Heteroaryl derivatives as DDR inhibitors

Abstract

The present invention relates to a compound of formula (I) that inhibits the discoidin domain receptor (DDR inhibitor), a method for preparing the compound, an intermediate compound useful for its preparation, a pharmaceutical composition containing the same, and therapeutic uses thereof. The compounds of the present invention may be useful, for example, in treating many diseases related to the DDR mechanism. JPEG2026521440000314.jpg3178(I)

Description

[Technical Field]

[0001] The present invention relates to compounds that inhibit discoidin domain receptors (DDR inhibitors), methods for preparing such compounds, intermediate compounds useful in such preparations, pharmaceutical compositions containing the same, and therapeutic uses thereof.

[0002] The compounds of the present invention may be useful, for example, in treating many disorders related to the DDR mechanism. [Background technology]

[0003] Discoidin domain receptors (DDRs) are type I transmembrane receptor tyrosine kinases (RTKs). The DDR family includes two distinct members, DDR1 and DDR2.

[0004] DDR is a unique receptor among the other members of the RTK superfamily; DDR is activated by collagen, while other members of the RTK superfamily are typically activated by soluble peptide-like growth factors (see Vogel, W. (1997) Mol. Cell 1, 13-23; Shrivastava A. Mol Cell. 1997; 1:25-34). Furthermore, DDR is an unusual RTK because it forms a non-covalently bound ligand-dependent stable dimer (see Noordeen, NA (2006) J. Biol. Chem. 281, 22744-22751; Mihai C. J Mol Biol. 2009; 385:432-445).

[0005] The DDR1 subfamily consists of five membrane-anchored isoforms, while the DDR2 subfamily is represented by a single protein. All five DDR1 isoforms share an extracellular domain and a transmembrane domain, but differ in their cytoplasmic regions (see Valiathan, RR (2012) Cancer Metastasis Rev. 31, 295-321; Alves, F. (2001) FASEB J. 15, 1321-1323).

[0006] The DDR receptor family has been found to be involved in pulmonary fibrosis and a range of fibrotic diseases, particularly idiopathic pulmonary fibrosis (IPF) or renal fibrosis. The first evidence for the protective role of DDR1 deficiency in pulmonary fibrosis was presented in 2006 by Dr. Vogel's research group (see Avivi-Green C, Am J Respir Crit Care Med 2006;174:420-427). The authors showed that DDR1-null mice were significantly protected against bleomycin (BLM)-induced injury. Furthermore, these animals showed significantly reduced myofibroblast proliferation and apoptosis compared to wild-type mice. Bronchoalveolar lavage cell count and cytokine ELISA confirmed the absence of inflammation in the knockout mice. These results indicate that DDR1 expression is required for the development of pneumonia and fibrosis.

[0007] DDR2 deficiency or downregulation reduces bleomycin-induced pulmonary fibrosis (see Zhao H, Bian H, Bu X, Zhang S, Zhang P, Yu J, et al Mol Ther 2016; 24:1734-1744). Zhao et al. showed that DDR2 plays a crucial role in inducing fibrosis and angiogenesis in the lung, and in particular, that DDR2 synergistically interacts with transforming growth factor (TGF)-β to induce myofibroblast differentiation. Furthermore, they showed that treating injured mice with specific siRNA against DDR2 demonstrated therapeutic efficacy against pulmonary fibrosis. In a second publication, Jia et al. showed that DDR2-deficient mice are protected from bleomycin-induced pulmonary fibrosis (see Jia S, Am J Respir Cell Mol Biol 2018; 59:295-305). Furthermore, DDR2-null fibroblasts are significantly more prone to apoptosis than wild-type fibroblasts, supporting the idea that apoptosis-resistant fibroblasts are important in the progression of fibrosis.

[0008] Discoidin domain receptor 1 (DDR1) is a key factor in renal disease by promoting inflammation and fibrosis, and blocking DDR1 expression after the onset of renal disease can delay or halt the progression of this pathology (see Kerroch et al., Sci Rep 6, 21262, 2016). DDR1 contributes to acute and chronic kidney injury by regulating the phosphorylation of BCR and STAT3, and consequently modulating the production of MCP-1 and TGF-β. In a DDR1-null mouse model, acute tubular injury, inflammation, and tubulointerstitial fibrosis were reduced, and monocyte chemotactic protein (MCP-1) levels and STAT3 activation were decreased throughout the kidney. These findings identify DDR1 as a promising therapeutic target that improves both pro-inflammatory and pro-fibrotic signaling in renal disease (see CM Borza et al., JCI Insight. 2022;7(3):e150887).

[0009] In the literature, some compounds are described as DDR1 or DDR2 antagonists.

[0010] Expert Opin. Ther. Patents 2020, Vol. 30, No. 5, 341-350, by Guo Jing et al. is a review article on discoidin domain receptor 1 (DDR1) modulators.

[0011] WO2023021278 and WO2023079291 disclose compounds as DDR1 and DDR2 inhibitors that are useful for the treatment of cancer and fibrous diseases, particularly in the lungs and kidneys.

[0012] US 2018 / 148450 A1 discloses triaza-spirodecanone as a DDR1 inhibitor.

[0013] US 2019 / 374526 A1 discloses an inhibitor of PR domain-containing protein 9. This discloses the conversion of 1-(3,5-dichlorophenyl)-3-(2-azaspiro[3.3]heptan-6-yl)urea HCl salt to 1-(3,5-dichlorophenyl)-3-(2-(2-methylpyridine-4-yl)-2-azaspiro[3.3]heptan-6-yl)urea (compound 239).

[0014] WO2023064370A1 discloses epoxide hydrolase (sEH) inhibitors. Page 53, paragraph 219 of this document discloses 1-(2-azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea.

[0015] Of particular note is the potential usefulness of antagonizing DDR receptors in treating fibrosis and diseases, disorders, or conditions resulting from fibrosis. Furthermore, antagonizing both receptors DDR1 and DDR2 may be especially effective in treating the aforementioned diseases, disorders, or conditions.

[0016] Over the past few years, several efforts have been made to develop novel DDR1 and DDR2 receptor antagonists useful for treating several diseases, and some of these compounds have shown efficacy in humans. However, there is still potential to develop selective inhibitors of both DDR1 and DDR2 receptors that would be useful for treating diseases, disorders, or conditions associated with DDR receptor dysregulation in the respiratory field, particularly idiopathic pulmonary fibrosis (IPF), and in the field of more common fibrotic diseases, especially renal fibrosis.

[0017] Novel selective inhibitors targeting both receptors DDR1 and DDR2 can be administered via inhalation to minimize systemic exposure and associated safety issues if they have a favorable inhalation profile (good activity in the lungs, good intrapulmonary retention, and low metabolic stability). Alternatively, novel inhibitors can be administered orally if they have a favorable oral profile, high oral bioavailability and low clearance, and appropriate physicochemical properties.

[0018] To this end, a novel series of compounds of general formula (I), as shown below, has been found to remarkably solve the problem of providing receptor DDR1 and DDR2 inhibitors for inhalation administration that act as selective inhibitors of DDR1 and DDR2 receptors to other human protein kinases. Such compounds exhibit high efficacy, a good inhalation profile, low metabolic stability, low systemic exposure, and improved safety and tolerability.

[0019] In a first embodiment, the present invention relates to formula (I): [ka] (I) [In the formula, A is [ka] (Here, [ka] (This indicates direct bonding to NH.) It is a ring selected from the group consisting of; W1, W2, and W3 are independently hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) halohydroxyalkyl, (C1-C4) alkoxy, (C1-C4) alkoxy-(C1-C4) alkyl, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, halogen, cyano, SF5, NR1R2-(C1-C4) alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7) cycloalkyl, (C1-C4) alkyl-heterocycloalkyl (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO-heterocycloalkyl-oxy, (C3-C7)cycloalkyl-(C1 -C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, (C1-C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1-C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl- Selected from the group consisting of sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl, preferably hydrogen, CH3, OCH3, OCF3, CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF3, SF5, F, Cl, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N-acetylazetidinyl-oxy, 2,2,A substituent on ring A selected from the group consisting of 2-trifluoro-1-hydroxyethyl, oxetanyloxy, CH2N(CH3)2, and 4-methylpiperazine-1-yl; or W1 and W2 are located adjacent to each other on ring A, and W1 and W2 form a (C5-C6) cycloalkyl or a 5-membered or 6-membered heterocycloalkyl, where the (C5-C6) cycloalkyl or 5-membered or 6-membered heterocycloalkyl may optionally be substituted with 1 to 3 halogen atoms; preferably, the 6-membered heterocycloalkyl is a pyranyl ring; L is selected from CO and CH2, or is absent; L1 is selected from NR, CH2, and O, where R is selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, and deuterated (C1-C4)alkyl, preferably from the group consisting of hydrogen, CD3, cyclopropylmethyl, cyclopropyl, CH2CF3, CH2CH3, and CH3; If L1 is NR, then R S It is selected from hydrogen and methyl; If L1 is CH2 or O, then R S is hydrogen; B is a monocyclic or bicyclic heteroaryl ring or a bicyclic semisaturated heteroaryl ring, preferably pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, imidazolyl, pyrazolyl, pyrazolo[1,5-a]pyradinyl, pyrazolo[1,5-a]pyradinyl, pyrazolo[3,4-d]pyradinyl, pyrazolo[1,5-a]pyradinyl, 1H-pyrazolo[3,4-b]pyradinyl, imidazo[1,2-b]pyradinyl, imidazo[1,2-a]pyradinyl, 1H-imidazo[1,2-b]pyrazolyl, imidazo[2,1-b]thiazolyl, pyrrolo[ Selected from the group consisting of 2,3-c]pyrimidinyl, pyrrolo[3,2-b]pyrimidinyl, 1H-pyrrolo[2,3-b]pyrimidinyl, pyrazolo[5,1-b]thiazolyl, imidazo[1,5-a]pyrimidinyl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazinyl, thieno[3,2-d]pyrimidinyl, thieno[3,2-b]pyrimidinyl, thieno[2,3-d]pyrimidinyl, pyrazolo[5,1-b][1,3]thiadinyl, pyrrolo[3,2-d]pyrimidinyl, pyrrolo[2,3-d]pyrimidinyl, and imidazo[1,2-a]pyrimidinyl; Y1 and Y2 are independently hydrogen, (C1-C4)alkyl, deuterated (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, halogen, cyano, SF5, (C1-C4)cyanoalkyl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, CONR1R2, NHCOR1, NR1R2, NR1R2-(C1-C4)alkyl, heterocycloalkyl which may be optionally substituted with 1 to 3 halogens, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, (C3-C7)cycloalkyl-( A substituent on ring B selected from the group consisting of monocyclic heteroaryls that may optionally be substituted with 1 to 3 groups selected from the group consisting of (C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, phenyl, (C1-C4)alkoxy-substituted phenyl, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-heterocycloalkyl-carbonyl, and monocyclic heteroaryls that may optionally be substituted with 1 to 3 groups selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy, and (C1-C4)alkoxy-(C1-C4)alkyl;Here, Y1 is preferably hydrogen, CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H, CF2H, CF2CH3, CF2CF3, CH2CF3, CH2OH, CH2CH2OH, CH2CH2OCH3, CH2CH2SCH3, CH2CH2F, CH2SCH3, SCF3, SO2CF3, CD3, cyano, NHCOCH3, NH2, (C1-C4) alkyl-piperazinyl, 4-methylpiperazin-1-yl, piperazinyl, morpholinyl, or pylori. Selected from the group consisting of dinyl, hydroxypyrrolidinyl, N-methyl-oxopiperazinyl, S,S-dioxide-thiomorpholinyl, oxetanyl-methyl, oxetanyl, (oxetanylamino)methyl, 1H-pyrazole-4-yl, oxazole-5-yl, pyridine-3-yl, pyrimidine-5-yl, pyridine-4-yl, dimethoxyphenyl, thiazole-5-yl, 3-isoxazole-5-yl, and 1-methyl-1H-pyrazole-4-yl, where Y2 is preferably hydrogen; R1 and R2 are independently from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylamino-(C1-C4)alkyl, di-(C1-C4)alkylamino-(C1-C4)alkyl, optionally substituted (C3-C7)cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted heterocycloalkyl-(C1-C4)alkoxy. R1 and R2 are selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, and carbamoyl; preferably, R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, and optionally substituted heterocycloalkyl; more preferably, R1 and R2 are independently selected from the group consisting of hydrogen, methyl, and oxetanyl; R3 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkylphenyl, and monocyclic heteroaryl; preferably, R3 is CH3 or p-tolyl. Compounds thereof or their stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts, This relates to a compound of formula (I) that is not 1-(3,5-dichlorophenyl)-3-(2-(2-methylpyridine-4-yl)-2-azaspiro[3.3]heptan-6-yl)urea, or its stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts.

[0020] In a second embodiment, the present invention refers to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt of formula (I) in a mixture with at least one pharmaceutically acceptable carrier and / or additive.

[0021] In a third embodiment, the present invention means a pharmaceutical composition for use as a pharmaceutical, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0022] In a further embodiment, the present invention means a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of diseases, disorders or conditions related to dysregulation of DDR.

[0023] In another embodiment, the present invention means a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of fibrosis, and / or the prevention and / or treatment of diseases, disorders or conditions associated with fibrosis.

[0024] In yet another embodiment, the present invention means a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF).

[0025] In a further embodiment, the present invention refers to a method for preparing a compound of formula (I), and intermediate compounds useful for preparing a compound of formula (I).

[0026] Detailed description of the present invention definition Unless otherwise specified, the compounds of formula (I) of the present invention are intended to include stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0027] Unless otherwise specified, the compounds of formula (I) of the present invention are intended to include the compounds of formulas (Ia), (Ib), (Ic), (Id), and (Ie).

[0028] As used herein, the term “pharmaceutically acceptable salt” means a derivative of the compound of formula (I), wherein the parent compound is appropriately modified by converting either a free acidic or basic group, if present, to any base or acid conventionally intended to be pharmaceutically acceptable and its corresponding addition salt. Suitable examples of such salts include inorganic acid or organic acid addition salts of salty residues such as amino groups, and inorganic base or organic base addition salts of acidic residues such as carboxyl groups.

[0029] The cations of inorganic bases that can be appropriately used to produce salts include ions of alkali metals or alkaline earth metals such as potassium, sodium, calcium, or magnesium.

[0030] Salts obtained by reacting a compound, specifically a major compound acting as a base, with an inorganic or organic acid include, for example, hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, camphorsulfonate, acetate, oxalate, maleate, fumarate, succinate, and citrate.

[0031] The term "stereoisomer" refers to isomers of the same composition but with different arrangements of atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0032] The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and cannot be superimposed.

[0033] The term "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomer species that does not exhibit optical activity.

[0034] If the compound of formula (I) of the present invention contains one or more chiral carbons, all of its stereoisomers are included in the scope of the present invention, both as a racemic mixture and as a mixture of all proportions of other stereoisomers.

[0035] As used herein, the terms "halogen," "halogen atom," or "halo" include fluorine (F), chlorine (Cl), bromine, and iodine atoms.

[0036] The term "(C1-C4) alkyl" refers to a linear or branched alkyl group having 1 to 4 carbon atoms. This term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Such groups are also referred to herein by their atomic arrangement, i.e., CH3, CH2CH3, etc.

[0037] The term "(C1-C4)haloalkyl" refers to a linear or branched alkyl group having 1 to 4 carbon atoms and containing at least one halogen substituent. For example, the term includes CF3 and C(CH3)2CF3.

[0038] The term "(C1-C4)alkoxy" refers to a linear or branched alkyl group having 1 to 4 carbon atoms, including at least one oxygen atom, particularly an oxygen atom directly bonded to ring A or ring B, that is, when W1, W2, W3, Y1, or Y2 are each independently (C1-C4)alkoxy. Examples include OCH3 and OCH2CH3.

[0039] The term "(C1-C4)haloalkoxy" refers to a (C1-C4) alkoxy containing at least one halogen substituent. Examples include OCF3 and OCF2H.

[0040] The term "(C1-C4) hydroxyalkyl" refers to an alkyl group containing at least one hydroxyl substituent. Examples include CH2OH, CH(OH)CH3, and CH2CH2OH.

[0041] The term "(C3-C7) cycloalkyl" refers to a saturated hydrocarbon ring containing 3 to 7 ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0042] The term "oxy" refers to the oxygen atom of the substituent immediately preceding "oxy" as a bonding site to ring A or ring B. For example, "heterocycloalkyl-oxy" refers to a heterocycloalkyl substituent bonded to ring A or ring B via an oxygen atom.

[0043] The term "deuterated" refers to a substituent in which one or more hydrogen atoms are replaced by deuterium, such as in CD3.

[0044] A "monocyclic or bicyclic heteroaryl (ring)" means a monocyclic or bicyclic aromatic group containing 5 to 10 ring atoms and 1 to 4 or 1 to 3 heteroatoms independently selected from N, S, and O, including groups having two such monocyclic rings, or groups in which such monocyclic rings are fused via a common bond with a monocyclic aryl ring such as a phenyl ring, or are linked by a single bond.Monocyclic or bicyclic heteroaryl rings include pyrazolyl, furanil, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, imidazolyl, benzofuranil, 1H-benzo[d]imidazolyl, 1H-indazolyl, benzothiophenyl, benzo[c]thiophenyl, quinazolinyl, pteridinyl, 1H-pyrazolo[5,1-c][1,2,4]triazolyl, pyrrolidinyl, indolidinyl, benzothiazolyl, pyrazolo[5,1-b]thiazolyl, 1H-imidazo[1,2-b]pyrazolyl, and 1H-pyrazolo[3 ,4-b]pyridinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, 1,6-dihydropyrrolo[2,3-b]pyrrolyl, 1,4-dihydropyrrolo[3,2-b]pyrrolyl, 4H-thieno[3,2-b]pyrrolyl, thieno[3,2-b]pyridinyl, isobenzofuranil, 1,2,4-triazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, tetrazolyl, 6H-floo[2,3-b]pyrrolyl, 6H-thieno[2,3-b]pyrrolyl, 4H-floo[3,2-b]pyridinyl Loryl, benzo[d]isothiazolyl, thiazolo[4,5-b]pyridinyl, 1,3,5-triazinyl, 1,2,3,4-thiatriazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,4-tetradinyl, 1,2,4,5-tetradinyl, 1,2,3,5-tetradinyl, 1H-imidazo[4,5-b]pyridinyl, 7H-purinyl, 1H-pyrrolyl, 1-methyl-1H-pyrrolyl, 1-methyl-1H-1,2,4-triazolyl, 1-methyl-1H-tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, imidazo This includes dazo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridazinyl, imidazo[1,2-a]pyridazinyl, imidazo[1,2-a]pyridazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrrolo[2,3-d]pyridinyl, pyrrrolo[3,2-d]pyridinyl, pyrrrolo[2,3-c]pyridinyl, thieno[3,2-d]pyridinyl, imidazo[2,1-b]thiazolyl, and imidazo[1,5-a]pyridinyl.

[0045] The term "bicyclic semisaturated heteroaryl ring" refers to a bicyclic group containing 7 to 11 ring atoms, 1 to 4 or 1 to 3 heteroatoms independently selected from N, S, and O, in which a monocyclic heteroaryl or phenyl ring is condensed with a monocyclic heterocycloalkyl or (C3-C7)cycloalkyl group. Suitable examples of bicyclic semisaturated heteroaryl rings include, for example, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 6,7-dihydro-5H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrzolo[4,3-b]pyridinyl, 2,3,4,5-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazinyl, 6,7-dihydro-5H-pyrzolo[5,1-b][1,3]thiadinyl, and 1-(4,5,6,7-tetrahydropyrzolo[1,5-a]pyridinyl).

[0046] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or spirocyclic ring system containing 3 to 12 ring atoms, each containing one or more heteroatoms, for example, 1 to 3, independently selected from N, S, and O. This definition includes ring systems where S can be in different oxidation states, e.g., S, SO, or SO2. This definition also includes ring systems where any ring carbon atom can be in different oxidation states, e.g., CH2, CH(OH), or CO. Examples of heterocycloalkyls include piperadinyl, pyrrolidinyl, azetidinyl, morpholinyl, S,S-dioxide-thiomorpholinyl, oxopiperazinyl, and piperidinyl.

[0047] The term "spirocyclic ring system" refers to a saturated or partially unsaturated bicyclic system of 5 to 12 ring atoms, containing one or more heteroatoms selected from N, S, and O, for example, 1 to 3 heteroatoms, where the two rings share only one carbon atom. Examples of spirocyclic ring systems include spiro[3.5]nonanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, 2-azaspiro[3.3]heptanyl, and 7L2 - Azaspiro[3.5]nonanyl and 2l 2 - Azaspiro[3.5]nonanil is one example.

[0048] For example, compound terms such as "(C1-C4)alkyl-heterocycloalkyl-carbonyl" should be intended to be conventionally interpreted by the groups from which they are derived; in this example, it must be interpreted by the (C1-C4)alkyl, heterocycloalkyl, and carbonyl groups linked together in the given sequence, where the last group in the sequence, the carbonyl group in this example, is the binding site to the residue portion of the compound of formula (I).

[0049] When referring to substituents, a dash ("-") not placed between two letters, words, or symbols indicates the bonding point of such substituents.

[0050] Unless otherwise specified, the carbonyl group is represented as CO in this specification.

[0051] When a basic amino group is present in the compound of formula (I), a physiologically acceptable anion may be present, which can be selected from chlorides, bromides, iodides, trifluoroacetates, formates, sulfates, phosphates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates, oxalates, succinates, benzoates, p-toluenesulfonates, pamoates, and naphthalenedisulfonates. Similarly, in the presence of an acidic group, a corresponding physiological cation may also be present, which may include, for example, alkali metal ions or alkaline earth metal ions.

[0052] The term "Ki" represents the dissociation constant for an enzyme-inhibitor complex, expressed in molar units. It is an indicator of the binding affinity between the inhibitor and the DDR1 or DDR2 receptor.

[0053] As described above, the present invention refers to a series of compounds represented by general formula (I), which are described in detail below herein, that have inhibitory activity against receptors DDR1 and DDR2. Antagonism to receptors DDR1 and DDR2 may be particularly effective in treating diseases in which DDR receptors play a role, such as fibrosis and any other disease, disorder, or condition associated with fibrosis.

[0054] In fact, as described in the experimental section below, the compounds of formula (I) of the present invention can act as inhibitors of both DDR1 and / or DDR2 receptors in a substantially efficient manner. In particular, Table 44 below shows that the inhibitory activity (expressed as Ki) against DDR1 and DDR2 receptors in binding assays for representative compounds of the present invention is less than 100 nM. This indicates that the two isoforms of the DDR receptor, which are primarily involved in fibrosis and diseases arising from fibrosis, can be inhibited. Therefore, the compounds of formula (I) can be used in the treatment of fibrosis, particularly pulmonary fibrosis, when DDR1 and DDR2 are involved.

[0055] In contrast to compounds C1 and C2, which are characterized by having different linkers substituting the -NH-CO-L1-linker of the compounds of the present invention, and in contrast to compound C3, which is characterized by an inverted central core, the presence of the above-mentioned -NH-CO-L1-linker and the central core defined above in the compounds of the present invention unexpectedly and significantly determines the high inhibitory activity against DDR1 and DDR2 receptors.

[0056] Advantageously, the compounds of the present invention are highly potent and can be administered to humans at very low doses, thus potentially reducing the adverse events that can typically occur when administering drugs.

[0057] In addition to its notable efficacy in terms of inhibitory activity against both DDR1 and DDR2 receptors, the compounds of the present invention are also characterized as selective inhibitors of DDR1 and DDR2 receptors to other human protein kinases, enabling them to act efficiently on the lung compartment with a favorable inhalation profile, while simultaneously minimizing drawbacks related to systemic exposure, such as safety and tolerability issues.

[0058] Therefore, the compounds of the present invention are useful for the treatment of fibrosis, particularly idiopathic pulmonary fibrosis, and are administered via inhalation. They feature a good inhalation profile that corresponds to good activity in the lungs, good lung retention, and low metabolic stability, and are particularly valuable when considering appropriate and effective compounds that minimize systemic exposure and associated safety issues.

[0059] Alternatively, the compounds of the present invention may be administered orally for the treatment of fibrosis if they are characterized by a good oral profile, high oral bioavailability and low clearance, and appropriate physicochemical properties.

