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl methanesulfonate (185 mg, 0.51 mmol, Intermediate-A), tert-butyl 5'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (150 mg, 0.51 mmol, Step-4 of Intermediate-15), and cesium carbonate (334 mg, 1.02 mmol) in DMSO (2 mL) is stirred at 80 oC for 1 day. After cooling to rt, the mixture is diluted with EtOAc and washed with water. The organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography on silica-gel eluting with 0-50% EtOAc in n-hexane to give 286 mg (quantitative yield) of the title compound as a colorless oil.
1H-NMR (400 MHz, CDCl3) delta 8.49 (1H, d, J = 2.3 Hz), 7.61 (1H, d, J = 2.7 Hz), 7.32 (1H, dd, J = 7.8, 2.7 Hz), 7.02 (1H, td, J = 8.7, 2.3 Hz), 6.75 (1H, dd, J = 8.7, 4.1 Hz), 5.56 (1H, d, J = 8.2 Hz), 4.38 (2H, d, J = 8.2 Hz), 4.04 (2H, d, J = 8.2 Hz), 3.99-3.87 (1H, m), 3.55 (2H, d, J = 6.9 Hz), 2.60 (3H, s), 2.20-2.10 (2H, m), 1.84-1.73 (3H, m), 1.59 (9H, s), 1.35-1.12 (4H, m).
MS (ESI) m/z: 557.2 (M+H)+.
<Step-2>: 5-chloro-N-((1r,4r)-4-((5'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide
To a solution of tert-butyl 1'-(((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl)-5'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (293 mg, 0.53 mmol, Step-1 of Intermediate-20) in DCM (3 mL) and MeOH (0.2 mL) is added TfOH (0.3 mL, 3.38 mmol) at 0 oC. The mixture is stirred at rt for 30 min. The mixture is diluted with saturated aqueous sodium bicarbonate, followed by extraction with DCM. The organic layer is dried over Na2SO4, filtered and concentrated to give 160 mg (67% yield) of the title compound as a yellow solid.
MS (ESI) m/z: 457.4 (M+H)+.
Intermediate-21:
5-chloro-N-((1r,4r)-4-((6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide
Figure JPOXMLDOC01-appb-C000041
The title compound is prepared in 65% yield (152 mg, pale yellow solid) by the similar manner to Step-1 and Step-2 of Intermediate-20 using tert-butyl 6'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (150 mg, 0.51 mmol) in place of tert-butyl 5'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate.
MS (ESI) m/z: 457.4 (M+H)+.
Intermediate-22:
5-chloro-2-methyl-N-((1r,4r)-4-((2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000042
The title compound is prepared in 43% yield (97 mg, pale yellow solid) by the similar manner to Step-1 and Step-2 of Intermediate-20 using tert-butyl 2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (141 mg, 0.51 mmol) in place of tert-butyl tert-butyl 5'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate.
MS (ESI) m/z: 439.4 (M+H)+.
Intermediate-23:
5-chloro-N-((1r,4r)-4-((4'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide
Figure JPOXMLDOC01-appb-C000043
<Step-1>: tert-butyl 1'-(((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl)-4'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate
The title compound is prepared in 90% yield (278 mg, pale yellow gum) by the similar manner to Step-1 of Intermediate-20 using tert-butyl 4'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (162 mg, 0.55 mmol, Step-4 of Intermediate-17) in place of tert-butyl 5'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate.
1H-NMR (400 MHz, CDCl3) delta 8.48 (1H, t, J = 2.3 Hz), 7.60 (1H, br s), 7.33-7.26 (1H, m), 6.82 (1H, t, J = 8.7 Hz), 6.64 (1H, d, J = 8.2 Hz), 5.67-5.56 (1H, m), 4.34 (2H, d, J = 7.8 Hz), 4.30 (2H, d, J = 7.8 Hz), 4.00-3.84 (1H, m), 3.56 (2H, d, J = 6.9 Hz), 2.60 (3H, s), 2.19-2.10 (2H, m), 1.83-1.75 (3H, m), 1.49 (9H, s), 1.35-1.12 (4H, m).
MS (ESI) m/z: 557.2 (M+H)+.
<Step-2>: 5-chloro-N-((1r,4r)-4-((4'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide
To a solution of tert-butyl 1'-(((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl)-4'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (278 mg, 0.50 mmol, Step-1 of Intermediate-23) in DCM (3 mL) and MeOH (0.2 mL) is added TfOH (0.1 mL, 1.13 mmol) at 0 oC. The mixture is stirred at rt for 30 min. The mixture is diluted with saturated aqueous sodium bicarbonate. The precipitate is collected and washed with diisopropyl ether to give 228 mg (quantitative yield) of the title compound as a yellow solid.
1H-NMR (400 MHz, DMSO-d6) delta 8.53 (1H, d, J = 2.7 Hz), 8.38 (1H, d, J = 7.8 Hz), 7.78 (1H, d, J = 2.3 Hz), 7.42 (1H, td, J = 8.2, 2.7 Hz), 7.05-6.95 (2H, m), 4.32 (2H, d, J = 11.4 Hz), 4.17 (2H, d, J = 11.4 Hz), 3.75-3.63 (1H, m), 3.53 (2H, d, J = 7.3 Hz), 2.46 (3H, s), 1.96-1.83 (2H, m), 1.80-1.58 (3H, m), 1.26-1.05 (4H, m). A signal due to NH is not observed.
MS (ESI) m/z: 457.2 (M+H)+.
Intermediate-24:
5-chloro-N-((1r,4r)-4-((5'-methoxy-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide
Figure JPOXMLDOC01-appb-C000044
The title compound is prepared in quantitative yield (280 mg, pale yellow solid) by the similar manner to Step-1 and Step-2 of Intermediate-23 using tert-butyl 5'-methoxy-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (169 mg, 0.55 mmol, Step-1 of Intermediate-18) in place of tert-butyl 4'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate.
1H-NMR (400 MHz, DMSO-d6) delta 8.54 (1H, d, J = 2.3 Hz), 8.37 (1H, d, J = 7.8 Hz), 7.78 (1H, d, J = 2.7 Hz), 7.54 (1H, d, J = 2.7 Hz), 7.03 (1H, d, J = 8.7 Hz), 6.93 (1H, dd, J = 8.7, 2.3 Hz), 4.30-4.13 (4H, m), 3.80 (3H, s), 3.73-3.60 (1H, m), 3.50 (2H, d, J = 6.9 Hz), 2.33 (3H, s), 1.94-1.83 (2H, m), 1.78-1.60 (3H, m), 1.25-1.05 (4H, m). A signal due to NH is not observed.
MS (ESI) m/z: 469.3 (M+H)+.
Intermediate-25:
5-chloro-N-((1r,4r)-4-((6'-methoxy-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide
Figure JPOXMLDOC01-appb-C000045
<Step-1>: tert-butyl 6'-methoxy-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate
The title compound is prepared in 16% yield (270 mg, pale yellow solid) by the similar manner to Step-1, Step-2, Step-3, and Step-4 of Intermediate-17 using 2-bromo-5-methoxyaniline (1.00 g, 4.97 mmol) in place of 2-bromo-3-fluoroaniline.
1H-NMR (400 MHz, CDCl3) delta 8.20-7.91 (1H, m), 7.41 (1H, d, J = 8.2 Hz), 6.63 (1H, dd, J = 8.2, 2.3 Hz), 6.48 (1H, d, J = 2.3 Hz), 4.36 (2H, d, J = 8.2 Hz), 4.04 (2H, d, J = 8.2 Hz), 3.81 (3H, s), 1.49 (9H, s).
MS (ESI) m/z: 305.4 (M+H)+.
<Step-2>: 5-chloro-N-((1r,4r)-4-((6'-methoxy-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide
The title compound is prepared in 79% yield (154 mg, pale yellow solid) by the similar manner to Step-1 and Step-2 of Intermediate-20 using tert-butyl 6'-methoxy-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (127 mg, 0.42 mmol, Step-1 of Intermediate-25) in place of tert-butyl 5'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate.
1H-NMR (400 MHz, CDCl3) delta 8.48 (1H, d, J = 2.3 Hz), 7.67 (1H, d, J = 8.2 Hz), 7.60 (1H, d, J = 2.3 Hz), 6.64 (1H, dd, J = 8.2, 2.3 Hz), 6.39 (1H, d, J = 2.3 Hz), 5.59 (1H, br d, J = 7.3 Hz), 4.21 (2H, d, J = 8.2 Hz), 4.00-3.88 (1H, m), 3.88 (3H, s), 3.72 (2H, d, J = 8.2 Hz), 3.53 (2H, d, J = 6.9 Hz), 2.60 (3H, s), 2.20-2.05 (2H, m), 1.93-1.65 (3H, m), 1.39-1.10 (4H, m). A signal due to NH is not observed.
MS (ESI) m/z: 469.4 (M+H)+.
Intermediate-26:
5-chloro-2-methyl-N-((1r,4r)-4-((6'-methyl-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000046
<Step-1>: tert-butyl 6'-methyl-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate
The title compound is prepared in 21% yield (380 mg, pale yellow gum) by the similar manner to Step-1, Step-2, Step-3, and Step-4 of Intermediate-17 using 2-bromo-5-methylaniline (925 mg, 4.97 mmol) in place of 2-bromo-3-fluoroaniline.
1H-NMR (400 MHz, CDCl3) delta 7.99 (1H, br s), 7.40 (1H, d, J = 7.3 Hz), 6.93 (1H, br d, J = 7.3 Hz), 6.74 (1H, s), 4.37 (2H, d, J = 8.7 Hz), 4.05 (2H, d, J = 8.7 Hz), 2.36 (3H, s), 1.49 (9H, s).
MS (ESI) m/z: 289.4 (M+H)+.
<Step-2>: 5-chloro-2-methyl-N-((1r,4r)-4-((6'-methyl-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
The title compound is prepared in 97% yield (183 mg, pale yellow solid) by the similar manner to Step-1 and Step-2 of Intermediate-20 using tert-butyl 6'-methyl-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (120 mg, 0.42 mmol, Step-1 of Intermediate-26) in place of tert-butyl 5'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate.
1H-NMR (400 MHz, CDCl3) delta 8.48 (1H, d, J = 2.3 Hz), 7.66 (1H, d, J = 7.3 Hz), 7.60 (1H, d, J = 2.3 Hz), 6.96 (1H, d, J = 7.3 Hz), 6.62 (1H, s), 5.60 (1H, br d, J = 7.8 Hz), 4.21 (2H, d, J = 8.2 Hz), 4.00-3.87 (1H, m), 3.72 (2H, d, J = 8.2 Hz), 3.54 (2H, d, J = 6.9 Hz), 2.60 (3H, s), 2.40 (3H, s), 2.20-2.05 (2H, m), 1.95-1.65 (3H, m), 1.37-1.11 (4H, m). A signal due to NH is not observed.
MS (ESI) m/z: 453.4 (M+H)+.
Intermediate-27:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methoxy-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000047
The title compound is prepared in 73% yield (163 mg, pale yellow solid) by the similar manner to Step-1 and Step-2 of Intermediate-20 using tert-butyl 6'-methoxy-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (134 mg, 0.44 mmol, Step-1 of Intermediate-25) and Intermediate-B (175 mg, 0.44 mmol) in place of tert-butyl 5'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate and Intermediate-A.
1H-NMR (400 MHz, CDCl3) delta 8.64 (1H, d, J = 2.3 Hz), 7.92 (1H, d, J = 2.3 Hz), 7.67 (1H, d, J = 8.2 H), 6.85 (1H, t, J = 54.4 Hz), 6.64 (1H, dd, J = 8.2, 2.3 Hz), 6.38 (1H, d, J = 2.3 Hz), 5.89 (1H, br s), 4.21 (2H, d, J = 7.8 Hz), 4.00-3.89 (1H, m), 3.88 (3H, s), 3.72 (2H, d, J = 7.8 Hz), 3.52 (2H, d, J = 6.9 Hz), 2.20-2.07 (2H, m), 1.89-1.64 (3H, m), 1.38-1.10 (4H, m). A signal due to NH is not observed.
MS (ESI) m/z: 505.3 (M+H)+.
Intermediate-28:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methyl-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000048
The title compound is prepared in 85% yield (184 mg, pale yellow solid) by the similar manner to Step-1 and Step-2 of Intermediate-20 using tert-butyl 6'-methyl-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate (127 mg, 0.44 mmol, Step-1 of Intermediate-26) and Intermediate-B (175 mg, 0.44 mmol) in place of tert-butyl 5'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate and Intermediate-A.
