Compounds and compositions for inhibiting HIF2α activity and methods of use thereof

Abstract

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salt forms thereof, wherein the substituents are as defined in the specification; intermediates in the preparation of the compounds; pharmaceutical compositions containing the compounds; and the use of the compounds in the treatment of diseases. [Formula 1] TIFF2023530530000383.tif42170

Description

[Technical Field]

[0001] The present invention provides compounds of the spiro[imidazo[1,2-α]pyridine type, their use for inhibiting or modulating HIF2α, and methods of treating diseases using the compounds. [Background technology]

[0002] Hypoxia-inducible factors (HIFs), such as HIF1α and HIF2α, are well-known transcription factors that act as master regulators of oxygen homeostasis, controlling the transcriptional response to reduced oxygen availability (hypoxia). HIFs are heterodimeric proteins composed of the O2-regulating HIF-α subunit and the constitutively expressed HIF-1β subunit, also known as ARNT. Under well-oxygenated or normoxic conditions, HIF-α binds to the von Hippel-Lindau (VHL) protein, which recruits ubiquitin ligases that target HIF-α for proteasomal degradation (Kaelin and Ratcliffe, 2008). VHL binding depends on the hydroxylation of specific proline residues in HIF-α by the prolyl hydroxylase PHD, which uses O2 as a substrate such that its activity is inhibited under hypoxic conditions. HIF1α and HIF2α are transcription factors that regulate the expression of many genes involved in important physiological functions, such as development, metabolism, angiogenesis, cell proliferation, and cell survival. While HIF1α is widely expressed, HIF2α transcripts are restricted to specific cell types, including vascular endothelial cells, neural crest cell derivatives, lung type II pneumocytes, liver parenchyma, and renal interstitial cells. HIF2α has been described as a key mediator of cellular adaptation to oxygen deprivation (hypoxia) and plays a crucial role in physiological processes such as erythropoiesis and angiogenesis. HIF2α is required for normal embryonic development, and postnatal ablation of HIF2α results in severe anemia and impaired erythroid development. Consistent with these findings, it has been reported that erythropoietin (EPO) is primarily regulated by HIF2α, while several other HIF-dependent genes can be regulated by both HIF-α isoforms.

[0003] Hypoxia plays a key role in the progression of many common disorders, and there is emerging evidence that modulation of the HIF transcriptional program may be a beneficial therapeutic strategy in a wide variety of diseases, such as ischemia, inflammation, chronic lung disease, and cancer (Semenza, 2011). In cancer in particular, intratumoral hypoxia is associated with poor patient prognosis and resistance to radiation and chemotherapy treatments.

[0004] HIF activation has been reported in many advanced human cancers, including brain, breast, colon, lung, and renal cell carcinoma. In clear cell renal cell carcinoma (ccRCC), frequently reported genetic alterations (e.g., mutations or silencing) in the VHL gene result in the accumulation of HIF-α in tumors, independent of oxygen levels. HIF-2α is expressed in most ccRCC tumor samples, whereas only a subset accumulates HIF-1α (Gordan, 2008). Furthermore, in ccRCC, HIF-2α has been described as a key oncogenic event, while HIF-1α exhibits tumor-suppressive properties (Shen and Kaelin, 2013; Gordan 2008). For example, overexpression of HIF-2α results in increased in vivo growth of VHL-deficient 786-0 RCC tumor xenografts. In contrast, downregulation of HIF2α by inducible shRNA or pharmacological inhibition appears sufficient to suppress tumor growth in VHL-deficient 786-0 and A498 RCC models (Kondo et al., 2002; Kondo et al., 2003; Zimmer et al., 2004; Cho et al., 2016). These results support HIF2α as an attractive target for anticancer therapy. Summary of the Invention [Means for solving the problem]

[0005] The present invention provides compounds of formula (I), as defined below, or pharmaceutically acceptable salts thereof. The compounds of formula (I) are HIF2α inhibitors or modulators and therefore may be useful in the treatment of conditions, diseases and disorders mediated by HIF2α.

[0006] In one aspect of the invention, a compound of formula (I), in free form or in pharmaceutically acceptable salt form, [ka] or a pharmaceutically acceptable salt thereof, During the ceremony: R 1 is F, Cl, Br, OCH3, OCH2F, OCHF2, or OCF3; R 2 is F, Cl, CF3, or CN; X is (CH2) 1~2 , CHF, CHD, CD2 or CF2; Y is (CH2) 0~2 , CHF, CHD, CD2, O, S, OCH2 or CF2; Z is CH2, CD2, CHF, CDF, CF2, CH(OH), CO, CH(CH3), O or S; wherein when Y is O, OCH2, or S, Z is CH2; where Z is O, S, or NCH3, then Y is (CH2) 0~2 or CF2; where, when Z is CH(OH), Y is CHF or CF2; J is for CR J and; where R J is H, F, Cl, Br, CH3, CD3, CF3, CHF2, CDF2, or CN; E is CR E or N; where R E is H, F, Cl, Br, I, CN, CH3, CH2CH3, CH(CH3)2, CD3, CHD2, CH2D, CHF2, CDF2, C(CH3)F2, C(CD3)F2, CF3, cyclopropyl, OCH3, OCH2CH2OH, OCF3, SCH3 or SCHF2; G is CH or N.

[0007] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0008] In another aspect, the present invention provides combinations, particularly pharmaceutical combinations, comprising a compound of Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents. In certain instances, the compounds of the present invention are combined with other therapeutic agents, such as other anti-cancer agents (particularly mTOR inhibitors such as everolimus), anti-nausea agents (or anti-emetic agents), chemotherapy, analgesics, cytoprotective agents, and combinations thereof.

[0009] mTOR inhibitors include temsirolimus (Torisel®); ridaforolimus (formerly known as deferolimus, (1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0] 4,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669, and described in PCT Publication WO 03 / 064383; everolimus (Afinitor® or RAD001); rapamycin (AY22989, Sirolimus®); simapimod (CAS 164301-51-3;(5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055);2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one (PF04691502, CAS 1013101-36-4);N 2 -[1,4-Dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-α-aspartylL-serine-, inner salt (SF1126, CAS 936487-67-1); and N-[4-[[[3-[(3,5-dimethoxyphenyl)amino]-2-quinoxalinyl]amino]sulfonyl]phenyl]-3-methoxy-4-methyl-benzamide (also known as XL765, SAR245409); and (1r,4r)-4-(4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[1,5-f][1,2,4]triazin-7-yl)cyclohexanecarboxylic acid (OSI-027).

[0010] Common chemotherapy drugs that may be considered for use in combination therapy include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxan®), busulfan (Mylan®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukemia®), and fluconazole (Feverkiller®). cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubicin®), daunorubicin citrate liposome injection (Daunoxome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Bepcid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrsil®, Efudex®), flutamide (Eurexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®) ), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Plinasol®), methotrexate (Forex®), mitoxantrone (Novantrone®), Mylotarg, paclitaxel (Taxol®), nab-paclitaxel (Abraxane®), Phoenix (yttrium 90 / MX-DTPA),These include pentostatin, porifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Bumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), injectable topotecan hydrochloride (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0011] In another aspect, the present invention provides a method for inhibiting or modulating HIF2α activity in a subject in need thereof, the method comprising administering to a subject in need thereof a compound of formula (I), or a subformula thereof, or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, the present invention provides a compound of formula (I), or a subformula thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of cancer, wherein the cancer is selected from adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer (which may include colon cancer), germ cell tumors (e.g., cranial and extracranial germ cell tumors, gonadal and extragonadal germ cell tumors), glioblastoma multiforme (GBM), glioma, head and neck cancer (which may include lip, oral cavity, mouth cancer), hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, eye cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, and renal cell carcinoma.

[0013] In another aspect, the present invention provides a crystalline form of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] free form.

[0014] In another aspect, the present invention provides a crystalline form of the fumarate salt of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline].

[0015] In another aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, the process comprising reacting a compound of formula (IV) [ka] or a salt, solvate, stereoisomer, complex, co-crystal, ester, or oxazoline thereof, and a compound of formula (II) [ka] or a salt, solvate, stereoisomer, complex, co-crystal, ester, or oxazoline thereof, optionally in the presence of a base selected from KCO or EtN, Compound of formula (III) [ka] or a salt, solvate, stereoisomer, complex, co-crystal, ester, or oxazoline thereof (In the formula, R 1 is F, Cl, Br, OCH3, OCH2F, OCHF2, or OCF3; R 2 is F, Cl, CF3, or CN; X is CH2, CHF, or CF2; Y is CH2, CHF, O, S, a single bond, CH2CH2, OCH2, or CF2; Z is CH2, CD2, CHF, CDF, CF2, CH(OH), CO, CH(CH3), O or S; wherein when Y is O, OCH2, or S, Z is CH2; where, when Z is O, S, or NCH3, Y is CH2, a single bond, CH2CH2, or CF2; where, when Z is CH(OH), Y is CHF or CF2; J is for CR J and; where R J are H, F, Cl, Br, CH3, CD3, CF3, CHF2, CDF2, CN; E is CR E or N; where R E is H, F, Cl, Br, I, CN, CH3, CH2CH3, CH(CH3)2, CD3, CHD2, CH2D, CHF2, CDF2, C(CH3)F2, C(CD3)F2, CF3, cyclopropyl, OCH3, OCH2CH2OH, OCF3, SCH3, or SCHF2; G is CH or N; LG is a leaving group selected from F, Cl, or Br. to obtain a compound of formula (1) or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawings]

[0016] [Figure 1] 1 shows a representative X-ray powder diffraction (XRPD) pattern for Form A of (S)-1′-chloro-8-(difluoromethoxy)-8′,8′-difluoro-6-(trifluoromethyl)-7′,8′-dihydro-3H,6′H-spiro[imidazo[1,2-α]pyridine-2,5′-isoquinoline] of the present invention, where the x-axis represents the scattering angle in °2θ and the y-axis represents the intensity of the scattered X-ray beam in counts of detected photons. [Figure 2]1 shows a representative differential scanning calorimetry (DSC) curve for Form A of (S)-1′-chloro-8-(difluoromethoxy)-8′,8′-difluoro-6-(trifluoromethyl)-7′,8′-dihydro-3H,6′H-spiro[imidazo[1,2-α]pyridine-2,5′-isoquinoline] of the present invention, where the x-axis represents temperature in degrees Celsius (° C.) and the y-axis represents heat flow in watts per gram (W / g) at which the endothermic peak rises. [Figure 3] 1 shows a representative thermogravimetric analysis (TGA) of crystalline Form A of (S)-1′-chloro-8-(difluoromethoxy)-8′,8′-difluoro-6-(trifluoromethyl)-7′,8′-dihydro-3H,6′H-spiro[imidazo[1,2-α]pyridine-2,5′-isoquinoline] of the present invention, where the x-axis represents temperature in degrees Celsius (° C.) and the y-axis represents sample mass (loss) in weight percent (wt%). [Figure 4]

[0023] Figure 1 shows a representative dynamic vapor sorption analysis (DVS) of crystalline Form A of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] of the present invention over the range of 0 to 95% relative humidity. The x-axis shows relative humidity in percent (%) measured at a temperature of (25.0±0.1) °C, and the y-axis shows equilibrium mass change in weight percent (wt%). Adsorption cycles are indicated by triangles, while desorption cycles are indicated by squares. Values ​​are displayed as uncorrected values. [Figure 5] 1 shows a representative X-ray powder diffraction (XRPD) pattern of Form A of the (S)-1′-chloro-8-(difluoromethoxy)-8′,8′-difluoro-6-(trifluoromethyl)-7′,8′-dihydro-3H,6′H-spiro[imidazo[1,2-α]pyridine-2,5′-isoquinoline] fumarate salt of the present invention, where the x-axis represents the scattering angle in °2θ and the y-axis represents the intensity of the scattered X-ray beam in detected photon counts. [Figure 6]1 shows a representative differential scanning calorimetry curve (DSC) of Form A of the (S)-1′-chloro-8-(difluoromethoxy)-8′,8′-difluoro-6-(trifluoromethyl)-7′,8′-dihydro-3H,6′H-spiro[imidazo[1,2-α]pyridine-2,5′-isoquinoline] fumarate salt of the present invention, where the x-axis represents temperature in degrees Celsius (° C.) and the y-axis represents heat flow in watts per gram (W / g) at the time of the increase in the endothermic peak. [Figure 7] 1 shows a representative thermogravimetric analysis (TGA) of crystalline Form A of (S)-1′-chloro-8-(difluoromethoxy)-8′,8′-difluoro-6-(trifluoromethyl)-7′,8′-dihydro-3H,6′H-spiro[imidazo[1,2-α]pyridine-2,5′-isoquinoline] fumarate salt of the present invention, where the x-axis represents temperature in degrees Celsius (° C.) and the y-axis represents sample mass (loss) in weight percent (wt%). [Figure 8] 1 shows a representative dynamic vapor sorption analysis (DVS) of crystalline Form A of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] fumarate salt of the present invention over the range of 0 to 95% relative humidity. The x-axis shows relative humidity in percent (%) measured at a temperature of (25.0±0.1)°C, and the y-axis shows equilibrium mass change in weight percent (wt%). Adsorption cycles are indicated by triangles, while desorption cycles are indicated by squares. Values ​​are displayed as uncorrected values. [Figure 9-1] Figure 9: Figure 9A shows the effect of Example 31 on tumor growth in the 786-O mouse model (*: p<0.05 vs. vehicle control) (ANOVA on ranks and post-hoc Tukey's test). Figure 9B shows the effect of Example 31 on hCCNDI transcript levels in the 786-O mouse model (*: p<0.05 vs. vehicle control) (unpaired two-tailed T-test). [Figure 9-2] (As mentioned above.) [Figure 10-1]Figure 10: Figure 10A shows the effect of Example 31 on tumor growth in the SKRC-01 mouse model (*: p<0.05 vs. vehicle control) (ANOVA on ranks and post-hoc Tukey's test). Figure 10B shows the effect of Example 31 on hCCNDI transcript levels in the SKRC-01 mouse model (*: p<0.05 vs. vehicle control) (unpaired two-tailed T-test). [Figure 10-2] (As mentioned above.) [Figure 11-1] Figure 11: Figure 11A shows the effect of Example 32 on tumor growth in the SKRC-01 mouse model (*: p<0.05 vs. vehicle control) (ANOVA on ranks and post-hoc Dunn's test). Figure 11B shows the effect of Example 32 on hCCNDI transcript levels in the SKRC-01 mouse model (*: p<0.05 vs. vehicle control) (ANOVA on ranks and post-hoc Dunn's test). [Figure 11-2] (As mentioned above.) [Figure 12] Female nude mice bearing HKIX2207 subcutaneous xenografts were treated with 30 mg / kg poqd of Compound A or 2 mg / kg poqd of Compound C, or the combination or vehicle control. Treatment began 25 days after tumor inoculation and continued for 26 days. Values ​​are mean ± SEM; sample size (n = 5-6 mice per group). Initial tumor volume on day 0 was approximately 307 mm3. The significance level for statistical analysis was set at p < 0.05 vs. vehicle control (rank-based ANOVA and post-hoc Tukey's test) and p < 0.05 vs. best single agent, one-way ANOVA (Tukey's test). [Figure 13]Female nude mice bearing HKIX2967 subcutaneous xenografts were treated with 30 mg / kg poqd of Compound A or 2 mg / kg poqd of Compound C, or the combination or vehicle control. Treatment began 20 days after tumor inoculation and continued for 35 days. Values ​​are mean ± SEM; sample size (n = 5-6 mice per group). Initial tumor volume on day 0 was approximately 283 mm3. The significance level for statistical analysis was set at p < 0.05 vs. vehicle control (rank-based ANOVA and post-hoc Tukey's test) and p < 0.05 vs. best single agent, one-way ANOVA (Tukey's test). [Figure 14] Female nude mice bearing HKIX2967 subcutaneous xenografts were treated with 30 mg / kg poqd of Compound A or 10 mg / kg poqd of Compound C, or the combination or vehicle control. Treatment began 20 days after tumor inoculation and continued for 35 days. Values ​​are mean ± SEM; sample size (n = 5-6 mice per group). The initial tumor volume on day 0 was approximately 283 mm3. The significance level for statistical analysis was set at p < 0.05 vs. vehicle control (rank-based ANOVA and post-hoc Tukey's test) and p < 0.05 vs. best single agent, one-way ANOVA (Tukey's test). DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention provides a compound of formula (I), in free form or in pharmaceutically acceptable salt form. [ka] or a pharmaceutically acceptable salt thereof, During the ceremony R 1 is F, Cl, Br, OCH3, OCH2F, OCHF2, or OCF3; R 2 is F, Cl, CF3, or CN; X is (CH2) 1~2 , CHF, CHD, CD2 or CF2; Y is (CH2) 0~2, CHF, CHD, CD2, O, S, OCH2 or CF2; Z is CH2, CD2, CHF, CDF, CF2, CH(OH), CO, CH(CH3), O, or S; wherein when Y is O, OCH2, or S, Z is CH2; where Z is O, S, or NCH3, then Y is (CH2) 0~2 or CF2; where, when Z is CH(OH), Y is CHF or CF2; J is for CR J and; where R J is H, F, Cl, Br, CH3, CD3, CF3, CHF2, CDF2, OCH3 or CN; E is CR E or N; where R E is H, F, Cl, Br, I, CN, CH3, CH2CH3, CH(CH3)2, CD3, CHD2, CH2D, CHF2, CDF2, C(CH3)F2, C(CD3)F2, CF3, cyclopropyl, OCH3, OCH2CH2OH, OCF3, SCH3 or SCHF2; G is CH or N.

[0018] Various embodiments of the invention are described herein, and it will be appreciated that the features specified in each embodiment may be combined with other specified features to form further embodiments of the invention.

[0019] In embodiment 1, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof.

[0020] In embodiment 2, the present invention provides a compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is F, Cl or OCHF2; R 2 is CF3 or CN; X is CH or CHF; Y is (CH2) 0~2 or CHF; Z is CHF, CDF, CF, O, or S; J is for CR J and; where R J is H, F, Cl, CH3 or CD3; E is CR E or N; where R E is H, F, Br, or CF3; G is CH.

[0021] In embodiment 3, the present invention provides a compound of formula (I) according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is OCHF2; R 2 is CF3; X is CH or CHF; Y is (CH) 0~2 and; Z is CF2 or O; J is for CR J and; where R J is H, F, Cl, CH3 or CD3; E is CR E or N; where R E is H, F, Br or CF3; G is CH.

[0022] In embodiment 4, the present invention provides a compound of formula (I) in free form or in pharmaceutically acceptable salt form according to embodiments 1-3, wherein the stereochemistry is of formula (Ia): [ka] It is defined as shown in

[0023] In embodiment 5, the present invention provides a compound of formula (I) in free form or in pharmaceutically acceptable salt form according to any one of claims 1 to 4, wherein the stereochemistry is of formula (Ib): [ka] It is defined as shown in

[0024] In embodiment 6, the present invention provides a compound of formula (I) according to embodiment 5, or a pharmaceutically acceptable salt thereof, where X is CH or CHF; Y is (CH2) 0~2 and; Z is O, S or CF2; E is CR E or N; where R E is H, F, Br or CF3; J is CR J and; where R J is H, F, Cl, CH3 or CD3.

[0025] In embodiment 7, the present invention provides a compound of Formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (S)-5'-Bromo-8-(difluoromethoxy)-4'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-8-(Difluoromethoxy)-4',5'-difluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-8'-(Difluoromethoxy)-3,6'-bis(trifluoromethyl)-5,6-dihydro-3'H-spiro[cyclopenta[c]pyridine-7,2'-imidazo[1,2-α]pyridine]; (S)-5'-Bromo-8-(difluoromethoxy)-4'-fluoro-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]-6-carbonitrile; (S)-5'-Bromo-4'-fluoro-8-(fluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-8-(Difluoromethoxy)-5',6-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-6'-Bromo-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-6'-Bromo-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one; (1'S,3'R)-6'-bromo-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one; (1'S,3'R,4'S)-6'-bromo-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'-ol; (S)-6'-Bromo-8-(difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-8-(Difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-6'-Bromo-8-(difluoromethoxy)-5'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile; (S)-6'-Bromo-8-(difluoromethoxy)-4',4',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-8-(Difluoromethoxy)-4',4',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile; (S)-6'-Bromo-8-chloro-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-6'-Bromo-8-(difluoromethoxy)-3',3',5'-trifluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one; (1'S,4'S)-6'-Bromo-8-(difluoromethoxy)-3',3',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'-ol; (1'S,4'R)-6'-Bromo-8-(difluoromethoxy)-3',3',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'-ol; (1'S,3'R)-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one; (1'S,3'R)-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one; (S)-8-(Difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile; (S)-8-(Difluoromethoxy)-4',4',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (2S,4'S)-6'-Bromo-8-(difluoromethoxy)-4',5'-difluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile; (1'S,4'S)-8-(difluoromethoxy)-4',5'-difluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile; (S)-8-(Difluoromethoxy)-5'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile; d2-(S)-8-(Difluoromethoxy)-5'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile; (S)-8-(Difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-5',6',8-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-1'-chloro-8',8'-difluoro-8-methoxy-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-1'-Chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-8-(Difluoromethoxy)-8',8'-difluoro-1'-methyl-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-8-(Difluoromethoxy)-8',8'-difluoro-1'-(methyl-d3)-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-8-(Difluoromethoxy)-8',8'-difluoro-1'-methoxy-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-8-(Difluoromethoxy)-6'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile; (S)-1'-Chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-3'-chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-6',7'-dihydro-3H,5'H-spiro[imidazo[1,2-α]pyridine-2,8'-isoquinoline]; (S)-8-(Difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile; (S)-7-Bromo-8'-(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(Difluoromethoxy)-8-fluoro-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7-chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7-Bromo-8-fluoro-8'-(fluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7-chloro-8'-(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(Difluoromethoxy)-7,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(Difluoromethoxy)-8-fluoro-7-methyl-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8-Chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7-Bromo-8'-(difluoromethoxy)-8-fluoro-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]-6'-carbonitrile; (S)-7-Bromo-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(Difluoromethoxy)-8-fluoro-7-iodo-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]-6'-carbonitrile; (S)-7-Bromo-6'-chloro-8'-(difluoromethoxy)-8-fluoro-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-chloro-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7,8'-Bis(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-8-(difluoromethyl)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-pyrano[2,3-c]pyridine]; (2'S,3R)-7-Bromo-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (2'S,3S)-7-Bromo-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (2'S,3R)-7-Bromo-8'-(difluoromethoxy)-3-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (2'S,3R)-8'-(difluoromethoxy)-3-fluoro-7-iodo-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (2'S,3R)-8'-(difluoromethoxy)-3-fluoro-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (2'S,3R)-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8-(Difluoromethoxy)-8'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isochroman]; (S)-7'-chloro-8-(difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile; (S)-8-(Difluoromethoxy)-8'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]; (S)-8-(Difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile; (S)-8-(Difluoromethoxy)-8'-fluoro-6,7'-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiopyrano[3,2-c]pyridine]; (S)-8-(Difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isothiochroman]-6-carbonitrile; (S)-8'-(difluoromethoxy)-9-fluoro-6'-(trifluoromethyl)-3,4-dihydro-2H,3'H-spiro[benzo[b]oxepin-5,2'-imidazo[1,2-α]pyridine]; (S)-8-(Difluoromethoxy)-1'-(difluoromethyl)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-5'-Bromo-4',8-dichloro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-5'-Bromo-8-(difluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-8-(Difluoromethoxy)-5'-iodo-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]-6-carbonitrile; (S)-8-(Difluoromethoxy)-4'-fluoro-5',6-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-8-(Difluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-5',8-Difluoro-6'-methoxy-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-8-Fluoro-6,6'-bis(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; rac-5',6',8-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-8-chloro-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-6'-Bromo-5'-fluoro-8-methoxy-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; rac-5'-bromo-8-(difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-5'-chloro-8-(difluoromethoxy)-6'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (2S,3'R,4'R)-6'-Bromo-8-(difluoromethoxy)-3',4',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-8-(Difluoromethoxy)-5'-fluoro-6'-methoxy-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-8-(Difluoromethoxy)-5',6'-difluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-8-(Difluoromethoxy)-6,6'-bis(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; rac-8-(difluoromethoxy)-5',6-bis(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-5'-chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-6'-Bromo-6-chloro-8-(difluoromethoxy)-5'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-6'-Bromo-8-(difluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H,4'H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'-one; (S)-8-(Difluoromethoxy)-5',6'-difluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile; (S)-6'-Bromo-8-(difluoromethoxy)-4',4',5'-trifluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile; rac-8-(difluoromethoxy)-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-1'-Chloro-8-(difluoromethoxy)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]-6-carbonitrile; (S)-8-chloro-8'-(fluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8-Chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]-7-carbonitrile; (3R,4S)-7-chloro-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (3R,4S)-8'-(difluoromethoxy)-3,7,8-trifluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-8-fluoro-7-(methylthio)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7-Bromo-8-chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; rac-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7,8-Dibromo-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-8-fluoro-7-methoxy-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(Difluoromethoxy)-6',8-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-8-fluoro-7-(trifluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-7-((difluoromethyl)thio)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8-Bromo-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; rac-8-(difluoromethoxy)-8'-fluoro-6,7'-bis(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isochroman]; (2S)-8-(Difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile-2',2',3'-d3; (S)-7'-Bromo-8-(difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile; (S)-8-(Difluoromethoxy)-8'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-7'-carbonitrile; (S)-8-(Difluoromethoxy)-7',8'-difluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile; (S)-8-(Difluoromethoxy)-7',8'-difluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]; (S)-8'-Fluoro-8-(fluoromethoxy)-6,7'-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiopyrano[3,2-c]pyridine]; (S)-8-(Difluoromethoxy)-8'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isothiochroman]; (S)-8-(Difluoromethoxy)-7'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isothiochroman]; (S)-8'-(Difluoromethoxy)-8,9-difluoro-6'-(trifluoromethyl)-3,4-dihydro-2H,3'H-spiro[benzo[b]oxepin-5,2'-imidazo[1,2-α]pyridine]; rac-9-chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3,4-dihydro-2H,3'H-spiro[benzo[b]oxepin-5,2'-imidazo[1,2-α]pyridine]; and (S)-8-Chloro-8'-(difluoromethoxy)-9-fluoro-6'-(trifluoromethyl)-3,4-dihydro-1H,3'H-spiro[benzo[c]oxepin-5,2'-imidazo[1,2-α]pyridine].

[0026] In embodiment 8, the present invention provides a compound of Formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (S)-8-(Difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile; (S)-8'-(difluoromethoxy)-9-fluoro-6'-(trifluoromethyl)-3,4-dihydro-2H,3'H-spiro[benzo[b]oxepin-5,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7-Bromo-8'-(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (2'S,3R)-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(Difluoromethoxy)-7,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-1'-Chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-8-(Difluoromethoxy)-8',8'-difluoro-1'-(methyl-d3)-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; and (S)-8-(Difluoromethoxy)-8',8'-difluoro-1'-methyl-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline].

[0027] In embodiment 9, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: [ka] The present invention provides a compound or a pharmaceutically acceptable salt form selected from the group consisting of:

[0028] In embodiment 10, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0029] In embodiment 11, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0030] In embodiment 12, the invention provides a combination comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

[0031] In embodiment 13, this invention provides a combination according to embodiment 8, wherein the therapeutic agent is temsirolimus; ridaforolimus; everolimus (RAD001); rapamycin; simapimod; (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one; N 2 -[1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-α-aspartylL-serine-; N-[4-[[[3-[(3,5-dimethoxyphenyl)amino]-2-quinoxalinyl]amino]sulfonyl]phenyl]-3-methoxy-4-methyl-benzamide; or (1r,4r)-4-(4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[1,5-f][1,2,4]triazin-7-yl)cyclohexanecarboxylic acid.

[0032] In embodiment 14, the invention provides a combination according to embodiment 9, wherein the mTOR inhibitor is everolimus.

[0033] In embodiment 15, the present invention provides a method or use for regulating HiF2α activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 10 or a pharmaceutically acceptable salt thereof.

[0034] In embodiment 16, the present invention provides a method or use for treating a disorder or disease, which is cancer, comprising administering to a subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof.

[0035] In embodiment 17, the present invention provides a method of treatment or use according to embodiment 12, comprising administering to a subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, and renal cell carcinoma.

[0036] In embodiment 18, the present invention provides a compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0037] In embodiment 19, the present invention provides a compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder or disease that is cancer.

[0038] In embodiment 120, the present invention provides a compound according to any one of embodiments 1 to 10 or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder or disease selected from adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, and renal cell carcinoma.

[0039] In embodiment 21, the present invention provides a crystalline form of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] fumarate, characterized by having a powder X-ray diffraction pattern comprising reflections at 2θ angles of (24.9±0.2)°, (6.2±0.2)°, and (20.9±0.2)°, when measured at a temperature in the range of 20 to 30°C using Cu-Kα1,2 radiation having a wavelength of 0.15406 nm.

[0040] In embodiment 22, the present invention provides a crystalline form of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] fumarate, characterized by having a powder X-ray diffraction pattern comprising reflections at 2θ angles of (24.9±0.2)°, (6.2±0.2)°, (20.9±0.2)°, (10.9±0.2)°, and (18.5±0.2)°, when measured at a temperature in the range of 20 to 30°C using Cu-Kα1,2 radiation having a wavelength of 0.15406 nm.

[0041] In embodiment 23, the present invention provides a crystalline form of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] fumarate, characterized in that it has a powder X-ray diffraction pattern comprising reflections at 2θ angles of (24.9±0.2)°, (6.2±0.2)°, (20.9±0.2)°, (10.9±0.2)°, (18.5±0.2)°, (22.8±0.2)°, (12.9±0.2)°, and (16.1±0.2)°, when measured at a temperature in the range of 20 to 30°C using Cu-Kα1,2 radiation having a wavelength of 0.15406 nm.

[0042] In embodiment 24, the present invention provides a crystalline form according to any one of embodiments 21 to 23, characterized by having a thermogravimetric analysis curve that exhibits a mass loss of 0.4 wt. % or less, based on the weight of the crystalline form, when heated from 10 to 250° C. at a rate of 10 K / min.

[0043] In embodiment 25, the present invention provides a crystalline form of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] free form, characterized by having a powder X-ray diffraction pattern comprising reflections at 2θ angles of (9.7±0.2)°, (18.4±0.2)°, and (19.4±0.2)°, when measured at a temperature in the range of 20 to 30°C using Cu-Kα1,2 radiation having a wavelength of 0.15406 nm.

[0044] In embodiment 26, the present invention provides a crystalline form of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] free form, characterized in that it has a powder X-ray diffraction pattern comprising reflections at 2θ angles of (9.7±0.2)°, (18.4±0.2)°, (19.4±0.2)°, (13.4±0.2)°, and (20.7±0.2)°, when measured at a temperature in the range of 20 to 30°C using Cu-Kα1,2 radiation having a wavelength of 0.15406 nm.

[0045] In embodiment 27, the present invention provides a crystalline form of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] free form, characterized in that it has a powder X-ray diffraction pattern comprising reflections at 2θ angles of (9.7±0.2)°, (18.4±0.2)°, (19.4±0.2)°, (13.4±0.2)°, (20.7±0.2)°, (24.2±0.2)°, (22.1±0.2)°, and (10.3±0.2)°, when measured at a temperature in the range of 20 to 30°C using Cu-Kα1,2 radiation having a wavelength of 0.15406 nm.

[0046] In embodiment 28, the present invention provides a crystalline form according to any one of embodiments 25 to 27, characterized by having a thermogravimetric analysis curve that exhibits a mass loss of 0.2 wt. % or less, based on the weight of the crystalline form, when heated from 10 to 250° C. at a rate of 10 K / min.

[0047] In embodiment 29, the present invention provides a compound according to any one of embodiments 21 to 28, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0048] In embodiment 30, the present invention provides a compound according to embodiment 29, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder or disease, which is cancer.

[0049] In embodiment 31, the present invention provides a compound according to embodiment 30 or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder or disease selected from adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, and renal cell carcinoma.

[0050] In embodiment 32, the present invention provides a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof, the process comprising: [ka] or a salt, solvate, stereoisomer, complex, co-crystal, ester, or oxazoline thereof, and a compound of formula (II) [ka] or a salt, solvate, stereoisomer, complex, co-crystal, ester, or oxazoline thereof, optionally in the presence of a base selected from K2CO3 or Et3N, to give a compound of formula (III) [ka] or a salt, solvate, stereoisomer, complex, co-crystal, ester, or oxazoline thereof (In the formula, R 1 is F, Cl, Br, OCH3, OCH2F, OCHF2 or OCF3; R 2 is F, Cl, CF3 or CN; X is (CH2) 1~2 , CHF, CHD, CD2 or CF2; Y is (CH2) 0~2 , CHF, CHD, CD2, O, S, OCH2 or CF2; Z is CH2, CD2, CHF, CDF, CF2, CH(OH), CO, CH(CH3), O or S; wherein when Y is O, OCH2, or S, Z is CH2; where Z is O, S, or NCH3, then Y is (CH2) 0~2 or CF2; where, when Z is CH(OH), Y is CHF or CF2; J is for CR J and; where R J is H, F, Cl, Br, CH3, CD3, CF3, CHF2, CDF2, OCH3 or CN; E is CR E or N; where R E are H, F, Cl, Br, I, CN, CH3, CH2CH3, CH(CH3)2, CD3, CHD2, CH2D, CHF2, CDF2, C(CH3)F2, C(CD3)F2, CF3, cyclopropyl, OCH3, OCH2CH2OH, OCF3, SCH3, SCHF2; G is CH or N; LG is a leaving group selected from F, Cl, or Br. to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0051] In embodiment 33, the present invention provides a process according to embodiment 32, wherein a compound of formula (II) is cyclized with a reagent selected from SOCl2, toluenesulfonyl chloride, or methanesulfonyl chloride in toluene in the presence of a base selected from pyridine or Et3N to provide a compound of formula (I).

[0052] definition As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds of the present invention. "Salt" specifically refers to "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and that are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0053] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0054] Examples of inorganic acids from which salts can be derived include hydrochloric, hydrobromic, sulfuric, nitric, and phosphoric acid.

[0055] Examples of organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid.

[0056] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0057] Examples of inorganic bases from which salts can be derived include ammonium salts and metals from Groups I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper. Particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0058] Examples of organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0059] Any formula given herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen.

[0060] Furthermore, certain isotopes, especially deuterium (i.e. 2Incorporation of H or D) may confer certain therapeutic benefits resulting from greater metabolic stability, e.g., increased in vivo half-life, reduced dosing requirements, or improved therapeutic index or tolerability. It is understood that deuterium, in this context, is considered a substituent of the compounds of the invention. The concentration of deuterium can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. When a substituent in a compound of the present invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" can apply to any isotope in the same manner as described for deuterium.

[0061] Other examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 I. Thus, the present invention relates to, for example, radioisotopes, e.g. 3 H and 14 Compounds incorporating any one or more of the above isotopes, including C, or non-radioactive isotopes, e.g. 2 H and13 It should be understood that this includes compounds in which C is present. Such isotope-labeled compounds may be used in metabolic studies ( 14 C), reaction kinetic studies (e.g., 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) (including drug or substrate tissue distribution assays) or radioactive treatment of patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention can be prepared by conventional techniques known to those skilled in the art, typically substituting the appropriate isotopically labeled reagent for a previously used non-labeled reagent, or by processes analogous to those described in the accompanying Examples and Preparations.

[0062] As used herein, the term "pharmaceutical composition" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof, in a form suitable for oral or parenteral administration, together with at least one pharmaceutically acceptable carrier.

[0063] The term "pharmaceutically acceptable carrier" as used herein refers to a substance useful in the preparation or use of a pharmaceutical composition, and examples thereof include suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonicity agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof known to those skilled in the art (see, e.g., Remington: The Science and Practice of Pharmacy, 22 nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[0064] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that elicits a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity, improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, prevent, and / or ameliorate a condition, disorder, or disease that is (i) mediated by HIF2α, or (ii) associated with HIF2α activity, or (iii) characterized by HIF2α activity (normal or abnormal); or (2) reduce or inhibit the activity of HIF2α; or (3) reduce or inhibit the expression of HIF2α. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a cell, or tissue, or non-cellular biological material, or medium, is effective to at least partially reduce or inhibit the activity of HIF2α; or to at least partially reduce or inhibit the expression of HIF2α.

[0065] As used herein, the term "subject" refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet another embodiment, the subject is a human.

[0066] The term "inhibition" or "inhibiting" as used herein refers to the reduction or suppression of a given condition, symptom, disorder or disease, or a significant decrease in the baseline activity of a biological activity or biological process.

[0067] As used herein, the term "treating" or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or inhibiting the progression of the disease or at least one of its clinical symptoms); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder (including those that may not be discernible to the patient).

[0068] As used herein, the term "preventing" any disease or disorder or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0069] As used herein, a subject is "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0070] As used herein, the terms "a," "an," "the," and similar terms as used in connection with the present invention (especially in connection with the claims) are to be construed to encompass both the singular and the plural, unless otherwise expressly stated herein or clearly contradicted by context.

[0071] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended solely to better clarify the invention and does not pose a limitation on the scope of the invention unless claimed.

[0072] Any asymmetric atom (e.g., carbon) of the compounds of the present invention may be present in racemic or enantiomerically enriched form, for example, in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has an enantiomeric excess of at least 50% in the (R)- or (S)-configuration, an enantiomeric excess of at least 60%, an enantiomeric excess of at least 70%, an enantiomeric excess of at least 80%, an enantiomeric excess of at least 90%, an enantiomeric excess of at least 95%, or an enantiomeric excess of at least 99%. Substituents at atoms having unsaturated double bonds may, where possible, exist in the cis (Z)- or trans (E)-form.