[0060] Therefore, the present invention is based on formula (I): [ka] (I) [In the formula, A is [ka] (Here, [ka] (This indicates direct bonding to NH.) It is a ring selected from the group consisting of; W1, W2, and W3 are independently hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) halohydroxyalkyl, (C1-C4) alkoxy, (C1-C4) alkoxy-(C1-C4) alkyl, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, halogen, cyano, SF5, NR1R2-(C1-C4) alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7) cycloalkyl, (C1-C4) alkyl-heterocycloalkyl (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO-heterocycloalkyl-oxy, (C3-C7)cycloalkyl-(C1 -C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, (C1-C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1-C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl- Selected from the group consisting of sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl, preferably hydrogen, CH3, OCH3, OCF3, CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF3, SF5, F, Cl, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N-acetylazetidinyl-oxy, 2,2,A substituent on ring A selected from the group consisting of 2-trifluoro-1-hydroxyethyl, oxetanyloxy, CH2N(CH3)2, and 4-methylpiperazin-1-yl; or W1 and W2 are located adjacent to each other on ring A, and W1 and W2 form a (C5-C6) cycloalkyl or a 5-membered or 6-membered heterocycloalkyl, where the (C5-C6) cycloalkyl or 5-membered or 6-membered heterocycloalkyl may optionally be substituted with 1 to 3 fluorine atoms; preferably, the 6-membered heterocycloalkyl is a pyranyl ring; L is selected from CO and CH2, or is absent; L1 is selected from NR, CH2, and O, where R is selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, and deuterated (C1-C4)alkyl, preferably hydrogen, CD3, cyclopropylmethyl, CH2CF3, CH2CH 3および Selected from the group consisting of CH3; If L1 is NR, then R S It is selected from hydrogen and methyl; If L1 is CH2 or O, then R S is hydrogen; B is a monocyclic or bicyclic heteroaryl ring or a bicyclic semisaturated heteroaryl ring; Y1 and Y2 are independently hydrogen, (C1-C4) alkyl, deuterated (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, halogen, cyano, SF5, (C1-C4) cyanoalkyl, (C1-C4) alkyl-sulfonyl, (C1-C4) haloalkyl-sulfonyl, CONR1R2, NHCOR1, NR1R2, NR1R2- (C1-C4)alkyl, heterocycloalkyl which may be optionally substituted with 1 to 3 halogens, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocyclo A substituent on ring B selected from the group consisting of alkyl-(C1-C4)alkoxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, phenyl, (C1-C4)alkoxy-substituted phenyl, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-heterocycloalkyl-carbonyl, and monocyclic heteroaryl which may be optionally substituted with 1 to 3 groups selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy, and (C1-C4)alkoxy-(C1-C4)alkyl; where Y1 is preferably hydrogen, CH3, OCH3, OCF3, CF 3、Selected from the group consisting of C(CH3)3, C(CH3)2CF3, CONH2, OCF2H, CF2H, CF2CH3, CF2CF3, CH2CF3, CH2OH, CH2CH2OH, CH2CH2OCH3, CH2CH2SCH3, CH2CH2F, CH2SCH3, SCF3, SO2CF3, CD3, cyano, NHCOCH3, NH2, (C1-C4)alkyl-piperazinyl, 4-methylpiperazin-1-yl, piperazinyl, morpholinyl, pyrrolidinyl, hydroxypyrrolidinyl, N-methyl-oxopiperazinyl, S,S-dioxide-thiomorpholinyl, oxetanyl-methyl, oxetanyl, (oxetanylamino)methyl, 1H-pyrazol-4-yl, oxazol-5-yl, pyridin-3-yl, pyrimidin-5-yl, pyridin-4-yl, dimethoxyphenyl, thiazol-5-yl, 3-isoxazol-5-yl and 1-methyl-1H-pyrazol-4-yl, Y2 is preferably hydrogen; in a preferred embodiment, Y1 is selected from the group consisting of hydrogen, CH3 and 1-methyl-1H-pyrazol-4-yl, and Y2 is hydrogen; in another preferred embodiment, both Y1 and Y2 are hydrogen relates to the compound of

[0061] R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylamino-(C1-C4)alkyl, di-(C1-C4)alkylamino-(C1-C4)alkyl, optionally substituted (C3-C7)cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heterocycloalkyl-(C1-C4)alkoxy, where the optional substituents are 1 to 3 in number and are selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy and carbamoyl; the optional substituents are preferably selected from the group consisting of CH3, OCH3, OCF3, CF 3、 selected from the group consisting of C(CH3)3, C(CH3)2CF3, CONH2, OCF2H and CF2H

[0062] R3 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkylphenyl and monocyclic heteroaryl; preferably R3 is CH3 or p-tolyl, and is a compound or its stereoisomers, tautomers, solvates and pharmaceutically acceptable salts, wherein the compound of formula (I) is not 1-(3,5-dichlorophenyl)-3-(2-(2-methylpyridine-4-yl)-2-azaspiro[3.3]heptan-6-yl)urea.

[0063] All meanings described for each variable part A, B, L, L1, R, W1, W2, W3, Y1, Y2, R1, R2, R3, and Rs of the compound of formula (I) of the present invention are intended as alternatives and can be combined with each other in embodiments included in the scope of the invention.

[0064] Preferred halogens are fluorine and chlorine, either alone or in groups containing them (e.g., (C1-C4)haloalkyl and (C1-C4)haloalkoxy substituents), with fluorine being more preferred.

[0065] W1, W2, and W3 are substituents on ring A and can be attached to any available position on A. Ortho and meta positions are preferred.

[0066] In one embodiment, when the A ring is phenyl and L1 is NH, W1, W2, and W3 are independently hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1-C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, fluorine, bromine, iodine, cyano, SF5, NR1R2-(C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7) Chloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO-heterocycloalkyl-oxy, ( C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, (C1-C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1-C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C 4) Selected from the group consisting of alkyl-sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl; or W1 and W2 are located in adjacent positions on ring A, and W1 and W2 form a (C5-C6)cycloalkyl or a 5-membered or 6-membered heterocycloalkyl, where the (C5-C6)cycloalkyl or 5-membered or 6-membered heterocycloalkyl may optionally be substituted with 1 to 3 halogen atoms; preferably, the 6-membered heterocycloalkyl is a pyranyl ring;W1, W2, and W3 are preferably selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF3, SF5, F, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N-acetylazetidinyl-oxy, 2,2,2-trifluoro-1-hydroxyethyl, oxetanyl-oxy, CH2N(CH3)2, and 4-methylpiperazin-1-yl; more preferably, W1, W2, and W3 are selected from the group consisting of H, CH3, OCH3, OCF3, CF3, OCF2H, cyano, SF5, F, Br, I, CH2OH, CF2CF3, and CH2CF3.

[0067] In another embodiment, W1, W2, and W3 are independently hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1-C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, fluorine, bromine, iodine, cyano, SF5, NR1R2-(C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl Kill-heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO-heterocycloalkyl-oxy, (C3-C7)cycloalkyl alkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, (C1-C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1-C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl Selected from the group consisting of l-sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl; or W1 and W2 are located adjacent to each other on ring A, and W1 and W2 form a (C5-C6)cycloalkyl or a 5-membered or 6-membered heterocycloalkyl, where the (C5-C6)cycloalkyl or 5-membered or 6-membered heterocycloalkyl may optionally be substituted with 1 to 3 halogen atoms; preferably, the 6-membered heterocycloalkyl is a pyranyl ring;W1, W2, and W3 are preferably selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF3, SF5, F, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N-acetylazetidinyl-oxy, 2,2,2-trifluoro-1-hydroxyethyl, oxetanyl-oxy, CH2N(CH3)2, and 4-methylpiperazin-1-yl; more preferably, W1, W2, and W3 are selected from the group consisting of H, CH3, OCH3, OCF3, CF3, OCF2H, cyano, SF5, F, Br, I, CH2OH, CF2CF3, and CH2CF3.

[0068] L is a linker, which can be selected from CO and CH2, or may be absent.

[0069] L1 is a linker and can be selected from NR, CH2, and O, where R can preferably be selected from the group consisting of hydrogen, CD3, cyclopropylmethyl, cyclopropyl, CH2CF3, CH2CH3, and CH3.

[0070] If L1 is NR, then Rs is hydrogen or methyl; if L1 is CH2 or O, then R S It is hydrogen.

[0071] B is preferably pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, imidazolyl, pyrazolyl, pyrazolo[1,5-a]pyradinyl, pyrazolo[1,5-a]pyradinyl, pyrazolo[3,4-d]pyradinyl, pyrazolo[1,5-a]pyradinyl, 1H-pyrazolo[3,4-b]pyradinyl, imidazo[1,2-b]pyradinyl, imidazo[1,2-a]pyradinyl, 1H-imidazo[1,2-b]pyrazolyl, imidazo[2,1-b]thiazolyl, pyrrolo[2,3-c]pyradinyl, pyrrolo[3,2 Selected from the group consisting of -b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[5,1-b]thiazolyl, imidazo[1,5-a]pyridinyl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazinyl, thieno[3,2-d]pyridinyl, thieno[3,2-b]pyridinyl, thieno[2,3-d]pyridinyl, pyrazolo[5,1-b][1,3]thiadinyl, pyrrolo[3,2-d]pyridinyl, pyrrolo[2,3-d]pyridinyl, and imidazo[1,2-a]pyridinyl. Any ring B can be attached to the L portion at any available position in its monocyclic or bicyclic ring system.

[0072] Y1 is a substituent of ring B and can be bonded to any available position on B. Y1 is preferably hydrogen, CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H, CF2H, CF2CH3, CF2CF3, CH2CF3, CH2OH, CH2CH2OH, CH2CH2OCH3, CH2CH2SCH3, CH2CH2F, CH2SCH3, SCF3, SO2CF3, CD3, cyano, NHCOCH3, NH2, (C1-C4) alkyl-piperazinyl, 4-methylpiperazin-1-yl, piperazinyl, morpholinyl, pyrrolidinyl, hydroxypyrrolidinyl, N-methyl Y1 is selected from the group consisting of tyl-oxopiperazinyl, S,S-dioxide-thiomorpholinyl, oxetanyl-methyl, oxetanyl, (oxetanylamino)methyl, 1H-pyrazole-4-yl, oxazole-5-yl, pyridine-3-yl, pyrimidine-5-yl, pyridine-4-yl, dimethoxyphenyl, thiazole-5-yl, 3-isoxazole-5-yl, and 1-methyl-1H-pyrazole-4-yl; more preferably, Y1 is selected from the group consisting of hydrogen, CH3, and 1-methyl-1H-pyrazole-4-yl.

[0073] Y2 is a substituent of ring B and can be bonded to any available position on B. Y2 may have a similar preferred meaning to Y1. In a more preferred embodiment, Y2 is hydrogen.

[0074] R1 and R2 are preferably independently selected from the group consisting of hydrogen, (C1-C4) alkyl and optionally substituted heterocycloalkyl; more preferably, R1 and R2 are independently selected from the group consisting of hydrogen, methyl and oxetanyl.

[0075] R3 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkylphenyl, and monocyclic heteroaryl, and is preferably CH3 or p-tolyl.

[0076] Therefore, in a preferred embodiment, the present invention relates to a compound of formula (I), A is [ka] It is a ring selected from the group consisting of; More preferably, A is selected from the group consisting of phenyl, 3-pyridinyl, 2-pyridinyl, 3-pyridazinyl, 3-isoxazolyl, and pyrazolyl, where R3 is CH3 or p-tolyl; W1, W2, and W3 are selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF3, SF5, F, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N-acetylazetidinyl-oxy, 2,2,2-trifluoro-1-hydroxyethyl, oxetanyl-oxy, and CH2N(CH3)2; more preferably, W1, W2, and W3 are selected from the group consisting of H, CH3, OCH3, OCF3, CF3, OCF2H, cyano, SF5, F, Br, I, CH2OH, CF2CF3, and CH2CF3.

[0077] L is selected from CO and CH2, or is absent, preferably CO; L1 is selected from NR, CH2, and O, preferably NR, where R is preferably selected from the group consisting of hydrogen, CD3, cyclopropylmethyl, cyclopropyl, CH2CF3, CH2CH3, and CH3; B includes pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyridinyl, pyrazolo[1,5-a]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridinyl, 1H-imidazo[1,2-b]pyrazolyl, imidazo[2,1-b]thiazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b Selected from the group consisting of ]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[5,1-b]thiazolyl, imidazo[1,5-a]pyridinyl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazinyl, thieno[3,2-d]pyridinyl, thieno[3,2-b]pyridinyl, thieno[2,3-d]pyridinyl, pyrazolo[5,1-b][1,3]thiadinyl, pyrrolo[3,2-d]pyridinyl, pyrrolo[2,3-d]pyridinyl, and imidazo[1,2-a]pyridinyl; Y1 is hydrogen, CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H, CF2H, CF2CH3, CF2CF3, CH2CF3, CH2CH2OH, CH2CH2OCH3, CH2CH2SCH3, CH2CH2F, CH2SCH3, SCF3, SO2CF3, CD3, cyano, NHCOCH3, NH2, (C1-C4) alkyl-piperazinyl, 4-methylpiperazin-1-yl, piperazinyl, morpholinyl, pyrrolidinyl Selected from the group consisting of hydroxypyrrolidinyl, N-methyl-oxopiperazinyl, S,S-dioxide-thiomorpholinyl, oxetanyl-methyl, oxetanyl, (oxetanylamino)methyl, 1H-pyrazole-4-yl, oxazole-5-yl, pyridine-3-yl, pyrimidine-5-yl, pyridine-4-yl, dimethoxyphenyl, thiazole-5-yl, 3-isoxazole-5-yl, and 1-methyl-1H-pyrazole-4-yl, where Y2 is hydrogen; R1 and R2 are preferably independently selected from the group consisting of hydrogen, (C1-C4) alkyl and optionally substituted heterocycloalkyl; more preferably, R1 and R2 are independently selected from the group consisting of hydrogen, methyl and optionally substituted oxetanyl, and optionally substituents, if present, are selected from the group consisting of CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H and CF2H, and are compounds or their stereoisomers, tautomers, solvates and pharmaceutically acceptable salts.

[0078] In another preferred embodiment, the present invention relates to a compound of formula (I) in which L is CO and L1 is NR, and formula (Ia): [ka] (Ia) [In the formula, W1, W2, W3, A, B, R, Rs, Y1, and Y2 are as defined above.] This relates to the compound shown.

[0079] In yet another preferred embodiment, the present invention relates to a compound of formula (I) in which L is CH2 and L1 is NR, and formula (Ib): [ka] (Ib) [In the formula, W1, W2, W3, A, B, R, Rs, Y1, and Y2 are as defined above.] This relates to the compound shown.

[0080] In a more preferred embodiment, the present invention relates to a compound of formula (I) in which L is absent and L1 is NR, wherein formula (Ic): [ka] (I C) [In the formula, W1, W2, W3, A, B, R, Rs, Y1, and Y2 are as defined above.] This relates to the compound shown.

[0081] In another preferred embodiment, the present invention relates to a compound of formula (I) in which L1 is CH2, and formula (Id): [ka] (Id) [In the formula, W1, W2, W3, A, B, L, Y1 and Y2 are as defined above, and Rs is hydrogen.] The present invention relates to compounds represented by [formula]. In a particularly preferred embodiment, the present invention relates to compounds of formula (Id) where L is CO.

[0082] In another preferred embodiment, the present invention relates to a compound of formula (I) in which L1 is O, and formula (Ie): [ka] (Ie) [In the formula, W1, W2, W3, A, B, L, Y1 and Y2 are as defined above, and Rs is hydrogen.] The present invention relates to compounds represented by [formula]. In a particularly preferred embodiment, the present invention relates to compounds of formula (Ie) where L is CO.

[0083] Particularly preferred embodiments of the present invention are compounds of formula (Ia) listed in Table 1 below and their pharmaceutically acceptable salts. These compounds are particularly active on receptors DDR1 and DDR2, as further shown in Table 44 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 [Table 1-39] [Table 1-40] [Table 1-41] [Table 1-42] [Table 1-43] [Table 1-44] [Table 1-45] [Table 1-46] [Table 1-47] [Table 1-48]

[0084] A particularly preferred embodiment of the present invention is a compound of formula (Ib) defined above [wherein A is optionally substituted phenyl, L1 is NH, and B is selected from imidazo[1,2-a]pyradinyl and 1H-pyrazolo[3,4-b]pyridinyl].

[0085] More particularly preferred compounds of formula (Ib) are the compounds listed in Table 2 below and their pharmaceutically acceptable salts. These compounds are particularly active against receptors DDR1 and DDR2, as further shown in Table 44 below. [Table 2]

[0086] Further particularly preferred embodiments of the present invention are compounds of formula (Ic) defined above [wherein A is optionally substituted phenyl or pyridinyl, B is selected from 1H-pyrazolo[3,4-b]pyridinyl, imidazo[1,5-a]pyridinyl and 1H-pyrrolo[2,3-b]pyridinyl, and R is preferably hydrogen or CH3].

[0087] More particularly preferred compounds of formula (Ic) are the compounds listed in Table 3 below and their pharmaceutically acceptable salts. These compounds are particularly active against receptors DDR1 and DDR2, as further shown in Table 44 below. [Table 3-1] [Table 3-2]

[0088] Further particularly preferred embodiments of the present invention are compounds of formula (Id) defined above [wherein A is optionally substituted phenyl or pyridinyl, L is CO, and B is selected from pyrazolo[5,1-b]thiazolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,5-a]pyridinyl, thieno[3,2-b]pyridinyl, 1H-imidazo[1,2-b]pyrazolyl and pyrazolo[5,1-b]thiazolyl].

[0089] More particularly preferred compounds of formula (Id) are the compounds listed in Table 4 below and their pharmaceutically acceptable salts. These compounds are particularly active against receptors DDR1 and DDR2, as further shown in Table 44 below. [Table 4-1] [Table 4-2] [Table 4-3]

[0090] Furthermore, a particularly preferred embodiment of the present invention is a compound of formula (Ie) defined above [wherein A is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridinyl, and optionally substituted isoxazolyl, L is CO, and B is selected from pyrazolo[5,1-b]thiazolyl and 1H-imidazo[1,2-b]pyrazolyl].

[0091] More particularly preferred compounds of formula (Ie) are the compounds listed in Table 5 below and their pharmaceutically acceptable salts. These compounds are particularly active against receptors DDR1 and DDR2, as further shown in Table 44 below. [Table 5-1] [Table 5-2] [Table 5-3]

[0092] The compounds of the present invention, including all the compounds listed above herein, can be prepared from readily available starting materials using the following general methods and procedures, or using slightly modified methods readily available to those skilled in the art. Specific embodiments of the present invention may be shown or described herein, but those skilled in the art will recognize that all embodiments or aspects of the present invention can be obtained using the methods described herein or other known methods, reagents, and starting materials. Given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be readily determined by those skilled in the art through routine optimization procedures. Therefore, the processes described below should not be considered to limit the range of synthetic methods available for the preparation of the compounds of the present invention.

[0093] In some cases, a commonly known protecting group (PG) may be used to mask or protect the sensitive or reactive moiety, in accordance with the general principles of chemistry (Protective group in organic syntheses, 3rd edition, TW Greene, PGMWuts).

[0094] The compounds of formula (I) can be prepared as shown in Figures 1 to 6 below, which provide at least one non-restrictive synthetic route for the preparation of the illustrated compounds (i.e., the examples).

[0095] Compounds of formula (I), in particular, compounds of formula (Ia) [wherein L is CO and L1 is NR], can be prepared, for example, according to Scheme 1 described below.

[0096] Scheme 1 [ka] According to Scheme 1, intermediate urea III can be prepared by reacting amine II [wherein Rs is hydrogen or methyl] with isocyanate X at room temperature in a suitable solvent such as DCM. Next, intermediate compound IVa can be obtained from intermediate III by deprotecting Boc under acidic conditions, for example, by using TFA at room temperature in a suitable solvent such as DCM.

[0097] Alternatively, intermediate urea III can be prepared by reacting amine II with a suitable 2,2,2-trichloroethyl carbamate (Troc carbamate) XXII obtained from a suitable amine XV and 2,2,2-trichloroethyl chloroformate in a microwave oven at a temperature range of 80°C to 150°C in a suitable solvent mixture such as ACN, in the presence of a base such as DIPEA.

[0098] Next, carboxylic acid XI and intermediate compound IVa can be reacted under appropriate amide coupling conditions, for example, in the presence of an activator such as HATU or TBTU and an organic base such as DIPEA or TEA, in a suitable organic solvent such as DCM or DMF, at room temperature for several hours to overnight, to obtain the compound of formula (Ia). Alternatively, the compound of formula (Ia) can be prepared from amine IVa and acyl chloride XIV obtainable from carboxylic acid XI, in a solvent such as DCM, in the presence of a suitable chlorinating agent such as POCl3, thionyl chloride, or oxalyl chloride, and in the presence of a catalytic amount of DMF if necessary, at a temperature in the range of 5°C to 50°C. Alternatively, the compound of formula (Ia) can also be prepared by direct amidation, in which carboxylic acid XI is converted to a transiently activated acylimidazolinium intermediate in the presence of TCFH and 1-methylimidazole, and then reacted with amine IVa in a solvent such as DMF, usually at room temperature.

[0099] Compounds of formula (Ia) in which Y1 is bromine can be converted to different compounds of formula (Ia) in which Y1 may be substituted phenyl or heteroaryl boronic acid esters / acids by palladium-catalyzed cross-coupling. The reaction can be carried out by the usual Suzuki protocol at high temperature (about 100°C) for several hours in a suitable organic solvent such as dioxane, in the presence of an inorganic base such as potassium carbonate, and using a suitable palladium catalyst system such as Pd(dppf)Cl2. Compounds of formula (Ia) in which Y1 is bromine can be converted to different compounds of formula (Ia) in which Y1 is heterocycloalkyl by electrochemical reaction with heterocycloalkylamines (i.e., heterocycloalkyls in which the NH group is part of the ring) in a suitable solvent such as DMA, in the presence of dibromonique and an electrolyte such as TBAB.

[0100] Compounds of formula (I), in particular compounds of formula (Ib) [wherein L is CH2 and L1 is NR], or compounds of formula (Ic) [wherein L is absent and L1 is NR], can be prepared, for example, according to Scheme 2 described below.

[0101] Scheme 2 [ka] As shown in Scheme 2, intermediate compound IVa can be converted to the compound of formula (Ib) by applying reductive amination conditions with appropriate aldehyde XII in a suitable solvent such as DCM or EtOH, in the presence of an acid such as acetic acid, and optionally in the presence of a dehydrating agent such as magnesium sulfate, at a temperature in the range of room temperature to 50°C, using a suitable reducing agent such as STAB or NaCNBH3.

[0102] Otherwise, intermediate compound IVa can be converted to the compound of formula (Ic) by a cross-coupling reaction, such as a Buchwald coupling, with a suitable aryl halide XIII, preferably an aryl bromide (X=Br), at a high temperature (about 100°C) for several hours in an organic solvent such as DMA, using a suitable base such as Cs2CO3, in the presence of a palladium catalyst such as Pd(dppf)Cl2, or another palladium source / phosphine-based ligand.

[0103] If a protecting group is present on aryl halide XIII or intermediate compound IVa, the compound of formula (I) may be obtained after an additional step of removing the protecting group using TFA or HCl in 4-dioxane, or using TBAF, under necessary conditions such as acidic conditions.

[0104] The compound of formula (Ic) can also be prepared according to scheme 2a described below.

[0105] Scheme 2a [ka] According to Scheme 2a, intermediate compound XXIII can be obtained by protecting amine II, as defined above, with phenyl chloroformate in a suitable solvent such as DCM or siRNA, and / or water, at a temperature of -5°C to room temperature, optionally in the presence of TEA. Similarly, N-(benzyloxycarbonyloxy)succinimide or 4-nitrophenyl chloroformate can be used for the protection of amine II. Next, intermediate compound XXIV can be prepared by deprotecting intermediate compound XXIII under acidic conditions, for example, by using TFA in a suitable solvent such as DCM, at room temperature. Intermediate compound XXIV can be converted to intermediate compound XXV by a cross-coupling reaction with a suitable aryl halide XIII', for example, by Buchwald coupling, in an organic solvent such as DMA or Me-THF, using a suitable base such as Cs2CO3, at a high temperature (about 100°C) for several hours, in the presence of a palladium catalyst such as Pd-175 or Pd(dppf)Cl2, or another palladium source / phosphine ligand, where Y1' / Y2' may be Y1 / Y2, or may have a protecting group such as Boc or SEM, and halide X is preferably a bromide. Next, the compound of formula XXVI can be prepared by subjecting intermediate compound XXV to an amine deprotection reaction for several hours at around room temperature in a suitable solvent such as ethanol in the presence of a palladium catalyst, triethylsilane or 10% Pd / C, and hydrogen (optionally, if a protecting group is present on the Y substituent, deprotection can then be carried out at room temperature under acidic conditions, for example, by using TFA in a suitable solvent such as DCM, or by using TBAF in THF).

[0106] Next, the compound of formula (Ic) can be prepared by reacting intermediate compound XXVI with either a suitable 2,2,2-trichloroethyl carbamate (Troc carbamate) XXII, which can be obtained from a suitable amine XV and 2,2,2-trichloroethyl chloroformate, or intermediate compound XVI, which can be obtained from a suitable amine XV and phenyl chloroformate, in a suitable solvent mixture such as ACN or THF, in the presence of a base such as DIPEA, at a temperature ranging from room temperature to 150°C, and in a few cases in a microwave oven, followed by deprotection of any protecting group on the W1, W2, or W3 substituent. For example, acidic conditions can be used for room temperature cleavage of SEM protecting groups such as TFA in DCM or TBAF in THF.

[0107] The compound of formula (Ia) can also be prepared according to scheme 3 described below.

[0108] Scheme 3 [ka] Intermediate VI can be prepared from amine V and acyl chloride XIV (defined in Scheme 1), which can be obtained from carboxylic acid XI (defined in Scheme 1), in a solvent such as DCM, in the presence of a suitable chlorinating agent such as POCl3, thionyl chloride, or oxalyl chloride, at a temperature in the range of 5°C to 50°C, and optionally in the presence of a catalytic amount of DMF; amine V and acyl chloride XIV can undergo amide bonding at room temperature in a suitable solvent such as DCM, in the presence of a suitable base such as TEA. Alternatively, intermediate VI can be prepared by direct amidation of carboxylic acid XI, by converting it to a transient activated acylimidazolinium intermediate in the presence of TCFH and 1-methylimidazole, followed by reaction with amine V in a solvent such as DMF, generally at room temperature. Intermediate VII can then be obtained by Boc deprotection of intermediate VI under acidic conditions, for example, by using TFA in a suitable solvent such as DCM at room temperature. The compound of formula (Ia) can be prepared by reacting intermediate VII with isocyanate X (see Scheme 1) in a suitable solvent such as DCM at room temperature. Alternatively, the compound of formula (Ia) can be prepared by reacting intermediate VII with amine XV (see Scheme 1) and triphosgene in a suitable solvent such as DCM at a temperature in the range of 0°C to room temperature.