1H-NMR (400 MHz, CDCl3) delta 8.64 (1H, d, J = 2.3 Hz), 7.92 (1H, d, J = 2.3 Hz), 7.66 (1H, d, J = 7.8 Hz), 6.96 (1H, d, J = 8.2 Hz), 6.85 (1H, t, J = 54.9 Hz), 6.62 (1H, s), 5.92 (1H, br d, J = 7.8 Hz), 4.21 (2H, d, J = 7.8 Hz), 4.01-3.88 (1H, m), 3.73 (2H, d, J = 7.8 Hz), 3.54 (2H, d, J = 6.9 Hz), 2.40 (3H, s), 2.18-2.06 (2H, m), 1.95-1.72 (3H, m), 1.38-1.11 (4H, m). A signal due to NH is not observed.
MS (ESI) m/z: 489.3 (M+H)+.
Example synthesis part
Each chemical structure of Example synthesis part is described as a free-base.
Representative procedure for Method A1
The following preparation of Example 1 represents the Method A1
Example 1:
1-(((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl)-N,N-dimethyl-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxamide
Figure JPOXMLDOC01-appb-C000049
　 To a stirred solution of 5-chloro-2-methyl-N-((1r,4r)-4-((2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide dihydrochloride (20 mg, 0.037 mmol, Intermediate-1) and N,N-diisopropylethylamine (0.026 mL, 0.15 mmol) in DMF (0.5 mL) is added dimethylcarbamic chloride (8.0 mg, 0.074 mmol) at room temperature. The mixture is stirred at room temperature for 1 hr. The mixture is diluted with water. The mixture is extracted with EtOAc. The organic layer is dried over sodium sulfate, filtered and concentrated. The residue is purified by column chromatography on amino-functional silica gel eluting with EtOAc and then purified by preparative LC-MS to give 11.2 mg (56% yield) of the title compound.
Representative procedure for Method B1
The following preparation of Example 3 represents the Method B1
Example 3:
5-chloro-N-((1r,4r)-4-((1'-(3-methoxyphenyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide
Figure JPOXMLDOC01-appb-C000050
　 A mixture of 5-chloro-2-methyl-N-((1r,4r)-4-((2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide dihydrochloride (20 mg, 0.037 mmol, Intermediate-1), (3-methoxyphenyl)boronic acid (11 mg, 0.074 mmol), copper(II) acetate (20 mg, 0.11 mmol), MS 4A (30 mg), and triethylamine (0.052 mL, 0.37 mmol) in dichloromethane (1 mL) is stirred at room temperature for 16 hrs. The mixture is filtered through column chromatography on amino-functional silica gel eluting with EtOAc, and the filtrate is concentrated. The residue is purified by a strong anion exchange cartridge (ISOLUTE (registered trademark) SCX-2, 1 g/6 mL, Biotage), and then purified by preparative LC-MS to give 5.5 mg (26% yield) of the title compound.
Representative procedure for Method C1
The following preparation of Example 4 represents the Method C1
Example 4:
5-chloro-N-((1r,4r)-4-((1'-(5-chloropyridin-2-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide
Figure JPOXMLDOC01-appb-C000051
　 A mixture of 5-chloro-2-methyl-N-((1r,4r)-4-((2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide dihydrochloride (20 mg, 0.037 mmol, Intermediate-1), 5-chloro-2-fluoropyridine (49 mg, 0.37 mmol), and potassium carbonate (51 mg, 0.37 mmol) in DMF (1 mL) is stirred at 120 oC for 3 hrs. After cooling to room temperature, the mixture is diluted with water. The mixture is extracted with EtOAc. The organic layer is dried over sodium sulfate, filtered and concentrated. The residue is purified by column chromatography on amino-functional silica gel eluting with EtOAc, a strong anion exchange cartridge (ISOLUTE (registered trademark) SCX-2, 1 g/6 mL, Biotage), and then purified by preparative LC-MS to give 4.1 mg (19% yield) of the title compound.
Representative procedure for Method D1
The following preparation of Example 10 represents the Method D1
Example 10:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1'-(2-methoxyacetyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000052
　 To a mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide (25 mg, 0.046 mmol, Intermediate-2), 2-methoxyacetic acid (6.6 mg, 0.074 mmol), and DIEA (0.04 mL, 0.23 mmol) in DMF (1 mL) is added HATU (31 mg, 0.083 mmol) at rt. The mixture is stirred at ambient temperature overnight. The mixture is added aqueous NaHCO3 and water, extracted with EtOAc. The organic layer is dried over sodium sulfate, filtered and concentrated. The residue is purified by preparative LC-MS to give 8.6 mg (33% yield) of the title compound.
Representative procedure for Method E1
The following preparation of Example 23 represents the Method E1
Example 23:
5-chloro-2-methyl-N-((1r,4r)-4-((2-oxo-1'-(piperidine-1-carbonyl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000053
　 To a mixture of 5-chloro-2-methyl-N-((1r,4r)-4-((2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide dihydrochloride (15 mg, 0.028 mmol, Intermediate-1) and DIEA (0.024 ml, 0.139 mmol) in acetonitrile (1 mL) is added 4-nitrophenyl carbonochloridate (8.4 mg, 0.042 mmol). The mixture is stirred at ambient temperature for 15 min (The color of the reaction mixture is changed from colorless to yellow). To the mixture is added piperidine (7.1 mg, 0.083 mmol). The mixture is stirred at 110oC for 5 hrs. The mixture is added aqueous NaHCO3 and water, extracted with EtOAc. The organic layer is dried over sodium sulfate, filtered and concentrated. The residue is purified by preparative LC-MS to give 7.4 mg (46% yield) of the title compound.
Representative procedure for Method B2
The following preparation of Example 24 represents the Method B2
Example 24:
5-chloro-2-methyl-N-((1r,4r)-4-((1'-(1-methyl-1H-pyrazol-3-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000054
A mixture of 5-chloro-2-methyl-N-((1r,4r)-4-((2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide dihydrochloride (15 mg, 0.028 mmol, Intermediate-1), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.8 mg, 0.042 mmol), copper(II) acetate (10 mg, 0.056 mmol), and triethylamine (0.019 mL, 0.14 mmol) in acetonitrile (1 mL) is stirred at 80oC for 12 hrs. After concentrated, the mixture is filtered through column chromatography on amino-functional silica gel eluting with 20% MeOH in EtOAc, and the filtrate is concentrated. The residue is purified by preparative LC-MS to give 2.4 mg (16% yield) of the title compound.
Representative procedure for Method F1
The following preparation of Example 104 represents the Method F1
Example 104:
5-chloro-N-((1r,4r)-4-((1-(cyclopropylmethyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000055
　 To a mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (10 mg, 0.019 mmol, Intermediate-12), cyclopropanecarbaldehyde (6.6 mg, 0.094 mmol), and AcOH (0.1 mL) in DMF (1 mL) is added sodium triacetoxyborohydride (20 mg, 0.094 mmol). The mixture is stirred at ambient temperature for 3 hrs. The mixture is added aqueous NaHCO3 and water, extracted with EtOAc. The organic layer is dried over sodium sulfate, filtered and concentrated. The residue is purified by preparative LC-MS to give 3.7 mg (37% yield) of the title compound.
Representative procedure for Method G1
The following preparation of Example 107 represents the Method G1
Example 107:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazol-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000056
A mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (15 mg, 0.029 mmol, Intermediate-14), 2-bromothiazole (9.6 mg, 0.059 mmol), XPhos Pd G3 (5.0 mg, 20 mol%), and sodium tert-butoxide (7.5 mg, 0.078 mmol) in 1,4-dioxane (1 mL) is stirred at 110oC overnight. The mixture is added aqueous NH4Cl and water, extracted with EtOAc. The organic layer is dried over sodium sulfate, filtered and concentrated. The residue is purified by preparative LC-MS to give 1.5 mg (9% yield) of the title compound.
Example 120:
N-((1r,4r)-4-((1-(3-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000057
<Step-1>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
A mixture of Intermediate-14 (150 mg, 0.29 mmol), 2-fluoro-3-nitropyridine (63 mg, 0.44 mmol), and potassium carbonate (122 mg, 0.88 mmol) in DMF (1 mL) is stirred at 90 oC for 4 hrs. The mixture is added to water, extracted with EtOAc and passed through amino-functional silica gel. The solvent is removed under vacuum. The residue is purified by column chromatography on silica-gel eluting with 10-100% EtOAc in n-hexane to give 104 mg (59% yield) of the title compound as a solid.
MS (ESI) m/z: 596.9 (M+H)+.
<Step-2>: N-((1r,4r)-4-((1-(3-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
A mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (104 mg, 0.017 mmol, Step-1 of Example 120) and SnCl2 (330 mg, 1.7 mmol) in MeOH (3 mL) is stirred at 60oC for 6 hrs. The mixture is added to 2 M aqueous NaOH, followed by extraction with EtOAc. The organic layer is dried over sodium sulfate, filtered and concentrated. The crude product is purified by a strong anion exchange cartridge (ISOLUTE (registered trademark) SCX-2, 1 g/6 mL, Biotage) to give 83 mg (84% yield) of the title compound as a solid.
Example 121:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-(dimethylamino)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000058
To a mixture of N-((1r,4r)-4-((1-(3-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide (15 mg, 0.026 mmol, Example 120), formaldehyde (4 mg, 0.13 mmol), and AcOH (0.1 mL) in DMF (1 mL) is added sodium triacetoxyborohydride (28 mg, 0.13 mmol). The mixture is stirred at rt for 4 hrs. The mixture is diluted with saturated aqueous sodium bicarbonate, followed by extraction with EtOAc. The organic layer is passed through amino-functional silica gel. The solvent is removed. The crude product is purified by preparative LC-MS to give 6.2 mg (39% yield) of the title compound.
Representative procedure for Method G2
The following preparation of Example 122 represents the Method G2
Example 122:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazol-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000059
A mixture of Intermediate-14 (20 mg, 0.039 mmol), 4-bromothiazole (13 mg, 0.078 mmol), XPhos Pd G3 (6.6 mg, 0.0078 mmol), and sodium tert-butoxide (7.5 mg, 0.078 mmol) in 1,4-dioxane (1 mL) is stirred at 110oC overnight. The mixture is diluted with saturated aqueous ammonium chloride, followed by extraction with EtOAc. The organic layer is concentrated. The residue is purified by preparative LC-MS to give 2.9 mg (13% yield) of the title compound.
Example 125:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-hydroxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000060
A mixture of Intermediate-14 (20 mg, 0.039 mmol), 2-bromo-3-(methoxymethoxy)pyridine (15 mg, 0.070 mmol), XPhos Pd G3 (7 mg, 0.0078 mmol), and sodium tert-butoxide (7.5 mg, 0.078 mmol) in 1,4-dioxane (1 mL) is stirred at 110oC overnight. The mixture is diluted with saturated aqueous ammonium chloride, followed by extraction with EtOAc. The organic layer is passed through amino-functional silica gel and concentrated. The residue and 4 M HCl in 1,4-dioxane (1 mL) are stirred at rt for 1 hr. The mixture is concentrated. The residue is purified by preparative LC-MS to give 3.4 mg (15% yield) of the title compound.
Representative procedure for Method H1
The following preparation of Example 126 represents the Method H1
Example 126:
N-((1r,4r)-4-((1-(3-amino-6-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000061
<Step-1>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methyl-3-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
A mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (20 mg, 0.039 mmol, Intermediate-14), 2-chloro-6-methyl-3-nitropyridine (8.8 mg, 0.051 mmol), and potassium carbonate (16 mg, 0.12 mmol) in DMF (0.5 mL) is stirred at 80 oC overnight. After cooling to rt, the mixture is diluted with saturated aqueous ammonium chloride. The mixture is extracted with EtOAc and concentrated. The residue is purified by column chromatography on silica-gel eluting with 8-100% EtOAc in n-hexane to give 10 mg (42% yield) of the title compound as a brown solid.
1H-NMR (400 MHz, CDCl3) delta 8.64 (1H, d, J = 2.3 Hz), 8.18 (1H, d, J = 8.2 Hz), 7.92 (1H, d, J = 2.3 Hz), 7.67 (1H, d, J = 7.3 Hz), 7.34 (1H, td, J = 7.8, 0.9 Hz), 7.17 (1H, t, J = 7.5 Hz), 6.98-6.71 (2H, m), 6.64 (1H, d, J = 8.2 Hz), 5.90 (1H, d, J = 7.8 Hz), 4.50 (2H, d, J = 9.1 Hz), 4.43 (2H, d, J = 9.1 Hz), 3.98-3.92 (1H, m), 3.58 (2H, d, J = 6.9 Hz), 2.49 (3H, s), 2.15-2.13 (2H, m), 1.82-1.79 (3H, m), 1.31-1.10 (4H, m).