[0073] Thus, as used herein, the compounds of the invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, such as substantially pure geometric (cis or trans) stereoisomers, diastereoisomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0074] Any resulting mixture of stereoisomers can be separated on the basis of the physical chemical differences of the components into pure or substantially pure geometric or optical isomers, diastereoisomers, racemates, for example, by chromatography and / or fractional crystallization.

[0075] The stereochemistry of the spirocyclic center has been assigned for a subset of examples by single crystal X-ray structure analysis, either alone or bound within the PAS-B domain of HIF2α, or from intermediates used in the preparation of the examples. The stereochemistry of the remaining examples has been assigned by inference based on their HIF2α affinity: e.g., IC determined in the HIF2α SPA assay for Example 44. 50 was compared with the corresponding enantiomer (R)-8'-(difluoromethoxy)-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] (HIF2α SPA IC 50 It was found to be more than 700-fold lower than the ATP (>10,000 nM).

[0076] General conditions: Typically, compounds of formula (I) can be prepared according to the schemes provided below.

[0077] The schemes provided below are intended to represent single diastereomers / enantiomers as well as isomeric mixtures thereof. Separation of diastereomers / enantiomers can be carried out according to the techniques described herein.

[0078] Scheme 1: General synthesis of compounds of formula (I) [ka] Step 1: Arylation of a compound of formula (IV) with a pyridine of formula (III) (LG is a leaving group) to give a compound of formula (II). The arylation reaction can be a nucleophilic aromatic substitution reaction, where LG is a group such as fluoro, chloro, or bromo, and the reaction can be carried out in the presence of a base such as K2CO3 or Et3N, with heating. Alternatively, the reaction can be a transition metal-catalyzed coupling reaction, such as a Buchwald reaction, using, for example, a Pd catalyst or a Cu catalyst such as CuI, CuBr, or copper(I) thiophene-2-carboxylate, in the presence of a base such as K0tBu or K3PO4, or an Ullmann-type amination reaction, where LG is a group such as chloro, bromo, or iodo.

[0079] Step 2: Cyclization of compounds of formula (II) to give compounds of formula (I). The alcohol group can be activated to a leaving group by heating a reagent such as SOCl in toluene, or using toluenesulfonyl chloride or methanesulfonyl chloride in the presence of a base such as pyridine or EtN, with or without heat.

[0080] In some cases, both steps 1 and 2 can be carried out in a one-pot reaction by carrying out step 1 with two or more equivalents of pyridine (III), in a reaction in which the alcohol is also arylated with pyridine to provide a leaving group for the cyclization reaction.

[0081] Scheme 2: General synthesis of compounds of formula (I) [ka] Step 1: In some cases, the arylation reaction is carried out with a protected amino alcohol. A suitable protected form of the amino alcohol (IV) is the oxazolidinone (VI), which is prepared by reaction with phosgene or a phosgene equivalent, such as carbonyldiimidazole or triphosgene, and the reaction may be carried out in the presence of a base.

[0082] Step 2: Arylation of a compound of formula (VI) with pyridine (III) (LG is a leaving group) provides a compound of formula (II). The arylation reaction can be a transition metal-catalyzed coupling reaction using a Pd catalyst in the presence of a base such as KOtBu. Alternatively, the arylation reaction can be an Ullmann-type amination reaction using a Cu catalyst such as CuI, CuBr, or copper(I) thiophene-2-carboxylate in the presence of a base such as KOtBu or KPO.

[0083] Step 3: The oxazolidinone of formula (V) is deprotected in a hydrolysis reaction to give the amino alcohol of formula (II) in aqueous acid or in a base such as NaOH in EtOH, Cs2CO3 in MeOH, and such hydrolysis reaction can be carried out in the presence of an additional solvent such as THF.

[0084] Step 4: The cyclization reaction can be carried out in a manner similar to that described in Scheme 1, Step 2.

[0085] Scheme 3: General synthesis of compounds of formula (I) [ka] Step 1: An alcohol of formula (VIII) is converted to a carbamate of formula (VII) in an acylation reaction, which can be carried out using an acylating agent such as trichloroacetyl isocyanate, which is then hydrolyzed in a second step under basic conditions such as K2CO3 in MeOH or NaOH in EtOH.

[0086] Step 2: The carbamate of formula (VII) is cyclized to the oxazolidinone of formula (VI) in a nitrene insertion reaction. The nitrene intermediate can be formed by an oxidation process using an oxidizing agent such as iodosobenzene diacetate, and the reaction is stabilized in the insertion step through the addition of a catalyst such as Rh(OAc), Rh[OC(O)Ph], Rh(esp), and the like, and with an additive such as MgO.

[0087] Steps 3-5: Conversion of oxazolidinone (VI) to compounds of formula (I) can be carried out in a manner similar to that described in the equivalent steps of Scheme 2.

[0088] Scheme 4: General synthesis of compounds of formula (I) [ka] Step 1: Preparation of a compound of formula (I) 1 is F, Cl, or Br) undergoes nucleophilic aromatic substitution with sodium or potassium alkoxides to give R 1 is an ether group, which can be further deprotected to the corresponding phenol of formula (IX). When the alkoxide is derived from 2-(methylsulfonyl)ethanol and NaH in DMF, the ether is deprotected in situ to directly give the compound of formula (IX).

[0089] Step 2: Alkylation of the phenol group of the compound of formula (IX) to form R 1The alkylation reaction can be carried out using reagents such as bromodifluoromethyl)trimethylsilane and KOH, or dibromodifluoromethane and NaH, followed by AgBF in DCM.

[0090] R 1 Compounds of formula (I) where is OMe are 1 Compounds of formula (I) where is F, Cl, or Br can be obtained directly by reaction with MeOH and NaOtBu.

[0091] Scheme 5: General synthesis of compounds of formula (I) [ka] Step 1: E or J is CR J or CR E where R J and R E Compounds of formula (I) where R is independently Cl, Br, or I can be converted to R by a transition metal catalyzed coupling reaction. J or R Ecan be converted to a compound of formula (I) where is Cl, H, CN, Me, d3-Me, SCF3, CHF2, CF2Me, MeO. Transition metal catalyzed coupling reactions can be, for example, ether formation using tButylBrettPhos-Pd-G3, NaOtBu, and MeOH in 1,4-dioxane; thiol formation using, for example, 2-ethylhexyl 3-mercaptopropanoate, Pd2(dba)3, Xantphos, and iPr2NEt in 1,4-dioxane, followed by reaction with NaOEt in EtOH to form the free thiol; difluoromethylation using, for example, 2,2-difluoro-1-phenylethanone, Pd(dba)2, SPhos, and Cs2CO3 in toluene; deacylation of the intermediate using a reagent such as aqueous KOH in toluene; thiomethylation using, for example, DMSO, CuI, and DABCO; hydrogenation using Pd on carbon with hydrogen in MeOH and THF; potassium hexacyanoferrate(II), XPhos, XPhos Pd in ​​water and 1,4-dioxane. Cyanation reactions using G3 and KOAc, for example, trifluoromethylation reactions using diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate and Cu powder in DMF, or boronation reactions using bis(pinacolato)diboron, PdCl(dppf).CHCl adduct and KOAc in 1,4-dioxane, the boronic esters can then be further converted to the corresponding chloro derivatives by treatment with reagents such as CuCl in MeOH and water.

[0092] The product of the transition metal catalyzed coupling reaction of formula (I) may be converted to further derivatives of formula (I) using reactions such as trifluoromethylation using diethyl(bromodifluoromethyl)phosphonate and KOH in AcCN to convert the thiol to trifluoromethylthiol.

[0093] Scheme 6: General synthesis of compounds of formula (I) [ka] Step 1: Compounds of formula (I) where Z=C=O can be converted to compounds of formula (I) where Z=C=O and Y=CHF using a fluorination reaction such as reacting the silyl enol ether intermediate with Selectfluor in AcCN; the silyl enol ether intermediate can be prepared from compounds of formula (I) where Z=C=O by a silylation reaction using, for example, tert-butyldimethylsilyl trifluoromethanesulfonate and EtN in DCM; this sequence can be repeated to give compounds of formula (I) where Z=C=O and Y=CF (where Z=CH(OH)) using a reduction reaction using, for example, NaBH in EtOH; the alcohol can be further converted to compounds of formula (I) where Z=CHF using a fluorination reaction using, for example, DAST in DCM.

[0094] Compounds of formula (I) where Z=C=O can be prepared from compounds of formula (I) where Z=thioketal by oxidation of compounds of formula (I) where Z=CH, for example by oxidation with oxygen in AcCN, N-hydroxyphthalimide and iron(III) nitrate, or by deprotection reaction with, for example, N-bromosuccinimide in aqueous acetone.

[0095] Scheme 7: General synthesis of compounds of formula (I) [ka] Process 1:CR J or CR E Compounds of formula (I) where is Br or I can be prepared by lithiation and addition of the resulting organolithium intermediate to a carbonyl compound, followed by fluorination to give CR J or CR E can be converted to a compound of formula (I) where is CHF, for example using nBuLi in THF, followed by addition of DMF, and then the formylated intermediate is fluorinated in a fluorination reaction, for example using DAST in DCM.

[0096] The present invention further includes any variation of the process, in which intermediate products available at any stage thereof are used as starting materials and the remaining steps are carried out, or in which starting materials are formed in situ under the reaction conditions, or in which reaction components are used in the form of their salts or optically pure materials. The compounds and intermediates of the present invention can also be converted into each other according to methods generally known to those skilled in the art.

[0097] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition may be formulated for a specific route of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal administration, or topical administration), and rectal administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical composition of the present invention may be prepared in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets may be film-coated or enteric-coated according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with one or more of the following: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; also for tablets, c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired, d) disintegrants, such as starch, agar, alginic acid or its sodium salt or effervescent mixtures; and e) Absorbents, colorants, flavorings and sweeteners.

[0098] Methods of using the present invention Compounds of any one of formulas (I) and (Ia), in free form or in the form of a pharmaceutically acceptable salt, exhibit valuable pharmacological properties, such as inhibition or modulation of HIF2a, as shown, for example, in the in vitro and in vivo tests described in the following section, and are therefore indicated for use in therapy or as research chemicals, e.g., as tool compounds.

[0099] The compounds of the invention may be useful for the treatment or prevention of cancer, wherein the cancer is selected from adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer (which may include colon cancer), germ cell tumors (e.g., cranial and extracranial germ cell tumors, gonadal and extragonadal germ cell tumors), glioblastoma multiforme (GBM), glioma, head and neck cancer (which may include lip, oral cavity, mouth cancer), hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, eye cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, and renal cell carcinoma.

[0100] Thus, as a further aspect, the present invention provides the use of a compound of Formula (I) or (Ia), or a compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, in therapy. In a further embodiment, the therapy is selected from diseases that can be treated by inhibiting or modulating HIF2α. In another embodiment, the disease is selected from adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer (which may include colon cancer), germ cell tumors (e.g., cranial and extracranial germ cell tumors, gonadal and extragonadal germ cell tumors), glioblastoma multiforme (GBM), glioma, head and neck cancer (which may include lip, oral cavity, and mouth cancer), hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, and renal cell carcinoma.

[0101] Thus, in a further aspect, the present invention provides a compound of any one of formula (I) or (Ia), or a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, for use in therapy. In a further embodiment, the therapy is selected from a disease that can be treated by inhibiting or modulating HIF2α. In another embodiment, the disease is selected from the foregoing list, suitably in particular cancer.

[0102] Thus, as a further aspect, the present invention provides the use in therapy of a compound of formula (I) or (Ia), or a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament. In a further embodiment, the therapy is selected from diseases that can be treated by inhibiting or modulating HIF2a. In another embodiment, the disease is selected from the list above, suitably cancer.

[0103] The pharmaceutical composition or combination of the present invention may be in a unit dosage of about 1 to 1000 mg of the active ingredient, or about 1 to 500 mg, about 1 to 250 mg, about 1 to 150 mg, about 0.5 to 100 mg, or about 1 to 50 mg of the active ingredient for a subject weighing about 50 to 70 kg. The therapeutically effective dosage of the compound, pharmaceutical composition, or combination thereof depends on the subject's species, weight, age, and individual symptoms, and the disorder or disease being treated or its severity. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat, or inhibit the progression of the disorder or disease.

[0104] The dosage characteristics cited above can be demonstrated using in vitro and in vivo tests, advantageously using mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues, and preparations thereof. The compounds of the present invention can be administered in vitro in the form of solutions, for example, aqueous solutions, and in vivo, for example, as suspensions or in aqueous solutions, enterally, parenterally, advantageously intravenously. The in vitro dosage is about 10 -3 Molar ~ 10 -9A therapeutically effective in vivo amount may range from about 0.1 to 500 mg / kg, or from about 1 to 100 mg / kg, depending on the route of administration.

[0105] "Combination" refers to either a fixed combination in a single unit dosage form or combined administration, where a compound of the present invention and a combination partner (e.g., another drug described below, also referred to as a "therapeutic agent" or "co-agent") can be administered independently and simultaneously, or separately within a time interval, particularly one that allows the combination partners to exhibit a synergistic, e.g., synergistic, effect. Single components may be packaged in a kit or separately. One or both components (e.g., powder or liquid) may be reconstituted or diluted to the desired dosage before administration. As used herein, the terms "co-administration" or "administration in combination," etc., are meant to encompass the administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which agents are not necessarily administered by the same route of administration or simultaneously. As used herein, the term "pharmaceutical combination" refers to a product resulting from mixing or combining multiple therapeutic agents, and includes both fixed combinations of therapeutic agents and non-fixed combinations of therapeutic agents. The term "fixed combination" means that both therapeutic agents, e.g., a compound of the present invention and a combination partner, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that both therapeutic agents, e.g., a compound of the present invention and a combination partner, are administered to a patient simultaneously, concurrently, or sequentially as separate entities, with no specific time constraints, such that therapeutically effective levels of the two compounds are achieved in the patient's body. The latter also lends itself to cocktail therapy, e.g., the administration of three or more therapeutic agents.

[0106] The term "pharmaceutical combination" as used herein refers to either a fixed combination in a single unit dosage form, or a loose combination, or a kit of parts for combined administration, where the therapeutic agents may be administered independently and simultaneously, or separately within a time interval, particularly such that the combination partners can exhibit a synergistic, e.g., synergistic, effect.

[0107] The term "combination therapy" refers to the administration of multiple therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes co-administration of these therapeutic agents substantially simultaneously, e.g., in a single capsule with a fixed ratio of active ingredients. Alternatively, such administration includes co-administration of each active ingredient in multiple or separate containers (e.g., tablets, capsules, powders, and liquids). The powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. Such administration also includes sequential use of each type of therapeutic agent, either at approximately the same time or at different times. In any case, the treatment regimen will provide the beneficial effects of the drug combination in treating the condition or disorder described herein.

[0108] The compounds of the present invention can be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention can be administered separately by the same or different administration route, or together with other agents in the same pharmaceutical composition. Therapeutic agents are, for example, compounds, peptides, antibodies, antibody fragments, or nucleic acids that are therapeutically active or enhance therapeutic activity when administered to a patient in combination with the compounds of the present invention.

[0109] In one embodiment, the present invention provides a product comprising a compound of formula (I) or (Ia) or a compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.

[0110] In one embodiment, the therapy is the treatment or prevention of a disease or condition mediated by the inhibition or modulation of HIF2a. Products provided as combined preparations include compositions comprising a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof and another therapeutic agent together in the same pharmaceutical composition, or any one of the compounds of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof and another therapeutic agent in separate form, for example in the form of a kit.

[0111] In one embodiment, the present invention provides a pharmaceutical combination comprising a compound comprising any one of formula (I) or (Ia), or a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and another therapeutic agent. Optionally, the pharmaceutical combination may include a pharmaceutically acceptable carrier, as described above.

[0112] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula (I) or (Ia), or a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof. In one embodiment, the kit comprises means for retaining the compositions separately, such as containers, separate bottles, or separate foil packets. An example of such a kit is a blister pack typically used to package tablets, capsules, and the like.

[0113] The kits of the invention can be used to administer the separate compositions at different dosage intervals or to administer different dosage forms, e.g., oral and parenteral, to titrate the separate compositions relative to one another. To aid compliance, the kits of the invention typically include directions for administration.

[0114] In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent may be manufactured and / or formulated by the same manufacturer or different manufacturers. Furthermore, the compound of the present invention and the other therapeutic agent may be combined into a combination therapy (i) prior to release of the combination product to the physician (e.g., in the case of a kit containing the compound of the present invention and the other therapeutic agent); (ii) by the physician (or under the physician's guidance) immediately prior to administration; or (iii) in the patient himself / herself, for example, during sequential administration of the compound of the present invention and the other therapeutic agent.

[0115] Thus, the present invention provides the use of a compound of formula (I) or (Ia), or a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, for treating or preventing a disease or condition mediated by the inhibition or modulation of HIF2a, wherein the medicament is prepared for administration with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating or preventing a disease or condition mediated by the inhibition or modulation of HIF2a, wherein the medicament is administered with a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof.

[0116] The present invention also provides a compound of Formula (I) or (Ia), or a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing a disease or condition mediated by the inhibition or modulation of HIF2A, wherein the compound of Formula (I) or (Ia), or a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, is formulated for administration with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating or preventing a disease or condition mediated by the inhibition or modulation of HIF2A, wherein the other therapeutic agent is formulated for administration with the compound of Formula (I) or (Ia), or a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof. The present invention also provides a compound of Formula (I) or (Ia), or a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing a disease or condition mediated by the inhibition or modulation of HIF2A, wherein the compound of Formula (I) or (Ia), or a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, is administered with another therapeutic agent. The present invention also provides a further therapeutic agent for use in a method of treating or preventing a disease or condition mediated by the inhibition or modulation of HIF2A, wherein the other therapeutic agent is administered with the compound of Formula (I) or (Ia), or a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof.

[0117] Mass spectra were acquired on LC-MS, SFC-MS, or GC-MS systems using electrospray, chemical, and electron impact ionization methods using a series of instruments configured as follows: Waters Acquity UPLC equipped with a Waters SQ detector, [M+H] + refers to the protonated molecule of a chemical species, [MH] - refers to the deprotonated molecule of the chemical species.

[0118] NMR spectra were performed using Bruker Ultrashield™ 400 (400 MHz) and Bruker Ultrashield™ 600 (600 MHz) spectrometers, with and without tetramethylsilane as an internal standard. Chemical shifts (δ values) are reported in ppm downfield from tetramethylsilane, and spectral splitting patterns are designated as singlet (s), doublet (d), triplet (t), quartet (q), multiplet, unresolved or more overlapping signals (m), or broad signals (br). Solvents are indicated in parentheses.

[0119] Celite: Celite® (Celite Corporation) = a filter aid based on diatomaceous earth Phase separator: Biotage Isolute Phase Separator (Part Number: 120-1908-F for 70 mL and Part Number: 120-1909-J for 150 mL).

[0120] equipment Microwave: All microwave reactions were performed in a Biotage Initiator irradiated from a 2.45 GHz magnetron with Robot Eight / Robot Sixty throughput at 0-400 W unless otherwise stated. UPLC-MS method: Waters Acquity UPLC equipped with a Waters SQ detector was used.

[0121] Overview Column: Acquity HSS T3, 1.8 μm, 2.1 × 50 mm Column temperature: 60°C Eluent A: Water + 0.05% formic acid + 3.75 mM ammonium acetate (pH 3.8), B: Acetonitrile + 0.04% formic acid Flow rate 1.0mL / min

[0122] [Table 1]

[0123] UPLC-MS 6 Column: Acquity HSS T3, 1.8 μm, 2.1 x 100 mm Column temperature: 60°C Eluent A: Water + 0.05% formic acid + 3.75 mM ammonium acetate (pH 3.8), B: Acetonitrile + 0.04% formic acid Gradient: 5% to 98% B in 9.4 min Flow rate 0.8mL / min

[0124] UPLC-MS 7 Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm Column temperature: 80℃ Eluent A: Water + 0.05% formic acid + 3.75 mM ammonium acetate, B: iPrOH + 0.05% formic acid Gradient: 5% to 98% B in 1.7 min Flow rate 0.6mL / min

[0125] Chiral HPLC / SFC Method: C-HPLC 1 Instrument: Agilent 1200 HPLC system Injection: 10μL Mobile phase: Heptane:EtOH:[MeOH+0.05% EtNH] 80:10:10 Flow rate: 1mL / min Column: Chiralcel OZ-I 20 μm 4.6 × 250 mm Detection UV: 220 or 260 nm

[0126] C-HPLC 7 Instrument: Agilent 1200 HPLC system Injection: 10μL Mobile phase: Heptane:TBME:EtOH + 0.05% Et2NH 80:10:10 Flow rate: 1mL / min Column: Chiralcel ID 5μm 4.6×250mm Detection UV: 230 nm

[0127] C-SFC 8 Machine: Water UPC2 Analytical SFC Mobile Phase: CO2: MeOH containing 0.05% Et2NH Flow Rate: 2.5 mL / min Column: ChiralPak AD 3μm 4.6×150mm Temperature: 35 °C Backpressure: 100 bar Detection UV: 220 nm

[0128] C-HPLC 9 Machine: Agilent 1100 HPLC System Injection: 5 μL Mobile Phase: Heptane:DCM:MeOH 80:10:10 Flow Rate: 1 mL / min Column: Chiralcel IC 5μm 4.6×250mm Detection UV: 270 nm

[0129] C-SFC 10 Machine: Water UPC 2 Analytical SFC Mobile Phase: CO2: [MeOH + 0.05% Et2NH] Gradient: 5~40% B Flow Rate: 2.5 mL / min Column: Chiralpak AD, 150×4.6mm I.D., 3μm, 35 °C BPR: 100 bar Detection UV: 220 nm

[0130] C-HPLC 12 Machine: Agilent 1100 HPLC System Injection: 10 μL Mobile Phase: Heptane:MeOH:EtOH + 0.1% Et2NH 80:10:10 Flow Rate: 1 mL / min Column: Chiralcel AD-H 5μm 4.6×250mm Detection UV: 220 nm

[0131] C-HPLC 15 Machine: Agilent 1100 HPLC System Injection: 10 μL Mobile Phase: Heptane:iPrOH + 0.05% Et2NH 60:40 Flow Rate: 1 mL / min Column: Chiralpak IC 5 μm 4.6×250 mm Detection UV: 280 nm

[0132] C-HPLC 16 Machine: Agilent 1100 HPLC System Injection: 10 μL Mobile Phase: Heptane:MeOH:EtOH + 0.1% Et2NH 80:10:10 Flow Rate: 1 mL / min Column: Chiralcel AD-H 5 μm 4.6×250 mm Detection UV: 230 nm

[0133] C-HPLC 17 Machine: Shimadzu prominence HPLC System Injection: 5 μL Mobile Phase: Heptane:MeOH:EtOH:Et2NH 90:5:5:0.1 Flow Rate: 1 mL / min Column: Chiralpak OZ-H 5 μm 4.6×250 mm Detection UV: 225 nm

[0134] C-SFC 19 Machine: Thar Analytical SFC (SFC-A) Mobile Phase: CO2:[MeOH + 0.05% Et2NH] Gradient: 5~40% B Flow Rate: 2.4 mL / min Column: Chiralpak AD, 150×4.6 mm I.D., 3 μm, 35 °C BPR: 100 bar Detection UV: 220 nm

[0135] C-SFC 20 Instrument: ACQUITY UPLC System Mobile phase: CO2: iPrOH containing 0.1% Et2NH Flow rate: 2.5mL / min Column: Chiralpak IG 5μm 4.6×100mm Temperature: 35℃ Back pressure: 100bar Detection UV: DAD 190~400nm

[0136] HPLC 22 Mobile phase: Solvent A: water 0.05% TFA, B: acetonitrile isocratic with 0.05% TFA; gradient: 0 min 56% B; 13 min 56% B; 13.5 min 100% B; 21.5 min 100% B; 22 min 56% B; 254 nm Flow rate: 1.0mL / min Column: Macherey+Nagel Nucleodur Sphinx RP 5 μm, 4.6 x 250 mm Temperature: 30℃

[0137] C-HPLC 28 Equipment: Shimadzu SCL-10A prominence HPLC system Injection: 10μL Mobile phase: Heptane:EtOH 80:20 + 0.1% Et2NH, RT Flow rate: 1mL / min Column: Chiralpak ID 5μm 4.6×250mm Detection UV: 250nm

[0138] C-HPLC 29 Instrumentation: Shimadzu Prominence HPLC system Injection: 10μL Mobile phase: n-heptane: iPrOH + 0.1% Et2NH 90:10 Flow rate: 1mL / min Column: Chiralcel AD-H 5μm 4.6×250mm, RT Detection UV: 230 nm

[0139] C-SFC 30 Equipment category: Water UPC 2 Analytical SFC (SFC-H) Column: Chiralpak AD, 150×4.6 mm I.D., 3 μm Mobile phase: A is CO2 and B is ethanol + 0.05% Et2NH Gradient: B 5 - 40% Flow rate: 2.5 mL / min Column temperature: 35 °C Wavelength: 220 nm

[0140] C-HPLC 31 Equipment category: Shimadzu Prominence HPLC system Injection volume: 10 μL Mobile phase: Heptane:iPrOH + 0.1% Et2NH 80:20 Flow rate: 1 mL / min Column: Chiralcel OD-H 5 μm 4.6×250 mm, RT UV detection: 250 nm

[0141] C-HPLC 33 Equipment category: Gilson PLC2020 HPLC system Mobile phase: Heptane:EtOH + 0.1% Et2NH 80:20 Flow rate: 1 mL / min Column: Chiralpak ID 5 μm 250×20 mm, 25 °C UV detection: 220 nm

[0142] C-HPLC 37 Equipment: Ultimate 3000 Injection volume: 0.5 μL Mobile phase: Heptane:EtOH + 0.1% Et2NH 70:30 Flow rate: 0.42 mL / min Column: Chiralpak OJ-3 3 μm 3.0×100 mm, 30 °C UV detection: 265 nm

[0143] C-SFC 42 Machine type: Water UPC 2 Analysis SFC (SFC-H) Mobile phase: CO2: [EtOH + 0.05% Et2NH] Gradient: 5~40% B Flow rate: 2.5 mL / min Column: Chiralpak IC 3μm 150×4.6mm, 35℃ Detection UV: 220nm

[0144] C-SFC 43 Machine type: Water UPC 2 Analysis SFC (SFC-H) Mobile phase: CO2: [MeOH + 0.05% Et2NH] Gradient: 5~40% B Flow rate: 2.5 mL / min Column: Chiralpak IC 3μm 150×4.6mm, 35℃ BPR: 100 bar Detection UV: 220nm

[0145] C-HPLC 44 Machine type: Agilent 1200 HPLC system Injection: 10 μL Mobile phase: Heptane: EtOH: [MeOH + 0.1% Et2NH] 80:10:10 Flow rate: 1 mL / min Column: Chiralpak AD 20μm 4.6×250mm, RT Detection UV: 225nm

[0146] C-HPLC 45 Machine type: Agilent 1200 DAD Mobile phase: Heptane: MeOH (+0.1% Et2NH] Eluent: Uniform concentration 80:20 Flow rate: 1.0 mL / min Column: Chiralpak AD-H Detection UV: 220nm

[0147] C-HPLC 47 Equipment: Agilent 1200 DAD Magellan system Injection: 5μL Mobile phase: Heptane:EtOH:MeOH+0.1% Et2NH 90:5:5 Flow rate: 1mL / min Column: Chiralcel OD-H 5 μm 4.6 × 250 mm, RT Detection UV: 225 nm

[0148] C-HPLC 49 Mobile phase: heptane:EtOH:MeOH Eluent: uniform concentration 70:15:15 Flow rate: 1.0mL / min Column: Chiralpak IC Detection UV: 225 nm

[0149] C-SFC 50 Mobile phase: CO2:EtOH (1% iPrNH2) Gradient: 70:30 uniform density Flow rate: 4mL / min Column: Chiralcel ID 4.6 μm 250 × 4.6 mm, 40 °C Detection UV: 220nm

[0150] Preparative method: Normal Phase Chromatography: Normal phase chromatography was carried out on silica gel using pre-packed columns as detailed below, or using glass columns according to standard flash chromatography methodology, unless otherwise stated. System 1 Teledyne ISCO, CombiFlash Rf System 2 Biotage Isolera Column: Pre-packed RediSep Rf cartridge or SNAP cartridge Sample Adsorption: Apply on Isolute, or on silica gel, or as a solution

[0151] Supercritical Fluid Chromatography (SFC) 1: Purification was achieved on a Waters preparative SFC-100-MS system equipped with a Waters 2998 photodiode array detector and a Waters MS single quadrupole detector. Modifier: Methanol Pressure 120bar Column temperature: 40°C Flow rate 100g / min

[0152] Reverse phase HPLC: RP-HPLC 1 System Gilson PLC 2020 Column Dr.Maisch Reprosil 100 C18 5um;250×30mm Column temperature RT Eluent A: Water + 0.1% TFA, B: Acetonitrile

[0153] RP-HPLC 2 System Waters Column: Waters Sunfire C18, OBD 5um; 100 x 30mm Column temperature RT Eluent A: Water + 0.1% TFA, B: Acetonitrile Flow rate 40mL / min Standard gradient: 5 to 100% B in 20 minutes with a 1 minute plateau at 100%

[0154] RP-HPLC 3 System Waters Column: Waters X-Bridge C18, OBD 5µm; 100 x 30mm Column temperature RT Eluent A: Water + 7.3mM NH4OH, B: Acetonitrile + 7.3mM NH4OH Flow rate 40mL / min Standard gradient: 5 to 100% B in 20 minutes with a 1 minute plateau at 100%

[0155] RP-HPLC 6 System: Macherey+Nagel Nucleodur Sphinx RP (5 μm, 10 × 250 mm) Column temperature: 20°C Eluent: Isocratic using solvent A: water 0.1% TFA; B: acetonitrile 0.1% TFA; 0 min 57% B; 13 min 57% B; 13.5 min 100% B; 21 min 100% B; 21.5 min 57% B. Flow rate 4.7ml / min Detection UV 254nm and 240nm

[0156] Solid Samples: Solids were analyzed using the following instrumentation and methods.

[0157] [Table 2]

[0158] [Table 3]

[0159] [Table 4]

[0160] [Table 5]

[0161] [Table 6]

[0162] The following examples are intended to illustrate the present invention and should not be construed as limiting thereof. Temperatures are given in degrees Celsius. Unless otherwise noted, all evaporations are carried out under reduced pressure, typically between about 15 mmHg and 100 mmHg (=20 to 133 mbar). Abbreviations used are those conventional in the art.

[0163] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts used in the synthesis of the compounds of the invention are commercially available or can be prepared by organic synthesis methods known to those skilled in the art. Additionally, the compounds of the invention can be prepared by organic synthesis methods known to those skilled in the art, as illustrated in the examples below. [Example]

[0164] Preparation of final compounds Example 1: (S)-5'-Bromo-8-(difluoromethoxy)-4'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene] [ka] (S)-5'-Bromo-8-(difluoromethoxy)-4'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene] (Intermediate G, 12.5 g, 21.5 mmol) was dissolved in toluene (100 mL) in an Ar-flushed flask. SOCl2 (9.89 mL, 135 mmol) in toluene (10 mL) was added dropwise, and the RM was heated to 80 °C for 2 h. The RM was partitioned between TBME (100 mL), EtOAc (100 mL), MeOH (100 mL), and saturated aqueous NaHCO3 (200 mL). The aqueous layer was extracted with EtOAc, and the combined organic layers were then washed with brine, dried over Na2SO4, and evaporated. The crude product was adsorbed onto Isolute and purified by normal-phase chromatography (2 × 120 g SiO2 columns; eluent hexane:[DCM:MeOH 5:1] 100:0 to 50:50) followed by reverse-phase chromatography (RP-HPLC 1). Product-containing fractions were combined and the AcCN was removed by evaporation. The remaining mainly aqueous solution was treated with solid NaHCO3 until basic and then extracted three times with DCM. The organic layers were combined, dried over Na2SO4, and evaporated to give the title compound as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ 7.97(s,1H),7.57-7.12(m,2H),7.07(d,1H),6.98(s,1H),4.27(q,2H),3.06-2.88(m,2H),2.29-2.19(m,2H). LC-MS: Rt = 0.91 min; MS m / z [M+H] + 453 / 455;UPLC-MS 1.

[0165] Example 2: (S)-8-(Difluoromethoxy)-4',5'-difluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene] [ka] A mixture of (S)-(1-amino-4,5-difluoro-2,3-dihydro-1H-inden-1-yl)methanol (Intermediate K, 504 mg, 2.53 mmol), 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (Intermediate A, 1.38 g, 5.56 mmol), CuI (337 mg, 1.77 mmol), KPO (1.01 g, 5.06 mmol), and DMF (1.8 mL) was heated in a microwave at 160 °C for 1 h. The RM was cooled, and additional CuI (337 mg, 1.77 mmol) was added before heating at 160 °C for an additional 1 h. Toluene (1.8 mL) and SOCl (922 μL, 12.64 mmol) were added to the cooled RM, which was then heated at 80 °C for 40 min. The cooled RM was then diluted with EtOAc, and the organic phase was washed with saturated aqueous NaHCO3 and brine, and the organic layer was evaporated and placed under high vacuum for 1 h. The residue was then taken up in DCM, and the organic phase was washed with saturated aqueous NaHCO3 and brine (phase separator cartridge), and then evaporated. Purification of the crude product by normal-phase chromatography (25 g SiO2 SNAP column, eluent hexane:EtOAc 100:0 to 75:25) followed by reverse-phase chromatography (RP-HPLC 3, gradient: 30% to 70% B in 20 min) and crystallization from MeOH afforded the title compound as a yellow powder. 1 H NMR(400MHz,MeOH-d4)δ 7.81(s,1H),7.00-7.08(m,1H),6.97(s,1H),6.67-7.24(m,2H),4.22- 4.45(m,2H),3.08-3.19(m,1H),2.88-3.05(m,1H),2.23-2.51(m,2H). LC-MS: Rt = 0.71 min; MS m / z [M+H] + 393.0;UPLC-MS 1.

[0166] Example 3: (S)-8'-(Difluoromethoxy)-3,6'-bis(trifluoromethyl)-5,6-dihydro-3'H-spiro[cyclopenta[c]pyridine-7,2'-imidazo[1,2-α]pyridine] [ka] A 50 mL flask was charged with (S)-3,6'-bis(trifluoromethyl)-5,6-dihydro-3'H-spiro[cyclopenta[c]pyridin-7,2'-imidazo[1,2-α]pyridin]-8'-ol (Intermediate M, 50 mg, 133 μmol), an aqueous solution of KOH (4.1 M, 114 μL, 466 μmol), and DCM (6 mL). The RM was cooled to 0 °C using an ice bath, and (bromodifluoromethyl)trimethylsilane (27 μL, 173 μmol) was added dropwise. The RM was stirred at 0 °C for 5 min, then quenched with water and extracted with ethyl acetate. The organic layer was washed successively with brine, dried on a phase separator, and concentrated under vacuum. The crude mixture was purified by reverse-phase chromatography (RP HPLC 3). Product-containing fractions were pooled and lyophilized to give the title compound. 1 H-NMR(400MHz,DMSO-d6):δ 8.69(s,1H),8.02(s,1H),7.85(s,1H),7.52-7.15(t,1H),7.03(s,1H),4.44-4.35(q,2H),3.13-2.98(m,2H),2.31-2.28(t,2H). LC-MS:Rt=2.95min;MS(m / z)=[M+H]+ 426.2;UPLC-MS 4.

[0167] Example 4: (S)-5'-Bromo-8-(difluoromethoxy)-4'-fluoro-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]-6-carbonitrile [ka] To a solution of (S)-(1-amino-5-bromo-4-fluoro-2,3-dihydro-1H-inden-1-yl)methanol (Intermediate J, 50.0 mg, 0.19 mmol) in DMF (1.80 mL) was added 6-chloro-5-(difluoromethoxy)nicotinonitrile (Intermediate B, 89.0 mg, 0.30 mmol), KPO (81.0 mg, 0.38 mmol), and CuBr (8.19 mg, 0.06 mmol), and the RM was stirred in a microwave at 120 °C for 2.5 h. The RM was partitioned between TBME and HO, and the layers were separated. The aqueous layer was washed with TBME, and the combined organic layers were then washed with brine, dried over NaSO, filtered, and evaporated. The residue was dissolved in MeOH and purified by SFC (SFC 1). Product-containing fractions were combined and evaporated to give the title compound as a yellow foam. 1 H NMR(600MHz,DMSO-d6)δ 8.21(d,1H),7.58-7.53(m,1H),7.32(t,1H),7.11-7.05(m,2H),4.36-4.25(m,2H),3.07-2.92(m,2H),2.34-2.22(m,2H). LC-MS: Rt = 0.76 min; MS m / z [M+H] + 409.9 / 411.9;UPLC-MS 1.

[0168] Example 5: (S)-5'-Bromo-4'-fluoro-8-(fluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene] [ka] A solution of (S)-5-bromo-4-fluoro-3'-(3-(fluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydrospiro[indene-1,4'-oxazolidin]-2'-one (Intermediate N, 40 mg, 62 μmol) in 4 M aqueous NaOH (0.154 mL, 618 μmol) and EtOH (2 mL) was stirred at 80 °C for 20 min. The cooled RM was diluted with EtOAc, the organic layer was washed with saturated aqueous NaHCO, the layers were separated using a phase separator, and concentrated. The residue was redissolved in toluene (2 mL), SOCl (6.76 μl, 0.093 mmol) was added, and the RM was heated at 80 °C for 20 min. After cooling, the RM was quenched with MeOH, concentrated, and partitioned between EtOAc and saturated aqueous NaHCO, and the organic layer was dried and concentrated. The residue was purified by reverse phase chromatography (RP-HPLC 3) and the product-containing fractions were combined and evaporated to give the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.90(s,1H),7.55(t,1H),7.07(d,1H),6.78(s,br,1H),5.89(d,2H),4.34-4.35(m,2H),3.09-2.91(m,2H),2.32-2.22(m,2H). LC-MS: Rt = 3.25 min; MS m / z [M+H] + 435.1 / 437.1;UPLC-MS 4.