[0109] Furthermore, the compound of formula (Ic) can be prepared according to scheme 3a described below.

[0110] Scheme 3a [ka] Intermediate compound XXVII can be obtained by cross-coupling, for example, Buchwald coupling, with a suitable aryl halide XIII, preferably an aryl bromide (X=Br), starting from amine V, in an organic solvent such as DMA, using a suitable base such as Cs2CO3, and at a high temperature (about 100°C) for several hours, in the presence of a palladium catalyst such as Pd(dppf)Cl2, or another palladium source / phosphine ligand. Next, intermediate compound XXVIII can be obtained by Boc-deprotecting intermediate XXVII at room temperature using TFA in a suitable solvent such as DCM under acidic conditions. The compound of formula (Ic) can be prepared by reacting intermediate XXVIII with a suitable 2,2,2-trichloroethyl carbamate (Troc carbamate) XXII, which can be obtained from a suitable amine XV (see scheme 1) and 2,2,2-trichloroethyl chloroformate, in a microwave oven at a temperature in the range of 80°C to 150°C in a suitable solvent mixture such as ACN, in the presence of a base such as DIPEA.

[0111] The compound of formula (Ia) can be prepared according to scheme 4 described below.

[0112] Scheme 4 [ka] The compound of formula (Ia) can be prepared by reacting intermediate VII with a suitable phenylcarbamate XVI, which can be obtained from a suitable amine XV (see Scheme 1) and phenyl chloroformate, in a suitable solvent mixture such as a mixture of Â, DCM and water, at a temperature of 0°C to room temperature. Alternatively, a suitable amine XV can be reacted with N-(benzyloxycarbonyloxy)succinimide in a suitable solvent such as DCM, in the presence of TEA, at a temperature of -5°C to room temperature to obtain a benzyloxycarbonyl protected amine XV.

[0113] The compound of formula (Ia) can also be prepared by reacting intermediate VII with a suitable 2,2,2-trichloroethylcarbamate (Troc carbamate) XXII (see scheme 1), which can be obtained as described above.

[0114] Alternatively, the compound of formula (Ia) may be prepared by reacting a suitable amine XV with intermediate VII and intermediate VIII, which can be obtained from phenyl chloroformate, in a suitable solvent mixture such as a mixture of ¼, DCM, and water at a temperature that varies from 0°C to room temperature.

[0115] A compound of formula (Id) whose L1 is CH2 can be prepared, for example, according to scheme 5 described below.

[0116] Scheme 5 [ka] According to Scheme 5, intermediate XVIII can be prepared by reacting commercially available carboxylic acid XVII (wherein Rs is hydrogen) with a suitable amine XV (see Scheme 1) in a suitable organic solvent such as DCM or DMF, generally at around room temperature, for a period ranging from several hours to overnight, under appropriate amide coupling conditions, for example, in the presence of an activator such as HATU or TBTU and an organic base such as DIPEA or TEA. Alternatively, compound XVIII can be prepared by the direct amidation of carboxylic acid XVII, i.e., a transient conversion to an activated acylimidazolinium intermediate in the presence of TCFH and 1-methylimidazole, followed by a reaction with amine XV in a solvent such as DMF, generally at around room temperature.

[0117] Next, intermediate compound IVb can be obtained by deprotecting intermediate XVIII under acidic conditions, for example, by using TFA at room temperature in a suitable solvent such as DCM. Subsequently, intermediate compound IVb can be reacted with carboxylic acid XI as described in Scheme 1, or with aldehyde XII or aryl halide XIII as described in Scheme 2 to obtain the compound of formula (Id) [wherein L is CO or CH2, or is absent]. Intermediate compound IVb can be reacted with aryl halide XIII', followed by a deprotection reaction as described for the synthetic route in Scheme 2a, to finally obtain the compound of formula (Id).

[0118] Compounds of formula (Ie) that are compounds of formula (I) where L1 is O can be prepared, for example, according to scheme 6 described below.

[0119] Scheme 6 [ka] According to Scheme 6, a commercially available compound IX [wherein Rs is hydrogen] can be reacted with any of the following to obtain intermediate compound XIX [wherein L is CO, CH2, or absent]: carboxylic acid XI (see Scheme 1), aldehyde XII, or aryl halide XIII (see Scheme 2). The compound of formula (Ie) can be prepared by reacting intermediate compound XIX with a chloroformate, such as 4-nitrophenyl chloroformate, and a suitable amine XV (see Scheme 1) in the presence of a base such as pyridine, in a suitable solvent such as DCM, at room temperature. Alternatively, the compound of formula (Ie) can be prepared by reacting intermediate compound XIX with isocyanate X (see Scheme 1) in a suitable solvent such as DCM, in the presence of a base such as DIPEA, at room temperature.

[0120] According to another synthetic approach, a commercially available compound XX may be reacted with isocyanate X in a suitable solvent such as DCM, in the presence of a base such as DIPEA, at room temperature, or compound XX may be reacted with a suitable chloroformate and amine XV in a suitable solvent such as DCM, in the presence of a base such as pyridine, at room temperature, to obtain intermediate compound XXI. Next, intermediate IVc can be obtained by deprotecting intermediate XXI by using TFA under acidic conditions, for example, in a suitable solvent such as DCM at room temperature. Next, intermediate IVc may be reacted with any of carboxylic acid XI, aldehyde XII, or aryl halide XIII as described for schemes 1 and 2 to obtain the compound of formula (Ie) [wherein L is CO or CH2, or is absent]. Alternatively, intermediate compound IVc may be reacted with aryl halide XIII', followed by a deprotection reaction as described for the synthetic route of scheme 2a, to finally obtain the compound of formula (Ie).

[0121] Therefore, the present invention relates to intermediate compound IV: [ka] IV [In the formula, A is [ka] (Here, [ka] (This indicates direct bonding to NH.) It is a ring selected from the group consisting of; W1, W2, and W3 are independently hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) halohydroxyalkyl, (C1-C4) alkoxy, (C1-C4) alkoxy-(C1-C4) alkyl, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, halogen, cyano, SF5, NR1R2-(C1-C4) alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7) cycloalkyl, and (C1-C4) alkyl-heterocycloalkyl. Kill, (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO-heterocycloalkyl-oxy, (C3-C7)cycloalkyl-(C (1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, (C1-C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1-C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl Selected from the group consisting of ru-sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl, preferably hydrogen, CH3, OCH3, OCF3, CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF3, SF5, F, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N-acetylazetidinyl-oxy, 2,2,A substituent on ring A selected from the group consisting of 2-trifluoro-1-hydroxyethyl, oxetanyloxy, CH2N(CH3)2, and 4-methylpiperazine-1-yl; or W1 and W2 are located adjacent to each other on ring A, and W1 and W2 form a (C5-C6) cycloalkyl or a 5-membered or 6-membered heterocycloalkyl, where the (C5-C6) cycloalkyl or 5-membered or 6-membered heterocycloalkyl may optionally be substituted with 1 to 3 halogen atoms; preferably, the 6-membered heterocycloalkyl is a pyranyl ring; L1 is selected from NR, CH2, and O, where R is selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, and deuterated (C1-C4)alkyl, preferably from the group consisting of hydrogen, CD3, cyclopropylmethyl, cyclopropyl, CH2CF3, CH2CH3, or CH3; If L1 is NR, Rs is selected from hydrogen and methyl; If L1 is CH2 or O, then R S is hydrogen; R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4) alkyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy-(C1-C4) alkyl, (C1-C4) alkylamino-(C1-C4) alkyl, di-(C1-C4) alkylamino-(C1-C4) alkyl, optionally substituted (C3-C7) cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heterocycloalkyl-(C1-C4) alkoxy, wherein the optional substituents are 1 to 3 in number and are selected from the group consisting of (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy and carbamoyl; preferably, R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4) alkyl and optionally substituted heterocycloalkyl, wherein the optional substituents, when present, are selected from the group consisting of CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H and CF2H; more preferably, R1 and R2 are independently selected from the group consisting of hydrogen, methyl and optionally substituted oxetanyl; R3 is selected from the group consisting of (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkyl-phenyl and monocyclic heteroaryl] Intermediate compound IV or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof, where intermediate compound IV is not 1-(3,5-dichlorophenyl)-3-(2-azaspiro[3.7]heptan-6-yl)urea, when the A ring is phenyl, L1 is NH, and W1 and W2 are hydrogen, W3 is not para-OCF3, There is provided intermediate compound IV or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof.

[0122] Intermediate compound IV is not 1-(2-azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea.

[0123] When L1 is NR, the intermediate compound IV corresponds to intermediate compound IVa; when L1 is CH2, the intermediate compound IV corresponds to intermediate compound IVb; when L1 is O, the intermediate compound IV corresponds to intermediate compound IVc.

[0124] Preferably, the substituents W1, W2 and W3 (also shown as W substituents) in the intermediate compound IV occupy the ortho and / or meta positions on ring A. More preferred W substituents are hydrogen, CH3, OCH3, OCF3, CF3, CHF2, CH2CF3, OCF2H, CH2OH, SF5, F, Br and I. More preferably, such substituents occupy the ortho and / or meta positions. When both W1 and W2 are hydrogen and W3 is OCF3, W3 preferably occupies the ortho or meta position.

[0125] When ring A is a phenyl group, L1 is NH, and W1 and W2 are hydrogen, W3 is not para-OCF3.

[0126] When ring A is a phenyl group, L1 is an NH group, and W1 is hydrogen, both W2 and W3 are not meta-Cl.

[0127] In one preferred embodiment, when the A ring is phenyl and L1 is NH, W1, W2 and W3 are independently hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1-C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, fluorine, bromine, iodine, cyano, SF5, NR1R2-(C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl (C3-C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO- Heterocycloalkyl-oxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, (C1-C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1-C4)haloalkyl-thio, (C1-C4)alkyl Selected from the group consisting of ru-thio-(C1-C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl, and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl; or W1 and W2 are located at adjacent positions on ring A, and W1 and W2 form a (C5-C6)cycloalkyl or a 5-membered or 6-membered heterocycloalkyl, where the (C5-C6)cycloalkyl or 5-membered or 6-membered heterocycloalkyl may optionally be substituted with 1 to 3 halogen atoms.

[0128] The present invention further provides the use of intermediate compound IV, as defined above, in the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0129] Therefore, the present invention relates to a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, a) Intermediate compound IV: [ka] IV The present invention provides a method comprising the step of reacting with one of the carboxylic acid XI, aldehyde XII, or aryl halide XIII as defined above to obtain a compound of formula (I) as defined above [wherein A, L1, Rs, W1, W2, and W3 are as defined above], wherein X in aryl halide XIII is a halogen, preferably bromine.

[0130] This method may include an additional deprotection step if either substituent on ring A or B has a protecting group that a person skilled in the art would expect to use to achieve the synthesis of the compound of formula (I).

[0131] Accordingly, the present invention provides the intermediate compounds III, IV, IVa, IVb, IVc, VI, VII, VIII, XVIII, XIX, XXI, XXIII, XXIV, XXV, XXVI, XXVII, and XXVIII as defined above, as well as their use in the preparation of the compound of formula (I).

[0132] The compounds of formula (I) of the present invention have been found to remarkably efficiently inhibit both receptors DDR1 and DDR2. Advantageously, inhibition of receptors DDR1 and DDR2 may result in the effective treatment of diseases, disorders, or conditions involving DDR receptors.

[0133] In this regard, it has been found that the compounds of formula (I) of the present invention have extremely high antagonistic drug efficacy against DDR1 and DDR2. Table 44 in the experimental section of this specification shows such efficacy as the inhibition constant Ki of representative compounds of formula (I) of the present invention. Preferred compounds of the present invention have a Ki of less than 100 nM against DDR1 and DDR2. More preferred compounds have a Ki of 25 to 5 nM. Even more preferred compounds of the present invention have a Ki of less than 5 nM against DDR1 and DDR2.

[0134] In one embodiment, the present invention refers to a compound of formula (I) according to any of the embodiments disclosed above, for use as a pharmaceutical.

[0135] In a preferred embodiment, the present invention refers to compounds of formula (I) and pharmaceutically acceptable salts for use in the treatment of diseases, disorders or conditions related to dysregulation of DDR.

[0136] In another embodiment, the present invention refers to the use of the compound of formula (I) described above and its pharmaceutically acceptable salts in the preparation of a pharmacopoeia for treating disorders associated with dysregulation of DDR.

[0137] In another preferred embodiment, the present invention refers to a compound of formula (I) and a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of diseases, disorders or conditions related to the mechanism of the DDR receptor. In a preferred embodiment, the present invention refers to a compound of formula (I) for use in the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions associated with fibrosis.

[0138] As used herein, the terms “fibrosis” or “fibrotic disorder” mean a condition associated with the abnormal accumulation of cells and / or fibronectin and / or collagen, and / or increased fibroblast recruitment, including, but not limited to, fibrosis of individual organs or tissues such as the heart, kidneys, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal system, and gastrointestinal tract.

[0139] Preferably, the compound of formula (I) above is useful for the treatment and / or prevention of fibrosis such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, progressive pulmonary fibrosis, sarcoidosis, familial pulmonary fibrosis, chronic hypersensitivity pneumonia (CHP), kidney or renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, and systemic sclerosis. More preferably, the compound of formula (I) is useful for the treatment of idiopathic pulmonary fibrosis (IPF).

[0140] In another preferred embodiment, the compound of formula (I) above is useful for the treatment of renal fibrosis.

[0141] Thus, in a preferred embodiment, the present invention refers to a compound of formula (I) or a pharmaceutical composition thereof for use in the prevention and / or treatment of IPF.

[0142] In another preferred embodiment, the present invention refers to the use of a compound of formula (I) or a pharmaceutical composition thereof for the preparation of a medicament for treating and / or preventing IPF.

[0143] In another preferred embodiment, the present invention refers to a method for treating and / or preventing IPF, comprising administering a compound of formula (I) or a pharmaceutical composition comprising the compound of formula (I) and one or more pharmaceutically acceptable carriers and / or additives.

[0144] In another preferred embodiment, the present invention refers to a compound of formula (I) or a pharmaceutical composition thereof for use in the prevention and / or treatment of renal fibrosis.

[0145] In another aspect, the present invention refers to the use of a compound of formula (I) or a pharmaceutical composition thereof for the preparation of a medicament for treating and / or preventing renal fibrosis.

[0146] In another preferred embodiment, the present invention means a method for treating and / or preventing renal fibrosis, comprising administering a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and / or additives.

[0147] In one embodiment, the present invention also refers to a method for preventing and / or treating a disease, disorder or condition related to the mechanism of the DDR receptor, comprising the step of administering a therapeutically effective amount of the compound of formula (I) above to a patient in need thereof.

[0148] In a further embodiment, the present invention relates to the use of compounds of formula (I) above for treating diseases, disorders, or conditions related to the mechanism of the DDR receptor.

[0149] In another embodiment, the present invention refers to the use of the compound of formula (I) in the preparation of a pharmaceutical for treating a disease, disorder, or condition related to the mechanism of the DDR receptor.

[0150] In a further embodiment, the present invention means a method for preventing and / or treating a disease, disorder or condition associated with dysregulation of DDR receptors 1 and 2, comprising administering a therapeutically effective dose of the compound of formula (I) to a patient in need of such treatment.

[0151] In a further embodiment, the present invention refers to the use of the compound of formula (I) above for treating diseases, disorders, or conditions associated with dysregulation of DDR receptors 1 and 2.

[0152] In this specification, the “safe and effective amount” as used with respect to the compound of formula (I) or a pharmaceutically acceptable salt thereof, or other pharmaceutically active agent, means an amount of the compound sufficient to treat a patient’s condition, but low enough to avoid serious side effects, and still determined routinely by a skilled technician.

[0153] The compound of formula (I) may be administered as a single dose, or according to a dosing regimen in which several doses are administered at various time intervals over a predetermined period. A typical daily dose may vary depending on the chosen route of administration.

[0154] The present invention also refers to a pharmaceutical composition comprising a compound of formula (I) according to any embodiment in a mixture with one or more pharmaceutically acceptable carriers and / or additives.

[0155] In one embodiment, the present invention refers to a pharmaceutical composition obtained by mixing a compound of formula (I) with one or more pharmaceutically acceptable carriers and / or additives, for example, as described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0156] The compounds of the present invention and their pharmaceutical compositions can be administered, for example, orally, nasally, non-enterally (subcutaneous, intravenously, intramuscularly, intrasternally, and by infusion), and by inhalation, depending on the patient's needs.

[0157] Preferably, the compounds of the present invention are administered orally or by inhalation.

[0158] In one preferred embodiment, the pharmaceutical composition comprising the compound of formula (I) is in the form of a solid oral dosage form such as a tablet, gel cap, capsule, caplet, granule, lozenge, or bulk powder.

[0159] In one embodiment, the pharmaceutical composition containing the compound of formula (I) is a tablet.

[0160] The compounds of the present invention may be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, and starch), and known additives including suspenders, solubilizers, buffers, binders, disintegrants, preservatives, colorants, fragrances, and lubricants.

[0161] In further embodiments, the pharmaceutical composition comprising the compound of formula (I) is a liquid oral dosage form such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such liquid dosage forms may also include a suitable known inert diluent such as water, and suitable known additives such as preservatives, humectants, sweeteners, and flavorings, as well as agents for emulsifying and / or suspending the compound of the present invention.

[0162] In a further embodiment, a pharmaceutical composition comprising a compound of formula (I) is an inhalable formulation such as an inhalable powder, a propellant-containing metered aerosol, or an inhalable formulation without a propellant.

[0163] For administration as a dry powder, single-dose or multi-dose inhalers known from the prior art can be used. In this case, the powder may be filled into gelatin, plastic, or other capsules, cartridges, or blister packs, or into a reservoir.

[0164] A chemically inert diluent or carrier, such as lactose, or any other additive suitable for improving the respiratory fraction, may be added to the powder compound of the present invention.

[0165] Inhalation aerosols containing propellant gases such as hydrofluoroalkanes may contain the compounds of the present invention in either solution or dispersion form. The propellant-driven formulation may also contain other components such as cosolvents, stabilizers, and optionally other additives.

[0166] Inhalable formulations containing the compound of the present invention, which do not include propellants, may be in the form of solutions or suspensions in aqueous, alcoholic, or water-alcoholic media, and may be delivered by jet or ultrasonic nebulizers known from the prior art, or by soft mist nebulizers.

[0167] The compounds of the present invention can be administered as a single active agent or in combination with other pharmaceutically active ingredients.

[0168] The dosage of the compound of the present invention depends on various factors, including the specific disease being treated, the severity of the symptoms, and the route of administration.

[0169] The present invention also relates to an apparatus comprising a pharmaceutical composition containing a compound of formula (I) according to the present invention, in the form of a single-dose or multiple-dose dry powder inhaler or a measuring inhaler.

[0170] All of the preferred groups or embodiments described above for the compounds of formula (I) may be combined with each other and applied with the necessary modifications.

[0171] Various aspects of the present invention described in this application are illustrated by the following embodiments, which are not intended to limit the present invention in any way.

[0172] Preparation of intermediates and examples Unless otherwise specified, the chemical names of compounds are either generated using the Structure-To-Name tool in the PerkinElmer ChemDraw® Professional application (v. 20.0.0.41.) or are common chemical names. All reagents whose synthesis is not described in the experimental section may be commercially available, known compounds, or formed from known compounds by methods known to those skilled in the art.

[0173] In the following procedure, some of the starting materials are identified by an “intermediate” or “example” number indicating the step number. This is provided solely for the assistance of experienced chemists.

[0174] As those skilled in the art will understand, where referring to the use of a “similar” or “analogous” procedure, such a procedure may include slight variations, as those skilled in the art will understand, such as reaction temperature, reagent / solvent amounts, reaction time, workup conditions, or chromatographic purification conditions. Unless otherwise specified, all final compounds were obtained as free bases.

[0175] abbreviation AcOH = acetic acid; Acetone-d6 = deuterated acetone; ACN = acetonitrile; ACN-d3 = deuterated acetonitrile; CDCl3 = deuterated chloroform; cHex = cyclohexane; CV = column volume; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMA = N,N-dimethylacetamide; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; DMSO-d6 = deuterated dimethyl sulfoxide; ee = enantiomeric excess; Et2O = diethyl ether; Ã = ethyl acetate; eq = equivalent; FCC = f Rush column chromatography; h = hours / second; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HCOOH = formic acid; HPLC = high-performance liquid chromatography; LCMS = liquid chromatography / mass spectrometry; MeOH = methyl alcohol; Me-THF = 2-methyltetrahydrofuran; min = minutes / second; NMR = nuclear magnetic resonance; Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0); XPhos Pd G3 = 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate; RT / rt = room temperature; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; SCX = strong cation exchange; SFC = supercritical fluid chromatography; STAB = sodium triacetoxyborohydride; SM = starting material; tBu = tert-butyl; tBuOK = potassium tert-butoxide; TCFH = chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin-layer chromatography; t R=Retention time; ULC = Ultra-high performance liquid chromatography; TBAF = Tetrabutylammonium fluoride; TBAB = Tetrabutylammonium bromide; DBU = 1,8-Diazabicyclo[5.4.0]undeca-7-ene; CPME = Cyclopentyl methyl ether; mCPBA = 3-Chloroperbenzoic acid; CDI = 1,1'-Carbonyldiimidazole; Xantphos = 4,5-Bis(diphenylphosphin)-9,9-Dimethylxanthene; MeI = Methyl iodide; SEM = 2-(trimethylsilyl)ethoxymethyl; Boc = tert-butyloxycarbonyl; Troc = 2,2,2-Trichloroethylcarbamate; LiOH = Lithium hydroxide.

[0176] Details of a typical experiment NMR characterization: 1 ¹H NMR spectra were recorded using a Bruker instrument operating at 400 MHz (proton frequency) with solvents specified in approximately rt unless otherwise noted. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts are reported as δ values ​​in ppm (parts per million). Coupling constants (J values) are given in Hertz (Hz), and multiplicity is reported using the following conventional abbreviations for designating the main peak: s=singlet, d=doublet, t=triplet, q=quadruplet, dd=doublet of doublet, dt=doublet of triplet, m=multitlet, br=broad, nd=undetermined.

[0177] In some cases, the NH signal originating from amide or amine bonds (exchangeable protons) is invisible. In a few cases, some signals may be hidden or partially obscured by water or DMSO peaks or residual solvent signals.

[0178] LC / UV / MS analysis method The LC / MS retention time is expected to be affected by an experimental error of ±0.5 minutes.

[0179] Method 1: Agilent Zorbax column 4.6 × 50 mm, 3.5 μm, maintained at 40°C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), 5% to 95% in 2 minutes. Flow rate: 3.0 ml / min. Wavelength: 210-400 nm DAD. Waters TM 2795 / 2695 Separation Module + Waters TM DAD+Micromass ZQ, single quadrupole LCMS.

[0180] Method 2: Waters TM Acquity UPLC HSS C18 column, 100 × 2.1 mm, 1.8 μm (Plus Guard cartridge), maintained at 40°C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), 5% to 95% in 5.6 mins. Flow rate: 0.4 ml / min. Wavelength: 210-400 nm DAD. UPLC + Waters TM DAD+Waters TM SQD2, Single Quadrupole ULCMS

[0181] Method 3: Waters TM Acquity UPLC BEH Shield RP18 column, 100 × 2.1 mm, 1.72 μm (Plus Guard cartridge), maintained at 40°C. Mobile phase: Water + MeCN in 10 nM ammonium bicarbonate, 5% to 95% in 5.6 mins. Flow rate: 0.4 ml / min. Wavelength: 210-400 nm DAD. UPLC + Waters TM DAD+Waters TM SQD2, Single Quadrupole ULCMS

[0182] Method 4: Waters TM Sunfire C18 column, 4.6 × 50 mm, 3.5 μm, maintained at 40°C. Mobile phase: Water + 10 mM ammonium bicarbonate with MeCN, 5% to 95% after 2.5 mins. Flow rate: 2.0 mL / min. Wavelength: 210–400 nm. DAD. Waters TM 2795 Separation Module + Waters TM DAD+Micromass ZQ, single quadrupole LCMS.

[0183] Method 5: Waters Acquity QSM, Kinetex C8 column 100 mm × 2.1 mm 1.7 μm, maintained at 55°C; mobile phase: eluent A (HCOONH4 0.025 M pH 3), eluent B (ACN + 0.1% FA). Gradient mode: Increase eluent B from 1% to 30% at 0-3 mins, increase from 30% to 50% at 3-6.50 mins, increase from 50% to 80% at 6.50-7.50 mins, hold at 80% at 7.50-8 mins, decrease from 80% to 1% at 8-8.10 mins, and hold at 1% until the end of 10 mins at 8.10 mins. Flow rate: 0.5 mL / min. Wavelength: 210-400 nm PAD. UPLC + Waters PDA + Xevo TQS MS instrument.

