Compounds, pharmaceutical compositions, combination products, kits of parts, and processes

Abstract

The present invention provides compounds of formula I: TIFF2025503995000109.tif4146 A compound of formula I or a pharma- ceutically acceptable salt thereof, wherein A is a medicament for use in the treatment of cancer and / or in the treatment or prophylaxis of a viral infection. 1 , A 2 , L 1 and R 1 have the meanings given herein).

Description

[Technical field]

[0001] The present invention relates to novel compounds, compositions and their pharmaceutical uses. In particular, the present invention relates to certain tetrahydropyranopyrazoles that are useful in the treatment of cancer and / or the treatment or prevention of viral infections. [Background technology]

[0002] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0003] In the past decade, several small molecules and peptides have been identified that activate p53 tumor suppressor function in a DNA damage-independent manner (see, e.g., CJ Brown et al., Nature reviews: Cancer, 9, 862(2009)). Some of these compounds disrupt the interaction of p53 with mdm2 and / or mdmx (also called mdm4), two key negative regulators of p53 (see Hoe, CS et al., Nat Rev Drug Discov. 13, 217 (2014)).

[0004] There are several chemically distinct classes of mdm2 / p53 binding antagonists, of which Nutlin-3 is the most readily available and is commonly used to protect p53 from degradation (see LT Vassilev et al., Science. 303, 844 (2004); IR Hardcastle et al., Bioorganic & medicinal chemistry letters, 15, 1515 (2005); K. Ding et al., Journal of medicinal chemistry, 49, 3432 (2006); and CJ Brown et al., ACS chemical biology, 8, 506 (2013)). RG7112 (Roche), a derivative of Nutlin-3, recently completed phase I clinical trials (see I. Ray-Coquard et al., The Lancet Oncology, 13, 1133 (2012)).

[0005] Although mdm2 / p53 binding antagonists have cytotoxic effects, they also have reversible cytostatic effects that may limit their efficacy, which may be due in part to the strong induction of p21(waf1 / cip1) by these compounds.

[0006] In the past few years, the ATM kinase inhibitors KU-55933 and BRAF V600EA series of reports have demonstrated increased efficacy of Nutlin-3 in killing tumor cells when administered in combination with other targeted small molecules, such as the inhibitor vemurafenib (see KD Sullivan et al., Nature Chemical Biology, 8, 646 (2012); Z. Ji et al., Clinical cancer research: an official journal of the American Association for Cancer Research, 19, 4383 (2013); and M. Lu et al., Cancer Cell, 23, 618 (2013)).

[0007] Previous disclosures have utilized a series of phenotypic screens to search for novel p53 activators. These screens were performed using a mouse fibroblast cell line (T22 RGCΔFos-LacZ cells) and led to the identification of compounds that activate p53 in all TP53 wild-type cells tested, as described for Nutlin-3 (see S. Lain et al., Cancer Cell, 13, 454 (2008); GM Marshall et al., PLoS genetics, 7, e1002135 (2011); H. Yuan et al., Blood, 119, 1904 (2012); A. Menssen et al., Proc Natl Acad Sci USA, 109, E187 (2012)).

[0008] Targeted therapeutic agents such as mdm2 / p53 binding antagonists and BCR / ABL tyrosine kinase inhibitors can reduce cancer growth but rarely lead to complete eradication of malignant cells. Thus, there is a need to identify compounds that can increase the pro-apoptotic function of tumor suppressors that could improve the chances of achieving a cure for cancer patients.

[0009] Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), Western / Eastern equine encephalitis (WEE / EEE), and Ebola, as well as pandemic influenza (e.g., H1N1), are deadly and can be transmitted by travelers. The rapid spread of these diseases poses a major threat to public health worldwide, and broad-spectrum antiviral drugs will be required to prevent pandemic outbreaks, if possible, and allow time for the development of effective vaccines (“Broad-spectrum antiviral agents,” Jun-Da Zhu, WenMeng, Xiao-JiaWang and Hwa-Chain, R. Wang, Frontiers in Microbiology, doi: 10.3389 / fmicb.2015.00517). Additionally, inhibition of DHODH, or de novo pyrimidine biosynthesis, has been reported as an antiviral approach, particularly against Ebola, HIV, HCV, hCMV, influenza (Hoffmann et al., Proc. Natl. Acad. Sci. 2011; 108: 5777; Wang et al., J. Virol. 2011; 85: 6548, Hahn et al., Viruses 2020; 12: 1394), and rotavirus (Chen et al., Antiviral Research 2019; 167: 35).

[0010] WO2017 / 077280 discloses 4,5,6,7-tetrahydroindazole compounds for use in the treatment of cancer and viral infections.

[0011] Ladds, MJGW et al., Nature Communications, 9, 1-14 (2018) describe tetrahydroindazole-based human dihydrorotate dehydrogenase (hDHODH) inhibitors that increase p53 synthesis and enhance tumor cell killing via blocking p53 degradation.

[0012] Popova, G. et al., Journal of Medicinal Chemistry, 63 (8), 3915-3934 (2020) describe tetrahydroindazole-based hDHODH inhibitors that were evaluated for their activity and in vitro metabolic stability. Summary of the Invention

[0013] The compounds described by Ladds et al. (2018) and Popova et al. (2020) are tetrahydroindazoles that suffer from metabolic disorders and have specific cytochrome P450 (CYP) impairment. The inventors have surprisingly found that by introducing an oxygen atom into the central ring system, the resulting tetrahydropyranopyrazoles are more stable in human liver microsomes and human hepatocytes, while exhibiting relatively low inhibition against a range of CYPs in human liver microsomes.

[0014] compound In a first aspect of the invention, there is provided a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0015] [ka] Where: A 1 represents an optionally substituted aryl or heteroaryl; A 2 represents an optionally substituted aryl or heteroaryl; L 1 -C(O)-, -C(O)N(R 2 )-, -C(O)O-, -S(O) j -or-S(O) k N(R 3 )-represents; R 1 is H or C optionally substituted with one or more halo 1-3 represents alkyl; R 2 and R 3each independently represents H or C optionally substituted with one or more halo 1-3 represents alkyl; each j independently represents 0, 1, or 2; and each k independently represents 1 or 2; These compounds (including the pharma- ceutically acceptable salts) may be referred to herein as compounds of the first aspect of the invention.

[0016] According to a first aspect of the present invention there is provided a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0017] [ka] Where: A 1 is G 1 or an aryl optionally substituted with one or more groups independently selected from 2 represents a heteroaryl optionally substituted by one or more groups independently selected from A 2 is G 3 or an aryl optionally substituted with one or more groups independently selected from 4 represents a heteroaryl optionally substituted by one or more groups independently selected from L 1 -C(O)-, -C(O)N(R 2 )-, -C(O)O-, -S(O) j -or-S(O) k N(R 3 )-represents; R 1 is H or C optionally substituted with one or more halo 1-3 represents alkyl; R 2 and R 3 each independently represents H or C optionally substituted with one or more halo 1-3 represents alkyl; each G 1 are independent, halo, R a1、 -CN, -A a1 -C(Qa1 )R b1 , -A b1 -C(Q b1 )N(R c1 )R d1 , -A c1 -C(Q c1 ) OR e1 , -A d1 -S(O) p R f1 , -A e1 -S(O) q N(R g1 )R h1 , -A f1 -S(O) p OR i1 , -N3, -N(R j1 )R k1 , -N(H)CN, -NO 2、 -ONO2, -OR l1 or -SR m1 represents; Each Q a1 ~Q c1 are independently: =O, =S, =NR n1 OR=N o1 ) ; Each A a1 ~A f1 are independently a single bond, -N(R p1 )- or -O-; each G 2 are independent, halo, R a2 , -CN, -A a2 -C(Q a2 )R b2 , -A b2 -C(Q b2 )N(R c2 )R d2、 -A c2 -C(Q c2 ) OR e2 , -A d2 -S(O) p R f2 , -A e2 -S(O) q N(R g2 )R h2 , -A f2 -S(O) p OR i2 , -N3, -N(R j2 )R k2, -N(H)CN, -NO 2、 -ONO2, -OR l2 or -SR m2 represents; Each Q a2 ~Q c2 are independently: =O, =S, =NR n2 OR=N o2 ) ; Each A a2 ~A f2 are independently a single bond, -N(R p2 )- or -O-; each G 3 are independent, halo, R a3 , -CN, -A a3 -C(Q a3 )R b3 , -A b3 -C(Q b3 )N(R c3 )R d3 , -A c3 -C(Q c3 ) OR e3 , -A d3 -S(O) p R f3、 -A e3 -S(O) q N(R g3 )R h3 , -A f3 -S(O) p OR i3 , -N3, -N(R j3 )R k3 , -N(H)CN, -NO 2、 -ONO2, -OR l3 or -SR m3 represents; Each Q a3 ~Q c3 are independently: =O, =S, =NR n3 OR=N o3 ) ; Each A a3 ~A f3 are independently a single bond, -N(R p3 )- or -O-; each G 4 are independent, halo, R a4 , -CN, -A a4 -C(Q a4 )Rb4 , -A b4 -C(Q b4 )N(R c4 )R d4 , -A c4 -C(Q c4 ) OR e4 , -A d4 -S(O) p R f4 , -A e4 -S(O) q N(R g4 )R h4 , -A f4 -S(O) p OR i4 , -N3, -N(R j4 )R k4 , -N(H)CN, -NO 2、 -ONO2, -OR l4 or -SR m4 represents; Each Q a4 ~Q c4 are independently: =O, =S, =NR n4 OR=N o4 ) ; Each A a4 ~A f4 are independently a single bond, -N(R p4 )- or -O-; Each R a1 and R f1 are independent, G 5a C may be substituted with one or more groups independently selected from 1-6 Alkyl, G 5b Heterocycloalkyl optionally substituted with one or more groups independently selected from 5c or G 5d represents a heteroaryl optionally substituted with one or more groups independently selected from Each R p1 are independently H or C optionally substituted with one or more halo 1-6 represents alkyl; Each R b1 , R c1 , R d1 , R e1 , R g1 , Rh1 , R i1 , R j1 , R k1 , R l1 , R m1 , R n1 and R o1 are independent, H, G 5a C may be substituted with one or more groups independently selected from 1-6 Alkyl, G 5b Heterocycloalkyl, optionally substituted by one or more groups independently selected from 5c or G 5d or Instead, R c1 and R d1 , R g1 and R h1 and / or R j1 and R k1 or any one of these is linked to each other to form a 3- to 6-membered ring together with the nitrogen atom to which they are attached, and the ring may optionally further contain one heteroatom, and the ring may be optionally substituted by halo, C 1-3 optionally substituted with one or more groups selected from alkyl, and =O; Each R a2 and R f2 are independent, G 6a C optionally substituted with one or more groups independently selected from 1-6 Alkyl, G 6b heterocycloalkyl optionally substituted with one or more groups independently selected from 6c or G 6d represents heteroaryl optionally substituted with one or more groups independently selected from: Each R p2 are independently H or C optionally substituted with one or more F. 1-6 represents alkyl; Each R b2、 R c2, R d2 , Re2 , R g2 , R h2 , Ri2 , R j2 , R k2 , R l2 , R m2 , R n2 and R o2 are independent, H, G 6a C may be substituted by one or more groups independently selected from 1-6 Alkyl, G 6b Heterocycloalkyl, optionally substituted by one or more groups independently selected from 6c or G 6d or Instead, R c2 and R d2 , R g2 and R h2 and / or R j2 and R k2 are linked to each other to form a 3- to 6-membered ring together with the nitrogen atom to which they are attached, and the ring may optionally further contain one heteroatom, and the ring may be optionally substituted with halo, C 1-3 optionally substituted with one or more groups selected from alkyl, and =O; each Ra3 and R f3 are independent, G 7a C optionally substituted with one or more groups independently selected from 1-6 Alkyl, G 7b heterocycloalkyl optionally substituted with one or more groups independently selected from 7c or G 7d represents heteroaryl optionally substituted with one or more groups independently selected from: Each R p3 are independently H or C optionally substituted with one or more F. 1-6represents alkyl; Each R b3、 R c3 , R d3 , R e3 , R g3 , R h3 , Ri3 , R j3 , R k3 , R l3 , R m3 , R n3 and R o3 are independent, H, G 7a C may be substituted by one or more groups independently selected from 1-6 Alkyl, G 7b Heterocycloalkyl, optionally substituted by one or more groups independently selected from 7c or G 7d or Instead, R c3 and R d3 , R g3 and R h3 and / or R j3 and R k3 are linked to each other to form a 3- to 6-membered ring together with the nitrogen atom to which they are attached, and the ring may optionally further contain one heteroatom, and the ring may be optionally substituted with halo, C 1-3 optionally substituted with one or more groups selected from alkyl, and =O; each Ra4 and R f4 are independent, G 8a C optionally substituted with one or more groups independently selected from 1-6 Alkyl or G 8b heterocycloalkyl optionally substituted with one or more groups independently selected from 8c or G 8d represents heteroaryl optionally substituted with one or more groups independently selected from Each R p4are independently H or C optionally substituted with one or more F. 1-6 represents alkyl; Each R b4、 R c4 , R d4 , R e4 , R g4 , R h4 , R i4 , R j4 , R k4 , R l4 , R m4 , R n4 and R o4 are independent, H, G 8a C may be substituted by one or more groups independently selected from 1-6 Alkyl or G 8b or Instead, R c4 and R d4 , R g4 and R h4 and / or R j4 and R k4 are linked to each other to form a 3- to 6-membered ring together with the nitrogen atom to which they are attached, and the ring may optionally further contain one heteroatom, and the ring may be optionally substituted with halo, C 1-3 optionally substituted with one or more groups selected from alkyl, and =O; each G 5a、 G 5b , G 6a , G 6b、 G 7a、 G 7b、 G 8a and G 8b are independently halo, -CN, -N(R b5 )R c5 , -OR d5 , -SR e5 or =O; each G 5c、 G 5d , G 6c , G 6d、 G 7c、 G 7d , G 8c and G 8dare independent, halo, R a5 , -CN, -N(R b5 )R c5 , -OR d5 , -SR e5 or =O; each Ra5 each independently represents C optionally substituted with one or more F; 1-6 represents alkyl; Each R b5、 R c5 , R d5 and Re5 are independently H or C optionally substituted with one or more F or ═O. 1-6 represents alkyl; Or R b5 and R c5 are bonded to each other to form a 3- to 6-membered ring together with the nitrogen atom to which they are bonded, and the ring may optionally further contain one heteroatom, and the ring may be substituted with F, C 1-3 optionally substituted with one or more groups selected from alkyl, and =O; each j independently represents 0, 1, or 2; and each k, p, and q independently represents 1 or 2; These compounds (including the pharma- ceutically acceptable salts) may be referred to herein as compounds of the first aspect of the invention.

[0018] Those skilled in the art will understand that reference herein to a compound of a particular aspect of the invention includes reference to all embodiments and specific forms thereof, and that these embodiments and specific forms can be combined to form further embodiments.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0020] Pharmaceutically acceptable salts include acid addition salts and base addition salts.Such salts can be formed by conventional means, for example, by reacting the free acid or free base form of the compound of the present invention with one or more equivalents of suitable acid or base, optionally in a solvent or medium in which the salt is insoluble, followed by removing the solvent or medium using standard techniques (for example, in vacuum, by lyophilization, or by filtration).Salts can also be prepared by exchanging the counterion of the compound of the present invention in the form of a salt with another counterion, for example, by using a suitable ion exchange resin.

[0021] Specific acid addition salts include carboxylates (e.g., formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propionate, ascorbate, citrate, glucuronate, glutamate, glycolate, alpha-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, cobalt salts, tert-butyl benzoate ... Succinates, suberates, sebacates, fumarates, malates, maleates, hydroxymaleates, hippurates, phthalates or terephthalates), halides (e.g. chlorides, bromides, iodides), sulfonates (e.g. benzenesulfonates, methyl-, bromo- or chloro-benzenesulfonates, xylenesulfonates, methanesulfonates, ethanesulfonates, propanesulfonates, hydroxyethanesulfonates, 1- or 2-naphthalenesulfonates or 1,5-naphthalenedisulfonates), or sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates or nitrates.

[0022] Particular base addition salts include those formed with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine, and lysine), and inorganic bases (such as ammonia and aluminium hydroxide).More particularly, base addition salts that may be mentioned include Mg salts, Ca salts, and most particularly K salts and Na salts.

[0023] For the avoidance of doubt, the compound of the first aspect of the present invention may exist as a solid, and therefore the scope of the present invention includes all amorphous, crystalline and partially crystalline forms thereof, and may also exist as an oil. When the compound of the first aspect of the present invention exists in crystalline and partially crystalline form, such forms may include solvates that are included within the scope of the present invention. The compound of the first aspect of the present invention may also exist in solution.

[0024] The compounds of the first aspect of the present invention may contain double bonds and therefore may exist as E (inverted) and Z (together) geometric isomers about each individual double bond, and all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0025] The compounds of the first aspect of the invention may also exhibit tautomerism, and all tautomeric forms and mixtures thereof are included within the scope of the invention.

[0026] The compounds of the present invention may also contain one or more asymmetric carbon atoms and therefore may exhibit optical isomerism and / or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, such as chromatography or fractional crystallization. The various stereoisomers (i.e., enantiomers) may be isolated by separation of racemic or other mixtures of compounds using conventional techniques, such as fractional crystallization or HPLC. Alternatively, the desired optical isomer may be prepared by reaction of suitable optically active starting materials under conditions that do not cause racemization or epimerization (i.e., the "chiral pool" method), by reaction of suitable starting materials with "chiral auxiliaries" that can be subsequently removed at a suitable stage, by derivatization (i.e., resolution, including dynamic resolution), for example, by derivatization with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with a suitable chiral reagent or chiral catalyst (all under conditions known to those skilled in the art). All stereoisomers and mixtures thereof are encompassed within the scope of the present invention.

[0027] In particular, the compounds of the first aspect of the invention exhibit stereoisomerism at the carbon indicated in the compound of formula I below with an asterisk (*), and the compounds of the first aspect of the invention exist in the R- and S-configurations at that carbon (this configuration can be determined by one of skill in the art).

[0028] [ka]

[0029] As used herein, references to halo and / or halogen groups each independently refer to fluoro, chloro, bromo, and iodo (eg, fluoro (F) and chloro (Cl)).

[0030] Unless otherwise specified, C as defined herein 1-zThe alkyl group (where z is the upper limit of the range) may be straight chain or, provided there is a sufficient number (i.e., a minimum of 2 or 3, as appropriate) of carbon atoms, may be branched chain and / or cyclic (hence, C 3-z Forming a cycloalkyl group). When there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may be part cyclic. Part cyclic alkyl groups which may be mentioned include cyclopropylmethyl and cyclohexylethyl. When there is a sufficient number of carbon atoms, such groups may be polycyclic (e.g. bicyclic or tricyclic) or spirocyclic. Such alkyl groups may be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, may be unsaturated (e.g. C 2-z Alkenyl or C 2-z forming an alkynyl group).

[0031] As used herein, the term aryl refers to 6-14 (For example, C 6-10 ) aromatic groups. Such groups may be monocyclic or bicyclic, and if bicyclic, may be either fully aromatic or partially aromatic. 6-10 Aryl groups include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, etc. (e.g., phenyl, naphthyl, etc., e.g., phenyl). For the avoidance of doubt, the point of attachment of substituents on an aryl group may be via any carbon atom of the ring system.

[0032] As used herein, the term heteroaryl (or heteroaromatic) includes reference to 5-14 (e.g., 5-10) membered heteroaromatic groups containing one or more heteroatoms selected from oxygen, nitrogen, and / or sulfur. Such heteroaryl groups may contain one, two, or three rings, at least one of which is aromatic (e.g., a heteroaryl group may contain two rings, one of which is aromatic). Substituents on the heteroaryl / heteroaromatic group may be located on any atom in the ring system, including the heteroatom, where appropriate. The point of attachment of the heteroaryl / heteroaromatic group may be through any atom in the ring system, including the heteroatom (where appropriate). In particular, a bicyclic heteroaryl / heteroaromatic group may contain a benzene ring fused to one or more further aromatic or non-aromatic heterocyclic rings, in which case the point of attachment of the polycyclic heteroaryl / heteroaromatic group may be through the benzene ring or any ring, including the heteroaryl / heteroaromatic or heterocycloalkyl ring. Examples of heteroaryl / heteroaromatic groups that may be mentioned include pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thienothiophenyl, pyrimidinyl, furopyridinyl, indolyl, azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, and purinyl. Oxides of heteroaryl / heteroaromatic groups are also included within the scope of the present invention (e.g. N-oxides). As noted above, heteroaryl includes polycyclic (eg, bicyclic) groups in which one ring is aromatic (the other ring(s) may or may not be aromatic).Thus, other heteroaryl groups which may be mentioned include, for example, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, dihydrobenzo[d]isothiazole, 3,4-dihydrobenz[1,4]oxazinyl, dihydrobenzothiophenyl, indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, tetrahydro 1,2-benzisoxazolyl, 1,2,3,4-tetrahydroquinolinyl, thiochromanyl, etc.

[0033] As used herein, the term heterocycloalkyl can refer to non-aromatic monocyclic and bicyclic heterocycloalkyl groups (which groups can be further bridged) in which at least one (e.g., 1-4) of the atoms in the ring system is other than carbon (i.e., a heteroatom) and the total number of atoms in the ring system is 3-12 (e.g., 5-10, most preferably 3-8, e.g., 5- or 6-membered heterocycloalkyl groups). Further, such heterocycloalkyl groups can include, for example, C 2-z (For example, C 4-z ) heterocycloalkenyl (where z is the upper limit of the range) or C 7-z The heterocycloalkynyl group may be saturated or unsaturated, containing one or more double and / or triple bonds. 2-zHeterocycloalkyl groups include 7-azabicyclo-[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, 2,3-dihydroisothiazoyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, isothiocyanyl, ... Examples of heterocycloalkyl groups include thiazolidinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, tetrahydrothiopyranyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl, and the like. Substituents on a heterocycloalkyl group may, where appropriate, be located on any atom in the ring system, including a heteroatom. Additionally, when the substituent is another cyclic compound, the cyclic compound may be attached via a single atom on the heterocycloalkyl group, forming a so-called "spiro" compound. The point of attachment of the heterocycloalkyl group may be via any atom in the ring system, including (where appropriate) additional heteroatoms (such as nitrogen atoms), or atoms on any fused carbocyclic rings that may be present as part of the ring system. Heterocycloalkyl groups may also be in N- or S-oxidized forms.

[0034] At each occurrence, as mentioned herein, particular heterocycloalkyl groups that may be mentioned include 3- to 8-membered heterocycloalkyl groups (for example 4- to 6-membered heterocycloalkyl groups).

[0035] For the avoidance of doubt, as used herein, references to heteroatoms have their ordinary meaning as understood by those skilled in the art. Specific heteroatoms that may be mentioned include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen, and sulfur (e.g., oxygen, nitrogen, and sulfur).

[0036] For the avoidance of doubt, reference to polycyclic (e.g., bicyclic) groups (e.g., when used in the context of heterocycloalkyl groups) refers to ring systems in which more than two breaks are required to convert such rings into a linear chain, with the minimum number of such breaks corresponding to the number of rings defined (e.g., the term bicyclic may indicate that a minimum of two breaks are required to convert such rings into a linear chain). For the avoidance of doubt, the term bicyclic (e.g., when used in the context of heterocycloalkyl groups) refers to groups in which the second ring of the bicyclic system is formed between two adjacent atoms of the first ring, and may also refer to groups in which two non-adjacent atoms are linked by either an alkylene chain or a heteroalkylene chain (as appropriate), with the latter group being considered a bridge.

[0037] For the avoidance of doubt, it is understood that when an aryl or heteroaryl group is substituted with a group by a double bond such as =O, the aryl or heteroaryl group is partially aromatic, i.e., the aryl or heteroaryl group consists of at least two rings, at least one of which is not aromatic.

[0038] The present invention also includes the isotopically labeled compounds of the present invention that are the same as those listed herein, but due to the fact that one or more atoms are replaced by an atom that has a different atomic mass or mass number from the atomic mass or mass number that is usually found in nature (or the most abundant atom found in nature).All isotopes of any specific atom or element specified herein are contemplated within the scope of the compounds of the present invention.Therefore, the compounds of the present invention also include deuterated compounds, i.e., deuterated compounds in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

[0039] For the avoidance of doubt, where the identities of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are in no way interdependent. For example, two or more R 3 When groups are present, the R 3 The groups may be the same or different. Similarly, more than one R a1 are present and each independently is one or more G 1a C substituted with a group 1-6 When representing alkyl, each G 1a The identities of the two are never interdependent.

[0040] To avoid any misunderstanding, a1 ~A f1 " and other terms are used herein, which refer inclusively to A a1 , A b1 , A c1 , A d1 , A e1 , and A f1 It will be understood by those skilled in the art to mean "a" or "b". The same reasoning applies to other such terms used herein unless otherwise stated.