MS (ESI) m/z: 611.2 (M+H)+.
<Step-2>: N-((1r,4r)-4-((1-(3-amino-6-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
A mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methyl-3-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (10 mg, 0.017 mmol, Step-1 of Example 126) and tin(II) chloride anhydrous (28 mg, 0.15 mmol) in EtOH/1,2-dichloroethane (1:1, 1 mL) is stirred at 80oC overnight. The residue is purified by column chromatography on amino-functional silica gel eluting with MeOH and then purified by preparative LC-MS to give 3.5 mg (35% yield) of the title compound.
MS (ESI) m/z: 581.2 (M+H)+.
Example 128:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-(methyl-l2-azaneyl)pyrazin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000062
<Step-1>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-fluoropyrazin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
The title compound is prepared in 48% yield (25 mg, yellow solid) by the similar manner to Step-1 of Example 126 using 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (46 mg, 0.087 mmol, Intermediate-12) and 2,3-difluoropyrazine (13 mg, 0.11 mmol) in place of Intermediate-14 and 2-chloro-6-methyl-3-nitropyridine.
1H-NMR (400 MHz, CDCl3) delta 8.64 (1H, d, J = 2.3 Hz), 7.97 (1H, dd, J = 4.4, 2.6 Hz), 7.93 (1H, d, J = 2.3 Hz), 7.58 (1H, dd, J = 8.7, 5.0 Hz), 7.49 (1H, t, J = 2.6 Hz), 6.84 (1H, t, J = 54.0 Hz), 6.87-6.82 (1H, m), 6.60 (1H, dd, J = 8.7, 2.2 Hz), 5.87 (1H, d, J = 7.8 Hz), 4.64 (2H, dd, J = 8.7, 1.4 Hz), 4.33 (2H, dd, J = 8.7, 1.4 Hz), 3.98-3.90 (1H, m), 3.57 (2H, d, J = 6.9 Hz), 2.20-2.13 (2H, m), 1.87-1.74 (3H, m), 1.33-1.17 (4H, m).
MS (ESI) m/z: 589.1 (M+H)+.
<Step-2>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-(methyl-l2-azaneyl)pyrazin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
A mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-fluoropyrazin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (12 mg, 0.020 mmol, Step-1 of Example 128), methylamine hydrochloride (6.9 mg, 0.10 mmol), and DIEA (0.018 mL, 0.102 mmol) in NMP (0.5 mL) is stirred at 220 oC for 35 min under microwave irradiation. The mixture is poured into water, extracted with EtOAc and concentrated. The residue is purified by a strong anion exchange cartridge (ISOLUTE (registered trademark) SCX-2, 1 g/6 mL, Biotage) and then purified by preparative LC-MS to give 3.3 mg (28% yield) of the title compound.
Representative procedure for Method G3
The following preparation of Example 130 represents the Method G3
Example 130:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(4-fluorophenyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000063
A mixture of Intermediate-14 (20 mg, 0.039 mmol), 1-bromo-4-fluorobenzene (9 mg, 0.051 mmol), XPhos Pd G3 (3 mg, 0.0039 mmol), and sodium tert-butoxide (7.5 mg, 0.078 mmol) in 1,4-dioxane (2 mL) is stirred at 130oC for 12 hrs under nitrogen atmosphere. The mixture is diluted with saturated aqueous ammonium chloride, followed by extraction with EtOAc. The organic layer is dried over sodium sulfate, filtered and concentrated. The residue is purified by preparative LC-MS to give 4.0 mg (18% yield) of the title compound.
Representative procedure for Method B3
The following preparation of Example 136 represents the Method B3
Example 136:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000064
A mixture of Intermediate-14 (20 mg, 0.039 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (16 mg, 0.078 mmol), copper(II) acetate (14 mg, 0.078 mmol), and triethylamine (20 mg, 0.20 mmol) in acetonitrile (1 mL) is stirred at rt for 1 day under oxygen atmosphere. The mixture is diluted with aqueous ammonia, followed by extraction with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by a strong anion exchange cartridge (ISOLUTE (registered trademark) SCX-2, 1 g/6 mL, Biotage). The solvent is removed by flowing nitrogen gas, the crude product is purified by preparative LC-MS to give 1.6 mg (7% yield) of the title compound.
Representative procedure for Method I1
The following preparation of Example 138 represents the Method I1
Example 138:
N-((1r,4r)-4-((1-(4-aminopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000065
<Step-1>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(4-nitropyridin-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
A mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (20 mg, 0.038 mmol, Intermediate-12), 3-bromo-4-nitropyridine (15 mg, 0.076 mmol), XPhos Pd G3 (3.2 mg, 10 mol%), and sodium tert-butoxide (11 mg, 0.11 mmol) in 1,4-dioxane (1 mL) is stirred at 130oC for 16 hrs. The mixture is added with celite and concentrated. The solid is purified by column chromatography on silica-gel eluting with 4-100% EtOAc in n-hexane to give 9.0 mg (39% yield) of the title compound as a brown gum.
MS (ESI) m/z: 615.1 (M+H)+.
<Step-2>: N-((1r,4r)-4-((1-(4-aminopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
A mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(4-nitropyridin-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (9.0 mg, 0.015 mmol, Step-1 of Example 138), iron (3.3 mg, 0.060 mmol), and ammonium chloride (4.7 mg, 0.088 mmol) in MeOH/1,2-dichloroethane/water (1:1:1, 1.5 mL) is stirred at 60oC overnight. After concentrated, the mixture is purified by a strong anion exchange cartridge (ISOLUTE (registered trademark) SCX-2, 1 g/6 mL, Biotage) and then purified by preparative LC-MS to give 1.6 mg (18% yield) of the title compound.
Representative procedure for Method F2
The following preparation of Example 139 represents the Method F2
Example 139:
N-((1r,4r)-4-((1-benzyl-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000066
To a mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide hydrochloride (17 mg, 0.033 mmol, Intermediate-14) and benzaldehyde (7 mg, 0.066 mmol) in DCM (3 mL) is added sodium triacetoxyborohydride (28 mg, 0.133 mmol) at rt. The mixture is stirred at rt for 1 hr. The mixture is diluted with saturated aqueous sodium bicarbonate, followed by extraction with DCM. The organic layer is dried over sodium sulfate, filtered and concentrated. The residue is purified by a strong anion exchange cartridge (ISOLUTE (registered trademark) SCX-2, 1 g/6 mL, Biotage), and then purified by preparative LC-MS to give 7.2 mg (38% yield) of the title compound.
Example 154:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-(2-hydroxyethoxy)pyrazin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000067
<Step-1>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyrazin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
A mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-fluoropyrazin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (17 mg, 0.029 mmol, Step-1 of Example 128), 2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (0.0059 mL, 0.043 mmol), and potassium tert-butoxide (4.9 mg, 0.043 mmol) in THF (0.5 mL) is stirred overnight at 60 oC. The mixture is added with saturated aqueous ammonium chloride, extracted with EtOAc and concentrated. The residue is purified by column chromatography on silica-gel eluting with 24-100% EtOAc in n-hexane to give 19 mg (93% yield) of the title compound as a brown gum.
MS (ESI) m/z: 714.9 (M+H)+.
<Step-2>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-(2-hydroxyethoxy)pyrazin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
A solution of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyrazin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (19 mg, 0.027 mmol, Step-1 of Example 154) in TFA (0.5 mL) is stirred at rt for 1 hr. The mixture is concentrated. The residue is purified by preparative LC-MS to give 3.8 mg (22% yield) of the title compound.
Example 159:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(dimethylamino)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000068
<Step-1>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
A mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (70 mg, 0.13 mmol, Intermediate-12), 2-fluoro-5-nitropyridine (28 mg, 0.20 mmol), and potassium carbonate (55 mg, 0.40 mmol) in DMSO (0.5 mL) is stirred at 60 oC for 1 hr. After cooling to rt, the mixture is diluted with saturated aqueous ammonium chloride. The mixture is extracted with EtOAc and concentrated. The residue is purified by column chromatography on silica-gel eluting with 8-100% EtOAc in n-hexane to give 53 mg (66% yield) of the title compound as a brown solid.
1H-NMR (400 MHz, CDCl3) delta 9.10 (1H, d, J = 2.7 Hz), 8.65 (1H, d, J = 2.3 Hz), 8.28 (1H, dd, J = 9.0, 2.7 Hz), 7.94 (1H, d, J = 2.3 Hz), 7.53-7.49 (1H, m), 6.87-6.82 (1 H, m), 6.84 (1H, t, J = 54 Hz), 6.63 (1H, dd, J = 9.0, 2.2 Hz), 6.33 (1H, d, J = 9.0 Hz), 5.86 (1H, d, J = 6.9 Hz), 4.59 (2H, d, J = 8.7 Hz), 4.33 (2H, d, J = 8.7 Hz), 4.00-3.89 (1H, m), 3.58 (2H, d, J = 6.4 Hz), 2.18-2.15 (2H, m), 1.83-1.78 (3H, m), 1.30-1.20 (4H, m).
MS (ESI) m/z: 614.9 (M+H)+.
<Step-2>: N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
A mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (53 mg, 0.087 mmol, Step-1 of Example 159) and tin(II) chloride anhydrous (150 mg, 0.79 mmol) in MeOH/1,2-dichloroethane (1:1, 1 mL) is stirred at 60oC overnight. The residue is purified by column chromatography on amino-functional silica gel eluting with MeOH to give 48 mg (94% yield) of the title compound as a brown gum.
MS (ESI) m/z: 585.2 (M+H)+.
<Step-3>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(dimethylamino)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
To a mixture of N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide (15 mg, 0.026 mmol, Step-2 of Example 159), paraformaldehyde (3.9 mg, 0.13 mmol), and AcOH (0.1 mL) in DMF (0.5 mL) is added sodium triacetoxyborohydride (27 mg, 0.13 mmol). The reaction mixture is stirred at rt overnight. The reaction mixture is purified by a strong anion exchange cartridge (ISOLUTE (registered trademark) SCX-2, 1 g/6 mL, Biotage) and then purified by preparative LC-MS to give 5.4 mg (34% yield) of the title compound.
Example 160:
N-((1r,4r)-4-((1-(5-acetamidopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000069
A mixture of N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide (15 mg, 0.026 mmol, Step-2 of Example 159), acetyl chloride (0.0055 mL, 0.077 mmol), and DIEA (0.022 mL, 0.13 mmol) in DMF (0.5 mL) is stirred at rt for 1 hr. The mixture is added with water, extracted with EtOAc and concentrated. The residue is purified by a strong anion exchange cartridge (ISOLUTE (registered trademark) SCX-2, 1 g/6 mL, Biotage) and then purified by preparative LC-MS to give 3.2 mg (20% yield) of the title compound.
Representative procedure for Method H2
The following preparation of Example 161 represents the Method H2
Example 161:
N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000070
<Step-1>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
A mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (20 mg, 0.039 mmol, Intermediate-14), 2-fluoro-5-nitropyridine (7.2 mg, 0.051 mmol), and potassium carbonate (16 mg, 0.12 mmol) in DMSO (0.5 mL) is stirred at 60 oC overnight. After cooling to rt, the mixture is diluted with saturated aqueous ammonium chloride. The mixture is extracted with EtOAc and concentrated. The residue is purified by column chromatography on silica-gel eluting with 8-100% EtOAc in n-hexane to give 17 mg (72% yield) of the title compound as a brown solid.
1H-NMR (400 MHz, CDCl3) delta 9.10 (1H, d, J = 2.3 Hz), 8.65 (1H, d, J = 2.3 Hz), 8.27 (1H, dd, J = 9.1, 2.3 Hz), 7.93 (1H, d, J = 2.3 Hz), 7.58 (1H, d, J = 7.5 Hz), 7.37 (1H, td, J = 7.8, 1.4 Hz), 7.17 (1H, t, J = 7.5 Hz), 6.89 (1H, d, J = 7.8 Hz), 6.84 (1H, t, J = 55.0 Hz), 6.34 (1H, d, J = 9.1 Hz), 5.86 (1H, d, J = 8.2 Hz), 4.60 (2H, d, J = 8.9 Hz), 4.36 (2H, d, J = 8.9 Hz), 3.96-3.91 (1H, m), 3.61 (2H, d, J = 6.9 Hz), 2.17-2.14 (2H, m), 1.84-1.81 (3H, m), 1.31-1.17 (4H, m).
MS (ESI) m/z: 596.9 (M+H)+.
<Step-2>: N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
A mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (17 mg, 0.028 mmol, Step-1 of Example 161) and tin(II) chloride anhydrous (48 mg, 0.25 mmol) in EtOH/1,2-dichloroethane (1:1, 1 mL) is stirred at 60oC overnight. The residue is purified by column chromatography on amino-functional silica gel eluting with MeOH and then purified by preparative LC-MS to give 2.9 mg (18% yield) of the title compound.