[0184] Method 6: Waters TM Acquity QSM, Acquity UPLC CSH C18 column 50mm × 2.1mm 1.7μm, maintained at 50°C; mobile phase: eluent A (HCOONH 40.025M pH3), eluent B (ACN + 0.1% FA). Gradient mode: Eluent B was increased from 20% to 80% from 0 to 5.50 mins, held at 80% from 5.50 to 7.50 mins, decreased from 80% to 20% from 7.50 to 8 mins, and held at 20% until the end of 10 mins. Flow rate: 0.35 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters TM PDA + Xevo TQS MS system.

[0185] Method 7: Acquity CSH C18 column 50 mm × 2.1 mm 1.7 μm, maintained at 40°C; mobile phase: eluent B (ACN) in eluent A (water + 0.1% HCOOH), 1% to 99.9% per 1.5 min. Flow rate: 1 mL / min. Wavelength: 210 to 400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0186] Method 8: Kinetex® XB-C18 column, 4.6 × 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 80% to 5% over 3.90 mins; flow rate: 1.0 ml / min; wavelength: 190 to 340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC mass spectrometer.

[0187] Method 9: Kinetex® XB-C18 column, 4.6 × 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 90% to 5% in 3.90 mins; flow rate: 1.0 ml / min; wavelength: 190 to 340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC mass spectrometer.

[0188] Method 10: Acquity UPLC BEH-Waters, 1.7 μm C18 (2.1 × 100 mm), 130 Å, maintained at 25°C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 80% to 5% in 2.70 mins; flow rate: 0.5 ml / min; wavelength: 254 nm. Shimadzu LCMS-2020 single quadrupole liquid chromatograph mass spectrometer.

[0189] Method 11: Waters Acquity UPLC BEH C18 column 2.1 × 100 mm, 1.7 μm, (Plus Guard cartridge), maintained at 40°C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), 5% to 95% in 8 minutes. Flow rate: 0.4 ml / min. Wavelength: 200 to 400 nm. DAD, Waters Aquity PDA, separation module + Waters PDA + Micromass ZQ, single quadrupole LC-MS.

[0190] Method 12: Waters Acquity UPLC BEH C18 column 2.1 × 100 mm, 1.7 μm, (Plus Guard cartridge), maintained at 40°C. Mobile phase: MeCN (0.1% ammonium hydroxide) in water (0.1% ammonium hydroxide), 5% to 95% over 8 minutes. Flow rate: 0.4 ml / min. Wavelength: 200-400 nm. DAD, Waters Acquity PDA, separation module + Waters PDA + Micromass ZQ, single quadrupole LC-MS.

[0191] Method 13: Acquity CSH C18 column, 50 mm × 2.1 mm, 1.7 μm, maintained at 40°C; mobile phase: eluent B (ACN) in eluent A (water + 0.1% HCOOH), 1% to 99.9% in 3.5 minutes. Flow rate: 1 mL / min. Wavelength: 210 to 400 nm. DAD. UPLC + Waters PDA + Waters QDA.g

[0192] Method 14: Acquity UPLC BEH-Waters, 1.7 μm C18 (2.1 × 100 mm), 130 Å, maintained at 25°C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 80% to 5% in 3.9 mins; flow rate: 0.5 mL / min; wavelength: 220 nm and 254 nm. Shimadzu LCMS-2020 single quadrupole liquid chromatograph mass spectrometer.

[0193] Method 15: Phenomenex Kinetex EVO C18 HPLC column, 4.6 × 50 mm, 5 μm, operating at room temperature: Mobile phase: MeCN (0.1% NH4OH) in water (0.1% NH4OH), 5–95% in 2.5 mins. Flow rate: 1.5 mL / min. Wavelength: 210–400 nm. DAD. Acquity H-Class UPLC with PDA detector and QDa.

[0194] Method 16: Waters Aquity UPLC HSS C18 column, 2.1 × 50 mm, 1.8 μm, maintained at 40°C: MeCN (0.1% FA) in water (0.1% FA), 5–95% in 2.5 mins. Flow rate: 1.5 mL / min. Wavelength: 210–400 nm. DAD. Acquity H-Class UPLC with PDA detector and QDa.

[0195] Method 17: Waters Aquity UPLC BEH C18 column 2.1 × 100 mm, 1.7 μm, (Plus Guard cartridge), maintained at 40°C. Mobile phase: MeCN (0.1% FA) in water (0.1% FA), 5% to 50% over 8 minutes. Flow rate: 0.4 mL / min. Wavelength: 200 to 400 nm. DAD, Waters Aquity PDA, separation module + Waters PDA + Micromass ZQ, single quadrupole LCMS.

[0196] Method 18: Waters Aquity UPLC BEH C18 column 2.1 × 100 mm, 1.7 μm, (Plus Guard cartridge), maintained at 40°C. Mobile phase: MeCN (0.1% FA) in water (0.1% FA), 10% to 50% over 8 minutes. Flow rate: 0.4 mL / min. Wavelength: 200 to 400 nm. DAD, Waters Aquity PDA, separation module + Waters PDA + Micromass ZQ, single quadrupole LCMS.

[0197] The purification of several compounds is performed by Waters TM This was achieved by achiral supercritical fluid chromatography (SFC) using the Thar Prep100 preparative SFC system.

[0198] Method 19: (TORUS DEA 20×150mm, 5μm 10~20%MeOH(0.1%NH4OH) / CO2, 100ml / min, 120bar, 40℃

[0199] Method 20: YMC Amylose-C MeOH, Waters VIRIDIS 2-EP 20×250mm, 5μm 5~15%MeOH(0.1%NH4OH) / CO2, 100mL / min, 120bar, 40℃, DAD 235nm.

[0200] Other compounds were tested under both basic conditions (ACN + 0.1% NH3, H2O + 0.1% NH3) and acidic conditions (ACN + 0.1% HCOOH, H2O + 0.1% HCOOH) by Waters. TM Fractionlynx TM The product was purified by reverse-phase HPLC using a preparative HPLC system or an equivalent system, where, in the last case, the fraction containing the desired product (identified by TLC and / or LCMS analysis) was pooled and the solvent was removed under reduced pressure or lyophilized; or, unless otherwise specified, the free base of the product was obtained by extraction with SCX(NH₃).

[0201] Flash chromatography (FCC) is used by Biotage® Isolera. TM This was performed using a system or similar device.

[0202] For reverse-phase FCC (RF FCC), the following gradient / eluent ratio was used: in 12 CV, gradient eluent A:eluent B 100:0~0:10; eluent A:H2O / ACN / HCOOH 95:5:0.1; eluent B:H2O / ACN / HCOOH 5:95:0.1. After purification, unless otherwise specified, the free base of the product was obtained using SCX(NH).

[0203] All solvents were purchased from commercial sources and used without further purification.

[0204] General synthesis procedure Intermediate 1: 6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid [ka] Step 1 - Methyl 6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carboxylate (intermediate 2) [ka] To a solution of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (807 mg, 3.00 mmol) in toluene (10 mL), Pd2(dba)3 (275 mg, 0.300 mmol), BINAP (560 mg, 0.900 mmol), and sodium tert-butoxide (403 mg, 4.20 mmol) were added. Nitrogen was blown into the reaction mixture, and then 1-methylpiperazine (0.37 mL, 3.30 mmol) was added. The reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was cooled to rt, filtered through a Celite® pad, and then washed with MeOH. The organic phases were combined and concentrated under reduced pressure, and the residue was purified by FCC (0-100% ethyl in cHex, followed by 0-100% MeOH in ethyl). The resulting substance, as a mixture of methyl and ethyl esters, was subjected to the next step without further purification. LCMS(ESI): Method 1, t R = 0.65 min, m / z(M+1) = 275 (methyl ester); LCMS(ESI): Method 1, t R =0.75 min, m / z(M+1)=289 (ethyl ester)

[0205] Similarly, the following intermediates were prepared using a suitable amine, a bromo intermediate, the catalysts shown in Table 6, and, in some cases, dioxane or Me-THF as a solvent and Cs2CO3 as a base. [Table 6-1] [Table 6-2]

[0206] Step 2 - 6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate 1) At 0°C, intermediate 2 (1200 mg, 4.37 mmol) in THF (1 mL) was mixed with LiOH (314 mg, 13.1 mmol) in water (1 mL). The reaction mixture was heated to RT and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was washed with water, and the aqueous phase was diluted with 1 M HCl. (aq) The solution was adjusted to pH 7 and washed with DCM. The aqueous fraction was concentrated under reduced pressure to obtain a mixture of the product and the inorganic salt. The obtained substance was used in the next step without further purification. LCMS(ESI): Method 1, t R =0.87 min, m / z(M+1)=261

[0207] Similarly, the following intermediates were prepared as carboxylic acids or salts (see Table 7 below). [Table 7-1] [Table 7-2]

[0208] Intermediate 3: Phenyl (5-(tert-butyl)isoxazole-3-yl)carbamate [ka] At 0°C, a suspension of 5-(tert-butyl)isoxazole-3-amine (321 mg, 2.29 mmol) and Na2CO3 (171 mg, 1.61 mmol) in Depositphotos (20.00 mL) was added with THF (4.00 mL) and water (4.00 mL), and phenyl chloroformate (0.37 mL, 2.95 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 20 minutes, then heated to rt and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, Depositphotos (20 mL) was added, and the mixture was washed with water (30 mL). The organic phase was dried on hydrophobic lit and concentrated under reduced pressure to obtain the title compound (487 mg, 1.25 mmol, 55% yield). LCMS(ESI): Method 4, t R =1.69 min, m / z(M+1)=261

[0209] Similarly, the following intermediates were prepared (see Table 8 below). [Table 8]

[0210] Intermediate 114: (3-amino-2-methoxy-5-(trifluoromethoxy)phenyl)methanol [ka] (2-methoxy-3-nitro-5-(trifluoromethoxy)phenyl)methanol (2.64 g, 9.88 mmol) was prepared according to the procedure described in US10280145.

[0211] Intermediate 5: 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine [ka] At 0°C, 2-(trimethylsilyl)ethoxymethyl chloride (1.2 mL, 7.03 mmol) was added dropwise to a solution of 4-bromo-1H-pyrazolo[3,4-b]pyridine (1160 mg, 5.86 mmol) and tBuOK (986 mg, 8.79 mmol) in DMF (15.00 mL). The mixture was warmed to rt and stirred overnight. The reaction mixture was quenched with sat.aq.NH4Cl and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by FCC (0-60% ethyl acetate in cHex) to obtain the title compound (959 mg, 2.92 mmol, 50% yield). LCMS(ESI): Method 4, t R =1.96 min, m / z(M+1)=328.0;330.0 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J=4.9 Hz, 1H), 8.40 (s, 1H), 7.72 (d, J=4.9 Hz, 1H), 5.90 (s, 2H), 3.71 (t, J=8.0 Hz, 2H), 0.93 (t, J=8.0 Hz, 2H), 0.01 (s, 9H).

[0212] Similarly, the following intermediates were prepared using sodium hydride as the base (see Table 9). [Table 9]

[0213] Intermediate 29: 2,2,2-Trichloroethyl(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazole-5-yl)carbamate [ka] A solution of 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazole-5-amine (100 mg, 0.436 mmol) and NaOH (1 M aq., 1.3 mL, 1.31 mmol) in HCl (3 mL) was cooled in an ice / water bath, and 2,2,2-trichloroethyl chloroformate (0.066 mL, 0.480 mmol) was added dropwise. The reaction mixture was stirred under rt for 1.5 hours, and then concentrated under reduced pressure to obtain the title compound (100 mg, 0.247 mmol, 57% yield), which was used as the crude product in the next reaction. LCMS(ESI): Method 1, t R =1.86 min, m / z(M+1)=404.0, 406.0 1 H NMR (400 MHz, CDCl3) δ 7.36 - 7.26 (m, 4H), 6.82 (br s, 1H), 6.41 (s, 1H), 4.81 (s, 2H), 2.41 (s, 3H), 1.34 (s, 9H).

[0214] All of the following Troc carbamates were prepared using the same procedure; starting with a suitable amine, DIPEA was sometimes used as the base and THF or pyridine as the solvent (see Table 10). [Table 10-1] [Table 10-2] [Table 10-3]

[0215] Intermediate 30: Ethyl 1-(oxetan-3-yl)-1H-imidazo[1,2-b]pyrazole-7-carboxylate [ka] Under a nitrogen atmosphere, potassium carbonate (231 mg, 1.67 mmol) was added in a single addition to a solution of ethyl 1H-imidazo[1,2-b]pyrazole-7-carboxylate (150 mg, 0.837 mmol) and 3-iodooxetane (0.22 mL, 2.51 mmol) in DMF (3.5 mL) with stirring. The reaction mixture was stirred at 50°C for 18 hours. The reaction mixture was cooled to rt and diluted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by FCC (0-100% 3:1 ethyl acetate:EtOH in cHex) to obtain the title compound (126 mg, 0.536 mmol, 64% yield). LCMS(ESI): Method 4, t R =1.26 min, m / z(M+1)=236.2

[0216] Similar to intermediate 30, the following intermediates were prepared (see Table 11). [Table 11-1] [Table 11-2]

[0217] Intermediate 32: 1-(oxetan-3-yl)-1H-imidazo[1,2-b]pyrazole-7-carboxylic acid [ka] To a solution of ethyl 1-(oxetan-3-yl)-1H-imidazo[1,2-b]pyrazole-7-carboxylate (120 mg, 0.51 mmol) in THF (10 mL), sodium hydroxide (204 mg, 5.10 mmol) and MeOH (5.0 mL) were added, and the mixture was heated at 50°C for 24 hours. The reaction mixture was cooled to rt, the pH was reduced to approximately 2 with 2N aqueous HCl, and ethyl acetate was extracted. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The title compound (100 mg, 0.48 mmol, 95% yield) was used in the next step without further purification. LCMS(ESI): Method 1 min, t R =1.02 min, m / z(M+1)=208.0

[0218] The following compounds were prepared following the same synthesis procedure (Table 12). [Table 12]

[0219] Intermediate 34: Methyl 6-((oxetane-3-ylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate [ka] To a solution of methyl 6-formylpyrazolo[1,5-a]pyridine-3-carboxylate (85 mg, 0.416 mmol) and oxetane-3-amine (0.037 mL, 0.520 mmol) in DCM (2 mL), AcOH (20 μL) was added; after 10 minutes, NaBH(OAc)3 (176 mg, 0.833 mmol) was added, and the mixture was stirred at rt for 3 hours. The reaction mixture was diluted with DCM and washed with NaHCO3 and water. The organic phase was dried over MgSO4 and concentrated under reduced pressure to obtain the title compound (95 mg, 0.364 mmol, 87% yield). LCMS(ESI): Method 7, t R =1.01 min, m / z(M+1)=262.0

[0220] Intermediate 35: Lithium 6-((oxetane-3-ylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate [ka] Intermediate 35 was prepared according to the procedure of step 2 of intermediate 1 to obtain the title compound (66 mg, 0.268 mmol, quantitative). LCMS(ESI): Method 4 min, t R =0.60 min, m / z(M+1)=248.2

[0221] Intermediate 36: 4-(2,2,2-trifluoroethyl)pyridine-2-amine [ka] Step 1 - 2-Chloro-4-(2,2,2-trifluoroethyl)pyridine (intermediate 37) [ka] To a solution of 2-chloroisosonicotinaldehyde (250 mg, 1.77 mmol) in MeOH (2.0 mL), hydrazine monohydrate (0.10 mL, 2.12 mmol) was added, and the reaction mixture was stirred under nitrogen at rt for 1 hour. The solvent was removed under reduced pressure, and 1-(trifluoromethyl)-1λ was added. 3-Benzo[d][1,2]iodaoxol-3(1H)-one (Togni Reagent II, 1.023 g, 1.94 mmol) was added to the crude solid. The vial containing the two solids and a stirring bar was subjected to a vacuum / nitrogen cycle before adding DMSO (2.0 mL) and TFA (0.14 mL, 1.77 mmol), and the reaction mixture was heated at 50°C for 72 hours. The reaction mixture was cooled to rt, diluted with water, extracted with Et2O, and the organic layer was washed with water and brine and dried over MgSO4. The organic layer was concentrated under reduced pressure. The residue was purified by FCC (0-50% SiO in cHex) to obtain the title compound (60 mg, 0.307 mmol, 17% yield). LCMS(ESI): Method 1 min, t R =1.57 min, m / z(M+1)=196.0, 198.0

[0222] Step 2 - 4-(2,2,2-trifluoroethyl)pyridine-2-amine (intermediate 36) Intermediate 37 (60 mg, 0.307 mmol), tert-butyl carbamate (93 mg, 0.798 mmol), cesium carbonate (130 mg, 0.399 mmol), Xantphos (30 mg, 0.0522 mmol), Pd2(dba)3 (25 mg, 0.0276 mmol), and CPME (3.0 mL) were added to the reactor, and nitrogen was incorporated into the mixture for 20 minutes. The container was sealed, and the reaction mixture was heated at 130°C for 18 hours. The reaction mixture was cooled to rt, filtered through Celite®, and washed with Â. The solvent was removed under reduced pressure. The crude mixture was redissolved in DCM (3.0 mL) and TFA (1.0 mL), and the reaction mixture was then stirred for 3 hours. The reaction was concentrated to dryness, and the crude residue was dissolved in MeOH, passed through an SCX isolute column, and eluted with 7N methanolic NH3. The ammonia solution was evaporated under reduced pressure, and the title compound was used in the next step without further purification (44 mg, 31%). LCMS(ESI): Method 1 min, t R =1.32 min, m / z(M+1)=177.1

[0223] Intermediate 124: Lithium 2-(2-methoxyethyl)-1-methyl-1H-imidazo[1,2-b]pyrazole-7-carboxylate [ka] Step 1: Ethyl 2-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carboxylate (intermediate 125) [ka] Ethyl 5-amino-1H-pyrazole-4-carboxylate (1.48 g, 9.5 mmol) was dissolved in dry ACN (20 mL), then DIPEA (1.28 mL, 7.3 mmol), tetrabutylammonium bromide (2.36 g, 7.3 mmol), and 1-chloro-4-methoxybutan-2-one (1 g, 7.3 mmol) were added, and the reaction was stirred overnight at 90 °C. The solvent was removed, and the crude product was purified by RF FCC to obtain the title compound (0.57 g, 2.4 mmol, 33% yield). 1 H NMR (600 MHz, DMSO-d6) δ ppm 11.88 (1 H, br s), 7.82 (1 H, s), 7.47 (1 H, s), 4.21 (2 H, q, J=7.09 Hz), 3.60 (2 H, t, J=6.75 Hz), 3.26 (3 H, s), 2.85 (2 H, m), 1.28 (3 H, t, J=7.12 Hz)

[0224] Step 2: Ethyl 2-(2-methoxyethyl)-1-methyl-1H-imidazo[1,2-b]pyrazole-7-carboxylate (intermediate 126) [ka] To a solution of intermediate 125 (380 mg, 1.6 mmol), MeI (0.10 ml, 1.60 mmol) and NaH 95% w / w (40.5 mg, 1.60 mmol) were added, and the mixture was stirred overnight at 50°C. After removing the solvent, the crude product was purified by RF FCC to obtain the title compound (50 mg, 0.20 mmol, 12% yield). LCMS(ESI): Method 7, t R =0.8 min, m / z(M+1)=252.0

[0225] Step 3: Lithium 2-(2-methoxyethyl)-1-methyl-1H-imidazo[1,2-b]pyrazole-7-carboxylate (intermediate 124) Intermediate 124 was prepared according to the procedure of step 2 of intermediate 1 to obtain the title compound (45 mg, 98% yield). LCMS(ESI): Method 7, t R =0.54 min, m / z(M+1)=224

[0226] Intermediate 127: Lithium 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate [ka] Step 1: Methyl 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (intermediate 128) [ka] Tripotassium phosphate (385 mg, 1.813 mmol) was added to a suspension of methyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate (185 mg, 0.725 mmol) and (1-methylpyrazole-4-yl)boronic acid (137 mg, 1.088 mmol) in Me-THF (1.5 mL). After applying three N2 / vacuum cycles, XPhos Pd G3 (61.4 mg, 0.073 mmol) was added, and the vial was sealed. The reaction mixture was heated at 75°C for 12 hours. Ether and brine were added, and the organic layer was concentrated under vacuum. The crude product was purified by FCC (Sfar NH, with a gradient of 0-60% Ether / EtOH = 3:1 in heptane) to obtain the title compound (61 mg, 0.24 mmol, 33% yield). LCMS(ESI): Method 7, t R =0.77 min, m / z(M+1)=256.99

[0227] Step 2: Lithium 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (intermediate 127) Intermediate 127 was prepared according to the procedure of step 2 of intermediate 1 to obtain the title compound (59 mg, 100% yield). LCMS(ESI): Method 7, t R =0.54 min, m / z(M+1)=224

[0228] Intermediate 177: 4-(perfluoroethyl)pyridine-2-amine [ka] In a microwave vial, 2-chloro-4-(perfluoroethyl)pyridine (250 mg, 1.08 mmol) was suspended in 35% aqueous ammonia (4.0 mL, 72.3 mmol). The vial was capped and heated in a microwave at 150°C for 8 hours. The contents were then transferred to a separatory funnel and diluted with water and pharmaceutically acceptable phosphate. Phase separation was performed, and the aqueous layer was extracted with pharmaceutically acceptable phosphate. The organic matter was combined, washed with brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to obtain the title compound (450 mg, 2.54 mmol, quantified), which was used without further purification. LCMS(ESI): Method 16, t R =1.50 min, m / z(M+1)=213.1

[0229] Intermediate 178: (3-amino-2-methoxy-5-(trifluoromethyl)phenyl)methanol [ka] Intermediate 178 was prepared according to the procedure described in WO 2017038873.

[0230] Intermediate 179: (3-amino-2-methoxy-5-(trifluoromethoxy)phenyl)methanol [ka] Intermediate 179 was prepared according to the procedure described in WO 2017038873.

[0231] Example 1: 1-(2-(imidazo[1,2-a]pyridine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea [ka] Example 1 Step 1 - tert-butyl 6-(3-(3-(trifluoromethyl)phenyl)ureido)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate 6) [ka] A solution of tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.36 mmol) in DCM (15.00 mL) was cooled to 0°C, and 1-isocyanato-3-(trifluoromethyl)benzene (0.32 mL, 2.36 mmol) was added. The reaction mixture was heated to rt and stirred for 5 minutes, followed by 2 hours. The mixture was then concentrated under reduced pressure to obtain the title compound (1 g, 2.50 mmol, quantitative yield) as a clear oil. LCMS(ESI): Method 1, t R = 1.70 minutes, m / z(M+1-tBu)=344.0 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.86 (s, 1H), 7.44 - 7.34 (m, 2H), 7.14 (d, J=7.5 Hz, 1H), 6.45 (d, J=7.5 Hz, 1H), 3.97 - 3.85 (m, 1H), 3.81 (s, 2H), 3.70 (s, 2H), 2.42 - 2.35 (m, 2H), 2.02 - 1.91 (m, 2H), 1.29 (s, 9H).

[0232] Starting with commercially available compounds or previously described intermediates, the following intermediates were prepared following the same synthetic procedure (see Table 13). [Table 13-1] [Table 13-2]

[0233] Step 2 - 1-(2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 7, compound IVa) [ka] A solution of intermediate 6 (900 mg, 2.25 mmol) and TFA (2.6 mL, 33.8 mmol) in DCM (15.00 mL) was stirred at rt for 1 hour and then concentrated under reduced pressure. The residue was loaded into an isolute SCX cartridge and washed with 1:1 DCM:MeOH (50 mL) and 100% MeOH (20 mL), and released with 1:1 7N NH3 in MeOH:DCM (50 mL) and 100% 7N NH3 in MeOH (20 mL). The ammonia eluent was concentrated under reduced pressure to obtain the title compound (550 mg, 1.84 mmol, 82% yield). LCMS(ESI): Method 1, t R =1.29 min, m / z(M+1)=300.0 1 H NMR (400 MHz, CDCl3) δ 7.60 - 7.55 (m, 1H), 7.53 - 7.49 (m, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.17 (s, 1H), 5.24 (d, J=7.3 Hz, 1H), 4.15 - 4.05 (m, 1H), 3.62 (s, 2H), 3.52 (s, 2H), 2.63 - 2.56 (m, 2H), 1.94 - 1.83 (m, 2H).

[0234] The following compounds were prepared following the same synthetic procedure as for intermediate 7 (see Table 14). [Table 14-1] [Table 14-2]

[0235] Step 3 - 1-(2-(imidazo[1,2-a]pyridine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 1) To a solution of intermediate 7 (75 mg, 0.251 mmol, 1.00 eq), imidazo[1,2-a]pyridine-3-carboxylic acid (41 mg, 0.251 mmol), and DIPEA (0.13 mL, 0.752 mmol) in DMF (2.00 mL), HATU (124 mg, 0.326 mmol) was added, and the reaction mixture was stirred overnight in rt. Next, it was diluted with ethyl acetate and washed with K2CO3 (half-saturated aqueous solution) and brine. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by achiral SFC (Method 19) to obtain the title compound (3.0 mg, 6.70 μmol, 3% yield). LCMS(ESI): Method 2, t R =3.41 min, m / z(M+1)=444.2 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (d, J=6.8 Hz, 1H), 8.84 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.53 - 7.41 (m, 3H), 7.24 - 7.20 (m, 1H), 7.15 - 7.11 (m, 1H), 6.67 (d, J=7.6 Hz, 1H), 4.58 - 4.03 (m, 5H), 2.60 - 2.52 (m, 2H), 2.20 - 2.13 (m, 2H).