[0041] Those of skill in the art will appreciate that the compounds of the invention that are the subject of the present invention include stable compounds, i.e., compounds that are sufficiently robust to survive isolation to a useful degree of purity from, for example, a reaction mixture.

[0042] All embodiments and specific features of the invention described herein may be used alone or in combination with any other embodiment and / or specific features described herein without departing from the disclosure of the present invention (and thus the more specific embodiments and specific features disclosed herein are described).

[0043] As used herein, the term "optionally substituted" means that the referenced group may be substituted with one or more additional groups.

[0044] In a specific embodiment of the first aspect of the present invention, A1 is phenyl optionally substituted by one or more (one, two, or three, for example, one or two, etc.) groups independently selected from G 1 or heteroaryl optionally substituted by one or more (one, two, or three, for example, one or two, etc.) groups independently selected from G 2 and represents heteroaryl optionally substituted by one or more (one, two, or three, for example, one or two, etc.) groups independently selected from G

[0045] In a more specific embodiment, A 1 is heteroaryl optionally substituted by one or more (one, two, or three, for example, one or two, etc.) groups independently selected from G 2 and represents heteroaryl optionally substituted by one or more (one, two, or three, for example, one or two, etc.) groups independently selected from G

[0046] In an even more specific embodiment, A 1 is monocyclic or bicyclic heteroaryl optionally substituted by one or more (for example, one or two) groups independently selected from halo, R a2 , -C(O)OR e2 , -OR l2 , and -SR m2 (i.e., G 2 groups).

[0047] In an even more specific embodiment, A 1 is monocyclic or bicyclic heteroaryl optionally substituted by one or more (for example, one or two) groups independently selected from halo (for example, F), C 1-3 alkyl optionally substituted by one or more fluoros (-CF3, etc.), -C(O)OH, -C(O)OC 1-3 alkyl, -OH, -OC 1-3 alkyl, -SH, and -SC 1-3 alkyl (F, C 1-2 alkyl, -OH, and -SCH3, etc.) (i.e., G 2 groups).

[0048] In an even more specific embodiment, A 1 is halo (for example, F), C 1-3 alkyl, -CF3, -C(O)OH, -C(O)OC1-3 Alkyl, -OH, -OC 1-3 Alkyl, -SH, and -SC 1-3 Alkyl (F, C 1-2 One or more (e.g., one or two) groups independently selected from alkyl, -OH, and -SCH3, etc. (i.e., G 2 group) optionally substituted by a monocyclic or bicyclic heteroaryl.

[0049] In a more specific embodiment, A 1 is halo (e.g., F), C 1-3 alkyl, -C(O)OH, -C(O)OC 1-3 alkyl, -OH, -OC 1-3 alkyl, -SH, and -SC 1-3 alkyl (F, C 1-2 One or more (e.g., one or two) groups independently selected from alkyl, -OH, and -SCH3, etc. (i.e., G 2 group) optionally substituted by a monocyclic or bicyclic heteroaryl.

[0050] For example, A 1 is halo, R a2 , -C(O)OR e2 , -OR l2 , and -SR m2 One or two groups independently selected from (i.e., G 2 group) (e.g., halo (e.g., F), C 1-3 alkyl, -C(O)OH, -C(O)OC 1-3 alkyl, -OH, -OC 1-3 alkyl, -SH, and -SC 1-3 One or two groups independently selected from alkyl, e.g., F, C 1-2 One or two groups independently selected from alkyl, -OH, and -SCH3 (i.e., G 2For the avoidance of doubt, such bicyclic heteroaryl (e.g. 9-membered bicyclic heteroaryl, for example tetrahydro 1,2-benzisoxazolyl, for example tetrahydro 1,2-benzisoxazol-3-yl) groups may be unsubstituted.

[0051] Furthermore, A 1 Halo, R a2 , -C(O)OR e2 , -OR l2 , and -SR m2 (i.e., G 2 groups) (e.g., halo (e.g., F), C 1-3 Alkyl, -C(O)OH, -C(O)OC 1-3 Alkyl, -OH, -OC 1-3 Alkyl, -SH, and -SC 1-3 One or two groups independently selected from alkyl, e.g., F, C 1-3 Alkyl, -C(O)OH, and -C(O)OC 1-3 one or two groups selected from alkyl, e.g., one -C(O)OC 1-3 It may represent a monocyclic heteroaryl (e.g. a 6-membered monocyclic heteroaryl, such as pyridinyl, e.g. pyridin-2-yl) optionally substituted by an alkyl group or a -C(O)OH group). For the avoidance of doubt, such monocyclic heteroaryl (e.g. a 6-membered monocyclic heteroaryl, such pyridinyl, e.g. pyridin-2-yl) groups may be unsubstituted.

[0052] In a specific embodiment, A 1The monocyclic or bicyclic heteroaryl represented by may be a 5- or 6-membered monocyclic or 9-membered bicyclic heteroaryl. Specifically, the monocyclic or bicyclic heteroaryl may be selected from pyridinyl (e.g., pyridin-2-yl and pyridin-3-yl), pyrazinyl (e.g., pyrazin-2-yl), benzofuranyl (e.g., benzofuran-3-yl), thiozolyl (e.g., thiozol-4-yl), thiophenyl (e.g., thiophen-2-yl), isoxazolyl (e.g., isoxazol-3-yl), 4,5,6,7-tetrahydrobenzo[c]isoxazolyl (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazol-3-yl), 1,3-benzoxazolyl (e.g., 1,3-benzoxazol-2-yl), and 1,2-benzisoxazolyl (e.g., 1,2-benzisoxazol-3-yl).

[0053] In an alternative embodiment, A 1 The monocyclic or bicyclic heteroaryl representing may be a 5 or 6 membered monocyclic or a 9 membered bicyclic heteroaryl. Specifically, the monocyclic or bicyclic heteroaryl may be selected from tetrahydro 2,1-benzisoxazolyl (e.g., tetrahydro 2,1-benzisoxazol-3-yl), benzoxazolyl (e.g., 1,3-benzisoxazol-3-yl or 1,2-benzisoxazol-3-yl), pyrazinyl, indazolyl, quinolinyl, 5H,6H,7H,8H-imidazo[1,5-a]pyridin-3-yl, imidazo[1,5-a]pyridin-3-yl, pyridinyl (e.g., pyridin-2-yl), thiozolyl (e.g., thiozol-4-yl), isoxazolyl (e.g., isoxazol-3-yl), and tetrahydro 1,2-benzisoxazolyl (e.g., tetrahydro 1,2-benzisoxazol-3-yl). More specifically, the monocyclic or bicyclic heteroaryl may be selected from pyridinyl (e.g., pyridin-2-yl), thiozolyl (e.g., thiozol-4-yl), isoxazolyl (e.g., isoxazol-3-yl), and tetrahydro-1,2-benzisoxazolyl (e.g., tetrahydro-1,2-benzisoxazol-3-yl).1 is 5H,6H,7H,8H-imidazo[1,5-a]pyridin-3-yl or 5H,6H,7H,8H-imidazo[1,5-a]pyridin-1-yl.

[0054] In a specific embodiment of the first aspect of the present invention, A 2 is G 3 or G 4 represents a 5- or 6-membered heteroaryl optionally substituted by one or more (preferably 1, 2 or 3, for example 1 or 2) groups independently selected from:

[0055] In a specific embodiment of the first aspect of the present invention, 2 is G 3 embedded image represents aryl optionally substituted by one or more (preferably 1, 2 or 3, e.g. 1 or 2) groups independently selected from

[0056] In yet another specific embodiment of the first aspect of the present invention, 2 is G 3 embedded image represents phenyl optionally substituted by one or more (preferably 1, 2 or 3, for example 1 or 2) groups independently selected from

[0057] In a more specific embodiment, A 2 Halo, R a3 , and -OR l3 one or more (e.g., one or two) groups independently selected from 3 Groups), which may be optionally substituted with phenyl.

[0058] In a further embodiment, G 3 ,Halo,-A c3 -C(Q c3 ) OR e3 (For example, -C(O)OR e3 , for example, R e3 is C1-3 alkyl), R a3 , and -OR l3 represents a group selected from

[0059] In yet a further embodiment, G 3 ,Halo,-A a3 -C(Q a3 )R b3 (e.g., -C(O)heteroaryl, e.g., -C(O)-morpholinyl, e.g., -C(O)-morpholin-4-yl), or -A c3 -C(Q c3 ) OR e3 (For example, -C(O)OR e3 For example, in the formula R e3 is C 1-3 alkyl), R a3 , and -OR l3 represents a group selected from

[0060] In an alternative embodiment, G 3 ,Halo,-R a3 , and -OR l3 represents a group selected from

[0061] More specifically, A 2 is halo (e.g., F), -C(O)OC 1-3 Alkyl (such as -C(O)OCH2CH3) and C 1-4 one or more (e.g., one or two) groups independently selected from alkyl (e.g., -CH3 and -C(CH3)3) (i.e., G 3 For example, A may represent phenyl optionally substituted with 2 is one or two groups independently selected from F, -CH3, -C(O)OCH2CH3, and -C(CH3)3 (i.e., G 3 It may represent phenyl optionally substituted by one or two F groups, for example phenyl substituted by one or two F groups.

[0062] Or, A 2 is halo (e.g., F), -C(O)-morpholinyl (e.g., -C(O)-morpholin-4-yl), -C(O)OC1-3 Alkyl (such as -C(O)OCH2CH3) and C 1-4 one or more (e.g., one or two) groups independently selected from alkyl (e.g., -CH3 and -C(CH3)3) (i.e., G 3 Groups).

[0063] In a more specific embodiment, A 2 is unsubstituted at least at the 2-position (i.e., relative to the point of attachment to the requisite tetrahydroindazole as shown in Formula I (one of ordinary skill in the art would understand that the point of attachment is considered to be the 1-position)).

[0064] Thus, in certain embodiments, A 2 The group representing may be represented as follows: [ka] In the formula, G 3 is as defined herein (i.e. as defined in any embodiment of the first aspect of the invention, or any combination thereof, e.g., G 3 Halo, R a3 , and -OR l3 for example, a group independently selected from F, -CH, and -C(CH) (e.g., an F group), t is 0 to 5 (e.g., 0 to 2), and the bond broken by the wavy line indicates the point of attachment to the required tetrahydroindazole group.

[0065] More specifically, A 2 A can be phenyl substituted with one or two substituents at the 3-, 4-, 5-, and / or 6-position(s). For example, A 2 can be a phenyl substituted at the 6-position only (and therefore unsubstituted at the 2-, 3-, 4-, and 5-positions), at the 4- and 6-positions only, or at the 3- and 4-positions only.

[0066] In another embodiment, A 2is optionally substituted at least at the 2-position with halo (eg, chloro or fluoro).

[0067] In a specific embodiment of the first aspect of the invention, L 1 is -C(O)N(R 2 )-, -C(O)O-, -S(O)2N(R 3 In a more specific embodiment, L represents -C(O)-, -C(O)-, or -S(O)- (such as -C(O)- or -S(O)-). 1 represents -C(O)-.

[0068] In a specific embodiment of the first aspect of the invention, R 1 is H, or C optionally substituted by one or more F 1-3 Represents an alkyl (e.g., C alkyl) (e.g., H or -CH). More specifically, R 1 may represent H.

[0069] In a specific embodiment of the first aspect of the invention, R 2 and R 3 each independently represents H or C optionally substituted with one or more halo 1-3 In a more particular embodiment, R 2 represents H. In a more particular embodiment, R 3 represents H. Thus, in a more particular embodiment, R 2 and R 3 Each represents H.

[0070] In a specific embodiment of the first aspect of the invention, each G 1 are independent, -CN, -A a1 -C(Q a1 )R b1 , -A b1 -C(Q b1 )N(R c1 )R d1 , -A c1 -C(Q c1 ) OR e1 , -A d1 -S(O) p Rf1 , -A e1 -S(O) q N(R g1 )R h1 , -A f1 -S(O) p OR i1 , -N3, -N(R j1 )R k1 , -N(H)CN, -NO2, -ONO2, Halo, R a1 , -OR l1 , or -SR m1 (Haro, R a1 , -C(O)OR e1 , -OR l1 , and -SR m1 etc.), Each Q a1 ~Q c1 are independently =O, =S, =NR n1 , or =N(OR o1 ) (=O, etc.) and / or (for example, and) Each A a1 ~A f1 are independently a single bond, -N(R p1 )-, or -O-.

[0071] In a specific embodiment of the first aspect of the invention, each G 2 are independent, -CN, -A a2 -C(Q a2 )R b2 , -A b2 -C(Q b2 )N(R c2 )R d2 , -A c2 -C(Q c2 ) OR e2 , -A d2 -S(O) p R f2 , -A e2 -S(O) q N(R g2 )R h2 , -A f2 -S(O) p OR i2 , -N3, -N(R j2 )R k2 , -N(H)CN, -NO2, -ONO2, Halo, Ra2 , -OR l2 , or -SR m2 (Haro, R a2 , -C(O)OR e2 , -OR l2 , or -SR m2 etc.), Each Q a2 ~Q c2 are independently =O, =S, =NR n2 , or =N(OR o2 ) (=O, etc.) and / or (for example, and) Each A a2 ~A f2 are independently a single bond, -N(R p2 )-, or -O-.

[0072] In a specific embodiment, each G 2 are independent, halo, R a2 , -C(O)OR e2 , -OR l2 , and -SR m2 Represents.

[0073] In a more specific embodiment, each G 2 is independently halo, R a2 , -C(O)OR e2 , -OR l2 and -SR m2 In a more particular embodiment, each G 2 are independent halo (e.g. F), C 1-3 Alkyl, -C(O)OH, -C(O)OC 1-3 Alkyl, -OH, -OC 1-3 Alkyl, -SH and -SC 1-3 Alkyl (F, C 1-2 -alkyl, -OH, -SCH3, etc.

[0074] In a specific embodiment of the first aspect of the invention, each G 3 are independent, -CN, -A a3 -C(Q a3 )R b3 , -A b3 -C(Q b3 )N(R c3)R d3 , -A c3 -C(Q c3 ) OR e3 , -A d3 -S(O) p R f3 , -A e3 -S(O) q N(R g3 )R h3 , -A f3 -S(O) p OR i3 , -N3, -N(R j3 )R k3 , -N(H)CN, -NO2, -ONO2, Halo, R a3 , -OR l3 , or -SR m3 (Haro, R a3 , -OR l3 , or -SR m3 etc.), Each Q a3 ~Q c3 are independently =O, =S, =NR n3 , or =N(OR o3 ) (=O, etc.) and / or Each A a3 ~A f3 are independently a single bond, -N(R p3 )-, or -O-.

[0075] In a more specific embodiment, each G 3 are independent, halo, R a3 -OR l3 Represents.

[0076] In still more specific embodiments, each G 3 are independently halo (e.g., F) or C 1~4 It represents alkyl, for example, F, -CH3, or -C(CH3)3. In still more specific embodiments, each G 3 independently represent F or -CH3, e.g., F.

[0077] In a specific embodiment of the first aspect of the invention, each G 4are independent, -CN, -A a4 -C(Q a4 )R b4 , -A b4 -C(Q b4 )N(R c4 )R d4 , -A c4 -C(Q c4 ) OR e4 , -A d4 -S(O) p R f4 , -A e4 -S(O) q N(R g4 )R h4 , -A f4 -S(O) p OR i4 , -N3, -N(R j4 )R k4 , -N(H)CN, -NO2, -ONO2, Halo, R a4 , -OR l4 , or -SR m4 (Haro, R a4 , -OR l4 , or -SR m4 etc.), Each Q a4 ~Q c4 are independently =O, =S, =NR n4 , or =N(OR o4 ) (=O, etc.) and / or (for example, and) Each A a4 ~A f4 are independently a single bond, -N(R p4 )-, or -O-.

[0078] In specific embodiments, p represents 2 and / or (eg, and) q represents 2.

[0079] In one embodiment, A 1 is G 2 A represents a 9-membered bicyclic heteroaryl (e.g., 5H,6H,7H,8H-imidazo[1,5-a]pyridin-3-yl or 5H,6H,7H,8H-imidazo[1,5-a]pyridin-1-yl) optionally substituted by one or more groups independently selected from 2 is G3 Phenyl (e.g., A optionally substituted at least at the 2-position with halo (e.g., chloro or fluoro)) is optionally substituted with one or more groups independently selected from 2 ) represents;R 1 stands for H; and L 1 represents -C(O)-.

[0080] In some embodiments, A 1 is a 9-membered bicyclic heteroaryl (e.g., 5H,6H,7H,8H-imidazo[1,5-a]pyridin-3-yl, 5H,6H,7H,8H-imidazo[1,5-a]pyridin-1-yl, 4H,5H,6H,7H-1,2-benzisoxazol-3-yl, 4H,5H,6H,7H-2,1-benzisoxazol-3-yl or 4H,5H,6H,7H-indazol-3-yl); a 6-membered heteroaryl (such as pyridinyl) or a 5-membered heteroaryl (such as pyrazolyl or imidazolyl), where the 5- or 6-membered heteroaryl is G 2 and optionally substituted with one or more groups independently selected from 2 is G 3 R is phenyl, optionally substituted with one or more groups independently selected from 1 is H; and / or L 1 is C(O)-.

[0081] In some embodiments, each G 2 is independently R a2 (C 1-2 alkyl, etc.; and / or each G 3 are independent, halo, R a3 , -A b3 -C(Q b3 )N(R c3 )R d3 , -A c3 -C(Q c3 ) OR e3 , -A d3 -S(O) p R f3 , -OR l3 Optionally, Halo is fluoro or chloro, Ra3 is CH3 or CF 3、 A b3 , A c3 and A d3 is a single bond, Q b3 and Q c3 is =O, p is 2, R c3 and R d3 are CH3 or are linked together with the nitrogen atom to which they are attached to form a 5- or 6-membered ring, which ring optionally contains one further heteroatom (such as oxygen); R e3 is C 1-3 Alkyl, R f3 is CH3 、 R l3 are CH3, CF3, and N(CH3) 2、 It is a C2 alkyl substituted with OH, OCH3 or N(C=O)CH3, and / or a C1 alkyl substituted with C(=O)N(CH3)2.

[0082] In certain embodiments of the first aspect of the invention, the compound of formula I is not: [Table 1]

[0083] Specific compounds according to the first aspect of the invention that may be mentioned include the example compounds provided herein, and pharma- ceutically acceptable salts thereof.

[0084] More specific compounds of the first aspect of the invention that may be mentioned are: N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (R)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (R)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; N-1-[3,4-c]-5-1,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-((4S)-1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-((4R)-1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-1-[3,4-c]-5-1,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-((4S)-1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-((4R)-1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-(1-(2,6-dichlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2,6-dichlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2,6-dichlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (R)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (R)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (R)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (R)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide; (R)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide; (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (R)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (R)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (R)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (R)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (R)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide; (R)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide; (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (R)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (R)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (R)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro; (R)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (R)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide; (R)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide; (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (R)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (R)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (R)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (R)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (R)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide; (R)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide; (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (R)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)-5-Ethyl-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-1-methyl-1H-imidazole 4-carboxamide; (R)-5-Ethyl-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-1-methyl-1H-imidazole 4-carboxamide; (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (R)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (R)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)-4-Ethyl-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-methyl-1H-pyrazole-3-carboxamide; (R)-4-Ethyl-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-methyl-1H-pyrazole 3-carboxamide; (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (R)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)-N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (R)-N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (S)-N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (R)-N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)-N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (R)-N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)-N-(1-(3-(methylsulfonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(3-(methylsulfonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-3-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(o-tolyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(o-tolyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-5-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-5-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(3-(trifluoromethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(3-(trifluoromethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-fluoro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-fluoro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2,6-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2,6-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-6-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-6-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-methoxy-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-methoxy-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-hydroxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-3-hydroxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(2-(dimethylamino)ethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-3-(2-(dimethylamino)ethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(2-(dimethylamino)-2-oxoethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-3-(2-(dimethylamino)-2-oxoethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(2-(methylamino)-2-oxoethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-3-(2-(methylamino)-2-oxoethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(3-(2-acetamidoethoxy)-2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(3-(2-acetamidoethoxy)-2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(2-methoxyethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-3-(2-methoxyethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; Isopropyl (S)-2-chloro-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamido)-4,7-dihydropyrano[3,4-c]pyrazol-1(5H)-yl)benzoate; Isopropyl (R)-2-chloro-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamido)-4,7-dihydropyrano[3,4-c]pyrazol-1(5H)-yl)benzoate; (S)-N-(1-(2-chloro-3-(dimethylcarbamoyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-3-(dimethylcarbamoyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(pyrrolidine-1-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-3-(pyrrolidine-1-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(piperidine-1-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-3-(piperidine-1-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(morpholine-4-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-3-(morpholine-4-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(diethylcarbamoyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-N-(1-(2-chloro-3-(diethylcarbamoyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; and pharma-ceutically acceptable salts thereof.

[0085] As described herein, the compound of the first aspect of the invention can exist as stereoisomers. Specifically, the compound of the first aspect of the invention can exist as stereoisomers at the positions marked with an asterisk in formula I herein above, where a person skilled in the art will understand that the compound of the first aspect of the invention can exist in the R or S configuration.

[0086] For the avoidance of doubt, those skilled in the art will understand that when the carbon marked with an asterisk in formula I herein above is the only stereocenter in the compound of formula I, the compound of formula I may exist in the form of two enantiomers having different configurations at that stereocenter, and these enantiomers may be referred to as the R enantiomer and the S enantiomer (indicating the configuration at that position, as will be understood by those skilled in the art).

[0087] In particular, the compounds of the first aspect of the invention may exist as a mixture of stereoisomers (e.g., an approximately equal mixture), i.e., a mixture of each possible stereoisomer. In particular, when the compounds of the invention exist as R and S enantiomers (i.e., the R and S configurations at the carbons marked with an asterisk in the compounds of formula I above), the compounds of the first aspect of the invention may be a mixture of those enantiomers, in particular, an approximately equal mixture (e.g., a racemic mixture).

[0088] In other embodiments, the compound of the first aspect of the invention may exist in the R or S configuration at the marked carbon (e.g. as either the R or S enantiomer), in which case the compound may be present in the substantial absence of compounds of the alternative configuration (e.g. greater than 60%, e.g. greater than 70%, greater than 80%, or greater than 90% (e.g. greater than 99%, such as 99.9% or greater) purity compared to the alternative configuration).

[0089] For example, when the compound of the first aspect of the invention exists as either the R or S enantiomer as described herein above, the compound may have an enantiomeric excess (ee) of greater than 60%, for example greater than 70%, greater than 80%, or greater than 90% (e.g. greater than 99%, such as 99.9% or more), as will be appreciated by one of skill in the art.

[0090] In particular, the compounds of the first aspect of the invention may exist as the S enantiomer as described herein above.

[0091] Thus, in a specific embodiment of the first aspect of the invention, the compound of formula I is a compound of formula Ia: [ka] In the formula, A 1 , A 2 , L 1 and R 1 is as defined in the first aspect of the invention (including all embodiments and combinations of those embodiments).

[0092] In particular, the compound of formula Ia may be prepared in the substantial absence of a compound of formula I or a pharma- ceutically acceptable salt thereof, in an alternative configuration, such as a compound of formula Ib [ka] In the formula, A 1 , A 2 , L 1 and R 1 is provided as defined in the first aspect of the invention (including all embodiments and combinations of these embodiments) or as a pharma- ceutically acceptable salt thereof.

[0093] Specifically, the compound of formula Ia or a pharma- ceutically acceptable salt thereof may be provided in a purity of greater than 60%, e.g., greater than 70%, greater than 80%, or greater than 90% (e.g., greater than 99%, such as 99.9% or greater) relative to the compound of formula Ib or a pharma- ceutically acceptable salt thereof (e.g., when present in a purity of greater than 90%, the compound of formula Ia or a pharma- ceutically acceptable salt thereof constitutes greater than 90% of the combined weight of the compounds of formulas Ia and Ib and their pharma- ceutically acceptable salts).

[0094] In alternative embodiments, references to the S enantiomer or compound of formula Ia may be replaced with references to the R enantiomer or compound of formula Ib, and vice versa.

[0095] For example, the compound of the first aspect of the invention may be provided as a compound of formula Ib, or a pharma- ceutically acceptable salt thereof, with a purity of more than 60%, such as more than 70%, more than 80%, or more than 90% (e.g. more than 99%, such as 99.9% or more) compared to a compound of formula Ia, or a pharma- ceutically acceptable salt thereof.