[0169] Example 6: (S)-8-(Difluoromethoxy)-5',6-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene] [ka] To a solution of (S)-5',6-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridin-2,1'-inden]-8-ol (Intermediate Q, 138 mg, 369 μmol) in DCM (1 mL) cooled in an ice bath was added KOH (20% in water, 352 μL, 1.25 mmol) and (bromodifluoromethyl)trimethylsilane (82 mg, 396 μmol). The RM was stirred at 0 °C for 30 min, diluted with DCM, and the organic phase was washed with HO and then brine, separated by passing through a phase separator cartridge, and concentrated. Purification by reverse-phase chromatography (RP-HPLC 3) was then performed. The product-containing fractions were lyophilized, diluted with MeOH, and evaporated to give the title compound as a yellow solid. 1 H NMR(400MHz,MeOH-d4)δ 7.82(s,1H),7.49-7.66(m,2H),7.43(d,1H),6.99(s,1H),6.95(br t,1H),4.22-4.51(m,2H),3.08-3.22(m,1H),2.93-3.07(m,1H),2.24-2.52(m,2H). LC-MS: Rt = 3.66 min; MS m / z [M+H] + 424.2;UPLC-MS 4.

[0170] Example 7: (S)-6'-Bromo-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] A mixture of (S)-(1-amino-6-bromo-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol (Intermediate R, 1.0 g, 3.61 mmol), 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (Intermediate A, 1.81 g, 7.22 mmol), CuBr (264 mg, 1.81 mmol), KPO (1.53 g, 7.22 mmol), and DMF (12 mL) was heated in a microwave under argon at 140 °C for 7 h. The cooled RM was diluted with saturated aqueous NaHCO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (120 g SiO2-column; eluent heptane:EtOAc 100:0 to 75:25). Product-containing fractions were combined and evaporated to give a brown solid, which was dissolved in toluene (10.5 mL) and SOCl2 (0.17 mL, 2.33 mmol) was added. The RM was heated to 70 °C for 45 min. The RM was quenched with saturated aqueous NaHCO3 and eluted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (80 g SiO2-column, eluent heptane:EtOAc 100:0 to 75:25). Product-containing fractions were combined, evaporated, and dried to give the title compound as a yellow solid. 1 H NMR(600MHz,DMSO-d6)δ 7.93(s,1H),7.53-7.45(m,1H),7.32(d,1H),7.07(d,1H),7.01(s,1H),4.22(d,1H),4.0 7(d,1H),2.83-2.75(m,1H),2.75-2.67(m,1H),1.96(s,1H),1.85(dd,2H),1.72(s,1H). LC-MS: Rt = 0.87 min; MS m / z [M+H] + 467.1 / 469.1;UPLC-MS 1.

[0171] Example 8: (S)-6'-Bromo-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one [ka] Water (6 mL) was added to a solution of (S)-6'-bromo-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H,4'H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'-one (Intermediate S, 2.66 g, 4.58 mmol) in acetone (60 mL), and the RM was cooled to 0 °C. NBS (6.52 g, 36.7 mmol) was added, and the RM was stirred at 0 °C for 5 min, then quenched with saturated aqueous sodium thiosulfate solution, basified with saturated aqueous NaHCO3, and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (80 g SiO2-column, eluent DCM:MeOH 100:0 to 95:5). Product-containing fractions were combined and evaporated to give the title compound as an orange solid. 1 H NMR(600MHz,DMSO-d6)δ 8.03-7.88(m,2H),7.54-7.23(m,2H),7.07(s,1H),4.44(d,1H),4.18(d,1H),2.77(dtq,2H),2.24(dtd,2H). LC-MS: Rt = 0.76 min; MS m / z [M+H] + 480.9 / 482.9;UPLC-MS 1.

[0172] Example 9: (1'S,3'R)-6'-Bromo-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one [ka] (S)-6'-Bromo-4'-((tert-butyldimethylsilyl)oxy)-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] (Intermediate U, 137 mg, 228 μmol) was dissolved in AcCN (2 mL) under argon. The RM was cooled to 0 °C, and Selectfluor® (89 mg, 251 μmol) was added. The RM was stirred at 0 °C for 30 min and then at RT for 1.3 h. The RM was quenched with saturated aqueous NaHCO3 and eluted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (40 g SiO2 column, eluent heptane:EtOAc 100:0 to 75:25). The product-containing fractions were combined, evaporated, and subjected to SFC (SFC 1). Evaporation of the product-containing fractions gave (1'S,3'S)-6'-bromo-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'(3'H)-one as the first eluting peak, Rt 5.86 min (SFC 1). 1 H NMR(600MHz,DMSO-d6)δ 8.03-7.97(m,2H),7.36(t,1H),7.26(d,1H),7.13(s,1H),5.61(ddd, 1H),4.69(d,1H),4.03(d,1H),2.75-2.67(m,1H),2.49-2.41(m,1H). LC-MS: Rt = 0.98 min; MS m / z [M+H] + 499.0 / 500.9;UPLC-MS 1. (1'S,3'R)-6'-Bromo-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'(3'H)-one was obtained as the second eluting peak, Rt 8.32 min (SFC 1). 1H NMR(400MHz,DMSO-d6)δ 8.07(d,1H),7.99-7.95(m 1H),7.32(t,1H),7.28(d,1H),7.06(d,1H),5.86-5.63(m,1H),4.61(d,1H),4.28(d,1H),2.72-2.54(m,2H). LC-MS: Rt = 0.89 min; MS m / z [M+H] + 499.0 / 500.9;UPLC-MS 1.

[0173] Example 10 (1'S,3'R,4'S)-6'-Bromo-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'-ol [ka] (1'S,3'R)-6'-Bromo-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one (Example 9, 60 mg, 118 μmol) was dissolved in EtOH (2 mL). The RM was cooled to 0 °C, and sodium borohydride (5.11 mg, 0.13 mmol) was added. The RM was stirred at 0 °C for 30 min. The RM was quenched with 2 M aqueous HCl, stirred at RT for 5 min, basified with saturated aqueous NaHCO3, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. The residue was purified by SFC (SFC 1) and the product-containing fractions were evaporated to give (1'S,3'R,4'R)-6'-bromo-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'-ol as the first eluting peak, Rt 6.06 min (SFC 3). 1H NMR(400MHz,DMSO-d6)δ 7.93(s,1H),7.63(t,1H),7.36(t,1H),7.05(d,2H),6.07(d,1H),4.96(d t,2H),4.83(d,1H),4.39(d,1H),4.03(d,1H),2.39(d,1H),2.15(q,1H). LC-MS: Rt = 0.74 min; MS m / z [M+H] + 501.1 / 503.1;UPLC-MS 1. (1'S,3'R,4'S)-6'-Bromo-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'-ol was obtained as the second eluting peak, Rt 7.79 min (SFC 3). 1 H NMR(400MHz,DMSO-d6)δ 7.91(s,1H),7.66(t,1H),7.36(t,1H),7.14-6.95(m,2H),5.79(d,1H),5.06(s,1H),4.88(dd,1H),4.42(d,1H),3.84(d,1H),2.09(t,1H). LC-MS: Rt = 0.74 min; MS m / z [M+H] + 501.0 / 503.0;UPLC-MS 1.

[0174] Example 11: (S)-6'-Bromo-8-(difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] (S)-6'-Bromo-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-8-ol (Intermediate W, 305 mg, 764 μmol) was dissolved in DCM (7 mL) and cooled to 0 °C. Aqueous KOH (20%, 0.4 mL, 1.64 mmol) was added to the RM, followed by (bromodifluoromethyl)trimethylsilane (127 μL, 802 μmol). The RM was stirred at 0 °C for 10 min, then diluted with DCM, washed with brine, dried over Na2SO4, and evaporated. The residue was absorbed onto Isolute and purified by normal-phase chromatography (40 g SiO2 column, eluent heptane:EtOAc 100:0 to 75:25). Product-containing fractions were combined and evaporated to give the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.05-7.80(br,m,1H),7.34-6.90(br,m,4H),7.32(t,1H),4.30-3.96(br,m,2H),2.79-2.72(m,2H),1.98-1.62(br,m,4H). LC-MS: Rt = 0.85 min; MS m / z [M+H] + 449.1 / 451.1;UPLC-MS 1.

[0175] Example 12: (S)-8-(Difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] (S)-6'-Bromo-8-(difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] (Example 11, 43 mg, 85 μmol) was dissolved in MeOH:THF (1:1) and 5% Pd / C (20 mg) was added. The RM was stirred at RT under a positive pressure of hydrogen (0.1 bar) for 10.5 h. After flushing with N2, the RM was filtered through a Celite pad, washed with MeOH, and the filtrate was evaporated. The residue was absorbed onto Isolute and purified by normal-phase chromatography (24 g SiO2 column, eluent heptane:EtOAc 100:0 to 75:25). Product-containing fractions were combined and evaporated to give the title compound as a yellow film. 1 H NMR(400MHz,DMSO-d6)δ 7.91(s,1H),7.59-7.98(m,6H),4.30-3.98(m,2H),2.77(t,2H),1.97-1.83(m,3H),1.73(dt,1H). LC-MS: Rt = 0.76 min; MS m / z [M+H] + 371.2;UPLC-MS 1.

[0176] Example 13: (S)-6'-Bromo-8-(difluoromethoxy)-5'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile [ka] A microwave vial was charged with (S)-(1-amino-6-bromo-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol (Intermediate R, 1.5 g, 5.42 mmol), 6-chloro-5-(difluoromethoxy)nicotinonitrile (Intermediate B, 2.22 g, 10.8 mmol), KPO (2.3 g, 10.8 mmol), CuBr (0.389 g, 2.65 mmol), and DMF (15 mL) under Ar. The RM was heated in a microwave at 120 °C for 145 min, diluted with saturated aqueous NaHCO solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (120 g SiO2-column, eluent heptane:EtOAc 100:0 to 70:30). Product-containing fractions were combined and evaporated to give the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.12(s,1H),7.57-6.97(m,4H),4.35-3.92(m,2H),2.72(dt,2H),1.84(dt,4H). LC-MS: Rt = 0.82 min; MS m / z [M+H] + 424.2 / 426.2;UPLC-MS 1.

[0177] Example 14: (S)-6'-Bromo-8-(difluoromethoxy)-4',4',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] NIS (194 mg, 861 μmol) was suspended in DCM (3 mL) under Ar and cooled to −78° C. To the RM was added pyridine hydrogen fluoride (107 μL, 861 μmol; 70%), followed by a solution of (S)-6′-bromo-8-(difluoromethoxy)-5′-fluoro-6-(trifluoromethyl)-2′,3′-dihydro-3H-dispiro[imidazo[1,2-α]pyridine-2,1′-naphthalene-4′,2″-[1,3]dithiolane] (Intermediate S, 120 mg, 215 μmol) in DCM (5 mL), dropwise. The RM was stirred at −78° C. for 4.5 h, then diluted with EtOAc, quenched with saturated aqueous sodium thiosulfate, and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (40 g SiO2-column; eluent heptane:EtOAc 100:0 to 50:50). The product-containing fractions were combined, evaporated and further purified by SFC (SFC 1), and the product-containing fractions were evaporated to dryness to give the title compound. 1 H NMR(600MHz,DMSO-d6)δ 7.97(s,1H),7.87(t,1H),7.49-7.21(m,2H),7.06(s,1H),4.36(d,1H),4.21(d,1H),2.58(d,1H),2.38(s,1H),2.09(s,1H),2.03(t,1H). LC-MS: Rt = 0.94 min; MS m / z [M+H] + 503.0 / 505.0;UPLC-MS 1.

[0178] Example 15: (S)-8-(Difluoromethoxy)-4',4',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile [ka] A microwave vial was charged with (S)-6'-bromo-8-(difluoromethoxy)-4',4',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] (Example 14, 160 mg, 312 μmol), XPhos Pd G3 (26.4 mg, 31 μmol), XPhos (30.3 mg, 62 μmol), potassium hexacyanoferrate(II) (65.8 mg, 156 μmol), potassium acetate (6.12 mg, 62 μmol), and 1,4-dioxane (1.5 mL) and water (1.5 mL) under Ar. The RM was heated in a microwave at 100 °C for 1.5 h, then diluted with saturated aqueous NaHCO and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was diluted with THF, SiliaMetS® thiol (0.212 mmol, 150 mg, particle size: 40-63 μm, loading 1.41 mmol / g, Silicycle) was added, and the RM was stirred at 40 °C for 1 h. The RM was filtered, washed with THF, and the filtrate was evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (SiO2-column; eluent heptane:EtOAc 100:0 to 75:25). The product-containing fractions were combined and evaporated. The residue was triturated with hexane, filtered, and dried to give the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.08(t,1H),7.99(s,1H),7.56-7.13(m,2H),7.08(s,1H),4.38(d,1H),4.25(d,1H),2.60(s,2H),2.13(d,1H),2.05(d,1H). LC-MS: Rt = 0.87 min; MS m / z [M+H] + 450.1;UPLC-MS 1.

[0179] Example 16: (S)-6'-Bromo-8-chloro-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] (S)-(6-Bromo-1-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol (Intermediate P1, 215 mg, 427 μmol) was dissolved in toluene (2 mL) under Ar, and SOCl (0.05 mL, 685 μmol) was added. The RM was heated to 80 °C for 1 h, cooled, and then quenched with saturated aqueous NaHCO and eluted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal-phase chromatography (40 g SiO column; eluent heptane:EtOAc 100:0 to 70:30). The product-containing fractions were combined and evaporated. The residue was dissolved in EtO with a few drops of EtOAc, and then heptane was added. The resulting solution was kept in a refrigerator at 4° C. for 18 hours. The precipitated impurities were removed by filtration. The mother liquor was evaporated and the remaining solid was dried to give the title compound as a yellow foam. 1 H NMR(400MHz,DMSO-d6)δ 8.00(s,1H),7.57-7.39(m,2H),7.05(d,1H),4.20(dd,2H),2.86-2.63(m,2H),2.05-1.92(m,1H),1.92-1.77(m,2H),1.77-1.63(m,1H). LC-MS: Rt = 0.82 min; MS m / z [M+H] + 435.1 / 437.1;UPLC-MS 1.

[0180] Example 17: (S)-6'-Bromo-8-(difluoromethoxy)-3',3',5'-trifluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one [ka] (S)-6'-Bromo-4'-((tert-butyldimethylsilyl)oxy)-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] (Intermediate X, 177 mg, 274 μmol) was dissolved in AcCN (5 mL) under Ar. The RM was cooled to 0 °C, and Selectfluor® (126 mg, 356 μmol) was added. The RM was stirred at RT for 5 h, then quenched with saturated aqueous NaHCO3 and eluted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (24 g SiO2 column; eluent heptane:EtOAc 100:0 to 75:25). The product-containing fractions were combined, evaporated and dried to give the title compound. 1 H NMR(600MHz,DMSO-d6)δ 8.11(dd,1H),8.04(s,1H),7.49-7.21(m,2H),7.15(d,1H),4.54(d,1H),4.21(d,1H),3.10-2.95(m,2H). LC-MS: Rt = 1.08 min broad peak; MS m / z [M+H] + 516.9 / 518.9;UPLC-MS 1.

[0181] Examples 18 and 19: (1'S,4'S)-6'-Bromo-8-(difluoromethoxy)-3',3',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'-ol and (1'S,4'R)-6'-Bromo-8-(difluoromethoxy)-3',3',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'-ol [ka] (S)-6'-Bromo-8-(difluoromethoxy)-3',3',5'-trifluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one (Example 17, 116 mg, 213 μmol) was dissolved in EtOH (5 mL) under Ar. The RM was cooled to 0 °C, and sodium borohydride (9.2 mg, 234 μmol) was added. The RM was stirred at 0 °C for 1 h, then quenched with 4 drops of 2 M aqueous HCl, and the RM was stirred at RT for 5 min. The RM was diluted with saturated aqueous NaHCO and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated. The residue was purified by SFC (SFC 1), and the product-containing fractions were combined and evaporated to give (1'S,4'S)-6'-bromo-8-(difluoromethoxy)-3',3',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'-ol as the first eluting peak, Rt 7.54 min (SFC 1). 1 H NMR(600MHz,DMSO-d6)δ 7.97(q,1H),7.73(dd,1H),7.35(t,1H),7.15(dd,1H),7.11(d,1H),6.69 (d,1H),4.87-4.81(m,1H),4.46(d,1H),3.95(d,1H),2.69-2.53(m,2H). LC-MS: Rt = 0.86 min; MS m / z [M+H] + 518.9 / 520.9;UPLC-MS 1. (1'S,4'R)-6'-Bromo-8-(difluoromethoxy)-3',3',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'-ol was obtained as the second eluting peak, Rt 8.80 min (SFC 1). 1H NMR(600MHz,DMSO-d6)δ 8.01(q,1H),7.70(dd,1H),7.34(t,1H),7.12(dd,1H),7.06(d,1H),6.54(d,1H),4 .99-4.93(m,1H),4.41(d,1H),4.25(d,1H),2.76-2.66(m,1H),2.53-2.43(m,1H). LC-MS: Rt = 0.77 min; MS m / z [M+H] + 519.0 / 521.0;UPLC-MS 1.

[0182] Examples 20 and 21: (1'S,3'R)-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one and (1'S,3'R)-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one [ka] Selectfluor® (1.64 g, 4.62 mmol) was added to (S)-4'-((tert-butyldimethylsilyl)oxy)-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] (Intermediate AB, 2.05 g, 3.85 mmol) in AcCN (40 mL) under Ar and cooled to 0 °C. The RM was stirred at 0 °C for 3.5 h, then quenched with saturated aqueous NaHCO and eluted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (120 g SiO column; eluent heptane:EtOAc 100:0 to 70:30). The product-containing fractions were combined and evaporated to give the title compound. The diastereomers were separated by chiral HPLC: (Instrument: Gilson Trilution I System; Column: Lux Cellulose-5, 5 μM 250 × 30 mm, 25 ° C; Eluent: n-heptane (saturated with MeOH) / iPrOH 8:2; Detection: UV 230 nm; Flow rate: 20 mL / min; Injection volume: 1.0 mL) to give (1'S,3'R)-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one as the second eluting peak, Rt 8.8 min (C-HPLC-18). 1 H NMR(600MHz,DMSO-d6)δ 7.99(s,1H),7.71(m,1H),7.57-7.22(m,3H),7.12(s,1H),5.61(m,1H),4.69(d,1H),4.03(d,1H),2.71(m,1H),2.47-2.38(m,1H). LC-MS: Rt = 0.68 min; MS m / z [M+H] + 421.0;UPLC-MS 1. (1'S,3'S)-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one was obtained as the first eluting peak, Rt 4.9 min (C-HPLC-18). 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.70 (td, 1H), 7.58-7.17 (m, 3H), 7.06 (s, 1H), 5.69 (m, 1H), 4.64 (d, 1H), 4.29 (d, 1H), 2H unassigned due to solvent peak. LC-MS: Rt = 0.77 min; MS m / z [M+H] + 421.0;UPLC-MS 1.

[0183] Example 22: (S)-8-(Difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile [ka] A microwave vial was charged with (S)-6'-bromo-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] (Example 7, 245 mg, 524 μmol), XPhos Pd G3 (44.4 mg, 52 μmol), XPhos (51 mg, 105 μmol), potassium hexacyanoferrate(II) (111 mg, 262 μmol), potassium acetate (6.4 mg, 66 μmol), 1,4-dioxane (2 mL), and water (1 mL) under Ar. The RM was heated in a microwave at 100 °C for 1.5 h. The RM was diluted with saturated aqueous NaHCO3 solution and eluted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal-phase chromatography (80 g SiO2 column; eluent heptane:EtOAc 100:0 to 75:25). Product-containing fractions were combined and evaporated. The residue was dissolved in MeOH (4 mL) and filtered through a Stratosphere SPE PL-thiol cartridge (500 mg / 6 mL; Agilent Technologies), and the filtrate was evaporated. The residue was repurified by reverse-phase chromatography (RP-HPLC 2). Product-containing fractions were combined and purified by elution with DCM and saturated NaHCO 33 The combined organic layers were dried over Na2SO4, filtered and evaporated to give the title compound as a yellow foam. 1 H NMR (600 MHz, DMSO-d6, TFA added): δ 8.76 (s, 1H), 8.22 (d, 1H), 7.90 (dd, 1H), 7.77 (d, 1H), 7.51 (t, 1H), 4.93 (d, 1H), 4.71 (d, 1H), 2.87-2.79 (m, 1H), 2.78-2.71 (m, 1H), 2.35-2.28 (m, 1H), 2.09-1.98 (m, 2H), 1.86-1.76 (m, 1H). LC-MS: Rt = 0.77 min; MS m / z [M+H] + 414.2;UPLC-MS 1.

[0184] Example 23: (S)-8-(Difluoromethoxy)-4',4',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] NIS (261 mg, 1.16 mmol) was suspended in DCM (5 mL) under Ar and cooled to −78° C. To the RM was added pyridine hydrogen fluoride (0.144 mL, 1.16 mmol), followed by a solution of (S)-8-(difluoromethoxy)-5′-fluoro-6-(trifluoromethyl)-2′,3′-dihydro-3H-dispiro[imidazo[1,2-α]pyridine-2,1′-naphthalene-4′,2″-[1,3]dithiolane] (Intermediate Y, 140 mg, 0.29 mmol) in DCM (10 mL), dropwise. The RM was stirred at −78° C. for 4 h. The RM was diluted with EtOAc and saturated aqueous sodium thiosulfate and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (40 g SiO2-column; eluent heptane:EtOAc 100:0 to 80:20). The product-containing fractions were combined, evaporated and dried to give the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.96(s,1H),7.62-7.13(m,4H),7.04(s,1H),4.36(d,1H),4.22(d,1H),2.64-2.27(m,2H),2.10 1.95(m,2H). LC-MS: Rt = 0.78 min; MS m / z [M+H] + 425.0;UPLC-MS 1.

[0185] Example 24: (2S,4'S)-6'-Bromo-8-(difluoromethoxy)-4',5'-difluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile and (2S,4'R)-6'-Bromo-8-(difluoromethoxy)-4',5'-difluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile [ka] DAST (6.5 μL, 48 μmol) was added to (1'S)-6'-bromo-8-(difluoromethoxy)-5'-fluoro-4'-hydroxy-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile (Intermediates AC and AD, 11 mg, 24 μmol) in DCM (0.5 mL) cooled to −78 °C under Ar. The RM was stirred at RT for 1 h, then additional DAST (6.5 μL, 48 μmol) was added, and the RM was stirred at RT for an additional 45 min. The RM was quenched with saturated aqueous NaHCO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated. The residue was purified by SFC (SFC 1) and the product-containing fractions were evaporated to give the first eluting diastereomer with the highest affinity for the HIF2 PAS-B domain, whose data are included in the activity table. LC-MS: Rt=0.82 min; MS m / z [M+H] + 442.0 / 444.0;UPLC-MS 1.

[0186] The second eluting diastereomer was absorbed onto Isolute and re-purified by normal phase chromatography (12 g SiO2-column; eluent heptane:EtOAc 100:0 to 30:70). Product-containing fractions were combined and evaporated. 1H NMR(400MHz,DMSO-d6)δ 8.13(d,1H),7.79-7.72(m,1H),7.31(t,1H),7.14-7.09(m,2H),5.86( d,1H),4.33(d,1H),3.85(d,1H),2.26-1.95(m,3H),1.88-1.80(m,1H). LC-MS: Rt = 0.78 min; MS m / z [M+H] + 442.0 / 444.0;UPLC-MS 1.

[0187] Example 25: (1'S,4'S)-8-(difluoromethoxy)-4',5'-difluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile [ka] DAST (0.02 ml, 151 μmol) was added to the first eluting diastereomer from the reduction of (S)-8-(difluoromethoxy)-5′-fluoro-4′-oxo-6-(trifluoromethyl)-3′,4′-dihydro-2′H,3H-spiro[imidazo[1,2-α]pyridine-2,1′-naphthalene]-6′-carbonitrile (Intermediate AE / AF, 30 mg, 68 μmol) in DCM (2 mL) cooled to −78° C. under Ar. The RM was stirred at 0° C. for 2.5 h, then quenched with saturated aqueous NaHCO and eluted with EtOAc. Product-containing fractions were combined and evaporated, and the diastereomers were separated by SFC (SFC-1) to give the title compound as the first eluting peak, Rt=5.7 min, as a yellow solid. 1 H NMR(600MHz,DMSO-d6)δ 7.99-7.91(m,2H),7.44(d,1H),7.31(t,1H),7.07(d,1H),5.89(dd,1H),4.36 (d,1H),3.88(d,1H),2.31-2.20(m,1H),2.18-1.98(m,2H),1.94-1.87(m,1H). LC-MS: Rt = 0.79 min; MS m / z [M+H]+ 432.1;UPLC-MS 1. (1'S,4'R)-8-(difluoromethoxy)-4',5'-difluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile was obtained as the second eluting peak, Rt = 8.1 min, as a yellow solid. 1 H NMR(600MHz,DMSO-d6)δ 8.02-7.99(m,1H),7.97-7.93(m,1H),7.48(d,1H),7.29(t,1H),7.02(d,1H),5.96(d,1 H),4.53(d,1H),4.26(d,1H),2.46-2.32(m,1H),2.17-2.08(m,2H),1.94-1.89(m,1H). LC-MS: Rt = 0.74 min; MS m / z [M+H] + 432.1;UPLC-MS 1.

[0188] Example 26: (S)-8-(Difluoromethoxy)-5'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile [ka] A solution of (S)-(1-amino-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol (Intermediate AA, 700 mg, 3.59 mmol), 6-chloro-5-(difluoromethoxy)nicotinonitrile (Intermediate B, 1.47 g, 7.17 mmol), copper iodide (205 mg, 1.08 mmol), and potassium phosphate (1.52 g, 7.17 mmol) in DMF (18 mL) was heated in a microwave at 140 °C for 1.5 h. The RM was poured into saturated aqueous NaHCO3 and extracted three times with EtOAc. The combined organic extracts were washed twice with water, dried (phase separator), and evaporated. The crude material was dissolved in THF (20 mL), SiliaMetS® thiol (particle size: 40-63 μm, loading 1.35 mmol / g, 6.45 mmol, 4.78 g) was added, and the mixture was vortexed at 40° C. for 1 h. The mixture was filtered, and the filtrate was evaporated. The crude residue was purified by normal-phase flash chromatography (120 g SiO column, eluent EtOAc:c-hexane 0:100-25:75) to afford the title compound as a yellow foam. 1 H NMR(400MHz,DMSO-d6)δ 8.14(d,1H),7.30(t,1H),7.22(m,1H),7.07-7.03(m,2H),7.06(d,1H),4.22(d,1H),4.09( d,1H),2.77-2.72(m,1H),2.69-2.64(m,1H),1.97(m,1H),1.90-1.82(m,2H),1.73(m,1H). LC-MS: Rt = 2.51 min; MS m / z [M+H] + 346.2;UPLC-MS 6.

[0189] Example 27: d2-(S)-8-(difluoromethoxy)-5'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile [ka] A solution of (S)-(1-amino-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl-4,4-d2)methanol (Intermediate AG, 22 mg, 0.10 mmol), 6-chloro-5-(difluoromethoxy)nicotinonitrile (Intermediate B, 39.7 mg, 0.19 mmol), copper iodide (5.54 mg, 0.03 mmol), and potassium phosphate (41.2 mg, 0.19 mmol) in DMF (0.5 mL) was heated in a microwave at 140 °C for 1.5 h. The RM was poured into saturated aqueous NaHCO3 and extracted three times with EtOAc. The combined organic extracts were washed twice with water, dried (phase separator), and evaporated. The crude residue was dissolved in THF (2 mL), SiliaMetS® thiol (particle size: 40-63 μm, loading 1.35 mmol / g, 0.09 mmol, 64 mg) was added, and the mixture was vortexed at 40 °C for 1 h. The mixture was filtered, washed with THF, and the filtrate was evaporated. The crude product was purified by reverse-phase preparative HPLC (RP-HPLC 2), and the product-containing fractions were neutralized with saturated aqueous NaHCO3, extracted with DCM, and evaporated. The residue was again purified by reverse-phase preparative HPLC (RP-HPLC 3), and the product-containing fractions were extracted with DCM and evaporated to give the title compound as a yellow foam. 1 H NMR(400MHz,DMSO-d6)δ 8.14(s,1H),7.30(t,1H),7.23(m,1H),7.09-7.02(m,3H),4.24(d,1H) ,4.10(d,1H),2.00-1.94(m,1H),1.91-1.82(m,2H),1.76-1.68(m,1H). LC-MS: Rt = 2.52 min; MS m / z [M+H] + 348.2;UPLC-MS 6.

[0190] Example 28: (S)-8-(Difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] SOCl (0.07 mL, 0.959 mmol) was added to (S)-(1-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol (Intermediate CK, 290 mg, 607 μmol) dissolved in toluene (6 mL) under Ar. The RM was heated to 80 °C for 45 min, cooled, then quenched with saturated aqueous NaHCO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated. The residue was dissolved in MeOH and filtered through a Stratosphere SPE PL-thiol cartridge (500 mg / 6 mL; Agilent Technologies), and the filtrate was evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (80 g SiO2-column; eluent heptane:EtOAc 100:0 to 80:20). The product-containing fractions were combined, evaporated and dried to give the title compound. 1 H NMR(600MHz,DMSO-d6)δ 7.92(s,1H),7.37(t,1H),7.20(dt,1H),7.08(dd,1H),7.03(ddd,1H),6.99(d,1H),4.21(d,1H),4.07( d,1H),2.78-2.70(m,1H),2.70-2.59(m,1H),2.00-1.92(m,1H),1.91-1.80(m,2H),1.76-1.65(m,1H). LC-MS: Rt = 0.78 min; MS m / z [M+H] + 389.2;UPLC-MS 1.

[0191] Example 29: (S)-5',6',8-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] To a solution of (S)-(5,6-difluoro-1-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-1,2,3,4-tetrahydronaphthalen-1-yl)methanol (Intermediate O1, 90 mg, 167 μmol) in toluene (5 mL) was added SOCl (122 μL, 1.67 mmol). The vial was sealed, stirred at 80 °C for 5 min, cooled to RT, and diluted with EtOAc. This mixture was washed twice with saturated aqueous NaSO. The aqueous layer was extracted with EtOAc, and the combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by normal phase chromatography (silica gel, eluent heptane: 1% 7M NH in MeOH with EtOAc) to give the title compound as a light brown solid. 1 H NMR(600MHz,DMSO-d6)δ 7.90(s,1H),7.32-7.18(m,2H),7.13 7.09(m,1H),4.22(d,1H),4.09(d,1H),2.82-2.69(m,2H),2.01-1.94(m,1H),1.93-1.80(m,2H),1.77-1.70(m,1H). LC-MS: Rt = 0.74 min; MS m / z [M+H] + 359.2;UPLC-MS 1.

[0192] Example 30: (S)-1'-chloro-8',8'-difluoro-8-methoxy-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] [ka] MeOH (41 μL, 1.006 mmol) was added to a mixture of (S)-1′-chloro-8,8′,8′-trifluoro-6-(trifluoromethyl)-7′,8′-dihydro-3H,6′H-spiro[imidazo[1,2-α]pyridine-2,5′-isoquinoline] (Intermediate AH, 80 mg, 201 μmol) and NaOtBu (26 mg, 262 μmol) in 1,4-dioxane (2 mL) at RT under an argon atmosphere. The RM was heated at 50° C. for 18 h, cooled, and diluted with saturated aqueous NaHCO. The mixture was extracted three times with DCM, and the combined organic layers were dried by passing through a phase separator and concentrated. The residue was purified by normal phase column chromatography (silica gel, eluent heptane:EtOAc 100:0 to 0:100) followed by chiral SFC (column: Chiralpak IC, 5 μm, 250 × 30 mm; eluent: 40% iPrOH + 0.1% aqueous NH OH; temperature: 40 °C; flow rate: 80 mL / min; pressure: 120 bar) to give the title compound as a white powder. 1 H NMR(400MHz,DMSO-d6)δ 8.47(d,1H),7.69(s,1H),7.38(d,1H),6.50(s,1H),4.31(q,2H),3.77(s,3H),2.69-2.31(m,2H),2.18-1.91(m,2H). LC-MS: Rt = 0.64 min; MS m / z [M+H] + 406.1 / 408.0;UPLC-MS 1.

[0193] Example 31: (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] [ka] SOCl2 (3.87 ml, 53.1 mmol) was added dropwise to a solution of (S)-(1-chloro-5-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)-8,8-difluoro-5,6,7,8-tetrahydroisoquinolin-5-yl)methanol (Intermediate AJ, 12.84 g, 26.5 mmol) in toluene (160 mL) at RT under an atmosphere of argon. The RM was then heated at 80 °C for 30 min, cooled to 0 °C, MeOH was added and evaporated. The residue was partitioned between EtOAc and saturated aqueous NaHCO3, extracted with EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by normal phase chromatography (330 g silica gel, eluent heptane: EtOAc 100:0 to 70:30), and the product-containing fractions were evaporated, taken up in a minimum amount of MeOH, and left at RT for 18 h. After drying under vacuum, filtration afforded the title compound as a yellow solid. A second crop of the title compound could be obtained from the filtrate after normal phase chromatography and crystallization from MeOH. 1 H NMR(600MHz,DMSO-d6)δ 8.49(d,1H),8.00(s,1H),7.51(d,1H),7.33(t,1H),7.09(d,1H),4.37(d,1H),4.27 (d,1H),2.68-2.54(m,1H),2.47-2.33(m,1H),2.17-2.10(m,1H),2.06-1.97(m,1H). LC-MS: Rt = 0.80 min; MS m / z [M+H] + 442.4 / 444.4;UPLC-MS 1.

[0194] The following salts were prepared from the above free base form of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] by precipitation with the appropriate counterion.

[0195] A 1:1 stoichiometry of the fumarate salt (mw 557.77), mp (DSC) 171.9 and 179.8 °C (onset): The free base (76.0 mg, 172 μmol) was placed in a 2 mL glass vial, iPrOH (500 μL) was added, and the yellow suspension was stirred at 55 °C. After stirring at 55 °C for 4 h, fumaric acid (19.95 mg, 172 μmol) was added, and the RM remained a slurry. Heating was stopped, and the slurry was stirred at RT for 18 h. The solid was isolated by centrifugation, and the powder was dried under vacuum at 40 °C to give the title compound.

[0196] A 1:1 stoichiometry of the sulfate salt (mw 539.78), mp (DSC) 135.8 °C (start): The free base (56.67 mg, 128 μmol) was placed in a 2 mL glass vial, iPrOH (400 μL) was added, and the yellow suspension was stirred at RT. AqHSO (1 N, 128 μL) was then added, converting the RM to an off-white slurry in approximately 10 min. The slurry was stirred at RT for 18 h, the solid was isolated by centrifugation, and the powder was dried under vacuum at 40 °C for 18 h to give the title compound.

[0197] Example 32: (S)-8-(Difluoromethoxy)-8',8'-difluoro-1'-methyl-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] [ka] A mixture of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] (Example 31, 50 mg, 112 μmol), trimethylboroxine (13 μL, 90 μmol), CsCO (73 mg, 224 μmol), and PdCl(dppf).CHCl complex (9.2 mg, 11 μmol) in 1,4-dioxane (0.9 mL) and water (0.1 mL) was heated at 100 °C for 20 h and then at 120 °C for 4 h under an argon atmosphere. The cooled RM was partitioned between saturated aqueous NaHCO and DCM, extracted twice with DCM, and the combined organic layers were dried by passing through a phase separator cartridge and evaporated. The residue was taken up in MeOH and vortexed with Biotage SPE-PL thiol resin, followed by SFC purification (SFC 1 with a Princeton 4-EP 60 A 5 μm 250 × 30 mm column, eluent 2–22% MeOH) to give (S)-8-(difluoromethoxy)-8′,8′-difluoro-1′-methyl-6-(trifluoromethyl)-7′,8′-dihydro-3H,6′H-spiro[imidazo[1,2-α]pyridine-2,5′-isoquinoline] as the first eluting peak, Rt 6.73 min. 1 H NMR(600MHz,DMSO-d6)δ 8.51(d,1H),7.97(m,1H),7.34(t,1H),7.26(d,1H),7.06(s,1H),4.36( d,1H),4.21(d,1H),2.67(s,3H),2.61-2.36(m,2H),2.11-1.98(m,2H). LC-MS: Rt = 0.68 min; MS m / z [M+H] + 422.1;UPLC-MS 1. (S)-8-(Difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] was obtained as the second eluting peak, Rt 7.36 min. 1H NMR (400 MHz, chloroform-d) δ 8.97 (s, 1H), 8.72 (d, 1H), 7.47 (s, 1H), 7.28-7.22 (m, 1H), 7.06 (s, 1H), 7.03 (t, 1H), 4.39 (d, 1H), 4.27 (d, 1H), 2.78-2.69 (m, 1H), 2.51-2.27 (m, 2H), 2.25-2.19 (m, 1H). LC-MS: Rt = 0.64 min; MS m / z [M+H] + 408.1;UPLC-MS 1.