[0236] Starting from a suitable commercially available carboxylic acid intermediate, or alternatively from the aforementioned acid intermediate or its corresponding lithium salt, the following examples were prepared in a manner similar to that described for step 3 of Example 1. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] Table 15-5 Table 15-6 Table 15-7 Table 15-8 Table 15-9 Table 15-10 Table 15-11 Table 15-12 Table 15-13 Table 15-14 Table 15-15 Table 15-16 Table 15-17 Table 15-18 Table 15-19 Table 15-20 Table 15-21

[0237] Example 11: 1-(2-(imidazo[1,2-a]pyrazine-3-ylmethyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea [ka] Example 11 The solution of intermediate 7 (115 mg, 0.384 mmol), imidazo[1,2-a]pyrazine-3-carbaldehyde (62 mg, 0.423 mmol), STAB (122 mg, 0.576 mmol), and AcOH (2 drops) in DCM (3.00 mL) and MeOH (0.50 mL) was stirred overnight at rt. The reaction mixture was concentrated under reduced pressure, and the residue was purified by achiral SFC (Method 19) to obtain the title compound (33 mg, 0.0766 mmol, 20% yield). LCMS(ESI): Method 3, t R =3.65 min, m / z(M+1)=431.27 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J=1.5 Hz, 1H), 8.72 (s, 1H), 8.45 (dd, J=1.5, 4.8 Hz, 1H), 7.93 - 7.90 (m, 2H), 7.72 (s, 1H), 7.49 - 7.40 (m, 2H), 7.20 (d, J=7.6 Hz, 1H), 6.55 (d, J=7.6 Hz, 1H), 4.02 - 3.91 (m, 1H), 3.89 (s, 2H), 3.21 (s, 2H), 3.09 (s, 2H), 2.41 - 2.34 (m, 2H), 2.00 - 1.93 (m, 2H).

[0238] Starting with a suitable commercially available aldehyde, the following examples were prepared in a manner similar to that described in Example 11 (see Table 16). [Table 16]

[0239] Example 15: 1-(2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea [ka] Example 15 Step 1 - 1-(3-(trifluoromethyl)phenyl)-3-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-azaspiro[3,3]heptan-6-yl)urea (intermediate 8) [ka] A suspension of intermediate 5 (165 mg, 0.501 mmol), intermediate 7 (150 mg, 0.501 mmol), RuPhos (47 mg, 0.100 mmol), and Cs2CO3 (490 mg, 1.50 mmol) in THF (5.00 mL) was degassed with N2 for 10 minutes, then Pd2(dba)3 (46 mg, 0.0501 mmol) was added, and the reaction mixture was stirred overnight at 80°C. Next, it was cooled to rt, filtered through a Celite® pad, washed with SiO (50 mL), and concentrated under reduced pressure. The residue was purified by FCC (a gradient of 20-100% SiO in cHex) to obtain the title compound (274 mg, 0.501 mmol, 100%). LCMS(ESI): Method 4, t R =1.77 min, m / z(M+1)=547.6

[0240] Using a suitable commercially available bromo or chloro derivative or the intermediate already described, the following examples and intermediates were prepared using the procedure described for intermediate 8 (see Table 17). [Table 17-1] [Table 17-2]

[0241] Step 2 - 1-(2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 15) A solution of intermediate 8 (274 mg, 0.501 mmol) and HCl (4 M in 1,4-dioxane, 3.0 mL) in 1,4-dioxane (4.00 mL) was stirred at rt for 4 hours and then concentrated under reduced pressure. The residue was purified by achiral SFC (Method 19) to obtain the title compound (67 mg, 0.161 mmol, 29% yield). LCMS(ESI): Method 2, t R =3.32 min, m / z(M+1)=417.2 1 H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.82 (s, 1H), 8.00 - 7.94 (m, 3H), 7.54 - 7.42 (m, 2H), 7.24 - 7.20 (m, 1H), 6.69 - 6.64 (m, 1H), 5.86 (d, J=5.6 Hz, 1H), 4.34 - 4.03 (m, 5H), 2.63 - 2.56 (m, 2H), 2.24 - 2.17 (m, 2H).

[0242] Example 163: 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-2-yl)urea [ka] Example 163 Intermediate 54 (0.07 g, 0.13 mmol) was placed in a vial and diluted with 1 M TBAF solution in THF (3.5 mL, 3.5 mmol). The solution was heated at 70°C for 8 hours. The mixture was cooled, the organic mixture was diluted with siRNA, and washed with 32% aq KHCO, then brine / water in a 1:4 ratio. The organic layer was evaporated, and the crude product was dissolved in DMF / CH3CN in a 2:1 ratio and purified by RF FCC. The fractions containing the product were combined and evaporated to obtain the title compound (0.025 g, 0.06 mmol, 47% yield). LC-MS(ESI): Method 5, t R =5.50 min, m / z(M+1)=418.30 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.27 (1 H, s), 9.45 (1 H, s), 8.46 (1 H, d, J=5.26 Hz), 7.92 (3 H, m), 7.69 (1 H, br d, J=7.23 Hz), 7.27 (1 H, dd, J=5.26, 0.88 Hz), 7.09 (1 H, d, J=2.41 Hz), 4.12 (1 H, d, J=7.89 Hz), 3.93 (2 H, s), 3.83 (2 H, s), 2.57 (2 H, m), 2.16 (2 H, m)

[0243] The following examples and intermediates were prepared using the procedure described in Example 163 (see Table 18). [Table 18]

[0244] Example 16: 1-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea [ka] Example 16 Step 1 - tert-butyl (2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)carbamate (intermediate 9) [ka] A solution of pyrazolo[1,5-a]pyrazine-3-carboxylic acid (384 mg, 2.36 mmol) and thionyl chloride (1.7 mL, 23.6 mmol) was stirred under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure and dissolved in DCM (2.00 mL). This solution was added dropwise to a solution of tert-butyl N-(2-azaspiro[3.3]heptan-6-yl)carbamate (500 mg, 2.36 mmol) and TEA (0.98 mL, 7.07 mmol) in DCM (2.00 mL), and the reaction mixture was stirred under rt for 16 hours. Water was added, and the organic phase was separated. The organic phase was dried on hydrophobic lit and concentrated under reduced pressure to obtain the title compound (750 mg, 2.10 mmol, 89% yield). LCMS(ESI): Method 1, t R =1.34 min, m / z(M+1)=358 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J=1.4 Hz, 1H), 8.91 (dd, J=1.4, 4.6 Hz, 2H), 8.44 (s, 1H), 8.11 (d, J=4.7 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 4.50 (d, J=50.8 Hz, 2H), 4.04 (d, J=48.4 Hz, 2H), 3.91 - 3.79 (m, 1H), 2.48 - 2.43 (m, 2H), 2.15 - 2.07 (m, 2H), 1.38 (s, 9H).

[0245] Similarly, the following examples and intermediates were prepared starting from suitable analogues and carboxylic acids (see Table 19). [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4] [Table 19-5]

[0246] Step 2 - (6-amino-2-azaspiro[3,3]heptan-2-yl)(pyrazolo[1,5-a]pyrazine-3-yl)methanone (intermediate 10) [ka] Intermediate 10 was prepared according to the procedure described for intermediate 7. SM: Intermediate 9: 750mg (1eq); TFA: 3.4mL (20eq) Quantity / Yield: 460 mg, 1.79 mmol, 80% LCMS(ESI): Method 1, t R =0.94 min, m / z(M+1)=258

[0247] Starting from a suitable precursor, the following intermediates were prepared using a method similar to that described for intermediate 10 (see Table 20). [Table 20]

[0248] Step 3 - 1-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea (Example 16) To a solution of intermediate 10 (50 mg, 0.194 mmol) in DCM (1.00 mL), 1-fluoro-3-isocyanato-5-(trifluoromethyl)benzene (0.028 mL, 0.194 mmol) was added, and the reaction mixture was stirred under reduced pressure for 4 hours. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm 20-80% ACN / H2O (10 mM NH4CO3), 20 mL / min, RT) to obtain the title compound (7.5 mg, 0.0162 mmol, 8% yield). LCMS(ESI): Method 2, t R =4.04 min, m / z(M+1)=463.2 1 H NMR (400 MHz, DMSO-d6) δ 9.55 - 9.54 (m, 1H), 9.06 (s, 1H), 8.91 (dd, J=1.1, 4.7 Hz, 1H), 8.44 (s, 1H), 8.11 (d, J=4.8 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J=11.6 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.83 - 6.79 (m, 1H), 4.58 (s, 1H), 4.48 (s, 1H), 4.15 (s, 1H), 4.07 - 4.02 (m, 2H), 2.60 - 2.54 (m, 2H), 2.22 - 2.14 (m, 2H).

[0249] Starting with a suitable intermediate and a suitable commercially available isocyanate, the following examples and intermediates were prepared in a manner similar to that described in Step 3 of Example 16 (see Table 21). [Table 21-1] [Table 21-2] [Table 21-3] [Table 21-4]

[0250] Example 18: 1-(5-(tert-butyl)isoxazole-3-yl)-3-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea [ka] Example 18 Solutions of intermediate 10 (50 mg, 0.194 mmol) and intermediate 3 (51 mg, 0.194 mmol) in pyridine (1.00 mL) were stirred at 80°C for 6 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm 5-60% ACN / H2O (10 mM NH4CO3), 20 mL / min, RT) to obtain the title compound (19 mg, 0.0458 mmol, 24% yield). LCMS(ESI): Method 2, t R =3.75 min, m / z(M+1)=424.2 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J=1.5 Hz, 1H), 9.26 (s, 1H), 8.91 (dd, J=1.3, 4.8 Hz, 1H), 8.44 (s, 1H), 8.11 (d, J=4.8 Hz, 1H), 6.74 (d, J=7.3 Hz, 1H), 6.33 (s, 1H), 4.59 - 4.44 (m, 2H), 4.15 - 4.01 (m, 3H), 2.59 - 2.52 (m, 2H), 2.19 - 2.11 (m, 2H), 1.27 - 1.26 (m, 9H).

[0251] The following examples were prepared using a method similar to that described for Example 18, starting from a suitable intermediate (see Table 22). [Table 22]

[0252] Example 20: 1-(5-(tert-butyl)isoxazole-3-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea [ka] Example 20 Step 1: tert-butyl (2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)carbamate (intermediate 11) [ka] To a solution of tert-butyl (2-azaspiro[3.3]heptan-6-yl)carbamate (350 mg, 1.65 mmol), pyrazolo[5,1-b]thiazole-7-carboxylic acid (277 mg, 1.65 mmol), and TCFH (463 mg, 1.65 mmol) in DMF (2.00 mL), 1-methyl-1H-imidazole (0.13 mL, 1.65 mmol) was added, and the reaction mixture was stirred overnight in rt. Water was added, and the product was extracted with RINKAN. The organic phase was dried on hydrophobic lit and concentrated under reduced pressure to obtain the title compound (467 mg, 1.29 mmol, 78% yield). LCMS(ESI): Method 4, t R =1.39 min, m / z(M+1)=363.1

[0253] Starting with a suitable intermediate, the following examples and intermediates were prepared in a manner similar to that described for intermediate 11 (see Table 23). [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4] [Table 23-5] [Table 23-6] [Table 23-7] [Table 23-8] [Table 23-9]

[0254] Step 2 - (6-amino-2-azaspiro[3,3]heptan-2-yl)(pyrazolo[5,1-b]thiazole-7-yl)methanone (intermediate 12) [ka] Intermediate 12 was prepared according to the procedure described for the synthesis of intermediate 7. SM: Intermediate 11: 467 mg (1 eq); TFA: 0.99 mL (10 eq) Quantity / Yield: 314 mg, 1.20 mmol, 93% LCMS(ESI): Method 4, t R =0.98 min, m / z(M+1)=263.1

[0255] Starting with a suitable intermediate, the following intermediates were prepared using a method similar to that described for intermediate 12 (see Table 24). [Table 24-1] [Table 24-2]

[0256] Step 3 - 1-(5-(tert-butyl)isoxazole-3-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 20) Example 20 was prepared according to the procedure described for the synthesis of intermediate 18. SM: Intermediate 12: 50mg (1eq); Intermediate 3: 50mg (1eq) Quantity / Yield: 34 mg, 0.0799 mmol, 42% LCMS(ESI): Method 2, t R =3.97 min, m / z(M+1)=429.3 1 H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.31 (d, J=4.3 Hz, 1H), 8.06 (s, 1H), 7.52 (dd, J=1.4, 4.2 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.33 (s, 1H), 4.44 (d, J=44.9 Hz, 2H), 4.09 - 3.94 (m, 3H), 2.58 - 2.53 (m, 2H), 2.17 - 2.07 (m, 2H), 1.26 (s, 9H).

[0257] Example 21: 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethoxy)phenyl)urea [ka] Example 21 Step 1 - Phenyl (2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)carbamate (intermediate 13) [ka] A suspension of intermediate 12 (250 mg, 0.953 mmol) and Na2CO3 (61 mg, 0.572 mmol) in SiO2 (20.00 mL), THF (4.00 mL), and water (4.00 mL) was cooled to 0°C, and phenylchloroformate (0.13 mL, 1.05 mmol) was added dropwise. The resulting suspension was stirred at 0°C for 20 minutes, and then warmed to rt. DMF (4 mL) was added, and the reaction was stirred at rt for a further 16 hours. Water was added, and the product was extracted with SiO2. The organic phase was dried on hydrophobic lit and concentrated under reduced pressure to obtain the title compound (420 mg, 0.769 mmol, 81% yield). LCMS(ESI): Method 4, t R =1.37 min, m / z(M+1)=383.1

[0258] Starting with a suitable intermediate, the following compounds were prepared using a method similar to that described for intermediate 13 (see Table 25). [Table 25]

[0259] Step 2 - 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethoxy)phenyl)urea (Example 21) A solution of 3-(trifluoromethoxy)aniline (0.035 mL, 0.261 mmol) and intermediate 13 (100 mg, 0.261 mmol) in pyridine (1.00 mL) was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was loaded into an isolute SCX-II cartridge and released with MeOH. The MeOH eluent was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm 5-60% ACN / H2O (10 mM NH4CO3), 20 mL / min) to obtain the title compound (5.7 mg, 0.0122 mmol, 5% yield). LCMS(ESI): Method 2, t R =4.24 min, m / z(M+1)=466.2 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.31 (d, J=4.3 Hz, 1H), 8.07 (s, 1H), 7.63 (s, 1H), 7.52 (dd, J=1.3, 4.0 Hz, 1H), 7.32 (t, J=8.2 Hz, 1H), 7.21 (dd, J=1.6, 7.7 Hz, 1H), 6.87 - 6.84 (m, 1H), 6.61 (d, J=7.6 Hz, 1H), 4.55 - 4.34 (m, 1H), 4.10 - 4.00 (m, 3H), 2.58 - 2.53 (m, 2H), 2.17 - 2.10 (m, 2H).

[0260] Starting from the corresponding aniline / amine and a suitable intermediate, the following examples and intermediates were prepared in a manner similar to that described in Step 2 of Example 21 (Table 26). [Table 26-1] [Table 26-2] [Table 26-3] [Table 26-4] [Table 26-5]

[0261] Example 25: 1-Methyl-1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea [ka] Example 25 Step 1 - tert-butyl 6-(1-methyl-3-(3-(trifluoromethyl)phenyl)ureido)-2-azaspiro[3,3]heptane-2-carboxylate (intermediate 14) [ka] Intermediate 14 was prepared using the same procedure as reported for the synthesis of intermediate 6. SM: tert-butyl 6-(methylamino)-2-azaspiro[3.3]heptane-2-carboxylate: 300 mg (1 eq); 1-Isocyanato-3-(trifluoromethyl)benzene (1 eq) Quantity / Yield: 478 mg, 1.16 mmol, 87% LCMS(ESI): Method 4, t R =1.76 min, m / z(M+1)=414.1

[0262] Step 2 - 1-Methyl-1-(2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 15, compound IVa) [ka] Intermediate 15 was prepared according to the procedure described for the synthesis of intermediate 7. SM: Intermediate 14: 467 mg (1 eq); TFA: 0.99 mL (10 eq) Quantity / Yield: 314 mg, 1.20 mmol, 93% LCMS(ESI): Method 4, t R =1.40 min, m / z(M+1)=314.1 1 H NMR (400 MHz, DMSO-d6) δ 8.58 - 8.55 (m, 1H), 7.88 (s, 1H), 7.72 - 7.68 (m, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.27 - 7.24 (m, 1H), 4.52 - 3.96 (m, 5H), 2.84 (s, 3H), 2.34 - 2.26 (m, 2H), 2.23 - 2.14 (m, 2H).

[0263] Step 3 - 1-Methyl-1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 25) Example 25 was prepared by following the procedure described for the synthesis in step 3 of Example 1. SM: Intermediate 15: 100 mg (1 eq); Pyrazolo[1,5-a]pyrazine-3-carboxylic acid: 52 mg mL (1 eq) Quantity / Yield: 36 mg, 0.0790 mmol, 25% LCMS(ESI): Method 4, t R =4.11 min, m / z(M+1)=459.6 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J=1.5 Hz, 1H), 8.91 (dd, J=1.3, 4.8 Hz, 1H), 8.60 (s, 1H), 8.45 - 8.44 (m, 1H), 8.11 (d, J=4.8 Hz, 1H), 7.91 (s, 1H), 7.77 - 7.74 (m, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.28 - 7.25 (m, 1H), 4.63 - 4.47 (m, 3H), 4.21 - 4.02 (m, 2H), 2.90 (s, 3H), 2.47 - 2.38 (m, 4H).

[0264] Starting with the corresponding intermediate and a suitable carboxylic acid, the examples and intermediates were prepared in a manner similar to that described in step 3 of Example 25 (see Table 27). [Table 27-1] [Table 27-2] [Table 27-3]

[0265] Intermediate 77: 1-(2-azaspiro[3,3]heptan-6-yl)-1-(2,2,2-trifluoroethyl)-3-(3-(trifluoromethyl)phenyl)urea [ka] Step 1 - tert-butyl 6-((2,2,2-trifluoroethyl)amino)-2-azaspiro[3,3]heptane-2-carboxylate (intermediate 78) [ka] A solution of 2,2,2-trifluoroethane-1-amine (0.14 mg, 1.42 mmol, 1.20 eq) and tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 1.18 mmol) in MeOH (1.5 mL) was stirred at rt for 18 hours. The reaction mixture was cooled to 0°C, NaBH4 (0.067 mg, 1.8 mmol) was added, and stirring was continued at rt for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between DCM and saturated Na2CO3. The organic extract was filtered through hydrophobic lit and concentrated under reduced pressure. The title compound was used without further purification (350 mg, 1.18 mmol, quantified). LCMS(ESI): Method 4, t R = 1.57 minutes, m / z(M+1-tBu)=239.2

[0266] Starting from the corresponding intermediate, the following intermediates were prepared using a method similar to that described for intermediate 78 (see Table 28). [Table 28]

[0267] Step 2- tert-butyl 6-(1-(2,2,2-trifluoroethyl)-3-(3-(trifluoromethyl)phenyl)ureido)-2-azaspiro[3,3]heptane-2-carboxylate (intermediate 80) [ka] Intermediate 80 was prepared using the same procedure as reported for the synthesis of intermediate 6. SM: Intermediate 78: 350 mg (1 eq); 1-Isocyanato-3-(trifluoromethyl)benzene: 0.163 mL (1 eq) Quantity / Yield: 127 mg, 22% LCMS(ESI): Method 4, t R = 1.85 minutes, m / z(M+1-tBu)=426.2

[0268] Starting from a suitable intermediate, the following compounds were prepared using a method similar to that described for intermediate 80 (see Table 29). [Table 29]

[0269] Step 3 - 1-(2-azaspiro[3,3]heptan-6-yl)-1-(2,2,2-trifluoroethyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 77) Intermediate 77 was prepared using the same procedure as reported for the synthesis of intermediate 7. SM: Intermediate 80: 127mg (1eq) Quantity / Yield: 100 mg, quantitative determination LCMS(ESI): Method 4, t R =1.57 min, m / z(M+1)=382.1

[0270] Starting from a suitable intermediate, the following compounds were prepared using a method similar to that described for intermediate 77 (see Table 30). [Table 30]

[0271] Example 27: 2-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(3-(trifluoromethyl)phenyl)acetamide [ka] Example 27 Step 1 - tert-butyl 6-(2-oxo-2-((3-(trifluoromethyl)phenyl)amino)ethyl)-2-azaspiro[3,3]heptane-2-carboxylate (intermediate 16) [ka] Intermediate 16 was prepared according to the procedure described for the synthesis in step 3 of Example 1. SM: 2-(2-tert-butoxycarbonyl-2-azaspiro[3,3]heptan-6-yl)acetic acid: 300 mg (1 eq.); 3-(trifluoromethyl)aniline: 0.15 mL (1 eq.) Quantity / Yield: 430 mg, 1.08 mmol, 92% LC-MS(ESI): Method 1, t R =1.75 min, m / z(M +H-tBu)=343.0

[0272] The following compounds were prepared starting from a suitable intermediate, similar to the preparation described for intermediate 16 (see Table 31). [Table 31]

[0273] Step 2 - 2-(2-azaspiro[3,3]heptan-6-yl)-N-[3-(trifluoromethyl)phenyl]acetamide (intermediate 17, compound IVb) [ka] Intermediate 17 was prepared according to the procedure described for the synthesis of intermediate 7. SM: Intermediate 16: 430 mg (1 eq.); TFA: 1.7 ml, (20 eq.) Quantity / Yield: 230 mg, 0.270 mmol, 25% LC-MS(ESI): Method 1 t R =1.30 min, m / z(M+1)=299.0

[0274] The following compounds were prepared starting from appropriate intermediates in the same manner as described for Intermediate 17 (see Table 32). [Table 32]

[0275] Step 3 - 2-(2-(Pyrazolo[5,1 - b]thiazole - 7 - carbonyl)-2 - azaspiro[3.3]heptan - 6 - yl)-N-(3-(trifluoromethyl)phenyl)acetamide (Example 27) Example 27 was prepared by following the procedure described for Step 3 of the synthesis of Example 1. SM: Intermediate 17: 230 mg (1 eq.); Pyrazolo[5,1 - b]thiazole - 7 - carboxylic acid: 45 mg, (1 eq.) Amount / Yield: 31 mg, 0.0694 mmol, 26% LC - MS (ESI): Method 3 t R = 4.35 min, m / z(M + 1)=449.2 1 H NMR (400 MHz, DMSO - d6) δ 10.20 (s, 1H), 8.31 (d, J = 4.3 Hz, 1H), 8.08 (d, J = 10.8 Hz, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.56 - 7.51 (m, 2H), 7.38 (d, J = 7.8 Hz, 1H), 4.49 - 4.37 (m, 2H), 4.06 - 3.96 (m, 2H), 2.61 - 2.52 (m, 1H), 2.46 (d, J = 7.6 Hz, 2H), 2.42 - 2.34 (m, 2H), 2.01 - 1.94 (m, 2H).

[0276] The following compounds were prepared as described in Step 3 of Example 27 starting from Intermediate 17 and appropriate carboxylic acids (see Table 33). [Table 33]

[0277] Example 47: 1-Methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea [ka] Example 47 At 0°C, a solution of triphosgene (258 mg, 0.87 mmol) in DCM (2 mL) was mixed dropwise with a solution of 5-(trifluoromethyl)pyridine-3-amine (94 mg, 0.579 mmol, 2.00 eq) and Et3N (0.12 mL, 0.87 mmol) in DCM (2 mL). The reaction mixture was then stirred at 0°C for 1 hour. Intermediate 68 (80 mg, 0.289 mmol, 1.00 eq) and Et3N (0.16 mL, 1.15 mmol) in DCM were then mixed dropwise with the reaction mixture, warmed to rt, and stirred overnight. The reaction mixture was diluted with DCM and washed with NaHCO3 and brine. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by FCC (0-10% MeOH in DCM) to obtain the title compound (20.7 mg, 0.045 mmol, 15%). LCMS(ESI): Method 3, t R =3.72 min, m / z(M+1)=465.2 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J=2.3 Hz, 1H), 8.84 (s, 1H), 8.52 (d, J=1.0 Hz, 1H), 8.31 (dd, J=3.8, 3.8 Hz, 2H), 8.07 (s, 1H), 7.53 (dd, J=1.4, 4.2 Hz, 1H), 4.62 - 4.36 (m, 3H), 4.17 - 3.96 (m, 2H), 2.92 (s, 3H), 2.47 - 2.39 (m, 4H).

[0278] Similarly, the following examples were prepared starting from a suitable intermediate, as described in Example 47 (see Table 34). [Table 34-1] [Table 34-2] [Table 34-3]

[0279] Example 146: 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl (5-(trifluoromethyl)pyridine-3-yl)carbamate [ka] Example 146 Intermediate 56 (120 mg, 0.46 mmol) in DCM (2 mL) was added to 4-nitrophenyl chloroformate (112 mg, 0.553 mmol) and pyridine (0.056 mL). The solution was stirred at rt for 2 hours, and then the solvent was removed under vacuum. The solid was dissolved in 1 mL of pyridine, and 5-(trifluoromethyl)pyridine-3-amine (90 mg, 0.55 mmol) was added. The solution was stirred at 60°C. Then the solvent was removed under vacuum. The solid was dissolved in DCM and washed with NaHCO3sat. After purification by RF FCC, the appropriate fractions were combined and concentrated. The aqueous phase was quenched with NaHCO3sat and extracted with DCM and MeTHF. The organic layer was evaporated to obtain the title product (45 mg, 0.10 mmol, 22% yield). LCMS(ESI): Method 5, t R =5.23 min, m / z(M+1)=449.30 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (1 H, s), 8.84 (1 H, d, J=2.19 Hz), 8.60 (1 H, s), 8.27 (1 H, br s), 7.76 (1 H, d, J=1.10 Hz), 7.66 (1 H, d, J=2.19 Hz), 7.26 (1 H, dd, J=1.97, 1.10 Hz), 4.92 (1 H, m), 4.32 (4 H, m), 3.96 (3 H, s), 2.70 (2 H, td, J=6.96, 3.62 Hz), 2.32 (2 H, m).