[0096] Further compounds according to the first aspect of the invention which may be mentioned include: (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; N-((4S)-1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-((4S)-1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2,6-dichlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide; (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide; (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide; (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide; (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)-5-Ethyl-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-1-methyl-1H-imidazole 4-carboxamide; (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)-4-Ethyl-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-methyl-1H-pyrazole-3-carboxamide; (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)-N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; (S)-N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)-N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)-N-(1-(3-(methylsulfonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(o-tolyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-5-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(3-(trifluoromethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-fluoro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2,6-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-6-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-methoxy-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-hydroxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(2-(dimethylamino)ethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(2-(dimethylamino)-2-oxoethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(2-(methylamino)-2-oxoethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(3-(2-acetamidoethoxy)-2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(2-methoxyethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; Isopropyl (S)-2-chloro-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamido)-4,7-dihydropyrano[3,4-c]pyrazol-1(5H)-yl)benzoate; (S)-N-(1-(2-chloro-3-(dimethylcarbamoyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(pyrrolidine-1-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(piperidine-1-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(morpholine-4-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-N-(1-(2-chloro-3-(diethylcarbamoyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; and pharma-ceutically acceptable salts thereof.

[0097] Treatment methods and medical uses As described herein, the compounds of the first aspect of the invention are therapeutically active.

[0098] Thus, in a second aspect of the invention, there is provided a compound as defined in the first aspect of the invention (including all embodiments and combinations thereof), or a pharma- ceutically acceptable salt thereof, for use in medicine (which may also be referred to as use as a medicine).

[0099] In another second aspect of the present invention there is provided a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in the first aspect of the present invention (including all embodiments and combinations thereof), or a pharma- ceutically acceptable salt thereof.

[0100] In yet another second aspect of the invention there is provided a compound, or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease as defined in the first aspect of the invention (including all embodiments and combinations thereof).

[0101] The compounds of the present invention are useful in the treatment of cancer and / or viral infections.Accordingly, in a third aspect of the present invention there is provided a compound or a pharma- ceutically acceptable salt thereof as defined in the first aspect of the present invention (including all embodiments and combinations thereof) for use in the treatment of cancer and / or the treatment or prophylaxis of a viral infection.

[0102] In an alternative third aspect of the invention there is provided a method of treating cancer and / or treating or preventing a viral infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in the first aspect of the invention (including all embodiments and combinations of those embodiments) or a pharma- ceutically acceptable salt thereof.

[0103] In a further alternative first aspect of the present invention there is provided a compound or a pharma- ceutically acceptable salt thereof as defined in the first aspect of the invention (including all embodiments and combinations of those embodiments) for use in the manufacture of a medicament for the treatment of cancer and / or the treatment or prophylaxis of a viral infection.

[0104] Those skilled in the art will understand that the reference to the treatment of a particular condition (or, equivalently, treating the condition) has its usual meaning in the pharmaceutical field. Specifically, these terms can refer to the achievement of reducing the severity of one or more clinical symptoms associated with the condition. For example, in the case of cancer, this term can refer to the achievement of reducing the amount of cancer cells present (for example, in the case of cancer that forms solid tumors, as shown by reducing tumor volume). Similarly, in the case of viral infection, this term can refer to the achievement of reducing viral load (i.e., the number of viral units present in a given amount of plasma in the relevant patient, for example, the number of viral units per mL of plasma).

[0105] Those skilled in the art will understand that reference to the prevention of a particular condition (and similarly, preventing the condition) has its usual meaning in the pharmaceutical art and includes reference to preventing the onset of the condition (and vice versa). Specifically, the term can refer to achieving a reduction (e.g., at least a 10% reduction, e.g., at least a 20%, 30%, or 40% reduction, e.g., at least a 50% reduction) in the likelihood that a patient (or healthy subject) will develop the condition.

[0106] As used herein, reference to a patient refers to the living organism being treated, including a mammalian (e.g., human) patient. Thus, in specific embodiments of all aspects of the invention, the treatment is in a mammalian (e.g., human) patient.

[0107] As used herein, the term therapeutically effective amount refers to an amount of a compound that confers a therapeutic effect on the treated patient. The effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of and / or feels an effect).

[0108] While the compounds of the first aspect of the invention may have pharmacological activity as such, certain pharma- ceutically acceptable (e.g., "protected") derivatives of the compounds of the invention may exist or may be prepared which may have no such activity but which may be administered parenterally or orally and then metabolized in the body to form the compounds of the invention. Such compounds (which may have some pharmacological activity, provided that such activity is appreciably less than the activity of the active compounds to which they are metabolized) may thus be described as "prodrugs" of the compounds of the invention.

[0109] As used herein, reference to a prodrug includes a compound that forms an experimentally detectable amount of a compound of the invention within a given time following enteral or parenteral administration (e.g., oral or parenteral administration). All prodrugs of the compounds of the first aspect of the invention are included within the scope of the invention.

[0110] Various forms of prodrugs are known in the art, see below for examples of such prodrug derivatives. a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

[0111] As non-limiting examples, hydroxy or carboxylic acid groups may be protected as esters and amines may be protected as carbamates.

[0112] For the avoidance of doubt, the compounds of the first aspect of the invention are useful because they have pharmacological activity and / or are metabolized in the body after oral or parenteral administration to form compounds that have pharmacological activity. Specifically, as described herein, the compounds of the first aspect of the invention are useful in the treatment of cancer, a term that will be readily understood by those skilled in the art.

[0113] In specific embodiments of all aspects of the invention, references to the treatment of cancer and / or the treatment or prevention of viral infection specifically refer to the treatment of cancer.

[0114] In alternative embodiments of all aspects of the invention, references to the treatment of cancer and / or the treatment or prevention of a viral infection specifically refer to the treatment or prevention (more specifically the treatment) of a viral infection.

[0115] In a specific embodiment of the first aspect of the invention, the cancer is a cancer selected from the list consisting of: Soft tissue cancers, such as sarcoma, myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung cancer, for example, bronchogenic, alveolar or bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; Gastrointestinal cancer, e.g., esophageal cancer, stomach cancer, pancreatic cancer, small intestine cancer, large intestine cancer (e.g., colon cancer); Genitourinary tract cancers, e.g., kidney cancer, bladder and urethra cancer, prostate cancer, testicular cancer; Liver cancer, e.g., hepatoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone cancers, such as osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell chordoma, osteochondroma, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; Head and / or nervous system cancers, e.g., skull cancer, meningeal cancer, brain cancer, spinal cancer; Gynecologic cancers, such as uterine, cervical, ovarian, vulvar, vaginal, and fallopian tube cancer; Hematological cancers, e.g., blood and bone marrow cancers (e.g., leukemias such as acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia), Hodgkin's disease, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, marginal zone lymphoma, follicular lymphoma, Waldenstrom's macroglobulinemia Burkitt's lymphoma, multiple myeloma, Lifier's syndrome, T-cell lymphoma; Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid; neurofibromatosis, adrenal gland; and Neuroblastoma.

[0116] As used herein, reference to a cancer cell or the like includes reference to a cell afflicted by any one of the above mentioned conditions.

[0117] More specific cancers that may be mentioned include those that correspond to the cell lines used in the examples provided herein. For example, specific cancers that may be mentioned include: colon cancer, Skin cancer (e.g., as defined herein, such as malignant melanoma); Lymphoma, Leukemia (chronic myeloid leukemia, etc.), and and sarcomas (such as those described herein).

[0118] In more specific embodiments, the cancer is selected from the group consisting of skin cancer (such as malignant melanoma) and hematological cancer (such as chronic myeloid leukemia). For example, the cancer can be a skin cancer known to those of skill in the art, such as a skin cancer described herein.

[0119] More specifically, the cancer may be chronic myeloid leukemia (CML) or malignant melanoma. Most specifically, the cancer may be malignant melanoma.

[0120] In specific embodiments of all aspects of the invention, reference to a viral infection refers to an infection caused by one or more viruses that can cause human diseases such as AIDS, Ebola, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), Western / Eastern Equine Encephalitis (WEE / EEE), Dengue, Zika, influenza, hepatitis, West Nile, polio, and measles.

[0121] The virus may be an RNA virus, such as a single-stranded RNA (ssRNA) or double-stranded RNA (dsRNA) virus, where the ssRNA virus may be a positive-sense or negative-sense ssRNA virus. For the purposes of the present invention, an RNA virus is a virus contained in Group III, IV, V or VI of the Baltimore Classification System, unless otherwise indicated. Such viruses include, but are not limited to:

[0122] Double-stranded (ds) RNA viruses (group III), including rotaviruses and picobirnaviruses. Positive sense ssRNA viruses (Group IV) including coronaviruses, bymoviruses, comoviruses, nepoviruses, nodaviruses, picornaviruses, potyviruses, sobemoviruses, luteoviruses, carmoviruses, giantoviruses, flaviviruses, pestiviruses, tombusviruses, hepatitis C virus, alphaviruses, carraraviruses, floraviruses, hordeiviruses, potexisviruses, tobraviruses, tricornaviruses, tymoviruses, and hepatitis E virus. Negative-sense ssRNA viruses (group V), including Ebola virus, Marburg virus, measles virus, mumps virus, Nipah virus, Hendra virus, RSV, NOV, rabies virus, Niya virus, Lassa virus, Hantavirus, Crimean-Congo hemorrhagic fever, influenza virus, and Hepatitis D virus. Retroviruses (Group VI), including lentiviruses, such as HIV-1 and HIV-2.

[0123] Those skilled in the art will appreciate that treatment with a compound of the first aspect of the invention may further comprise (i.e., be combined with) further (i.e., additional / other) treatment(s) for the same condition. These further treatments may be known treatments and may, for example, represent standard of care treatments for that particular condition.

[0124] For example, when used in the treatment of cancer, treatment with the compounds of the invention may be combined with other means for the treatment of cancer, e.g., treatment with one or more other therapeutic agents useful in the treatment of cancer (including treatment with chemotherapeutic agents and cell-based therapies such as immunotherapy), and / or one or more physical methods used in the treatment of cancer known to those of skill in the art (such as treatment with surgery and / or radiation therapy).

[0125] Thus, treatment with a compound of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional / other) treatment(s) for cancer (such treatment with an additional agent for the treatment of cancer as described herein, e.g. malignant melanoma).

[0126] In particular, treatment with the compounds of the invention may be administered in combination with (e.g., in a patient who is also being treated with) one or more (e.g., one) additional compounds (i.e., therapeutic agents), which may include, but are not limited to, (i) capable of reducing the levels of nucleosides and / or nucleotides in a cell (e.g., a cancer cell); and / or (ii) a p53 activator (such as an MDM2 inhibitor), Both of these are described herein below.

[0127] Similarly, when used to treat or prevent a viral infection, treatment or prevention using the compounds of the invention may be performed in combination with one or more other therapeutic agents (such as anti-viral compounds or vaccines) useful in treating or preventing viral infections known to those of skill in the art.

[0128] Pharmaceutical Compositions As described herein, the compounds of the present invention are useful as pharmaceuticals. Such compounds can be administered alone or in known pharmaceutical compositions / formulations.

[0129] In a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention (of the first aspect), and optionally one or more pharma- ceutically acceptable adjuvants, diluents and / or carriers.

[0130] Those skilled in the art will appreciate that references herein to compounds of the first aspect of the invention for a particular use (and similarly to uses relating to compounds of the invention and methods of use thereof) also apply mutatis mutandis to pharmaceutical compositions comprising compounds of the invention as described herein.

[0131] In a fifth aspect of the invention there is provided a pharmaceutical composition comprising a compound as defined in the first aspect of the invention and optionally one or more pharma- ceutically acceptable adjuvants, diluents and / or carriers for use in the treatment of cancer (as defined in the first aspect of the invention) and / or the treatment or prophylaxis of a viral infection.

[0132] Those skilled in the art will appreciate that the compounds of the present invention may act systemically and / or locally (ie, at a particular site).

[0133] Those skilled in the art will appreciate that the compounds and compositions described in all aspects of the present invention may be administered in a pharma- ceutically acceptable dosage form, orally, intravenously, subcutaneously, buccal, rectal, dermal, nasal, tracheal, bronchial, sublingual, intranasal, topical, by any other parenteral route, or by inhalation. Pharmaceutical compositions described herein include compositions in the form of tablets, capsules, or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. Alternatively, pharmaceutical compositions may be formulated for topical administration, particularly where such compounds of the present invention act locally.

[0134] Thus, in specific embodiments of all relevant aspects of the invention, the pharmaceutical formulations are provided in a pharma- ceutically acceptable dosage form, including tablets or capsules, liquid forms taken orally or by injection, suppositories, creams, gels, foams, inhalants (e.g. applied intranasally), or forms suitable for topical administration. For the avoidance of doubt, in such embodiments, the compounds of the invention may exist as a solid (e.g. a solid dispersion), as a liquid (e.g. in solution), or in other forms, for example in the form of micelles.

[0135] For example, in preparing pharmaceutical formulations for oral administration, the compounds can be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or other suitable ingredients, as well as disintegrants and lubricants, such as magnesium stearate, calcium stearate, sodium stearyl fumarate, and polyethylene glycol waxes. The mixture can then be processed into granules or compressed into tablets.

[0136] Soft gelatin capsules may be prepared with capsules containing one or more active compounds (e.g., a compound of the present invention, and optionally additional therapeutic agents) together with, for example, vegetable oil, fat, or other vehicle suitable for soft gelatin capsules. Similarly, hard gelatin capsules may contain such compound(s) in combination with solid powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin.

[0137] Dosage units for rectal administration may be prepared (i) in the form of suppositories containing the compound(s) mixed with a neutral fatty base, (ii) in the form of gelatin rectal capsules containing the active substance in a mixture with vegetable oil, paraffin oil, or other vehicle suitable for gelatin rectal capsules, (iii) in the form of ready-made microenemas, or (iv) in the form of a dry microenema preparation to be reconstituted in a suitable solvent immediately prior to administration.

[0138] Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g., solutions or suspensions, which contain the compound(s) and the remainder of the formulation consists of sugar or sugar alcohol, as well as mixtures of ethanol, water, glycerol, propylene glycol, and polyethylene glycol. If desired, such liquid preparations may contain colorants, flavorings, saccharin, and carboxymethylcellulose or other thickening agents. Liquid preparations for oral administration may also be prepared in the form of dry powders that are reconstituted with a suitable solvent before use.

[0139] Solutions for parenteral administration can be prepared as a solution of compound(s) in a pharma- ceutically acceptable solvent. These solutions can also contain stabilizing components and / or ingredients and are dispensed in unit doses in the form of ampoules or vials. Solutions for parenteral administration can also be prepared as dry preparations that are extemporaneously reconstituted with a suitable solvent before use.

[0140] In specific embodiments of the fourth and fifth aspects of the invention, the pharmaceutical composition does not comprise liposomes.

[0141] Those skilled in the art will appreciate that the compounds of the invention (e.g., as compositions according to the fourth and fifth aspects of the invention) can be administered in a variety of doses, with suitable doses being readily determined by those skilled in the art. Oral, pulmonary, and topical dosages (and thus subcutaneous dosages, although these dosages can be relatively lower) can range from about 0.01 mg / kg of body weight per day (mg / kg / day) to about 200 mg / kg / day, preferably from about 0.01 to about 10 mg / kg / day, and more preferably from about 0.1 to about 5.0 mg / kg / day. For example, when administered orally, treatment with such compounds and compositions can typically include administration of a composition containing about 0.01 mg to about 2000 mg, e.g., from about 0.1 mg to about 500 mg, or 1 mg to about 100 mg of active ingredient. When combined intravenously, the most preferred dosages are in the range of about 0.001 to about 10 mg / kg / hour during a constant rate infusion. Advantageously, treatment may involve administration of such compounds and compositions in a single dose per day, or the total daily dosage may be administered in divided doses of two, three or four times daily (with reference to the doses described herein).

[0142] In any event, one of ordinary skill in the art (e.g., a physician) can determine the actual dosage that will be most suitable for an individual patient, which may vary depending on the route of administration, the type and severity of the condition being treated, and the species, age, weight, sex, renal function, hepatic function, and response of the particular patient being treated. The dosage amounts set forth above are exemplary of the average case, and there may, of course, be individual instances in which higher or lower dosage ranges are merited, and such dosage ranges are within the scope of the invention.

[0143] As described herein above, those skilled in the art will understand that the treatment with the compound of the present invention can further include (i.e., can be combined with) further (i.e., additional / other) treatment(s) for the same condition. Specifically, the treatment with the compound of the present invention can be combined with other measures for the treatment of cancer, for example, treatment with one or more other therapeutic agents useful for the treatment of cancer, or other measures for the treatment or prevention of viral infection.

[0144] In specific embodiments of the fourth and fifth aspects of the invention, the pharmaceutical composition may further comprise one or more additional (ie, other) therapeutic agents.

[0145] In more specific embodiments, the one or more additional therapeutic agents is an agent for the treatment of cancer (such as an additional agent for the treatment of a cancer described herein, e.g., malignant melanoma).

[0146] In other embodiments, the one or more additional therapeutic agents are agents for the treatment or prevention of a viral infection (eg, a viral infection described herein).

[0147] Those skilled in the art will appreciate that combinations of therapeutic agents may also be described as combination products and / or provided as a kit-of-parts.

[0148] In a sixth aspect of the invention there is provided a combination product comprising: (A) a compound as defined in the first aspect of the present invention; and (B) one or more additional therapeutic agents, Combination products are provided in which component (A) and component (B) are each formulated, optionally in admixture with one or more pharma- ceutically acceptable adjuvants, diluents, or carriers.

[0149] According to a seventh aspect of the present invention there is provided a kit of parts comprising: (a) a compound as defined in the first aspect of the invention, or a pharmaceutical composition as defined in the fourth or fifth aspect of the invention; (b) one or more additional therapeutic agents, optionally in admixture with one or more pharma- ceutically acceptable adjuvants, diluents, or carriers; A kit of parts is provided in which component (a) and component (b) are each provided in a form suitable for administration in combination with the other.

[0150] In specific embodiments of the sixth and seventh aspects of the invention, the additional therapeutic agent is a therapeutic agent for the treatment of cancer (such as an additional agent for the treatment of a cancer described herein, e.g., malignant melanoma).

[0151] In specific embodiments of the sixth and seventh aspects of the invention, the additional therapeutic agent is an agent for the treatment of malignant melanoma.

[0152] In specific embodiments of the sixth and seventh aspects of the invention, the additional therapeutic agent is (i) capable of reducing the levels of nucleosides and / or nucleotides in cells (e.g., cancer cells, such as cells that form part of the cancers described herein); and / or (ii) A drug that is a p53 activator (such as an MDM2 inhibitor).

[0153] To avoid any misunderstanding, (i) capable of reducing the levels of nucleosides and / or nucleotides in cells (e.g., cancer cells, such as cells that form part of the cancers described herein); and / or (ii) A compound (i.e., a therapeutic agent) that is a p53 activator (e.g., an MDM2 inhibitor), These are readily identifiable by one of ordinary skill in the art and specifically include marketed therapeutic agents (e.g., agents that are the subject of a Marketing Authorization in one or more marketing territories, such as a European or US Marketing Authorization).

[0154] Those skilled in the art will understand that reference to a therapeutic agent capable of reducing the level of a nucleoside and / or nucleotide in a cell (e.g., a cancer cell, such as a cell forming part of a cancer described herein) may refer to a compound that can reduce the level of such nucleoside and / or nucleotide (such as the level of uridine and / or uridine phosphate, e.g., uridine monophosphate, diphosphate, and triphosphate) in such cell by at least 10% (at least 20%, at least 30%, or at least 40%, e.g., at least 50%, at least 60%, at least 70%, or at least 80%, e.g., at least 90%) compared to the level of such nucleoside and / or nucleotide in such cell prior to treatment with the relevant compound.

[0155] Those skilled in the art will further appreciate that reference to therapeutic agents capable of reducing the levels of nucleosides and / or nucleotides in a cell (e.g., a cancer cell, such as a cell forming part of a cancer described herein) may include reference to compounds that act by inhibiting uptake of such nucleosides and / or nucleotides by such cells. For example, such therapeutic agents may include uridine uptake inhibitors known to those skilled in the art (such as the therapeutic agents nilotinib or dipyridamole).

[0156] Specific therapeutic agents capable of reducing intracellular levels of nucleosides and / or nucleotides include nilotinib, dipyridamole, imatinib, gefitinib, ibrutinib, varlitinib, voritinib, and vemurafenib (e.g., nilotinib and imatinib).

[0157] For example, therapeutic agents that can reduce intracellular levels of nucleosides and / or nucleotides include nilotinib, dipyridamole, imatinib, ibrutinib, and vemurafenib.

[0158] More specific therapeutic agents capable of reducing intracellular levels of nucleosides and / or nucleotides include nilotinib, ibrutinib, and dipyridamole.

[0159] Even more specific therapeutic agents capable of reducing intracellular levels of nucleosides and / or nucleotides include imatinib.

[0160] Even more specific therapeutic agents capable of reducing intracellular levels of nucleosides and / or nucleotides include vemurafenib.

[0161] For example, therapeutic agents capable of reducing intracellular nucleoside and / or nucleotide levels include ASLAN001 (vallitinib), ibrutinib, rapamycin, vemurafenib, gehinitib, antimycin A, BI-2536, VX-680, roscovitine, olomoucine, imatinib (STI-571), AG1879, AG1517, AG1478, AG825, AG18, AG490, vinblastine, etoposide, genistein, U0126, Raf-1 inhibitor 1, H89, KN93, staurosporine, ZM336372, and indirubin-3'-monoxime.

[0162] Specifically, therapeutic agents capable of reducing intracellular levels of nucleosides and / or nucleotides include ASLAN001 (vallitinib).

[0163] Specifically, therapeutic agents capable of reducing intracellular levels of nucleosides and / or nucleotides include ibrutinib.

[0164] Other compounds that may reduce intracellular nucleoside and / or nucleotide levels include BIBW2992, AG013736, PF-02341066 / PF-2341066, BMS-354825, 5-aza-2'-deoxycytidine, LY317615, CP-358774 / OSI-774, RAD001 / SDZ-RAD / Certican, GW572016 / GW2016, AMN-107, GW786034 / Armala, AP24534, BAY73-4506, INCB018424, Bay 43-9006 / Nexaxar, Sutent / SU-11248, Torisel / CCI-779, tasocitinib / CP-690550, GSK1120212, ZD6474, PLX4032 / RG7204 / RO5185426, SAHA / Zolinza / MK-0683, AT-877 / HA-1077, and quizartinib.

[0165] Those skilled in the art will understand that reference to a p53 activator can refer to a therapeutic agent that can increase the synthesis and / or stability of p53 (e.g., by increasing thermostability or by inhibiting degradation) and / or increase transcription factor function in a cell (e.g., a cancer cell, such as a cell that forms part of a cancer described herein).

[0166] Specifically, this may refer to increasing the synthesis and / or stability of p53 such that the level of p53 in a cell (e.g., a cancer cell, such as a cell forming part of a cancer described herein) is increased by at least at least 10% (at least 20%, at least 30%, or at least 40%, e.g., at least 50%, at least 60%, at least 70%, or at least 80%, such as at least 90% or at least 100%) compared to the level of p53 in such cell prior to treatment with the related compound. Additionally, this may refer to increasing the transcription factor function of p53 in a cell (e.g., a cancer cell, such as a cell forming part of a cancer described herein) by at least 10% (at least 20%, at least 30%, or at least 40%, e.g., at least 50%, at least 60%, at least 70%, or at least 80%, such as at least 90% or at least 100%) compared to the level of p53 in such cell prior to treatment with the related compound.

[0167] Those skilled in the art will further appreciate that reference to a p53 activator can include reference to a therapeutic agent that acts by inhibiting MDM2 (such as the therapeutic agent Nutlin-3).

[0168] Those skilled in the art will understand that reference to a therapeutic agent that acts by inhibiting MDM2 can refer to a compound that can inhibit MDM2 activity in a cell (e.g., a cancer cell, such as a cell forming part of a cancer described herein) by at least 10% (at least 20%, at least 30%, or at least 40%, e.g., at least 50%, at least 60%, at least 70%, or at least 80%, e.g., at least 90%) compared to the level of such activity in such cell prior to treatment with the relevant compound.

[0169] Specific therapeutic agents that can activate p53 (e.g., by inhibiting MDM2) include nutlin-3, RO5045337, idasanutlin, AMG-232, DS3032b, celdemethane, ALRN-6924, SAR-405838, CGM-097, RO-5503781, RO-6839921, and HDM-201.

[0170] A more specific therapeutic agent capable of activating p53 (eg, by inhibiting MDM2) includes nutlin-3.

[0171] Additional therapeutic agents that can activate p53 (eg, by increasing p53 levels) include PS-341 / MS-341, Ara-C, adriamycin, 5-FU, Camptosar, and mithramycin A.

[0172] In alternative embodiments of the sixth and seventh aspects of the invention, the additional therapeutic agent is a therapeutic agent for the treatment or prevention of a viral infection, such as a viral infection described herein.

[0173] Preparation of Compounds / Compositions The pharmaceutical compositions / formulations, combination products, and kits described herein may be prepared in accordance with standard and / or accepted pharmaceutical practices.

[0174] Thus, in a further aspect of the invention there is provided a process for the preparation of a pharmaceutical composition / formulation as described herein above, the process comprising bringing into association a compound of the invention as described herein above with one or more pharma- ceutically acceptable adjuvants, diluents or carriers.