[0198] Example 32 can also be synthesized by the following alternative procedure: A solution of trimethylboroxine (5.1 g, 40.7 mmol) in iPrOAc (10 mL) was added to a mixture of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] (Example 31, 18.0 g, 40.7 mmol) and CsCO (26.6 g, 81.5 mmol) in iPrOAc (290 mL) under N atmosphere. PdCl(dppf) (298 mg, 0.4 mmol) was then added under N protection, and the mixture was purged with N for 10 min. The reactor was transferred to a preheated oil batch and stirred at 100 °C for 24 h. Additional PdCl(dppf) (298 mg, 0.4 mmol) and trimethylboroxine (1.4 g, 11.2 mmol) were added under N protection, and the RM was refluxed for an additional 17 h. The cooled RM was filtered and washed with iPrOAc (150 mL), and the filtrate was then washed with water (250 mL). The separated aqueous phase was extracted with iPrOAc (200 mL). The combined organic phase was washed with 10% aqueous NaCl (200 mL), dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by normal phase chromatography (200–300 mesh silica gel, eluent heptane:EtOAc 77:34–50:50) to give an off-white solid. MTBE / heptane 1:5 (240 mL) was added, and the mixture was stirred on a rotary evaporator at a bath temperature of 60 °C without vacuum. After dissolution to a bright red / yellow solution, a solid precipitated from the mixture, which was allowed to cool to RT. The solid was collected by filtration, and heptane (120 mL) was added to the mother liquor to give a second crop of material. The title compound was obtained after further recrystallization from MTBE:heptane 1:5 and drying.

[0199] The following crystalline forms and salts were prepared from the above free base form of (S)-8-(difluoromethoxy)-8',8'-difluoro-1'-methyl-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] by seeding and precipitation with the appropriate counter ion.

[0200] Crystalline variant A mp (DSC) 129.9 °C (start): The free base (3.13 g, 7.06 mmol, assay 95.5%) and iPrOH (3 mL) were added to a 100 mL vessel, and the mixture was heated to 65 °C (jacket temperature) with mechanical stirring at 250 RPM. n-Heptane (9 mL) was added to the mixture over 1 hour, and then seed crystals of variant A (30 mg) were added at 65 °C. The resulting mixture became cloudy and was maintained at 65 °C for approximately 1 hour. Additional n-heptane (51 mL) was added over 10 hours, the temperature was maintained at 65 °C for an additional 1 hour, and the mixture was then cooled to 4 °C over 4 hours. The slurry was maintained at 4 °C for 2.5 hours, after which the solid was collected by filtration at 25 °C using a glass filter and washed with a mixture of iPrOH and n-heptane (v / v = 1:20, 4.2 mL). The solid was dried under vacuum at 60° C. for 3.5 hours to give the title compound as a powder (2.46 g).

[0201] A 1:1 stoichiometry of the fumarate salt (mw 537.37), mp (DSC) 172.3 (starting):free base (2.0 g) was placed in a 100 mL EasyMax Reactor and a mixture of iPrOH and heptane (80:20, 40 mL) was added. Fumaric acid (1.73 mg) was added, and the RM was heated to 50 °C and then maintained at 50 °C for 18-24 h. The mixture was cooled to 25 °C over 4 h and then stirred at 25 °C for 4-6 h. The resulting solid was collected by filtration at 25 °C using a glass filter and washed with a mixture of iPrOH and n-heptane (4:1, 10 mL). The solid was dried under vacuum at 40 °C for 12 h to give the title compound as an off-white powder.

[0202] Example 33: (S)-8-(Difluoromethoxy)-8',8'-difluoro-1'-(methyl-d3)-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] [ka] 2-(Methyl-d3)-1,3,2-dioxaborinane (Intermediate AV, 127 mg, 1.11 mmol) was added to a mixture of (S)-1′-chloro-8-(difluoromethoxy)-8′,8′-difluoro-6-(trifluoromethyl)-7′,8′-dihydro-3H,6′H-spiro[imidazo[1,2-α]pyridine-2,5′-isoquinoline] (Example 31, 200 mg, 444 μmol), KCO (153 mg, 1.11 mmol), and tetrakis(triphenylphosphine)palladium (51 mg, 44 μmol) in 1,4-dioxane (1.5 mL), THF (1.5 mL), and water (1.5 mL) under argon. The RM was stirred at 90 °C for 48 h, then additional d3-2-(methyl-d3)-1,3,2-dioxaborinane (23 mg, 222 μmol), K2CO3 (31 mg, 222 μmol), and tetrakis(triphenylphosphine)palladium (26 mg, 22 μmol) were added, and the RM was stirred for an additional 5 h at 90 °C. The cooled RM was partitioned between EtOAc and saturated aqueous NaHCO3, the aqueous layer was extracted with more EtOAc, and the combined organic layers were washed with brine, dried by passing through a phase separator, and evaporated. The residue was dissolved in MeOH, treated with 2.0 g of SPE-PL thiol resin (Biotage), vortexed at 40 °C for 1 h, then filtered, washed with MeOH, and the filtrate was evaporated. The crude product was absorbed onto Isolute and purified by normal-phase chromatography (40 g SiO2 cartridge, eluent heptane / EtOAc 10:90 to 50:50) followed by chiral SFC: (column: Chiralcel OD-H, 250 × 30 mm ID, 5 μm, 40 °C; eluent: CO2 / iPrOH (+0.1% NH3) 94:6; flow rate: 80 mL / min; detection: DAD 190–400 nm) to give the title compound as the first eluting peak (RT 10.5 min). (S)-8-(Difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] eluted with a retention time of 16.7 min.The desired product (360 mg) was dissolved in EtOH (1.5 mL) and HO (1.5 mL) was added, followed by seed crystals of (S)-8-(difluoromethoxy)-8',8'-difluoro-1'-methyl-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]. The resulting suspension was sonicated for 5 min, and the solid was collected by filtration, washed with HO, and then dried to give the title compound as yellow crystals.

[0203] Example 33 can also be synthesized by the following alternative procedure: In a glove box, a round-bottom flask was charged with Ni(glyme)Br (6.46 g, 20.9 mmol), 1,10-phenanthroline (7.54 g, 41.8 mmol), and DMF (300 mL). The reaction mixture was stirred at room temperature for 30 minutes in the glove box to form a dark green suspension. Co(salen) (3.40 g, 10.5 mmol) was added to the above mixture, and the mixture was stirred in the glove box for 10 minutes to form a dark brown solution. In parallel, a second round-bottom flask was charged with (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] (Example 31, 61.6 g, 139.5 mmol), Mn (38.31 g, 697.3 mmol), DMF (300 mL), and TsOCD (84.0 g, 94.3% assay, 418.6 mmol). In a glovebox, the first Ni catalyst-containing solution was transferred to the second reaction mixture, the flask was sealed with a rubber stopper, and the mixture was stirred under N at 40–45 °C for 16 h. The reaction mixture was then cooled to room temperature, and the solid material was removed by filtration and washed with EtOH. The filtrates were combined and concentrated at 50°C, then EtOAc (1.0 L) was added with vigorous stirring. A precipitate formed, and the suspension was filtered through a silica gel pad (100 g) and washed with EtOAc (1.5 L). The filtrate was concentrated to form a dark green oil and then filtered again through a silica gel pad (200 g) with heptane / EtOAc (2:1, 3 L). The filtrate was concentrated, and IPA (60 mL) and water (300 mL) were added. The crude product was obtained by filtration as a pale yellow solid. The crude product was slurried with IPA (240 mL) and HO (480 mL), filtered, and dried under vacuum at 40°C to give the title compound as a yellow solid. 1 H NMR(600MHz,DMSO-d6)δ 8.52(d,1H),7.98(d,1H),7.49-7.19(m,2H),7.08(d,1H),4.29(dd,2H),2.58(dd,1H),2.43-2.39(m,1H),2.17-1.95(m,2H). LC-MS: Rt = 0.59 min; MS m / z [M+H]+ 425.2;UPLC-MS 7.

[0204] Example 34: (S)-8-(Difluoromethoxy)-8',8'-difluoro-1'-methoxy-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] [ka] Purification of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] (Example 31, 1.99 g, 4.37 mmol) by normal phase chromatography (220 g RediSep Gold Column, eluent c-hexane / EtOAc 100:0 to 73:27) revealed that a minor component eluted before the desired product. Further purification of the minor component by normal phase chromatography (4 g RediSep Gold Column, eluent c-hexane:EtOAc 100:0 to 81:19) afforded the title compound as a yellow solid. 1 H NMR(600MHz,DMSO-d6)δ 8.24(d,1H),7.97(s,1H),7.34(t,1H),7.07(s,1H),6.98(d,1H),4.34(d,1H),4. 20(d,1H),3.92(s,3H),2.60-2.49(m,1H),2.37-2.26(m,1H),2.10-1.94(m,2H). LC-MS: Rt = 3.11 min; MS m / z [M+H] + 438.0;UPLC-MS 6.

[0205] Example 35: (S)-8-(Difluoromethoxy)-6'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile [ka] A mixture of (S)-(1-amino-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol free base (Intermediate AO, 100 mg, 461 μmol), 6-chloro-5-(difluoromethoxy)nicotinonitrile (Intermediate B, 277 mg, 1.01 mmol), KPO (196 mg, 922 μmol), and CuI (62 mg, 323 μmol) in DMF (3 mL) was heated in a microwave under an atmosphere of argon at 160 °C for 30 min. The RM was partitioned between TBME (20 mL) and HO (20 mL), the aqueous layer was extracted with TBME, and the combined organic layers were washed with brine, dried over NaSO, and evaporated. The residue was purified by normal-phase chromatography (12 g SiO column, eluent hexane:TBME 0–50%) followed by reverse-phase chromatography (RP-HPLC 1). The product-containing fractions were combined, AcCN was removed in vacuo, the main aqueous phase was basified with Na2CO3 and extracted three times with DCM, and the combined organic layers were dried over Na2SO4 and evaporated to give the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.10(s,1H),7.27(t,1H),7.25-7.20(m,1H),7.03-6.89(m,3H),4.19(d,1H),4.02(d,1H),2.79-2.73(m,2H),1.95-1.62(m,4H). LC-MS: Rt = 0.62 min; MS m / z [M+H] + 346.1;UPLC-MS 1. Chiral HPLC (C-HPLC 9) showed that the sample had an ee of 72%: the title compound eluted at Rt = 17.8 min, and (R)-8-(difluoromethoxy)-6'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile eluted at Rt = 15.7 min.

[0206] Example 36: (S)-1'-chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] [ka] To a solution of (S)-(1-chloro-5-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)-5,6,7,8-tetrahydroisoquinolin-5-yl)methanol (Intermediate AP, 330 mg, 0.78 mmol) in toluene (4.8 mL) was added thionyl chloride (0.11 mL, 1.56 mmol), and the reaction mixture was stirred at 80 °C for 45 min. The cooled RM was poured into saturated aqueous NaHCO and extracted twice with DCM. The combined organic extracts were dried (phase separator) and evaporated. The crude compound was purified by normal-phase flash chromatography (12 g SiO column, eluent EtOAc:c-hexane 0:100 to 23:77) to afford the title compound as a yellow foam. 1 H NMR(600MHz,DMSO-d6)δ 8.20(d,1H),7.96(m,1H),7.36(t,1H),7.34(d,1H),7.05(d,1H),4.25(d,1H),4.1 3(d,1H),2.80-2.68(m,2H),2.01(m,1H),1.91(m,1H),1.84(td,1H),1.78(m,1H). LC-MS: Rt = 2.64 min; MS m / z [M+H] + 406.2 / 408.2;UPLC-MS 6.

[0207] Example 37: (S)-3'-chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-6',7'-dihydro-3H,5'H-spiro[imidazo[1,2-α]pyridine-2,8'-isoquinoline] [ka] SOCl2 (0.04 mL, 548 μmol) was added to (3-chloro-8-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)-5,6,7,8-tetrahydroisoquinolin-8-yl)methanol (Intermediate AQ, 130 mg, 279 μmol) in toluene (2 mL) under Ar. The RM was heated to 80 °C for 45 min, cooled, then quenched with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (40 g SiO2 column; eluent heptane:EtOAc 100:0 to 70:30). Product-containing fractions were combined, evaporated, and dried to give the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.30(s,1H),7.93(s,1H),7.30(t,1H),7.27(s,1H),7.02(d,1H),4.24(d,1H),4.14(d,1H),2.79(t,2H),1.95-1.66(m,4H). LC-MS: Rt = 0.68 min; MS m / z [M+H] + 406.1 / 408.1;UPLC-MS 1.

[0208] Example 38: (S)-8-(Difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile [ka] A microwave vial was charged with (S)-6'-bromo-8-(difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] (Example 11, 223 mg, 402 μmol), XPhos Pd G3 (34 mg, 40 μmol), XPhos (39.1 mg, 80 μmol), potassium hexacyanoferrate(II) (85 mg, 201 μmol), potassium acetate (4.93 mg, 50 μmol), 1,4-dioxane (2 mL), and water (1 mL) under Ar. The RM was heated in a microwave at 100 °C for 1.5 h. The cooled RM was diluted with saturated aqueous NaHCO and eluted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal-phase chromatography (80 g SiO2-column; eluent heptane:EtOAc 100:0 to 70:30). Product-containing fractions were combined and evaporated. The residue was dissolved in MeOH (4 mL) and filtered through a Stratosphere SPE PL-thiol cartridge (500 mg / 6 mL; Agilent Technologies), and the filtrate was evaporated to dryness to give the title compound as a yellow foam. 1 H NMR (600 MHz, DMSO-d6, TFA added): δ 8.75 (t, 1H), 8.21 (d, 1H), 7.90 (d, 1H), 7.78 (dd, 1H), 7.75 (d, 1H), 7.51 (t, 1H), 4.93 (d, 1H), 4.72 (d, 1H), 2.87 (d, 2H), 2.36-2.29 (m, 1H), 2.13-2.05 (m, 1H), 1.99 (td, 1H), 1.86-1.76 (m, 1H). LC-MS: Rt = 0.71 min; MS m / z [M+H] + 396.2;UPLC-MS 1.

[0209] Example 39: (S)-7-Bromo-8'-(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] To a solution of (S)-(7-bromo-4-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)-8-fluorochroman-4-yl)methanol (Intermediate AR, 5.32 g, 10.9 mmol) in toluene (43 mL) was added thionyl chloride (1.59 mL, 21.8 mmol) and the RM was stirred at 80 °C for 15 min. The cooled RM was quenched with MeOH and evaporated. The residue was dissolved in DCM and poured into saturated aqueous NaHCO3. The layers were separated and the aqueous layer was back-extracted twice with DCM. The combined organic extracts were dried (Phase separator) and evaporated. The crude material was purified by normal phase flash chromatography (120 g SiO2 column, eluent EtOAc:c-hexane 0:100 to 20:80 then switched to MeOH:CH2Cl2 0:100 to 40:60) to give the title compound as a yellow foam. 1 H NMR(400MHz,DMSO-d6)δ 7.98(br s,1H),7.36(t,1H),7.16(dd,1H),7.06(dd,1H),7.03(d,1H),4.46(m,1H),4.49(m,1H),4.27(s,2H),2.17-2.04(m,2H). LC-MS: Rt = 3.70 min; MS m / z [M+H] + 469.0 / 471.0;UPLC-MS 6.

[0210] Example 40: (S)-8'-(Difluoromethoxy)-8-fluoro-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] A mixture of (S)-8'-(difluoromethoxy)-8-fluoro-7-iodo-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] (Intermediate AW, 147 mg, 285 μmol), diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate (173 mg, 427 μmol), and Cu powder (54 mg, 854 μmol) in DMF (2.5 mL) was heated in a sealed tube at 60° C. for 18 h. The cooled RM was partitioned between EtOAc and saturated aqueous NaHCO, the aqueous phase was extracted with EtOAc, and the combined organic layers were washed with brine, dried, and concentrated. The residue was purified by reverse phase chromatography (RP-HPLC 2), the product-containing fractions were neutralized with saturated aqueous NaHCO3 and extracted with DCM, and the combined organic phases were dried by passing through a phase separator cartridge and concentrated to give the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.00(s,1H),7.33-7.25(m,1H),7.25-7.18(m,1H),7.62-7.11(m,1H),7.05(s,1H),4.58-4.43(m,1H),4.40-4.19(m,2H),4.27(br s,1H),2.24-1.98(m,2H). LC-MS: Rt = 4.09 min; MS m / z [M+H] + 459.2;UPLC-MS 4.

[0211] Example 41: (S)-7-Chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] To a solution of (S)-(7-chloro-4-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)chroman-4-yl)methanol (Intermediate AX, 4.79 g, 11.3 mmol) in toluene (75 mL) was added thionyl chloride (1.65 mL, 22.6 mmol) and the reaction mixture was stirred at 80 °C for 1 h. The cooled RM was quenched by the addition of saturated aqueous NaHCO3. EtOAc was added and the layers were separated. The aqueous layer was back-extracted twice with EtOAc and the combined organic extracts were dried (phase separator) and evaporated. The crude material was purified by normal phase chromatography (220 g RediSep Gold Column, eluent: c-hexane:EtOAc 70:30) to give the title compound. TLC, Rf (cyclohexane / EtOAc 1:1): 0.55 1 H NMR(400MHz,DMSO-d6)δ 7.96(br s,1H),7.36(t,1H),7.27(d,1H),7.02(br s,1H),7.94(dd,1H),6.87(d,1H),4.37(m,1H),4.25(s,2H),4.19(m,1H),2.06(m,2H). LC-MS: Rt = 3.49 min; MS m / z [M+H] + 407.1 / 409.1;UPLC-MS 6.

[0212] Example 42: (S)-7-Bromo-8-fluoro-8'-(fluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] A solution of (S)-7-bromo-8-fluoro-3'-(3-(fluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)spiro[chroman-4,4'-oxazolidin]-2'-one (Intermediate AY, 70 mg, 117 μmol) in aqueous NaOH (2 M, 293 μL, 1.17 mmol) and EtOH (3 mL) was stirred at 80 °C for 20 min. The RM was diluted with EtOAc, washed with saturated aqueous NaHCO, dried, and concentrated. The residue was dissolved in toluene (3 mL), SOCl (13 μL, 176 μmol) was added, and the RM was stirred at 80 °C for 20 min. MeOH was added to the cooled RM, which was then concentrated, partitioned between EtOAc and saturated aqueous NaHCO, dried, and concentrated. The residue was purified by normal phase chromatography (silica gel, eluent c-hexane:EtOAc 100:0 to 50:50) to give the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.87(s,br,1H),7.15(t,1H),7.02(d,1H),6.79(s,br,1H),5.90(d,2H),4.52-4.40(m,1H),4.31-4.18(m,3H),2.20-2.05(m,2H). LC-MS: Rt = 0.79 min; MS m / z [M+H] + 451.2 / 453.2;UPLC-MS 1.

[0213] Example 43: (S)-7-Chloro-8'-(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] A solution of (S)-8'-(difluoromethoxy)-8-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] (Intermediate AZ, 550 mg, 1.07 mmol) and copper(II) chloride (430 mg, 3.20 mmol) in a mixture of MeOH (5 mL) and water (5 mL) was stirred at 100 °C for 8 h. The RM was poured into saturated aqueous NaHCO and extracted twice with EtOAc. Saturated aqueous NH4Cl was added to the combined organic extracts and the mixture was stirred at RT for 1 h. The organic layer was separated, washed with saturated aqueous NH4Cl, dried (phase separator), and evaporated. The crude material was dissolved in THF (10 mL), SiliaMetS® thiol (particle size: 40-63 μm, loading 1.39 mmol / g, 13 mmol, 9.86 g) was added, and the mixture was vortexed at 40 °C for 1 h. The mixture was filtered, and the filtrate was evaporated. The crude residue was purified by reverse-phase preparative HPLC (RP HPLC 3), and the product-containing fractions were extracted with DCM and evaporated to give the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.94(s,br,1H),7.33(t,1H),7.12(m,1H),7.02(m,2H),4.50(m,1H),4.34-4.29(m,3H),2.16(m,2H). LC-MS: Rt = 3.65 min; MS m / z [M+H] + 425.1 / 427.1;UPLC-MS 6.

[0214] Example 44: (S)-8'-(Difluoromethoxy)-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] To a solution of (S)-(4-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)-7-(trifluoromethyl)chroman-4-yl)methanol (Intermediate BA, 3.18 g, 6.24 mmol) in toluene (40 mL) was added thionyl chloride (0.91 mL, 12.5 mmol), and the yellow suspension was stirred at 80 °C for 1 h. The cooled RM was quenched with saturated aqueous NaHCO and extracted twice with EtOAc. The combined organic extracts were dried (phase separator) and evaporated. The residue was purified by conventional flash chromatography (120 g SiO column; eluent c-hexane:EtOAc 100:0 to 70:30) to give the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.98(br,s,1H),7.49(d,1H),7.37(t,1H),7.22(d,1H),7.10(s,1H),7.04(s,1H),4.41(m,1H),4.29(s,2H),4.23(m,1H),2.16-2.03(m,2H). LC-MS: Rt = 3.92 min; MS m / z [M+H] + 441.1;UPLC-MS 6.

[0215] The following salts were prepared from the above free base form of (S)-8'-(difluoromethoxy)-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] by precipitation with the appropriate counterion:

[0216] A 1:1 stoichiometry of the hydrochloride salt (mw 476.76), mp (DSC) 58.3 °C (start): The free base (50.12 mg, 114 μmol) was placed in a 2 mL glass vial, EtOAc (100 μL) was added, and the clear yellow solution was stirred at RT. Hydrochloric acid (1 N, 114 μL) was then added at RT, and the solution was stirred at RT for 18 h. Heptane (500 μL) was then added to the solution at RT, resulting in precipitation within 10 min of addition. The suspension was stirred at RT for 2 h, the solid was separated by centrifugation, and the powder was dried under vacuum at 40 °C for 18 h to give the title compound.

[0217] Example 45: (S)-8'-(Difluoromethoxy)-7,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] A solution of (S)-(4-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)-7,8-difluorochroman-4-yl)methanol (Intermediate BC, 2.7 g, 6.33 mmol) and thionyl chloride (0.93 mL, 12.7 mmol) in toluene (38 mL) was stirred at 80 °C for 1 h. The cooled RM was quenched by the addition of MeOH and evaporated. The residue was diluted with DCM, washed with saturated aqueous NaHCO, dried (phase separator), and evaporated. The crude residue was purified by normal phase flash chromatography (120 g SiO column; eluent c-hexane:EtOAc 100:0 to 75:25) to give the title compound as a yellow foam. 1 H NMR(600MHz,DMSO-d6)δ 7.99(br,s,1H),7.37(t,1H),7.15-7.09(m,1H),7.04(d,1H),6.97-6.89(m ,1H),4.49-4.45(m,1H),4.34-4.27(m,1H),4.26(s,2H),2.16-2.04(m,2H). LC-MS: Rt = 3.12 min; MS m / z [M+H] + 409.2;UPLC-MS 6.

[0218] The following salts were prepared from the above free base form of (S)-8'-(difluoromethoxy)-7,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] by precipitation with the appropriate counterion:

[0219] A 1:1 stoichiometry of the hydrochloride salt (mw 444.76), mp (DSC) 67°C (start):free base (44.24 mg, 108 μmol) was placed in a 2 mL glass vial, tBuOMe (500 μL) was added, and the mixture was stirred at 55°C to give a clear yellow solution. Hydrochloric acid (1 N, 108 μL) was added at 55°C, and the solution was stirred at 55°C for 4 hours, followed by stirring at RT for 18 hours. Heptane (200 μL) was then added, and the clear solution was evaporated to give a glass. Heptane (200 μL) was added again to the glass, and the mixture was stirred at RT for 24 hours, resulting in the formation of a slurry. The slurry was centrifuged, and the solid was dried under vacuum at 40°C for 18 hours to give the title compound.

[0220] Example 46: (S)-8'-(Difluoromethoxy)-8-fluoro-7-methyl-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] (S)-7-Bromo-8'-(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] (Example 39, 100 mg, 0.21 mmol), trimethylboroxine (26.8 mg, 0.21 mmol), tBuOK (71.8 mg, 0.64 mmol), XPhos-Pd-G3 (18.0 mg, 0.021 mmol), THF (2 mL), and water (1 mL) were added to a microwave vial, purged with argon, sealed, and stirred at 100 °C under microwave heating for 1.5 h. The RM was poured into saturated aqueous NaHCO3 and extracted twice with EtOAc. The combined organic extracts were dried (phase separator) and evaporated. The crude material was dissolved in THF (3 mL), SiliaMetS® thiol (particle size: 40-63 μm, loading 1.39 mmol / g, 0.085 mmol, 64 mg) was added, and the mixture was vortexed at 40 °C for 1 h. The mixture was filtered, and the filtrate was evaporated. The crude residue was purified by reverse-phase preparative HPLC (RP-HPLC 3), and the product-containing fractions were lyophilized to give the title compound. 1H NMR(400MHz,DMSO-d6)δ 7.97(br,s,1H),7.37(t,1H),7.01(br s,1H),6.93(d,1H),6.75(t,1H),4.40(m,1H),4.24(s,2H),4.22(m,1H),2.19(s,3H),2.09-2.05(m,2H). LC-MS: Rt = 3.37 min; MS m / z [M+H] + 405.1;UPLC-MS 6.

[0221] Example 47: (S)-8'-(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] Pd—C (5%, 75 mg, 0.71 mmol) was added to a solution of (S)-7-bromo-8′-(difluoromethoxy)-8-fluoro-6′-(trifluoromethyl)-3′H-spiro[chroman-4,2′-imidazo[1,2-α]pyridine] (Example 39, 600 mg, 1.28 mmol) in THF (15 mL) and MeOH (15 mL), and the mixture was shaken under a hydrogen atmosphere at RT for 3 h. The RM was filtered through a pad of Celite, washed with MeOH, the filtrate was evaporated, and the crude residue was purified by normal-phase chromatography (80 g SiO column, eluent DCM:MeOH 100:0 to 70:30) followed by reverse-phase preparative HPLC (RP-HPLC 3). The product-containing fractions were extracted with DCM and evaporated to give the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.97(br,s,1H),7.37(t,1H),7.13-7.05(m,2H),7.02(d,1H),6.89-6.81(m,1H),4.45-4.37(m,1H),4.30-4.19(m,3H),2.14-2.06(m,2H). LC-MS: Rt = 2.85 min; MS m / z [M+H] + 391.1;UPLC-MS 6.

[0222] Example 48: (S)-8-Chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] A mixture of (S)-(4-amino-8-chlorochroman-4-yl)methanol (Intermediate BE, 423 mg, 1.98 mmol), 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (Intermediate A, 1.00 g, 4.05 mmol), CuBr (113 mg, 791 μmol), and KPO (839 mg, 3.95 mmol) in DMF (5 mL) was heated at 140° C. for 90 min in a sealed vial under a N atmosphere. To the cooled RM was added additional 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (1.00 g, 4.05 mmol), CuBr (113 mg, 791 μmol), and KPO (839 mg, 3.95 mmol), and heating was continued at 140° C. for an additional 90 min. The RM was partitioned between EtOAc and saturated aqueous NaHCO3, extracted twice with EtOAc, dried, and evaporated. The residue was purified by normal-phase chromatography (50 g SNAP SiO2 cartridge, eluent hexane:EtOAc 100:0 to 65:35) and then reverse-phase chromatography (RP-HPLC 2). The product-containing fractions were evaporated to leave the main aqueous phase, which was basified with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was dried and evaporated to give the title compound as a yellow foam. 1 H NMR(400MHz,DMSO-d6)δ 7.97(s,1H),7.34-7.19(m,2H),7.61-7.14(m,1H),7.02(d,1H),6.90(t,1H),4.55-4.38(m,1H),4.35-4.20(m,3H),2.17-2.00(m,2H). LC-MS: Rt = 3.10 min; MS m / z [M+H] + 407.2 / 409.2;UPLC-MS 4.

[0223] Example 49: (S)-7-Bromo-8'-(difluoromethoxy)-8-fluoro-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]-6'-carbonitrile [ka] A solution of (S)-(4-amino-7-bromo-8-fluorochroman-4-yl)methanol (Intermediate AT, 200 mg, 0.72 mmol), 6-chloro-5-(difluoromethoxy)nicotinonitrile (Intermediate B, 326 mg, 1.59 mmol), copper(I) bromide (31.2 mg, 0.22 mmol), and potassium phosphate (308 mg, 1.45 mmol) in DMF (4.8 mL) was heated in a microwave at 120 °C for 1.5 h. The RM was poured into saturated aqueous NaHCO3 and extracted three times with EtOAc. The combined organic extracts were washed twice with water, dried (phase separator), and concentrated. The residue was dissolved in THF (3 mL), and SiliaMetS® thiol (particle size: 40–63 μm, loading 1.35 mmol / g, 0.087 mmol, 64 mg) was added, and the mixture was vortexed at 40 °C for 1 h. The mixture was filtered and the filtrate was evaporated. The crude residue was purified by normal phase flash chromatography (40 g SiO2 column, eluent EtOAc:c-hexane 0:100 to 50:50) to give the title compound as a yellow foam. 1 H NMR(600MHz,DMSO-d6)δ 8.21(d,1H),7.28(t,1H),7.19-7.15(m,1H),7.11(d,1H),7.05(dd,1H) ,4.48-4.43(m,1H),4.33-4.27(m,1H),4.27(s,2H),2.19-2.05(m,2H). LC-MS: Rt = 3.34 min; MS m / z [M+H] + 426.1 / 428.1;UPLC-MS 6.

[0224] Example 50: (S)-7-Bromo-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] SOCl2 (0.15 mL, 2.06 mmol) was added to (S)-(7-bromo-4-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)chroman-4-yl)methanol (Intermediate BF, 615 mg, 1.11 mmol) in toluene (10 mL) under Ar. The RM was heated to 80 °C for 1 h, cooled, then quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (80 g SiO2 column; eluent heptane:EtOAc 100:0 to 70:30). Product-containing fractions were combined and evaporated to give a yellow foam. The product was dissolved in iPrOH (12 mL) and stirred at 80° C. for 5 min, then the solution was allowed to cool to RT and stirred for 5 days to recrystallize. The crystals were isolated by filtration, washed with iPrOH, and then dried to give the title compound as yellow crystals. 1 H NMR(400MHz,DMSO-d6)δ 7.96(s,1H),7.36(t,2H),7.20(d,1H),7.07(dd,1H),7.04-6.97(m,2H) ,4.44-4.31(m,1H),4.23(s,2H),4.21-4.13(m,1H),2.11-1.98(m,2H). LC-MS: Rt = 0.79 min; MS m / z [M+H] + 451.1 / 453.1;UPLC-MS 1.

[0225] Example 51: (S)-8'-(Difluoromethoxy)-8-fluoro-7-iodo-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]-6'-carbonitrile [ka] A mixture of (S)-7-bromo-8'-(difluoromethoxy)-8-fluoro-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]-6'-carbonitrile (Example 49, 232 mg, 544 μmol), CuI (52 mg, 272 mmol), NaI (163 mg, 1.09 mmol), and trans-N,N'-dimethyl-1,2-cyclohexanediamine (8.6 μL, 54 μmol) in 1,4-dioxane (2 mL) was heated in a sealed tube under a nitrogen atmosphere at 110 °C for 18 h. The cooled RM was partitioned between DCM and 30% aqueous NH3, the aqueous phase was extracted three times with DCM, and the combined organic phases were dried by passing through a separatory cartridge and concentrated. The residue was purified by reverse phase chromatography (RP-HPLC 2) and the product-containing fractions were lyophilized and then triturated with MeOH to afford the title compound as a yellow powder. 1 H NMR(400MHz,MeOH-d4)δ 7.95(s,1H),7.29(dd,1H),7.01(s,1H),6.86(d,1H),7.20-6.71(m,1H),4.56-4.42(m,1H),4.41-4.22(m,3H),2.33-2.06(m,2H). LC-MS: Rt = 3.45 min; MS m / z [M+H] + 474.1;UPLC-MS 4.

[0226] Example 52: (S)-7-Bromo-6'-chloro-8'-(difluoromethoxy)-8-fluoro-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] A mixture of (S)-(4-amino-7-bromo-8-fluorochroman-4-yl)methanol (Intermediate AT, 100 mg, 0.36 mmol), 2-bromo-5-chloro-3-(difluoromethoxy)pyridine (Intermediate F, 186 mg, 0.72 mmol), CuBr (15.6 mg, 0.11 mmol), and potassium phosphate (154 mg, 0.72 mmol) in DMF (3.6 mL) was heated in a microwave at 140 °C for 4 h. The RM was poured into saturated aqueous NaHCO3 and extracted three times with EtOAc. The combined organic extracts were dried (phase separator) and concentrated. The crude material was dissolved in THF (5 mL), SiliaMetS® thiol (particle size: 40-63 μm, loading 1.35 mmol / g, 0.44 mmol, 323 mg) was added, the mixture was vortexed at 40 °C for 1 h, filtered, and the filtrate was evaporated. The crude residue was purified by normal-phase flash chromatography (12 g SiO column, eluent c-hexane:EtOAc 100:0 to 50:50) followed by reverse-phase preparative HPLC (RP-HPLC 2), and the product-containing fractions were purified by filtration with saturated NaHCO. 33 Basified with aqueous solution and extracted with DCM, the organic layer was dried and evaporated to give the title compound as a yellow solid. 1 H NMR(600MHz,DMSO-d6)δ 7.60(br,s,1H),7.36(t,1H),7.16(dd,1H),7.04(d,1H),6.98(br,s,1H),4.45(m,1H),4.29(m,1H),4.20(s,2H),2.12-2.03(m,2H). LC-MS: Rt = 3.20 min; MS m / z [M+H] + 435.1 / 437.1;UPLC-MS 6.

[0227] Example 53: (S)-8'-chloro-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] To a solution of (4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-7-(trifluoromethyl)chroman-4-yl)methanol (Intermediate P2, 57 mg, 135 μmol) in toluene (2 mL) was added thionyl chloride (0.05 mL, 0.67 mmol) and the RM was stirred at 80 °C for 2.5 h. The RM was allowed to cool to RT, poured into saturated aqueous NaHCO and extracted three times with DCM. The combined organic extracts were dried (Phase separator) and concentrated. The crude residue was purified by reverse-phase preparative HPLC (RP-HPLC 2), the product-containing fractions were basified with saturated aqueous NaHCO and extracted with DCM, and the organic layer was dried (Phase separator) and evaporated to give the racemic title compound. The enantiomers were separated by preparative chiral HPLC (instrument: Gilson PLC2020; column: Chiralpak ID; 5 μm, 250 × 20 mm, RT; eluent: heptane / EtOH 80 / 20 + 0.1% EtNH; flow rate: 10 mL / min; detection: 250 nm; injection volume: 1.5 mL) to give the title compound as the second eluting peak (yellow solid). 1 H NMR(600MHz,DMSO-d6)δ 8.08(br,s,1H),7.53(d,1H),7.48(d,1H),7.24(dd,1H),7.12(d,1H),4.44- 4.39(m,1H),4.37(d,1H),4.33(d,1H),4.27-4.22(m,1H),2.18-2.05(m,2H). LC-MS: Rt = 3.68 min; MS m / z [M+H] + 409.2 / 411.2;UPLC-MS 6. Chiral-HPLC: Rt = 9.99 min; (R)-8'-chloro-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] eluted as the first peak, Chiral-HPLC: Rt = 3.95 min; (C-HPLC 28).

[0228] Example 54: (S)-7,8'-Bis(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] To a solution of (S)-8'-(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridin]-7-ol (Intermediate BI, 20 mg, 46 μmol) and KOH (52 mg, 925 μmol) in a mixture of AcCN (1 mL) and water (1 mL) was added diethyl(bromodifluoromethyl)phosphonate (37.1 mg, 139 μmol), and the RM was stirred at RT for 30 min. The RM was then extracted with EtOAc, and the combined organic layers were washed with brine, filtered through a phase separator, and the filtrate was evaporated. The residue was purified by reverse-phase chromatography (RP-HPLC 2). The product-containing fractions were combined and partitioned between DCM and saturated aqueous NaHCO3. The combined organic layers were filtered through a phase separator, and the filtrate was evaporated. The residue was absorbed onto Isolute and re-purified by normal phase chromatography (4 g SiO2-column; eluent DCM:MeOH 100:0 to 80:20). The product-containing fractions were combined, evaporated and dried to give the title compound. 1 H NMR(600MHz,DMSO-d6)δ 7.99(s,1H),7.52-7.32(m,1H),7.24(d,1H),7.17-7.08(m,1H),7.05(d ,1H),6.88(t,1H),4.47(ddd,1H),4.33-4.23(m,3H),2.18-2.05(m,2H). LC-MS: Rt = 0.84 min; MS m / z [M+H] + 457.2;UPLC-MS 1.

[0229] Example 55: (S)-8'-(Difluoromethoxy)-8-(difluoromethyl)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] DAST (20 μL, 148 μmol) was added to a solution of (S)-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]-8-carbaldehyde (Intermediate BJ, 40 mg, 74 μmol) in DCM (1 mL) at RT and stirred for 16 h. Additional DAST (10 μL, 74 μmol) was added, and the RM was stirred at RT for 5 days. The RM was then partitioned between DCM (20 mL) and saturated aqueous NaHCO (20 mL), extracted twice with DCM (5 mL), and the combined organic layers were dried by passing through a phase separator cartridge and evaporated. The residue was purified by normal-phase chromatography (4 g SiO column, eluent hexane:TBME 90:10 to 10:90) to give the title compound as a beige solid. 1 H NMR (400 MHz, chloroform-d) δ 7.52-7.42 (m, 2H), 7.30-7.21 (m, 1H), 7.04-6.72 (m, 4H), 4.61-4.56 (m, 1H), 4.40-4.21 (m, 3H), 2.45-2.36 (m, 1H), 2.21-2.08 (m, 1H). LC-MS: Rt = 0.78 min; MS m / z [M+H] + 423.2;UPLC-MS 1.