[0280] The following examples were prepared starting from a suitable intermediate, similar to the one described for Example 146 (see Table 35). [Table 35]

[0281] Intermediate 154: (benzyl (2-(1-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)(methyl)carbamate) [ka] Intermediate 154 was prepared starting from intermediate 132 (860 mg, 3.6 mmol) and 2-bromoethyl methyl ether (0.3 ml, 5.5 mmol) following the procedure for intermediate 30. Quantity / Yield: 430 mg, 0.95 mmol / mmol, 44% LC-MS(ESI): Method 7, t R =0.95 min, m / z(M+1)=452.25

[0282] Intermediate 155: (1-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7-yl)(6-(methylamino)-2-azaspiro[3,3]heptan-2-yl)methanone [ka] Using a screw-type two-chamber glass reaction vessel, Intermediate 154 was dissolved in ethanol (5 mL), and then Pd / C (50% wet) (10.13 mg, 0.05 mmol) was added in two portions to the two chambers. The vessel was sealed, and vacuum-N2 was repeated three times to condition the reaction system. Triethylsilane (1.52 ml, 9.5 mmol) was slowly added to Chamber 1, and then the reaction mixture was stirred at rt for 2 hours. The reaction mixture was filtered through filter paper to remove the catalyst, washed with EtOH, and then the organic phase was concentrated under vacuum to give the title product (260 mg, 0.82 mmol, 86%). LCMS(ESI): Method 7, t R = 0.31 min, m / z(M+1) = 318.17

[0283] The following compounds were prepared according to the same synthetic procedure (see Table 36).

Table 36

[0284] Intermediate 157: tert-butyl 6-(((benzyloxy)carbonyl)(methyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

Chem.

[0285] Intermediate 83: (1-methyl-1H-imidazo[1,2-b]pyrazole-7-yl)(6-((methyl-d3)amino)-2-azaspiro[3,3]heptan-2-yl)methanone [ka] Step 1 - Benzyl (methyl-d3)(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)carbamate (intermediate 84) [ka] Under a nitrogen atmosphere, a solution of intermediate 51 (250 mg, 0.635 mmol) in THF (2.0 mL) was added dropwise to a suspension of sodium hydride in THF (0.50 mL) (60% suspension in mineral oil, 51 mg, 1.3 mmol). The mixture was stirred at rt for 2 hours, and then iodomethane-d3 (0.40 mL, 6.4 mmol) was added dropwise. The reaction mixture was stirred at rt for 18 hours. The mixture was carefully quenched with water, diluted with brine, and partitioned with RINKAN. The organic layer was washed with brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by FCC (40 g silica gel, 0-10% MeOH in DCM) to obtain the title compound (247 mg, 0.60 mmol, 95%). LC-MS(ESI): Method 1, t R =1.44 min, m / z(M+1)=411.3

[0286] Starting from a suitable intermediate, the following compounds were prepared using a method similar to that described for intermediate 84 (see Table 37). [Table 37]

[0287] Step 2 - (1-methyl-1H-imidazo[1,2-b]pyrazole-7-yl)(6-((methyl-d3)amino)-2-azaspiro[3,3]heptan-2-yl)methanone (intermediate 83) A suspension of intermediate 84 (247 mg, 0.602 mmol) and palladium (10% on carbon, 64 mg, 0.0602 mmol) in EtOH (5.0 mL) was subjected to a vacuum / nitrogen cycle, then a vacuum / hydrogen cycle, and finally to a hydrogen gas atmosphere. The reaction was stirred at rt for 18 hours. The mixture was filtered with Celite®, washed with siRNA, and the solvent was removed under reduced pressure to obtain the title compound (161 mg, 0.583 mmol, 97%), which was used without further purification. LC-MS(ESI): Method 1 t R =1.04 min, m / z(M+1)=277.2

[0288] Intermediate 86: 1-(2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2-azaspiro[3,3]heptan-6-yl)urea [ka] Step 1 - tert-butyl 6-(3-(2-methoxy-5-(trifluoromethoxy)phenyl)ureido)-2-azaspiro[3,3]heptane-2-carboxylate (intermediate 87) [ka] Under microwave radiation, a solution of 2,2,2-trichloroethyl (2-methoxy-5-(trifluoromethoxy)phenyl)carbamate (649 mg, 1.70 mmol), tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 1.41 mmol), and DIPEA (0.74 mL, 4.24 mmol) in ACN (5.0 mL) was stirred at 150 °C for 30 minutes, then cooled and concentrated under reduced pressure to obtain the title compound (882 mg, 1.98 mmol, quant.). LC-MS(ESI): Method 1 t R = 1.76 minutes, m / z(M+1-tBu)=390.1

[0289] The following intermediates were prepared using a method similar to the procedure described for intermediate 87 (see Table 38). [Table 38-1] [Table 38-2]

[0290] Step 2 - 1-(2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2-azaspiro[3,3]heptan-6-yl)urea (intermediate 86) Intermediate 86 was prepared according to the procedure described for intermediate 7. SM: Precursor / Intermediate: 882 mg (1 eq); TFA: 3.0 mL (20 eq) Quantity / Yield: 450 mg, 1.79 mmol, 66% LC-MS(ESI): Method 1 t R =1.32 min, m / z(M+1-)=346.0

[0291] Starting from the intermediate described above, the following compounds were prepared using a method similar to that described for intermediate 86 (see Table 39). [Table 39-1] [Table 39-2] [Table 39-3]

[0292] Intermediate 172: Benzyl methyl (2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)carbamate [ka] 1-Methyl-1H-imidazo[1,2-b]pyrazole-7-carboxylic acid (0.866 g, 5.2 mmol) was dissolved in DMF (25 mL), and CDI was added. The solution was stirred at rt until an activated ester was formed, then intermediate 167 (1.3 g, 5 mmol) was added to the solution and stirred at rt. The solution was then diluted with siRNA and washed with NaHCO3sat solution. The organic phase was then evaporated under vacuum and purified by FCC (Sfar NH, from 100% n-heptane to 40% EtOac / EtOH 3:1). The appropriate fractions were combined and evaporated under vacuum to obtain the title compound (550 mg, 1.3 mmol, 27% yield). LCMS(ESI): Method 2, t R =0.92 min, m / z(M+1)=408.19

[0293] Intermediate 173: tert-butyl 6-(((benzyloxy)carbonyl)amino)-2-azaspiro[3,3]heptane-2-carboxylate [ka] Tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (30 g, 141 mmol) and triethylamine (21.7 ml, 155 mmol) were dissolved in DCM (70 mL). The solution was cooled to -5°C and stirred for 10 minutes. Then, N-(benzyloxycarbonyloxy)succinimide (37.0 g, 148 mmol) was carefully added. The reaction mixture was stirred at rt until complete, and then sol. The mixture was washed with NH4Cl and HCl 0.5N, the organic layer was dried over MgSO4, filtered, and essicated to obtain the title compound (48 g, 139 mmol, 98% yield). LCMS(ESI): Method 2, t R =0.92 min, m / z(M+1)=408.19

[0294] Example 52: 3-(2-Methoxy-5-(trifluoromethoxy)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea [ka] Example 52 To a stirred solution of intermediate 57 (70 mg, 0.26 mmol) and 2,2,2-trichloroethyl (2-methoxy-5-(trifluoromethoxy)phenyl) carbamate (147 mg, 0.38 mmol) in ACN (3 mL), DIPEA (0.13 mL, 0.77 mmol) was added, and the reaction mixture was heated in a microwave at 150 °C for 30 minutes. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue was purified by preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm 20-80% ACN / H2O (0.1% FA), 20 mL / min) to obtain the title compound (73 mg, 0.144 mmol, 56% yield). LCMS(ESI): Method 2, t R =4.42 min, m / z(M+1)=507.2 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J=2.0 Hz, 1H), 7.83 (s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.51 (s, 1H), 7.32 (d, J=1.3 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.01 (dd, J=2.3, 8.8 Hz, 1H), 4.58 - 4.48 (m, 1H), 4.39 - 4.08 (m, 4H), 4.02 (s, 3H), 3.94 (s, 3H), 2.94 (s, 3H), 2.54 - 2.37 (m, 4H).

[0295] Starting with a suitable Troc carbamate and intermediate, the following examples and intermediates were prepared using ACN or DMF as a solvent at a temperature in the range of 80°C to 150°C in a manner similar to that described for Example 52 (see Table 40). [Table 40-1] [Table 40-2] [Table 40-3] [Table 40-4] [Table 40-5] [Table 40-6] [Table 40-7] [Table 40-8] [Table 40-9] [Table 40-10] Table 40-11 Table 40-12 Table 40-13 Table 40-14 Table 40-15 Table 40-16 Table 40-17 Table 40-18 Table 40-20 Table 40-21 Table 40-22 Table 40-23 Table 40-24 Table 40-25 Table 40-26 Table 40-27 Table 40-28 Table 40-29 Table 40-30 Table 40-31 Table 40-32 Table 40-33 Table 40-34 Table 40-35 Table 40-36 Table 40-37 Table 40-38 Table 40-39 Table 40-40 Tables 40-41 Tables 40-42 Tables 40-43 Tables 40-44 [Table 40-45] [Table 40-46]

[0296] Example 292: 2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(6-(trifluoromethyl)pyrimidine-4-yl)carbamate [ka] To a stirred solution of (6-hydroxy-2-azaspiro[3,3]heptan-2-yl)(pyrazolo[5,1-b]thiazole-7-yl)methanone (100 mg, 0.380 mmol) in DMF (1 mL), sodium hydride (45 mg, 1.1 mmol) was added, and the mixture was stirred for 20 minutes. Then, 2,2,2-trichloroethyl (6-(trifluoromethyl)pyrimidine-4-yl)carbamate (231 mg, 0.684 mmol) was added, and the mixture was stirred overnight.

[0297] The crude product was purified by preparative HPLC (Xbridge C18 19×150mm, 10um 20-80% ACN / H2O (10mM NH4CO3), 20mL / min, rt) to obtain the title compound (48mg, 0.105 mmol, 28% yield). LCMS(ESI): Method 11, t R =3.84 min, m / z(M+1)=453.4 1H NMR (400 MHz, DMSO-d6) δ 11.37 (bs, 1H), 9.02 (s, 1H), 8.31 (d, J=4.1 Hz, 1H), 8.20 - 8.18 (m, 1H), 8.07 - 8.05 (m, 1H), 7.54 - 7.51 (m, 1H), 4.99 - 4.92 (m, 1H), 4.49 - 4.49 (m, 2H), 4.07 - 4.07 (m, 2H), 2.76 - 2.68 (m, 2H), 2.39 - 2.31 (m, 2H).

[0298] The following examples were prepared using a method similar to that described for Example 292 (Table 41). [Table 41-1] [Table 41-2]

[0299] Example 202: 1-(2-(1-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethoxy)pyridine-2-yl)urea [ka] Intermediate 155 was dissolved in DMF (1 mL), then DIPEA (0.235 mL, 1.34 mmol) was added, followed by phenyl (4-(trifluoromethoxy)pyridine-2-yl)carbamate (66.8 mg, 0.22 mmol) at 0°C. The reaction mixture was stirred at rt for 12 hours. The reaction mixture was diluted with ELISA and then washed with brine. The organic layer was concentrated under vacuum.

[0300] The crude product was purified by RF FCC to obtain the title compound (20 mg, 0.04 mmol, 17% yield). LCMS(ESI): Method 5, t R =5.88 min, m / z(M+1)=522.50 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.31 (1 H, s), 8.34 (1 H, d, J=5.70 Hz), 7.83 (1 H, s), 7.77 (1 H, s), 7.65 (1 H, d, J=2.19 Hz), 7.27 (1 H, m), 6.98 (1 H, m), 4.60 (3 H, m), 4.13 (4 H, m), 3.60 (2 H, t, J=5.15 Hz), 3.21 (3 H, s), 2.89 (3 H, s), 2.38 (4 H, m).

[0301] Example 182: 1-(2-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea [ka] Example 182 Intermediate 53 (0.100 g, 0.19 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.040 g, 0.19 mmol), and K2CO3 (0.066 g, 0.48 mmol) were placed in the reactor, and dioxane (0.55 mL) was added via syringe under an argon atmosphere. The solution was filled with argon, and then Pd(dppf)Cl2 (0.014 g, 0.019 mmol) was added. The tube was sealed and heated overnight at 110°C. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated using a rotary evaporator. The crude product was purified by FCC (DCM / MeOH 100 / 0 to 90 / 10) to obtain the title compound (20 mg, 0.038 mmol, 20% yield). LCMS(ESI): Method 8, t R =3.45 min, m / z(M+1)=524.23 1H NMR (400 MHz, DMSO-d6) δ 9.10 (t, J=1.3 Hz, 1H), 8.75 (s, 1H), 8.27 (d, J=10.3 Hz, 2H), 8.17 (dd, J=9.1, 1.0 Hz, 1H), 8.03 (d, J=0.8 Hz, 1H), 7.94 (d, J=2.2 Hz, 1H), 7.75 (dd, J=9.2, 1.6 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 6.58 (d, J=7.6 Hz, 1H), 4.48 (d, J=47.4 Hz, 2H), 4.06 (td, J=17.7, 17.3, 9.3 Hz, 3H), 2.59 - 2.52 (m, 2H), 2.15 (dd, J=12.0, 8.7 Hz, 2H).

[0302] Example 192: 1-(2-(1-methyl-3-morpholino-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea [ka] Example 192 Dibromonickel; 1-methoxy-2-(2-methoxyethoxy)ethane (84 mg, 0.24 mmol), 2,2'-bipyridine (111 mg, 0.71 mmol), TBAB (2.38 ml, 0.48 mmol), intermediate 52 (250 mg, 0.48 mmol), morpholine (0.062 ml, 0.71 mmol), DBU (0.143 ml, 0.95 mmol), and DMA (6 mL) were placed in an ElectraSyn vial (5 mL) equipped with a stirrer bar. The vial was sealed with an ElectraSyn 2.0 vial cap, with the anode ((+) RVC, 47 mm × 8 mm × 2 mm) and cathode ((-) Ni foam, 0.8 cm × 4.7 cm × 0.1 cm) inserted into the mixture. The vial was then evacuated and backfilled with an argon balloon. The reaction mixture was electrolyzed under a constant current of 4 mA until the starting materials were completely consumed, as determined by LC-MS. Next, the ElectraSyn vial cap was removed, and the electrode was washed with a SiO:hexane = 1:1 mixture, and the washings were combined with the crude mixture. To this combined solution, aqueous sat.NH4Cl was added; the resulting solution was extracted with a SiO:hexane = 1:1 mixture. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by RF FCC to obtain the desired product (4 mg, 0.008 mmol, 2% yield).

[0303] LCMS(ESI): Method 5, t R =5.82 min, m / z(M+1)=532.40 1H NMR (600 MHz, DMSO-d6) δ ppm 8.88 (1 H, br s), 7.94 (1 H, s), 7.75 (1 H, m), 7.51 (1 H, m), 7.43 (1 H, t, J=7.92 Hz), 7.21 (1 H, br d, J=7.63 Hz), 6.69 (1 H, br d, J=7.34 Hz), 6.62 (1 H, d, J=1.03 Hz), 4.03 (2 H, m), 3.89 (2 H, s), 4.16 (4 H, m), 3.76 (3 H, m), 3.10 (3 H, m), 2.52 (2 H, m), 2.12 (2 H, td, J=9.13, 2.71 Hz).

[0304] Example 227: 1-(2-(6-(1-(2-methoxyethyl)-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea [ka] To a suspension of intermediate 129 (70 mg, 0.13 mmol) and 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (49.3 mg, 0.195 mmol) in Me-THF (1.5 mL), tripotassium phosphate (69 mg, 0.33 mmol) was added. After applying three N2 / vacuum cycles, tetrakis(triphenylphosphine)palladium(0) polymer conjugate (15.05 mg, 0.013 mmol) was added, and the vial was sealed. The reaction mixture was heated at 75°C for 12 hours. Ether and brine were added, and the organic layer was concentrated under vacuum. The crude product was purified by RF FCC to obtain the title compound (28 mg, 0.05 mmol, 37% yield). LCMS(ESI): Method 5, t R =5.66 min, m / z(M+1)=583.50 1H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (1 H, s), 8.94 (1 H, d, J=2.41 Hz), 8.85 (1 H, s), 8.52 (1 H, s), 8.32 (1 H, s), 8.31 (1 H, t, J=1.97 Hz), 8.26 (1 H, s), 8.18 (1 H, d, J=9.17 Hz), 8.06 (1 H, s), 7.77 (1 H, dd, J=9.32, 1.43 Hz), 4.56 (3 H, m), 4.29 (2 H, t, J=5.26 Hz), 4.05 (2 H, m), 3.72 (2 H, t, J=5.26 Hz), 3.25 (3H, s), 2.93 (3H, s), 2.43 (4H, m)

[0305] Starting from the corresponding intermediate, the following examples were prepared using XPhos Pd G in a manner similar to that described for Example 227 (see Table 42). [Table 42-1] [Table 42-2] [Table 42-3] [Table 42-4] [Table 42-5]

[0306] By applying the experimental conditions described above, the compound of formula (I) below was prepared: 1-(4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(4-(2-morpholinoethoxy)-3-(trifluoromethyl)phenyl)urea; 1-(2-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(3-fluorophenyl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-(2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(3-fluorophenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-(2-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(pyrazolo[1,5-a]pyrimidine-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(3-(tert-butyl)-1-methyl-1H-pyrazole-5-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-(5-(tert-butyl)-1-methyl-1H-pyrazole-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-(5-cyclopropylpyridine-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(2-(trifluoromethyl)pyridine-4-yl)urea; 1-(5-cyanopyridine-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(4-(trifluoromethyl)pyrimidine-2-yl)urea; 1-(2-(5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(3-(tert-butyl)-1-(pyridine-3-yl)-1H-pyrazole-5-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(2-(1-(2-(dimethylamino)ethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)phenyl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)urea; 1-(2-((1-acetylazetidine-3-yl)oxy)-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-(2-((1-acetylpiperidine-4-yl)oxy)-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-(2-(pyrazolo[1,5-a]pyrazine-3-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)urea; 1-(2-(2,3-dihydropyrazolo[5,1-b]oxazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(imidazo[2,1-b]thiazole-2-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(7-methylthieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(pyrazolo[1,5-a]pyrimidine-6-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(pyrazolo[1,5-a]pyridin-3-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(thieno[3,2-b]pyridine-6-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(imidazo[2,1-b]thiazole-6-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(5-isopropylpyridine-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(cyclopropylmethyl)-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(6-(trifluoromethyl)pyrazine-2-yl)urea; 1-(5-(difluoromethyl)pyridine-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(S-(trifluoromethyl)sulfonimidoyl)phenyl)urea; 1-(5-(tert-butyl)pyridine-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-(3-(hydroxymethyl)-2-methoxy-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(2-methyl-5-(trifluoromethyl)pyridine-3-yl)urea; 1-Methyl-3-(2-methyl-5-(trifluoromethyl)pyridine-3-yl)-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(2-methyl-5-(trifluoromethyl)pyridine-3-yl)urea; 1-Isobutyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-Methyl-1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(6-(trifluoromethyl)pyrimidine-4-yl)urea; 1-(5-(1,1-difluoroethyl)pyridine-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea; 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(6-(trifluoromethyl)pyrimidine-4-yl)urea; 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(5-(trifluoromethoxy)pyridine-2-yl)urea; 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(6-(trifluoromethoxy)pyridine-3-yl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(5-(trifluoromethoxy)pyridine-2-yl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(6-(trifluoromethoxy)pyridine-3-yl)urea; 1-(2-(1-(cyanomethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(6-(trifluoromethyl)pyridazine-4-yl)urea; 1-Methyl-3-(2-methyl-5-(trifluoromethoxy)phenyl)-1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethoxy)pyridine-3-yl)urea; 1-(6-methyl-2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethyl)pyridine-2-yl)urea; 1-Methyl-1-(2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(6-(trifluoromethyl)pyrimidine-4-yl)urea; 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridine-3-yl)urea; 1-(2-(1-((methylsulfonyl)methyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1-(2-hydroxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1-((2-methoxyethoxy)methyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea; 3-(2-methoxy-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-(2-(6-aminopyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea; 3-(3-cyclopropylisoxazole-5-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)isoxazole-5-yl)urea; 1-Methyl-1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(5-(1,1,1-trifluoro-2-methylpropane-2-yl)isoxazole-3-yl)urea; 1-Methyl-1-(2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole-3-yl)urea; 1-Methyl-3-(1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridine-3-yl)-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 3-(3-fluoro-4-(trifluoromethyl)pyridine-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-Methyl-1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(6-(trifluoromethyl)pyrimidine-4-yl)urea; 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(4-bromopyridine-2-yl)-1-methylurea; 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole-3-yl)urea; 2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-N-(6-(trifluoromethyl)pyrimidine-4-yl)acetamide; 2-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(4-(trifluoromethoxy)pyridine-2-yl)propanamide; 2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(4-(trifluoromethoxy)pyridine-2-yl)propanamide; 2-methyl-2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-N-(4-(trifluoromethoxy)pyridine-2-yl)propanamide; 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole-3-yl)urea; 1-Methyl-1-(2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(4-(trifluoromethyl)pyridine-2-yl)urea; 1-(2-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(3-(trifluoromethyl)phenyl)urea; 3-(5-bromopyridazine-3-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-(2-(1H-pyrazolo[3,4-b]pyridine-5-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(4-bromopyridine-2-yl)urea; 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(6-(trifluoromethyl)pyrimidine-4-yl)urea; 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethyl)pyridine-2-yl)urea; 1-Methyl-3-(2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)-1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea; 1-Methyl-3-(5-(perfluoroethyl)pyridazin-3-yl)-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea and 1-Methyl-1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridazine-3-yl)urea.

[0307] For comparison, the newly synthesized compounds C1, C2, and C3 were prepared as follows.

[0308] C1 is characterized by having a -CO-NH-linker that replaces the -NH-CO-L1-linker in the compound of the present invention.

[0309] C2 is characterized by having a -CH2-CO-NH-linker that replaces the -NH-CO-L1-linker in the compound of the present invention.

[0310] C3 is structure XXIII: [ka] XXIII [Here, the central core of the compound of formula (I): [ka] (Rs is hydrogen) It is characterized by having the following features.

[0311] Compound C1 :N-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(trifluoromethyl)benzamide [ka] C1 Compound C1 was prepared according to the procedure described for the synthesis in step 3 of Example 1. SM: Intermediate 10: 50 mg (1 eq); 3-(trifluoromethyl)benzoic acid: 37 mg (1 eq) Quantity / Yield: 23 mg, 0.0544 mmol, 28% LCMS(ESI): Method 3, t R 3.73 minutes, m / z(M+1)=430.2 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J=1.5 Hz, 1H), 8.92 - 8.87 (m, 2H), 8.46 (s, 1H), 8.19 (s, 1H), 8.15 (d, J=8.1 Hz, 1H), 8.11 (d, J=4.8 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 4.56 (d, J=52.8 Hz, 1H), 4.38 - 4.33 (m, 1H), 4.13 (d, J=50.2 Hz, 1H), 2.68 - 2.58 (m, 2H), 2.39 - 2.31 (m, 2H).

[0312] Compound C2 (N-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-2-(3-(trifluoromethyl)phenyl)acetamide) was prepared starting from commercially available 2-(3-(trifluoromethyl)phenyl)acetic acid by a method similar to that described for compound C1 (see Table 43). [Table 43]

[0313] Compound C3 :N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)-2-azaspiro[3,3]heptan-6-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (compound of formula XX, where L is CO, L1 is NR, and R is hydrogen) [ka] C3 Step 1 - tert-butyl (2-((3-(trifluoromethyl)phenyl)carbamoyl)-2-azaspiro[3,3]heptan-6-yl)carbamate (intermediate 18) [ka] Intermediate 18 was prepared using the same procedure as reported for the synthesis of intermediate 6. SM: tert-butyl (2-azaspiro[3,3]heptan-6-yl)carbamate: 200 mg (1 eq); 1-isocyanato-3-(trifluoromethyl)benzene (1 eq) Quantity / Yield: 376 mg, 0.941 mmol, 100% LCMS(ESI): Method 4, t R =1.67 min, m / z(M+1)=400.2

[0314] Step 2 - 6-amino-N-(3-(trifluoromethyl)phenyl)-2-azaspiro[3,3]heptane-2-carboxamide (intermediate 19) [ka] Intermediate 19 was prepared using the same procedure as reported for the synthesis of intermediate 7. SM:Intermediate 18:376mg(1eq) TFA: 1.4 mL (20 eq) Quantity / Yield: 270 mg, 0.902 mmol, 96% LCMS(ESI): Method 4, t R =1.34 min, m / z(M+1)=300

[0315] Step 3 - N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)-2-azaspiro[3,3]heptan-6-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (compound C3) Compound C3 was prepared according to the procedure described for the synthesis in step 3 of Example 1. SM: Intermediate 19: 100 mg (1 eq); Pyrazolo[1,5-a]pyrazine-3-carboxylic acid: 55 mg (1 eq) Quantity / Yield: 34 mg, 0.0755 mmol, 23% LCMS(ESI): Method 3, t R =3.82 min, m / z(M+1)=445.2 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J=1.3 Hz, 1H), 8.87 (dd, J=1.4, 4.7 Hz, 1H), 8.75 (s, 1H), 8.66 - 8.59 (m, 2H), 8.07 (d, J=4.8 Hz, 1H), 7.96 (s, 1H), 7.78 - 7.74 (m, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.27 - 7.23 (m, 1H), 4.40 - 4.32 (m, 1H), 4.08 (s, 2H), 3.97 (s, 2H), 2.62 - 2.55 (m, 2H), 2.33 - 2.26 (m, 2H).