[0175] In a further aspect of the invention there is provided a process for the preparation of a combination product or kit-of-parts as described herein above, the process comprising bringing into association a compound of the invention as described herein above, or a pharma- ceutically acceptable salt thereof, with other therapeutic agents useful for the treatment of cancer and / or the treatment or prevention of viral infection, and at least one pharma- ceutically acceptable adjuvant, diluent or carrier.

[0176] As used herein, reference to associating means that the two components are rendered suitable for co-administration with one another.

[0177] Thus, with respect to the process for the preparation of the kit of parts described herein above, "associating" two components with each other means that the two components of the kit of parts are (i) provided as separate formulations (i.e., independent of each other) which are then combined for combination in a combination therapy; or (ii) Packaged and presented together as separate components of a "combination pack" for use in combination therapy.

[0178] The compounds of the invention defined herein may be prepared according to techniques well known to those skilled in the art, such as those described in the examples provided herein below.

[0179] In an eighth aspect of the present invention there is provided a process for preparing a compound of formula I as defined in the first aspect of the present invention, or a pharma- ceutically acceptable salt thereof, the process comprising:

[0180] (i) a compound of formula II, [ka] In the formula, R 1 and A 2 is as defined in the first aspect of the invention, a compound of formula III, [ka] In the formula, A 1 and L 1 is as defined in the first aspect of the invention, and LG1 represents a suitable leaving group, under conditions known to the skilled person, in the presence of a suitable solvent and optionally in the presence of a suitable base and / or a suitable catalyst (e.g. where LG1 represents -OH and the reaction can be carried out in the presence of suitable reagents for carrying out peptide coupling reactions known to the skilled person, for example in the presence of HOBt and EDC.HCl, or alternatively in the presence of HATU or HBTU, and optionally in the presence of a suitable base, for example Et3N);

[0181] (ii) In the formula, L 1 -C(O)N(R 2 ), and R 2 represents H, the compound of formula II with the compound of formula IV, [ka] In the formula, A 1 is as defined in the first aspect of the invention, in the presence of a suitable solvent and optionally in the presence of a suitable base and / or a suitable catalyst, under conditions known to those skilled in the art; or

[0182] (iii) a compound of formula (V), [ka] In the formula, R 1 , A 1 and L 1 is as defined in the first aspect of the invention, With a compound of formula VI, [ka] In the formula, A 2is as defined in the first aspect of the invention, and LG2 represents a suitable leaving group. This is carried out under conditions well known to those skilled in the art, in the presence of a suitable solvent and optionally in the presence of a suitable base and / or a suitable catalyst (e.g. under Buchwald-Hartwig conditions well known to those skilled in the art, for example where LG2 represents a suitable leaving group such as halo and a suitable Pd catalyst (e.g. Pd2(dba) 3) and a suitable base, or under Chan-Lam conditions known to those skilled in the art, for example where LG2 represents a suitable leaving group such as -B(OH)2 and in the presence of a suitable catalyst such as a suitable Cu catalyst (e.g. Cu(OAc)2) and a suitable base).

[0183] The compounds of formulae II, III, IV, V, and VI are either commercially available, known in the literature, or can be obtained from available starting materials using suitable reagents and reaction conditions, either by analogy with the processes described herein or by conventional synthetic techniques. In this respect, the skilled artisan can refer, inter alia, to "Comprehensive Organic Synthesis" (BM Trost and I. Fleming, Pergamon Press, 1991). Further references that can be used include "Heterocyclic Chemistry" (JA Joule, K. Mills and GF Smith, 3 rd edition (published by Chapman & Hall), "Comprehensive Heterocyclic Chemistry II" (AR Katritzky, CW Rees and EFV Scriven, Pergamon Press, 1996) and "Science of Synthesis" (Volumes 9-17) (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

[0184] For example, a compound of formula II can be prepared by reaction of a compound of formula VII. [ka]

[0185] In the formula, R 1 and A 2 is as defined herein for compounds of formula I (and formula Ia), and S )-2-methyl-2-propanesulfinamide) under conditions known to one skilled in the art (e.g., in the presence of a suitable catalyst (e.g., Ti(OEt)4) and a suitable reducing agent (e.g., L-selectride) and in the presence of a suitable solvent), followed by cleavage of the amide under conditions known to one skilled in the art (i.e., to provide the free amine of the compound of formula II).

[0186] Additionally, compounds of formula VII can be prepared by reaction of a compound of formula VIII. [ka] In the formula, R 1 is as defined herein for a compound of formula VII and can be reacted with a compound of formula IX. [ka] In the formula, A 2 is as defined herein for compounds of formula I (and formula Ia) under conditions known to those of skill in the art.

[0187] Or, R 1 Compounds of formula VII, in which represents H, can be reacted with compounds of formula X, under conditions known to those skilled in the art, [ka] It can be prepared by reaction with a compound of formula IX as defined herein.

[0188] Those skilled in the art will recognize that compounds of formula III are commercially available, known in the literature, or can be prepared by analogy with the synthesis of compounds of formula I. 2represents H or a suitable protecting group known to those skilled in the art, it being understood that in the latter case preparation requires removal of the protecting group under conditions known to those skilled in the art to yield a compound of formula III.

[0189] Compounds of formula VII, VIII, IX, and X are either commercially available, known in the literature, or may be obtained from available starting materials using appropriate reagents and reaction conditions, either by analogy with the processes described herein or by conventional synthetic techniques.

[0190] Those skilled in the art will appreciate that the compounds of formula Ia and Ib, and pharma- ceutically acceptable salts thereof as defined herein, may be prepared by analogy with the synthesis of the compounds of formula Ia and pharma- ceutically acceptable salts thereof as described in the eighth aspect of the invention. In particular, such a process may be carried out according to the eighth aspect of the invention, wherein the compounds of formula II and V are substituted as follows: [ka]

[0191] For example, a compound of formula II, but with the reverse of the stereochemistry shown (i.e., the opposite enantiomer is provided), can be prepared by reacting a compound of formula VII as defined herein with a suitable chiral amide ((S S The compound of formula II can be prepared by reaction of a compound of formula II with a suitable amide such as Ti(OEt)4, a suitable reducing agent such as NaBH4, and a suitable solvent, under conditions known to one of skill in the art, followed by cleavage of the amide under conditions known to one of skill in the art (i.e., to provide the free amine of the compound corresponding to the compound of formula II).

[0192] A as defined herein 1 , A 2 , L 1 and R 1The substituents on the groups may be modified one or more times by methods well known to those skilled in the art after or during the process described above for the preparation of the compounds of formula Ia (and similarly the compounds of formula Ib). Examples of such methods include substitution, reduction, oxidation, dehydrogenation, alkylation, dealkylation, acylation, hydrolysis, esterification, etherification, halogenation, and nitration. The precursor groups may be transformed into different such groups or into the groups defined in formula I at any time during the reaction sequence. Those skilled in the art may also refer to "Comprehensive Organic Functional Group Transformations" (AR Katritzky, O. Meth-Cohn and CW Rees, Pergamon Press, 1995) and / or "Comprehensive Organic Transformations" (RC Larock, Wiley-VCH, 1999).

[0193] Such compounds can be isolated from their reaction mixtures and, if necessary, purified using conventional techniques known to those skilled in the art. Thus, the processes for the preparation of the compounds of the invention described herein can include, as a final step, the isolation and optional purification of the compounds of the invention (e.g., the isolation and optional purification of the compound of formula I).

[0194] It will be appreciated by those skilled in the art that in the processes described above and below, the functional groups of intermediate compounds may need to be protected by protecting groups. Protection and deprotection of functional groups may occur before or after the reactions in the above-mentioned schemes.

[0195] Protecting groups can be applied and removed according to techniques well known to those skilled in the art and described herein below. For example, the protected compounds / intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemistry involved will dictate the need and type of protecting groups, as well as the sequence for accomplishing the synthesis. The use of protecting groups is fully explained in "Protective Groups in Organic Synthesis", 3rd edition, TW Greene & P. ​​GMWutz, Wiley-Interscience (1999).

[0196] The compounds described herein (particularly those defined in the first aspect of the invention), whether used in the above-mentioned indications or otherwise, may have the advantage that they may be more effective, less toxic, longer acting, more potent, cause fewer side effects, be more easily absorbed, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance) and / or have other useful pharmacological, physical, or chemical properties than compounds known in the prior art. In particular, such compounds may have the advantage that they are more effective and / or exhibit advantageous properties in vivo.

[0197] Without wishing to be bound by theory, it is believed that the compounds described herein are potent DHODH inhibitors that provide activity as inhibitors of de novo pyrimidine nucleotide synthesis. Cancer cells are known to be more sensitive to nucleotide level regulation due to their defective cell cycle checkpoints. This allows for potent and selective inhibition of cancer cell growth and promotion of cancer cell death. Furthermore, it is believed that the compounds described herein can be combined with therapeutic agents that can reduce the levels of nucleotides and nucleosides, such as pyrimidine nucleotides and nucleosides, in cells (e.g., by inhibiting uptake or preventing retention in cells, such as therapeutic agent nilotinib), providing effective and synergistic combination therapy.

[0198] Surprisingly, despite their activity in reducing the levels of nucleotides and nucleosides in such cells, it has also been found that the compounds described herein can increase the synthesis of p53, a known tumor suppressor.Furthermore, it has been found that the compounds described herein can also be combined with other p53 activators (such as MDM2 inhibitors, e.g., Nutlin-3) to provide effective and synergistic combination therapy.

[0199] Again, without wishing to be bound by theory, it is believed that the observed synergy between the DHODH inhibitors described herein and p53 degradation inhibitors such as Nutlin-3 is due to the ability of the DHODH inhibitors to increase the synthesis of p53, which, together with inhibition of p53 degradation by Nutlin-3 (an MDM2 inhibitor), results in a more potent increase in p53 levels, which serves to induce p53 pro-apoptotic function.

[0200] Furthermore, the compounds described herein are believed to be potent inhibitors of viral replication making them of particular use in the treatment or prevention of viral infections. [Brief description of the drawings]

[0201] [Figure 1] FIG. 1 shows a simple illustration of the de novo synthesis (blue) and salvage (black) pathways of pyrimidine nucleotides. [Diagram 2] Figure 2 shows the results obtained from Biological Example 2, where the compounds of Synthetic Examples 6, 9, 11 and 13 reduce the proliferation and / or viability of MOLM13 cells, an effect that is largely prevented by the addition of excess uridine. EXAMPLES

[0202] Chemicals and reagents were obtained from commercial suppliers and used as received unless otherwise stated. All reactions involving moisture sensitive reagents were carried out in oven- or flame-dried glassware under positive nitrogen pressure. Thin-layer chromatography was performed using aluminum plates coated with silica gel (containing fluorescent indicator UV254). Developed plates were air-dried and analyzed under a UV lamp or by KMnO4 immersion staining. Flash column chromatography was performed using silica gel (60-120 μm). Low-resolution (LR) electrospray mass spectrometry (LC-MS) analyses were acquired by electrospray ionization (ESI) on a Shimadzu LCMS (SQD)-2010EV or an Agilent LCMS (SQD)-1200 series LC / G6125B-MS. Nuclear magnetic resonance (NMR) spectra were obtained by electrospray ionization (ESI) on a Shimadzu LCMS (SQD)-2010EV or an Agilent LCMS (SQD)-1200 series LC / G6125B-MS. 1 HNMR is 400MHz, carbon ( 13 CNMR) and fluorine ( 19 F NMR (F NMR) was recorded on a Varian / Bruker spectrometer at 100 MHz. Chemical shifts relative to residual protons of deuterated solvent peaks are expressed in ppm (δ). Coupling constants (J) are expressed in Hz and reported to the nearest 0.1 Hz. The following abbreviations are used; s, singlet; d, doublet; dd, doublet of doublets; t, triplet; m, multiplet; q, quartet; and br, broad. Signal assignments are proposed based on observed values. HPLC analysis was performed on a Shimadzu HPLC 2010CHT HPLC consisting of a LC20AD Prominence pump, a DGU-A3 Prominence degasser, a SPD-MA Prominence DAD detector, and a SIL-HTC autosampler. Separation was achieved using a Waters X-Select CSHC18 (4.6 x 150) mm, 5u column.

[0203] Analytical RPLC-MS was performed using HPLC-MS Shimadzu HPLC2010CHT and Shimadzu LCMS(SQD)-2010EV under the following conditions: Column: Waters X-Select C18CSH (3.0×50) mm; 2.5μ mobile phase: ACN / water gradient (0.05% HCOOH); flow rate, 1.2 mL / min; detection, UV (214, 254, 280 nm) and MS (ESI, pos, neg polarity) or Agilent LCMS(SQD)-1200 series LC / G6125B-MS mass spectrometer, electrospray ionization (ESI+). The HPLC-MS methods were as follows: Method 1 - Waters X-Select C18CSH (3.0×50) mm 2.5μ, 4 min gradient mobile phase ACN / [5 mM NH4HCO 3 / H2O]; Method2-Column: Waters X-Select C18CSH (3.0×50) mm2.5μ; Mobile phase, ACN / water gradient (0.05% HCOOH) with positive and negative electrospray ionization.

[0204] Preparative RP-LC was performed using a Shimadzu preparative HPLC system consisting of a CBM-20A system controller, LC-8A binary-gradient pump, SPD-M20A photodiode array detector, FRC-10A fraction collector equipped with an Xselect CSH rep C185mm OBDTM 30x250mm, 5μm column, with an ACN / H2O (0.05% HCOOH) gradient at a flow rate of 30mL / min and UV (220 or 254nm) detection. The Xselect CSH rep C185mm OBDTM 30x250mm, 5μm column was prepared on a GILSON 333 / 334 Prep-Scale system with a flow rate of 30mL / min, detection wavelength of 254nm, and an ACN / H2O (0.05% HCOOH) gradient system.

[0205] Preparative and analytical chiral HPLC were performed using a variety of columns and conditions. [Table 2]

[0206] Examples of Compounds The invention is illustrated by the following compound examples.

[0207] In case of discrepancy between the nomenclature and the structure of a compound, the latter shall prevail (unless contradicted by experimental details which may be given and / or clear from the context).

[0208] The following compounds were prepared by the methods described below.

[0209] Example 1: N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0210] Step-1: Synthesis of 4-((dimethylamino)methylene)-2H-pyran-3,5(4H,6H)-dione (INT-1.1): A solution of tetrahydropyran-3,5-dione (5.00 g, 43.85 mmol) in toluene (50 mL) was added and DMF-DMA (10.45 g, 87.71 mmol) was heated at 90 °C for 6 h. After completion of the reaction (5.1 g (crude)), the solvent was evaporated under reduced pressure and the residue was subsequently triturated with n-pentane to give INT-1.2 as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1H), 4.02 (s, 4H), 3.45 (s, 3H), 3.16 (s, 3H).

[0211] Step-2: Synthesis of 1-(2-fluorophenyl)-1,7-dihydropyrano[3,4-c]pyrazol-4(5H)-one (INT-1.2): A solution of INT-1.1 (4.10 g, 24.23 mmol), 1-(2-fluorophenyl)hydrazine (3.94 g, 24.23 mmol) in AcOH (3.6 mL, 63.0 mmol) and ethanol (40 mL) was refluxed for 16 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude solid was purified by column chromatography on silica gel (100-200 mesh) eluted with 5-10% methanol in DCM to give INT-1.2 (2.85 g, 50.7%) as a white solid; LCMS (ESI) m / z=233.1 [M+H]+.

[0212] Step-3: Synthesis of 1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-amine (INT-1.3): To a solution of INT-1.2 (2.00 g, 8.61 mmol) in 2-propanol (50 mL) was added ammonium acetate (6.63 g, 86.13 mmol) and molecular sieves (4 Å). After vigorous stirring, NaBH3CN (2.70 g, 43.06 mmol) was carefully added. The reaction was heated to 70° C. for 48 h. After completion (monitored by TLC), the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (100-200 mesh) eluted with 5-10% methanol in DCM to give INT-1.3 (1.40 g, 70%) as a white solid; LCMS (ESI) m / z=234.2 [M+H]+.

[0213] Step-4: Synthesis of N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-1): A solution of INT-1.3 (0.200 g, 0.861 mmol) in DCM (5 mL) was cooled to 0° C. 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid (0.157 g, 0.947 mmol) and triethylamine (0.3 mL, 2.584 mmol) were added. The resulting mixture was stirred for 5 minutes, after which T3P (50% ethyl acetate, 0.4 mL, 1.29 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound. The crude solid material was purified by column chromatography on silica gel (100-200 mesh) eluting with 5-10% MeOH in DCM to give pure Ex-1. LCMS (ESI) m / z=381.9 [M+H]+.

[0214] Ex-1 was separated and purified by chiral HPLC to give Ex-2 (22 mg, 8.5%) and Ex-3 (22 mg, 7.8%) as off-white solids (Daicel Chiral Pack-IG (250x30mm, 5μ) / Mobile phase: An-hexane + 0.1% DEA; B. DCM:MEOH (50:50) isocratic 50% B / Flow rate: 30 mL / min) R (Peak 1) 9.1, t R (Peak 2) 10.4.

[0215] Example 2: (R)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Peak 1) [ka] LCMS (ESI) m / z = 381.9 [M+H]+; HPLC: 98.7% (t R = 5.920 min); 1H NMR (400 MHz, DMSO-d6): δ 7.71 (s, 1H), 7.62-7.43 (m, 5H), 7.42-7.32 (m, 1H), 5.10-4.99 (m, 1H), 4.77-4.51 (m, 2H), 3.99 (br t, J = 5.9 Hz, 2H), 3.85 (d, J = 3.9 Hz, 2H), 2.99 (br t, J = 6.6 Hz, 2H), 1.90 - 1.83 (m, 2H), 1.80 - 1.72 (m, 2H).

[0216] Example 3: (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Peak 2) [ka] LCMS (ESI) m / z = 381.9 [M+H]+; HPLC: 99.8% (tR = 5.926 min); 1H NMR (400 MHz, DMSO-d6): δ 7.71 (s, 1H), 7.61 - 7.44 (m, 5H), 7.41-7.34 (m, 1H), 5.17-4.98 (m, 1H), 4.75-4.53 (m, 2H), 4.01-3.98 (m, 2H), 3.86-3.82 (m, 2H), 3.01-2.98 (m, 2H), 1.89-1.81 (m, 2H), 1.81-1.72 (m, 2H).

[0217] Example 4: N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide [ka]

[0218] Step-1: Synthesis of N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide (Ex-4): To a solution of INT-1.3 (0.100 g, 0.430 mmol) in DCM (5 mL) at 0° C., 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylic acid (0.768 g, 0.473 mmol) and triethylamine (0.3 mL, 1.29 mmol) were added. The mixture was stirred for 5 minutes, after which T3P (50% ethyl acetate) was added. The reaction was stirred at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a solid residue. The crude title compound was purified by column chromatography on silica gel (100-200 mesh) eluted with 5-10% MeOH in DCM to give pure Ex-4. LCMS (ESI) m / z=381.8 [M+H]+. Ex-4 was separated and purified by chiral HPLC to give Ex-5 (17 mg, 7.8%) and Ex-6 (18 mg, 8.5%) as off-white solids (Daicel Chiral Pack-IG (250x30mm, 5μ) / Mobile phase: An-hexane + 0.1% DEA; B. DCM:MEOH (50:50) isocratic 50% B / Flow rate: 30 mL / min) R (Peak 1) 8.9, t R (Peak 2) 11.5.

[0219] Example 5: (R)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide (Peak 1) [ka]

[0220] LCMS (ESI) m / z = 381.8 [M+H]+; HPLC: 98.9% (t R = 7.011 min); 1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.51 (t, J = 7.1 Hz, 1H), 7.47-7.36 (m, 1H), 7.30-7.28 (m, 1H), 7.25-7.21 (m, 1H), 6.75 (s, 1H), 5.22-5.20 (m, 1H), 4.80 - 4.63 (m, 2H), 4.55 - 4.35 (m, 2H), 4.09-4.05 (m, 1H), 3.92-3.88 (m, 1H), 2.81 (br t, J = 6.4 Hz, 2H), 2.04-1.94 (m, 2H), 1.85-1.79 (m, 2H).

[0221] Example 6: (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide (Peak 2) [ka]

[0222] LCMS (ESI) m / z = 380.8 [M+H]+; HPLC: 97.7% (t R = 7.023 min); 1H NMR (400 MHz, CDCl3): δ 7.76-7.72 (m, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.55-7.48 (m, 1H), 7.45-7.37 (m, 1H), 7.33-7.27 (m, 1H), 7.23-7.20 (m, 1H), 6.75 (s, 1H), 5.29-5.08 (m, 1H), 4.69-4.65 (m, 2H), 4.52-4.49 (m, 2H), 4.09-4.05 (m, 1H), 3.92-3.88 (m, 1H), 2.82 (br t, J = 6.1 Hz, 2H), 2.05 - 1.95 (m, 2H), 1.91 - 1.75 (m, 2H).

[0223] Example 7: N-1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0224] Step-1: Synthesis of (2-chloro-6-fluoro-3-methoxyphenyl)hydrazine hydrochloride (4,00 g, 22.8 mmol). To a stirred solution of concentrated 2-chloro-6-fluoro-3-methoxyaniline (1.91 g, 27.33 mmol) was added HCl (20 mL) at 0° C. The reaction was stirred at 0° C. for 1 h. After 1 h, concentrated SnCl2 (12.84 g, 56.95 mmol). HCl (20 mL) was added dropwise at 0° C. and the resulting reaction mixture was stirred at room temperature for 16 h. After workup, the formed precipitate was filtered and dried under vacuum to obtain compound INT-7-1 (6.03 g (crude)) as a white solid. LCMS (ESI) m / z=190.9 [M+H]+

[0225] Step-2: Synthesis of 1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,7-dihydropyrano[3,4-c]pyrazol-4(5H)-one (INT7.2): A solution of INT-1.1 (5.00 g, 29.55 mmol) and INT-7.1 (5.60 g, 29.55 mmol) in 4M HCl in dioxane (10 mL, 29.55 mmol) was heated at 100° C. for 16 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography eluting with 5-10% MeOH in DCM to give INT-7.2 (2.5 g, 57%) as a white solid. LCMS (ESI) m / z=296.9[M+H]+

[0226] Step-3: Synthesis of (S,Z)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,7-dihydropyrano[3,4-c]pyrazole 4(5H)-ylidene)-2-methylpropane-2-sulfinamide (INT-7.3): To a room temperature solution of ketone INT-7.2 (3.5 g, 11.8 mmol) and (S)-2-methylpropane-2-sulfinamide (0.77 g, 34.54 mmol) in THF (10 mL) was added Ti(OiPr)4 (3.61 g, 70.8 mmol). The reaction mixture was heated to 100° C. for 4 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 5-10% MeOH in DCM to give compound 6 (2.3 g, 18%) as a white solid. LCMS (ESI) m / z=400.1 [M+H]+

[0227] Step-4: Synthesis of (S)-N-((S)-1-(2,6-dichlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-2-methylpropane-2-sulfinamide (INT-7.4): To a solution of INT-7.3 (2.3 g, 0.775 mmol) in anhydrous THF (5 mL) at 0° C., L-selectride (1M in THF, 1.55 mL, 1.55 mmol) was added. The reaction mixture was stirred at room temperature for 3 h and after completion (monitored by TLC), the reaction mixture was quenched with saturated aq. Extracted with DCM (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give INT-7.4 (2.5 g (crude)) as an off-white solid. This material was used directly in the next step without further purification.

[0228] Step-5: Synthesis of (S)-1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole 4-amine hydrochloride (INT-7.5): To a solution of INT-7.4 (0.110 g, 0.284 mmol) in DCM (2 mL) at 0° C., 4M HCl in dioxane (5 mL) was added. The reaction mixture was stirred at room temperature for 4 h. After completion (monitored by TLC), the volatiles were removed under reduced pressure to give an oily residue, which was triturated with diethyl ether to give INT-7.5 (0.100 g (crude)) as an off-white solid. LCMS (ESI) m / z=283.90 [M+H]+

[0229] Step-6: Synthesis of N-((4R)- and N-((4S)-1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-8 and Ex-9): To a solution of INT-7.5 (0.250 g, 0.823 mmol) and 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid (0.137 g, 0.823 mmol) in DMF (5 mL) at 0° C., DIPEA (0.437 mL, 2.469 mmol) was added followed by HAT. U (0.470 g, 1.234 mmol) was added. The resulting reaction mixture was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude material. The crude compound was purified by silica gel column chromatography eluting with 5–10% MeOH in DCM. The column purified compound (mixture of Ex-8 and Ex-9) was separated and purified by chiral HPLC to give Ex-8 (0.010 g, 3%) and Ex-9 (0.050 g, 15%) as off-white solids.