[0230] Example 56: (S)-8'-chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-pyrano[2,3-c]pyridine] [ka] A mixture of (S)-8'-chloro-3-(3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)-2',3'-dihydrospiro[oxazolidine-4,4'-pyrano[2,3-c]pyridin]-2-one (Intermediate BK, 408 mg, 813 μmol), aqueous NaOH (4 M, 2.03 mL, 8.13 mmol), and EtOH (10 mL) was stirred at 80 °C for 20 min. The cooled RM was extracted with EtOAc, washed with saturated aqueous NaHCO, dried, and concentrated. The residue was taken up in toluene (10 mL), SOCl (89 μL, 1.22 mmol) was added, and the RM was stirred at 80 °C for 20 min. MeOH was added to the cooled RM, which was concentrated and partitioned between EtOAc and saturated aqueous NaHCO, and the combined organic layers were dried and concentrated. The residue was purified by reverse phase chromatography (RP-HPLC 2), and the product-containing fractions were combined and evaporated. The residue was partitioned between DCM and saturated aqueous NaHCO3, and the combined organic layers were dried and concentrated to give the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.03(s,br,1H),7.93(d,1H),7.61-6.96(m,3H),4.56-4.46(m,1H),4.39-4.20(m,3H),2.24-2.05(m,br,2H). LC-MS: Rt = 2.42 min; MS m / z [M+H] + 408.1 / 410.1;UPLC-MS 4.

[0231] Example 57: (2'S,3R)-7-Bromo-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] A mixture of ((3R,4S)-4-amino-7-bromo-3,8-difluorochroman-4-yl)methanol (Intermediate BO, 273 mg, 928 μmol), 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (Intermediate A, 306 mg, 1.11 mmol), CuBr (53 mg, 371 μmol), KPO (394 mg, 1.86 mmol) and DMF (1.5 mL) was sealed in a vial under a N atmosphere and heated in a microwave at 140 °C for 90 min. The cooled RM was partitioned between saturated aqueous NaHCO and EtOAc, and the combined organic layers were dried and concentrated. Additional 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (306 mg, 1.11 mmol), CuBr (53 mg, 371 μmol), KPO (394 mg, 1.86 mmol), and DMF (1.5 mL) were added, and the mixture was sealed in a vial under a N atmosphere and heated in a microwave at 140 °C for an additional 90 min. The cooled RM was partitioned between saturated aqueous NaHCO and EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by normal-phase chromatography (50 g SiO SNAP cartridge, eluent hexane:(95:5 TBME:MeOH) 100:0 to 65:35) followed by reverse-phase chromatography (RP-HPLC 3). Product-containing fractions were extracted with DCM, and the combined organic layers were dried and concentrated. The residue was taken up in MeOH and the volume reduced to crystallize the title compound as a yellow solid which was collected by filtration. 1 H NMR(400MHz,DMSO-d6)δ 7.98(s,1H),7.63-7.17(m,2H),7.16-6.97(m,2H),5.23-4.93(m,1H),4.73-4.53(m,1H),4.51-4.33(m,1H),4.33-4.08(m,2H). LC-MS: Rt = 3.83 min; MS m / z [M+H] + 487.1 / 489.0;UPLC-MS 4.

[0232] Example 58: (2'S,3S)-7-Bromo-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] The title compound was prepared by a method similar to that of Example 57 by substituting ((3R,4S)-4-amino-7-bromo-3,8-difluorochroman-4-yl)methanol (Intermediate BO) with ((3S,4S)-4-amino-7-bromo-3,8-difluorochroman-4-yl)methanol (Intermediate BU). After normal phase chromatography (25 g SiO SNAP cartridge, eluent hexane:EtOAc 100:0 to 80:20), the title compound was obtained as a pale orange powder. 1 H NMR(400MHz,DMSO-d6)δ 8.10(br,s,1H),7.57-7.11(m,4H),5.12-4.85(m,1H),4.69-4.35(m,4H).LC-MS:Rt=5.20min;MS m / z[M+H] + 487.1 / 489.0;UPLC-MS 4.

[0233] Example 59: (2'S,3R)-7-Bromo-8'-(difluoromethoxy)-3-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] The title compound was prepared by a method similar to that of Example 57, by substituting ((3R,4S)-4-amino-7-bromo-3,8-difluorochroman-4-yl)methanol (Intermediate BV) for ((3R,4S)-4-amino-7-bromo-3-fluorochroman-4-yl)methanol (Intermediate BV). After normal phase chromatography (50 g silica SNAP column, eluent hexane:EtOAc 100:0 to 80:20), the title compound was obtained as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.97(s,1H),7.63-7.17(m,2H),7.16-7.11(m,1H),7.08(dd,2H),5.14-4.89(m,1H),4.59-4.42(m,1H),4.40-4.14(m,3H). LC-MS: Rt = 3.42 min; MS m / z [M+H] + 469.0 / 471.0;UPLC-MS 4.

[0234] Example 60: (2'S,3R)-8'-(difluoromethoxy)-3-fluoro-7-iodo-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] The title compound was prepared by a method similar to that of Example 51, by substituting (2'S,3R)-7-bromo-8'-(difluoromethoxy)-3-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] (Example 59) for (S)-7-bromo-8'-(difluoromethoxy)-8-fluoro-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] (Example 49). After trituration with MeOH, the title compound was obtained as a yellow powder. 1H NMR(400MHz,DMSO-d6)δ 7.96(br,s,1H),7.66-7.14(m,3H),7.12-6.92(m,2H),5.14-4.85(m,1H),4.47-4.34(m,1H),4.38-4.10(m,3H). LC-MS: Rt = 3.69 min; MS m / z [M+H] + 517.0;UPLC-MS 4.

[0235] Example 61: (2'S,3R)-8'-(difluoromethoxy)-3-fluoro-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] The title compound was prepared by a method similar to that of Example 40 by replacing (S)-8'-(difluoromethoxy)-8-fluoro-7-iodo-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] (Intermediate AW) with (2'S,3R)-8'-(difluoromethoxy)-3-fluoro-7-iodo-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] (Example 60). After normal phase chromatography (40 g SiO2 Redisep cartridge, eluent hexane:TBME 100:0 to 0:100) followed by reverse phase chromatography (RP-HPLC 2), partitioning of the product-containing fractions between DCM and saturated aqueous NaHCO3, extracting twice with DCM, drying the combined organic layers by passing through a phase separator cartridge, and evaporation, the title compound was obtained as yellow needles. 1 H NMR(400MHz,DMSO-d6)δ 7.98(s,1H),7.61-7.21(m,4H),7.12(s,1H),5.21-4.93(m,1H),4.65-4.48(m,1H),4.46-4.15(m,3H). LC-MS: Rt = 4.06 min; MS m / z [M+H] +459.1;UPLC-MS 4.

[0236] Example 62: (2'S,3R)-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] A mixture of ((3R,4S)-4-amino-3,8-difluorochroman-4-yl)methanol (Intermediate BW, 5.0 g, 22.77 mmol), 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (Intermediate A, 11.27 g, 45.5 mmol), CuBr (1.31 g, 9.11 mmol), and KPO (9.67 g, 45.5 mmol) in DMF (24 mL) was heated in a sealed vial under an argon atmosphere at 140 °C for 1.5 h. The cooled RM was filtered and washed with EtOAc (150 mL), and the filtrate was washed with saturated aqueous NaHCO, dried, and concentrated. Additional 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (11.27 g, 45.5 mmol), CuBr (1.31 g, 9.11 mmol), KPO (9.67 g, 45.5 mmol), and DMF (5 mL) were added to the residue, and the mixture was heated in a sealed vial at 140 °C under argon for 1.5 h. The cooled RM was filtered and washed with EtOAc (150 mL), and the filtrate was washed with saturated aqueous NaHCO, dried, and concentrated. The residue was purified by normal-phase chromatography (340 g silica gel, eluent c-hexane:EtOAc 100:0 to 70:30). Product-containing fractions were combined and evaporated, and the residue was taken up in 1 N aqueous HCl. The aqueous layer was washed with EtOAc and three additional times with EtOAc. The acidic aqueous layer was made basic with saturated aqueous NaHCO3 (pH 8) and extracted three times with DCM, and the combined DCM layers were dried and evaporated. The residue was then taken up in a minimum amount of MeOH, and the solution was slowly evaporated on a rotary evaporator until the first solid material precipitated. The solution was then left to stand at RT for 3 hours, and the formed precipitate was collected by filtration and dried to obtain the title compound as a pale yellow powder. 1 H NMR(400MHz,DMSO-d6)δ 7.98(s,1H),7.40(t,1H),7.19(t,1H),7.11(s,1H),7.07(d,1H),6.97-6.89(m,1H),5.08(dd,1H),4.62-4.53(m,1H),4.42-4.22(m,3H). LC-MS: Rt = 0.67 min; MS m / z [M+H] +409.0;UPLC-MS 1.

[0237] The following salts were prepared from the above free base form of (2'S,3R)-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] by precipitation with the appropriate counterion:

[0238] A 1:1 stoichiometry of hydrochloride salt (mw 444.76):free base (50.8 mg, 124 μmol) was placed in a 2 mL glass vial, tBuOMe (1 mL) was added, and the clear solution was stirred at 55° C. Hydrochloric acid (1 N, 124 μL) was then added slowly at 55° C., and the solution slowly became a suspension. Stirring was continued at 55° C. for 4 h and then at RT for 18 h, the solid was separated by centrifugation, and the powder was dried under vacuum at 40° C. for 18 h to give the title compound.

[0239] A 1:1 stoichiometric iPrOH solvate of the sulfate salt (1:1) (mw 506.38), mp (DSC) broad endothermic transition 147 °C and 206 °C (onset): The free base (50.74 mg, 124 μmol) was placed in a 2 mL glass vial and iPrOH (1.2 mL) was added. Hydrochloric acid (1 N, 124 μL) was then added at 55 °C, and the solution was stirred at 55 °C for 4 h and then at RT for 18 h to allow precipitation. The solid was isolated by centrifugation, and the powder was dried under vacuum at 40 °C for 18 h to give the title compound.

[0240] 1:1 stoichiometric AcCN solvate of the citrate salt (1:1) (mw 600.42), mp (DSC) broad endothermic transition 140°C and 176°C (onset): The free base (51.84 mg, 126 μmol) was placed in a 2 mL glass vial and AcCN (0.6 mL) was added. Citric acid (24.4 mg, 127 μmol) was then added at 55°C, and the slurry was stirred at 55°C for 4 hours and then at RT for 18 hours. The solid was isolated by centrifugation, and the powder was dried under vacuum at 40°C for 18 hours to give the title compound.

[0241] Example 63: (S)-8-(Difluoromethoxy)-8'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isochroman] [ka] To a solution of rac-(4-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)-8-fluoroisochroman-4-yl)methanol (Intermediate BZ, 598 mg, 1.39 mmol) in toluene (9 mL) was added thionyl chloride (0.20 mL, 2.78 mmol), and the RM was stirred at 80 °C for 1 h. The RM was quenched by the addition of saturated aqueous NaHCO and extracted twice with EtOAc. The combined organic extracts were dried (phase separator), evaporated, and the crude residue was purified by normal-phase flash chromatography (80 g silica column, eluent c-hexane:EtOAc 100:0 to 50:50) to give the racemic title compound. The enantiomers were separated by preparative chiral HPLC (instrument: Gilson Trilution HPLC system; column: Chiralcel OJ-H; 5 μm, 250 × 30 mm, RT; eluent: heptane / iPrOH 70 / 30 + 0.1% EtNH; flow rate: 20 mL / min; detection: 230 nm; injection volume: 1.5 mL) to give the title compound as the second eluting peak (yellow solid). 1 H NMR(600MHz,DMSO-d6)δ 7.97(br s,1H),7.36(t,1H),7.33(m,1H),7.21(d,1H),7.11(t,1H),7.07(br s,1H),4.75(d,1H),4.87(d,1H),4.43(d,1H),4.00(d,1H),3.86(d,1H),3.58(d,1H). LC-MS: Rt = 2.85 min; MS m / z [M+H] + 391.1;UPLC-MS 6. Chiral-HPLC: Rt = 7.37 min; ((R)-8-(difluoromethoxy)-8'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isochroman] was obtained as the first eluting peak, Rt = 5.89 min; (C-HPLC 29).

[0242] Example 64: (S)-7'-chloro-8-(difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile [ka] Cs2CO3 (1.15 g, 3.54 mmol) was added to a suspension of 6-(7'-chloro-8'-fluoro-2-oxospiro[oxazolidine-4,4'-thiochroman]-3-yl)-5-(difluoromethoxy)nicotinonitrile (Intermediate CA, 3.43 g, 5.90 mmol) in MeOH (113 mL), and the RM was stirred at 90 °C for 2 h. The RM was cooled to RT and extracted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3, dried on a phase separator, and concentrated in vacuo. The residue was dissolved in toluene (113 mL), SOCl2 (1.29 mL, 17.70 mmol) was added, and the resulting mixture was stirred at 90 °C for 1 h. The RM was cooled to RT, MeOH was added slowly, and the resulting mixture was concentrated in vacuo. The residue was taken up in EtOAc, washed with saturated aqueous NaHCO3, dried on a phase separator, and concentrated. The residue was purified by flash column chromatography (silica gel, eluent heptane:EtOAc 100:0 to 30:70) to give the racemic title compound. The enantiomers were separated by chiral SFC: (Instrument: MG II preparative SFC; Column: Chiralpak AD, 250 × 30 mm 5 μm at 38 °C; Eluent: CO2:EtOH with 0.1% aqueous NH3; Gradient: 35% EtOH with 0.1% CO2; Flow rate: 50 mL / min; Detection: 220 nm) to give the title compound as the second eluting peak. 1H NMR(400MHz,DMSO-d6)δ 8.16(s,1H),7.50-7.15(m,3H),7.10(s,1H),4.36-4.08(m,2H),3.26-3.08(m,2H),2.30-2.01(m,2H). LC-MS: Rt = 3.78 min; MS m / z [M+H] + 398.0;UPLC-MS 4. Chiral-SFC: Rt = 5.28 min; (R)-7'-chloro-8-(difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile was obtained as the first eluting peak, Rt = 4.83 min; C-SFC 30.

[0243] Example 65: (S)-8-(Difluoromethoxy)-8'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman] [ka] (4-Amino-8-fluorothiochroman-4-yl)methanol (Intermediate CE, 100 mg, 445 μmol), 2-bromo-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (Intermediate CC, 199 mg, 668 μmol), KCO (123 mg, 891 μmol), and CuI (8.48 mg, 45 μmol) were dissolved in DMF (2.6 mL). The resulting green suspension was irradiated in a microwave oven at 160 °C for 30 min. The cooled RM was diluted with EtOAc, and the organic phase was washed with saturated aqueous NaHCO and brine, filtered through a phase separator, and concentrated. The residue was purified by normal phase chromatography (silica gel, eluent heptane:EtOAc) to give the racemic title compound. The enantiomers were separated by chiral HPLC: (Instrument: Gilson PLC2020 HPLC system; Column: Chiralcel OD-H; 5 μm 250 × 20 mm at 25 °C; Eluent: Heptane: Isopropanol = 80:20 + 0.1% EtNH; Flow rate: 10 mL / min; Detection: 250 nm) to give the title compound as a yellow powder, the second eluting peak. 1 H NMR(600MHz,DMSO-d6)δ 7.94(d,1H),7.38(ddd,1H),7.17(d,1H),7.14-7.06(m,2H),7.04(d,1H),4.30-4.12(m,2H),3.25-3.01(m,2H),2.25-2.05(m,2H). LC-MS: Rt = 3.20 min; MS m / z [M+H] + 407.1;UPLC-MS 4. Chiral-HPLC: Rt = 11.52 min; (R)-8-(difluoromethoxy)-8'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman was obtained as the first eluting peak, Rt = 6.10 min; C-HPLC 31.

[0244] Example 66: (S)-8-(Difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile [ka] (S)-5-(Difluoromethoxy)-6-(8'-fluoro-2-oxospiro[oxazolidine-4,4'-thiochroman]-3-yl)nicotinonitrile (Intermediate CD, 4.11 g, 9.99 mmol) was dissolved in MeOH (75 mL) to give a clear yellow solution, which was placed in two microwave vials. To each vial was added CsCO (976 mg, 2 × 2.99 mmol). The vials were sealed, heated to 90 °C, and stirred at this temperature for 60 min. The RM was cooled to RT, diluted with EtOAc (300 mL) and water (100 mL), and the phases were separated. The aqueous phase was extracted with EtOAc (2 × 200 mL), and the combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was dissolved in toluene (75 mL) and SOCl (2.5 mL, 35.0 mmol) was added to give a yellow slurry, which was stirred at 90 °C for 15 min. The cooled RM was quenched by adding saturated aqueous NaHCO. The mixture was then extracted twice with EtOAc, and the combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by normal phase chromatography on (silica gel, eluent heptane: EtOAc) to provide the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.14(d,1H),7.28(t,1H),7.17-7.02(m,4H),4.25(d,1H),4.16(d,1H),3. 21-3.13(m,1H),3.12-3.03(m,1H),2.21-2.15(m,1H),2.14-2.07(m,1H). LC-MS: Rt = 0.72 min; MS m / z [M+H] + 364.2;UPLC-MS 1.

[0245] Example 67: (S)-8-(Difluoromethoxy)-8'-fluoro-6,7'-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiopyrano[3,2-c]pyridine] [ka] SOCl (88 μL, 1.20 mmol) was added to a solution of (S)-(4-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)-8-fluoro-7-(trifluoromethyl)-3,4-dihydro-2H-thiopyrano[3,2-c]pyridin-4-yl)methanol (Intermediate CF, 66 mg, 120 μmol) in toluene (2 mL), and the RM was stirred at 80° C. for 1 h. The cooled RM was partitioned between saturated aqueous NaCO (20 mL) and DCM (20 mL), extracted with DCM (20 mL), and the combined organic layers were washed with brine (20 mL), dried, and evaporated. The residue was dissolved in EtOAc and adsorbed onto Isolute for normal phase purification (12 g SiO2 column, eluent hexane:(TBME:MeOH 95:5) 90:10 to 50:50) to give the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.47(s,1H),7.97(s,1H),7.34(t,1H),7.08(s,1H),4.31(dd,2H),3.34 -3.26(m,1H),3.23-3.16(m,1H),2.24-2.17(m,1H),2.16-2.09(m,1H). LC-MS: Rt = 0.97 min; MS m / z [M+H] + 476.1;UPLC-MS 1.

[0246] Example 68: (S)-8-(Difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isothiochroman]-6-carbonitrile [ka] (4-Amino-8-fluoroisothiochroman-4-yl)methanol (Intermediate CG, 50 mg, 232 μmol), 6-chloro-5-(difluoromethoxy)nicotinonitrile (Intermediate B, 99 mg, 348 μmol), KPO (99 mg, 464 μmol), and CuI (4.42 mg, 23 μmol) were suspended in DMF (1.37 mL). The brown suspension was then irradiated in a microwave oven at 160 °C for 30 min. EtOAc was added to the cooled RM, and the organic phase was washed with saturated aqueous NaHCO and brine, filtered over a phase separator, and concentrated. The residue was purified by normal phase chromatography (silica gel, eluent heptane:EtOAc 100:0 to 30:70, followed by a second purification with DCM:MeOH 100:0 to 90:10) to give the racemic title compound. The enantiomers were separated by chiral HPLC: (Instrument: Gilson PLC2020 HPLC system; Column: Chiralcel ID; 5 μm 250 × 20 mm at 25 °C; Eluent: Heptane:EtOH 80:20 + 0.1% EtNH; Flow rate: 10 mL / min; Detection: 220 nm) to give the title compound as a yellow powder, the second eluting peak. 1 H NMR(600MHz,DMSO-d6)δ 8.18(d,1H),7.44-7.07(m,5H),4.54(d,1H),4.04(d,1H),3.95(d,1H),3.65(d,1H),2.98(dd,1H),2.80(dd,1H). LC-MS: Rt = 2.84 min; MS m / z [M+H] + 364.1;UPLC-MS 4. Chiral-HPLC: Rt=10.82 min; (R)-8-(difluoromethoxy)-8′-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4′-isothiochroman]-6-carbonitrile was obtained as the first eluting peak, Rt=7.04 min; C-HPLC 33.

[0247] Example 69: (S)-8'-(difluoromethoxy)-9-fluoro-6'-(trifluoromethyl)-3,4-dihydro-2H,3'H-spiro[benzo[b]oxepin-5,2'-imidazo[1,2-α]pyridine] [ka] Aqueous NaOH (2 M, 20.18 mL, 40.4 mmol) was added to a solution of 3'-(3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)-9-fluoro-3,4-dihydro-2H-spiro[benzo[b]oxepin-5,4'-oxazolidin]-2'-one (Intermediate CH, 2.08 g, 4.04 mmol) in EtOH (42.9 mL), and the RM was stirred at 80 °C for 1 h. LC-MS analysis indicated the formation of the intermediate (5-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)-9-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)methanol). The RM was cooled to RT, diluted with the EtOAc phase, and the organic layer was washed with saturated aqueous NaHCO, dried on a phase separator, and concentrated. Toluene (43 mL) was added to the residue, followed by SOCl (2.95 mL, 40.4 mmol) and heating at 90 °C for 15 min. The cooled RM was quenched by the addition of MeOH and concentrated. The residue was taken up in EtOAc, washed with saturated aqueous NaHCO, dried on a phase separator, and concentrated. The residue was purified by normal-phase chromatography (silica gel, eluent heptane: EtOAc = 100:0 to 60:40) to give the racemic title compound. The enantiomers were separated by chiral HPLC: (Instrument: Gilson Trilution I system; Column: Chiralpak AD-H; 5 μm, 250 × 30 mm at 25 °C; Eluent: n-heptane (saturated with MeOH): EtOH 80:20 + 0.1% EtNH; Flow rate: 20 mL / min; Detection: 265 nm) to give the title compound as a yellow powder as the first eluting peak. 1H NMR(400MHz,DMSO-d6)δ 7.88(s,1H),7.48(t,1H),7.24(d,1H),7.15-7.11(m,1H),7.09-7.02(m,1H),7.01(s,1H),4.59(d,1H),4. 47-4.41(m,1H),3.96(d,1H),3.60-3.53(m,1H),2.26-2.18(m,1H),1.96-1.92(m,2H),1.82-1.76(m,1H). LC-MS:Rt=3.15min Broad peak;MS m / z[M+H] + 405.1;UPLC-MS 4. Chiral-HPLC: Rt = 3.06 min; (R)-8'-(difluoromethoxy)-9-fluoro-6'-(trifluoromethyl)-3,4-dihydro-2H,3'H-spiro[benzo[b]oxepin-5,2'-imidazo[1,2-α]pyridine] was obtained as the second eluting peak, Rt = 5.23 min; C-HPLC 37.

[0248] Example 70: (S)-8-(Difluoromethoxy)-1'-(difluoromethyl)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] [ka] DAST (58 μL, 436 μmol) was added to a stirred solution of (S)-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]-1'-carbaldehyde (Intermediate CI, 80 mg, 175 μmol) in DCM (1 mL) and cooled in an ice bath under positive Ar pressure. After 1 h at 0 °C, additional DAST (58 μL, 436 μmol) was added, and the RM was stirred at 0 °C for 1 h and then at RT for 1 h. The RM was partitioned between DCM and saturated aqueous NaHCO3, and the aqueous layer was extracted with DCM, dried by passing through a phase separator, and evaporated. The residue was purified by normal phase chromatography (12 g SiO2 cartridge, eluent heptane:EtOAc 90:10 to 0:100) to give the title compound as a yellow foam. 1 H NMR(400MHz,DMSO-d6)δ 8.83(d,1H),8.01(s,1H),7.70(d,1H),7.32(t,1H),7.24(t,1H),7.09(d,1H),4.35(dd,2H),2.73-2.40(m,2H),2.22-2.02(m,2H). LC-MS: Rt = 0.83 min; MS m / z [M+H] + 458.3;UPLC-MS 1.

[0249] The following examples were prepared using methods similar to those used to prepare Examples 1-70.

[0250] Example 71: (S)-5'-Bromo-4',8-dichloro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene] [ka] Prepared following procedures similar to those described in the preparation of Intermediate J, Steps 4A, K, P and Example 28. LC-MS: Rt=0.89 min; MS m / z [M+H] + 437.0 / 439.0 / 441.0;UPLC-MS 1.

[0251] Example 72: (S)-5'-Bromo-8-(difluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene] [ka] Prepared following a procedure similar to that described in the preparation of Intermediate A, AT, Step 2 and Example 4. LC-MS: Rt=0.83 min; MS m / z [M+H] + 434.9 / 436.9;UPLC-MS 1.

[0252] Example 73: (S)-8-(Difluoromethoxy)-5'-iodo-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]-6-carbonitrile [ka] Prepared following a procedure similar to that described in the preparation of Intermediate AT, Step 2B and Example 2. LC-MS: Rt=3.18 min; MS m / z [M+H] + 440.1;UPLC-MS 4.

[0253] Example 74: (S)-8-(Difluoromethoxy)-4'-fluoro-5',6-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene] [ka] Prepared according to procedures similar to those described in the preparation of Intermediate J, Steps 4A and 5A, Intermediates P, Q, AW and Examples 28, 40 and 3. LC-MS: Rt=0.87 min; MS m / z [M+H] + 443.2;UPLC-MS 1.

[0254] Example 75: (S)-8-(Difluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene] [ka] Intermediate A, AT, was prepared following a procedure similar to that described in the preparation of Step 2 and Example 4. LC-MS: Rt=0.71 min; MS m / z [M+H] + 357.0;UPLC-MS 1.

[0255] Example 76: (S)-5',8-Difluoro-6'-methoxy-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] Intermediate K, P, prepared according to procedures similar to those described in the preparation of Example 28 and general procedure Scheme 5. LC-MS: Rt=0.72 min; MS m / z [M+H] + 371.2;UPLC-MS 1.

[0256] Example 77: (S)-8-Fluoro-6,6'-bis(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] Prepared following procedures similar to those described in the preparation of Intermediate J, steps 1 and 2, Intermediate K, P and Example 16. LC-MS: Rt=0.83 min; MS m / z [M+H] + 391.2;UPLC-MS 1.

[0257] Example 78: rac-5',6',8-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] Prepared following procedures similar to those described in the preparation of Intermediate J, steps 1 and 2, Intermediate K, P and Example 16. LC-MS: Rt=0.74 min; MS m / z [M+H] + 359.2;UPLC-MS 1.

[0258] Example 79: (S)-8-Chloro-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] Prepared following procedures similar to those described in Intermediate AT, steps 1 and 2, preparation of Intermediate P and Example 28. LC-MS: Rt=0.72 min; MS m / z [M+H] + 357.2 / 359.1;UPLC-MS 1.

[0259] Example 80: (S)-6'-Bromo-5'-fluoro-8-methoxy-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] Intermediate K, P, prepared according to procedures similar to those described in the preparation of Example 28 and general procedure Scheme 5. LC-MS: Rt=0.84 min; MS m / z [M+H] + 431.2 / 433.2 UPLC-MS 2.

[0260] Example 81: rac-5'-bromo-8-(difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, J, steps 1 and 2, Intermediate K, P and Example 28. LC-MS: Rt=0.84 min; MS m / z [M+H] + 449.1 / 451.1;UPLC-MS 1.

[0261] Example 82: (S)-5'-chloro-8-(difluoromethoxy)-6'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, J, steps 1 and 2, Intermediate K, P and Example 28. LC-MS: Rt=0.89 min; MS m / z [M+H] + 423.2 / 425.2;UPLC-MS 1.

[0262] Example 83: (2S,3'R,4'R)-6'-Bromo-8-(difluoromethoxy)-3',4',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] Prepared according to procedures similar to those described in the preparation of Examples 10 and 24. LC-MS: Rt=0.91 min; MS m / z [M+H] + 503.1 / 505.1;UPLC-MS 1.

[0263] Example 84: (S)-8-(Difluoromethoxy)-5'-fluoro-6'-methoxy-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] Prepared following procedures similar to those described in the preparation of Intermediate K, P, Example 28 and General Procedure Scheme 5. LC-MS: Rt=0.80 min; MS m / z [M+H] + 419.2;UPLC-MS 1.

[0264] Example 85: (S)-8-(Difluoromethoxy)-5',6'-difluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, J, steps 1 and 2, K, P and Example 28. LC-MS: Rt=0.79 min; MS m / z [M+H] + 407.1;UPLC-MS 1.

[0265] Example 86: (S)-8-(Difluoromethoxy)-6,6'-bis(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] Prepared following procedures similar to those described in the preparation of Intermediates A, J, steps 1 and 2, K, O, Q and Examples 28 and 3. LC-MS: Rt=0.90 min; MS m / z [M+H] + 439.2;UPLC-MS 1.

[0266] Example 87: rac-8-(difluoromethoxy)-5',6-bis(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] Prepared according to procedures similar to those described in the preparation of Intermediate J, steps 1 and 2, K, O, Q and Examples 28 and 3. LC-MS: Rt=0.88 min; MS m / z [M+H] + 439.2;UPLC-MS 1.

[0267] Example 88: (S)-5'-chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] Prepared according to procedures similar to those described in the preparation of Intermediate J, steps 1 and 2, K, O, Q and Examples 3 and 28. LC-MS: Rt=0.84 min; MS m / z [M+H] + 405.2 / 407.2;UPLC-MS 1.

[0268] Example 89: (S)-6'-Bromo-6-chloro-8-(difluoromethoxy)-5'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] Prepared according to procedures similar to those described in the preparation of intermediates K, O, Q and examples 3 and 28. LC-MS: Rt=0.85 min; MS m / z [M+H] + 433.1 / 435.1 / 437.1;UPLC-MS 1.

[0269] Example 90: (S)-6'-Bromo-8-(difluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H,4'H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'-one [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, AQ, steps 1-4, K, Z, steps 1-3 and Example 23. LC-MS: Rt=3.32 min; MS m / z [M+H] + 463.2 / 465.2;UPLC-MS 4.

[0270] Example 91: (S)-8-(Difluoromethoxy)-5',6'-difluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile [ka] Prepared following procedures similar to those described in the preparation of Intermediate B, J, steps 1 and 2, K and Example 2. LC-MS: Rt=0.72 min; MS m / z [M+H] + 364.2;UPLC-MS 1.

[0271] Example 92: (S)-6'-Bromo-8-(difluoromethoxy)-4',4',5'-trifluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile [ka] Intermediate B, J, steps 1 and 2, K, Z, steps 1-3, G, prepared according to procedures similar to those described in the preparation of Examples 4 and 23. LC-MS: Rt=4.17 min; MS m / z [M+H] + 460.2 / 462.2;UPLC-MS 4.

[0272] Example 93: rac-8-(difluoromethoxy)-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] [ka] Prepared according to procedures similar to those described in the preparation of Intermediate A, K and Example 4. LC-MS: Rt=0.52 min; MS m / z [M+H] + 372.3;UPLC-MS 1.

[0273] Example 94: (S)-1'-chloro-8-(difluoromethoxy)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]-6-carbonitrile [ka] Prepared following procedures similar to those described in the preparation of Intermediate B, J, steps 1 and 2, K and Example 2. LC-MS: Rt=0.59 min; MS m / z [M+H] + 363.2;UPLC-MS 1.

[0274] Example 95: (S)-8-Chloro-8'-(fluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] Prepared following procedures similar to those described in the preparation of Intermediate E, J, steps 1 and 2, K and Example 4. LC-MS: Rt=0.70 min; MS m / z [M+H] + 389.1 / 391.2;UPLC-MS 1.

[0275] Example 96: (S)-8-Chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]-7-carbonitrile [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, AQ, steps 1-4, G, H, I and Example 28. LC-MS: Rt=0.82 min; MS m / z [M+H] + 432.1 / 434.1;UPLC-MS 1.

[0276] Example 97: (3R,4S)-7-chloro-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] Prepared following procedures similar to those described in the preparation of Intermediates A, AB, AQ, steps 1-4, K, G, H, I and Examples 9 and 28 and general procedure Scheme 5. LC-MS: Rt=0.84 min; MS m / z [M+H] + 443.1 / 445.0;UPLC-MS 1.

[0277] Example 98: (3R,4S)-8'-(difluoromethoxy)-3,7,8-trifluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] Prepared following procedures similar to those described in the preparation of Intermediates A, AB, AQ, steps 1-4, K and Examples 4 and 9. LC-MS: Rt=0.78 min; MS m / z [M+H] + 427.1;UPLC-MS 1.

[0278] Example 99: (S)-8'-(Difluoromethoxy)-8-fluoro-7-(methylthio)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] Prepared following procedures similar to those described in the preparation of Intermediates A, J, steps 1 and 2, K, AW, BH and Example 4. LC-MS: Rt=0.80 min; MS m / z [M+H] + 437.0;UPLC-MS 1.

[0279] Example 100: (S)-7-Bromo-8-chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, AQ, steps 1-4, K, G, H, I and Example 28. LC-MS: Rt=0.88 min; MS m / z [M+H] + 485.1 / 487.0 / 489.0;UPLC-MS 1.

[0280] Example 101: rac-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] Prepared following procedures similar to those described in the preparation of Intermediates A, AB, AQ, steps 1-4, K, G, H, I and Examples 9 and 28. LC-MS: Rt=0.71 min; MS m / z [M+H] + 409.2;UPLC-MS 1.

[0281] Example 102: (S)-7,8-Dibromo-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, AQ, steps 1-4, K, G, H, I and Example 28. LC-MS: Rt=0.89 min; MS m / z [M+H] + 529.0 / 531.0 / 533.0;UPLC-MS 1.

[0282] Example 103: (S)-8'-(difluoromethoxy)-8-fluoro-7-methoxy-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] Prepared according to procedures similar to those described in the preparation of Intermediate A, J, steps 1 and 2, K, Example 4 and General Procedure Scheme 5. LC-MS: Rt=0.71 min; MS m / z [M+H] + 421.2;UPLC-MS 1.

[0283] Example 104: (S)-8'-(difluoromethoxy)-6',8-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, J, steps 1 and 2, K and Example 28. LC-MS: Rt=3.79 min; MS m / z [M+H] + 441.2;UPLC-MS 4.

[0284] Example 105: (S)-8'-(difluoromethoxy)-8-fluoro-7-(trifluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, AQ, steps 1-4, K, G, H, I and Example 28. LC-MS: Rt=0.92 min; MS m / z [M+H] + 475.2;UPLC-MS 1.

[0285] Example 106: (S)-8'-(Difluoromethoxy)-7-((difluoromethyl)thio)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, AQ, steps 1-4, K, AW, L, steps 1 and 2 and Example 28. LC-MS: Rt=0.89 min; MS m / z [M+H] + 473.1;UPLC-MS 1.

[0286] Example 107: (S)-8-Bromo-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine] [ka] Prepared following procedures similar to those described in the preparation of Intermediates A, J, steps 1 and 2, K, G, H, I and Example 28. LC-MS: Rt=0.77 min; MS m / z [M+H] + 451.0 / 453.0;UPLC-MS 1.

[0287] Example 108: rac-8-(difluoromethoxy)-8'-fluoro-6,7'-bis(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isochroman] [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, BZ, steps 1-6, O and Example 28. LC-MS: Rt=0.97 min; MS m / z [M+H] + 459.1;UPLC-MS 1.

[0288] Example 109: (2S)-8-(Difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile-2',2',3'-d3 [ka] Prepared following procedures similar to those described in the preparation of Intermediate B, AQ, steps 1-4, K, G, H, I, CF, step 2, CB, step 3 and Example 28. LC-MS: Rt=2.71 min; MS m / z [M+H] + 367.3 / 368.3;UPLC-MS 4.

[0289] Example 110: (S)-7'-Bromo-8-(difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile [ka] Prepared following procedures similar to those described in the preparation of Intermediate B, CB, steps 1-4, AO, J, steps 1 and 2, K and Example 2. LC-MS: Rt=3.94 min; MS m / z [M+H] + 442.1 / 444.1;UPLC-MS 4.

[0290] Example 111: (S)-8-(Difluoromethoxy)-8'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-7'-carbonitrile [ka] Intermediate A, CB, steps 1-4, AO, prepared according to procedures similar to those described in the preparation of Example 2 and Example 15. LC-MS: Rt=3.43 min; MS m / z [M+H] + 432.2 / 433.2;UPLC-MS 4.

[0291] Example 112: (S)-8-(Difluoromethoxy)-7',8'-difluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile [ka] Prepared following procedures similar to those described in the preparation of Intermediate B, CB, steps 1-4, AO, G, H, I and Example 28. LC-MS: Rt=0.79 min; MS m / z [M+H] + 382.2;UPLC-MS 1.

[0292] Example 113: (S)-8-(Difluoromethoxy)-7',8'-difluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman] [ka] Prepared following procedures similar to those described in the preparation of Intermediates A, CB, steps 1-4, AO, G, H, I and Example 28. LC-MS: Rt=0.81 min; MS m / z [M+H] + 425.2;UPLC-MS 1.

[0293] Example 114: (S)-8'-Fluoro-8-(fluoromethoxy)-6,7'-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiopyrano[3,2-c]pyridine] [ka] Intermediate E, CF, steps 1-9, prepared according to procedures similar to those described in the preparation of Example 4. LC-MS: Rt=0.82 min; MS m / z [M+H] + 458.1;UPLC-MS 1.

[0294] Example 115: (S)-8-(Difluoromethoxy)-8'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isothiochroman] [ka] Prepared following procedures similar to those described in the preparation of Intermediates A, CG, J, steps 1 and 2, K and Example 2. LC-MS: Rt=3.43 min; MS m / z [M+H] + 407.1;UPLC-MS 4.