[0316] Pharmacological activity of the compound of the present invention In vitro assay Binding assay Life Technologies LanthaScreen TM Europium kinase binding assays were performed for DDR1 and DDR2 binding. Compounds were incubated with 5nM DDR1 (Carna Biosciences) or 5nM DDR2 (Life Technologies) for 1 hour at room temperature in a white 384-well OptiPlate (PerkinElmer) containing 20nM or 10nM Kinase Tracer 178 and 2nM europium anti-GST antibody (Life Technologies), respectively, in assay buffer (50mM HEPES pH 7.5, 10mM MgCl2, 1mM EGTA, and 0.01% BRIJ35). The fluorescence emission ratio at 665nm / 615nm after excitation at 340nm was obtained using a Tecan Spark 20M plate reader. IC 50 The values ​​were determined using a 4-parameter model: log(inhibitor) vs. response with GraphPad Prism 7.0 software. The Cheng-Prusoff equation (Ki=IC) was used. 50 Using / (1+[Tracer] / Kd), IC 50 The value was converted to Ki.

[0317] Table 44 provides the results for representative compounds of the present invention, where the compounds are classified in terms of their binding potency (Ki, nM) with respect to their inhibitory activity against DDR1 and DDR2: [Table 44]

[0318] As can be understood, the compounds in Table 44, i.e., the compounds according to the present invention, exhibit good activity as antagonists of DDR1 and DDR2. Accordingly, the compounds of the present invention can be effectively used to treat DDR receptor-related diseases, disorders, or conditions such as fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, progressive pulmonary fibrosis, sarcoidosis, familial pulmonary fibrosis, chronic hypersensitivity pneumonitis (CHP), renal or renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, and systemic sclerosis.

[0319] Comparative compound Compounds C1, C2, and C3 were tested using the same binding assay as described above, and their Ki(nM) values ​​are reported in Table 45.

[0320] [Table 45]

[0321] The compounds of the present invention, whose activity is reported in Table 44, exhibit binding affinity to DDR1 and DDR2 receptors, expressed as Ki, with values ​​less than 100 nM, and in some cases less than 25 nM, and even less than 5 nM. Conversely, as seen in Table 45, comparative compounds C1, C2, and C3 did not show binding affinity to DDR1 and DDR2 receptors, and their Ki values ​​exceeded the detection limit of the binding assay.

[0322] Therefore, the presence of the -NH-CO-L1-linker (where L1 is NR, CH2, or O), the -CO-, -CH2-, or absent linker L, and the central core in the compound of formula (I) of the present invention unexpectedly and remarkably determines the significant inhibitory activity against DDR1 and DDR2 receptors.

Claims

1. Equation (I): 【Chemistry 1】 (I) [In the formula, A is 【Chemistry 2】 (Here, 【Transformation 3】 (This indicates direct bonding to NH.) It is a ring selected from the group consisting of; W1, W2, and W3 are independently hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) halohydroxyalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkoxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkoxy, (C 1 -C 4 ) hydroxyalkyl, halogen, cyano, SF 5 , NR1R2-(C 1 -C 4 ) alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C 3 -C 7 ) cycloalkyl, (C 1 -C 4 ) alkyl-heterocycloalkyl, (C 1 -C 4 ) alkyl-heterocycloalkyl-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl-cycloalkyl, (C 1 -C 4 ) alkyl-(C 3 -C 7 ) cycloalkyl, heterocycloalkyl-(C 1 -C 4 ) alkyl, heterocycloalkyl-NH-(C 1 -C 4 ) alkyl, (C 3 -C 7 ) cycloalkyl-(C 1 -C 4 ) alkyl, heterocycloalkyl-(C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkyl-CO-heterocycloalkyl-oxy, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkoxy, heterocycloalkyl-oxy, (C 3 -C 7 )Cycloalkyl-oxy, (C 1 -C 4 ) Alkyl-heterocycloalkyl-carbonyl, monocyclic (C 1 -C 4 )alkyl-heteroaryl, (C 1 -C 4 ) Alkyl-sulfonyl, (C 1 -C 4 ) Haloalkyl-sulfonyl, (C 1 -C 4 ) Haloalkyl-sulfonylamino, (C 1 -C 4 ) Haloalkyl-sulfinyl, (C 1 -C 4 ) Haloalkyl-thio, (C 1 -C 4 )alkyl-thio-(C 1 -C 4 ) alkyl, (C 1 -C 4 )alkyl-sulfonyl-(C 1 -C 4 )alkyl and (C 1 -C 4 )alkyl-sulfinyl-(C 1 -C 4 ) A substituent on ring A selected from the group consisting of alkyl groups; or W1 and W2 are adjacent to each other on ring A, and W1 and W2 are (C 5 -C 6 ) forms a cycloalkyl or a 5-membered or 6-membered heterocycloalkyl, where (C 5 -C 6 )Cycloalkyl or 5-membered or 6-membered heterocycloalkyl groups may optionally be substituted with 1 to 3 halogen atoms; L is CO and CH 2 It is either selected from or absent; L1 is selected from NR, CH 2 and O, where R is hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) hydroxyalkyl, (C 1 -C 4 ) haloalkyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) cycloalkyl-(C 1 -C 4 ) alkyl and deuterated (C 1 -C 4 ) alkyl; and is selected from the group consisting of If L1 is NR, then R S It is selected from hydrogen and methyl; L1 is CH 2 Or if O, R S is hydrogen; B is a monocyclic or bicyclic heteroaryl ring or a bicyclic semisaturated heteroaryl ring; Y1 and Y2 are independently hydrogen, (C 1 -C 4 ) alkyl, deuterated (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 ) Haloalkoxy, (C 1 -C 4 ) Hydroxyalkyl, halogen, cyano, SF 5 , (C 1 -C 4 )Cyanazole, (C 1 -C 4 ) Alkyl-sulfonyl, (C 1 -C 4 ) Haloalkyl-sulfonyl, CONR1R2, NHCOR1, NR1R2, NR1R2-(C 1 -C 4 )alkyl, heterocycloalkyl, which may be optionally substituted with 1 to 3 halogens, heterocycloalkyl-NH-(C 1 -C 4 ) alkyl, (C 3 -C 7 )Cycloalkyl, (C 1 -C 4 )Alkyl-heterocycloalkyl, (C 1 -C 4 )alkyl-(C 3 -C 7 )Cycloalkyl, heterocycloalkyl-(C 1 -C 4 ) alkyl, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-(C 1 -C 4 )alkoxy, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkoxy, heterocycloalkyl-oxy, (C 3 -C 7 )Cycloalkyl-oxy, phenyl, (C 1 -C 4 )alkoxy-substituted phenyl, (C 1 -C 4 )alkyl-thio-(C 1 -C 4 ) alkyl, (C 1 -C 4 )alkyl-sulfonyl-(C 1 -C 4 ) alkyl, (C 1 -C 4 )alkoxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl-cycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl-carbonyl and (C 1 -C 4 ) alkyl, (C 1 -C 4 )alkoxy and (C 1 -C 4 )alkoxy-(C 1 -C 4 A substituent on ring B, selected from the group consisting of monocyclic heteroaryls, which may optionally be substituted by 1 to 3 groups selected from the group consisting of alkyls; R1 and R2, independently, hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Hydroxyalkyl, (C 1 -C 4 )alkoxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 )alkylamino-(C 1 -C 4 ) alkyl, di-(C 1 -C 4 )alkylamino-(C 1 -C 4 ) Alkyl, may be substituted in some cases (C 3 -C 7 )cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heterocycloalkyl-(C 1 -C 4 ) Selected from the group consisting of alkoxys, where the substituents may be 1 to 3, and (C 1 -C 4 ) alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 ) Haloalkyl, (C 1 -C 4 ) Selected from the group consisting of haloalkoxys and carbamoyls; R3 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl, (C 1 -C 4 [Selected from the group consisting of alkylphenyls and monocyclic heteroaryls] Compounds thereof or their stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts, Compounds of formula (I) other than 1-(3,5-dichlorophenyl)-3-(2-(2-methylpyridine-4-yl)-2-azaspiro[3.3]heptan-6-yl)urea, or their stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts.

2. If ring A is phenyl and L1 is NH, W1, W2, and W3 are independently hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl, (C 1 -C 4 ) Halohydroxyalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkoxy, (C 1 -C 4 ) Hydroxyalkyl, fluorine, bromine, iodine, cyano, SF 5 NR1R2-(C 1 -C 4 )alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C 3 -C 7 )Cycloalkyl, (C 1 -C 4 )Alkyl-heterocycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl-cycloalkyl, (C 1 -C 4 )alkyl-(C 3 -C 7 )Cycloalkyl, heterocycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-NH-(C 1 -C 4 ) alkyl, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl-CO-heterocycloalkyl-oxy, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkoxy, heterocycloalkyl-oxy, (C 3 -C 7 )Cycloalkyl-oxy, (C 1 -C 4 ) Alkyl-heterocycloalkyl-carbonyl, monocyclic (C 1 -C 4 )alkyl-heteroaryl, (C 1 -C 4 ) Alkyl-sulfonyl 、 (C 1 -C 4 ) Haloalkyl-sulfonyl, (C 1 -C 4 ) Haloalkyl-sulfonylamino, (C 1 -C 4 ) Haloalkyl-sulfinyl, (C 1 -C 4 ) Haloalkyl-thio, (C 1 -C 4 )alkyl-thio-(C 1 -C 4 ) alkyl, (C 1 -C 4 )alkyl-sulfonyl-(C 1 -C 4 )alkyl and (C 1 -C 4 )alkyl-sulfinyl-(C 1 -C 4 ) A substituent on ring A selected from the group consisting of alkyl groups; or W1 and W2 are adjacent to each other on ring A, and W1 and W2 are (C 5 -C 6 ) forms a cycloalkyl or a 5-membered or 6-membered heterocycloalkyl, where (C 5 -C 6 ) The cycloalkyl or 5-membered or 6-membered heterocycloalkyl may optionally be substituted with 1 to 3 halogen atoms; preferably, the 6-membered heterocycloalkyl is a pyranyl ring. The compound described in claim 1 or its stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts.

3. W1, W2, and W3 are independently hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl, (C 1 -C 4 ) Halohydroxyalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkoxy, (C 1 -C 4 ) Hydroxyalkyl, fluorine, bromine, iodine, cyano, SF 5 NR1R2-(C 1 -C 4 )alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C 3 -C 7 )Cycloalkyl, (C 1 -C 4 )Alkyl-heterocycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl-cycloalkyl, (C 1 -C 4 )alkyl-(C 3 -C 7 )Cycloalkyl, heterocycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-NH-(C 1 -C 4 ) alkyl, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl-CO-heterocycloalkyl-oxy, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkoxy, heterocycloalkyl-oxy, (C 3 -C 7 )Cycloalkyl-oxy, (C 1 -C 4 ) Alkyl-heterocycloalkyl-carbonyl, monocyclic (C 1 -C 4 )alkyl-heteroaryl, (C 1 -C 4 ) Alkyl-sulfonyl 、 (C 1 -C 4 ) Haloalkyl-sulfonyl, (C 1 -C 4 ) Haloalkyl-sulfonylamino, (C 1 -C 4 ) Haloalkyl-sulfinyl, (C 1 -C 4 ) Haloalkyl-thio, (C 1 -C 4 )alkyl-thio-(C 1 -C 4 ) alkyl, (C 1 -C 4 )alkyl-sulfonyl-(C 1 -C 4 )alkyl and (C 1 -C 4 )alkyl-sulfinyl-(C 1 -C 4 ) A substituent on ring A selected from the group consisting of alkyl groups; or W1 and W2 are adjacent to each other on ring A, and W1 and W2 are (C 5 -C 6 ) forms a cycloalkyl or a 5-membered or 6-membered heterocycloalkyl, where (C 5 -C 6 The compound according to claim 1 or 2, or its stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof, wherein the cycloalkyl or 5-membered or 6-membered heterocycloalkyl may optionally be substituted with 1 to 3 halogen atoms; preferably, the 6-membered heterocycloalkyl is a pyranyl ring.

4. A 【Chemistry 4】 It is a ring selected from the group consisting of; More preferably, A is selected from the group consisting of phenyl, 3-pyridinyl, 2-pyridinyl, 3-pyridazinyl, 3-isoxazolyl, and pyrazolyl, where R3 is CH 3 or it is a p-trill; W1, W2, and W3 are hydrogen, CH 3 OCH 3 OCF 3 , CF 3 CHF 2 , C(CH 3 ) 3 CH 2 CF 3 , CF 2 CH 3 , CF 2 CF 3 , C(CH 3 ) 2 CF 3 OCF 2 H, CH 2 OH, cyano, CF 3 SO 2 SCF 3 ,SCIENCE FICTION 5 F, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N-acetylazetidinyl-oxy, 2,2,2-trifluoro-1-hydroxyethyl, oxetanyl-oxy and CH 2 N(CH 3 ) 2 Selected from the group consisting of; L is CO and CH 2 Selected from or absent, preferably CO; L1 is NR, CH 2 and are selected from O, where R is hydrogen, C is 3 , cyclopropylmethyl, cyclopropyl, CH 2 CF 3 CH 2 CH 3 and CH 3 Selected from the group consisting of; B is pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, imidazolyl, pyrazolyl, pyrazolo[1,5-a]pyradinyl, pyrazolo[1,5-a]pyradinyl, pyrazolo[3,4-d]pyradinyl, pyrazolo[1,5-a]pyradinyl, 1H-pyrazolo[3,4-b]pyradinyl, imidazo[1,2-b]pyradinyl, imidazo[1,2-a]pyradinyl, 1H-imidazo[1,2-b]pyrazolyl, imidazo[2,1-b]thiazolyl, pyrrolo[2,3-c]pyradinyl, pyrrolo[3,2-b Selected from the group consisting of ]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[5,1-b]thiazolyl, imidazo[1,5-a]pyridinyl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazinyl, thieno[3,2-d]pyridinyl, thieno[3,2-b]pyridinyl, thieno[2,3-d]pyridinyl, pyrazolo[5,1-b][1,3]thiadinyl, pyrrolo[3,2-d]pyridinyl, pyrrolo[2,3-d]pyridinyl, and imidazo[1,2-a]pyridinyl; Y1 is hydrogen, CH 3 OCH 3 OCF 3 , CF 3 , C(CH 3 ) 3 , C(CH 3 ) 2 CF 3 CONH 2 OCF 2 H, CF 2 H, CF 2 CH 3 , CF 2 CF 3 CH 2 CF 3 CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 CH 2 CH 2 SCH 3 CH 2 CH 2 F, CH 2 SCH 3 SCF 3 , SO 2 CF 3 CD 3 , cyano, NHCOCH 3 NH 2 , (C 1 -C 4 ) Selected from the group consisting of alkyl-piperazinyl, 4-methylpiperazin-1-yl, piperazinyl, morpholinyl, pyrrolidinyl, hydroxypyrrolidinyl, N-methyl-oxopiperazinyl, S,S-dioxide-thiomorpholinyl, oxetanyl-methyl, oxetanyl, (oxetanylamino)methyl, 1H-pyrazole-4-yl, oxazole-5-yl, pyridine-3-yl, pyrimidine-5-yl, pyridine-4-yl, dimethoxyphenyl, thiazole-5-yl, 3-isoxazole-5-yl, and 1-methyl-1H-pyrazole-4-yl, where Y2 is hydrogen; R1 and R2 are independently hydrogen, (C 1 -C 4 ) Selected from the group consisting of alkyl and optionally substituted heterocycloalkyl groups, where the optionally substituted substituents are CH 3 OCH 3 OCF 3 , CF 3 , C(CH 3 ) 3 , C(CH 3 ) 2 CF 3 CONH 2 OCF 2 H and CF 2 A compound according to any one of claims 1 to 3, selected from the group consisting of H, or its stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts.

5. Equation (Ia): L is CO and L1 is NR. 【Transformation 5】 (Ia) A compound according to any one of claims 1 to 4, as shown in [the provided text].

6. L is CH 2 And L1 is NR, equation (Ib): 【Transformation 6】 (Ib) A compound according to any one of claims 1 to 4, as shown in [the provided text].

7. Equation (Ic) where L is absent and L1 is NR: 【Transformation 7】 (I C) A compound according to any one of claims 1 to 4, as shown in [the provided text].

8. L1 is CH 2 Equation (Id): 【Transformation 8】 (Id) [In the formula, Rs is hydrogen.] A compound according to any one of claims 1 to 4, as shown in [the provided text].

9. Equation (Ie) where L1 is O: 【Chemistry 9】 (Ie) [In the formula, Rs is hydrogen.] A compound according to any one of claims 1 to 4, as shown in [the provided text].