[0230] Example 8: N-((4R)-1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Peak 1) [ka]

[0231] LCMS (ESI) m / z = 446.0 [M+H]+; HPLC: 99.1% (t R = 5.483 min); 1H NMR (400 MHz, DMSO-d6): δ 7.73 (d, J = 3.5 Hz, 1H), 7.59-7.36 (m, 4H), 5.14-4.98 (m, 1H), 4.64-4.36 (m, 2H), 4.00 (t, J = 5.9 Hz, 2H), 3.92 (s, 3H), 3.85-3.82 (m, 2H), 3.00 (t, J = 6.5 Hz, 2H), 1.90-1.70 (m, 4H).

[0232] Example 9: N-((4S)-1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Peak 2) [ka]

[0233] LCMS (ESI) m / z = 446.05 [M+H]+; HPLC: 99.8% (t R= 5.481 min); 1H NMR (400 MHz, DMSO-d6): δ 7.73 (d, J = 3.5 Hz, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.53-7.35 (m, 3H), 5.19-4.95 (m, 1H), 4.64-4.29 (m, 2H), 4.00 (t, J = 5.9 Hz, 2H), 3.92 (s, 3H), 3.85-3.82 (m, 2H), 3.00 (t, J = 6.5 Hz, 2H), 1.98-1.66 (m, 4H).

[0234] Additionally, the following compounds were prepared similarly to the above method:

[0235] Example 10: N-((4R)-1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Peak 1) [ka]

[0236] LCMS (ESI) m / z = 416.0 [M+H]+; HPLC: 99.1% (t R = 5.326 min); 1H NMR (400 MHz, DMSO-d6): δ 7.74 (d, J = 3.1 Hz, 1H), 7.69-7.35 (m, 5H), 5.22-4.90 (m, 1H), 4.62-4.34 (m, 2H), 4.00 (t, J = 5.9 Hz, 2H), 3.85-3.83 (m, 2H), 3.00 (t, J = 6.4 Hz, 2H), 1.95-1.69 (m, 3H), 1.20-1.13 (m, 1H).

[0237] Example 11: N-((4S)-1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Peak 2) [ka]

[0238] LCMS (ESI) m / z = 416.0 [M+H]+; HPLC: 99.8% (t R = 5.319 min); 1H NMR (400 MHz, DMSO-d6) δ 7.01 (s, 1H), 6.84-6.77 (m, 1H), 6.73-6.64 (m, 2H), 6.60-6.53 (m, 1H), 4.36 (br s, 1H), 3.89-3.58 (m, 2H), 3.26 (t, J = 5.9 Hz, 2H), 3.22-3.06 (m, 2H), 2.31 (t, J = 6.4 Hz, 2H), 1.24 - 1.01 (m, 4H), 0.55-0.37 (m, 1H).

[0239] Example 12: (S)-N-(1-(2,6-dichlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Peak 1) [ka]

[0240] LCMS (ESI) m / z = 416.0 [M+H]+; HPLC: 99.1% (t R= 5.326 min); 1H NMR (400 MHz, DMSO-d6): δ 7.74 (d, J = 3.1 Hz, 1H), 7.69-7.35 (m, 5H), 5.22-4.90 (m, 1H), 4.62-4.34 (m, 2H), 4.00 (t, J = 5.9 Hz, 2H), 3.85-3.83 (m, 2H), 3.00 (t, J = 6.4 Hz, 2H), 1.95-1.69 (m, 3H), 1.20-1.13 (m, 1H).

[0241] Example 13: (S)-N-(1-(2,6-dichlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Peak 2) [ka]

[0242] LCMS (ESI) m / z = 416.0 [M+H]+; HPLC: 99.8% (t R = 5.319 min); 1H NMR (400 MHz, DMSO-d6) δ 7.01 (s, 1H), 6.84-6.77 (m, 1H), 6.73-6.64 (m, 2H), 6.60-6.53 (m, 1H), 4.36 (br s, 1H), 3.89-3.58 (m, 2H), 3.26 (t, J = 5.9 Hz, 2H), 3.22-3.06 (m, 2H), 2.31 (t, J = 6.4 Hz, 2H), 1.24 - 1.01 (m, 4H), 0.55-0.37 (m, 1H).

[0243] Example 14: (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0244] Step-1: Synthesis of hydrazine (INT-14.1): To a solution of 2-chloro-3-methylaniline (5.0 g, 35.5 mmol) in concentrated hydrochloric acid HCl (25 mL) was added sodium nitrite (8.53 g, 124.0 mmol) at 0° C. The reaction was stirred at 0° C. for 1 h. After 1 h, stannous chloride dihydrate (31.9 g, 141.0 mmol) dissolved in hydrogen chloride (25 mL) was added dropwise at 0° C. The reaction was stirred at room temperature and the progress of the reaction was monitored by TLC. After 16 h, the precipitate was filtered, washed with diethyl ether and n-pentane, and dried under reduced pressure to obtain pure compound INT-1.1 (5.2 g, 94%) as a white solid. LCMS (ESI) m / z=157.06 [M+H]+.

[0245] Step-2: Synthesis of 1-(2-chloro-3-methylphenyl)-1,7-dihydropyrano[3,4-c]pyrazol-4(5H)-one (INT14.2): To a stirred solution of INT-14.1 (5.0 g, 31.9 mmol) in acetic acid (15 mL) was added INT-1.1 (3.78 g, 22.3 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 h. After completion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting crude material was purified by silica gel column chromatography using a gradient of 50-60% EtOAc in hexanes to give INT-1.3 (2.52 g, 30%) as a yellow solid. LCMS (ESI) m / z=263.12 [M+H]+.

[0246] Step-3: Synthesis of (S,Z)-N-(1-(2-chloro-3-methylphenyl)-1,7-dihydropyrano[3,4-c]pyrazole 4(5H)-ylidene)-2-methylpropane-2-sulfinamide (INT-14.3): To a stirred solution of INT-14.2 (2.0 g, 7.61 mmol) in THF (20 mL) was added titanium tetraisopropoxide (13.9 mL, 45.7 mmol) and (S)-2-methylpropane-2-sulfinamide (2.77 g, 22.8 mmol) at room temperature under N2 atmosphere. The reaction was stirred at 80° C. for 7 hours. After completion, the reaction was cooled to room temperature and quenched with brine. The solid precipitate was filtered through a bed of Celite and washed with EtOAc. The collective filtrate was extracted with EtOAc, dried over sodium sulfate and concentrated in vacuo to obtain the crude. The crude was purified by silica gel column chromatography using a gradient of 50-60% EtOAc in hexanes to give INT-1.4 (1.8 gm, 65%) as a yellow solid. LCMS (ESI) m / z=366.27 [M+H]+.

[0247] Step-4: Synthesis of (S)-N-((S)-1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-2-methylpropane-2-sulfinamide: To a stirred solution of INT-14.3 (1.8 g, 4.92 mmol) in THF (18 mL) was added L-selectride (1M in THF) (6.55 g, 34.4 mmol) at -78 °C under N2 atmosphere. The reaction was stirred at room temperature for 4 h. After completion, the reaction mixture was quenched with saturated brine and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, concentrated in vacuum and purified by flash column chromatography using a gradient of 60-70% EtOAc in hexane to give INT-1.5 (1.8 g, 99%) as a yellow solid. LCMS (ESI) m / z=368.28 [M+H]+.

[0248] Step-5: Synthesis of (S)-1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole 4-amine hydrochloride (INT-14.5): To a stirred solution of INT-14.4 (1.8 g, 4.89 mmol) in DCM (36 mL) was added 4M HCl in 1,4-dioxane (21 mL) at 0° C. The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was evaporated to obtain the crude. The crude was dissolved in DCM and reprecipitated with n-pentane to obtain INT-14.5 (1.25 g, 97%) as an off-white solid. LCMS (ESI) m / z=264.29 [M+H]+.

[0249] step-6: Synthesis of (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-14): To a stirred solution of 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid (0.075 g, 0.46 mmol) and INT-14.6 (0.12 g, 0.46 mmol) in dry DMF (1.2 mL) was added HATU (0.21 g, 0.55 mmol) and DIPEA (0.10 mL, 0.55 mmol) at 0° C. After completion of the reaction, the reaction mass was poured into ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 2-10% MeOH in DCM to give an enantiomeric mixture [74:26] of Ex-14 (120 mg) as an off-white solid compound. Further separation and purification of Ex-14 by chiral HPLC gave pure Ex-14 (70 mg, 36.8%) as a white solid [Column name: CHIRALCEL-OJH (4.6*250) mm, 5u; Mobile phase: CO2 / 0.1% AH in MeOH (80:20); Flow rate: 3.0 mL per minute; Flow mode: Isocratic; Column temperature: 35 °C; ABPR pressure: 1500 psi, t R (Peak 1) 3.19 minutes (74%), t R(Peak-2) 3.59 min (26%). LCMS (ESI) m / z = 412.28 [M+H] +; Chiral HPLC (Peak-1): 99.8% (t R =3.18 min); UPLC (E method): 96.6% (t R 1H NMR (400 MHz, DMSO-d6): δ 7.66 (s, 1H), 7.56 (s, 1H), 7.53 (dd, J = 6.8 Hz, J = 2.4 Hz, 1H), 7.42-7.39 (m, 3H), 5.07-5.03 (m, 1H), 4.53 (dd, J = 14.8 Hz, J = 11.6 Hz, 2H), 3.99 (t, J = 6.0 Hz, 2H), 3.83 (td, J = 11.6 Hz, J = 4.0 Hz, 2H), 2.99 (t, J = 6.4 Hz, 2H), 2.43 (s, 3H), 1.86-1.84 (m, 2H), 1.79-1.76 (m, 2H).

[0250] Example 15: (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide [ka]

[0251] To a stirred solution of 5-ethyl-1-methyl-1H-imidazole 4-carboxylic acid (0.25 g, 1.59 mmol) and INT-14.5 (0.35 g, 1.33 mmol) in dry DMF (3.5 mL) was added HATU (0.61 g, 1.59 mmol) and DIPEA (0.694 mL, 3.98 mmol) at 0° C., and then the reaction was stirred at room temperature for 16 h. After completion, the reaction mass was poured onto ice water and extracted with EtOAc. The collective organic layer was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to obtain the crude compound. The crude was purified by silica gel column chromatography using a gradient of 2-10% MeOH in DCM to obtain the enantiomeric mixture [28:78] of Ex-01 (250 mg) as an off-white solid compound. Furthermore, pure Ex-01 (30 mg, 5.6%) was obtained as a white solid by separation and purification using chiral HPLC [column name: Chiralpak-IG (4.6 × 250) mm, 5 um, mobile phase: 0.1% TEAinIPA / ACN = 70:30 (v / v), flow rate: 1.0 ml / min, temperature: 25 °C, flow mode: isocratic, t R (Peak 1) 4.82 minutes (28%), t R (Peak-2) 5.78 min (78%). LCMS (ESI) m / z = 400.11 [M+H] +; Chiral HPLC (Peak-2): 99.5% (t R 5.76 min); UPLC (Method B): 99.9%(t R 1H NMR (400 MHz, DMSO-d6): δ 7.67 (s, 1H), 7.56 (s, 1H), 7.55-7.52 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.42-7.37 (m, 2H), 5.07-5.03 (m, 1H), 4.53 (dd, J = 14.8 Hz, J = 11.2 Hz, 2H), 3.83 (qd, J = 11.6 Hz, J = 3.6 Hz, 2H), 3.60 (s, 3H), 2.98 (q, J = 7.6 Hz, 2H), 3.43 (s, 3H), 1.22 (t, J = 7.6 Hz, 3H).

[0252] Example 16: (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide [ka]

[0253] To a stirred solution of 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylic acid (0.38 g, 2.28 mmol) and INT-14.5 (0.4 g, 1.52 mmol) in dry DMF (4.0 mL) was added HATU (0.87 g, 2.28 mmol) and DIPEA (0.80 mL, 2.28 mmol) at 0° C., and the reaction was then stirred at room temperature for 16 h. After completion, the reaction mass was poured onto ice water and extracted with EtOAc. The collective organic layer was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to obtain the crude compound. The crude product was purified by silica gel column chromatography using a gradient of 2-10% MeOH in DCM to obtain the enantiomeric mixture [12:88] of Ex-16 (160 mg) as an off-white solid compound. Furthermore, Ex-16 was separated and purified by chiral HPLC to obtain pure Ex-16 (80 mg, 12.8%) as a white solid [Column name: CHIRALPAKIA (4.6*250) mm, 5u; Mobile phase: CO2 / 0.2% TEAinIPA:ACN (50:50) = (60:40) (v / v); Flow rate: 3.0 mL per minute; Flow mode: Isocratic; Column temperature: 35 °C; ABPR pressure: 1500 psi, t R (Peak 1) 2.93 minutes (12%), t R (Peak-2) 3.69 min (88%). LCMS (ESI) m / z = 412.09 [M+H] +; Chiral HPLC (Peak-2): 99.8% (t R 3.77 min); UPLC (Method A): 99.5% (t R1H NMR (400 MHz, DMSO-d6): δ 7.89 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.54 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.42-7.36 (m, 2H), 6.76 (s, 1H), 5.09-5.05 (m, 1H), 4.52 (dd, J = 14.8 Hz, J = 14.4 Hz, 2H), 4.44-4.33 (m, 2H), 3.85 (td, J = 11.6 Hz, J = 4.0 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.43 (s, 3H), 1.93-1.87 (m, 2H), 1.76-1.70 (m, 2H).

[0254] Example 17: (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide [ka]

[0255] To a stirred solution of 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.33 g, 1.99 mmol) and INT-14.5 (0.35 g, 1.33 mmol) in dry DMF (3.5 mL) was added HATU (0.76 g, 1.99 mmol) and DIPEA (0.70 mL, 3.98 mmol) at 0° C., and then the reaction was stirred at room temperature for 16 h. After completion, the reaction mass was poured onto ice water and extracted with EtOAc. The collective organic layer was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to obtain the crude compound. The crude product was purified by silica gel column chromatography using a gradient of 2-10% MeOH in DCM to obtain the enantiomeric mixture [24:76] of Ex-17 (250 mg) as an off-white solid compound. Furthermore, Ex-17 was separated and purified by chiral HPLC to obtain pure Ex-17 (66 mg, 12.1%) as a white solid [Column name: Chiralpak-IA (4.6*250) mm, 5u; Mobile phase: CO2 / 0.2% TEAinIPA=(60:40)(v / v); Flow rate: 3 mL per minute; Flow mode: Isocratic; Column temperature: 35°C; ABPR pressure: 1500 psi, t R (Peak 1) 2.79 minutes (24%), t R (Peak-2) 3.67 min (76%). LCMS (ESI) m / z = 412.19 [M+H] +; Chiral HPLC (Peak-2): 99.3% (t R 3.90 minutes); UPLC (B method): 97.2% (t R1H NMR (400 MHz, DMSO-d6): δ 7.89 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.54 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.42-7.36 (m, 2H), 6.76 (s, 1H), 5.09-5.05 (m, 1H), 4.52 (dd, J = 14.8 Hz, J = 14.4 Hz, 2H), 4.44-4.33 (m, 2H), 3.85 (td, J = 11.6 Hz, J = 4.0 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.43 (s, 3H), 1.93-1.87 (m, 2H), 1.76-1.70 (m, 2H).

[0256] Example 18: (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide [ka]

[0257] To a stirred solution of 4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxylic acid (0.38 g, 2.28 mmol) and INT-14.5 (0.40 g, 1.52 mmol) in dry DMF (4.0 mL) was added HATU (0.87 g, 2.28 mmol) and DIPEA (0.80 mL, 4.55 mmol) at 0° C., and the reaction was then stirred at room temperature for 16 h. After completion, the reaction mass was poured onto ice water and extracted with EtOAc. The collective organic layer was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to obtain the crude compound. The crude product was purified by silica gel column chromatography using a gradient of 2-10% MeOH in DCM to obtain the enantiomeric mixture [75:25] of Ex-18 (350 mg) as an off-white solid compound. Furthermore, Ex-18 was separated and purified by chiral HPLC to obtain pure Ex-18 (110 mg, 17.5%) as a white solid [Column name: CHIRALCELOJ-H (4.6*250) mm, 5u; Mobile phase: CO2 / 0.2% TEA (in MEOH) = (60:40) (v / v); Flow rate: 3.0 mL per minute; Flow mode: Isocratic; Column temperature: 35 °C; ABPR pressure: 1500 psi, t R (Peak-1) 2.08 minutes (75%), t R (Peak-2) 3.32 min (25%). LCMS (ESI) m / z = 413.16 [M+H] +; Chiral HPLC (Peak-1): 99.9% (t R 1.94 min); UPLC (Method A): 99.4%(t R1H NMR (400 MHz, DMSO-d6): δ 8.75 (d, J = 7.6 Hz, 1H), 7.67 (s, 1H), 7.53 (dd, J = 7.6 Hz, J = 0.8 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.33 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H), 5.14-5.10 (m, 1H), 4.51 (dd, J = 14.8 Hz, J = 6.0 Hz, 2H), 3.88 (dd, J = 11.6 Hz, J = 4.0 Hz, 1H), 3.81 (dd, J = 11.6 Hz, J = 4.8 Hz, 1H), 2.72 (t, J = 6.0 Hz, 2H), 2.63-2.55 (m, 2H), 2.43 (s, 3H), 1.82-1.76 (m, 2H), 1.72-1.66 (m, 2H).

[0258] Example 19: (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide [ka]

[0259] To a stirred solution of 4-ethyl-5-methyl-1H-pyrazole-3-carboxylic acid (0.35 g, 2.28 mmol) and INT-14.5 (0.40 g, 1.52 mmol) in dry DMF (4.0 mL) was added HATU (0.87 g, 2.28 mmol) and DIPEA (0.8 mL, 4.58 mmol) at 0° C. The reaction was then stirred at room temperature for 16 h. After completion, the reaction mass was poured onto ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient of 2-10% MeOH in DCM to obtain the enantiomeric mixture [18:82] of Ex-19 (300 mg) as an off-white solid compound. Further separation and purification by chiral HPLC gave pure Ex-19 (75 mg, 12.4%) as a white solid [Column name: Chiralpak-IA (4.6*250) mm, 5 u; Mobile phase: CO2 / 0.2% TEAinIPA=(60:40)(v / v); Flow rate: 3.0 mL per minute; Flow mode: Isocratic; Column temperature: 35°C; ABPR pressure: 1500 psi, t R (Peak 1) 2.11 minutes (18%), t R (Peak 2) 2.56 minutes (82%). 1H NMR (400 MHz, DMSO-d6): δ 12.7 (s, 1H), 7.67 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.54 (dd, J = 7.2 Hz, J = 1.6 Hz, 1H), 7.42-7.36 (m, 2H), 5.10-5.06 (m, 1H), 4.52 (dd, J = 14.8 Hz, J = 10.0 Hz, 2H), 3.85 (dd, J = 16.0 Hz, J = 12.4 Hz, 2H), 2.65 (q, J = 7.2 Hz, 2H), 2.43 (s, 3H), 2.17 (s, 3H), 1.07 (t, J = 7.6 Hz, 3H).

[0260] Example 20: (S)-N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide [ka]

[0261] To a stirred solution of 4,5-dimethylpicolinic acid (0.17 g, 1.14 mmol) and INT-14.5 (0.2 g, 0.76 mmol) in dry DMF (2.0 mL) was added HATU (0.72 g, 1.14 mmol) and DIPEA (0.41 mL, 2.28 mmol) at 0° C., and the reaction was then stirred at room temperature for 16 h. After completion, the reaction mass was poured onto ice water and extracted with EtOAc. The collective organic layer was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to obtain the crude compound. The crude product was purified by silica gel column chromatography using a gradient of 2-10% MeOH in DCM to obtain the enantiomeric mixture [78:22] of Ex-20 (200 mg) as an off-white solid compound. Furthermore, Ex-20 was separated and purified by chiral HPLC to obtain pure Ex-20 (70 mg, 23.2%) as a white solid [Column name: Lux-Amylose-1 (4.6*250) mm, 5 u; Mobile phase: CO2 / 0.2% TEAinIPA = (60:40) (v / v); Flow rate: 3.0 mL per minute; Flow mode: Isocratic; Column temperature: 35 °C; ABPR pressure: 1500 psi, t R (Peak 1) 2.91 minutes (78%), t R (Peak-2) 3.60 minutes (22%)]. LCMS(ESI)m / z=397.04[M+H]+;Chiral HPLC(peak-1):99.3%(t R 2.90 minutes); UPLC (A method): 99.9% (t R1H NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.70 (s, 1H), 7.53 (dd, J = 6.8 Hz, J = 2.8 Hz, 1H), 7.43-7.37 (m, 2H), 5.14-5.11 (m, 1H), 4.55 (dd, J = 14.8 Hz, J = 12.4 Hz, 2H), 3.93 (dd, J = 11.6 Hz, J = 4.0 Hz, 1H), 3.85 (dd, J = 7.6 Hz, J = 4.0 Hz, 1H), 2.43 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H).

[0262] Example 21: (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0263] Step-1: Synthesis of (2-chloro-3-methoxyphenyl)hydrazine hydrochloride (4.8 g, 87%): The reaction was carried out on a 5.0 g scale according to the experimental procedure of INT-14.1, and the product was obtained as a white solid. LCMS (ESI) m / z=173.01 [M+H]+.

[0264] Step-2: Synthesis of 1-(2-chloro-3-methoxyphenyl)-1,7-dihydropyrano[3,4-c]pyrazol-4(5H)-one (INT21.2): The reaction was carried out on a 2.5 g scale according to the experimental procedure of INT-14.2 to give INT-21.2 (0.75 g, 18%) as a yellow solid. LCMS (ESI) m / z=279.23 [M+H]+.

[0265] Step-3: Synthesis of (S,E)-N-(1-(2-chloro-3-methoxyphenyl)-1,7-dihydropyrano[3,4-c]pyrazole-4(5H)-ylidene)-2-methylpropane-2-sulfinamide (INT-21.3): The reaction was carried out on 2.0 g scale according to experimental procedure of INT-14.3 to give INT-213 (1.70 gm, 62%) as a yellow solid. LCMS (ESI) m / z=382.29[M+H]+.

[0266] Step-4: Synthesis of (S)-N-((S)-1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-2-methylpropane-2-sulfinamide (INT-21.4): The reaction was carried out on a 1.7 g scale according to the experimental procedure of INT-14.4 to give INT-21.4 (1.4 g, 82%) as a yellow solid. LCMS (ESI) m / z=384.27 [M+H]+.

[0267] Step-5: Synthesis of (S)-1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole 4-amine hydrochloride (INT-21.5): Following the experimental procedure of INT-14.5, the reaction was carried out on a 2.0 g scale to give INT-2.5 (1.4 g, 96%) as an off-white solid. LCMS (ESI) m / z=280.09 [M+H]+.

[0268] Step-6: Synthesis of (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-21): Following the experimental procedure of Ex-14, the reaction with 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid was carried out on a 0.15 g scale to give an enantiomeric mixture [82:18] of Ex-21 (120 mg) as an off-white solid compound. Further separation and purification of Ex-21 by chiral HPLC gave pure Ex-21 (25 mg, 11%) as a white solid. [Column name: Lux_Amylose_1(4.6*250)mm,5u; Mobile phase: CO2 / 0.1%AHinIPA(60:40); Flow rate: 3.0mL per minute; Flow mode: Isocratic; Column temperature: 35℃; ABPR pressure: 1500psi,t R (Peak 1) 5.64 minutes (82%), t R (Peak-2)7.63min(18%)]LCMS(ESI)m / z=428.23[M+H]+;Chiral HPLC(peak-1):99.9%(t R 5.64min);UPLC(MethodA):99.4%(t R 9.50min);1H NMR (400 MHz, DMSO-d6): δ 7.66 (s, 1H), 7.56 (s, 1H), 7.46 (t, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 5.07-5.03 (m, 1H), 4.53 (dd, J = 14.8 Hz, J = 11.2 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.93 (s, 3H), 3.83 (t, J = 3.2 Hz, 2H), 2.99 (t, J = 6.4 Hz, 2H), 1.86-1.84 (m, 2H), 1.78-1.77 (m, 2H).

[0269] Example 22: (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide [ka]

[0270] Following the experimental procedure for Ex-15, the reaction was carried out on a 0.25g scale to obtain the enantiomeric mixture [83:17] of Ex-22 as a white solid compound. It was further separated and purified by chiral HPLC to obtain pure Ex-22 (60mg, 16.1%) as a white solid. [Column name: LuxAmylose-1 (4.6*250) mm, 5u; Mobile phase: CO2 / 0.2%AH(IPA)=(60:40)(v / v); Flow rate: 3.0mL per minute; Flow mode: Isocratic; Column temperature: 35℃; ABPR pressure: 1500psi, t R (Peak 1) 3.39 minutes (83%), t R (Peak-2)4.19min(17%)]LCMS(ESI)m / z=416.22[M+H]+;Chiral HPLC(peak-1):99.8%(t R 3.38min);UPLC(MethodA):99.9%(t R 1H NMR (400 MHz, DMSO-d6): δ 7.67 (s, 1H), 7.56 (s, 1H), 7.50-7.48 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 7.6 Hz, J = 0.8 Hz, 1H), 5.07-5.03 (m, 1H), 4.55 (dd, J = 14.8 Hz, J = 10.4 Hz, 2H), 3.92 (s, 3H), 3.87-3.79 (m, 2H), 3.60 (s, 3H), 2.97 (q, J = 7.6 Hz, 2H), 1.12 (t, J = 7.6 Hz, 3H).