MS (ESI) m/z: 567.2 (M+H)+.
Representative procedure for Method C2
The following preparation of Example 177 represents the Method C2
Example 177:
5-chloro-N-((1r,4r)-4-((1-(3-cyanopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000071
A mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (50 mg, 0.095 mmol, Intermediate-12), 2-chloronicotinonitrile (20 mg, 0.14 mmol), and potassium carbonate (40 mg, 0.28 mmol) in DMSO (0.5 mL) is stirred at 60 oC overnight. After cooling to rt, the mixture is diluted with saturated aqueous ammonium chloride. The mixture is extracted with EtOAc and concentrated. The residue is purified by preparative LC-MS to give 1.7 mg (3% yield) of the title compound.
Example 180:
N-((1r,4r)-4-((1-(5-carbamoylpyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000072
<Step-1>: methyl 6-(1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1-yl)nicotinate
The title compound is prepared in 40% yield (48 mg, brown gum) by the similar manner to Step-1 of Example 138 using methyl 6-bromonicotinate (82 mg, 0.38 mmol) in place of 3-bromo-4-nitropyridine.
MS (ESI) m/z: 627.9 (M+H)+.
<Step-2>: 6-(1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1-yl)nicotinic acid
A solution of methyl 6-(1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1-yl)nicotinate (48 mg, 0.076 mmol, Step-1 of Example 180) in EtOH (0.5 mL) is added with 2 M aqueous NaOH (0.5 mL) and stirred for 1 hr at 60oC. After roughly concentrated, the reaction mixture is added with 2 M aqueous HCl and stirred for 30 minutes. The reaction mixture is added with NaCl, extracted with THF, dried over MgSO4, filtered and concentrated to obtain as a crude solid (54 mg, brown solid). The title compound is used for next step without further purification.
MS (ESI) m/z: 614.9 (M+H)+.
<Step-3>: N-((1r,4r)-4-((1-(5-carbamoylpyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
A mixture of 6-(1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1-yl)nicotinic acid (18 mg, 0.029 mmol, Step-2 of Example 180), ammonium chloride (7.8 mg, 0.15 mmol), HATU (22 mg, 0.059 mmol), and DIEA (0.026 mL, 0.15 mmol) in DMF/MeCN (1:6, 1.2 mL) is stirred at rt overnight. After the reaction mixture is concentrated, purified by a strong anion exchange cartridge (ISOLUTE (registered trademark) SCX-2, 1 g/6 mL, Biotage) and then purified by preparative LC-MS to give 3.8 mg (25% yield) of the title compound.
Example 181:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-(methylcarbamoyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000073
The title compound is prepared in 27% yield (4.3 mg) by the similar manner to Step-3 of Example 180 using 2 M methylamine in THF (0.073 mL, 0.15 mmol) in place of ammonium chloride.
Example 182:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(dimethylcarbamoyl)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000074
The title compound is prepared in 32% yield (5.1 mg) by the similar manner to Step-3 of Example 180 using 2 M dimethylamine in THF (0.073 mL, 0.15 mmol) in place of ammonium chloride.
Representative procedure for Method H3
The following preparation of Example 185 represents the Method H3
Example 185:
N-((1r,4r)-4-((1-(6-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000075
<Step-1>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
The title compound is prepared in 72% yield (25 mg, brown solid) by the similar manner to Step-1 of Example 159 using 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (20 mg, 0.039 mmol, Intermediate-14) and 2-fluoro-6-nitropyridine (82 mg, 0.38 mmol) in place of Intermediate-12 and 2-fluoro-5-nitropyridine.
1H-NMR (400 MHz, CDCl3) delta 8.65 (1H, d, J = 2.3 Hz), 7.93 (1H, d, J = 2.3 Hz), 7.76 (1H, t, J = 8.0 Hz), 7.59 (1H, d, J = 6.4 Hz), 7.58 (1H, d, J = 7.3 Hz), 7.35 (1H, td, J = 7.8, 1.4 Hz), 7.16 (1H, t, J = 7.5 Hz), 7.00-6.68 (3H, m), 5.85 (1H, d, J = 7.3 Hz), 4.55 (2H, d, J = 8.0 Hz), 4.32 (2H, d, J = 8.0 Hz), 3.96-3.93 (1H, m), 3.60 (2H, d, J = 6.9 Hz), 2.17-2.14 (2H, m), 1.82-1.80 (3H, m), 1.30-1.15 (4H, m)
MS (ESI) m/z: 596.9 (M+H)+.
<Step-2>: N-((1r,4r)-4-((1-(6-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
The title compound is prepared in 14% yield (3.3 mg, brown solid) by the similar manner to Step-2 of Example 126 using 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (25 mg, 0.042 mmol, Step-1 of Example 185) in place of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methyl-3-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide.
MS (ESI) m/z: 567.1 (M+H)+.
Example 193:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(dimethylamino)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000076
<Step-1>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
The title compound is prepared in 68% yield (79 mg, brown solid) by the similar manner to Step-1 of Example 159 using 2-fluoro-6-nitropyridine (27 mg, 0.19 mmol) in place of 2-fluoro-5-nitropyridine.
1H-NMR (400 MHz, CDCl3) delta 8.65 (1H, d, J = 2.3 Hz), 7.94 (1H, d, J = 2.3 Hz), 7.76 (1H, t, J = 7.8 Hz), 7.59 (1H, d, J = 7.8 Hz), 7.54-7.50 (1H, m), 6.87-6.81 (1H, m), 6.85 (1H, t, J = 55 Hz), 6.68 (1H, d, J = 8.2 Hz), 6.61 (1H, dd, J = 8.7, 2.3 Hz), 5.86 (1H, d, J = 7.3 Hz), 4.54 (2H, d, J = 8.0 Hz), 4.29 (2H, d, J = 8.0 Hz), 3.96-3.91 (1H, m), 3.57 (2H, d, J = 6.9 Hz), 2.17-2.14 (2H, m), 1.82-1.79 (3H, m), 1.30-1.20 (4H, m).
MS (ESI) m/z: 614.8 (M+H)+.
<Step-2>: N-((1r,4r)-4-((1-(6-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
The title compound is prepared in 95% yield (71 mg, brown solid) by the similar manner to Step-2 of Example 159 using 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (79 mg, 0.13 mmol, Step-1 of Example 193) in place of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide.
MS (ESI) m/z: 584.8 (M+H)+.
<Step-3>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(dimethylamino)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
The title compound is prepared in 23% yield (3.7 mg) by the similar manner to Step-3 of Example 159 using N-((1r,4r)-4-((1-(6-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide (15 mg, 0.026 mmol, Step-2 of Example 193) in place of N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide.
Example 194:
N-((1r,4r)-4-((1-(6-acetamidopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000077
The title compound is prepared in 28% yield (4.5 mg) by the similar manner to Example 160 using N-((1r,4r)-4-((1-(6-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide (15 mg, 0.026 mmol, Step-2 of Example 160) in place of N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide.
Representative procedure for Method I2
The following preparation of Example 195 represents the Method I2
Example 195:
N-((1r,4r)-4-((1-(2-aminopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000078
 <Step-1>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(2-nitropyridin-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
The title compound is prepared in 39% yield (14 mg, brown solid) by the similar manner to Step-1 of Example 138 using 3-bromo-2-nitropyridine (23 mg, 0.11 mmol) in place of 3-bromo-4-nitropyridine.
MS (ESI) m/z: 614.9 (M+H)+.
<Step-2>: N-((1r,4r)-4-((1-(2-aminopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
The title compound is prepared in 22% yield (2.8 mg, brown solid) by the similar manner to Step-2 of Example 126 using 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(2-nitropyridin-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (14 mg, 0.022 mmol, Step-1 of Example 195) in place of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methyl-3-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide.
Example 196:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(6-oxo-1,6-dihydropyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000079
<Step-1>: N-((1r,4r)-4-((1-(6-(tert-butoxy)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
The title compound is prepared in 61% yield (22 mg, brown solid) by the similar manner to Step-1 of Example 138 using 2-bromo-6-(tert-butoxy)pyridine (26 mg, 0.11 mmol) in place of 3-bromo-4-nitropyridine.
1H-NMR (400 MHz, CDCl3) delta 8.65 (1H, d, J = 2.3 Hz), 7.93 (1H, d, J = 2.3 Hz), 7.58 (1H, dd, J = 8.2, 5.5 Hz), 7.38 (1H, t, J = 7.8 Hz), 6.84-6.79 (1H, m), 6.84 (1H, t, J = 55 Hz), 6.58 (1H, dd, J = 9.1, 2.3 Hz), 6.09 (1H, d, J = 7.8 Hz), 5.92 (1H, d, J = 7.8 Hz), 5.86 (1H, d, J = 8.2 Hz), 4.37 (2H, d, J = 7.6 Hz), 4.09 (2H, d, J = 7.6 Hz), 3.96-3.90 (1H, m), 3.56 (2H, d, J = 6.9 Hz), 2.17-2.14 (2H, m), 1.82-1.80 (3H, m), 1.56 (9H, s), 1.30-1.20 (4H, m).
MS (ESI) m/z: 641.9 (M+H)+.
<Step-2>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(6-oxo-1,6-dihydropyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
A solution of N-((1r,4r)-4-((1-(6-(tert-butoxy)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide (22 mg, 0.035 mmol, Step-1 of Example 196) in TFA (0.5 mL) is stirred at rt for 2 hrs. The mixture is concentrated. The residue is purified by preparative LC-MS to give 6.0 mg (29% yield) of the title compound.
Example 199:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000080
A mixture of Intermediate-14 (25 mg, 0.049 mmol), 1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (32 mg, 0.098 mmol), copper(II) acetate (18 mg, 0.098 mmol), and triethylamine (15 mg, 0.15 mmol) in acetonitrile (2 mL) is stirred at rt for 2 days under oxygen atmosphere. The mixture is added to aqueous ammonia and extracted with EtOAc.The organic layer is dried over sodium sulfate, filtered and concentrated. The residue in AcOH/THF/water (4/2/1, 2 mL) is stirred at 45oC overnight. The solvent is removed by flowing nitrogen gas. To the resultant mixture is added aqueous NaHCO3 and extracted with EtOAc. The organic layer is dried over sodium sulfate, filtered and concentrated. The residue is purified by preparative LC-MS to give 2.5 mg (9% yield) of the title compound.
Example 201:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(hydroxymethyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000081
<Step-1>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-((methoxymethoxy)methyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
The title compound is prepared in 43% yield (16 mg, brown solid) by the similar manner to Step-1 of Example 138 using 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (30 mg, 0.059 mmol, Intermediate-14) and 2-bromo-6-((methoxymethoxy)methyl)pyridine (27 mg, 0.12 mmol) in place of Intermediate-12 and 3-bromo-4-nitropyridine.
MS (ESI) m/z: 625.9 (M+H)+.
<Step-2>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(hydroxymethyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
A solution of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-((methoxymethoxy)methyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (16 mg, 0.025 mmol, Step-1 of Example 201) in THF (0.5 mL) is added with 2 M aqueous HCl (0.5 mL) and stirred overnight at rt. The mixture is concentrated. The residue is purified by preparative LC-MS to give 3.0 mg (20% yield) of the title compound.
Example 213:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(hydroxymethyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000082
<Step-1>: 2-bromo-5-((methoxymethoxy)methyl)pyridine
A mixture of (6-bromopyridin-3-yl)methanol (108 mg, 0.58 mmol), chloromethyl methyl ether (0.065 mL, 0.86 mmol), and DIEA (0.151 mL, 0.86 mmol) in DCM (0.5 mL) is stirred overnight at rt. The mixture is purified by column chromatography on silica-gel eluting with 4-33% EtOAc in n-hexane to give 93 mg (70% yield) of the title compound as a colorless gum.
1H-NMR (400 MHz, CDCl3) delta 8.36 (1H, d, J = 2.1 Hz), 7.56 (1H, dd, J = 8.2, 2.1 Hz), 7.48 (1H, d, J = 8.2 Hz), 4.71 (2H, s), 4.57 (2H, s), 3.40 (3H, s).
MS (ESI) m/z: 232.0 (M+H)+.
<Step-2>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(hydroxymethyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
The title compound is prepared in 14% yield (4.6 mg) by the similar manner to Step-1 and Step-2 of Example 201 using 2-bromo-5-((methoxymethoxy)methyl)pyridine (27 mg, 0.12 mmol, Step-1 of Example 213) in place of 2-bromo-6-((methoxymethoxy)methyl)pyridine.