10. 1-(2-(imidazo[1,2-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 1); 1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 2); 1-(2-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 3); 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 4); 1-(2-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 5); 1-(2-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 6); 1-(2-(imidazo[1,2-b]pyridazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 7); 1-(2-(1-methyl-1H-imidazole-5-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 8); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 9); 1-(2-(imidazo[1,2-a]pyrazine-3-ylmethyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 11); 1-(2-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 12); 1-(2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 15); 1-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 16); 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 17); 1-(5-(tert-butyl)isoxazole-3-yl)-3-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 18); 1-(3-cyano-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 19); 1-(5-(tert-butyl)isoxazole-3-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 20); 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethoxy)phenyl)urea (Example 21); 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 22); 1-(2-Methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 23); 1-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 24); 1-Methyl-1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 25); 1-(2-(imidazo[1,2-a]pyridine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(3-(trifluoromethyl)phenyl)urea (Example 26); 2-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(3-(trifluoromethyl)phenyl)acetamide (Example 27); 2-(2-(imidazo[1,2-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(3-(trifluoromethyl)phenyl)acetamide (Example 28); 2-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(3-(trifluoromethyl)phenyl)acetamide (Example 29); 1-(2-(1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 30); 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(2,2,2-trifluoroethyl)phenyl)urea (Example 31); 1-(2-(4-aminopyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 32); 1-(3-methoxyphenyl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 33); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(2,2,2-trifluoroethyl)phenyl)urea (Example 34); 1-(5-isopropylpyridine-3-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 35); 1-(2-Methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 36); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 37); 1-(5-chloro-2-methoxyphenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 38); 1-(3-cyano-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 39); 1-(2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 40); 1-(3-(hydroxymethyl)-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 41); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(pentafluoro-16-sulfaneil)phenyl)urea (Example 42); 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazole-5-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 43); 1-(2-Isonicotinyl-2-Azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 44); 1-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 45); 1-(2-(1H-pyrrolo[3,2-b]pyridine-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 46); 1-Methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 47); 1-(2-Methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(thieno[3,2-b]pyridine-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 48); 1-(2-(thieno[3,2-b]pyridine-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 49); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(2,2,2-trifluoroethyl)phenyl)urea (Example 50); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethoxy)pyridine-3-yl)urea (Example 51); 3-(2-methoxy-5-(trifluoromethoxy)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 52); 3-(3-cyano-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 53); 1-(2-(imidazo[1,2-b]pyridazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2-methoxy-5-(trifluoromethoxy)phenyl)urea (Example 54); 1-(2-Methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 55); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)urea (Example 56); 1-(2-(imidazo[1,2-a]pyrazine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(2-methoxy-5-(trifluoromethoxy)phenyl)urea (Example 57); 1-(1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridine-3-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 58); 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethyl)pyridine-2-yl)urea (Example 59); 3 3-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 60); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2-methyl-5-(trifluoromethoxy)phenyl)urea (Example 61); -(2-Methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 62); 1-(3-(difluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 63); 3-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 64); 1-(2-Methoxy-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 65); 1-(4-(difluoromethyl)pyridine-2-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 66); 1-(3-(difluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 67); 1-(2-Methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 68); 1-(2-Methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(5-(4-methylpiperazine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 69); 1-(2-(1-ethyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 70); 1-(3-cyano-5-(trifluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 71); 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 72); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethoxy)pyridine-2-yl)urea (Example 73); 1-(4-(difluoromethyl)pyridine-2-yl)-3-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 74); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethyl)pyridine-2-yl)urea (Example 75); 1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 76); 3-(2-Methoxy-5-(trifluoromethoxy)phenyl)-1-methyl-1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 77); 1-(3-(hydroxymethyl)-2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 78); 1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 79); 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazole-5-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 80); 3-(2-methoxy-5-(trifluoromethoxy)phenyl)-1-methyl-1-(2-(5-(4-methylpiperazine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 81); 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazole-5-yl)-3-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 82); 1-(5-chloro-2-methoxypyridine-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 83); 1-(2-(5-(4-methylpiperazine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 84); 1-Ethyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 85); 1-Ethyl-3-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 86); 1-(3-cyano-5-(trifluoromethyl)phenyl)-3-(2-(5-(4-methylpiperazine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 87); 1-(2-(thieno[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 88); 1-(3-(difluoromethoxy)phenyl)-3-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 89); 1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(4-(trifluoromethyl)pyridine-2-yl)urea (Example 90); 1-(5-(difluoromethoxy)-2-methoxyphenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 91); 1-(2-chloro-5-(trifluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 92); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 93); 3-(3-(hydroxymethyl)-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 94); 1-(3-(tert-butyl)-1-methyl-1H-pyrazole-5-yl)-3-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 95); 1-(2-(imidazo[2,1-b]thiazole-5-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 96); 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethoxy)pyridine-2-yl)urea (Example 97); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(pentafluoro-16-sulfaneil)phenyl)urea (Example 98); 1-(2-(6-methylthieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 99); 1-(5-(tert-butyl)-1-methyl-1H-pyrazole-3-yl)-3-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 100); 1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(4-(trifluoromethoxy)pyridine-2-yl)urea (Example 101); 1-(2-(1-(2-hydroxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 102); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(6-(trifluoromethyl)pyrimidine-4-yl)urea (Example 103); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2-methyl-5-(trifluoromethoxy)phenyl)urea (Example 104); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethoxy)pyridine-2-yl)urea (Example 105); 1-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 106); 1-(2-Methoxy-5-(trifluoromethyl)pyridine-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 107); 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 108); 1-(2-Methoxy-5-(pentafluoro-16-sulfaneyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 109); 1-(3-(hydroxymethyl)-5-(trifluoromethyl)phenyl)-3-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 110); 3-(3-cyano-5-(trifluoromethoxy)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 111); 1-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea (Example 112); 1-(2-(6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 113); 1-Methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethoxy)pyridine-2-yl)urea (Example 114); 1-(2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 115); 1-(2-(6-((oxetane-3-ylamino)methyl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 116); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(perfluoroethyl)phenyl) urea (Example 117); 1-(4-fluoro-3-(trifluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 118); 1-(3-cyano-5-(pentafluoro-16-sulfaneyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 119); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(pentafluoro-16-sulfaneil)phenyl)urea (Example 120); 1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 121); 1-(2-(1H-pyrazolo[3,4-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 122); 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 123); 1-(3-fluoro-5-(trifluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 124); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-((trifluoromethyl)thio)phenyl)urea (Example 125); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2-(oxetane-3-yloxy)-5-(trifluoromethyl)phenyl)urea (Example 126); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(perfluoroethyl)phenyl)urea (Example 127); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(3-(trifluoromethyl)phenyl)urea (Example 128); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethyl)pyridine-2-yl)urea (Example 129); 1-Methyl-1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 130); 3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 131); 3-(2-fluoro-5-(trifluoromethoxy)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 132); 1-Methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 133); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 134); 1-(2-(2,3-dihydropyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 135); 1-(2-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 136); 1-(2-(thieno[3,2-b]pyridine-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 137); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 138); N-(2-Methoxy-5-(trifluoromethoxy)phenyl)-2-(2-(thieno[3,2-b]pyridine-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)acetamide (Example 139); 2-(2-(thieno[3,2-b]pyridine-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-N-(3-(trifluoromethyl)phenyl)acetamide (Example 140); 2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(3-(trifluoromethyl)phenyl)acetamide (Example 141); N-(2-methoxy-5-(trifluoromethoxy)phenyl)-2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)acetamide (Example 142); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(3-(trifluoromethyl)phenyl)carbamate (Example 143); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(2-methoxy-5-(trifluoromethoxy)phenyl)carbamate (Example 144); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(4-(trifluoromethyl)pyridine-2-yl)urea (Example 145); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(5-(trifluoromethyl)pyridine-3-yl)carbamate (Example 146); 2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(3-(trifluoromethyl)phenyl)carbamate (Example 147); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 148); 1-(2-(imidazo[1,5-a]pyrazine-8-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 149); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-(2,2,2-trifluoroethyl)pyridine-2-yl)urea (Example 150); 1-Methyl-3-(2-methyl-5-(trifluoromethoxy)phenyl)-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 151); 1-(2-Methoxy-5-(2,2,2-trifluoroethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 152); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(2,2,2-trifluoroethyl)phenyl)urea (Example 153); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(4-(trifluoromethoxy)pyridine-2-yl)urea (Example 154); 1-(4-cyclopropylpyridine-2-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 155); 3-(4-cyclopropylpyridine-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 156); 3-(5-cyclopropylpyridine-3-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 157); 1-(methyl-d3)-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 158); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 159); 1-(2-(5-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 160); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-((trifluoromethyl)sulfonyl)phenyl)urea (Example 161); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-((trifluoromethyl)thio)phenyl)urea (Example 162); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-2-yl)urea (Example 163); 3-(4-(difluoromethyl)pyridine-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 164); 1-(2-methyl-5-(trifluoromethyl)pyridine-3-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 165); 1-(2-(1-(oxetan-3-ylmethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 166); 1-(2-(1-(oxetan-3-yl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 167); 1-(6-cyano-4-(trifluoromethyl)pyridine-2-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 168); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 169); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(6-(trifluoromethyl)pyrimidine-4-yl)urea (Example 170); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2-methyl-5-(trifluoromethyl)pyridine-3-yl)urea (Example 171); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethoxy)pyridine-3-yl)urea (Example 172); 3-(5-(1,1-difluoroethyl)pyridine-3-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 173); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-(2,2,2-trifluoroethyl)-3-(3-(trifluoromethyl)phenyl)urea (Example 174); 1-Methyl-1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 175); 1-Methyl-1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethoxy)pyridine-3-yl)urea (Example 176); 3-(4-(difluoromethoxy)pyridine-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 177); 1-Methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(6-(trifluoromethyl)pyrimidine-4-yl)urea (Example 178); 1-Methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethoxy)pyridine-3-yl)urea (Example 179); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(6-methyl-5-(trifluoromethyl)pyridine-3-yl)urea (Example 180); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(6-methyl-5-(trifluoromethyl)pyridine-3-yl)urea (Example 181); 1-(2-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 182); 1-(2-(5-(1,1-dioxidethiomorpholino)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 183); 1-(2-(5-aminopyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 184); 1-(2-(5-(3-hydroxypyrrolidine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 185); 1-(2-(5-(4-methyl-2-oxopiperazine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 186); 1-Cyclopropyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 187); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(2-methyl-5-(trifluoromethoxy)phenyl)urea (Example 188); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethoxy)pyridine-2-yl)urea (Example 189); 1-Methyl-1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(4-(trifluoromethoxy)pyridine-2-yl)urea (Example 190) 1-(6-methyl-2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 191); 1-(2-(1-methyl-3-morpholino-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 192); 3-(2-fluoro-3-methyl-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 193); 1-(2-(1-(2-(methylthio)ethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 194); 1-(2-(1-(2-fluoroethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(3-(trifluoromethyl)phenyl)urea (Example 195); 1-(2-(1-((methylthio)methyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 196); 3-(5-bromopyridine-3-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 197); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)urea (Example 198); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole-3-yl)urea (Example 199); 3-(4-bromopyridine-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 200); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(2-methyl-5-(trifluoromethoxy)phenyl)urea (Example 201); 1-(2-(1-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethoxy)pyridine-2-yl)urea (Example 202); 1-(2-(1-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(3-(trifluoromethyl)phenyl)urea (Example 203); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethoxy)pyridine-3-yl)urea (Example 204); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethoxy)pyridine-2-yl)urea (Example 205); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 206); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-((trifluoromethyl)thio)pyridine-3-yl)urea (Example 207); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridazine-3-yl)urea (Example 208); 1-(2-(1-(2-hydroxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethyl)pyridine-2-yl)urea (Example 209); 1-(2-(1-(2-hydroxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(3-(pentafluoro-16-sulfaneil)phenyl)urea (Example 210); 1-(2-(1-(2-hydroxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethoxy)pyridine-2-yl)urea (Example 211); 1-(3-(hydroxymethyl)-2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 212); 1-(2-(1-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 213); 1-Methyl-1-(2-(5-(pyrroridine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 214); 3-(3-(tert-butyl)isoxazole-5-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 215); 1-Methyl-1-(2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 216); 1-Methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethyl)pyridine-2-yl)urea (Example 217); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(hydroxymethyl)-2-methoxy-5-(trifluoromethoxy)phenyl)-1-methylurea (Example 218); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethoxy)pyridin-2-yl)urea (Example 219); 1-(2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 220); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethoxy)pyridin-3-yl)urea (Example 221); 3-(5-(tert-butyl)isoxazole-3-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 222); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-methyl-5-(trifluoromethyl)phenyl)urea (Example 223); 3-(3-chloro-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 224); 1-(2-(2-(2-methoxyethyl)-1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 225); 3-(4-bromopyridine-2-yl)-1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 226); 1-(2-(6-(1-(2-methoxyethyl)-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 227); 1-Methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridazine-3-yl)urea (Example 228); 1-Methyl-1-(2-(6-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 229); 1-Methyl-1-(2-(6-(pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 230); 1-Methyl-1-(2-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 231); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2-methyl-5-(trifluoromethyl)phenyl)urea (Example 232); 1-(2-(6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 233); 1-Methyl-1-(2-(6-(2-methylthiazole-5-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 234); 1-Methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole-3-yl)urea (Example 235); 1-(2-(6-(2-methoxypyridine-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 236); 1-Methyl-1-(2-(6-(3-methylisoxazole-5-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 237); 1-Methyl-1-(2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethyl)pyridine-2-yl)urea (Example 238); 1-Methyl-1-(2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethoxy)pyridine-2-yl)urea (Example 239); 1-Methyl-1-(2-(6-(pyrroridine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 240); 1-Methyl-1-(2-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethyl)pyridine-2-yl)urea (Example 241); 1-(2-(6-(1,2-dimethyl-1H-2l4-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethoxy)pyridine-2-yl)urea (Example 242); 1-Methyl-1-(2-(5-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 243); 1-(2-(5-aminopyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 244); 1-Methyl-1-(2-(6-(pyrimidine-5-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 245); 1-Methyl-1-(2-(6-(2-methylpyrimidine-5-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 246); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(3-(trifluoromethyl)phenyl)urea (Example 247); 1-(2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(3-(trifluoromethyl)phenyl)urea (Example 248); 1-Methyl-1-(2-(6-(pyridine-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 249); 1-(2-(6-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 250); 1-(2-(5-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 251); 1-(2-(5-(3,3-difluoropyrrolidine-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 252); 1-(2-(6-(6-methoxypyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 253); 3-(4-iodopyridine-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 254); 3-(4-(difluoromethyl)pyridine-2-yl)-1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 255); 3-(6-methoxy-4-(trifluoromethyl)pyridine-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 256); 3-(3,5-bis(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 257); 1-(2-(6-(1,3-dimethyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 258); 1-Methyl-1-(2-(pyrazolo[1,5-a]pyridin-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridazine-3-yl)urea (Example 259); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)-1-methylurea (Example 260); 1-(2-(6-(1,5-dimethyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridine-3-yl)urea (Example 261); 1-(2-Methoxy-5-(trifluoromethyl)pyridine-3-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 262); 1-Methyl-1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(4-(trifluoromethyl)pyridine-2-yl)urea (Example 263); 3-(2-ethyl-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 264); 3-(3-fluoro-4-methyl-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 265); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-(perfluoroethyl)pyridine-3-yl)urea (Example 266); 3-(6-chloro-4-(trifluoromethyl)pyridine-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 267); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-1-methyl-3-(3-methyl-5-(trifluoromethyl)phenyl)urea (Example 268); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole-5-yl)urea (Example 269); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(2-methyl-5-(trifluoromethyl)phenyl)carbamate (Example 270); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole-3-yl)carbamate (Example 271); 2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(4-(trifluoromethoxy)pyridine-2-yl)carbamate (Example 272); 2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(5-(trifluoromethyl)pyridine-3-yl)carbamate (Example 273); 2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(5-(trifluoromethyl)pyridine-3-yl)acetamide (Example 274); 2-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(5-(trifluoromethoxy)pyridine-3-yl)acetamide (Example 275); N-(2-fluoro-5-(trifluoromethoxy)phenyl)-2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)acetamide (Example 276); 2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(4-(trifluoromethoxy)pyridine-2-yl)acetamide (Example 277); 2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(2-methyl-5-(trifluoromethoxy)phenyl)acetamide (Example 278); 2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(4-(trifluoromethyl)pyridine-2-yl)acetamide (Example 279); 1-Methyl-3-(2-methyl-5-(trifluoromethoxy)phenyl)-1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)urea (Example 280); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-methyl-5-(trifluoromethoxy)phenyl)urea (Example 281); 1-(2-ethyl-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 282); 3-(3-fluoro-2-methyl-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 283); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-cyano-5-(trifluoromethyl)phenyl)-1-methylurea (Example 284); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(2-chloro-5-(trifluoromethyl)phenyl)-1-methylurea (Example 285); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-chloro-5-(trifluoromethyl)phenyl)-1-methylurea (Example 286); 3-(3-methoxy-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 287); 3-(2-ethoxy-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 288); 1-Methyl-3-(2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 289); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)urea (Example 290); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethyl)thiophene-2-yl)urea (Example 291); 2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(6-(trifluoromethyl)pyrimidine-4-yl)carbamate (Example 292); 2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole-3-yl)carbamate (Example 293); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(4-(trifluoromethoxy)pyridine-2-yl)carbamate (Example 294); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(2-methyl-5-(trifluoromethoxy)phenyl)carbamate (Example 295); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(4-(trifluoromethyl)pyridine-2-yl)carbamate (Example 296); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(6-(trifluoromethyl)pyrimidine-4-yl)carbamate (Example 297); 1-(2-ethoxy-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 298); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(5-(trifluoromethoxy)pyridine-3-yl)carbamate (Example 299); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)urea (Example 300); 2-(2-(1-(methyl-d3)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(4-(trifluoromethoxy)pyridine-2-yl)acetamide (Example 301); 2-(2-(1-(difluoromethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(4-(trifluoromethoxy)pyridine-2-yl)acetamide (Example 302); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-methyl-4-(trifluoromethyl)pyridine-2-yl)urea (Example 303); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 304); 1-Methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-(perfluoroethyl)pyridine-2-yl)urea (Example 305); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridazine-3-yl)urea (Example 306); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(2-methyl-5-(trifluoromethoxy)phenyl)urea (Example 307); 3-(6-bromo-4-(trifluoromethyl)pyridine-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 308); 1-(2-ethyl-5-(trifluoromethyl)pyridine-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 309); 3-(2-ethyl-5-(trifluoromethyl)pyridine-3-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 310); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(5-(trifluoromethyl)pyridazine-3-yl)carbamate (Example 311); and 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3,3]heptan-6-yl)-3-(3-(hydroxymethyl)-2-methoxy-5-(trifluoromethyl)phenyl)urea (Example 312) A compound of formula (I) according to claim 1, or its stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts, selected from the group consisting of the above.

11. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 10 in a mixture with at least one pharmaceutically acceptable carrier and / or additive.

12. The pharmaceutical composition according to claim 11, formulated for administration by inhalation.

13. The pharmaceutical composition according to claim 11, formulated for oral administration.

14. A compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutical composition according to any one of claims 11 to 13, for use as a pharmaceutical.

15. Formula (I) for use in the prevention and / or treatment of diseases, disorders, or conditions related to DDR dysregulation: 【Chemistry 10】 (I) [In the formula, A is 【Chemistry 11】 (Here, 【Chemistry 12】 (This indicates direct bonding to NH.) It is a ring selected from the group consisting of; W1, W2, and W3 are independently hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl, (C 1 -C 4 ) Halohydroxyalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkoxy, (C 1 -C 4 ) Hydroxyalkyl, halogen, cyano, SF 5 NR1R2-(C 1 -C 4 )alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C 3 -C 7 )Cycloalkyl, (C 1 -C 4 )Alkyl-heterocycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl-cycloalkyl, (C 1 -C 4 )alkyl-(C 3 -C 7 )Cycloalkyl, heterocycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-NH-(C 1 -C 4 ) alkyl, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl-CO-heterocycloalkyl-oxy, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkoxy, heterocycloalkyl-oxy, (C 3 -C 7 )Cycloalkyl-oxy, (C 1 -C 4 ) Alkyl-heterocycloalkyl-carbonyl, monocyclic (C 1 -C 4 )alkyl-heteroaryl, (C 1 -C 4 ) Alkyl-sulfonyl, (C 1 -C 4 ) Haloalkyl-sulfonyl, (C 1 -C 4 ) Haloalkyl-sulfonylamino, (C 1 -C 4 ) Haloalkyl-sulfinyl, (C 1 -C 4 ) Haloalkyl-thio, (C 1 -C 4 )alkyl-thio-(C 1 -C 4 ) alkyl, (C 1 -C 4 )alkyl-sulfonyl-(C 1 -C 4 )alkyl and (C 1 -C 4 )alkyl-sulfinyl-(C 1 -C 4 ) A substituent on ring A selected from the group consisting of alkyl groups; or W1 and W2 are adjacent to each other on ring A, and W1 and W2 are (C 5 -C 6 ) forms a cycloalkyl or a 5-membered or 6-membered heterocycloalkyl, where (C 5 -C 6 )Cycloalkyl or 5-membered or 6-membered heterocycloalkyl groups may optionally be substituted with 1 to 3 halogen atoms; L is CO and CH 2 It is either selected from or absent; L1 is NR, CH 2 and are selected from O, where R is hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Hydroxyalkyl, (C 1 -C 4 ) Haloalkyl, (C 3 -C 7 )Cycloalkyl, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkyl and deuterated (C 1 -C 4 Selected from the group consisting of alkyl groups; If L1 is NR, then R S It is selected from hydrogen and methyl; L1 is CH 2 Or if O, R S is hydrogen; B is a monocyclic or bicyclic heteroaryl ring or a bicyclic semisaturated heteroaryl ring; Y1 and Y2 are independently hydrogen, (C 1 -C 4 )alkyl, deuterated (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 ) Haloalkoxy, (C 1 -C 4 ) Hydroxyalkyl, halogen, cyano, SF 5 , (C 1 -C 4 )Cyanazole, (C 1 -C 4 ) Alkyl-sulfonyl, (C 1 -C 4 ) Haloalkyl-sulfonyl, CONR1R2, NHCOR1, NR1R2, NR1R2-(C 1 -C 4 )alkyl, heterocycloalkyl, which may be optionally substituted with 1 to 3 halogens, heterocycloalkyl-NH-(C 1 -C 4 ) alkyl, (C 3 -C 7 )Cycloalkyl, (C 1 -C 4 )Alkyl-heterocycloalkyl, (C 1 -C 4 )alkyl-(C 3 -C 7 )Cycloalkyl, heterocycloalkyl-(C 1 -C 4 ) alkyl, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-(C 1 -C 4 )alkoxy, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkoxy, heterocycloalkyl-oxy, (C 3 -C 7 )Cycloalkyl-oxy, phenyl, (C 1 -C 4 )alkoxy-substituted phenyl, (C 1 -C 4 )alkyl-thio-(C 1 -C 4 ) alkyl, (C 1 -C 4 )alkyl-sulfonyl-(C 1 -C 4 ) alkyl, (C 1 -C 4 )alkoxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl-cycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl-carbonyl and (C 1 -C 4 ) alkyl, (C 1 -C 4 )alkoxy and (C 1 -C 4 )alkoxy-(C 1 -C 4 A substituent on ring B, selected from the group consisting of monocyclic heteroaryls, which may optionally be substituted by 1 to 3 groups selected from the group consisting of alkyls; R1 and R2 are independently hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Hydroxyalkyl, (C 1 -C 4 )alkoxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 )alkylamino-(C 1 -C 4 ) alkyl, di-(C 1 -C 4 )alkylamino-(C 1 -C 4 ) Alkyl, may be substituted in some cases (C 3 -C 7 )cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heterocycloalkyl-(C 1 -C 4 ) Selected from the group consisting of alkoxys, where the substituents may be 1 to 3, and (C 1 -C 4 ) alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 ) Haloalkyl, (C 1 -C 4 ) Selected from the group consisting of haloalkoxys and carbamoyls; R3 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl, (C 1 -C 4 [Selected from the group consisting of alkylphenyls and monocyclic heteroaryls] Compounds thereof or their stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts.

16. If ring A is phenyl and L1 is NH, W1, W2, and W3 are independently hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl, (C 1 -C 4 ) Halohydroxyalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkoxy, (C 1 -C 4 ) Hydroxyalkyl, fluorine, bromine, iodine, cyano, SF 5 NR1R2-(C 1 -C 4 )alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C 3 -C 7 )Cycloalkyl, (C 1 -C 4 )Alkyl-heterocycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl-cycloalkyl, (C 1 -C 4 )alkyl-(C 3 -C 7 )Cycloalkyl, heterocycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-NH-(C 1 -C 4 ) alkyl, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl-CO-heterocycloalkyl-oxy, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkoxy, heterocycloalkyl-oxy, (C 3 -C 7 )Cycloalkyl-oxy, (C 1 -C 4 ) Alkyl-heterocycloalkyl-carbonyl, monocyclic (C 1 -C 4 )alkyl-heteroaryl, (C 1 -C 4 ) Alkyl-sulfonyl, (C 1 -C 4 ) Haloalkyl-sulfonyl, (C 1 -C 4 ) Haloalkyl-sulfonylamino, (C 1 -C 4 ) Haloalkyl-sulfinyl, (C 1 -C 4 ) Haloalkyl-thio, (C 1 -C 4 )alkyl-thio-(C 1 -C 4 ) alkyl, (C 1 -C 4 )alkyl-sulfonyl-(C 1 -C 4 )alkyl and (C 1 -C 4 )alkyl-sulfinyl-(C 1 -C 4 ) Selected from the group consisting of alkyl groups; or W1 and W2 are located in adjacent positions on ring A, and W1 and W2 are (C 5 -C 6 ) forms a cycloalkyl or a 5-membered or 6-membered heterocycloalkyl, where (C 5 -C 6 The compound of formula (I) for use according to claim 15, wherein the cycloalkyl or five-membered or six-membered heterocycloalkyl may optionally be substituted with one to three halogen atoms.

17. A compound of formula (I) for use according to claim 15 or 16 in the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions associated with fibrosis.

18. A compound of formula (I) for use according to claim 17 in the prevention and / or treatment of fibrosis, including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, progressive pulmonary fibrosis, sarcoidosis, familial pulmonary fibrosis, chronic hypersensitivity pneumonitis (CHP), renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, and systemic sclerosis.

19. A compound of formula (I) for use according to claim 18 in the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF).

20. A compound of formula (I) for use according to claim 18 in the prevention and / or treatment of renal fibrosis.

21. Formula IV: 【Chemistry 13】 IV [In the formula, A is 【Chemistry 14】 (Here, 【Chemistry 15】 (This indicates direct bonding to NH.) It is a ring selected from the group consisting of; W1, W2, and W3 are independently hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl, (C 1 -C 4 ) Halohydroxyalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkoxy, (C 1 -C 4 ) Hydroxyalkyl, halogen, cyano, SF 5 NR1R2-(C 1 -C 4 )alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C 3 -C 7 )Cycloalkyl, (C 1 -C 4 )Alkyl-heterocycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl-cycloalkyl, (C 1 -C 4 )alkyl-(C 3 -C 7 )Cycloalkyl, heterocycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-NH-(C 1 -C 4 ) alkyl, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl-CO-heterocycloalkyl-oxy, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkoxy, heterocycloalkyl-oxy, (C 3 -C 7 )Cycloalkyl-oxy, (C 1 -C 4 ) Alkyl-heterocycloalkyl-carbonyl, monocyclic (C 1 -C 4 )alkyl-heteroaryl, (C 1 -C 4 ) Alkyl-sulfonyl, (C 1 -C 4 ) Haloalkyl-sulfonyl, (C 1 -C 4 ) Haloalkyl-sulfonylamino, (C 1 -C 4 ) Haloalkyl-sulfinyl, (C 1 -C 4 ) Haloalkyl-thio, (C 1 -C 4 )alkyl-thio-(C 1 -C 4 ) alkyl, (C 1 -C 4 )alkyl-sulfonyl-(C 1 -C 4 )alkyl and (C 1 -C 4 )alkyl-sulfinyl-(C 1 -C 4 ) A substituent on ring A selected from the group consisting of alkyl groups; or W1 and W2 are adjacent to each other on ring A, and W1 and W2 are (C 5 -C 6 ) forms a cycloalkyl or a 5-membered or 6-membered heterocycloalkyl, where (C 5 -C 6 )Cycloalkyl or 5-membered or 6-membered heterocycloalkyl groups may optionally be substituted with 1 to 3 halogen atoms; L1 is NR, CH 2 and are selected from O, where R is hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Hydroxyalkyl, (C 1 -C 4 ) Haloalkyl, (C 3 -C 7 )Cycloalkyl, (C 3 -C 7 )Cycloalkyl-(C 1 -C 4 )alkyl and deuterated (C 1 -C 4 Selected from the group consisting of alkyl groups, preferably hydrogen, CD 3 , cyclopropylmethyl, cyclopropyl, CH 2 CF 3 CH 2 CH 3 or CH 3 Selected from the group consisting of; If L1 is NR, then Rs is selected from hydrogen and methyl; L1 is CH 2 Or if O, R S is hydrogen; R1 and R2 are independently hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Hydroxyalkyl, (C 1 -C 4 )alkoxy-(C 1 -C 4 ) alkyl, (C 1 -C 4 )alkylamino-(C 1 -C 4 ) alkyl, di-(C 1 -C 4 )alkylamino-(C 1 -C 4 ) Alkyl, may be substituted in some cases (C 3 -C 7 )cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heterocycloalkyl-(C 1 -C 4 ) Selected from the group consisting of alkoxys, where the substituents may be 1 to 3, and (C 1 -C 4 ) alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 ) Haloalkyl, (C 1 -C 4 ) Selected from the group consisting of haloalkoxys and carbamoyls; R3 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) Haloalkyl, (C 1 -C 4 [Selected from the group consisting of alkylphenyls and monocyclic heteroaryls] Intermediate compounds or their stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof The intermediate compound in formula IV is not 1-(3,5-dichlorophenyl)-3-(2-azaspiro[3.3]heptan-6-yl)urea; If ring A is phenyl, L1 is NH, and W1 and W2 are hydrogen, then W3 is para-OCF. 3 isn't it, Intermediate compounds or their stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts.

22. If ring A is phenyl and L1 is NH, W1, W2, and W3 are independently hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )halohydroxyalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkoxy, (C 1 -C 4 )hydroxyalkyl, fluorine, bromine, iodine, cyano, SF 5 , NR1R2-(C 1 -C 4 )alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl-(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl-cycloalkyl, (C 1 -C 4 )alkyl-(C 3 -C 7 )cycloalkyl, heterocycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-NH-(C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl-CO-heterocycloalkyl-oxy, (C 3 -C 7 )cycloalkyl-(C 1 -C 4 )alkoxy, heterocycloalkyl-oxy, (C 3 -C 7 )cycloalkyl-oxy, (C 1 -C 4 )alkyl-heterocycloalkyl-carbonyl, monocyclic (C 1 -C 4 )alkyl-heteroaryl, (C 1 -C 4 )alkyl-sulfonyl, (C 1 -C 4 )haloalkyl-sulfonyl, (C 1 -C 4 )haloalkyl-sulfonylamino, (C 1 -C 4 )haloalkyl-sulfinyl, (C 1 -C 4 )haloalkyl-thio, (C 1 -C 4 )alkyl-thio-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl-sulfonyl-(C 1 -C 4 )alkyl and (C 1 -C 4 )alkyl-sulfinyl-(C 1 -C 4 )selected from the group consisting of alkyl, preferably hydrogen, CH 3 , OCH 3 , OCF 3 , CF 3 , CHF 2 , C(CH 3 ) 3 , CH 2 CF 3 , CF 2 CH 3 , CF 2 CF 3 , C(CH 3 ) 2 CF 3、 OCF 2 H, CH 2 OH, cyano, CF 3 SO 2 SCF 3 ,SCIENCE FICTION 5 F, Br, I, Cyclopropyl, Morpholino-N-Ethoxy, N-Acetylpiperidinyl-Oxy, N-Acetylazetidinyl-Oxy, 2,2,2-Trifluoro-1-Hydroxyethyl, Oxetanyl-Oxy, CH 2 N(CH 3 ) 2 Selected from the group consisting of and 4-methylpiperazin-1-yl; or W1 and W2 are in adjacent positions on ring A, and W1 and W2 are (C 5 -C 6 ) forms a cycloalkyl or a 5-membered or 6-membered heterocycloalkyl, where (C 5 -C 6 ) The cycloalkyl or 5-membered or 6-membered heterocycloalkyl may optionally be substituted with 1 to 3 halogen atoms. The intermediate compound according to claim 20, or its stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.

23. The use of intermediate compound IV as defined in claim 21 or 22 in the preparation of a compound of formula (I) as defined in claim 1.

24. A method for preparing a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, a) Intermediate compound IV: 【Chemistry 16】 IV carboxylic acid XI: 【Chemistry 17】 Or aldehyde XII: [Chemistry 18] Or, Ariel Halide XIII: 【Chemistry 19】 The process includes reacting with to obtain the compound of formula (I), Here, The compound of formula IV is as defined in claim 21 or 22, A method in which B, Y1 and Y2 are as defined in claim 1, and X is a halogen, preferably bromine.

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