[0295] Example 116: (S)-8-(Difluoromethoxy)-7'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isothiochroman] [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, CB, Steps 1 and 2, J, Steps 1 and 2, K and Example 2. LC-MS: Rt=3.33 min; MS m / z [M+H] + 407.1;UPLC-MS 4.

[0296] Example 117: (S)-8'-(Difluoromethoxy)-8,9-difluoro-6'-(trifluoromethyl)-3,4-dihydro-2H,3'H-spiro[benzo[b]oxepin-5,2'-imidazo[1,2-α]pyridine] [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, CH, steps 1-9, G and Example 28. LC-MS: Rt=0.78 min; MS m / z [M+H] + 423.2;UPLC-MS 1.

[0297] Example 118: rac-9-chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3,4-dihydro-2H,3'H-spiro[benzo[b]oxepin-5,2'-imidazo[1,2-α]pyridine] [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, CH, steps 1 and 2, J, steps 1 and 2 and Example 2. LC-MS: Rt=0.76 min; MS m / z [M+H] + 421.1 / 423.1;UPLC-MS 1.

[0298] Example 119: (S)-8-Chloro-8'-(difluoromethoxy)-9-fluoro-6'-(trifluoromethyl)-3,4-dihydro-1H,3'H-spiro[benzo[c]oxepin-5,2'-imidazo[1,2-α]pyridine] [ka] Prepared following procedures similar to those described in the preparation of Intermediate A, CJ, steps 1-10, G and Example 28. LC-MS: Rt=0.78 min; MS m / z [M+H] + 439.2 / 441.2;UPLC-MS 1.

[0299] Preparation of intermediates Intermediate A: 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine [ka] Using a Vapourtec (RC / R4 / Vapourtec Flow Commander R Series Platform Report Version: 1.9.9.5), a solution of 2-chloro-5-(trifluoromethyl)pyridin-3-ol in acetonitrile (0.5 mol / L, flow rate 3.08 mL / min) was mixed with an aqueous solution of KOH (6 mol / L, flow rate 3.85 mL / min). Then, a solution of diethyl(bromodifluoromethyl)phosphonate in acetonitrile (1 mol / L, flow rate 3.08 mL / min) was added via a second T-piece, followed by a 1-minute residence time in a 10 mL PFA coil. The resulting biphasic mixture was stirred overnight at RT, the layers were separated, and the aqueous layer was extracted with TBME. The combined organic layers were washed twice with 2 N aqueous NaOH, then twice with brine, dried over NaSO, filtered, and concentrated using a Rotavap (minimum pressure 10 mbar / bath temperature 40 °C). The crude product was distilled and the product-containing fractions were combined to give the title compound as a colorless liquid. 1 H NMR(600MHz,DMSO-d6)δ 8.77(dd,1H),8.30(d,1H),7.50(t,1H).

[0300] Intermediate A can also be synthesized by the following alternative route: Diethyl (bromodifluoromethyl)phosphonate (17.4 mL, 101 mmol) was added dropwise to an ice-bath cooled solution of 2-chloro-5-(trifluoromethyl)pyridin-3-ol (10 g, 50.6 mmol) and KOH (56.8 g, 1012 mmol) in acetonitrile (100 mL) and water (100 mL): (Caution: Exothermic reaction!) After stirring at 0 °C for 10 min, the reaction mixture was stirred at RT for an additional 1 h and then partitioned between water and DCM. The organic layer was washed with brine, dried over Na SO , and concentrated in vacuo to give the title compound as a yellow oil.

[0301] Intermediate B: 6-chloro-5-(difluoromethoxy)nicotinonitrile [ka] Tetrakis(triphenylphosphine)palladium(0) (0.61 g, 0.52 mmol) was added to a mixture of 2-chloro-3-(difluoromethoxy)-5-iodopyridine (Intermediate C, 2.0 g, 5.24 mmol) and zinc cyanide (0.62 g, 5.24 mmol) in DMF (15 mL) under an argon atmosphere, and the RM was heated in an oil bath at 90 °C for 16 h. The cooled RM was then partitioned between TBME and HO, and the suspension was then filtered through Hyflo and the layers separated. The aqueous layer was washed with TBME, and the combined organic layers were then washed with brine, dried over NaSO, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (24 g silica gel cartridge, eluent hexane:DCM 95:5 to 50:50). Product-containing fractions were combined and evaporated to give the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.80(d,1H),8.47(d,1H),7.39(t,1H).

[0302] Intermediate C: 2-chloro-3-(difluoromethoxy)-5-iodopyridine [ka] A mixture of 5-bromo-2-chloro-3-(difluoromethoxy)pyridine (Intermediate D, 20.8 g, 72.4 mmol), sodium iodide (21.7 g, 145 mmol), copper(I) iodide (0.69 g, 3.62 mmol), and trans-N,N'-dimethyl-1,2-cyclohexanediamine (1.14 mL, 7.24 mmol) in 1,4-dioxane (150 mL) was heated with stirring under N2 at 110 °C for 16 h. The cooled RM was filtered through Hyflo, evaporated, and the residue partitioned between TBME and brine. The aqueous layer was further extracted twice with TBME, and the combined organic layers were washed with saturated aqueous NH4Cl, then brine, dried over Na2SO4, and evaporated to give the title compound as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 8.54(s,1H),8.22(s,1H),7.38(t,1H). LC-MS: Rt = 1.04 min; MS m / z [M+H] + ;305.8 / 307.8;UPLC-MS 1.

[0303] Intermediate D: 5-bromo-2-chloro-3-(difluoromethoxy)pyridine [ka] The title compound was prepared by a method similar to that of Intermediate A, replacing 2-chloro-5-(trifluoromethyl)pyridin-3-ol with 5-bromo-2-chloro-3-hydroxypyridine. After the reaction, the two-phase system was collected and stirred at RT. The phases were separated, and the aqueous layer was extracted with TBME. The combined organic layers were washed twice with 2N aqueous NaOH, then three times with brine, dried over NaSO, filtered, and concentrated on a rotary evaporator (175 mbar / 40°C). The residue was dissolved in DCM, extracted twice with 2N aqueous HCl, washed with brine, and the phases were separated using a phase separator. The organic layer was concentrated on a rotary evaporator (minimum pressure 100 mbar / bath temperature 40°C) to give the title compound as a yellow liquid. 1 H NMR(600MHz,DMSO-d6)δ 8.50(d,1H),8.22(d,1H),7.42(t,1H).

[0304] Intermediate E: 2-chloro-3-(fluoromethoxy)-5-(trifluoromethyl)pyridine [ka] Sodium hydride (60% dispersion in mineral oil, 0.81 g, 20.2 mmol) was added portionwise to a solution of 2-chloro-5-(trifluoromethyl)pyridin-3-ol (3.50 g, 17.5 mmol) in DMF (40 mL) at RT. After stirring at RT for 30 min, bromofluoromethane in acetonitrile (17.5 mL, 35.1 mmol) was added dropwise over 2 min, and the RM was stirred at RT for 18 h. The RM was then partitioned between EtOAc and HO, the aqueous layer was further extracted with EtOAc, and the combined organic layers were then washed with brine, dried over NaSO, and evaporated. The crude product was adsorbed onto Isolute and purified by normal-phase chromatography (80 g silica gel cartridge, hexane:TBME 100:0 to 50:50). Product-containing fractions were combined and evaporated to give the title compound as a white crystalline solid. 1 H NMR(400MHz,DMSO-d6)δ 8.71-8.52(m,1H),8.13(s,1H),6.12(d,2H).

[0305] Intermediate F: 2-bromo-5-chloro-3-(difluoromethoxy)pyridine [ka] Sodium 2-chloro-2,2-difluoroacetate (731 mg, 4.80 mmol) was added to a mixture of 2-bromo-5-chloropyridin-3-ol (500 mg, 2.40 mmol) and potassium carbonate (398 mg, 2.88 mmol) in DMF (6 mL) and water (0.75 mL) at RT, and the RM was then heated at 100° C. for 17 h. The cooled RM was poured into water and extracted three times with EtOAc. The combined organic layers were washed twice with water and separated using a phase separator. The organic layer was concentrated in vacuo to give the title compound as a yellow liquid oil. 1 H NMR(600MHz,DMSO-d6)δ 8.44(d,1H),8.07(d,1H),7.43(t,1H).

[0306] Intermediate G: (S)-(5-bromo-1-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)-4-fluoro-2,3-dihydro-1H-inden-1-yl)methanol [ka] To a suspension of (S)-5-bromo-3'-(3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)-4-fluoro-2,3-dihydrospiro[indene-1,4'-oxazolidin]-2'-one (Intermediate H, 820 mg, 1.24 mmol) in EtOH (4 mL) was added THF (10 mL), followed by 30% aqueous NaOH (2.47 mL, 9.90 mmol). The RM was stirred at 70 °C for 4 h, cooled, and partitioned between saturated aqueous NaCO and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over NaSO, and evaporated. The crude product was adsorbed onto Isolute and purified by normal-phase chromatography (40 g SiO column, eluent hexane:[DCM-MeOH 95:5] 90:10 to 40:60). Product-containing fractions were combined and evaporated to give the title compound as a brown resin. 1H NMR(400MHz,DMSO-d6)δ 8.02(s,1H),7.57(s,1H),7.55-7.16(m,2H),6.88(d,1H),6.61(s,1H),5.54(t ,1H),3.59(m,2H),3.12(dd,1H),2.94(m,1H),2.65(q,1H),2.34-2.18(m,1H). LC-MS: Rt = 1.30 min; MS m / z [M+H] + 471.0 / 472.9;UPLC-MS 1.

[0307] Intermediate H: (S)-5-bromo-3'-(3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)-4-fluoro-2,3-dihydrospiro[indene-1,4'-oxazolidin]-2'-one [ka] To a solution of (S)-5-bromo-4-fluoro-2,3-dihydrospiro[indene-1,4'-oxazolidin]-2'-one (Intermediate I, 1.0 g, 3.29 mmol) in DMF (12 mL), 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (Intermediate A, 1.06 g, 4.27 mmol), CsCO (2.14 g, 6.57 mmol), and copper(I) bromide (0.24 g, 1.64 mmol) were added under an Ar atmosphere. The RM was stirred at 120 °C in a heating block for 1 h and then at 140 °C in a microwave for 1 h. Additional 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (Intermediate A, 400 mg, 1.62 mmol) was added, and the RM was stirred at 120 °C in a heating block for an additional 1.5 h. The cooled RM was then filtered through Hyflo filter aid, and the filtrate was partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with HO and brine, dried over Na2SO4, and evaporated. The crude product was adsorbed onto Isolute and purified by normal phase chromatography (40 g SiO2-column, eluent hexane:TBME 100:0 to 40:60). Product-containing fractions were combined and evaporated to give the title compound as a red-brown solid. 1 H NMR(400MHz,DMSO-d6)δ 8.63(s,1H),8.09(s,1H),7.64-7.16(m,2H),7.13(d,1H),4.67(dd,2H),2.97(q,3H),2.57(dt,1H). LC-MS: Rt = 1.26 min; MS m / z [M+H] + 496.8 / 498.8;UPLC-MS 1.

[0308] Intermediate I: (S)-5-Bromo-4-fluoro-2,3-dihydrospiro[indene-1,4'-oxazolidin]-2'-one [ka] To a solution of (S)-(1-amino-5-bromo-4-fluoro-2,3-dihydro-1H-inden-1-yl)methanol (Intermediate J, 10 g, 38.1 mmol) and EtN (11.1 mL, 80 mmol) in DCM (150 mL) was added triphosgene (4.52 g, 15.2 mmol) in DCM (50 mL) dropwise over 1 h, maintaining the temperature below 25 °C. The RM was stirred at RT for 1 h, quenched with saturated aqueous NH4Cl (100 mL), and then stirred at RT for 15 min. The mixture was diluted with saturated aqueous NH4Cl and DCM. The aqueous layer was extracted twice with DCM, and the combined organic layers were dried over Na2SO4 and evaporated to give the title compound as a beige solid. LC-MS: Rt=0.85 min; MS m / z [M+H] + 286.0 / 287.9;UPLC-MS 1.

[0309] Intermediate J: (S)-(1-amino-5-bromo-4-fluoro-2,3-dihydro-1H-inden-1-yl)methanol Step 1: rac-5'-bromo-4'-fluoro-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-2,5-dione [ka] To a mixture of 5-bromo-4-fluoroindanone (100 g, 436 mmol) and ammonium carbonate (502 g, 5.23 mol) in methanol (1.2 L) and water (1.2 L) was added KCN (35.5 g, 545 mmol), and the reaction mixture was stirred at 60° C. for 24 h. MeOH was then removed from the cooled RM under reduced pressure, and the precipitated product was collected by filtration. The solid was washed three times with water (500 mL) and dried under high vacuum at 50° C. for 8 h to give the title compound as a black solid. 1 H NMR:(400MHz,DMSO-d6)δ 10.93(br,s,1H),8.49(s,1H),7.60-7.55(m,1H),6.99(d,1H),3.12-2.98(m,2H),2.65-2.54(m,1H),2.26-15(m,1H).

[0310] Step 2: rac-1-amino-5-bromo-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid [ka] To 5'-bromo-4'-fluoro-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-2,5-dione (Step 1, 120 g, 401 mmol) in HO (1.2 L) was added KOH (225 g, 4.01 mol), and the RM was heated to reflux for 16 h. The RM was cooled to RT and neutralized with 6 N aqueous HCl to pH = 6-7. The precipitate was collected by filtration and washed with water (500 mL) and TBME (500 mL). The solid was dried under vacuum at 50 °C for 6 h to give the title compound as a black solid. 1 H NMR:(400MHz,DMSO-d6)δ 7.58-7.51(m,1H),7.19-7.12(m,1H),3.13-2.99(m,2H),2.75-2.60(m,1H),2.16-2.02(m,1H).

[0311] Step 3: rac-Ethyl 1-amino-5-bromo-4-fluoro-2,3-dihydro-1H-indene-1-carboxylate [ka] SOCl (156 mL) was added to EtOH (2.0 L) cooled to -10 °C, and the solution was stirred at -10 °C for 30 min. DMF (7 mL) and 1-amino-5-bromo-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid (Step 2, 130 g, 474 mmol) were then added to the solution, and the mixture was heated at 80 °C for 4.5 h. The RM was evaporated, and the residue was dissolved in HO (500 mL) and DCM (1.0 L). Saturated aqueous KCO (400 mL) was added, the aqueous phase was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried, and concentrated to give the title compound as a black oil. 1H NMR(400MHz,DMSO-d6)δ 7.64-7.49(m,1H),7.17(d,1H),4.13-4.01(m,2H),3.19-2.91(m,2H),2.77-2.58(m,1H),2.24-2.04(m,1H),1.13(t,3H).

[0312] Step 4: (S)-(1-amino-5-bromo-4-fluoro-2,3-dihydro-1H-inden-1-yl)methanol [ka] Ethyl 1-amino-5-bromo-4-fluoro-2,3-dihydro-1H-indene-1-carboxylate (Step 3, 135 g, 447 mmol) was dissolved in THF (1.5 L), and the solution was cooled in an ice bath. LiAlH (22 g, 581 mmol) was then added portionwise to the stirring RM at 0 °C, and stirring was continued at RT for an additional 3 h. The RM was then recooled to 0 °C, and water (20 mL) was carefully added dropwise, followed by 15% aqueous NaOH (60 mL) and water (20 mL). MgSO was added, the suspension was stirred for 30 min, and the mixture was filtered. The filtrate was concentrated, and the crude product was purified by normal-phase chromatography (silica gel, eluent petroleum ether: EtOAc 50:50 to 0:100) to give the racemic product as a gray solid. The racemate was then separated by SFC (instrument: Thar 200 preparative SFC; column: cellulose-2, 300 × 50 mm ID, 10 μm, 38 °C; eluent: CO:[isopropanol + 0.1% NHOH] 80:20; flow rate: 200 mL / min; detection: 220 nm; BPR: 100 bar; injection: 600 × 5 mL) to give the title compound as the first eluting peak. 1 H NMR(400MHz,DMSO-d6)δ 7.51-7.40(m,1H),7.08(d,1H),3.34(d,2H),3.00-2.84(m,1H),2.84-2.65(m,1H),2.33-2.19(m,1H),1.88-1.71(m,1H). LC-MS: Rt = 0.55 min; MS m / z [M+H] +260.1 / 262.0;UPLC-MS 2. Chiral-HPLC: Rt = 6.19 min; (R)-(1-amino-5-bromo-4-fluoro-2,3-dihydro-1H-inden-1-yl)methanol eluted as the second peak, Rt = 7.31 min; C-HPLC 3.

[0313] Intermediate J can also be synthesized by the following alternative route: Step 1A: rac-5-bromo-1-((tert-butoxycarbonyl)amino)-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid [ka] Boc anhydride (11.14 ml, 48.0 mmol) and Na2CO3 (8.48 g, 80 mmol) were added to a mixture of rac-1-amino-5-bromo-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid (Step 2, 10.96 g, 40 mmol) in water (20 mL) and AcCN (100 mL) and stirred at RT for 2 h. The RM was then cooled in an ice bath and acidified with 20% aqueous KHSO4. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was triturated with Et2O-hexane 2:1, filtered, and dried to give the title compound as a beige solid. LC-MS: Rt = 1.07 min; MS m / z [M−H] - 372.0 / 374.0;UPLC-MS 1.

[0314] Step 2A: (S)-5-Bromo-1-((tert-butoxycarbonyl)amino)-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid To a suspension of rac-5-bromo-1-((tert-butoxycarbonyl)amino)-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid (Step 1A, 12.72 g, 34 mmol) in EtOH (50 mL) was added cinchonidine (6.01 g, 20.40 mmol) and NEt (1.90 mL, 13.60 mmol), and the mixture was heated to give a clear solution. This clear solution was concentrated (removal of approximately 90-95% of the EtOH), and the remaining oil was dissolved in TBME (80 mL) at 55 °C. This was then seeded with crystals of (R)-5-bromo-1-((tert-butoxycarbonyl)amino)-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid cinchonidine salt, and the RM was allowed to cool slowly to RT. Hexane (25 mL) was added to the suspension and stirring was continued for 18 hours. Additional hexane (10 mL) was added, the RM was cooled in an ice bath, and the beige solid was collected by filtration. The solid was dissolved in iPrOH (40 mL) at 75 °C, TBME (30 mL) and heptane (40 mL) were added, and the solution was seeded with crystals of (R)-5-bromo-1-((tert-butoxycarbonyl)amino)-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid cinchonidine salt. The mixture was allowed to stand for 18 hours, and the crystals were collected by filtration and dried to give (R)-5-bromo-1-((tert-butoxycarbonyl)amino)-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid cinchonidine salt (99% ee). Crystallization of the mother liquor from a second crystallization 2x from iPrOH-TBME-hexane gave the cinchonidine salt of the title compound as a light beige solid (99.6% ee).

[0315] Step 3A: (S)-5-Bromo-1-((tert-butoxycarbonyl)amino)-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid [ka] A suspension of (S)-5-bromo-1-((tert-butoxycarbonyl)amino)-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid cinchonidine salt (Step 2A, 1.34 g, 2.0 mmol) was suspended in EtOH and cooled in an ice bath. Aqueous HCl (4 N) was added until pH 3-4, and the RM was stirred for 10 min and extracted three times with EtOAc. The combined organic layers were washed with cold aqueous HCl (0.2 N), washed twice with brine, dried over MgSO, filtered, and concentrated to give the title compound as a foam.

[0316] Alternatively, rac-5-bromo-1-((tert-butoxycarbonyl)amino)-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid was separated by chiral SFC (instrument: Thar 200 preparative SFC; column: Chiralpak AD 300 × 50 mm ID. 10 μm, 38 °C; eluent: CO:[MeOH + 0.1% NHOH] 70:30; flow rate: 200 mL / min; detection: 220 nm; BPR: 100 bar) to give the title compound as the first eluting peak. LC-MS: Rt = 1.03 min; MS m / z [M−H] - 372.1 / 374.1;UPLC-MS 2. Chiral-HPLC: Rt=2.74 min; (R)-5-bromo-1-((tert-butoxycarbonyl)amino)-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid eluted as the second peak, Rt=3.82 min; C-SFC 19.

[0317] Step 4A: (S)-1-amino-5-bromo-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid hydrochloride [ka] A solution of HCl in 1,4-dioxane (4N, 10 mL, 40 mmol) was added to a solution of (S)-5-bromo-1-((tert-butoxycarbonyl)amino)-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid (Step 3A, 2.13 g, 5.7 mmol) in DCM (3 mL), and the RM was stirred at RT for 1 h. The RM was concentrated, and the residue was triturated with EtO. After filtration and drying, the title compound was obtained as a white crystalline solid. 1 H NMR(400MHz,DMSO-d6)δ 7.72-7.63(m,1H),7.35(d,1H),3.33-3.25(m,1H),3.23-3.15(m,1H),2.86-2.82(m,1H),2.51-2.42(m,1H).

[0318] Step 5A: (S)-(1-amino-5-bromo-4-fluoro-2,3-dihydro-1H-inden-1-yl)methanol hydrochloride [ka] To a suspension of (S)-1-amino-5-bromo-4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid hydrochloride (Step 4A, 1.77 g, 5.7 mmol) in THF (30 mL) was added a solution of BH in THF (1 M, 17.10 mL, 17.10 mmol) at RT under a positive pressure of argon. The RM was stirred at RT for 18 h and then quenched by the dropwise addition of a MeOH / THF mixture. The RM was evaporated three times with MeOH, and a solution of HCl in EtO (2 M, 3.1 mL, 6.2 mmol) was added, and the mixture was diluted with additional EtO and stirred for 1 h with ice bath cooling. The white solid was collected by filtration and dried to give the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.62(s,2H),7.63(t,1H),7.47(d,1H),3.81-3.69(m,2H),3.25-2.90(m,2H),2.52-2.43(m,1H),2.35-2.22(m,1H).

[0319] Intermediate K: (S)-(1-amino-4,5-difluoro-2,3-dihydro-1H-inden-1-yl)methanol [ka] The title compound was prepared by a method similar to that of Intermediate M, Step 7, by substituting rac-1-amino-4,5-difluoro-2,3-dihydro-1H-indene-1-carboxylic acid for 7-amino-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid (Intermediate M, Step 6). The enantiomers were separated by chiral HPLC: (Instrument: VWR LaPrep HPLC Prep; Column: Chiralcel OZ-I 20 μm, 5 × 42 cm; Eluent: Heptane:EtOH:MeOH 95:2.5:2.5 + 0.1% EtNH; Flow rate: 100 mL / min; Detection: 260 nm) to give the title compound as the first eluting peak. LC-MS: Rt=0.41 min; MS m / z [M+H] + 200.1;UPLC-MS 1. Chiral-HPLC: Rt = 5.60 min; (R)-(1-amino-4,5-difluoro-2,3-dihydro-1H-inden-1-yl)methanol was obtained as the second eluting peak, Rt = 8.8 min; C-HPLC 1.

[0320] Intermediate L: (S)-8-(difluoromethoxy)-4'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]-5'-thiol Step 1: 2-Ethylhexyl 3-(((S)-8-(difluoromethoxy)-4'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridin-2,1'-indene]-5'-yl)thio)propanoate [ka] A mixture of (S)-5'-bromo-8-(difluoromethoxy)-4'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene] (Example 1, 30.0 mg, 0.07 mmol), 2-ethylhexyl 3-mercaptopropanoate (0.023 mL, 0.10 mmol), Xantphos (3.83 mg, 6.62 μmol), DIPEA (0.017 mL, 0.10 mmol), Pd(dba) (6.06 mg, 6.62 μmol), and 1,4-dioxane (0.5 mL) was stirred at 100° C. for 24 h. The cooled RM was partitioned between EtOAc and water, the aqueous phase was extracted twice with EtOAc, and the dried organic layer was evaporated. The isolated material was purified by normal phase chromatography (10 g SNAP cartridge, eluent hexane:EtOAc 100:0 to 0:100) and the product-containing fractions were evaporated to give the title compound. LC-MS: Rt=1.22 min; MS m / z [M+H] + 591.3;UPLC-MS 1.

[0321] Step 2: (S)-8-(Difluoromethoxy)-4'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]-5'-thiol [ka] NaOEt (28 μl, 0.075 mmol) in EtOH was added to a solution of 2-ethylhexyl 3-(((S)-8-(difluoromethoxy)-4'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridin-2,1'-indene]-5'-yl)thio)propanoate (Step 1, 22.49 mg, 0.038 mmol) in EtOH (0.5 mL). After stirring at RT for 1 h, the RM was partitioned between saturated aqueous NH4Cl and EtOAc, and the dried organic layer was evaporated. The isolated material was purified by normal phase chromatography (10 g SNAP cartridge, eluent hexane:EtOAc 100:0 to 50:50), and the product-containing fractions were evaporated to give the title compound as a yellow solid. LC-MS: Rt=0.76 min; MS m / z [M+H] + 407.2;UPLC-MS 1.

[0322] Intermediate M: (S)-3,6'-bis(trifluoromethyl)-5,6-dihydro-3'H-spiro[cyclopenta[c]pyridine-7,2'-imidazo[1,2-α]pyridin]-8'-ol Step 1: 5-Bromo-2-(trifluoromethyl)isonicotinaldehyde [ka] A solution of lithium diisopropylamide (2 M, 11.68 mL, 23.36 mmol) in THF (25 mL) was cooled to −78 °C using an acetone / dry ice bath, and a solution of 5-bromo-2-(trifluoromethyl)pyridine (4.4 g, 19.47 mmol) in THF (5 mL) was added dropwise. The RM was stirred at this temperature for 1 h, then DMF (1.81 mL, 23.36 mmol) was added, and the RM was stirred for an additional 1 h. The RM was quenched with saturated aqueous NaHCO3, allowed to warm slowly to RT, and extracted with EtOAc. The organic layer was washed successively with brine, dried on a phase separator, and concentrated in vacuo. The residue was purified by normal-phase chromatography (eluent cyclohexane:EtOAc 100:0 to 80:20) to give the title compound. 1H NMR (400MHz, DMSO-d6): δ 10.18(s,1H),9.19(s,1H),8.10(s,1H).

[0323] Step 2: (E)-3-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)-N-methoxy-N-methylacrylamide [ka] To a solution of 5-bromo-2-(trifluoromethyl)isonicotinaldehyde (Step 1, 2.0 g, 7.64 mmol) in DCM (50 mL) was added N-methoxy-N-methyl-2-(triphenylphosphoroanylidene)-acetamide (4.16 g, 11.46 mmol). The RM was stirred at RT for 30 min, then quenched with brine and extracted with DCM. The organic layers were combined, dried on a phase separator, and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent cyclohexane: EtOAc 100:0 to 80:20) to give the title compound. LC-MS: Rt = 1.00 min; MS m / z [M+H] + 339.0;UPLC-MS 1.

[0324] Step 3: 3-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)-N-methoxy-N-methylpropanamide [ka] A glass autoclave (Hastelloy) was charged with (E)-3-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)-N-methoxy-N-methylacrylamide (Step 2, 2.69 g, 7.93 mmol), Rh-alumina powder 5% (Engelhard 8011, 675 mg), and EtOAc (100 mL). The autoclave was sealed, and 2.1 bar of H pressure was applied. The reaction was stirred under these conditions at RT for 5 h. Additional catalyst was then added (0.2 g), and the reaction was stirred under an H atmosphere (2.1 bar) for 2 h. The RM was filtered through a pad of Celite. The Celite was washed twice with EtOAc, and the combined filtrates were concentrated in vacuo. The crude product was used in the next step without further purification. LC-MS: Rt=0.98 min; MS m / z [M+H] + 341.1;UPLC-MS 1.

[0325] Step 4: 3-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one [ka] A solution of 3-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)-N-methoxy-N-methylpropanamide (Step 3, 2.64 g, 7.20 mmol) in THF (60 mL) was cooled to −78 °C using an acetone / dry ice bath, and a solution of n-BuLi in hexanes (1.6 M, 6.75 mL, 10.80 mmol) was added dropwise. The reaction was stirred at −78 °C for 1 h. The reaction mixture was then quenched with saturated aqueous NH4OH, warmed to RT, and extracted with EtOAc. The organic layer was washed successively with 1 N aqueous HCl, dried on a phase separator, and concentrated. The residue was purified by normal phase chromatography (eluent cyclohexane:EtOAc 100:0 to 70:30) to give the title compound. LC-MS: Rt=0.77 min; MS m / z [M+H] + 202.1;UPLC-MS 1.

[0326] Step 5: 3-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,4'-imidazolidine]-2',5'-dione [ka] A mixture of 3-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one (Step 4, 1.25 g, 5.66 mmol), ammonium carbonate (6.52 g, 67.9 mmol), EtOH (25 mL), water (25 mL), and KCN (921 mg, 14.1 mmol) was heated at 50° C. for 15 h. Water was added to the cooled RM, and the RM was extracted with EtOAc. The combined organic layers were washed successively with 1 N aqueous HCl, dried on a phase separator, and concentrated in vacuo to give the title compound, which was used without further purification. LC-MS: Rt=0.62 min; MS m / z [M+H] + 272.1;UPLC-MS 1.

[0327] Step 6: 7-Amino-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid [ka] A mixture of 3-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,4'-imidazolidine]-2',5'-dione (Step 5, 1.31 g, 4.83 mmol), KOH (1.491 g, 26.6 mmol), and water (20 mL) was heated with stirring at 100 °C for 2 days. The cooled RM was acidified to pH 3-4 using 1 N aqueous HCl and washed with EtOAc. The aqueous layer was lyophilized to give the title compound containing NaCl, which was used in the following step without further purification. LC-MS: Rt=0.34 min; MS m / z [M+H] + 247.2;UPLC-MS 1.

[0328] Step 7: (S)-(7-amino-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)methanol [ka] To a solution of 7-amino-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid (Step 6, 2.40 g, 4.84 mmol) in THF (30 mL) was added borane tetrahydrofuran complex (1 M, 15.0 mL, 15.0 mmol) at RT. The RM was stirred at RT for 4 h, then carefully quenched with methanol and concentrated. The residue was redissolved in methanol and concentrated to dryness two more times. HCl in ethanol (1.25 N, 50 mL) was then added, and the resulting mixture was stirred at RT for 15 min and concentrated to dryness using a rotary evaporator. The residue was basified with saturated aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed successively with brine, dried on a phase separator, and concentrated in vacuo to give the racemic product. The racemate was then separated by chiral HPLC (Instrument: Gilson Prep HPLC system; Column: LuxCel-2, 5 μM, 21.2 × 250 mm, 25 °C; Eluent: Heptane:MeOH:EtOH 90:5:5 + 0.1% EtNH; Flow rate: 10 mL / min; Detection: 254 nm; Injection volume: 2 mL) to give the title compound as the first eluting peak. LC-MS: Rt=0.41 min; MS m / z [M+H] + 233.2;UPLC-MS 1. Chiral-HPLC: Rt = 11.82 min; (R)-(7-amino-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)methanol eluted as the second peak, Rt = 16.08 min; C-HPLC 17.

[0329] Step 8: (S)-(7-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)methanol [ka] A microwave vial was charged with (S)-(7-amino-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)methanol (Step 7, 148 mg, 637 μmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (95 μL, 765 μmol), iPrOH (3 mL), and diisopropylethylamine (334 μL, 1.91 mmol). The vial was sealed and heated to 160 °C in a microwave for 6 h. The RM was quenched with saturated aqueous NaHCO and eluted with EtOAc. The organic layer was dried on a phase separator and concentrated. The crude residue was purified by normal phase chromatography (eluent cyclohexane:EtOAc 100:0 to 50:50) to give the title compound. LC-MS: Rt=1.16 min; MS m / z [M+H] + 396.2;UPLC-MS 1.

[0330] Step 9: (S)-8'-Fluoro-3,6'-bis(trifluoromethyl)-5,6-dihydro-3'H-spiro[cyclopenta[c]pyridine-7,2'-imidazo[1,2-α]pyridine] [ka] To a solution of (S)-(7-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)methanol (Step 8, 140 mg, 350 μmol) in toluene (5 mL) was added thionyl chloride (260 μL, 3.54 mmol). The RM was heated to 80° C. for 1 h, then quenched with MeOH and concentrated to dryness. The residue was purified by filtration with saturated NaHCO 3 33The crude residue was purified by normal phase chromatography (eluent cyclohexane: EtOAc 100:0 to 0:100) to give the title compound. LC-MS: Rt=0.66 min; MS m / z [M+H] + 378.2;UPLC-MS 1.

[0331] Step 10: (S)-3,6'-bis(trifluoromethyl)-5,6-dihydro-3'H-spiro[cyclopenta[c]pyridine-7,2'-imidazo[1,2-α]pyridin]-8'-ol [ka] A solution of 2-(methylsulfonyl)ethanol (92 mg, 0.73 mmol) in DMF (3 mL) was cooled to 0 °C using an ice bath, and NaH (mineral oil 60%, 35.0 mg, 0.88 mmol) was added. After 30 min, a solution of (S)-8'-fluoro-3,6'-bis(trifluoromethyl)-5,6-dihydro-3'H-spiro[cyclopenta[c]pyridine-7,2'-imidazo[1,2-α]pyridine] (Step 9, 110 mg, 290 μmol) in DMF (1 mL) was added dropwise. The RM was allowed to warm to RT and stirred for 4 h. The RM was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (phase separator), and concentrated. The crude residue was purified by normal phase chromatography (eluent DCM:MeOH 100:0 to 80:20) to give the title compound. LC-MS: Rt=0.67 min; MS m / z [M+H] + 376.2;UPLC-MS 1.

[0332] Intermediate N: (S)-5-bromo-4-fluoro-3'-(3-(fluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydrospiro[indene-1,4'-oxazolidin]-2'-one [ka] A mixture of (S)-5-bromo-4-fluoro-2,3-dihydrospiro[indene-1,4'-oxazolidin]-2'-one (Intermediate I, 40 mg, 0.120 mmol), 2-chloro-3-(fluoromethoxy)-5-(trifluoromethyl)pyridine (Intermediate E, 41.4 mg, 0.180 mmol), CuI (11.45 mg, 0.060 mmol), and CsCO (78 mg, 0.240 mmol) in DMF (2 mL) was stirred at 120 °C for 4 h in an acetonitrile pressure tube. The cooled RM was diluted with EtOAc, and the organic phase was washed twice with saturated aqueous NaHCO, dried, and concentrated. The residue was purified by reverse-phase chromatography (silica gel, eluent c-hexane / EtOAc 100 / 0 to 50 / 50), and the product-containing fractions were combined and evaporated to give the title compound as a yellow solid. LC-MS: Rt=1.24 min; MS m / z [M+H] + 479.1 / 481.1;UPLC-MS 1.

[0333] Intermediate O: (S)-(5-bromo-4-fluoro-1-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)methanol [ka] A mixture of (S)-(1-amino-5-bromo-4-fluoro-2,3-dihydro-1H-inden-1-yl)methanol (Intermediate J, 900 mg, 3.39 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (517 μL, 4.07 mmol), and DIPEA (2.4 mL, 13.56 mmol) in iPrOH (2.6 mL) was heated in a microwave at 160 °C for 2 h. The cooled RM was evaporated, and the residue was taken up in DCM and evaporated onto an Isolute for purification by normal phase chromatography (12 g column, eluent 0% to 60% EtOAc in c-hexane). Product-containing fractions were combined and evaporated to give the title compound. LC-MS: Rt=6.59 min; MS m / z [M+H] +423.2 / 425.1;UPLC-MS 4.

[0334] The following intermediates O1, O2 and O3 were prepared using the method used to prepare intermediate O.

[0335] [Table 7]

[0336] Intermediate P: (S)-(5-bromo-1-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)methanol [ka] To a solution of (S)-(1-amino-5-bromo-2,3-dihydro-1H-inden-1-yl)methanol (Intermediate CL, 5.15 g, 21.27 mmol) in iPrOH (22 mL) was added 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (4.80 g, 24.04 mmol) and DIPEA (7.43 mL, 42.5 mmol) at RT. The RM was sonicated and stirred at RT for 10 min, then heated in a microwave at 170 °C for 80 min. The RM was poured into saturated aqueous NaHCO3 and extracted twice with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine, evaporated, and the residue was purified by normal phase chromatography (120 g silica RediSep column, eluent heptane:EtOAc) to give the title compound. LC-MS: Rt=1.36 min; MS m / z [M+H] + 421.1 / 423.1;UPLC-MS 1.

[0337] The following intermediates P1 and P2 were prepared using the method used to prepare intermediate P.

[0338] [Table 8]

[0339] Intermediate Q: (S)-5',6-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridin-2,1'-inden]-8-ol Step 1: (S)-8-Fluoro-5',6-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene] [ka] SOCl (0.54 mL, 7.41 mmol) was added to a solution of (S)-(1-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)methanol (Intermediate O, 292 mg, 0.741 mmol) in toluene (2 mL) in a sealed vial at RT. The RM was stirred and heated at 80 °C for 30 min, cooled, and then diluted with DCM. The organic phase was washed with saturated aqueous NaHCO, then brine and separated on a phase separator cartridge. Concentration of the organic layer gave a yellow oil, which was triturated with MeOH, filtered, and dried to give the title compound as a yellow powder. 1 H NMR(400MHz,MeOH-d4)δ 7.80(s,1H),7.49-7.64(m,2H),7.45(d,1H),7.11(d,1H),4.23-4.51(m,2H),3.08-3.22(m,1H),2.91-3.08(m,1H),2.26-2.52(m,2H). LC-MS: Rt = 3.30 min; MS m / z [M+H] + 377.1;UPLC-MS 4.