Example 214:
6-(1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2'-oxospiro[azetidine-3,3'-indolin]-1-yl)-N-methylpicolinamide
Figure JPOXMLDOC01-appb-C000083
The title compound is prepared in 11% yield (4.6 mg) by the similar manner to Step-1, Step-2, and Step-3 of Example 181 using methyl 6-bromopicolinate (63 mg, 0.29 mmol) in place of methyl 6-bromonicotinate.
Example 215:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(2-hydroxyethoxy)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000084
<Step-1>: 2-bromo-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine
A mixture of 2-bromo-6-fluoropyridine (100 mg, 0.57 mmol), 2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (0.12 mL, 0.85 mmol) and potassium tert-butoxide (96 mg, 0.85 mmol) in THF (1 mL) is stirred for 1 hr at 60 oC. The mixture is purified by column chromatography on silica-gel eluting with 4-32% EtOAc in n-hexane to give 118 mg (69% yield, pale yellow solid) of the title compound.
1H-NMR (400 MHz, CDCl3) delta 7.41 (1H, dd, J = 8.2, 7.3 Hz), 7.05 (1H, d, J = 7.3 Hz), 6.73 (1H, d, J = 8.2 Hz), 4.69 (1H, t, J = 3.7 Hz), 4.55-4.44 (2H, m), 4.06-4.01 (1H, m), 3.92-3.86 (1H, m), 3.82-3.76 (1H, m), 3.55-3.49 (1H, m), 1.87-1.79 (1H, m), 1.77-1.70 (1H, m), 1.66-1.48 (4H, m).
<Step-2>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
The title compound is prepared in 54% yield (22 mg, brown solid) by the similar manner to Step-1 of Example 201 using 2-bromo-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (36 mg, 0.12 mmol, Step-1 of Example 215) in place of 2-bromo-6-((methoxymethoxy)methyl)pyridine.
MS (ESI) m/z: 696.0 (M+H)+.
<Step-3>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(2-hydroxyethoxy)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
A solution of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (29 mg, 0.041 mmol, Step-2 of Example 215) in TFA (0.5 mL) is stirred at rt for 30 min. The mixture is concentrated. The residue is purified by preparative LC-MS to give 2.8 mg (11% yield) of the title compound.
Example 216:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(2-hydroxyethoxy)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000085
The title compound is prepared in 17% yield (4.3 mg) by the similar manner to Step-2 and Step-3 of Example 215 using 2-bromo-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (36 mg, 0.12 mmol) in place of 2-bromo-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine.
Example 218:
N-((1r,4r)-4-((1-(6-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000086
<Step-1>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
The title compound is prepared in 62% yield (14 mg, brown solid) by the similar manner to Step-1 of Example 161 using 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (20 mg, 0.038 mmol, Intermediate-12) and 2-fluoro-6-nitropyridine (8.1 mg, 0.057 mmol) in place of Intermediate-14 and 5-fluoro-2-nitropyridine.
1H-NMR (400 MHz, CDCl3) delta 8.65 (1H, d, J = 2.1 Hz), 7.94 (1H, d, J = 2.1 Hz), 7.76 (1H, t, J = 7.8 Hz), 7.59 (1H, d, J = 7.3 Hz), 7.52 (1H, dd, J = 8.0, 5.3 Hz), 6.86-6.81 (1H, m), 6.83 (1H, t, J = 55 Hz), 6.69 (1H, d, J = 7.8 Hz), 6.61 (1H, dd, J = 8.7, 2.3 Hz), 5.86 (1H, d, J = 7.8 Hz), 4.54 (2H, d, J = 7.8 Hz), 4.29 (2H, d, J = 7.8 Hz), 3.96-3.91 (1H, m), 3.57 (2H, d, J = 6.9 Hz), 2.21-2.14 (2H, m), 1.85-1.73 (3H, m), 1.29-1.20 (4H, m).
MS (ESI) m/z: 614.9 (M+H)+.
<Step-2>: N-((1r,4r)-4-((1-(6-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
The title compound is prepared in 14% yield (1.9 mg) by the similar manner to Step-2 of Example 161 using 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-nitropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (14 mg, 0.023 mmol, Step-1 of Example 218) in place of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-nitropyridin-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide.
Example 219:
N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000087
The title compound is prepared in 14% yield (3.5 mg) by the similar manner to Step-1 and Step-2 of Example 126 using 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (20 mg, 0.038 mmol, Intermediate-12) and 2-fluoro-5-nitropyridine (7.0 mg, 0.049 mmol) in place of Intermediate-14 and 2-chloro-6-methyl-3-nitropyridine.
MS (ESI) m/z: 585.2 (M+H)+.
Example 220:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyridin-3-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000088
A mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (30 mg, 0.057 mmol, Intermediate-12), 3-bromopyridine (18 mg, 0.11 mmol), XPhos Pd G3 (4.8 mg, 10 mol%), and sodium tert-butoxide (16.3 mg, 0.17 mmol) in 1,4-dioxane (0.5 mL) is stirred at 130oC overnight. The mixture is charged on silica-gel pad, eluted with EtOAc and concentrated. The residue is purified by preparative LC-MS to give 1.7 mg (5.3% yield) of the title compound.
Representative procedure for Method C3
The following preparation of Example 238 represents the Method C3
Example 238:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1,3,4-thiadiazol-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000089
A mixture of Intermediate-14 (25 mg, 0.049 mmol), 2-bromo-1,3,4-thiadiazole (16 mg, 0.098 mmol), and DIEA (32 mg, 0.24 mmol) in DMF (1 ml) is stirred at 70 oC for 2 days. The mixture is added saturated aqueous ammonium chloride and brine, extracted with EtOAc and passed through sodium sulfate/amino-functional silica gel. The solvent is removed under vacuum, the crude product is purified by preparative LC-MS to give 2.0 mg (7% yield) of the title compound.
Example 241:
5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1H-pyrazol-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
Figure JPOXMLDOC01-appb-C000090
<Step-1>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
A mixture of Intermediate-14 (25 mg, 0.049 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (27 mg, 0.098 mmol), copper(II) acetate (18 mg, 0.098 mmol), and triethylamine (25 mg, 0.24 mmol) in acetonitrile (1 mL) is stirred at rt overnight under oxygen atmosphere. The mixture is added aqueous ammonia and water, extracted with EtOAc and passed through sodium sulfate/amino-functional silica gel. The solvent is removed by flowing nitrogen gas, 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide is obtained as a crude solid. The crude product is used next step without further purification.
MS (ESI) m/z: 624.9 (M+H)+.
<Step-2>: 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1H-pyrazol-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide
To a mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide (Step 1 of Example 241) in MeOH (1 mL) is added acetic anhydride (5 drops) and stirred rt for 1 hr. The mixture is added 4 M HCl in 1,4-dioxane (10 drops) and stirred at rt for 20 min. The solvent is removed under vacuum, the crude product is purified by a strong anion exchange cartridge (ISOLUTE (registered trademark) SCX-2, 1 g/6 mL, Biotage). The solvent is removed by flowing nitrogen gas, the crude product is purified by preparative LC-MS to give 2.4 mg (9% yield) of the title compound.
Representative procedure for Method D2
The following preparation of Example 243 represents the Method D2
Example 243:
N-((1r,4r)-4-((1-benzoyl-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000091
To a mixture of 5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide hydrochloride (15 mg, 0.028 mmol, Itntermediate-12), benzoic acid (4.2 mg, 4.15 mmol), and TEA (0.02 mL, 0.142 mmol) in DCM (1 mL) is added propylphosphonic anhydride solution 50% in EtOAc (0.033 mL, 0.057 mmol) at rt. The mixture is stirred at rt for 3 hrs. The reaction mixture is diluted with saturated aqueous sodium bicarbonate, followed by extraction with DCM. The organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by preparative LC-MS to give 4.5 mg (26% yield) of the title compound.
Example 267:
5-chloro-N-((1r,4r)-4-((1-cyano-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide
Figure JPOXMLDOC01-appb-C000092
To a mixture of Intermediate-12 (25 mg, 0.047 mmol) and DIEA (18 mg, 0.14 mmol) in acetonitrile (2 mL) is added cyanic bromide (9 mg, 0.085 mmol) and stirred at rt for 2 hrs. The mixture is added water, extracted with EtOAc and passed through sodium sulfate/amino-functional silica gel. The solvent is removed under vacuum, the crude product is purified by preparative LC-MS to give 4.4 mg (18% yield) of the title compound.
Representative procedure for Method G4
The following preparation of Example 293 represents the Method G4
Example 293:
5-chloro-N-((1r,4r)-4-((5'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide
Figure JPOXMLDOC01-appb-C000093
A mixture of 5-chloro-N-((1r,4r)-4-((5'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide (26 mg, 0.057 mmol, Intermediate-20), 2-bromo-5-methyl-1,3,4-thiadiazole (20 mg, 0.113 mmol), XPhos Pd G3 (4.8 mg, 0.0057 mmol), and cesium carbonate (46 mg, 0.142 mmol) in 1,4-dioxane (0.5 mL) is stirred at 100oC for 1 day. The mixture is diluted with saturated aqueous ammonium chloride, followed by extraction with EtOAc. The organic layer is dried over sodium sulfate, filtered and concentrated. The residue is purified by a strong anion exchange cartridge (ISOLUTE (registered trademark) SCX-2, 1 g/6 mL, Biotage), and then purified by preparative LC-MS to give 3.4 mg (10% yield) of the title compound.
　 Other examples are prepared according to the same procedure (from Method A1 to I2) described in Example synthesis part, using reactants shown in Table 1. The reactants are commercially available materials or obtained by conventional methods known to those skilled in the art, unless otherwise noted in the synthesis part. Each chemical structure of Example is described as a free-base in Table 1.
　 The observed MS (positive or negative mode) and retention time by LC-MS of all examples are described in Table 2.
　 The 1H-NMR data of selected examples are described in Table 3.
(Examples)
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000116
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000128
Figure JPOXMLDOC01-appb-T000129
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000132
Figure JPOXMLDOC01-appb-T000133
Figure JPOXMLDOC01-appb-T000134
Figure JPOXMLDOC01-appb-T000135
Figure JPOXMLDOC01-appb-T000136
Figure JPOXMLDOC01-appb-T000137
Figure JPOXMLDOC01-appb-T000138
Figure JPOXMLDOC01-appb-T000139
Figure JPOXMLDOC01-appb-T000140
Pharmacological assays
　 The in vitro and in vivo inhibitory activities of the compounds of this invention against CRHR2 or CRHR1 are determined by the following procedures.
cAMP functional assay for human CRHR1 and CRHR2
　 The ability of the compounds of this invention to inhibit either CRHR2 or CRHR1 is assessed by 3’,5’-cyclic adenosine monophosphate (cAMP) production in cells using the LANCE Ultra cAMP assay kit (ParkinElmer), which are designed based on the homogeneous time-resolved fluorescence resonance energy transfer (TR-FRET) immunoassay.
　 CHO-K1 (Chinese hamster ovary) cells stably expressing either human CRHR2-alpha (DiscoveRX, Cat. 95-0048C2) or human CRHR1-beta (DiscoveRX, Cat. 95-0047C2) are grown in HAM’s F12 media supplemented with 10% fetal bovine serum (FBS), 100 units/mL penicillin G, 100 microg/mL hygromycin and 0.5 microg/mL geneticin at 37 oC in 5% CO2 humidified incubator to 80% confluence. After 7 hours starvation treatment in culture media containing 0.1% FBS, the cells are washed with Hank’s balanced salt solution (HBSS) and cryopreserved.
　 For cAMP assay, frozen cells are thawed and washed with HBSS, followed by resuspended in assay buffer (HBSS containing 0.1% bovine serum albumin, 0.5 mM isobutylmethylxanthine and 5 mM Hepes, pH 7.4) at the appropriate concentration for the assay. The cell suspensions are plated on 384-well microplates (Greiner Bio-One) at a density of 4,000 cells per well. After preincubating the cells with various concentrations of the compounds for 30 min at 25 oC, an assay buffer containing EC80 concentration of each agonist is added and the cells are incubated for 30 min at 25 oC. Human urocortin2 (Peptide Institute) and CRF (Peptide Institute) are used as agonists for CRHR2 and CRHR1, respectively. For the termination of assay, europium-labeled cAMP tracer and ULight (registered trademark) dye labeled cAMP antibodies, both prepared with Lance-Ultra cAMP detection reagent (PerkinElmer) are added in the plate and incubate for 60 min at 25 oC. After incubation, TR-FRET signal is detected by EnVision plate reader (PerkinElmer). The IC50 values for compounds are calculated from dose-response curves by fitting the percent inhibition using XLfit (ID Business Solutions).