[0271] Example 23: (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide [ka]

[0272] Following the experimental procedure for Ex-16, the reaction was carried out on a 0.20g scale to obtain the enantiomeric mixture [77:23] of Ex-23 as an off-white solid compound. It was further separated and purified by chiral HPLC to obtain pure Ex-23 (27mg, 8.83%) as a white solid. [Column name: ChiralcelOJ-H(4.6*250)mm,5u; Mobile phase: CO2 / 0.2%TEAinIPA=(80:20)(v / v); Flow rate: 3mL per minute; Flow mode: Isocratic; Column temperature: 35℃; ABPR pressure: 1500psi,t R (Peak 1) 4.07 minutes (77%), t R (Peak-2) 5.02 min (23%)]LCMS(ESI)m / z=428.38[M+H]+;Chiral HPLC(peak-1):99.5%(t R 4.10min);UPLC(MethodA):95.3%(t R 1H NMR (400 MHz, DMSO-d6): δ 7.90 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.32 (dd, J = 8.4 Hz, J = 0.8 Hz, 1H), 7.11 (dd, J = 6.8 Hz, J = 1.2 Hz, 1H), 6.76 (s, 1H), 5.08-5.04 (m, 1H), 4.53 (dd, J = 14.8 Hz, J = 10.4 Hz, 2H), 4.48-4.32 (m, 2H), 3.93 (s, 3H), 3.89-3.81 (m, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.07-1.87 (m, 2H), 1.76-1.70 (m, 2H).

[0273] Example 24: (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide [ka]

[0274] Following the experimental procedure for Ex-17, the reaction was carried out on a 0.30g scale to give Ex-24 (230mg) as an off-white solid compound with a mixture of enantiomers [74:26]. Ex-24 was further separated and purified by chiral HPLC to give pure Ex-24 (113mg, 24.6%) as a white solid. [Column name: ChiralcelOJH(4.6*250)mm,5u; Mobile phase: CO2 / 0.2%TEAinMeOH=(70:30)(v / v); Flow rate: 3mL per minute; Flow mode: Isocratic; Column temperature: 35℃; ABPR pressure: 1500psi,t R (Peak 1) 2.25 minutes (74%), t R (Peak-2)2.93min(26%)]LCMS(ESI)m / z=428.23[M+H]+;Chiral HPLC(peak-1):99.3%(t R 2.26min);UPLC(MethodA):99.0%(t R1H NMR (400 MHz, DMSO-d6): δ 12.77 (s, 1H), 7.67 (s, 1H), 7.57 (br, s, 1H), 7.46 (t, J = 8.4 Hz, 1H), 7.32 (dd, J = 8.8 Hz, J = 1.2 Hz, 1H), 7.11 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H), 5.10-5.06 (m, 1H), 4.52 (dd, J = 14.8 Hz, J = 10.0 Hz, 2H), 3.92 (s, 3H), 3.83 (d, J = 4.0 Hz, 2H), 2.69-2.66 (m, 2H), 2.58 (t, J = 5.6 Hz, 2H), 1.72-1.66 (m, 4H).

[0275] Example 25: (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide [ka]

[0276] Following the experimental procedure for Ex-18, the reaction was carried out on a 0.30g scale to give the enantiomeric mixture [25:75] of Ex-25 (300mg) as an off-white solid compound. Ex-25 was further separated and purified by chiral HPLC to give pure Ex-25 (138mg, 30.0%) as a white solid. [Column name: ChiralcelOJH(4.6*250)mm,5u; Mobile phase: CO 2 / 0.2% TEA in MeOH = (70:30) (v / v); flow rate: 3 mL per minute; flow mode: isocratic; column temperature: 35 °C; ABPR pressure: 1500 psi, t R (Peak 1) 3.18 minutes (25%), t R (Peak-2)4.16 min(75%)]LCMS(ESI)m / z=429.17[M+H]+;Chiral HPLC(peak-2):99.4%(t R4.18 min); UPLC (D method): 99.9% (t R 1H NMR (400 MHz, DMSO-d6): δ 8.77 (d, J = 7.6 Hz, 1H), 7.67 (s, 1H), 7.47 (t, J = 8.8 Hz, 1H), 7.32 (dd, J = 8.8 Hz, J = 1.2 Hz, 1H), 7.07 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H), 5.13-5.09 (m, 1H), 4.52 (dd, J = 14.8 Hz, J = 20.8 Hz, 2H), 3.93 (s, 3H), 3.90 (dd, J = 11.6 Hz, J = 4.4 Hz, 1H), 3.80 (dd, J = 11.6 Hz, J = 4.8 Hz, 1H), 2.72 (t, J = 6.0 Hz, 2H), 2.61-2.55 (m, 2H), 1.83-1.77 (m, 2H), 1.72-1.68 (m, 2H)

[0277] Example 26: (S)-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide [ka]

[0278] The reaction was carried out on a 0.40g scale following the experimental procedure for Ex-19, to give Ex-26 (150mg) as an off-white solid compound with an enantiomeric mixture [81:19]. Ex-26 was further separated and purified by chiral HPLC to give pure Ex-26 (60mg, 10.1%) as a white solid. [Column name: ChiralcelOJH(4.6*250)mm,5u; Mobile phase: CO2 / 0.2%TEAinIPA=(70:30)(v / v); Flow rate: 3mL per minute; Flow mode: Isocratic; Column temperature: 35℃; ABPR pressure: 1500psi,t R (Peak 1) 2.12 minutes (81%), t R(Peak-2)3.07min(19%)]LCMS(ESI)m / z=416.19[M+H]+;Chiral HPLC(peak-1):99.5%(t R 2.12min);UPLC(MethodA):99.9%(t R 1H NMR (400 MHz, DMSO-d6): δ 12.76 (s, 1H), 7.67 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.32 (dd, J = 8.4 Hz, J = 0.8 Hz, 1H), 7.12 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 5.10-5.06 (m, 1H), 4.53 (dd, J = 14.8 Hz, J = 24.4 Hz, 2H), 3.93 (s, 3H), 3.85 (d, J = 4.0 Hz, 2H), 2.68-2.62 (m, 2H), 2.18 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H).

[0279] Example 27: (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide [ka]

[0280] The reaction was carried out on a 0.20g scale according to the experimental procedure for Ex-20, and an enantiomeric mixture [79:21] of Ex-27 (210mg) was obtained as an off-white solid compound. Ex-27 was further separated and purified by chiral HPLC to obtain pure Ex-27 (90mg, 30.5%) as a white solid. [Column name: Lux-Amylose-1 (4.6*250)mm,5u; Mobile phase: CO2 / 0.2%TEAinIPA=(60:40)(v / v); Flow rate: 3.0mL per minute; Flow mode: Isocratic; Column temperature: 35℃; ABPR pressure: 1500psi,t R (Peak 1) 3.35 minutes (79%), tR (Peak-2)4.30min(21%)]LCMS(ESI)m / z=413.23[M+H]+;Chiral HPLC(peak-1):99.1%(t R 3.36min);UPLC(MethodA):99.8%(t R 1H NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.70 (s, 1H), 7.47 (t, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H), 7.12 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 5.14-5.10 (m, 1H), 4.55 (dd, J = 14.8 Hz, J = 12.0 Hz, 2H), 3.95 (s, 3H), 3.93-3.83 (m, 2H), 2.34 (s, 3H), 2.28 (s, 3H).

[0281] Example 28: (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide [ka]

[0282] The reaction was carried out on a 0.20g scale according to the experimental procedure for Ex-15, to obtain the enantiomeric mixture [22:78] of Ex-28 as an off-white solid compound. Ex-28 was further separated and purified by chiral HPLC to obtain pure Ex-28 (50mg, 17.1%) as a white solid. [Column name: Chiralpak IG (4.6*250) mm, 5u; Mobile phase: CO2 / 0.2% TEAinACN / IPA=(60:40)(v / v); Flow rate: 3.0mL per minute; Flow mode: Isocratic; Column temperature: 35℃; ABPR pressure: 1500psi, t R (Peak 1) 3.85 minutes (22%), tR (Peak-2) 5.69 min(78%)]LCMS(ESI)m / z=434.33[M+H]+;Chiral HPLC(peak-2):96.4%(t R 5.58min);UPLC(MethodA):99.5%(t R 10.51min);1H NMR (DMSO-d6) δ 7.74 (d, J = 3.6 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.54-7.47 (m, 2H), 7.42-7.38 (m, 1H), 5.08-5.04 (m, 1H), 4.55 (dd, J = 14.8 Hz, J = 2.8 Hz, 1H), 4.45 (d, J = 14.8 Hz, 1H), 3.92 (s, 3H), 3.89-3.80 (m, 2H), 3.60 (s, 3H), 2.97 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H).

[0283] Example 29: (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide [ka]

[0284] The reaction was carried out on a 0.20g scale following the experimental procedure for Ex-16, to give the enantiomeric mixture [22:78] of Ex-29 (150mg) as an off-white solid compound. Ex-29 was further separated and purified by chiral HPLC to give pure Ex-29 (50mg, 16.7%) as a white solid. [Column name: CHIRALPAK-IA (4.6*250)mm,5u; Mobile phase: CO2 / 100%MeOH (50:50); Flow rate: 4.0mL per minute; Flow mode: Isocratic; Column temperature: 35℃; ABPR pressure: 1500psi,t R (Peak 1) 2.01 min (22%), t R(Peak-2)2.57min(78%)]LCMS(ESI)m / z=446.26[M+H]+;Chiral HPLC(peak-2):99.8%(t R 2.62min);UPLC(MethodC):97.8%(t R 6.92min);1H NMR (400 MHz, DMSO-d6): δ 7.95 (dd, J = 8.4 Hz, J = 8.4 Hz, 1H), 7.74 (d, J = 2.8 Hz, 1H), 7.50 (td, J = 9.2 Hz, J = 2.8, 1H), 7.40 (dd, J = 4.8 Hz, J = 4.8 Hz, 1H), 6.76 (d, J = 1.6 Hz, 1H), 5.09-5.05 (m, 1H), 4.54 (d, J = 14.8 Hz, 1H), 4.46 (d, J = 19.6 Hz, 1H), 4.42-4.34 (m, 2H), 3.92 (s, 3H), 3.86 (d, J = 4.4 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 1.93-1.87 (m, 2H), 1.76-1.70 (m, 2H).

[0285] Example 30: (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide [ka]

[0286] Following the experimental procedure of Ex-17, the reaction was carried out on a 0.15g scale to obtain the enantiomeric mixture [22:78] of Ex-30 as an off-white solid compound. Ex-30 was further separated and purified by chiral HPLC to obtain pure Ex-30 (60mg, 26.7%) as a white solid. [Column name: CHIRALPAK-IG (4.6*250) mm, 5u; Mobile phase: CO 2 / 0.2% TEA / MeOH (50:50); Flow rate: 3 mL per minute; Flow mode: Isocratic; Column temperature: 35 °C; ABPR pressure: 1500 psi, t R (Peak 1) 4.39 minutes (22%), t R (Peak-2) 6.38 min(78%)]LCMS(ESI)m / z=446.19[M+H]+;Chiral HPLC(peak-2):99.8%(t R 6.38 min); UPLC (B method): 98.4% (t R 1H NMR (400 MHz, DMSO-d6): δ 12.77 (s, 1H), 7.72 (d, J = 2.8 Hz, 1H), 7.60 (dd, J = 8.0 Hz, J = 8.4 Hz, 1H), 7.50 (t, J=8.8 Hz, 1H), 7.42-7.38 (m, 1H), 5.10-5.08 (m, 1H), 4.49 (dd, J = 14.8 Hz, J = 18.4 Hz, 2H), 3.92 (s, 3H), 3.84 (s, 2H), 2.60 (s, 2H), 2.59 (s, 2H), 1.72-1.66 (m, 4H).

[0287] Example 31: (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide [ka]

[0288] Following the experimental procedure of Ex-18, the reaction was carried out on a 0.15g scale to give the enantiomeric mixture [75:25] of Ex-31 as an off-white solid compound. Ex-31 was further separated and purified by chiral HPLC to give pure Ex-31 (57mg, 25.3%) as a white solid. [Column name: CHIRALCEL-OJH (4.6*250) mm, 5u; Mobile phase: CO2 / 0.1% AH in MeOH (60:40); Flow rate: 3.0mL per minute; Flow mode: Isocratic; Column temperature: 35℃; ABPR pressure: 1500psi, t R (Peak 1) 1.95 min (75%), t R (Peak-2)2.39min(25%)]LCMS(ESI)m / z=447.17[M+H]+;Chiral HPLC(peak-1):99.9%(t R 1.95min);UPLC(MethodC):96.7%(t R 12.72min);1H NMR (DMSO-d6) δ 8.89-8.84 (m, 1H), 7.74 (s, 1H), 7.50 (t, J = 9.2 Hz, 1H), 7.42-7.38 (m, 1H), 5.14-5.10 (m, 1H), 4.49 (dd, J = 14.8 Hz, J = 12.8 Hz, 2H), 3.92 (s, 3H), 3.89-3.86 (m, 1H), 3.82-3.78 (m, 1H), 2.72 (t, J = 5.6 Hz, 2H), 2.57 (s, 2H), 1.83-1.77 (m, 2H), 1.72-1.66 (m, 2H).

[0289] Example 32: (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide [ka]

[0290] The reaction was carried out on a 0.15g scale according to the experimental procedure of Ex-19, and an enantiomeric mixture [75:15] of Ex-32 (220mg) was obtained as an off-white solid compound. It was further separated and purified by chiral HPLC to obtain pure Ex-32 (75mg, 34.3%) as a white solid. [Column name: CHIRALCEL-OJH (4.6*250) mm, 5u; Mobile phase: CO 2 / 0.2% isopropylamine / MeOH (80:20); flow rate: 3.0 mL per minute; flow mode: isocratic; column temperature: 35 °C; ABPR pressure: 1500 psi, t R (Peak 1) 2.17 minutes (75%), t R (Peak-2) 2.72 min(15%)]LCMS(ESI)m / z=434.24[M+H]+;Chiral HPLC(peak-1):99.9%(t R 2.18min);UPLC (C method):99.3%(t R 9.29min);1H NMR (400 MHz, DMSO-d6): δ 12.7 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.65 (broad, s, 1H), 7.50 (t, J = 9.2 Hz, 1H), 7.42-7.38 (m, 1H), 5.09-5.08 (m, 1H), 4.50 (dd, J = 14.8 Hz, J = 19.2 Hz, 2H), 3.92 (s, 3H), 3.85 (d, J = 3.6 Hz, 2H), 2.66-2.65 (m, 2H), 2.17 (s, 3H), 1.08 (t, J = 8.8 Hz, 3H).

[0291] Example 33: (S)-N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide [ka]

[0292] The reaction was carried out on a 0.50g scale following the experimental procedure for Ex-20, and the enantiomeric mixture [18:82] of Ex-33 (210mg) was obtained as an off-white solid compound. It was further separated and purified by chiral HPLC to obtain pure Ex-33 (44mg, 6.08%) as a white solid. [Column name: CHIRALPAK-IG (4.6*250)mm,5u; Mobile phase: CO2 / 0.2% AH in MeOH (50:50); Flow rate: 4.0mL per minute; Flow mode: Isocratic; Column temperature: 35℃; ABPR pressure: 1500psi,t R (Peak 1) 4.51 minutes (18%), t R (Peak-2) 5.83 min (82%)] LCMS (ESI) m / z=431.24 [M+H]+; Chiral HPLC (peak-2): 99.8% (t R 5.83min);UPLC (C method):98.7%(t R 1H NMR (400 MHz, DMSO-d6): δ 8.44 (dd, J = 8.4 Hz, J = 8.8 Hz, 1H), 8.35 (s, 1H), 7.90 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.50 (td, J = 2.8 Hz, J = 9.2 Hz, 1H), 7.40 (dd, J = 4.8 Hz, J = 4.8 Hz, 1H), 5.14-5.12 (m, 1H), 4.60 (dd, J = 15.2 Hz, J = 12.8 Hz, 1H), 4.48 (d, J = 14.8 Hz, 1H), 3.98 (s, 3H), 3.89-3.85 (m, 2H), 2.35 (s, 3H), 2.29 (s, 3H).

[0293] Example 34: (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0294] Step-1: Synthesis of (2-chloro-6-methylphenyl)hydrazine hydrochloride (1.9 g, 85%): The reaction was carried out on a 2.0 g scale according to the experimental procedure of INT-14.1 to give INT-4.1 as a white solid. LCMS (ESI) m / z=157.06 [M+H]+.

[0295] Step-2: Synthesis of 1-(2-chloro-6-methylphenyl)-1,7-dihydropyrano[3,4-c]pyrazol-4(5H)-one (INT34.2): The reaction was carried out on a 2.0 g scale according to the experimental procedure of INT-14.2 to give INT-4.2 (1.0 g, 29%) as a yellow solid. LCMS (ESI) m / z=263.06 [M+H]+.

[0296] Step-3: Synthesis of (S,Z)-N-(1-(2-chloro-6-methylphenyl)-1,7-dihydropyrano[3,4-c]pyrazol-4(5H)-ylidene)-2-methylpropane-2-sulfinamide (INT-34.3): The reaction was carried out on 2.0 g scale following the experimental procedure of INT-14.3 to give INT-4.3 (1.7 gm, 61%) as a yellow solid. LCMS (ESI) m / z=365.09 [M+H]+.

[0297] Step-4: Synthesis of (S)-N-((S)-1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-2-methylpropane-2-sulfinamide (INT-34.4): The reaction was carried out on a 1.7 g scale according to the experimental procedure of INT-14.4 to give INT-34.4 (1.6 g, 93%) as a yellow solid. LCMS (ESI) m / z=368.14 [M+H]+.

[0298] Step-5: Synthesis of (S)-1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole 4-amine hydrochloride (INT-34.5): Following the experimental procedure of INT-14.5, the reaction was carried out on a 1.6 g scale to give INT-34.5 (1.30 g, 99%) as an off-white solid. LCMS (ESI) m / z=265.14 [M+H]+.

[0299] Step-6: Synthesis of ((S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-34): Following the experimental procedure of Ex-14, reaction with 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid was carried out on a 0.10 g scale of 69 to obtain off-white. A 110-enantiomer mixture of Ex-34 was obtained as a solid compound in chiral HPLC. Ex-34 was further separated and purified by chiral HPLC to obtain pure Ex-34 (20 mg, 12.8%) as a white solid. [Column name: Chiralpak-IG (4.6X250) mm, 5 um; Mobile phase: 0.1% ammonium hydroxide in MeOH = 100% (v / v); Flow rate: 1.0 ml / min, Temperature: 25 °C; Flow mode: Isocratic, t R (Peak 1) 21.6 minutes (30%), t R (Peak-2) 25.7 min (69%)] Ex-34 was isolated and characterized as atropisomeric mixture. LCMS (ESI) m / z = 412.23 [M+H] +; Chiral HPLC (Peak-1): 80.7% (t R 22.12 min), (Peak-2): 19.2%(t R 28.27 min; UPLC (Method D): (Peak-1) 18.4% (t R 13.08 min), (Peak-2) 79.3%(t R13.42 min); Two rotamer peaks were observed in 1H NMR. 1H NMR (400 MHz, DMSO-d6): δ 7.89 (br, s, 1H), 7.68 (d, J = 4.0 Hz, 1H), 7.56 (s, 1H), 7.56-7.45 (m, 2H), 7.40 (d, J = 6.4 Hz, 1H), 5.08-5.05 (m, 1H), 4.49-4.37 (m, 2H), 4.00 (t, J = 5.6 Hz, 2H), 3.84-3.77 (m, 2H), 2.99 (t, J = 6.4 Hz, 2H), 2.02 (s, 2.4H), 1.98 (s, 0.6H), 1.79-1.78 (m, 2H), 1.77-1.75 (m, 2H).

[0300] Example 35: (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide [ka]

[0301] Following the experimental procedure for Ex-15, the reaction was carried out on a 0.40g scale to obtain the isomeric mixture [6:9:8:37:36] of Ex-35 (400mg) as an off-white solid compound. Ex-35 was further separated and purified by chiral HPLC to obtain pure Ex-35 (135mg, 22.2%) as a white solid. [Column name: Chiralpak-IG (4.6X250) mm, 5um; Mobile phase: 0.1% ammonium hydroxide / MeOH = 100%; Flow rate: 1.0ml / min, Temperature: 25℃; Flow mode: Isocratic, t R (Peak 1) 8.22 minutes (6%), t R (Peak 2) 9.48 minutes (9%), t R (Peak 3) 11.01 min (8%), t R (Peak-4) 13.36 minutes (37%), t R(peak-5) 16.8 min (36%)] Ex-35 was isolated and characterized as atropisomeric mixture. LCMS (ESI) m / z = 400.18 [M+H] +; Chiral HPLC (peak-4): 52.1% (t R 13.38min), (Peak-5): 47.5%(t R 16.8min); UPLC (C method): (Peak 1) 46.9% (t R 9.44min), (Peak-2) 52.3%(t R 9.59 min); Two rotamer peaks were observed in 1H NMR. 1H NMR (400 MHz, DMSO-d6): δ 7.70 (d, J = 4.0 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.55-7.45 (m, 3H), 7.41 (d, J = 7.2 Hz, 1H), 5.08-5.05 (m, 1H), 4.55-4.37 (m, 2H), 3.86-3.78 (m, 2H), 3.60 (s, 3H), 2.98 (q, J = 7.6 Hz, 2H), 2.01 (s, 1.5H), 1.98 (s, 1.5H), 1.12 (t, J = 7.2 Hz, 3H).

[0302] Example 36: (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide [ka]

[0303] To obtain the enantiomeric mixture [18:82] of Ex-36 (350 mg), the reaction was carried out on a 0.40 g scale according to the experimental procedure for Ex-16. Furthermore, Ex-36 was separated and purified by chiral HPLC to obtain pure Ex-36 (55 mg, 8.8%) as a white solid [Column name: Chiralpak-IA (4.6X250) mm, 5 um; Mobile phase: 0.1% ammonium hydroxide / MeOH = 100%; Flow rate: 1.0 ml / min, Temperature: 25 °C; Flow mode: Isocratic, t R (Peak 1 & 2) 6.10 minutes (18%), t R (Peak-3 & 4) 7.50 min (82%)]. Ex-36 was isolated and characterized as atropisomer mixture. LCMS (ESI) m / z = 412.19 [M + H] +; Chiral HPLC (Peak-3): 52.0% (t R 7.60 min), (Peak-4): 47.0%(t R 7.64 min; UPLC (Method G): (Peak-1) 47.1% (t R 9.34 minutes), (Peak-2) 52.8%(t R 9.49 min); Two rotamer peaks were observed in 1H NMR. 1H NMR (400 MHz, DMSO-d6): 8.03 (d, J = 8.4 Hz, 0.5H), 7.89 (d, J = 8.4 Hz, 0.5H), 7.69 (d, J = 5.2 Hz, 1H), 7.53-7.50 (m, 1H), 7.47 (dd, J = 8.8 Hz, J = 1.2 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 6.76 (s, 1H), 5.09-5.07 (m, 1H), 4.49-4.35 (m, 4H), 3.86-3.83 (m, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.02 (s, 1.5H), 1.98 (s, 1.5H), 1.93-1.87 (m, 2H), 1.76-1.70 (m, 2H).

[0304] Example 37: (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydroindazole-3-carboxamide [ka]

[0305] Following the experimental procedure for Ex-17, the reaction was carried out on a 0.40g scale to give the enantiomeric mixture [6:9:6:35:41] of Ex-37 as an off-white solid compound. Ex-37 was further separated and purified by chiral HPLC to give pure Ex-37 (40mg, 6.4%) as a white solid. [Column name: Chiralpak IG (4.6*250) mm, 5u; Mobile phase: CO 2 / 0.2% TEA in IPA = (60:40) (v / v); flow rate: 3.0 mL per minute; flow mode: isocratic; column temperature: 35 °C; ABPR pressure: 1500 psi, t R (Peak 1) 4.34 minutes (6%), t R (Peak 2) 5.27 minutes (9%), t R (Peak 3) 5.88 minutes (6%), t R (Peak-4) 6.54 minutes (35%), t R (Peak-5) 7.46 min (41%)] Ex-37 was isolated and characterized as atropisomeric mixture. LCMS (ESI) m / z = 412.19 [M+H] +; Chiral HPLC (Peak-4): 54.0% (t R 6.65 min), (Peak-5): 46.0%(t R 7.61 min; UPLC (Method G): (Peak-1) 53.6% (t R 11.77 min), (Peak-2) 44.6%(t R11.88 min); Two rotamer peaks were observed in 1H NMR. 1H NMR (400 MHz, DMSO-d6): δ 12.76 (s, 1H), 7.68 (d, J = 4.8 Hz, 1H), 7.66-7.49 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 5.10-5.08 (m, 1H), 4.48-4.37 (m, 2H), 3.87-3.81 (m, 2H), 2.69 (s, 2H), 2.59 (t, J = 5.6 Hz, 2H), 2.02 (s, 1.5H), 1.98 (s, 1.5H), 1.71-1.68 (m, 4H).