[0340] Step 2: (S)-5',6-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridin-2,1'-inden]-8-ol [ka] Sodium hydride (57 mg, 1.35 mmol) was added to a stirred solution of 2-(methylsulfonyl)ethanol (57 mg, 459 μmol) in DMF (1.5 mL) cooled in an ice bath. The RM was stirred at 0° C. for 10 min, after which (S)-8-fluoro-5′,6-bis(trifluoromethyl)-2′,3′-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1′-indene] (169 mg, 450 μmol from Step 1) was added. After stirring for 90 min, the RM was recooled to 0° C. and an additional 0.3 equivalents of sodium alkoxide in DMF was added. After an additional 30 min at RT, the RM was then poured into saturated aqueous NH4Cl and extracted twice with EtOAc. The combined organic phases were washed with brine and concentrated. The residue was purified by normal phase chromatography (10 g SiO2 SNAP cartridge, eluent DCM:MeOH 100:0 to 90:10) to give the title compound as a grey powder. LC-MS: Rt=0.78 min; MS m / z [M+H] + 375.1;UPLC-MS 1.

[0341] Intermediate R: (S)-(1-amino-6-bromo-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol hydrochloride [ka] (S)-1-Amino-6-bromo-5-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (5 g, 15.3 mmol) was suspended in THF (10 mL) under Ar and cooled to 0 °C. To the RM, borane THF complex in THF (1 M, 100 mL, 100 mmol) was added dropwise over 30 min. The RM was stirred at RT for 18 h, then carefully quenched with MeOH, evaporated, and coevaporated with MeOH three more times. The residue was diluted with MeOH, and a 2 M solution of HCl in EtO (10 mL, 20 mmol) was added. Additional EtO was added until a precipitate formed, and the RM was stirred at RT for 30 min. The solid was collected by filtration and dried to give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.52(s,3H),7.65(t,1H),7.51(d,1H),5.79(t,1H),3.65(d,2H),2.85-2.73( m,1H),2.73-2.60(m,1H),2.22(dd,1H),1.95-1.82(m,1H),1.82-1.69(m,2H). LC-MS: Rt = 0.57 min; MS m / z [M+H] + 274.1 / 276.1;UPLC-MS 1.

[0342] Intermediate S: (S)-6'-Bromo-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-dispiro[imidazo[1,2-α]pyridine-2,1'-naphthalene-4',2''-[1,3]dithiolane] Step 1: (S)-6'-Bromo-3-(3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)-5'-fluoro-2',3'-dihydrodispiro[oxazolidine-4,1'-naphthalene-4',2''-[1,3]dithiolane]-2-one [ka] A mixture of (S)-6'-bromo-5'-fluoro-2',3'-dihydrodispiro[oxazolidine-4,1'-naphthalene-4',2''-[1,3]dithiolane]-2-one (Intermediate T, 795 mg, 1.96 mmol), 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (Intermediate A, 963 mg, 3.85 mmol), copper(I) iodide (235 mg, 1.23 mmol) and cesium carbonate (1.28 g, 3.91 mmol) in DMF (13 mL) was heated in a microwave under Ar at 120 °C for 2.5 h. Additional 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (Intermediate A, 198 mg, 0.8 mmol) and copper(I) iodide (50 mg, 260 μmol) were added, and heating was continued at 120 °C for an additional 2 h. This procedure was repeated with 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (Intermediate A, 198 mg, 0.8 mmol) and copper(I) iodide (50 mg, 260 μmol). The cooled RM was diluted with saturated aqueous NaHCO and eluted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (120 g SiO column; eluent heptane:EtOAc 100:0 to 85:15). Product-containing fractions were combined and evaporated to give the title compound as an off-white foam. LC-MS: Rt=1.36 min; MS m / z [M+H] + 600.8 / 603.0;UPLC-MS 1.

[0343] Step 2: (S)-(7'-bromo-4'-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)-8'-fluoro-3',4'-dihydro-2'H-spiro[[1,3]dithiolane-2,1'-naphthalen]-4'-yl)methanol [ka] Aqueous NaOH (2 M, 11 mL, 22 mmol) was added to (S)-6'-bromo-3-(3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)-5'-fluoro-2',3'-dihydrodispiro[oxazolidine-4,1'-naphthalene-4',2''-[1,3]dithiolane]-2-one (Step 1, 1.8 g, 2.84 mmol) suspended in EtOH (15 mL), and the RM was stirred at 80 °C for 135 min. The RM was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated to give the title compound as an off-white foam, which was used directly in the following step. LC-MS: Rt=1.37 min; MS m / z [M+H] + 575.0 / 577.0;UPLC-MS 1.

[0344] Step 3: (S)-6'-Bromo-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-dispiro[imidazo[1,2-α]pyridine-2,1'-naphthalene-4',2''-[1,3]dithiolane] [ka] SOCl2 (0.35 ml, 4.8 mmol) was added dropwise to a solution of (S)-(7'-bromo-4'-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)-8'-fluoro-3',4'-dihydro-2'H-spiro[[1,3]dithiolane-2,1'-naphthalen]-4'-yl)methanol (Step 2, 1.6 g, 2.59 mmol) in toluene (15 mL), and the RM was heated at 80 °C under Ar for 1 h. The RM was quenched with saturated aqueous NaHCO3 and eluted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal-phase chromatography (120 g SiO2 column; eluent heptane:EtOAc 100:0 to 75:25). Product-containing fractions were combined and evaporated to give the title compound as a yellow solid. LC-MS: Rt=0.96 min; MS m / z [M+H] + 557.0 / 559.1;UPLC-MS 1.

[0345] Intermediate T: (S)-6'-Bromo-5'-fluoro-2',3'-dihydrodispiro[oxazolidine-4,1'-naphthalene-4',2''-[1,3]dithiolane]-2-one Step 1: (S)-6-Bromo-5-fluoro-3,4-dihydro-2H-spiro[naphthalene-1,4'-oxazolidin]-2'-one [ka] A solution of triphosgene (1.06 g, 3.57 mmol) in DCM (50 mL) was added dropwise to a solution of (S)-(1-amino-6-bromo-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol (Intermediate R, 2.5 g, 8.94 mmol) and EtN (2.62 mL, 18.77 mmol) in DCM (50 mL) at 0 °C and stirred at RT for 45 min. The RM was quenched with saturated aqueous NH Cl and DCM. The RM was stirred at RT for 20 min, extracted with DCM, and the combined organic layers were washed with brine, dried (phase separator), and concentrated to give the title compound, which was used directly in the following step. LC-MS: Rt=0.96 min; MS m / z [M+H] + 300.1 / 302.1;UPLC-MS 1.

[0346] Step 2: (S)-6-Bromo-5-fluoro-2H-spiro[naphthalene-1,4'-oxazolidine]-2',4(3H)-dione [ka] Iron(III) nitrate nonahydrate (662 mg, 1.61 mmol) was added to a solution of (S)-6-bromo-5-fluoro-3,4-dihydro-2H-spiro[naphthalene-1,4'-oxazolidin]-2'-one (Step 1, 2.51 g, 8.03 mmol) and N-hydroxyphthalimide (0.327 g, 2.01 mmol) in AcCN (50 mL), and the RM was stirred at 35 °C under an O atmosphere for 18 h. The RM was extracted with DCM, and the organic layer was washed with brine, dried (phase separator), and concentrated. The residue was triturated with DCM to give the title compound as a white solid after filtration. Additional material can be obtained by purification of the mother liquor by normal phase chromatography (silica gel: c-hexane: EtOAc 100:0 to 50:50), affording the title compound after trituration with DCM. LC-MS: Rt=0.69 min; no significant molecular ion signal; UPLC-MS 1.

[0347] Step 3: (S)-6'-Bromo-5'-fluoro-2',3'-dihydrodispiro[oxazolidine-4,1'-naphthalene-4',2''-[1,3]dithiolane]-2-one [ka] Boron trifluoride etherate (303 μL, 2.39 mmol) was added dropwise to a solution of (S)-6-bromo-5-fluoro-2H-spiro[naphthalene-1,4'-oxazolidine]-2',4(3H)-dione (Step 2, 1.5 g, 4.78 mmol) and ethane-1,2-dithiol (803 μL, 9.55 mmol) in DCM (30 mL) at 0 °C, and the RM was stirred at RT for 18 h. The RM mixture was poured into aqueous NaOH (1N, 100 mL), extracted with DCM, dried (phase separator), and concentrated. The residue was purified by normal phase chromatography (silica gel, eluent c-hexane: EtOAc 100:0 to 50:50) to give the title compound. LC-MS: Rt=0.98 min; no significant molecular ion signal; UPLC-MS 1.

[0348] Intermediate U: (S)-6'-bromo-4'-((tert-butyldimethylsilyl)oxy)-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] tert-Butyldimethylsilyl trifluoromethanesulfonate (90 μL, 381 μmol) was added dropwise to (S)-6′-bromo-8-(difluoromethoxy)-5′-fluoro-6-(trifluoromethyl)-2′H,3H-spiro[imidazo[1,2-α]pyridine-2,1′-naphthalen]-4′(3′H)-one (Example 8, 121 mg, 249 μmol) and triethylamine (173 μL, 1.25 mmol) in DCM (2 mL) under Ar at 0° C. The RM was stirred at 0° C. for 10 min and then at RT for 20 min, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (40 g SiO2-column, eluent heptane:EtOAc 100:0 to 75:25). The product-containing fractions were combined, evaporated and dried to give the title compound as a yellow solid. LC-MS: Rt=1.38 min; MS m / z [M+H] + 595.1 / 597.1;UPLC-MS 1.

[0349] Intermediate V: (S)-(1-amino-6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)methanol [ka] The title compound was prepared by a method similar to that of Intermediate M, Step 7, by substituting rac-1-amino-6-bromo-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (Intermediate AU8) for 7-amino-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid (Intermediate M, Step 6). The enantiomers were separated by chiral HPLC: (Instrument: Gilson Trilution HPLC Prep System; Column: Chiralpak ID 5 μm, 3 × 25 cm, 25 °C; Eluent: Heptane:TBME:EtOH 80:10:10 + 0.05% EtNH; Flow rate: 10 mL / min; Detection: 230 nm) to give the title compound as the first eluting peak, Rt = 8.82 min; C-HPLC 7. LC-MS: Rt=0.56 min; MS m / z [M+H] + 256.1 / 258.1;UPLC-MS 1. Chiral-HPLC: Rt=8.82 min; (R)-(1-amino-6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)methanol was obtained as the second eluting peak, Rt=11.87 min; C-HPLC 7.

[0350] Intermediate W: (S)-6'-Bromo-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-8-ol Step 1: (S)-6'-Bromo-8-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] SOCl2 (74 μl, 1.01 mmol) was added to (6-bromo-1-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-1,2,3,4-tetrahydronaphthalen-1-yl)methanol (Intermediate O3, 330 mg, 779 μmol) in toluene (2.5 mL) under argon. The RM was heated to 80 °C for 75 min. The RM was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (40 g SiO2-column, eluent heptane:EtOAc 100:0 to 70:30). Product-containing fractions were combined, evaporated, and dried to give the title compound. LC-MS: Rt=0.79 min; MS m / z [M+H] + 401.2 / 403.2;UPLC-MS 1.

[0351] Step 2: (S)-6'-Bromo-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-8-ol [ka] NaH (55% dispersion in mineral oil, 98 mg, 2.24 mmol) was added to 2-(methylsulfonyl)ethanol (122 mg, 972 μmol) in DMF (1.5 mL) at RT under Ar. The RM was cooled to 0 °C, stirred at 0 °C for 15 min, and a solution of (S)-6'-bromo-8-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] (Step 1, 300 mg, 748 μmol) in DMF (4.5 mL) was added. The RM was stirred at RT for 30 min, then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to give the title compound as an orange solid. LC-MS: Rt=0.83 min; MS m / z [M+H] +399.1 / 401.1;UPLC-MS 1.

[0352] Intermediate X: (S)-6'-bromo-4'-((tert-butyldimethylsilyl)oxy)-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] The title compound was prepared similarly to the method described for Intermediate U by replacing (S)-6'-bromo-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one (Example 8) with (1'S)-6'-bromo-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one (Example 9 as a diastereomeric mixture). The crude product was purified by normal phase chromatography (40 g SiO2 column; eluent heptane: EtOAc 100:0 to 80:20) to give the title compound as a yellow solid. LC-MS: Rt=1.49 min; MS m / z [M+H] + 613.0 / 614.9;UPLC-MS 1.

[0353] Intermediate Y: (S)-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-dispiro[imidazo[1,2-α]pyridine-2,1'-naphthalene-4',2''-[1,3]dithiolane] [ka] The title compound was prepared by a method similar to that of Intermediate S by substituting (S)-5'-fluoro-2',3'-dihydrodispiro[oxazolidine-4,1'-naphthalene-4',2''-[1,3]dithiolane]-2-one (Intermediate Z) for (S)-6'-bromo-5'-fluoro-2',3'-dihydrodispiro[oxazolidine-4,1'-naphthalene-4',2''-[1,3]dithiolane]-2-one (Intermediate T). The crude product was used in the following step without purification. 1 H NMR(600MHz,DMSO-d6)δ 7.91(s,1H),7.51-7.23(m,2H),7.07(q,2H),7.01(s,1H),4.31(d,1H),4.12(d,1H), 3.65-3.50(m,3H),3.43-3.36(m,1H),2.47(dd,1H),2.32(dd,1H),2.09-2.00(m,2H). LC-MS: Rt = 0.84 min; MS m / z [M+H] + 479.0;UPLC-MS 1.

[0354] Intermediate Z: (S)-5'-fluoro-2',3'-dihydrodispiro[oxazolidine-4,1'-naphthalene-4',2''-[1,3]dithiolane]-2-one Step 1: (S)-5-Fluoro-3,4-dihydro-2H-spiro[naphthalene-1,4'-oxazolidin]-2'-one [ka] To a solution of (S)-(1-amino-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol (Intermediate AA, 1.08 g, 5.53 mmol) and EtN (1.62 mL, 11.6 mmol) in DCM (30 mL) was added dropwise a solution of triphosgene (0.66 g, 2.21 mmol) in DCM (30 mL) at 0-5 °C. The yellow solution was stirred at RT for 30 min. The RM was poured into saturated aqueous NaHCO and extracted twice with DCM. The combined organic extracts were dried (phase separator) and evaporated to give the title compound as a beige solid. 1 H NMR(400MHz,DMSO-d6)δ 8.22(s,1H),7.33-7.29(m,2H),7.11(m,1H),4.35(d,1H),4.18(d,1H),2.70-2.57(m,2H),2.02-1.72(m,4H). LC-MS:Rt=0.81min;MS m / z[M+NH4] + 239.2;UPLC-MS 1.

[0355] Step 2: (S)-5-Fluoro-2H-spiro[naphthalene-1,4'-oxazolidine]-2',4(3H)-dione [ka] (S)-5-Fluoro-3,4-dihydro-2H-spiro[naphthalene-1,4'-oxazolidin]-2'-one (500 mg, 2.26 mmol), N-hydroxyphthalimide (92 mg, 0.56 mmol), and iron(III) nitrate nonahydrate (186 mg, 0.45 mmol) were placed in a microwave vial. CHCN (14 mL) was added, and the mixture was flushed with O. The vial was capped, and a balloon connected to the vial via a needle was filled with O. The RM was stirred under an O atmosphere at 35 °C for 16 h. The RM was then filtered through a pad of Celite, washed with EtOAc and MeOH, and the filtrate was evaporated. The crude mixture was suspended in CHCl and filtered to give the title compound as a brownish solid. 1 H NMR(400MHz,DMSO-d6)δ 8.45(s,1H),7.76(m,1H),7.43(d,1H),7.30(dd,1H),4.59(d,1H),4.26(d,1H),2.87-2.79(m,1H),2.66-2.60(m,1H),2.31-2.27(m,2H). LC-MS: Rt = 0.53 min; MS m / z [M−H] - 234.2;UPLC-MS 1.

[0356] Step 3: (S)-5'-Fluoro-2',3'-dihydrodispiro[oxazolidine-4,1'-naphthalene-4',2''-[1,3]dithiolane]-2-one [ka] The title compound was prepared by a method similar to that of Intermediate T, by substituting (S)-(1-amino-6-bromo-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol (Intermediate R) with (S)-(1-amino-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol (Intermediate AA). The crude product was purified by normal phase chromatography (80 g SiO column; eluent heptane:EtOAc 100:0 to 40:60) to give the title compound as a brown solid. 1 H NMR(600MHz,DMSO-d6)δ 8.26(s,1H),7.42(td,1H),7.28(d,1H),7.14(dd,1H),4.45(d,1H),4.21(d,1H),3 .66-3.58(m,1H),3.53(dd,2H),3.38-3.35(m,1H),2.44-2.30(m,2H),2.11(t,2H). LC-MS: Rt = 0.87 min; MS m / z [M+H] + 312.0;UPLC-MS 1.

[0357] Intermediate AA: (S)-(1-amino-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol [ka] The title compound was prepared by a method similar to that of Intermediate M, Step 7, by substituting rac-1-amino-5-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (Intermediate AU9) for 7-amino-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid (Intermediate M, Step 6). The enantiomers were separated by chiral SFC: (Instrument: Sepiatec SFC 100; Column: Lux i-Cel 5; 5 μm, 250 × 30 mm, 40 °C; Eluent: CO / MeOH 80:20 + 1% iPrNH; Flow rate: 80 mL / min; Detection: 260 nm; Injection volume: 4 mL ethanol (300 mg / injection)) to give the title compound as the first eluting peak as a beige solid. 1 H NMR(400MHz,DMSO-d6)δ 7.40(d,1H),7.16(m,1H),6.95(m,1H),4.79(br s,1H),3.45(d,1H),3.29(d,1H),2.65-2.61(m,2H),2.13-1.98(m,3H),1.84-1.76(m,1H),1.75-1.66(m,1H),1.48(m,1H). LC-MS: Rt = 0.45 min; MS m / z [M+H] + 196.1;UPLC-MS 1. Chiral-HPLC: Rt=7.45 min; (R)-(1-amino-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol eluted as the second peak, Rt=8.79 min; C-HPLC 47.

[0358] Intermediate AB: (S)-4'-((tert-butyldimethylsilyl)oxy)-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] Step 1: (S)-8-(Difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one [ka] (S)-8-(Difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-dispiro[imidazo[1,2-α]pyridine-2,1'-naphthalene-4',2''-[1,3]dithiolane] (Intermediate Y, 4.27 g, 8.03 mmol) in acetone (120 mL) and water (12 mL) was cooled to 0 °C, and NBS (11.4 g, 64.3 mmol) was added. After stirring at 0 °C for 5 min, saturated aqueous sodium thiosulfate solution was added to the RM. The RM was basified with saturated aqueous NaHCO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (120 g SiO2-column; eluent DCM:MeOH 100:0 to 94:6). Product-containing fractions were combined and evaporated to give the title compound. LC-MS: Rt=0.59 min; MS m / z [M+H] + 403.0;UPLC-MS 1.

[0359] Step 2: (S)-4'-((tert-butyldimethylsilyl)oxy)-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene] [ka] The title compound was prepared in a manner similar to that of intermediate U by replacing (S)-6'-bromo-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one (Example 8) with (S)-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one (Step 1). The crude product was purified by normal phase chromatography (120 g SiO2 column, eluent heptane: EtOAc 100:0 to 75:25) to give the title compound as a yellow solid. LC-MS: Rt=1.21 min; MS m / z [M+H] + 517.1;UPLC-MS 1.

[0360] Intermediates AC and AD: (2S,4'S)-6'-bromo-8-(difluoromethoxy)-5'-fluoro-4'-hydroxy-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile and (2S,4'R)-6'-bromo-8-(difluoromethoxy)-5'-fluoro-4'-hydroxy-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile Step 1: (S)-6-(6'-bromo-5'-fluoro-2-oxo-2',3'-dihydrodispiro[oxazolidine-4,1'-naphthalene-4',2''-[1,3]dithiolane]-3-yl)-5-(difluoromethoxy)nicotinonitrile [ka] The title compound was prepared by a method similar to that of Intermediate S, step 1, by substituting 6-chloro-5-(difluoromethoxy)nicotinonitrile for 2-chloro-3-(difluoromethoxy)-5-(trifluoromethyl)pyridine (Intermediate A). The crude product was purified by normal phase chromatography (80 g SiO column; eluent heptane:EtOAc 100:0 to 70:30) to afford the title compound as a white foam. LC-MS: Rt=1.24 min; MS m / z [M+H] + 558.1 / 559.9;UPLC-MS 1.

[0361] Step 2: (S)-6-((7'-bromo-8'-fluoro-4'-(hydroxymethyl)-3',4'-dihydro-2'H-spiro[[1,3]dithiolane-2,1'-naphthalen]-4'-yl)amino)-5-(difluoromethoxy)nicotinonitrile [ka] (S)-6-(6'-Bromo-5'-fluoro-2-oxo-2',3'-dihydrodispiro[oxazolidine-4,1'-naphthalene-4',2''-[1,3]dithiolane]-3-yl)-5-(difluoromethoxy)nicotinonitrile (Step 1, 1.57 g, 2.53 mmol) and cesium carbonate (495 mg, 1.52 mmol) were suspended in MeOH (16 mL) under Ar. The RM was stirred at 80 °C for 35 min, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to dryness to give the title compound as a white foam. LC-MS: Rt=1.22 min; MS m / z [M+H] + 532.0 / 534.0;UPLC-MS 1.

[0362] Step 3: (S)-6'-Bromo-8-(difluoromethoxy)-5'-fluoro-2',3'-dihydro-3H-dispiro[imidazo[1,2-α]pyridine-2,1'-naphthalene-4',2''-[1,3]dithiolane]-6-carbonitrile [ka] The title compound was prepared by a method similar to that of Intermediate S, Step 3, by substituting (S)-(7'-bromo-4'-((3-(difluoromethoxy)-5-(trifluoromethyl)pyridin-2-yl)amino)-8'-fluoro-3',4'-dihydro-2'H-spiro[[1,3]dithiolane-2,1'-naphthalen]-4'-yl)methanol (Intermediate S, Step 2) with (S)-6-((7'-bromo-8'-fluoro-4'-(hydroxymethyl)-3',4'-dihydro-2'H-spiro[[1,3]dithiolane-2,1'-naphthalen]-4'-yl)amino)-5-(difluoromethoxy)nicotinonitrile (Intermediates AC and AD, Step 2). The crude product was purified by normal phase chromatography (40 g SiO2-column; eluent heptane:EtOAc 100:0 to 70:30) to afford the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.13(d,1H),7.61(dt,1H),7.46-6.99(m,3H),4.31(dd,1H),4.12(dd,1H ),3.69-3.59(m,1H),3.57(d,2H),3.40(s,1H),2.35(d,2H),2.03(d,2H). LC-MS: Rt = 0.93 min; MS m / z [M+H] + 514.0 / 516.0;UPLC-MS 1.

[0363] Step 4: (S)-6'-Bromo-8-(difluoromethoxy)-5'-fluoro-4'-oxo-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile [ka] Water (2.5 mL) was added to (S)-6'-bromo-8-(difluoromethoxy)-5'-fluoro-2',3'-dihydro-3H-dispiro[imidazo[1,2-α]pyridine-2,1'-naphthalene-4',2''-[1,3]dithiolane]-6-carbonitrile (Step 3, 867 mg, 1.65 mmol) in acetone (25 mL) cooled in an ice bath. NBS (2.94 g, 16.5 mmol) was added, and the RM was stirred at 0 °C for 5 min. The reaction was quenched with saturated aqueous sodium thiosulfate solution, basified with saturated aqueous NaHCO3, and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by SFC (SFC 1), and the product-containing fractions were combined and evaporated to give the title compound. LC-MS: Rt=0.72 min, broad peak; MS m / z[M+H] + 438.0 / 440.0;UPLC-MS 1.

[0364] Step 5: (2S,4'S)-6'-Bromo-8-(difluoromethoxy)-5'-fluoro-4'-hydroxy-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile and (2S,4'R)-6'-Bromo-8-(difluoromethoxy)-5'-fluoro-4'-hydroxy-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile [ka] Sodium borohydride (20.3 mg, 514 μmol) was added to a 0° C.-cooled (S)-6′-bromo-8-(difluoromethoxy)-5′-fluoro-4′-oxo-3′,4′-dihydro-2′H,3H-spiro[imidazo[1,2-α]pyridine-2,1′-naphthalene]-6-carbonitrile (Step 4, 256 mg, 467 μmol) suspended in EtOH (5 mL) under Ar. The RM was stirred at 0° C. for 30 min, then quenched with saturated aqueous NaHCO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and evaporated. The residue was absorbed onto Isolute and purified by normal phase chromatography (40 g SiO2-column; eluent DCM:MeOH 100:0 to 95:5) then SFC (SFC 1) to afford the title compounds as a diastereomeric mixture. The diastereomers were separated by chiral SFC (Waters SFC100 preparative system, column: Chiralpak IG, 5 μm, 250 × 30 mm; eluent: CO:MeOH + 0.1% NH 65:35; temperature: 23 °C; flow rate: 80 mL / min) to give (1'S)-6'-bromo-8-(difluoromethoxy)-5'-fluoro-4'-hydroxy-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile (alcohol stereochemistry unassigned) as the first eluting peak, Rt 1.03 min. LC-MS: Rt=0.59 min; MS m / z [M+H] + 440.0 / 442.0;UPLC-MS 1. (1'S)-6'-Bromo-8-(difluoromethoxy)-5'-fluoro-4'-hydroxy-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile (alcohol stereochemistry not assigned) was obtained as the second eluting peak, Rt 2.01 min. LC-MS: Rt=0.59 min; MS m / z [M+H] + 440.1 / 442.1;UPLC-MS 1.

[0365] Intermediates AE and AF: (1'S,4'S)-8-(difluoromethoxy)-5'-fluoro-4'-hydroxy-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile and (1'S,4'R)-8-(difluoromethoxy)-5'-fluoro-4'-hydroxy-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile Step 1: (S)-8-(Difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-dispiro[imidazo[1,2-α]pyridine-2,1'-naphthalene-4',2''-[1,3]dithiolane]-6'-carbonitrile [ka] A mixture of (S)-6'-bromo-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-dispiro[imidazo[1,2-α]pyridine-2,1'-naphthalene-4',2''-[1,3]dithiolane] (Intermediate S, 150 mg, 223 μmol), XPhos Pd G3 (18.91 mg, 22 μmol), XPhos (21.73 mg, 45 μmol), potassium ferricyanide trihydrate (47.2 mg, 112 μmol), and KOAc (3.29 mg, 34 μmol) in 1,4-dioxane (2 mL) and water (2 mL) was stirred in a microwave at 100 °C for 1.5 h. The RM was diluted with EtOAc, washed with saturated aqueous NaHCO3, dried, and concentrated. The residue was taken up in DCM (5 mL), SiliaMetS® thiol (66 μmol, 48 mg) was added, the mixture was stirred for 0.5 h, then filtered, washed with DCM, and the filtrate was concentrated. The residue was purified by normal phase column chromatography (silica gel: eluent c-hexane: EtOAc 100:0 to 70:30) to give the title compound. LC-MS: Rt = 0.90 min; MS m / z [M+H] +504.3;UPLC-MS 1.

[0366] Step 2: (S)-8-(Difluoromethoxy)-5'-fluoro-4'-oxo-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile [ka] To a solution of N-iodosuccinimide (168 mg, 0.747 mmol) in DCM (1.5 mL) cooled in a dry ice / acetone bath was added hydrogen fluoride pyridine (70%, 93 μL, 0.747 mmol) dropwise, followed by a solution of (S)-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-dispiro[imidazo[1,2-α]pyridine-2,1'-naphthalene-4',2″-[1,3]dithiolane]-6'-carbonitrile (Step 1, 100 mg, 0.187 mmol) in DCM (1 mL). The RM was stirred at −70 °C for 1 h and then poured into a solution of saturated aqueous NaHCO (50 mL) cooled in an ice bath. An aqueous solution of NaSO (10%, 50 mL) was added, the mixture was extracted with DCM, and the organic layer was dried by passing through a phase separator cartridge and concentrated. The residue was purified by reverse-phase chromatography (RP-HPLC 3) to give (S)-8-(difluoromethoxy)-4',4',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile (Example 15), followed by the title compound as a yellow solid. LC-MS: Rt=2.67 min; MS m / z [M+H] + 428.3;UPLC-MS 4.

[0367] Step 3: (1'S,4'S)-8-(difluoromethoxy)-5'-fluoro-4'-hydroxy-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile and (1'S,4'R)-8-(difluoromethoxy)-5'-fluoro-4'-hydroxy-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile [ka] The title compound was prepared by a method similar to that of Intermediates AC and AD, by substituting (S)-6'-bromo-8-(difluoromethoxy)-5'-fluoro-4'-oxo-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile (Intermediates AC and AD, Step 1) with (S)-8-(difluoromethoxy)-5'-fluoro-4'-oxo-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile (Intermediates AE and AF, Step 2). The diastereomers were separated by SFC (SFC 1) to give the first eluting diastereomer, Rt 6.65 min. 1 H NMR(400MHz,DMSO-d6)δ 8.00(s,1H),7.79(t,1H),7.50-7.09(m,2H),7.00(s,1H),5.41(d,1H),4.93(s,1H),4.45(d,1H),4.22(d,1H),2.16(d,2H),1.80(d,2H). LC-MS: Rt = 0.62 min; MS m / z [M+H] + 430.2;UPLC-MS 1. The second eluting diastereomer was then obtained, Rt 8.51 min. 1H NMR(600MHz,DMSO-d6)δ 7.91(t,1H),7.80(dd,1H),7.41(t,1H),7.33(d,1H),7.06(d,1H),5.46(d,1H),4.90(s,b r,1H),4.30(d,1H),3.84(d,1H),2.25-2.19(m,1H),1.96-1.80(m,2H),1.76-1.72(m,1H). LC-MS: Rt = 0.63 min; MS m / z [M+H] + 430.2;UPLC-MS 1.

[0368] Intermediate AG: (S)-(1-amino-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl-4,4-d2)methanol Step 1: (1S,4S)-5-Fluoro-4-hydroxy-3,4-dihydro-2H-spiro[naphthalene-1,4'-oxazolidine]-2'-one-4-d and (1S,4R)-5-Fluoro-4-hydroxy-3,4-dihydro-2H-spiro[naphthalene-1,4'-oxazolidine]-2'-one-4-d [ka] A mixture of (S)-5-fluoro-2H-spiro[naphthalene-1,4'-oxazolidine]-2',4(3H)-dione (Intermediate Z, Step 2, 32 mg, 0.16 mmol) and NaBD4 (Cambridge Isotope Laboratories, 99 atom% D; 11.5 mg, 0.27 mmol) in MeOD (1.4 mL) was stirred at RT under a nitrogen atmosphere for 1.5 h. The reaction mixture was poured into water and extracted three times with DCM. The combined organic extracts were dried (phase separator) and evaporated to give the title compound as a white solid as a mixture of diastereomers (ratio 6:4). 1H NMR(600MHz,DMSO-d6)δ 8.42(s,0.6H),8.22(s,0.4H),7.42(m,1H),7.29(m,1H),7.15(m,1H),5.24(s,0.4H),5.17(s,0.6H),4.51 (d,0.6H),4.37(d,0.4H),4.34(d,0.6H),3.94(d,0.4H),2.24(m,1H),2.02(m,0.6H),1.85-1.74(m,2.4H). LC-MS: Rt = 0.44 and 0.54 min; MS m / z [M+NH] + 256.3;UPLC-MS 1.

[0369] Step 2: (S)-5-fluoro-3,4-dihydro-2H-spiro[naphthalene-1,4'-oxazolidin]-2'-one-4,4-d2 [ka] To a mixture of (1S,4S)-5-fluoro-4-hydroxy-3,4-dihydro-2H-spiro[naphthalene-1,4'-oxazolidin]-2'-one-4-d and (1S,4R)-5-fluoro-4-hydroxy-3,4-dihydro-2H-spiro[naphthalene-1,4'-oxazolidin]-2'-one-4-d (Step 1, 25 mg, 0.10 mmol) suspended in DCM (0.65 mL) cooled to -65 °C, EtSiD (50 μL, 0.31 mmol) and BF.EtO (27 μL, 0.21 mmol) were added under a nitrogen atmosphere. The RM was allowed to warm to RT and stirred for 2 h. The RM was poured into saturated aqueous NaHCO and extracted three times with DCM. The combined organic extracts were dried (phase separator) and evaporated to give the title compound as a white solid. 1 H NMR(600MHz,DMSO-d6)δ 8.25(s,1H),7.35-7.30(m,2H),7.11(t,1H),4.36(d,1H),4.18(d,1H),1.99(m,1H),1.90(m,1H),1.84(m,1H),1.74(m,1H). LC-MS:Rt=0.79min;MS m / z[M+NH4]+ 241.3;UPLC-MS 1.

[0370] Step 3: (S)-(1-amino-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl-4,4-d2)methanol [ka] A solution of (S)-5-fluoro-3,4-dihydro-2H-spiro[naphthalene-1,4'-oxazolidin]-2'-one-4,4-d2 (Step 2, 23 mg, 0.10 mmol) and NaOH (4 N, 0.25 mL, 1.01 mmol) in ethanol (0.4 mL) was stirred at 80 °C for 15 h. The RM was poured into water and extracted three times with EtOAc. The combined organic extracts were dried (phase separator) and evaporated to give the title compound as a white solid, which was used in the next step without further purification. 1 H NMR(600MHz,DMSO-d6)δ 7.40(d,1H),7.17(m,1H),6.95(t,1H),4.79(t,1H),3.45(dd,1H),3.29( dd,1H),2.03-1.98(m,1H),1.97-1.76(m,3H),1.71(m,1H),1.47(m,1H). LC-MS: Rt = 0.45 min; MS m / z [M+H] + 198.3;UPLC-MS 1.

[0371] Intermediate AH: (S)-1'-chloro-8,8',8'-trifluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] Step 1: (S)-1'-chloro-3-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-6',7'-dihydrodispiro[oxazolidine-4,5'-isoquinoline-8',2''-[1,3]dioxolan]-2-one [ka] A mixture of (S)-1'-chloro-6',7'-dihydrodispiro[oxazolidine-4,5'-isoquinoline-8',2''-[1,3]dioxolan]-2-one (Intermediate AI, 500 mg, 1.57 mmol), 2-chloro-3-fluoro-5-(trifluoromethyl)pyridine (494 mg, 2.35 mmol), CuBr (112 mg, 0.784 mmol), CsCO (1.02 g, 3.13 mmol), and DMF (15 mL) was heated in a sealed reaction vessel at 130 °C for 1.5 h under an argon atmosphere. Saturated aqueous NH4Cl was added to the cooled RM, which was extracted twice with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by normal phase chromatography (silica gel, eluent heptane:EtOAc 100:0 to 20:80) to afford the title compound as a yellow powder. LC-MS: Rt=1.03 min; MS m / z [M+H] + 460.1 / 462.1;UPLC-MS 1.

[0372] Step 2: (S)-1-chloro-3'-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-8H-spiro[isoquinoline-5,4'-oxazolidine]-2',8-dione [ka] A solution of (S)-1'-chloro-3-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-6',7'-dihydrodispiro[oxazolidine-4,5'-isoquinoline-8',2''-[1,3]dioxolan]-2-one (Step 1, 761 mg, 1.39 mmol) in THF (7.8 mL) and 1 N aqueous HCl (6.95 mL, 6.95 mmol) was heated at 80 °C for 18 h in a sealed reaction vessel. The cooled RM was poured into saturated aqueous NaHCO and extracted three times with DCM. The combined organic layers were dried and concentrated by passing through a phase separator. The residue was purified by normal phase chromatography (silica gel, eluent heptane:EtOAc 100:0 to 20:80) to give the title compound as a white powder. LC-MS: Rt = 1.00 min; MS m / z [M+H] + 416.1 / 418.1;UPLC-MS 1.

[0373] Step 3: (S)-1-chloro-8,8-difluoro-3'-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-7,8-dihydro-6H-spiro[isoquinolin-5,4'-oxazolidin]-2'-one [ka] DAST (1.49 mL, 11.24 mmol) was added to a solution of (S)-1-chloro-3'-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-8H-spiro[isoquinoline-5,4'-oxazolidine]-2',8-dione (Step 2, 492 mg, 1.12 mmol) in DCM (6 mL) at RT under argon, and the RM was heated at 40 °C in a sealed reaction vessel for 2 days. The cooled RM was slowly added to saturated aqueous NaHCO3, cooled in an ice bath (CAUTION: exothermic!), and the mixture was extracted three times with DCM. The combined organic layers were dried and concentrated by passing through a phase separator. The residue was purified by flash column chromatography (silica gel: eluent heptane: EtOAc 100:0 to 30:70) to give the title compound as a white powder. LC-MS: Rt=1.13 min; MS m / z [M+H] + 438.1 / 440.1;UPLC-MS 1.

[0374] Step 4: (S)-(1-chloro-8,8-difluoro-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-5,6,7,8-tetrahydroisoquinolin-5-yl)methanol [ka] (S)-1-Chloro-8,8-difluoro-3'-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-7,8-dihydro-6H-spiro[isoquinolin-5,4'-oxazolidin]-2'-one (Step 3, 487.4 mg, 1.10 mmol) was suspended in EtOH (9 mL) and aqueous NaOH (4 M, 2.76 mL, 11.02 mmol) was added at RT. The RM was stirred at RT for 30 min, then partitioned between saturated aqueous NaHCO3 and DCM, extracted three times with DCM, and the combined organic layers were dried by passing through a phase separator and evaporated to give the title compound, which was used directly without further purification. LC-MS: Rt=1.14 min; MS m / z [M+H] + 412.1 / 414.1;UPLC-MS 1.