　 All tested compounds show less than about 1 microM of IC50 against CRHR2 in the above assays. Preferable compounds show less than about 0.2 microM of IC50 against CRHR2 in the above assays.
　 Compounds with IC50 against CRHR2 < 0.2 microM are:
Examples 24, 46, 52, 53, 54, 55, 56, 59, 70, 71, 72, 73, 74, 80, 81, 82, 83, 94, 95, 100, 106, 107, 108, 109, 110, 113, 114, 115, 116, 120, 122, 123, 124, 126, 127, 129, 131, 132, 134, 136, 141, 142, 143, 145, 150, 151, 152, 153, 155, 156, 157, 158, 159, 161, 162, 165, 166, 172, 173, 174, 175, 177, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 194, 195, 197, 200, 201, 205, 206, 211, 212, 215, 218, 219, 220, 221, 225, 228, 233, 239, 241, 242, 243, 245, 247, 248, 249, 250, 251, 252, 253, 254, 255, 259, 262, 263, 264, 265, 266, 267, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 283, 284, 286, 287, 288, 290, 291, 294, 295, 296, 297, 298, 300, 302, 304, 307, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, and 323.
　 The compounds of this invention show preferable activity, which show the above-mentioned practical use.
　 On the other hand, Example 2.21 in WO2011/092293 showed >30 microM of IC50 against CRHR2 in the above assays.
Echocardiogram analysis of mice loaded with CRHR2 agonist
　 Male C57BL/6 mice at 8 weeks old are purchased from Charles River Japan, and housed in groups of 6 per cage under a 12-h light/dark cycle with access to food and water ad libitum. Under conscious condition, transthoracic echocardiography is performed using Vivo1100 imaging system (FUJIFILM VisualSonics). Left ventricular end-systolic diameter (LVDs) and left ventricular end-diastolic diameters (LVDd) are measured to calculate percent fractional shortening (%FS) in M-mode. The %FS is calculated by the following equation: %FS = (LVDd-LVDs) / LVDd x 100. After measuring %FS, the animals are anesthetized with an anesthetic mixture (medetomidine, midazolam and butorphanol), and an Alzet (registered trademark) osmotic pump (DURECT) that releases mouse urocortin 2 (Peptide Institute) at an infusion rate of 0.11 microL/h (100 ng/g/day) is implanted subcutaneously in the back. Two days after the implantation, examining urocortin 2-induced increase of the %FS, the animals are selected for evaluation and randomized to be nearly equal across all groups. The compounds of the invention or their vehicles are administered systemically. The post-value of %FS is measured at an appropriate time point after compound administration. Statistical analysis is performed by parametric methods.
Human dofetilide binding assay
　 hERG transfected HEK293S cells are prepared and grown in-house. The collected cells are suspended in 50 mM Tris-HCl (pH 7.4 at 4 oC) and homogenized using a hand held Polytron PT 1200 disruptor set at full power for 20 sec on ice. The homogenates are centrifuged at 48,000 x g at 4 oC for 20 min. The pellets are then resuspended, homogenized, and centrifuged once more in the same manner. The final pellets are resuspended in an appropriate volume containing 50 mM Tris-HCl, 10 mM KCl and 1 mM MgCl2 (pH 7.4 at 4oC), homogenized, ali-quoted and stored at -80 oC until use. An aliquot of membrane fractions is used for protein concentration determination using BCA protein assay kit (PIERCE) and ARVOsx plate reader (Wallac). Binding assays are conducted in a total volume of 30 microL in 384-well plates. The activity is measured by PHERAstar (BMG LABTECH) using fluorescence polarization technology. Ten microL of test compounds are incubated with 10 microL of fluorescence ligand (6 nM Cy3B tagged dofetilide derivative) and 10 microL of membrane homogenate (6 microgram protein) for 120 minutes at room temperature. Nonspecific binding is determined by 10 microM E4031 at the final concentration.
　 All tested compounds of the invention show higher IC50 values in human dofetilide binding than IC50 values in CRHR2 Assay. The high IC50 values in human dofetilide binding activities lead to reducing the risk of cardiovascular adverse events.
Metabolic stability assay:
Half-life in human liver microsomes (HLM)
　 Test compounds (1 microM) are incubated with 3.3 mM MgCl2 and 0.78 mg/mL HLM (HL101) or 0.74 mg/mL HLM (Gentest UltraPool 150) in 100 mM potassium phosphate buffer (pH 7.4) at 37 oC on the 96-deep well plate. The reaction mixture is split into two groups, a non-P450 and a P450 group. Nicotinamide Adenine Dinucleotide Phosphate Hydrogen (NADPH) is only added to the reaction mixture of the P450 group. (NADPH generation system is also used instead of NADPH.) An aliquot of samples of P450 group is collected at 0, 10, 30, and 60 min time point, where 0 min time point indicates the time when NADPH is added into the reaction mixture of P450 group.　An aliquot of samples of non-P450 group is collected at -10 min and 65 min time point. Collected aliquots are extracted with acetonitrile solution containing an internal standard. The precipitated protein is spun down in centrifuge (2000 rpm, 15 min). The compound concentration in supernatant is measured by LC/MS/MS system.
　 The half-life value is obtained by plotting the natural logarithm of the peak area ratio of compounds/ internal standard versus time. The slope of the line of best fit through the points yield the rate of metabolism (k). This is converted to a half-life value using following equations: Half-life = ln 2/k
　 The compounds of this invention show preferable stability, which show the above-mentioned practical use.
Drug-drug interaction assay
　 This method essentially involves determining the percent inhibition of metabolites formation from probes (Tacrine (Sigma A3773-1G) 2 microM, Dextromethorphan (Sigma D-9684) 5 microM, Diclofenac (Sigma D-6899-10G) 5 microM, and Midazolam (ULTRAFINE UC-429) 2 microM) at 3 microM of each compound.
　 More specifically, the assay is carried out as follows. The compounds (60 microM, 10 microL) are pre-incubated in 170 microL of mixture including 0.1 mg protein/mL human liver microsomes, 100 mM potassium phosphate buffer (pH 7.4), 1 mM MgCl2 and probes as substrate for 5 min. Reaction is started by adding a 20 microL of 10 mM NADPH (20 microL of NADPH generating system, which consist of 10 mM NADP+, 50 mM DL-lsocitric acid and 10 U/mL Isocitric Dehydrogenase, is also used). The assay plate is incubated at 37 oC. Acetonitrile is added to the incubate solution at appropriate time (e.g. 8 min).
The metabolites' concentration in the supernatant is measured by LC/MS/MS system.
The degree of drug-drug interaction is interpreted based on generation % of metabolites in the presence or absence of test compound.
　 The compounds of this invention show preferable results, which show the above-mentioned practical use.
Plasma protein binding assay
　 Plasma protein binding of the test compound (1 microM) is measured by the method of equilibrium dialysis using 96-well plate type equipment. HTD96a (registered trademark), i.e. regenerated cellulose membranes (molecular weight cut-off 12,000-14,000, 22 mm x 120 mm) are soaked for overnight in distilled water, then for 15 minutes in 30% ethanol, and finally for 20 minutes in dialysis buffer (Dulbecco's phosphate buffered saline, pH 7.4). Frozen plasma of human, Sprague-Dawley rats, and Beagle dogs are used. The dialysis equipment is assembled and added 150 microL of compound-fortified plasma to one side of each well and 150 microL of dialysis buffer to the other side of each well. After 4 hours incubation at 37 oC for 150 r.p.m, aliquots of plasma and buffer are sampled. The compound in plasma and buffer are extracted with 300 microL of acetonitrile containing a internal standard compound for analysis. The concentration of the compound is determined with LC/MS/MS analysis.
　 The fraction of the compound unbound (fu) is calculated by the following equation (A) or (B):
Figure JPOXMLDOC01-appb-M000141
 wherein [plasma]eq and [buffer]eq are the concentrations of the compound in plasma and buffer, respectively.
Figure JPOXMLDOC01-appb-M000142
 wherein Cp is the peak area of the compound in plasma sample;
Cis,p is the peak area of the internal standard in plasma sample;
Cb is the peak area of the compound in buffer sample;
Cis,b is the peak area of the internal standard in buffer sample;
4 and 4/3 are the reciprocal of the dilution rate in plasma and buffer, respectively.
The compounds of this invention show preferable plasma protein binding, which show the above-mentioned practical use.
Equilibrium aqueous solubility study
　 The DMSO solution (2 microL, 30 mM) of each compound is dispensed into each well of a 96-well glass bottom plate. Potassium phosphate buffer solution (50 mM, 198 microL, pH 6.5) is added to each well, and the mixture is incubated at 37 oC with rotate shaking for 24 hours. After centrifugation at 2000 xg for 5 minutes, the supernatant is filtered through the polycarbonate iso-pore membrane. The concentration of samples is determined by a general gradient HPLC method (J. Pharm. Sci.2006, 95, 2115-2122).
　 The compounds of this invention show preferable aqueous solubility, which show the above-mentioned practical use.
　 All publications, including but not limited to, issued patents, patent applications, and journal articles, cited in this application are each herein incorporated by reference in their entirety. Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.
　 The spiroheterocyclic derivatives of the present invention are useful in the treatment of a wide range of disorders in which CRHR2 is involved.

Claims (18)

  1. 　 A compound of the following formula (I):
    Figure JPOXMLDOC01-appb-C000001
     wherein:
    A is aryl or heteroaryl;
    W is S or O;
    Ra, Rb, Rc, and Rd are independently selected from the group consisting of: (1) hydrogen and (2) C1-6 alkyl; wherein the C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl;
    R1 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) C1-6 alkyl, and (4) -O-C1-6 alkyl, wherein the C1-6 alkyl or the -O-C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl;
    p is 1, 2, or 3;
    R2 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C1-6 alkyl, (5) -O-C1-6 alkyl, and (6) -CN;
    q is 1, 2, 3, or 4;
    Y1, Y2, Y3, and Y4 are independently selected from the group consisting of CH, CR2, in which R2 has the same meaning as above, and N,
    wherein the number of nitrogen atom(s) in the Y1, Y2, Y3, and Y4 is 0 to 2;
    X1, X2, and X3 are independently selected from the group consisting of a chemical bond, CH2, CH(C1-6 alkyl), and C(C1-6 alkyl)(C1-6 alkyl);
    R3 is selected from the group consisting of: (1) C1-6 alkyl, (2) C2-6 alkenyl, (3) C3-7 cycloalkyl, (4) C3-7 cycloalkylC1-6 alkyl, (5) heterocyclyl, wherein the C1-6 alkyl, the C2-6 alkenyl, the C3-7 cycloalkyl, the C3-7 cycloalkylC1-6 alkyl, or the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl, (6) aryl, (7) heteroaryl, (8) arylC1-6 alkyl, (9) heteroarylC1-6 alkyl, wherein the aryl, the heteroaryl, the arylC1-6 alkyl, or the heteroarylC1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, C3-7 cycloalkyl, -O-C3-7 cycloalkyl, heterocyclyl, hydroxyC1-6 alkyl, C1-6 alkoxyC1-6 alkyl, hydroxyC1-6 alkoxyl, (C=O)-R5, -CH2(C=O)C1-6 alkyl, -(C=O)-NR5R6, -CH2(C=O)-NR5R6, -NR6(C=O)R5, -NR5R6, -C1-6 alkyl-NR5R6, -C1-6 alkoxy-NR5R6, -NR6-S(O)2R5, -S(O)2-R5, and -CN, (10) -(C=O)-R4, (11) -S(O)2-R4, and (12) -CN;
    R4 is selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) -O-C1-6 alkyl, (4) C1-6 alkoxyC1-6 alkyl, (5) C3-7 cycloalkyl, (6) C3-7 cycloalkylC1-6 alkyl, (7) -O-C3-7 cycloalkyl, (8) C2-6 alkenyl, (9) aryl, (10) heteroaryl, (11) heterocyclyl, (12) -O-aryl, (13) -O-heteroaryl, (14) -O-heterocyclyl, and (15) -NR7R8, wherein the C1-6 alkyl, the -O-C1-6 alkyl, the C1-6 alkoxyC1-6 alky, the C3-7 cycloalkyl, the C3-7 cycloalkylC1-6 alkyl, the -O-C3-7 cycloalkyl, the C2-6 alkenyl, the heterocyclyl, or the -O-heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and -CN; wherein the aryl, the heteroaryl, the -O-aryl, or the -O-heteroaryl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NR7R8, and -CN;
    R5 is independently selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) C3-7 cycloalkyl, (4) heterocyclyl, (5) C3-7 cycloalkylC1-6 alkyl, (6) heterocyclylC1-6 alkyl, (7) aryl, (8) arylC1-6 alkyl, (9) heteroaryl, and (10) heteroarylC1-6 alkyl, wherein the C1-6 alkyl, the C3-7 cycloalkyl, the heterocyclyl, the C3-7 cycloalkylC1-6 alkyl, the heterocyclylC1-6 alkyl, the aryl, the arylC1-6 alkyl, the heteroaryl, or the heteroarylC1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxyl, and -CN;
    R6 is independently selected from the group consisting of: (1) hydrogen and (2) C1-6 alkyl;
    or R5 may form a 4 to 7 membered ring with R6 which may contain N, O, S, or carbonyl; wherein the 4 to 7 membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxyl; and
    R7 and R8 are independently selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) C3-7 cycloalkyl, (4) heterocyclyl, (5) C3-7 cycloalkylC1-6 alkyl, (6) heterocyclylC1-6 alkyl, (7) aryl, (8) arylC1-6 alkyl, (9) heteroaryl, and (10) heteroarylC1-6 alkyl, wherein the C1-6 alkyl, the C3-7 cycloalkyl, the heterocyclyl, the C3-7 cycloalkylC1-6 alkyl, the heterocyclylC1-6 alkyl, the aryl, the arylC1-6 alkyl, the heteroaryl, or the heteroarylC1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxyl, and -CN;
    or R7 may form a 4 to 7 membered ring with R8 which may contain N, O, S, or carbonyl; wherein the 4 to 7 membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxyl;
    or a pharmaceutically acceptable salt thereof or a prodrug thereof,
  2. 　 The compound according to claim 1:
    wherein:
    A is phenyl, naphthyl, or 5 to 10-membered heteroaryl with 1-4 heteroatoms independently selected from O, N, and S;
    Y1, Y2, Y3, and Y4 are independently selected from the group consisting of CH and CR2;
    or a pharmaceutically acceptable salt thereof or a prodrug thereof.