[0306] Example 38: (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide [ka]

[0307] Following the experimental procedure for Ex-18, the reaction was carried out on a 0.40 g scale to give the enantiomeric mixture of Ex-38 [12:10:33:45] as an off-white solid compound. Ex-38 was further separated and purified by chiral HPLC to give pure Ex-38 (100 mg, 16.0%) as a white solid. [Column name: Chiralpak IG (4.6x250 mm), 5 μ; Mobile phase: CO2 / 0.2% AH(IPA)=(65:35)(v / v); Flow rate: 3.0 mL per minute; Flow mode: Isocratic; Column temperature: 35 °C; ABPR pressure: 1500 psi; t R (Peak 1) 4.83 minutes (12%), t R (Peak 2) 6.46 minutes (10%), t R (Peak 3) 8.08 minutes (33%), t R(Peak-4) 9.90 min (45%)] Ex-38 was isolated and characterized as atropisomeric mixture. LCMS (ESI) m / z = 413.18 [M+H] +; Chiral HPLC (Peak-3): 44.0% (t R 8.34min), (Peak-4): 55.0%(t R 10.36 min); UPLC (Method G): (Peak-1) 42.9% (t R 11.20min), (Peak-2) 56.6%(t R 11.34 min); Two rotamer peaks were observed in 1H NMR. 1H NMR (400 MHz, DMSO-d6): δ 8.86 (d, J = 19.2 Hz, 0.5H), 8.79 (d, J = 7.6 Hz, 0.5H), 7.69 (s, 1H), 7.53-7.37 (m, 3H), 5.15-5.11 (m, 1H), 4.42 (td, J = 14.8 Hz, J = 6.8 Hz, 2H), 3.97-3.77 (m, 2H), 2.72 (t, J = 6.0 Hz, 2H), 2.57 (s, 2H), 2.02 (s, 1.5H), 1.97 (s, 1.5H), 1.81-1.79 (m, 2H), 1.71-1.68 (m, 2H).

[0308] Example 39: (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4-ethyl-5-methyl-1H-pyrazole-3-carboxamide [ka]

[0309] The reaction was carried out on a 0.40g scale following the experimental procedure for Ex-19, and a mixture of enantiomers [7:7:49:46] of Ex-25 (350mg) was obtained as an off-white solid compound. Ex-25 was further separated and purified by chiral HPLC to obtain pure Ex-25 (45mg, 7.4%) as a white solid [Column name: Chiralpak-IG (4.6X250) mm, 5um; Mobile phase: 0.1% ammonium hydroxide in MeOH / ACN = 50:50; Flow rate: 1.0ml / min, Temperature: 25℃; Flow mode: Isocratic, t R (Peak-1) 3.05 minutes (7%), t R (Peak 2) 3.3 minutes (7%), t R (Peak 3) 4.38 minutes (49%), t R (Peak-4) 5.02 min (46%)]. Ex-39 was isolated and characterized as atropisomeric mixture. LCMS (ESI) m / z = 400.18 [M + H] +; Chiral HPLC (Peak-3): 51.0% (t R 4.38min), (Peak-4): 45.0%(t R 5.02min); UPLC (L method): (Peak-1) 54.8% (t R 12.39min), (Peak-2) 44.7%(t R 12.56 min); Two rotamer peaks were observed in 1H NMR. 1H NMR (400 MHz, DMSO-d6): δ 12.7 (br, s, 1H), 7.70 (d, J = 4.0 Hz, 1H), 7.60 (br, s, 1H), 7.53-7.51 (m, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 5.10-5.08 (m, 1H), 4.48-4.37 (m, 2H), 3.87-3.82 (m, 2H), 2.65 (q, J = 6.8 Hz, 2H), 2.18 (s, 3H), 2.02 (s, 1.5H), 1.97 (s, 1.5H), 1.07 (t, J = 7.6 Hz, 3H).

[0310] Example 40: (S)-N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide [ka]

[0311] The reaction was carried out on a 0.20g scale following the experimental procedure for Ex-20, and the enantiomeric mixture [8:12:39:37] of Ex-40 was obtained as an off-white solid compound. Ex-40 was further separated and purified by chiral HPLC to obtain pure Ex-40 (45mg, 14.9%) as a white solid. [Column name: Chiralcel-OX-H(4.6X250)mm,5um; Mobile phase: 0.1% ammonium hydroxide / MeOH=100%; Flow rate: 1.0ml / min, Temperature: 25℃; Flow mode: Isocratic, t R (Peak 1) 7.13 minutes (8%), t R (Peak 2) 7.30 min (12%), t R (Peak-3) 8.03 minutes (39%), t R (Peak-4) 8.27 min (37%)] Ex-40 was isolated and characterized as atropisomeric mixture. LCMS (ESI) m / z = 397.17 [M+H] +; Chiral HPLC (Peak-3): 48.0% (t R 8.04min), (Peak-4): 51.5%(t R 8.28min); UPLC (C method): 99.8%(t R11.19 min); Two rotamer peaks were observed in 1H NMR. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (d, J = 8.4 Hz, 0.5H), 8.40 (d, J = 8.0 Hz, 0.5H), 8.35 (s, 1H), 7.90 (s, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.53-7.51 (m, 1H), 7.47 (dd, J = 7.6 Hz, J = 0.4 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 5.16-5.13 (m, 1H), 4.46 (m, 2H), 3.94-3.83 (m, 2H), 2.35 (s, 3H), 2.29 (s, 3H), 2.03 (s, 1.5H), 1.98 (s, 1.5H).

[0312] Example 41: (S)-5-Ethyl-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-1-methyl-1H-imidazole 4-carboxamide [ka]

[0313] Step-1: Synthesis of (S,Z)-N-(1-(2-fluorophenyl)-1,7-dihydropyrano[3,4-c]pyrazole-4(5H)-ylidene)-2-methylpropane-2-sulfinamide: The reaction was carried out on a 3.0 g scale according to the experimental procedure of INT-14.3 to give INT-41.1 (1.1 g, 25%) as a yellow solid. LCMS (ESI) m / z=336.08 [M+H]+.

[0314] Step-2: Synthesis of (S)-N-((S)-1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-2-methylpropane-2-sulfinamide: The reaction was carried out on a 1.1 g scale according to the experimental procedure of INT-14.4 to give INT-20.4 (0.8 g, 72%) as a yellow solid. LCMS (ESI) m / z=338.0 [M+H]+.

[0315] Step-3: Synthesis of (S)-1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-4-amine hydrochloride: The reaction was carried out on a 0.8 g scale according to the experimental procedure of INT-14.5 to give INT-20.5 (0.5 g, 78%) as a grey solid. LCMS (ESI) m / z=234.06 [M+H]+.

[0316] Step-4: Synthesis of (S)-5-ethyl-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-1-methyl-1H-imidazole-4-carboxamide: The reaction was carried out on a 0.10g scale according to the experimental procedure of Ex-14 to obtain an enantiomeric mixture [80:20] of Ex-41 as an off-white solid compound. Furthermore, Ex-41 was separated and purified by chiral HPLC to obtain pure Ex-41 (41mg, 25.9%) as a white solid [Column name: Chiralpak IE (250*4.6) mm, 5um; Mobile phase: CO2:0.1% IPamine / MEOH (60:40); Flow rate: 4.0mL per minute; Column temperature: 40℃; t R (Peak 1) 5.90 min (80%), t R (Peak-2) 9.18 min (20%). LCMS (ESI) m / z = 370.20 [M+H]+. Chiral HPLC (Peak-1): 99.6% (t R 5.90 minutes); UPLC (H method): 97.1% (t R 1H NMR (400 MHz, DMSO-d6): δ 7.72 (s, 1H), 7.61-7.46 (m, 5H), 7.37 (td, J = 7.6 Hz, J = 1.2 Hz, 1H), 5.07-5.04 (m, 1H), 4.65 (dd, J = 14.8 Hz, J = 12.4 Hz, 2H), 3.86 (td, J = 8.0 Hz, J = 4.0 Hz, 2H), 3.59 (s, 3H), 2.97 (q, J = 7.6 Hz, 2H), 1.12 (t, J = 7.6 Hz, 3H); 19F NMR (DMSO-d6) δ -123.88.

[0317] Example 42: (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide [ka]

[0318] The reaction was carried out on a 0.30g scale following the experimental procedure of Ex-17, to obtain the enantiomeric mixture [76:24] of Ex-42 (140mg) as an off-white solid compound. It was further separated and purified by chiral HPLC to obtain pure Ex-42 (67mg, 13.6%) as a white solid. [Column name: ChiralcelAS-H (250*4.6)mm, 5um; Mobile phase: CO2: 0.1% IPamine in MeOH (60:40); Flow rate: 3.0mL per minute; Column temperature: 40℃; t R (Peak 1) 1.83 minutes (76%), t R (Peak-2) 2.14 min (24%)] LCMS (ESI) m / z = 382.20 [M+H] +; Chiral HPLC (Peak-1): 99.8% (t R 1.81min); UPLC (H method): (Peak-1) 99.8% (t R 1H NMR (400 MHz, DMSO-d6): δ 12.75 (s, 1H), 7.72 (s, 1H), 7.67 (br, s, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.56-7.46 (m, 2H), 7.37 (t, J = 7.6 Hz, 1H), 5.11-5.07 (m, 1H), 4.65 (dd, J = 14.8 Hz, J = 8.0 Hz, 2H), 3.85 (td, J = 11.6 Hz, J = 4.0 Hz, 2H), 2.68 (d, J = 6.4 Hz, 2H), 2.58 (t, J = 5.2 Hz, 2H), 1.72-1.67 (m, 4H); 19 F NMR (DMSO-d6) δ -123.87.

[0319] Example 43: (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide [ka]

[0320] The reaction was carried out on a 0.30g scale following the experimental procedure of Ex-18, to obtain the enantiomeric mixture [78:22] of Ex-43 (25mg) as an off-white solid compound. Further, Ex-43 was separated and purified by chiral HPLC to obtain pure Ex-43 (7mg, 1.4%) as a white solid. [Column name: ChiralcelAS-H (250*4.6)mm, 5um; Mobile phase: CO2: 0.1% IPamine in MeOH (60:40); Flow rate: 3.0mL per minute; Column temperature: 40℃; t R (Peak 1) 2.26 minutes (78%), t R (Peak-2) 2.64 min (22%)] LCMS (ESI) m / z = 383.25 [M+H] +; Chiral HPLC (Peak-1): 99.9% (t R 2.26min); UPLC (H method): (Peak-1) 99.6% (t R 1H NMR (400 MHz, DMSO-d6): δ 8.81 (d, J = 7.6 Hz, 1H), 7.73 (s, 1H), 7.57-7.46 (m, 3H), 7.37 (t, J = 7.2 Hz, 1H), 5.13-5.09 (m, 1H), 4.68-4.61 (m, 2H), 3.90 (dd, J = 11.6 Hz, J = 4.4 Hz, 1H), 3.82 (dd, J = 11.6 Hz, J = 4.8 Hz, 1H), 2.72 (t, J = 5.6 Hz, 2H), 2.57-2.55 (m, 2H), 1.81-1.78 (m, 2H), 1.71-1.68 (m, 2H); 19 F NMR (DMSO-d6) δ -123.87.

[0321] Example 44: (S)-4-Ethyl-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-methyl-1H-pyrazole-3-carboxamide [ka]

[0322] The reaction was carried out on a 0.30g scale according to the experimental procedure for Ex-19, and an enantiomeric mixture [82:18] of Ex-44 (190mg) was obtained as an off-white solid compound. It was further purified by chiral HPLC to obtain pure Ex-44 (36mg, 7.5%) as a white solid. [Column name: Chiralpak IE (250*4.6) mm, 5um; Mobile phase: CO2: 0.1% IPamine / MEOH (60:40); Flow rate: 3.0mL per minute; Column temperature: 40℃; t R (Peak-1) 4.00 min (82%), t R (Peak-2) 4.85 min (18%)] LCMS (ESI) m / z = 370.3 [M+H] +; Chiral HPLC (Peak-3): 99.9% (t R 4.00 min; UPLC (H method): (Peak-1) 99.8% (t R 1H NMR (400 MHz, DMSO-d6): δ 12.76 (br, s, 1H), 7.72 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.58 (td, J = 8.0 Hz, J = 1.6 Hz, 1H), 7.55-7.46 (m, 2H), 7.37 (td, J = 7.6 Hz, J = 1.2 Hz, 1H), 5.10-5.08 (m, 1H), 4.65 (dd, J = 14.8 Hz, J = 8.4 Hz, 2H), 3.85 (td, J = 12.8 Hz, J = 4.4 Hz, 2H), 2.66 (q, J = 19 F NMR (DMSO-d6) δ -123.87.

[0323] Example 45: (S)-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide [ka]

[0324] The reaction was carried out on a 0.10g scale following the experimental procedure for Ex-20, to obtain the enantiomeric mixture [26:74] of Ex-45 (80mg) as an off-white solid compound. It was further separated and purified by chiral HPLC to obtain pure Ex-45 (40mg, 25.5%) as a white solid. [Column name: Chiralpak IA (250*4.6) mm, 5um; Mobile phase: CO2: 0.1% IPamine in MeOH (60:40); Flow rate: 3.0mL per minute; Column temperature: 40℃; t R (Peak 1) 2.61 minutes (26%), t R (Peak-2) 3.19 min (74%)] LCMS (ESI) m / z = 367.25 [M+H] +; Chiral HPLC (Peak-2): 98.6% (t R 3.10 minutes); UPLC (H method): 98.9% (t R 1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.55-7.47 (m, 2H), 7.37 (t, J = 8.0 Hz, 1H), 5.14-5.12 (m, 1H), 4.68 (dd, J = 14.8 Hz, J = 12.8 Hz, 2H), 3.91 (qd, J = 11.6 Hz, J = 3.6 Hz, 2H), 2.34 (s, 3H), 2.28 (s, 3H); 19 F NMR (DMSO-d6) δ -123.87.

[0325] Additionally, the following compounds were prepared similarly to the above method:

[0326] Example 46: (S)-N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide [ka]

[0327] LCMS (ESI) m / z = 416.2 [M+H]+; Chiral HPLC (peak-1): 99.5% (t R 2.48 min); UPLC (Method H): 99.6% (t R = 10.43 min); 1H NMR (400 MHz, DMSO-d6): δ 12.78 (s, 1H), 7.74 (d, J = 3.2 Hz, 1H), 7.69-7.50 (m, 4H), 5.10-5.08 (m, 1H), 4.52 (d, J = 15.2 Hz, J = 14.8 Hz, 2H), 3.84 (s, 2H), 2.67 (d, J = 1.6 Hz, 2H), 2.57 (t, J = 3.2 Hz, 2H), 1.71-1.66 (m, 4H); two rotamer peaks were observed in 19F NMR. 19F NMR (DMSO-d6) δ -118.17, -118.46.

[0328] Example 47: (S)-N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide [ka]

[0329] LCMS (ESI) m / z = 416.15 [M+H]+; Chiral HPLC (peak-1): 99.9% (t R8.30 min); UPLC (Method H): 99.8% (t R = 8.76 min); Two rotamer peaks were observed in 1H and 19F NMR. 1H NMR (400 MHz, DMSO-d6): δ 8.01 (d, J = 8.4 Hz, 0.5H), 7.94 (d, J = 8.0 Hz, 0.5H), 7.74 (d, J = 3.2 Hz, 1H), 7.68-7.58 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.53 (t, J = 8.8 Hz, 1H), 6.75 (s, 1H), 5.10-5.06 (m, 1H), 4.57 (dd, J = 14.8 Hz, J = 3.6 Hz, 1H), 4.48 (d, J = 14.8 Hz, 1H), 4.42-4.34 (m, 2H), 19F NMR (DMSO-d6) δ -118.18, -118.49.

[0330] Example 48: (S)-N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide [ka]

[0331] LCMS (ESI) m / z = 401.25 [M+H]+; Chiral HPLC (peak-1): 99.9% (t R 7.26 min); UPLC (Method H): 99.9% (t R= 10.27 min); Two rotamer peaks were observed in 1H and 19F NMR. 1H NMR (400 MHz, DMSO-d6): δ 8.48 (d, J = 8.0 Hz, 0.5H), 8.43 (d, J = 8.0 Hz, 0.5H), 8.34 (s, 1H), 7.90 (s, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.68-7.63 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.53 (t, J = 8.4 Hz, 1H), 5.14-5.12 (m, 1H), 4.60 (dd, J = 14.8 Hz, J = 5.6 Hz, 1H), 4.50 (d, J = 15.2 Hz, 1H), 3.95-3.85 (m, 2H), 2.35 (s, 3H), 2.29 (s, 3H); 19 F NMR (DMSO-d6) δ -118.15, -118.49.

[0332] Example 49: (S)-N-(1-(3-(methylsulfonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0333] LCMS (ESI) m / z = 442.22 [M+H]+; Chiral HPLC (peak-1): 99.8% (t R 5.63 min); UPLC (Method A): 99.4% (t R= 11.22 min); 1H NMR (400 MHz, DMSO-d6): 8.06-8.05 (m, 1H), 7.90 (td, J = 3.6 Hz, J = 1.6 Hz, 1H), 7.84-7.77 (m, 2H), 7.76 (s, 1H), 7.54 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 5.09-5.05 (m, 1H), 5.01 (s, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.86 (d, J = 4.0 Hz, 2H), 3.32 (s, 3H), 2.99 (t, J = 6.8 Hz, 2H), 1.88-1.83 (m, 2H), 1.79-1.75 (m, 2H).

[0334] Example 50: (S)-N-(1-(2-chloro-3-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0335] LCMS (ESI) m / z = 466.23 [M+H]+; Chiral HPLC (Method AR) (peak-1): 99.7% (t R 2.14 min); UPLC (Method A): 98.8% (t R= 8.80 min); 1H NMR (400 MHz, DMSO-d6): 8.05 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.74 (t, J = 6.8 Hz, 2H), 7.56 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 5.09-5.05 (m, 1H), 4.58 (dd, J = 15.6 Hz, J = 14.8 Hz, 2H), 3.99 (t, J = 6.0 Hz, 2H), 3.83 (t, J = 3.6 Hz, 2H), 2.99 (t, J = 6.4Hz, 2H), 1.88-1.85 (m, 2H), 1.79-1.75 (m, 2H).

[0336] Example 51: (S)-N-(1-(2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0337] LCMS (ESI) m / z = 398.16 [M+H]+; Chiral HPLC (peak-1): 99.9% (t R UPLC (Method D): 99.6% (t R = 11.06 min); 1H NMR (400 MHz, DMSO-d6): 7.72-7.69 (m, 2H), 7.59-7.50 (m, 4H), 7.43 (d, J = 8.4 Hz, 1H), 5.07-5.05 (m, 1H), 4.57 (dd, J = 15.6 Hz, J = 14.8 Hz, 2H), 4.00 (t, J = 5.6 Hz, 2H), 3.85 (t, J = 3.6 Hz, 2H), 3.00 (t, J = 6.4 Hz, 2H), 1.87-1.85 (m, 2H), 1.80-1.76 (m, 2H).

[0338] Example 52: (S)-N-(1-(o-tolyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0339] LCMS (ESI) m / z = 378.21 [M+H]+; Chiral HPLC (peak-2): 99.9% (t R 21.04 min); UPLC (Method A): 99.4% (t R = 10.43 min); 1H NMR (400 MHz, DMSO-d6): 7.63 (s, 1H), 7.56 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.42-7.40 (m, 2H), 7.35-7.30 (m, 2H), 5.07-5.03 (m, 1H), 4.53 (dd, J = 14.8 Hz, J = 4.8 Hz, 2H), 4.00 (t, J = 5.6 Hz, 2H), 3.82 (d, J = 3.6 Hz, 2H), 3.00 (t, J = 6.4 Hz, 2H), 2.08 (s, 3H), 1.89-1.83 (m, 2H), 1.79-1.73 (m, 2H).

[0340] Example 53: (S)-N-(1-(2-chloro-5-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0341] LCMS (ESI) m / z = 412.19 [M+H]+; Chiral HPLC (peak-2): 99.6% (t R14.27 min); UPLC (Method F): 99.8% (t R = 7.30 min); 1H NMR (400 MHz, DMSO-d6): 7.68 (s, 1H), 7.57 (t, J = 4.4 Hz, 2H), 7.44-7.38 (m, 3H), 5.08-5.06 (m, 1H), 4.58 (dd, J = 14.8 Hz, J = 10.8 Hz, 2H), 4.01 (t, J = 5.2 Hz, 2H), 3.83 (td, J = 11.6 Hz, J = 3.2 Hz, 2H), 3.01 (t, J = 5.6 Hz, 2H), 2.37 (s, 3H), 1.88-1.86 (m, 2H), 1.79-1.78 (m, 2H).

[0342] Example 54: (S)-N-(1-(2-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0343] LCMS (ESI) m / z = 394.22 [M+H]+; Chiral HPLC (peak-1): 99.9% (t R 5.40 min); UPLC (Method C): 99.8% (t R= 8.67 min); 1H NMR (400 MHz, DMSO-d6): 7.61 (s, 1H), 7.55 (s, 1H), 7.45 (t, J = 8.8 Hz, 1H), 7.36 (t, J = 6.4 Hz, 2H), 7.21 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 5.06-5.02 (m, 1H), 4.52 (dd, J = 14.8 Hz, J = 6.8 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.83 (s, 5H), 2.99 (t, J = 6.4 Hz, 2H), 1.88-1.83 (m, 2H), 1.79-1.75 (m, 2H).

[0344] Example 55: (S)-N-(1-(2-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0345] LCMS (ESI) m / z = 432.20 [M+H]+; Chiral HPLC (peak-2): 99.9% (t R 7.72 min); UPLC (Method C): 99.3% (t R= 9.30 min); 1H NMR (400 MHz, DMSO-d6): 7.96 (d, J = 7.6 Hz, 1H), 7.85 (t, J = 7.2 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.66 (s, 1H), 7.64 (d, J = 10.4 Hz, 1H), 7.56 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 5.06-5.04 (m, 1H), 4.55 (dd, J = 15.6 Hz, J = 14.8 Hz, 2H), 4.00 (t, J = 6.0 Hz, 2H), 3.82 (dd, J = 11.6 Hz, J 19F NMR (DMSO-d6) -58.62.

[0346] Example 56: (S)-N-(1-(3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0347] LCMS (ESI) m / z = 394.22 [M+H]+; Chiral HPLC (peak-1): 99.7% (t R 5.52 min); UPLC (Method F): 99.1% (t R= 6.03 min); 1H NMR (400 MHz, DMSO-d6): 7.66 (s, 1H), 7.54 (s, 1H), 7.45-7.39 (m, 2H), 7.07-7.04 (m, 2H), 6.94 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 5.06-5.04 (m, 1H), 4.93 (s, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.84 (d, J = 3.6 Hz, 2H), 3.81 (s, 3H), 2.99 (t, J = 6.4 Hz, 2H), 1.86-1.85 (m, 2H), 1.78-1.75 (m, 2H).

[0348] Example 57: (S)-N-(1-(3-(trifluoromethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0349] LCMS (ESI) m / z = 448.20 [M+H]+; Chiral HPLC (peak-1): 99.7% (t R 7.41 min); UPLC (Method F): 95.6% (t R = 7.35 min); 1H NMR (400 MHz, DMSO-d6): 7.73 (s, 1H), 7.66 (t, J = 8.4 Hz, 1H), 7.56-7.51 (m, 3H), 7.47 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 5.08-5.04 (m, 1H), 4.98 (s, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.84 (d, J = 3.6 Hz, 2H), 2.99 (t, J = 6.4 Hz, 2H), 1.88-1.83 (m, 2H), 1.79-1.74 (m, 2H).

[0350] Example 58: (S)-N-(1-(2-fluoro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0351] LCMS (ESI) m / z = 396.21 [M+H]+; Chiral HPLC (peak-2): 99.9% (t R 18.15 min); UPLC (Method D): 99.4% (t R = 11.30 min); 1H NMR (400 MHz, DMSO-d6): 7.69 (s, 1H), 7.56 (s, 1H), 7.56-7.45 (m, 2H), 7.31-7.26 (m, 2H), 5.08-5.04 (m, 1H), 4.57 (dd, J = 16.0 Hz, J = 14.8 Hz, 2H), 4.00 (t, J = 5.6 Hz, 2H), 3.82 (d, J = 3.6 Hz, 2H), 3.00 (t, J = 6.8 Hz, 2H), 2.06 (s, 3H), 1.87-1.85 (m, 2H), 1.80-1.74 (m, 2H).