[0375] Step 5: (S)-1'-chloro-8,8',8'-trifluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] [ka] SOCl (0.140 mL, 1.91 mmol) was added to a solution of (S)-(1-chloro-8,8-difluoro-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-5,6,7,8-tetrahydroisoquinolin-5-yl)methanol (Step 4, 458 mg, 957 μmol) in toluene (7 mL) at RT. The RM was heated at 80 °C for 20 min, cooled, MeOH was added, and evaporated. The residue was dissolved in DCM containing 1-2% MeOH and partitioned with saturated aqueous NaHCO solution. The aqueous phase was extracted twice with DCM, and the combined organic layers were dried by passing through a phase separator and concentrated. The residue was purified by normal-phase column chromatography (silica gel, eluent heptane:EtOAc 100:0 to 40:60) to give the title compound as a yellow powder. 1H NMR(400MHz,DMSO-d6)δ 8.49(d,1H),7.97(s,1H),7.51(d,1H),7.33(d,1H),4.35(q,2H),2.71-2.28(m,2H),2.21-1.98(m,2H). LC-MS: Rt = 3.03 min; MS m / z [M+H] + 394.3 / 396.3;UPLC-MS 4.

[0376] Intermediate AI: (S)-1'-chloro-6',7'-dihydrodispiro[oxazolidine-4,5'-isoquinoline-8',2''-[1,3]dioxolan]-2-one Step 1: rac-1-(2-chloro-4-iodopyridin-3-yl)pent-4-en-1-ol [ka] A solution of 2-chloro-4-iodopyridine (38 g, 157 mmol) in THF (140 mL) was added dropwise under a positive pressure of argon to a solution of LDA in THF [prepared by adding n-butyllithium (2.5 M, 79 mL, 196 mmol) to a solution of diisopropylamine (28.0 mL, 196 mmol) in THF (90 mL) while maintaining the internal temperature below 0° C.] and cooled in a dry-ice acetone bath to maintain the internal temperature below −75° C. After stirring the RM below −75° C. for 30 min, a solution of pent-4-enal (23.47 mL, 238 mmol) in THF (40 mL) was added over 30 min, and the RM was then warmed to 0° C. in an ice bath and stirred at 0° C. for 15 min. Saturated aqueous NaHCO3 (250 mL) and water (11 mL) were added, and the mixture was extracted with EtOAc (1 x 300 mL, 1 x 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was absorbed onto silica gel and purified by normal-phase column chromatography (2 x 220 g silica gel columns, eluent heptane:EtOAc 100:0 to 70:30) to afford the title compound as a clear brown oil. LC-MS: Rt=0.97 min; MS m / z [M+H] +324.1 / 326.1;UPLC-MS 1.

[0377] Intermediate AI, step 1, can also be synthesized by the following alternative route: A solution of but-3-en-1-yl magnesium bromide in THF (0.5 M, 1 L) was added to an ice-bath-cooled mixture of LiCl (21.7 g, 508 mmol) and ZnCl (71.4 g, 508 mmol) in THF (80 mL) under a positive pressure of N at a temperature such that the internal temperature remained below 15 °C. The RM was stirred at ambient temperature for 1 h. A solution of 2-chloro-4-iodonicotinaldehyde (27.0 g, 100 mmol) in THF (80 mL) was then added, and the RM was stirred at ambient temperature for 2 h. The RM was cooled to 0 °C, and saturated aqueous potassium sodium tartrate tetrahydrate (240 mL) was slowly added. The mixture was stirred for 1 h, then filtered, and the filter cake was washed with EtOAc (300 mL). The bilayer filtrate was separated, and the aqueous phase was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4 and evaporated to give the title compound.

[0378] Step 2: 1-(2-chloro-4-iodopyridin-3-yl)pent-4-en-1-one [ka] To a stirred solution of rac-1-(2-chloro-4-iodopyridin-3-yl)pent-4-en-1-ol (Step 1, 32.0 g, 94 mmol) in DCM (400 mL), Dess-Martin periodinane reagent (47.8 g, 113 mmol) was added portionwise over 30 min (slightly exothermic), warming the RM to 35 °C. After stirring the RM at RT for 1.5 h, saturated aqueous NaSO was added and stirring continued at RT for 0.5 h. The mixture was extracted three times with DCM, and the combined organic layers were washed with saturated aqueous NaHCO, dried by passing through a phase separator cartridge, and evaporated. The residue was absorbed onto Isolute and purified by normal-phase chromatography (2 × 120 g SiO columns, eluent hexane:EtOAc 0–15%) to give the title compound as a yellow oil. LC-MS: Rt=1.12 min; MS m / z [M+H] + 321.9 / 323.9;UPLC-MS 1.

[0379] Intermediate AI, step 2 can also be synthesized by the following alternative route: PhI(OAc) (4.45 g, 13.8 mmol, 1.95 equiv.) was added to an ice-bath cooled mixture of 1-(2-chloro-4-iodopyridin-3-yl)pent-4-en-1-ol (Step 1, 2.7 g, 7.1 mmol) and TEMPO (0.28 g, 1.8 mmol) in DCM (25 mL). The mixture was stirred at RT for 1 h, and water (50 mL) was added, followed by NaSO (1.5 g). The phases were separated, and the aqueous phase was extracted with DCM (2 × 25 mL). The combined organic layers were dried over anhydrous NaSO and concentrated to give the title compound as a brown oil.

[0380] Step 3: 1-chloro-5-methylene-6,7-dihydroisoquinolin-8(5H)-one [ka] A mixture of 1-(2-chloro-4-iodopyridin-3-yl)pent-4-en-1-one (Step 2, 34.7 g, 106 mmol), AgCO (21.98 g, 79 mmol), P(2-furyl) (3.76 g, 15.86 mmol), Pd(OAc) (1.80 g, 7.93 mmol), and AcCN (563 mL) was heated at 55–60 °C for 3.5 h under an atmosphere of argon. The RM was filtered through Hyflo filter aid, washed with acetonitrile, and evaporated. The residue was purified by normal phase chromatography (2 × 220 g silica gel columns, eluent heptane:EtOAc 10:90 to 45:55), and the product-containing fractions were combined, evaporated, and triturated with heptane:EtOAc 60:40 to give the title compound as a yellow powder. LC-MS: Rt=0.78 min; MS m / z [M+H] + 194.0 / 196.0;UPLC-MS 1.

[0381] Step 4: 1-chloro-5-methylene-6,7-dihydro-5H-spiro[isoquinoline-8,2'-[1,3]dioxolane] [ka] A mixture of 1-chloro-5-methylene-6,7-dihydroisoquinolin-8(5H)-one (Step 3, 16 g, 79 mmol), HC(OEt) (39.2 mL, 236 mmol), para-toluenesulfonic acid (2.70 g, 15.70 mmol), and ethylene glycol (88 mL, 1570 mmol) was heated at 60 °C for 1.5 h under an atmosphere of argon. The RM was partitioned between DCM and saturated aqueous NaHCO, and the aqueous layer was extracted twice with DCM. The combined organic layers were dried and concentrated by passing through a phase separator. Purification of the residue by normal-phase column chromatography (2 × 220 g silica gel columns, eluent heptane:EtOAc 0:100 to 40:60) afforded the title compound as a clear, pale yellow oil. LC-MS: Rt=3.71 min; MS m / z [M+H] + 238.2 / 240.2;UPLC-MS 4.

[0382] Step 5: (R)-(1-chloro-6,7-dihydro-5H-spiro[isoquinoline-8,2'-[1,3]dioxolan]-5-yl)methanol [ka] A solution of 9-BBN in THF (0.5 M, 616 mL, 308 mmol) was added dropwise to an ice-bath cooled solution of 1-chloro-5-methylene-6,7-dihydro-5H-spiro[isoquinoline-8,2'-[1,3]dioxolane] (Step 4, 37 g, 154 mmol) in THF (118 mL) under an atmosphere of argon. The RM was stirred at 0°C for 1 h, at RT for 30 min, at 50°C for 2 h, and then at RT for 18 h. The RM was then cooled in an ice bath, and aqueous NaOH (4N, 193 mL, 771 mmol) was added, followed by dropwise addition of aqueous hydrogen peroxide (30%, 79 mL, 771 mmol) (CAUTION: Exothermic!). The RM was stirred at RT for 30 min, diluted with brine, extracted twice with EtOAc, and the combined organic layers were washed twice with 10% aqueous NaSO (negative peroxide test for the organic layer), dried over sodium sulfate, and concentrated. The residue was purified by normal-phase chromatography (silica gel, 330 g column, eluent: DCM:EtOH 98:2 to 90:10). The product-containing fractions were evaporated and triturated with diethyl ether containing 2% DCM to give the racemic product as a white powder. Further normal-phase chromatography purification of the filtrate (silica gel, 330 g column, eluent: DCM:EtOH 98:2 to 90:10) afforded additional racemic product. The enantiomers were separated by chiral SFC: (Instrument: Thar 350 preparative SFC; Column: Chiralpak AD 10 μm, 300 × 50 mm 38 °C; Eluent: CO:MeOH with 0.1% NHOH, 80:20; Flow rate: 200 mL / min; Detection: 254 nm) to give the title compound as the major second eluting peak. LC-MS: Rt=2.02 min; MS m / z [M+H] + 256.3 / 258.3;UPLC-MS 4. Chiral-SFC: Rt=3.45 min; (S)-(1-chloro-6,7-dihydro-5H-spiro[isoquinoline-8,2′-[1,3]dioxolan]-5-yl)methanol was obtained as the first eluting peak, Rt=3.78 min; C-SFC 8.

[0383] Step 6: (R)-(1-chloro-6,7-dihydro-5H-spiro[isoquinoline-8,2'-[1,3]dioxolan]-5-yl)methylcarbamate [ka] Trichloroacetyl isocyanate (9.28 mL, 78 mmol) was slowly added to an ice-bath cooled solution of (R)-(1-chloro-6,7-dihydro-5H-spiro[isoquinoline-8,2'-[1,3]dioxolan]-5-yl)methanol (Step 5, 16.76 g, 64.9 mmol) in DCE (300 mL) under an argon atmosphere. After stirring at 0 °C for 30 min, KCO (897 mg, 6.49 mmol) was added, followed by MeOH (300 mL), and the RM was stirred at RT overnight. The RM was poured into saturated aqueous NaHCO, and the mixture was extracted twice with DCM. Upon standing, a precipitate formed in the organic extracts, which was collected by filtration and dried to give the title compound as a white powder. The filtrate was dried over sodium sulfate, evaporated, and triturated with diethyl ether to give additional product. LC-MS: Rt=2.26 min; MS m / z [M+H] + 299.3 / 301.3;UPLC-MS 4.

[0384] Step 7: (S)-1'-chloro-6',7'-dihydrodispiro[oxazolidine-4,5'-isoquinoline-8',2''-[1,3]dioxolan]-2-one [ka] A mixture of (R)-(1-chloro-6,7-dihydro-5H-spiro[isoquinoline-8,2'-[1,3]dioxolan]-5-yl)methylcarbamate (Step 6, 4.0 g, 13.26 mmol), diacetoxyiodobenzene (6.10 g, 18.56 mmol), MgO (1.29 g, 30.5 mmol), and Rh(esp) (262 mg, 331 μmol) in DCM (133 mL) was heated in an Ace pressure tube under an atmosphere of argon at 45 °C for 21 h. Additional diacetoxyiodobenzene (1.28 g, 3.98 mmol), MgO (267 mg, 6.63 mmol), and Rh(esp) (50 mg, 66 μmol) was added to RM, the vessel was flushed with argon, and heated at 45 °C for an additional 21 h. The cooled RM was poured into saturated aqueous NaHCO3, the mixture was extracted three times with DCM, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification of the residue by normal phase column chromatography (silica gel, eluent heptane:EtOAc 100:0 to 0:100) afforded the title compound as a beige powder. LC-MS: Rt=0.57 min; MS m / z [M+H] + 297.3 / 299.3;UPLC-MS 1.

[0385] Intermediate AI can also be synthesized by the following alternative route: Step 1A: (S)-1-chloro-5-methylene-5,6,7,8-tetrahydroisoquinolin-8-ol [ka] A solution of RuCl(p-cymene) [(S,S)-Ts-DPEN] (371 mg, 583 μmol) in DCM (20 mL) was added dropwise to a solution of 1-chloro-5-methylene-6,7-dihydroisoquinolin-8(5H)-one (Step 3, 8.0 g, 38.8 mmol) in DCM (100 mL) under a positive pressure of argon. The RM was cooled in an ice bath, and formic acid (4.47 mL, 117 mmol) was added dropwise. After stirring for 2 h at 5 °C and 18 h at RT, the RM was partitioned between DCM (200 mL) and saturated aqueous NaHCO (100 mL), extracted twice with DCM (50 mL), and the combined organic layers were dried by passing through a phase separator cartridge and evaporated. The residue was purified by normal phase chromatography (120 g SiO2 column, eluent hexane:EtOAc 100:0 to 70:30) to afford the title compound as a beige solid. LC-MS: Rt = 0.70 min; MS m / z [M+H] + 196.1 / 198.1;UPLC-MS 1.

[0386] Step 2A: (S)-8-((tert-butyldimethylsilyl)oxy)-1-chloro-5-methylene-5,6,7,8-tetrahydroisoquinoline [ka] tert-Butyldimethylsilyl chloride (9.31 g, 61.8 mmol) was added to a solution of (S)-1-chloro-5-methylene-5,6,7,8-tetrahydroisoquinolin-8-ol (Step 1A, 8.95 g, 41.2 mmol) and imidazole (4.48 g, 65.9 mmol) in DCM (150 mL) at RT under a positive pressure of argon. The RM was stirred at RT for 20 h, at 40 °C for 8 h, allowed to stand at RT for 66 h, diluted with water (150 mL), extracted twice with DCM (30 mL), and the combined organic layers were washed with saturated aqueous NaHCO3, dried, and evaporated. The residue was suspended in diethyl ether (30 mL) and hexane (120 mL), stirred at RT for 30 min, and filtered. The filtrate was evaporated and purified by normal phase chromatography (40 g SiO2 column, eluent hexane:EtOAc 100:0 to 70:30) to give the title compound as a white solid. LC-MS: Rt=1.59 min; MS m / z [M+H] + 310.2 / 312.1;UPLC-MS 1.

[0387] Step 3A: ((5R,8S)-8-((tert-butyldimethylsilyl)oxy)-1-chloro-5,6,7,8-tetrahydroisoquinolin-5-yl)methanol [ka] A solution of 9-borabicyclo[3.3.1]nonane in THF (0.5 M, 167 mL, 84 mmol) was added dropwise to a solution of (S)-8-((tert-butyldimethylsilyl)oxy)-1-chloro-5-methylene-5,6,7,8-tetrahydroisoquinoline (Step 2A, 10.9 g, 33.4 mmol) in 1,2-DCE (100 mL) at RT under a positive pressure of argon. The RM was stirred at 60 °C for 4 h, cooled to 5 °C, and aqueous NaOH (4 M, 37.6 mL, 150 mmol) and aqueous HO (30%, 17.1 mL, 167 mmol) were added, and stirring was continued at RT for 30 min. The RM was partitioned between DCM and saturated aqueous NaHCO and extracted twice with DCM. The combined organic layers were washed with aqueous NaSO, dried by passing through a phase separator cartridge, and evaporated. The residue was purified by normal phase chromatography (220 g SiO2 column, eluent hexane:EtOAc 95:5 to 60:40) to afford the title compound as a white solid. LC-MS: Rt=1.31 min; MS m / z [M+H] + 328.1 / 320.1;UPLC-MS 1.

[0388] Step 4A: ((5R,8S)-8-((tert-butyldimethylsilyl)oxy)-1-chloro-5,6,7,8-tetrahydroisoquinolin-5-yl)methylcarbamate [ka] Trichloroacetyl isocyanate (4.69 mL, 39.6 mmol) was added dropwise to an ice-bath cooled solution of ((5R,8S)-8-((tert-butyldimethylsilyl)oxy)-1-chloro-5,6,7,8-tetrahydroisoquinolin-5-yl)methanol (Step 3A, 11.5 g, 33.0 mmol) in 1,2-DCE (150 mL). The RM was stirred at 0 °C for 2.5 h, KCO (0.46 g, 3.30 mmol) and MeOH (150 mL) were added, and stirring was continued at RT for 16 h. The RM was diluted with saturated aqueous NaHCO (200 mL) and DCM (150 mL), the aqueous layer was extracted twice with DCM (100 mL), and the combined organic layers were dried by passing through a phase separator and evaporated to give the title compound as a white crystalline solid, which was used directly without further purification. LC-MS: Rt=1.27 min; MS m / z [M+H] + 371.2 / 373.2;UPLC-MS 1.

[0389] Step 5A: (5S,8S)-8-((tert-butyldimethylsilyl)oxy)-1-chloro-7,8-dihydro-6H-spiro[isoquinolin-5,4'-oxazolidin]-2'-one [ka] A mixture of ((5R,8S)-8-((tert-butyldimethylsilyl)oxy)-1-chloro-5,6,7,8-tetrahydroisoquinolin-5-yl)methylcarbamate (Step 4A, 14.0 g, 32.1 mmol), diacetoxyiodobenzene (14.76 g, 44.9 mmol), MgO (2.97 g, 73.8 mmol), and Rh(esp) (487 mg, 642 μmol) in DCM (170 mL) was stirred at 45 °C for 48 h under a positive pressure of N. Additional Rh(esp) (122 mg, 160 μmol) was added, and the RM was stirred at 45 °C for an additional 24 h. The RM was partitioned between saturated aqueous NaHCO (150 mL) and DCM (100 mL), the aqueous layer was extracted twice with DCM (60 mL), and the combined organic layers were dried by passing through a phase separator cartridge and evaporated. The residue was purified by normal phase chromatography (120 g SiO column, eluent hexane:EtOAc 90:10 to 50:50) to give the title compound. LC-MS: Rt=1.21 min; MS m / z [M+H] + 369.2 / 371.1;UPLC-MS 1.

[0390] Step 6A: (5S,8S)-1-chloro-8-hydroxy-7,8-dihydro-6H-spiro[isoquinolin-5,4'-oxazolidin]-2'-one [ka] A solution of tetra-n-butylammonium fluoride in THF (1 M, 30.0 mL, 30.0 mmol) was added to an ice-bath-cooled solution of (5S,8S)-8-((tert-butyldimethylsilyl)oxy)-1-chloro-7,8-dihydro-6H-spiro[isoquinolin-5,4'-oxazolidin]-2'-one (Step 5A, 9.72 g, 25.03 mmol) in THF (100 mL). The RM was stirred at 0 °C for 1 h and at RT for 16 h, then diluted with saturated aqueous NaHCO (250 mL) and DCM (150 mL). The aqueous layer was extracted three times with DCM (150 mL) and twice with EtOAc (100 mL). The combined organic layers were dried by passing through a phase separator cartridge and evaporated. The residue was triturated twice with EtOAc, and the off-white solid was collected by filtration to give the title compound, which was used directly without further purification. LC-MS: Rt=0.36 min; MS m / z [M+H] + 255.1 / 257.1;UPLC-MS 1.

[0391] Step 7A: (S)-1-chloro-6,7-dihydro-8H-spiro[isoquinoline-5,4'-oxazolidine]-2',8-dione [ka] Dess-Martin periodinane (4.41 g, 10.41 mmol) was added to a suspension of (5S,8S)-1-chloro-8-hydroxy-7,8-dihydro-6H-spiro[isoquinolin-5,4'-oxazolidin]-2'-one (Step 6A, 5.3 g, 5.20 mmol) in DCM (80 mL) at RT and stirred for 1.5 h at RT. The RM was then diluted with aqueous NaSO (40 mL), stirred for 30 min at RT, extracted four times with a...

Claims

1. A compound of formula (I) in free form or in pharma- ceutically acceptable salt form. 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof (In the formula, R １ is F, Cl, Br, OCH ３ , O.C.H. ２ F, O.C.H.F. ２ , or O.C.F. ３ and R ２ is F, Cl, CF ３ or CN; X is (CH ２ ) １～２ , CHF, CHD, CD ２ Or CF ２ and Y is (CH ２ ) ０～２ , CHF, CHD, CD ２ ,O.S.,O.C.H. ２ Or CF ２ and Z is CH ２ , C.D. ２ , CHF, CDF, CF ２ , CH(OH), CO, CH(CH ３ ), O, or S; Here, Y is O, OCH ２ , or if S, Z is CH ２ and where Z is O, S, or NCH ３ In the case of ２ ) ０～２ , or C.F. ２ and where Z is CH(OH), Y is CHF or CF ２ and J is for CR Ｊ and Here, R Ｊ is H, F, Cl, Br, CH ３ , C.D. ３ , C.F. ３ , C.H.F. ２ , C.D.F. ２ , O.C.H. ３ or CN; E is CR Ｅ or N; Here, R Ｅ are H, F, Cl, Br, I, CN, and CH ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , C.D. ３ , C.H.D. ２ , C.H. ２ D, CHF ２ , C.D.F. ２ , C(CH ３ ) F ２ , C(CD ３ ) F ２ , C.F. ３ , cyclopropyl, OCH ３ , O.C.H. ２ CH ２ O.H., O.C.F. ３ , S.C.H. ３ or SCH ２ and G is CH or N;

2. R １ is F, Cl or OCHF ２ and R ２ But, CF ３ or CN; X is CH ２ or CHF; Y is (CH ２ ) ０～２ or CHF; Z is CHF, CDF, CF ２ , O, or S; J is CR Ｊ and Here, R Ｊ is H, F, Cl, CH ３ or CD ３ and E is CR Ｅ or N; Here, R Ｅ is H, F, Br, or CF ３ and G is CH; 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof.

3. R １ However, O.C.H.F. ２ and R ２ But, CF ３ and X is CH ２ or CHF; Y is (CH ２ ) ０～２ and Z is CF ２ or O; J is CR Ｊ and Here, R Ｊ is H, F, Cl, CH ３ or CD ３ and E is CR Ｅ or N; Here, R Ｅ is H, F, Br or CF ３ and G is CH; 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof.

4. The stereochemistry is of formula (Ia) 【Chemistry 2】 4. A compound of formula (I) according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, as defined as follows:

5. The stereochemistry is of formula (Ib) 【Chemistry 3】 5. A compound of formula (I) according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, as defined as follows:

6. X is CH ２ or CHF; Y is (CH ２ ) ０～２ and Z is O, S or CF ２ and E is CR Ｅ or N; Here, R Ｅ is H, F, Br or CF ３ and J is CR Ｊ and Here, R Ｊ is H, F, Cl, CH ３ or CD ３ That is, The compound according to claim 5.

7. (S)-5'-bromo-8-(difluoromethoxy)-4'-fluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-8-(difluoromethoxy)-4',5'-difluoro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-8'-(difluoromethoxy)-3,6'-bis(trifluoromethyl)-5,6-dihydro-3'H-spiro[cyclopenta[c]pyridine-7,2'-imidazo[1,2-α]pyridine]; (S)-5'-bromo-8-(difluoromethoxy)-4'-fluoro-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]-6-carbonitrile; (S)-5'-bromo-4'-fluoro-8-(fluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-8-(difluoromethoxy)-5',6-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-6'-bromo-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-6'-bromo-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one; (1'S,3'R)-6'-bromo-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one; (1'S,3'R,4'S)-6'-bromo-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'-ol; (S)-6'-bromo-8-(difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-8-(difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-6'-bromo-8-(difluoromethoxy)-5'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile; (S)-6'-bromo-8-(difluoromethoxy)-4',4',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-8-(difluoromethoxy)-4',4',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile; (S)-6'-bromo-8-chloro-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-6'-bromo-8-(difluoromethoxy)-3',3',5'-trifluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one; (1'S,4'S)-6'-bromo-8-(difluoromethoxy)-3',3',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'-ol; (1'S,4'R)-6'-bromo-8-(difluoromethoxy)-3',3',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridin-2,1'-naphthalen]-4'-ol; (1'S,3'R)-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one; (1'S,3'R)-8-(difluoromethoxy)-3',5'-difluoro-6-(trifluoromethyl)-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'(3'H)-one; (S)-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile; (S)-8-(difluoromethoxy)-4',4',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (2S,4'S)-6'-bromo-8-(difluoromethoxy)-4',5'-difluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile; (1'S,4'S)-8-(difluoromethoxy)-4',5'-difluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile; (S)-8-(difluoromethoxy)-5'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile; d ２ -(S)-8-(difluoromethoxy)-5'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile; (S)-8-(difluoromethoxy)-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-5',6',8-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-1'-chloro-8',8'-difluoro-8-methoxy-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-8-(difluoromethoxy)-8',8'-difluoro-1'-methyl-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-8-(difluoromethoxy)-8',8'-difluoro-1'-(methyl-d ３ )-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-8-(difluoromethoxy)-8',8'-difluoro-1'-methoxy-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-8-(difluoromethoxy)-6'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile; (S)-1'-chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-3'-chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-6',7'-dihydro-3H,5'H-spiro[imidazo[1,2-α]pyridine-2,8'-isoquinoline]; (S)-8-(difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6'-carbonitrile; (S)-7-bromo-8'-(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-8-fluoro-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7-chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7-bromo-8-fluoro-8'-(fluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7-chloro-8'-(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-7,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-8-fluoro-7-methyl-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8-chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7-bromo-8'-(difluoromethoxy)-8-fluoro-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]-6'-carbonitrile; (S)-7-Bromo-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-8-fluoro-7-iodo-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]-6'-carbonitrile; (S)-7-bromo-6'-chloro-8'-(difluoromethoxy)-8-fluoro-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-chloro-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7,8'-bis(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-8-(difluoromethyl)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-pyrano[2,3-c]pyridine]; (2'S,3R)-7-bromo-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (2'S,3S)-7-bromo-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (2'S,3R)-7-bromo-8'-(difluoromethoxy)-3-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (2'S,3R)-8'-(difluoromethoxy)-3-fluoro-7-iodo-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (2'S,3R)-8'-(difluoromethoxy)-3-fluoro-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (2'S,3R)-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8-(difluoromethoxy)-8'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isochroman]; (S)-7'-chloro-8-(difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile; (S)-8-(difluoromethoxy)-8'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]; (S)-8-(difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile; (S)-8-(difluoromethoxy)-8'-fluoro-6,7'-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiopyrano[3,2-c]pyridine]; (S)-8-(difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isothiochroman]-6-carbonitrile; (S)-8'-(difluoromethoxy)-9-fluoro-6'-(trifluoromethyl)-3,4-dihydro-2H,3'H-spiro[benzo[b]oxepin-5,2'-imidazo[1,2-α]pyridine]; (S)-8-(difluoromethoxy)-1'-(difluoromethyl)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-5'-bromo-4',8-dichloro-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-5'-bromo-8-(difluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-8-(difluoromethoxy)-5'-iodo-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]-6-carbonitrile; (S)-8-(difluoromethoxy)-4'-fluoro-5',6-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-8-(difluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,1'-indene]; (S)-5',8-difluoro-6'-methoxy-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-8-Fluoro-6,6'-bis(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; rac-5',6',8-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-8-chloro-5'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-6'-bromo-5'-fluoro-8-methoxy-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; rac-5'-bromo-8-(difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-5'-chloro-8-(difluoromethoxy)-6'-fluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (2S,3'R,4'R)-6'-bromo-8-(difluoromethoxy)-3',4',5'-trifluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-8-(difluoromethoxy)-5'-fluoro-6'-methoxy-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-8-(difluoromethoxy)-5',6'-difluoro-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-8-(difluoromethoxy)-6,6'-bis(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; rac-8-(difluoromethoxy)-5',6-bis(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-5'-chloro-8-(difluoromethoxy)-6-(trifluoromethyl)-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-6'-bromo-6-chloro-8-(difluoromethoxy)-5'-fluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]; (S)-6'-bromo-8-(difluoromethoxy)-6-(trifluoromethyl)-2',3'-dihydro-3H,4'H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalen]-4'-one; (S)-8-(difluoromethoxy)-5',6'-difluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile; (S)-6'-bromo-8-(difluoromethoxy)-4',4',5'-trifluoro-3',4'-dihydro-2'H,3H-spiro[imidazo[1,2-α]pyridine-2,1'-naphthalene]-6-carbonitrile; rac-8-(difluoromethoxy)-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-1'-chloro-8-(difluoromethoxy)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]-6-carbonitrile; (S)-8-chloro-8'-(fluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8-chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]-7-carbonitrile; (3R,4S)-7-chloro-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (3R,4S)-8'-(difluoromethoxy)-3,7,8-trifluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-8-fluoro-7-(methylthio)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7-Bromo-8-chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; rac-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7,8-dibromo-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-8-fluoro-7-methoxy-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-6',8-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-8-fluoro-7-(trifluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-7-((difluoromethyl)thio)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8-Bromo-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; rac-8-(difluoromethoxy)-8'-fluoro-6,7'-bis(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isochroman]; (2S)-8-(difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile-2',2',3'-d3; (S)-7'-bromo-8-(difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile; (S)-8-(difluoromethoxy)-8'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-7'-carbonitrile; (S)-8-(difluoromethoxy)-7',8'-difluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile; (S)-8-(difluoromethoxy)-7',8'-difluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]; (S)-8'-fluoro-8-(fluoromethoxy)-6,7'-bis(trifluoromethyl)-2',3'-dihydro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiopyrano[3,2-c]pyridine]; (S)-8-(difluoromethoxy)-8'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isothiochroman]; (S)-8-(difluoromethoxy)-7'-fluoro-6-(trifluoromethyl)-3H-spiro[imidazo[1,2-α]pyridine-2,4'-isothiochroman]; (S)-8'-(difluoromethoxy)-8,9-difluoro-6'-(trifluoromethyl)-3,4-dihydro-2H,3'H-spiro[benzo[b]oxepin-5,2'-imidazo[1,2-α]pyridine]; rac-9-chloro-8'-(difluoromethoxy)-6'-(trifluoromethyl)-3,4-dihydro-2H,3'H-spiro[benzo[b]oxepin-5,2'-imidazo[1,2-α]pyridine]; and (S)-8-Chloro-8'-(difluoromethoxy)-9-fluoro-6'-(trifluoromethyl)-3,4-dihydro-1H,3'H-spiro[benzo[c]oxepin-5,2'-imidazo[1,2-α]pyridine] 2. The compound of formula (I) according to claim 1, selected from the group consisting of:

8. (S)-8-(difluoromethoxy)-8'-fluoro-3H-spiro[imidazo[1,2-α]pyridine-2,4'-thiochroman]-6-carbonitrile; (S)-8'-(difluoromethoxy)-9-fluoro-6'-(trifluoromethyl)-3,4-dihydro-2H,3'H-spiro[benzo[b]oxepin-5,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-6',7-bis(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-7-bromo-8'-(difluoromethoxy)-8-fluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (2'S,3R)-8'-(difluoromethoxy)-3,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-8'-(difluoromethoxy)-7,8-difluoro-6'-(trifluoromethyl)-3'H-spiro[chroman-4,2'-imidazo[1,2-α]pyridine]; (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; (S)-8-(difluoromethoxy)-8',8'-difluoro-1'-(methyl-d ３ )-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline]; and (S)-8-(Difluoromethoxy)-8',8'-difluoro-1'-methyl-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] 2. The compound of formula (I) according to claim 1, selected from the group consisting of:

9. 【Chemical 4】 or a pharma- ceutically acceptable salt thereof.

10. 【Chemical 5】 10. The compound of claim 9, wherein:

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers.

12. A combination comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, and one or more therapeutically active agents.

13. The therapeutic agent is selected from the group consisting of temsirolimus, ridaforolimus, everolimus (RAD001), rapamycin, simapimod, (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055), 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one, ２ 13. The combination of claim 12, wherein the mTOR inhibitor is selected from: -[1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-α-aspartyl-L-serine-; N-[4-[[[3-[(3,5-dimethoxyphenyl)amino]-2-quinoxalinyl]amino]sulfonyl]phenyl]-3-methoxy-4-methyl-benzamide; or (1r,4r)-4-(4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[1,5-f][1,2,4]triazin-7-yl)cyclohexanecarboxylic acid.

14. 14. The combination of claim 13, wherein the mTOR inhibitor is everolimus.

15. 13. A pharmaceutical composition for modulating HIF2α activity in a subject, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof.

16. 11. A pharmaceutical composition for treating a disorder or disease which is cancer, said pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof.

17. 17. The pharmaceutical composition of claim 16, wherein the cancer is selected from adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, and renal cell carcinoma.

18. A crystalline form of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] fumarate, characterized by having a powder X-ray diffraction pattern including reflections at 2θ angles of (24.9±0.2)°, (6.2±0.2)° and (20.9±0.2)° when measured at a temperature in the range of 20-30°C using Cu-Kα1,2 radiation having a wavelength of 0.15406 nm.

19. A crystalline form of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] fumarate, characterized by having a powder X-ray diffraction pattern including reflections at 2θ angles of (24.9±0.2)°, (6.2±0.2)°, (20.9±0.2)°, (10.9±0.2)° and (18.5±0.2)° when measured at a temperature in the range of 20-30°C using Cu-Kα1,2 radiation having a wavelength of 0.15406 nm.

20. A crystalline form of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] fumarate, characterized by having a powder X-ray diffraction pattern including reflections at 2θ angles of (24.9±0.2)°, (6.2±0.2)°, (20.9±0.2)°, (10.9±0.2)°, (18.5±0.2)°, (22.8±0.2)°, (12.9±0.2)° and (16.1±0.2)° when measured at a temperature in the range of 20-30°C using Cu-Kα1,2 radiation having a wavelength of 0.15406 nm.

21. 21. The crystal according to any one of claims 18 to 20, characterized by having a thermogravimetric analysis curve showing a mass loss of 0.4 wt.% or less based on the weight of the crystal when heated from 10 to 250°C at a rate of 10 K / min.

22. A crystalline form of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] free form, characterized by having a powder X-ray diffraction pattern including reflections at 2θ angles of (9.7±0.2)°, (18.4±0.2)° and (19.4±0.2)° when measured at a temperature in the range of 20-30°C using Cu-Kα1,2 radiation having a wavelength of 0.15406 nm.

23. A crystalline form of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] free form, characterized by having an X-ray powder diffraction pattern including reflections at 2θ angles of (9.7±0.2)°, (18.4±0.2)°, (19.4±0.2)°, (13.4±0.2)° and (20.7±0.2)° when measured at a temperature in the range of 20-30°C using Cu-Kα1,2 radiation having a wavelength of 0.15406 nm.

24. A crystal of (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2-α]pyridine-2,5'-isoquinoline] free form, characterized by having a powder X-ray diffraction pattern including reflections at 2θ angles of (9.7±0.2)°, (18.4±0.2)°, (19.4±0.2)°, (13.4±0.2)°, (20.7±0.2)°, (24.2±0.2)°, (22.1±0.2)° and (10.3±0.2)° when measured at a temperature in the range of 20-30°C using Cu-Kα1,2 radiation having a wavelength of 0.15406 nm.

25. 25. The crystal according to any one of claims 22 to 24, characterized by having a thermogravimetric analysis curve showing a mass loss of 0.2 wt.% or less based on the weight of the crystal when heated from 10 to 250°C at a rate of 10 K / min.

26. A pharmaceutical composition for treating cancer, comprising a compound according to any one of claims 18 to 25 or a pharma- ceutically acceptable salt thereof.

27. 27. The pharmaceutical composition of claim 26, wherein the cancer is selected from adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, eye cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, and renal cell carcinoma.

28. Compounds of formula (I) 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof, comprising the steps of: Compound of formula (IV) 【Chemistry 7】 or a salt, solvate, stereoisomer, or co-crystal thereof, optionally with K ２ CO ３ and Et ３ N in the presence of a base selected from the group consisting of a compound of formula (III) 【Chemistry 8】 or a salt, solvate, stereoisomer, or co-crystal thereof to produce a compound of formula (II) or a salt, solvate, stereoisomer, or co-crystal thereof; 【Chemistry 9】 (In the formula, R １ is F, Cl, Br, OCH ３ , O.C.H. ２ F, O.C.H.F. ２ , or O.C.F. ３ and R ２ is F, Cl, CF ３ or CN; X is (CH ２ ) １～２ , CHF, CHD, CD ２ Or CF ２ and Y is (CH ２ ) ０～２ , CHF, CHD, CD ２ ,O.S.,O.C.H. ２ , or C.F. ２ and Z is CH ２ , C.D. ２ , CHF, CDF, CF ２ , CH(OH), CO, CH(CH ３ ), O, or S; Here, Y is O, OCH ２ , or if S, Z is CH ２ and where Z is O, S, or NCH ３ In the case of ２ ) ０～２ , or C.F. ２ and where Z is CH(OH), Y is CHF or CF ２ and J is for CR Ｊ and Here, R Ｊ is H, F, Cl, Br, CH ３ , C.D. ３ , C.F. ３ , C.H.F. ２ , C.D.F. ２ , O.C.H. ３ or CN; E is CR Ｅ or N; Here, R Ｅ are H, F, Cl, Br, I, CN, and CH ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , C.D. ３ , C.H.D. ２ , C.H. ２ D, CHF ２ , C.D.F. ２ , C(CH ３ ) F ２ , C(CD ３ ) F ２ , C.F. ３ , cyclopropyl, OCH ３ , O.C.H. ２ CH ２ O.H., O.C.F. ３ , S.C.H. ３ , S.C.H.F. ２ and G is CH or N; LG is a leaving group selected from F, Cl, or Br; and subsequently cyclizing the compound of formula (II) to produce a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

29. The compound of formula (II) is a compound of pyridine and Et ３ SOCl in toluene in the presence of a base selected from ２ 29. The process according to claim 28, wherein the aryl group is cyclized with a reagent selected from toluenesulfonyl chloride and methanesulfonyl chloride to obtain the compound of formula (I).

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