  3. 　 The compound according to claim 1 or 2:
    wherein:
    A is selected from the group consisting of phenyl, naphthyl, benzoimidazolyl, dihydroisoquinolyl, indolyl, indazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridyl, quinolyl, isoquinolyl, and thiazolyl;
    or a pharmaceutically acceptable salt thereof or a prodrug thereof.
  4. 　 The compound according to claim 1, wherein the compound of the formula (I) is represented by a compound of the following formula (II):
    Figure JPOXMLDOC01-appb-C000002
     wherein:
    R1 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) C1-6 alkyl, and (4) -O-C1-6 alkyl, wherein the C1-6 alkyl or the -O-C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl;
    p is 1, 2, or 3;
    Z is selected from the group consisting of CH, CR1, in which R1 has the same meaning as above, and N,
    R2 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C1-6 alkyl, (5) -O-C1-6 alkyl, and (6) -CN;
    q is 1, 2, 3, or 4;
    X1, X2, and X3 are independently selected from the group consisting of a chemical bond and CH2;
    R3 is selected from the group consisting of: (1) C1-6 alkyl, (2) C2-6 alkenyl, (3) C3-7 cycloalkyl, (4) C3-7 cycloalkylC1-6 alkyl, (5) heterocyclyl, wherein the C1-6 alkyl, the C2-6 alkenyl, the C3-7 cycloalkyl, the C3-7 cycloalkylC1-6 alkyl, or the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl, (6) aryl, (7) heteroaryl, (8) arylC1-6 alkyl, (9) heteroarylC1-6 alkyl, wherein the aryl, the heteroaryl, the arylC1-6 alkyl, or the heteroarylC1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, C3-7 cycloalkyl, -O-C3-7 cycloalkyl, heterocyclyl, hydroxyC1-6 alkyl, C1-6 alkoxyC1-6 alkyl, hydroxyC1-6 alkoxyl, -(C=O)-R5, -CH2(C=O) C1-6 alkyl, -(C=O)-NR5R6, -CH2(C=O)-NR5R6, -NR6(C=O)R5, -NR5R6, -C1-6 alkyl-NR5R6, -C1-6 alkoxy-NR5R6, -NR6-S(O)2R5, -S(O)2-R5, and -CN, (10) -(C=O)-R4, (11) -S(O)2-R4, and (12) -CN;
    R4 is selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) -O-C1-6 alkyl, (4) C1-6 alkoxyC1-6 alkyl (5) C3-7 cycloalkyl, (6) C3-7 cycloalkylC1-6 alkyl, (7) -O-C3-7 cycloalkyl, (8) C2-6 alkenyl, (9) aryl, (10) heteroaryl, (11) heterocyclyl, (12) -O-aryl, (13) -O-heteroaryl, (14) -O-heterocyclyl, and (15) -NR7R8, wherein the C1-6 alkyl, the -O-C1-6 alkyl, the C1-6 alkoxyC1-6 alky, the C3-7 cycloalkyl, the C3-7 cycloalkylC1-6 alkyl, the -O-C3-7 cycloalkyl, the C2-6 alkenyl, the heterocyclyl, or the -O-heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and -CN; wherein the aryl, the heteroaryl, the -O-aryl, or the -O-heteroaryl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NR7R8, and -CN;
    R5 is independently selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) C3-7 cycloalkyl, (4) heterocyclyl, (5) C3-7 cycloalkylC1-6 alkyl, (6) heterocyclylC1-6 alkyl, (7) aryl, (8) arylC1-6 alkyl, (9) heteroaryl, and (10) heteroarylC1-6 alkyl, wherein the C1-6 alkyl, the C3-7 cycloalkyl, the heterocyclyl, the C3-7 cycloalkylC1-6 alkyl, the heterocyclylC1-6 alkyl, the aryl, the arylC1-6 alkyl, the heteroaryl, or the heteroarylC1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxyl, and -CN;
    R6 is independently selected from the group consisting of: (1) hydrogen and (2) C1-6 alkyl;
    or R5 may form a 4 to 7 membered ring with R6 which may contain N, O, S, or carbonyl; wherein the 4 to 7 membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxyl; and
    R7 and R8 are independently selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) C3-7 cycloalkyl, (4) heterocyclyl, (5) C3-7 cycloalkylC1-6 alkyl, (6) heterocyclylC1-6 alkyl, (7) aryl, (8) arylC1-6 alkyl, (9) heteroaryl, and (10) heteroarylC1-6 alkyl, wherein the C1-6 alkyl, the C3-7 cycloalkyl, the heterocyclyl, the C3-7 cycloalkylC1-6 alkyl, the heterocyclylC1-6 alkyl, the aryl, the arylC1-6 alkyl, the heteroaryl, or the heteroarylC1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxyl, and -CN;
    or R7 may form a 4 to 7 membered ring with R8 which may contain N, O, S, or carbonyl; wherein the 4 to 7 membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxyl;
    or a pharmaceutically acceptable salt thereof or a prodrug thereof.
  5. 　 The compound according to claim 1 or 4, wherein the compound of the formula (I) or (II) is represented by a compound of the following formula (III):
    Figure JPOXMLDOC01-appb-C000003
     wherein:
    R1 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) C1-6 alkyl, and (4) -O-C1-6 alkyl, wherein the C1-6 alkyl or the -O-C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl;
    p is 1, 2, or 3;
    R2 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C1-6 alkyl, (5) -O-C1-6 alkyl, and (6) -CN;
    q is 1, 2, or 3;
    X2 and X3 are independently selected from the group consisting of a chemical bond and CH2;
    R3 is selected from the group consisting of: (6) aryl, (7) heteroaryl, (8) phenylCH2-, (9) heteroarylCH2-, wherein the aryl, the heteroaryl, the phenylCH2-, or the heteroarylCH2- is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, C3-7 cycloalkyl, heterocyclyl, hydroxyC1-6 alkyl, C1-6 alkoxyC1-6 alkyl, hydroxyC1-6 alkoxyl, -(C=O)-NR5R6, -NR6(C=O)R5, -NR5R6, and -CN, and (10) -(C=O)-R4;
    R4 is selected from the group consisting of: (2) C1-6 alkyl, (3) -O-C1-6 alkyl, (4) C1-6 alkoxyC1-6 alkyl, (5) C3-7 cycloalkyl, (6) C3-7 cycloalkylC1-6 alkyl, (7) -O-C3-7 cycloalkyl, (8) C2-6 alkenyl, (9) aryl, (10) heteroaryl, (11) heterocyclyl, and (15) -NR7R8, wherein the C1-6 alkyl, the -O-C1-6 alkyl, the C1-6 alkoxyC1-6 alky, the C3-7 cycloalkyl, the C3-7 cycloalkylC1-6 alkyl, the -O-C3-7 cycloalkyl, the C2-6 alkenyl, or the heterocyclyl, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and -CN; wherein the aryl or the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -NR7R8, and -CN;
    R5 is independently selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) C3-7 cycloalkyl, and (5) C3-7 cycloalkylC1-6 alkyl; wherein the C1-6 alkyl, the C3-7 cycloalkyl, or the C3-7 cycloalkylC1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxyl, and -CN;
    R6 is independently selected from the group consisting of: (1) hydrogen and (2) C1-6 alkyl;
    or R5 may form a 4 to 7 membered ring with R6 which may contain N, O, S, or carbonyl; wherein the 4 to 7 membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxyl; and
    R7 and R8 are independently selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl, (3) C3-7 cycloalkyl, and (4) heterocyclyl, wherein the C1-6 alkyl, or the C3-7 cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxyl, and -CN;
    or R7 may form a 4 to 7 membered ring with R8 which may contain N, O, S, or carbonyl; wherein the 4 to 7 membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxyl;
    wherein the aryl is phenyl or naphthyl;
    wherein the heteroaryl is 5 to 10-membered heteroaryl with 1-4 heteroatoms independently selected from O, N, and S; and
    wherein the heterocyclyl is 4 to 8-membered heterocyclyl with 1-4 heteroatoms independently selected from O, N, S, in which the heterocyclyl optionally contains carbonyl;
    or a pharmaceutically acceptable salt thereof or a prodrug thereof.
  6. 　 The compound according to claim 5,
    wherein:
    R3 is is selected from the group consisting of: (6) aryl, (7) heteroaryl, and (10) -(C=O)-R4; wherein the aryl or the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, C3-7 cycloalkyl, oxetanyl, hydroxyC1-6 alkyl, C1-6 alkoxyC1-6 alkyl, hydroxyC1-6 alkoxyl, -(C=O)-NR5R6, -NR6(C=O)R5, -NR5R6, and -CN;
    R4 is selected from the group consisting of: (3) -O-C1-6 alkyl, (7) -O-C3-7 cycloalkyl, (9) aryl, and (10) heteroaryl, wherein the -O-C1-6 alkyl or the -O-C3-7 cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and -CN; wherein the aryl or the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, and -CN;
    or a pharmaceutically acceptable salt thereof or a prodrug thereof.
  7. 　 A compound which is selected from the group consisting of:
    1-(((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl)-N,N-dimethyl-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxamide;
    ethyl 1-(((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate;
    5-chloro-N-((1r,4r)-4-((1'-(3-methoxyphenyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((1'-(5-chloropyridin-2-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((1'-(5-cyanopyridin-2-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2-oxo-1'-propionylspiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1'-(cyclopropanecarbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-N,N-dimethyl-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxamide;
    5-chloro-N-((1r,4r)-4-((1'-(cyclobutanecarbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-N,N-diethyl-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((1'-(1-methyl-1H-pyrazol-3-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    ethyl 1-(((1r,4r)-4-(5-chloro-2-methylnicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate;
    5-chloro-2-methyl-N-((1r,4r)-4-((2-oxo-1'-(pyrrolidine-1-carbonyl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1'-(azetidine-1-carbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-5-chloro-2-methylnicotinamide;
    N-((1r,4r)-4-((1'-acetyl-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methyl-2H-indazole-3-carboxamide;
    N-((1r,4r)-4-((1'-acetyl-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(2,2,2-trifluoroethyl)-2H-indazole-3-carboxamide;
    1-(((1r,4r)-4-(5-chloro-2-(trifluoromethyl)nicotinamido)cyclohexyl)methyl)-N,N-dimethyl-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxamide;
    methyl 1-(((1r,4r)-4-(5-chloro-2-(trifluoromethyl)nicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate;
    ethyl 1-(((1r,4r)-4-(5-chloro-2-(trifluoromethyl)nicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate;
    methyl 1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate;
    ethyl 1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate;
    5-chloro-N-((1r,4r)-4-((1'-(cyclopropanecarbonyl)-6-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6-fluoro-N,N-dimethyl-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxamide;
    methyl 1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6-fluoro-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate;
    ethyl 1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6-fluoro-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate;
    5-chloro-N-((1r,4r)-4-((1'-(3-cyanopyridin-2-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((2-oxo-1'-(pyrazin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1'-(4-cyanopyridin-3-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((1'-(2-cyanopyridin-3-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((2-oxo-1'-(pyrimidin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1'-(cyclopropanecarbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    N-((1r,4r)-4-((1'-(cyclopropanecarbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methyl-2H-indazole-3-carboxamide;
    5-chloro-N-((1r,4r)-4-((1'-(cyclopropanecarbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethoxy)benzamide;
    ethyl 1-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-2-oxo-1'-propionylspiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-1'-(1-fluorocyclopropane-1-carbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-2-oxo-1'-(pyrrolidine-1-carbonyl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1'-(1-cyanocyclopropane-1-carbonyl)-6-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(cyclopropanecarbonyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    ethyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-2-oxo-1'-(pyrazin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1'-(2-cyanopyridin-3-yl)-6-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-2-oxo-1'-(pyrimidin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-1'-(5-fluoropyrimidin-2-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-1'-(4-methylpyrimidin-2-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2-oxo-1'-(pyrimidin-2-yl)spiro[indoline-3,3'-pyrrolidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2-oxo-1'-(pyrazin-2-yl)spiro[indoline-3,3'-pyrrolidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1'-(2-cyanopyridin-3-yl)-2-oxospiro[indoline-3,3'-pyrrolidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrimidin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrazin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-N,N-dimethyl-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxamide;
    methyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
    5-chloro-N-((1r,4r)-4-((1-(cyclobutanecarbonyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(1-cyanocyclopropane-1-carbonyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-propionylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(piperidine-1-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(2-cyclopropylacetyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrimidin-2-yl)-2'H-spiro[piperidine-4,3'-quinolin]-1'(4'H)-yl)methyl)cyclohexyl)nicotinamide;
    1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-N,N-dimethyl-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxamide;
    methyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
    ethyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrimidin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-propionylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(piperidine-1-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(cyclopropanecarbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-picolinoylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrazin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazol-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiophene-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-imidazole-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazole-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    isopropyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
    N-((1r,4r)-4-((1-(3-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(3-cyanopyrazin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(5-cyanopyrimidin-4-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(6-cyanopyrazin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrimidin-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(but-3-enoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    N-((1r,4r)-4-((1-acryloyl-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    N-((1r,4r)-4-((1-(3-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-(dimethylamino)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazol-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-hydroxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(3-amino-6-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-(methylamino)pyrazin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(3-amino-6-methoxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(4-fluorophenyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrimidin-5-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1,2,4-thiadiazol-5-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(4-(trifluoromethyl)thiazol-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-imidazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(5-aminopyrimidin-4-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    N-((1r,4r)-4-((1-(4-aminopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    N-((1r,4r)-4-((1-benzyl-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(tetrahydro-2H-pyran-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiophen-3-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methylpicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methylpicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(4-methylpicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-hydroxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methoxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-fluoro-3-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-methylpicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methoxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-fluoropicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(3-amino-6-methylpyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methyl-1,2,4-oxadiazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-(2-hydroxyethoxy)pyrazin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(5-cyanopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-fluoropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-methoxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(dimethylamino)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(5-acetamidopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(1-cyclobutyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-fluoro-4-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(2-methylpyrimidin-5-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-picolinoylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyridazine-3-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrazine-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyridazine-3-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrimidine-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(4-methyl-1,2,5-oxadiazole-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrimidin-5-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-fluoropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-methyl-1,2,4-oxadiazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(3-cyanopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    N-((1r,4r)-4-((1-(4-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methyl-1,3,4-oxadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(5-carbamoylpyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-(methylcarbamoyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(dimethylcarbamoyl)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(4-methylpyrimidin-5-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(4-methoxypyrimidin-5-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(6-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(isothiazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-ethyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(6-aminopyridin-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(dimethylamino)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(6-acetamidopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    N-((1r,4r)-4-((1-(2-aminopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(6-oxo-1,6-dihydropyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-benzoyl-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(5-(trifluoromethyl)picolinoyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyridin-3-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(hydroxymethyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyridin-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrimidine-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(isothiazole-5-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(6-(trifluoromethyl)picolinoyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(isoxazole-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(oxazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(isothiazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazole-5-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1,2,3-thiadiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(2-methylthiazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(hydroxymethyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    6-(1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2'-oxospiro[azetidine-3,3'-indolin]-1-yl)-N-methylpicolinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(2-hydroxyethoxy)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(2-hydroxyethoxy)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(6-aminopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyridin-3-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-fluoro-4-methoxypyrimidin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(2-methylpyrimidin-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methylcyclopropane-1-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-fluorocyclopropane-1-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1,3-dihydroisobenzofuran-5-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(1-cyanocyclopropane-1-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    N-((1r,4r)-4-((1-(6-acetamidopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methoxypyrimidin-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methylpyrimidin-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(2-cyanopyrimidin-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(6-(trifluoromethyl)pyrimidin-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-fluorobenzoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(2-fluorobenzoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-methoxybenzoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(2-methoxyisonicotinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1,3,4-thiadiazol-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(1,3,4-thiadiazol-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1H-pyrazol-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-fluoropyrimidin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-benzoyl-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrimidine-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(6-(pyrrolidin-1-yl)picolinoyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(oxazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(2-methylthiazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(isoxazole-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(1,2,3-thiadiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypyrazine-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbonyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-imidazole-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(thiazole-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(1,2,5-thiadiazole-3-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazole-5-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(oxazole-5-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carbonyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypyridazine-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(1,2,3-thiadiazole-5-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methoxypyrimidin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methylthiazole-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-fluorocyclopropane-1-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(imidazo[2,1-b]thiazole-6-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-cyano-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(cyclopropanecarbonyl)-5'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(1-fluorocyclopropane-1-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(1-cyanocyclopropane-1-carbonyl)-5'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-(thiazole-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-(1,2,3-thiadiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(oxazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(isoxazole-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-picolinoylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(6-methoxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(3-hydroxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((7'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((4'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methyl-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((7'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((4'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methyl-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((7'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((5'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((6'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((4'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((5'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((4'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((5'-methoxy-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((4'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((5'-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((5'-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((4'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((5'-methoxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((6'-methoxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((6'-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methoxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide; and
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    or a pharmaceutically acceptable salt thereof or a prodrug thereof.
  8. 　 The compound according to claim 7, which is selected from the group consisting of:
    5-chloro-2-methyl-N-((1r,4r)-4-((1'-(1-methyl-1H-pyrazol-3-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1'-(cyclopropanecarbonyl)-6-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1'-(3-cyanopyridin-2-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((2-oxo-1'-(pyrazin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1'-(4-cyanopyridin-3-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((1'-(2-cyanopyridin-3-yl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((2-oxo-1'-(pyrimidin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1'-(cyclopropanecarbonyl)-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-methyl-2H-indazole-3-carboxamide;
    5-chloro-N-((1r,4r)-4-((1-(cyclopropanecarbonyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    ethyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-2-oxo-1'-(pyrazin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1'-(2-cyanopyridin-3-yl)-6-fluoro-2-oxospiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6-fluoro-2-oxo-1'-(pyrimidin-2-yl)spiro[indoline-3,4'-piperidin]-1-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrimidin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrazin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-N,N-dimethyl-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxamide;
    methyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
    methyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
    ethyl 1'-(((1r,4r)-4-(5-chloro-2-(difluoromethyl)nicotinamido)cyclohexyl)methyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-picolinoylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrazin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazol-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiophene-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-imidazole-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazole-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(3-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(3-cyanopyrazin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(5-cyanopyrimidin-4-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(6-cyanopyrazin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    N-((1r,4r)-4-((1-(3-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazol-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(3-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(3-amino-6-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    N-((1r,4r)-4-((1-(3-amino-6-methoxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyrimidin-5-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1,2,4-thiadiazol-5-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiophen-3-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methylpicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(4-methylpicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-methoxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-fluoropicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(3-amino-6-methylpyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methyl-1,2,4-oxadiazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(5-cyanopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-fluoropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-methoxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-(dimethylamino)pyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(5-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(2-methylpyrimidin-5-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-picolinoylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyrimidin-5-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(3-fluoropyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-(3-cyanopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(4-methylpyrimidin-5-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(4-methoxypyrimidin-5-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(6-aminopyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(isothiazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-ethyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(6-aminopyridin-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methylpyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyridin-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(6-acetamidopyridin-2-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    N-((1r,4r)-4-((1-(2-aminopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    N-((1r,4r)-4-((1-benzoyl-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(pyridin-3-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(hydroxymethyl)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(6-(trifluoromethyl)picolinoyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(isoxazole-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1,2,3-thiadiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(2-methylthiazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(6-(2-hydroxyethoxy)pyridin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(6-aminopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(pyridin-3-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(1-fluorocyclopropane-1-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-(6-acetamidopyridin-3-yl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(1,3,4-thiadiazol-2-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((2'-oxo-1-(1H-pyrazol-4-yl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-fluoropyrimidin-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    N-((1r,4r)-4-((1-benzoyl-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-5-chloro-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(oxazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(2-methylthiazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(isoxazole-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(1,2,3-thiadiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypyrazine-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbonyl)-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-imidazole-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(thiazole-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(1,2,5-thiadiazole-3-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(6-methoxypyridazine-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((1-(5-methylthiazole-2-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(1-fluorocyclopropane-1-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(imidazo[2,1-b]thiazole-6-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-fluoro-1-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((1-cyano-6'-fluoro-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-(difluoromethyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-(thiazole-2-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-(1,2,3-thiadiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(oxazole-4-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(isoxazole-3-carbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-2'-oxo-1-picolinoylspiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(6-methoxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(3-hydroxypicolinoyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((4'-fluoro-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((7'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((4'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((7'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((6'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((4'-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((5'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((2'-oxo-1-(thiazole-4-carbonyl)spiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((5'-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((6'-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((4'-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-N-((1r,4r)-4-((6'-methoxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((6'-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methoxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-3-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)-2-methylnicotinamide;
    5-chloro-2-methyl-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide; and
    5-chloro-2-(difluoromethyl)-N-((1r,4r)-4-((6'-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)cyclohexyl)nicotinamide;
    or a pharmaceutically acceptable salt thereof or a prodrug thereof.
  9. 　 A use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, prodrug, solvate or composition thereof for the manufacture of a medicament for the treatment of a condition or disorder in which CRHR2 is involved.
  10. 　 The use according to claim 9, wherein said condition or disorder is selected from the group consisting of: gastrointestinal disorders, major depressive disorders, schizophrenic disorders, neurodegenerative diseases, pain, dysfunction of appetite and food intake, sleep disorders, cognitive disorders, tolerance to and dependence on a number of substances, inflammation, fertility problems, sexual dysfunctions and pre-term birth and non-inflammatory urogenital disorders, allergic disorders, mast cell activation disorders, Cushing’s syndrome, emesis, gastrointestinal disorders, neurotoxic injury, loss of hair, heart disease, and combinations thereof.
  11. 　 The use according to claim 10, wherein the heart disease is selected from the group consisting of: acute and chronic heart failure, cardiovascular disease, hyper tension, myocardial infarction, coronary artery disease, and abdominal aortic aneurysm.
  12. 　 A method for the treatment of a condition or disorder in which CRHR2 is involved, in an animal, including a human, which comprises administering to the animal in need of such treatment a therapeutically effective amount of a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8.
  13. 　 The method according to claim 12, wherein said condition or disorder is selected from the group consisting of: gastrointestinal disorders, major depressive disorders, schizophrenic disorders, neurodegenerative diseases, pain, dysfunction of appetite and food intake, sleep disorders, cognitive disorders, tolerance to and dependence on a number of substances, inflammation, fertility problems, sexual dysfunctions and pre-term birth and non-inflammatory urogenital disorders, allergic disorders, mast cell activation disorders, Cushing’s syndrome, emesis, gastrointestinal disorders, neurotoxic injury, loss of hair, heart disease and combinations thereof.
  14. 　 The method according to claim 13, wherein the heart disease is selected from the group consisting of: acute and chronic heart failure, cardiovascular disease, hyper tension, myocardial infarction, coronary artery disease, and abdominal aortic aneurysm.
  15. 　 A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof or a prodrug thereof, according to any one of claims 1 to 8, and a pharmaceutically acceptable carrier.
  16. 　 The pharmaceutical composition according to claim 15, further comprising another pharmacologically active agent.
  17. 　 A compound according to any one of claims 1 to 8 or a prodrug thereof or a pharmaceutically acceptable salt for use in the treatment of a condition or disorder in which CRHR2 is involved.
  18. 　 A process for preparing a pharmaceutical composition, wherein the process comprises mixing a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a prodrug thereof and a pharmaceutically acceptable carrier or excipient.
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