[0352] Example 59: (S)-N-(1-(2,6-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0353] LCMS (ESI) m / z = 400.25 [M+H]+; Chiral HPLC (peak-2): 99.9% (t R6.72 min); UPLC (Method A): 99.8% (t R = 8.83 min); 1H NMR (400 MHz, DMSO-d6): 7.75 (s, 1H), 7.67-7.63 (m, 1H), 7.55 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 8.8 Hz, 2H), 5.08-5.04 (m, 1H), 4.63 (d, J = 14.8 Hz, 1H), 4.53 (d, J = 14.8 Hz, 1H), 4.00 (t, J = 5.6 Hz, 2H), 3.83 (d, J = 4.0 Hz, 2H), 3.00 (t, J = 6.4Hz, 2H), 1.89-1.83 (m, 2H), 1.79-1.73 (m, 2H); 19F NMR (DMSO-d6) -120.09.

[0354] Example 60: (S)-N-(1-(2-chloro-6-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0355] LCMS (ESI) m / z = 428.19 [M+H]+; Chiral HPLC (peak-2): 99.7% (t R 2.63 min); UPLC (Method A): 98.8% (t R= 9.57 min); 1H NMR (400 MHz, DMSO-d6): 7.64 (s, 1H), 7.56 (d, J = 4.0 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.38-7.33 (m, 1H), 7.26-7.22 (m, 2H), 5.04-5.02 (m, 1H), 4.48-4.33 (m, 2H), 4.00 (t, J = 5.2 Hz, 2H), 3.83-3.78 (m, 5H), 3.00 (t, J = 6.4 Hz, 2H), 1.89-1.84 (m, 2H), 1.80-1.76 (m, 2H).

[0356] Example 61: (S)-N-(1-(2-methoxy-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0357] LCMS (ESI) m / z = 408.4 [M+H]+; Chiral HPLC (peak-1): 99.9% (t R 10.77 min); UPLC (Method H): 99.9% (t R= 8.33 min); 1H NMR (400 MHz, DMSO-d6): 7.60 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 6.0 Hz, 1H), 7.42-7.35 (m, 2H), 7.04 (t, J = 7.2 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 5.06-5.02 (m, 1H), 4.46-4.30 (m, 2H), 4.00 (t, J = 5.2 Hz, 2H), 3.82-3.79 (m, 2H), 3.76 (s, 1.5H), 3.73 (s, 1.5H), 3.00 (t, J = 6.4 Hz, 2H), 1.97 (s, 1.5H), 1.91 (s, 1.5H), 1.86-1.85 (m, 2H), 1.80-1.74 (m, 2H).

[0358] Example 62: (S)-N-(1-(2-chloro-3-hydroxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0359] Step-1: Synthesis of 1-(benzyloxy)-2-chloro-3-nitrobenzene: To a stirred solution of 2-chloro-3-nitrophenol (10.0 g, 57.6 mmol) in DMF (100 mL) was added K2CO3 (23.9 g, 3 eq, 173 mmol) and dropwise benzyl bromide (8.21 mL, 69.1 mmol) at room temperature. The reaction was stirred at 80° C. for 12 hours. After completion, the reaction mixture was diluted with ice water and stirred for 1 hour. The reaction mass was filtered through a sintered funnel, washed with pentane and dried under vacuum to obtain crude compound INT-62.1 (13.5 g, 89%) as a brown solid. LCMS (ESI) m / z=262.14 (MH)+.

[0360] Step-2: Synthesis of 3-(benzyloxy)-2-chloroaniline (INT62.2): To a stirred solution of INT-62.1 (9.0 g, 34.1 mmol) in EtOH (50 mL) and H2O (15 mL) was added NH4Cl (9.13 g, 171 mmol) and Fe powder (9.53 g, 171 mmol) at room temperature. The reaction mixture was heated at 70° C. for 4 h. After completion, the reaction mass was filtered through a bed of Celite and washed with DCM. The filtrate was washed with cold water, brine and the organic layer was dried over sodium sulfate, filtered and concentrated to give pure INT-62.2 (7.0 g, 88%) as a black sticky oil. LCMS (ESI) m / z=234.0 [M+H]+.

[0361] Step-3: Synthesis of (3-(benzyloxy)-2-chlorophenyl)hydrazine hydrochloride (8.0 g, 94%): The reaction was carried out on an 8.0 g scale according to the experimental procedure of INT-14.1, and the product was obtained as a white solid. LCMS (ESI) m / z=249.12 [M+H]+.

[0362] Step-4: Synthesis of 1-(3-(benzyloxy)-2-chlorophenyl)-1,7-dihydropyrano[3,4-c]pyrazol-4(5H)-one (0.65 g, 23%): The reaction was carried out on a 2.0 g scale according to the experimental procedure of INT-14.2, and obtained as a yellow solid. LCMS (ESI) m / z=355.18 [M+H]+.

[0363] Step-5: Synthesis of (S,Z)-N-(1-(3-(benzyloxy)-2-chlorophenyl)-1,7-dihydropyrano[3,4-c]pyrazole-4(5H)-ylidene)-2-methylpropane-2-sulfinamide (INT-62.5): According to the experimental procedure of INT-14.3, the reaction was carried out on a 2.0 g scale to give INT-62.5 (0.9 g, 35%) as a yellow solid. LCMS (ESI) m / z=458.28 [M+H]+.

[0364] Step-6: Synthesis of (S)-N-((S)-1-(3-(benzyloxy)-2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-2-methylpropane-2-sulfinamide. The reaction was carried out on a 0.80 g scale according to the experimental procedure of INT-14.4 to give INT-62.6 (0.78 g, 97%) as a yellow solid. LCMS (ESI) m / z=459.40 [M+H]+.

[0365] Step-7: Synthesis of (S)-1-(3-(benzyloxy)-2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole 4-amine hydrochloride (INT-62.7): Following the experimental procedure of INT-14.5, the reaction was carried out on a 0.78 g scale to give INT-62.7 (0.60 g, 99%) as an off-white solid. LCMS (ESI) m / z=356.80 [M+H]+.

[0366] Step-8: Synthesis of (S)-N-(1-(3-(benzyloxy)-2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (INT-62.8): Following the experimental procedure of Ex-14, the reaction with 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid was carried out on a 0.40 g scale to give the enantiomeric mixture INT-62.8 (0.40 g, 71%) as an off-white solid compound. LCMS (ESI) m / z=504.13 [M+H]+.

[0367] Step-9: Synthesis of (S)-N-(1-(2-chloro-3-hydroxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-62): To a stirred solution of INT-62.8 (0.18 g, 0.36 mmol) in EtOH (18 mL) was added 10% Pd / C (0.095 g, 50% W) at room temperature and 1-2 drops of conc. HCl was added at room temperature. The reaction mass was flushed with N2 and refilled with H2 atmosphere at bladder pressure at room temperature. The reaction mass was stirred for 16 hours at room temperature. After completion, H2 was released and the reaction mass was diluted with DCM and filtered through a bed of celite. The Celite layer was washed with DCM, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The resulting crude material was purified by silica gel column chromatography using a gradient of 1-5% DCM in MeOH to obtain an enantiomeric mixture [26:74] of EX-62 (85 mg) as an off-white solid compound. Further separation and purification of Ex-62 by chiral HPLC gave pure Ex-62 (12 mg, 8.1%) as a white solid [Column name: LUXAMYLOSE-1 (4.6*250) mm, 5u; Mobile phase: CO2 / 0.2% TEAinIPA=(60:40)(v / v); Flow rate: 3 mL per minute; Flow mode: Isocratic; Column temperature: 35°C; ABPR pressure: 1500 psi, tR(peak-1) 2.85 min (26%), tR(peak-2) 3.3 min (74%)]. LCMS(ESI)m / z=414.33[M+H]+; Chiral HPLC(Peak-2):99.8%(t R 3.33 minutes); UPLC (A method): 99.9% (t R1H NMR (400 MHz, DMSO-d6): 10.71 (br, s, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.28 (t, J = 8.4 Hz, 1H), 7.11 (dd, J = 8.4 Hz, J = 0.4 Hz, 1H), 6.95 (dd, J = 8.0 Hz, J = 0.3 Hz, 1H), 5.06-5.02 (m, 1H), 4.52 (dd, J = 14.4 Hz, J = 11.2 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.82 (td, J = 11.6 Hz, J = 3.6 Hz, 2H), 2.99 (t, J = 6.4 Hz, 2H), 1.88-1.83 (m, 2H), 1.79-1.75 (m, 2H).

[0368] Example 63: (S)-N-(1-(2-chloro-3-(2-(dimethylamino)ethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0369] Step-1: Synthesis of (S)-N-(1-(2-chloro-3-hydroxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-62): To a stirred solution of INT-62.8 (1.2 g, 2.38 mmol) in DCM (24 mL) was added BBr3 (0.23 mL, 2.38 mmol) in DCM (4 mL) dropwise at 0° C. The reaction was stirred at 0° C. for 30 minutes. After completion, the reaction mass was quenched with MeOH at 0° C. and stirred at room temperature for 30 minutes. Further, the reaction mixture was concentrated under reduced pressure to obtain the crude material. The crude material was purified by silica gel column chromatography using a gradient of 5-10% MeOH in DCM to give Ex-62 (0.5 g, 51%) as a brown solid. LCMS (ESI) m / z=414.28 [M+H]+

[0370] Step-2: Synthesis of (S)-N-(1-(2-chloro-3-(2-(dimethylamino)ethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-63): To a stirred solution of Ex-62 (0.20 g, 0.48 mmol) and 2-chloro-N,N-dimethylethan-1-amine hydrochloride (0.13 g, 1.21 mmol) in dry DMF (2 mL) was added K2CO3 (0.27 g, 1.93 mmol) in a screw-capped vial at room temperature. The vial was closed with a cap and the solution was stirred at 65° C. for 16 h. After completion, the reaction mass was distilled under reduced pressure and purified by silica gel column chromatography using gradient 5-20% MeOH in DCM with 1% trimethylamine in DCM to obtain enantiomeric mixture [25:75] of EX-63 (160 mg) as off-white solid compound. Further, Ex-463 was separated and purified by chiral HPLC to obtain pure Ex-63 (53 mg, 22.6%) as white solid [Column name: Chiralpak-IG (4.6X250) 5um; Mobile phase: 0.1% AH in MeOH / ACN = 50:50 (v / v); Flow rate: 1.0 ml / min, Temperature: 25°C; Flow mode: Isocratic; t R(Peak 1) 7.7 minutes (25%), t R (Peak-2) 10.2 min (75%). LCMS (ESI) m / z = 485.29 [M+H] +; Chiral HPLC (Peak-2): 99.9% (t R 10.27 minutes); UPLC (Method I): 95.0% (t R 1H NMR (400 MHz, DMSO-d6): 7.67 (s, 1H), 7.56 (s, 1H), 7.47-7.39 (m, 2H), 7.35 (dd, J = 8.4 Hz, J = 0.8 Hz, 1H), 7.12 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H), 5.07-5.03 (m, 1H), 4.53 (dd, J = 14.8 Hz, J = 10.8 Hz, 2H), 4.22 (t, J = 6.0 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.83 (td, J = 11.6 Hz, J = 4.4 Hz, 2H), 3.00 (t, J = 6.4 Hz, 2H), 2.71 (t, J = 5.6 Hz, 2H), 2.26 (s, 6H), 1.91-1.83 (m, 2H), 1.80-1.76 (m, 2H).

[0371] Example 64: (S)-N-(1-(2-chloro-3-(2-(dimethylamino)-2-oxoethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0372] Step-1: Synthesis of (S)-N-(1-(2-chloro-3-(2-(dimethylamino)-2-oxoethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-64): To a stirred solution of Ex-62 (0.25 g, 0.60 mmol) and 2-chloro-N,N-dimethylacetamide (0.15 mL, 1.51 mmol) in dry DMF (2 mL) was added NaH 60% w / w (0.06 g, 1.51 mmol) in a screw-capped vial at 0° C., the vial was closed with a cap and the solution was stirred at room temperature for 16 hours. After completion, the reaction mass was quenched in MeOH and distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient of 2-5% MeOH in DCM to give an enantiomeric mixture [23:69] of EX-64 (53 mg) as an off-white solid compound. Further, Ex-64 was separated and purified by chiral HPLC to give pure Ex-64 (21 mg, 6.97%) as a white solid [Column name: Chiralpak-IG (4.6X250) 5um; Mobile phase: 0.1% ammonium hydroxide in MeOH:ACN = 50:50 (v / v); Flow rate: 1.0 ml / min, Temperature: 25 °C; Flow mode: Isocratic; t R (Peak 1) 7.76 minutes (23%), t R (Peak-2) 9.48 min (69%). LCMS (ESI) m / z = 499.29 [M+H] +; Chiral HPLC (Peak-2): 99.4% (t R 9.50 min); UPLC (Method J): 99.5% (t R8.21 min); 1H NMR (400 MHz, DMSO-d6): 7.67 (s, 1H), 7.56 (s, 1H), 7.43-7.37 (m, 2H), 7.16 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H), 5.07-5.03 (m, 3H), 4.53 (dd, J = 14.8 Hz, J = 10.8 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.83 (td, J = 11.6 Hz, J = 3.6 Hz, 2H), 3.01-2.98 (m, 5H), 2.86 (s, 3H), 1.96-1.83 (m, 2H), 1.80-1.76 (m, 2H).

[0373] Example 65: (S)-N-(1-(2-chloro-3-(2-(methylamino)-2-oxoethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0374] Step-1: Synthesis of ((S)-N-(1-(2-chloro-3-(2-(methylamino)-2-oxoethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-65): To a stirred solution of Ex-62 (0.2 g, 0.48 mmol) in dry DMF (2.0 mL), Cs2CO3 (0.47 g, 1.45 mmol), KI (0.02 g, 0.12 mmol) and 2-chloro-N-methylacetamide (0.10 g, 0.97 mmol) were added at room temperature. The reaction was stirred at 100 °C for 6 h. After completion, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography using 26% MeOH in DCM to give crude product. The product was obtained. The crude product was purified by silica gel column chromatography using a gradient of 2-5% MeOH in DCM to obtain an enantiomeric mixture [25:75] of EX-65 (120 mg) as an off-white solid compound. Further separation and purification of Ex-65 by chiral HPLC gave pure Ex-65 (55 mg, 23.4%) as a white solid [Column name: ChiralpakAD-H (250*4.6) mm, 5 um; Mobile phase: CO2: 0.1% IPamine in MeOH (60:40); Flow rate: 3.0 mL per minute; Column temperature: 40 °C; tR (peak-1) 4.24 min (25%), tR (peak-2) 8.01 min (75%)]. LCMS (ESI) m / z = 485.25 [M+H] +; Chiral HPLC (peak-2): 99.3% (t R 8.02 min); UPLC (H method): 95.7% (t R1H NMR (400 MHz, DMSO-d6): 7.97 (q, J = 3.6 Hz, 1H), 7.67 (s, 1H), 7.56 (s, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.17 (t, J = 9.6 Hz, 2H), 5.07-5.04 (m, 1H), 4.68 (s, 2H), 4.54 (dd, J = 14.4 Hz, J = 11.6 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.83 (td, J = 12.0 Hz, J = 4.0 Hz, 2H), 2.98 (t, J = 6.4 Hz, 2H), 2.66 (d, J = 8.4 Hz, 3H), 1.88-1.83 (m, 2H), 1.78-1.76 (m, 2H).

[0375] Example 66: (S)-N-(1-(3-(2-acetamidoethoxy)-2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0376] Step-1: Synthesis of tert-butyl (S)-(2-(2-chloro-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide)-4,7-dihydropyrano[3,4-c]pyrazol-1(5H)-yl)phenoxy)ethyl)carbamate (INT-66.2): ​​To a stirred solution of Ex-62 (0.4 g, 0.97 mmol) in dry DMF (4 mL) was added CsCO (0.95 g, 2.9 mmol), KI (4 mg, 0.024 mmol) and tert-butyl (2-chloroethyl)carbamate (0.35 g, 1.93 mmol) at room temperature. The reaction was stirred at 80° C. for 16 h. After completion, the reaction mixture was concentrated under vacuum and purified by silica gel column chromatography using 26% MeOH in DCM to give pure INT-18.10 (0.35 g, 65%) as a yellow sticky mass. LCMS (ESI) m / z=557.21 [M+H]+.

[0377] Step-2: Synthesis of (S)-N-(1-(3-(2-aminoethoxy)-2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide hydrochloride (INT-66.2): ​​To a stirred solution of INT-66.1 (0.350 g, 0.63 mmol) in dry DCM (7 mL) was added 4M HCl in dioxane (3.5 mL) at room temperature. The reaction was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure to give INT-66.2 (0.300 g, 97%) as a yellow solid. LCMS (ESI) m / z=457.14 [M+H]+.

[0378] Step-3: Synthesis of (S)-N-(1-(3-(2-acetamidoethoxy)-2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-66): To a stirred solution of (0.30 g, 0.66 mmol) in MeOH (3 mL) and HO (3 mL), TEA (0.17 g, 1.64 mmol) and acetic anhydride (0.10 g, 0.99 mmol) were added dropwise at room temperature. The reaction mass was stirred for 2 hours at room temperature. After completion, the reaction mixture was concentrated under vacuum and purified by silica gel column chromatography using 26% MeOH in DCM to obtain enantiomeric mixture [30:70] of EX-66 (220 mg) as an off-white solid compound. Furthermore, Ex-66 was separated and purified by chiral HPLC to obtain pure Ex-66 (100 mg, 30.5%) as a white solid [Column name: Chiralpak-IG (4.6X250) 5um; Mobile phase: 0.1% AH in MeOH / ACN = 70:30 (v:v); Flow rate: 1.0 ml / min, Temperature: 25 °C; Flow mode: Isocratic; t R (Peak 1) 6.57 minutes (30%), t R (Peak-2) 7.71 min (70%). LCMS (ESI) m / z = 499.20 [M+H] +; Chiral HPLC (Peak-2): 99.9% (t R 7.73 minutes); UPLC (J method): 99.6% (t R1H NMR (400 MHz, DMSO-d6): 8.11 (t, J = 4.8 Hz, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.45-7.40 (m, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 5.07-5.03 (m, 1H), 4.53 (dd, J = 14.8 Hz, J = 10.8 Hz, 2H), 4.15 (t, J = 5.6 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.83 (td, J = 12.0 Hz, J = 4.0 Hz, 2H), 3.44 (q, J = 5.6 Hz, 2H), 2.99 (t, J = 6.4 Hz, 2H), 1.86-1.83 (m, 2H), 1.83 (s, 3H), 1.79-1.76 (m, 2H).

[0379] Example 67: (S)-N-(1-(2-chloro-3-(2-methoxyethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0380] Step-1: Synthesis of (S)-N-(1-(2-chloro-3-(2-methoxyethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-67): The reaction was carried out on a 0.25g scale according to the experimental procedure for Ex-67 to obtain an enantiomeric mixture 20 of Ex-67 (150mg80) as an off-white solid compound. Furthermore, Ex-67 was separated and purified by chiral HPLC to obtain pure Ex-67 (60mg, 21.0%) as a white solid. [Column name: Chiralpak-IG (4.6X250), 5um; Mobile phase: 0.1% ammonium hydroxide in MeOH / ACN = 50:50; Flow rate: 1.0ml / min, Temperature: 25℃; Flow mode: Isocratic; t R (Peak 1) 7.12 minutes (20%), t R (Peak-2)9.18min(80%)]LCMS(ESI)m / z=472.25[M+H]+;Chiral HPLC(peak-2):99.8%(t R 9.22min);UPLC(MethodJ):99.7%(t R 9.27min);1H NMR (400 MHz, DMSO-d6): 7.66 (s, 1H), 7.56 (s, 1H), 7.45-7.40 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 4.0 Hz, J = 0.8 Hz, 1H), 5.07-5.03 (m, 1H), 4.53 (dd, J = 14.8 Hz, J = 10.8 Hz, 2H), 4.27 (t, J = 4.4 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.83 (td, J = 11.6 Hz, J = 0.4 Hz, 2H), 3.72 (t, J = 4.4 Hz, 2H), 3.33 (d, J = 8.0 Hz, 3H), 2.99 (t, J = 6.4 Hz, 2H), 1.88-1.83 (m, 2H), 1.79-1.74 (m, 2H).

[0381] Example 68: (S)-N-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0382] Step-1: Synthesis of (S)-N-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-68): The reaction was carried out on a 0.25g scale according to the experimental procedure of Ex-64 to obtain the enantiomeric mixture 26 of Ex-68 (180mg 74) as an off-white solid compound. Further separation and purification of Ex-68 by chiral HPLC gave pure Ex-68 (48mg, 17.3%) as a white solid. [Column name: Chiralpak-IG (4.6X250) mm, 5um; Mobile phase: 0.1% ammonium hydroxide in MeOH / ACN = 50:50; Flow rate: 1.0ml / min, Temperature: 25℃; Flow mode: Isocratic; t R (Peak 1) 5.48 minutes (26%), t R (Peak-2) 6.54 min (74%)] LCMS (ESI) m / z = 458.23 [M+H] +; Chiral HPLC (Peak-2): 99.9% (t R 6.54 minutes); UPLC (K method): 97.9% (t R8.99 min);1H NMR (400 MHz, DMSO-d6): 7.66 (s, 1H), 7.56 (s, 1H), 7.45-7.40 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 4.0 Hz, J = 0.8 Hz, 1H), 5.07-5.03 (m, 1H), 4.93 (t, J = 5.2 Hz, 1H), 4.53 (dd, J = 14.8 Hz, J = 10.8 Hz, 2H), 4.15 (t, J = 4.8 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.83 (t, J = 3.2 Hz, 2H), 3.77 (q, J = 5.2 Hz, 2H), 2.99 (t, J = 6.8 Hz, 2H), 1.87-1.83 (m, 2H), 1.79-1.76 (m, 2H).

[0383] Example 69: Isopropyl (S)-2-chloro-3-nitrobenzoate (4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide)-4,7-dihydropyrano[3,4-c]pyrazol-1(5H)-yl) [ka]

[0384] Step-1: Synthesis of methyl 2-chloro-3-nitrobenzoate (10.0 g, 49.6 mmol): Concentrated and added to a solution of 2-chloro-3-nitrobenzoic acid in MeOH (100 mL). Hydrogen sulfate (1.35 mL, 24.8 mmol) was added at room temperature. The reaction mass was heated at 80° C. for 16 hours. After completion, the reaction mass was evaporated under reduced pressure and the crude product was diluted with ice cold water. The organic layer was extracted with EtOAc, the combined organic layer was washed with brine solution, dried over sodium sulfate, evaporated and purified by silica gel column chromatography using 10-30% EtOAc in hexane to give INT-69.1 (10.2 g, 95%) as a white solid. LCMS was not constant but confirmed by 1H NMR. 1HNMR (400MHz, DMSO-d6): 8.22 (dd, J = 8.0 Hz, J = 5.6 Hz), 8.06 (dd, J = 8.0 Hz, J = 1.6 Hz), 7.66 (t, J = 7.6 Hz, 1H), 3.91 (s, 3H).

[0385] Step-2: Synthesis of methyl 3-amino-2-chlorobenzoate (INT69.2): To a stirred solution of INT-69.1 (5.0 g, 23.2 mmol) in EtOH (50 mL) and water (15 mL) was added Fe powder (6.48 g, 116.0 mmol) and ammonium chloride (6.2 g, 116.0 mmol) at room temperature. The resulting reaction mixture was stirred at 70° C. for 4 hours. After completion, the precipitate was filtered off and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was dissolved in DCM and water and the organic layer was separated. The organic layer was dried over sodium sulfate and distilled under vacuum to obtain INT-69.3 (3.5 g, 81%) as a colorless oil. LCMS was not constant but confirmed by 1H NMR. 1HNMR (400MHz, DMSO-d6): 7.09 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 5.62 (s, 2H), 3.81 (s, 3H).

[0386] Step-3: Synthesis of methyl 2-chloro-3-hydrazinebenzoate hydrochloride (INT-69.3): Following the experimental procedure of INT-14.1, the reaction was carried out on a 4.0 g scale to give INT-69.3 (4.0 g, 90%) as a white solid. LCMS (ESI) m / z=201.22 [M+H]+.

[0387] Step-4: Synthesis of methyl 2-chloro-3-(4-oxo-4,7-dihydropyrano[3,4-c]pyrazol-1(5H)-yl)benzoate (INT-69.4): The reaction was carried out on a 5.0 g scale according to the experimental procedure of INT-14.2 to give INT-69.4 (0.72 g, 11%) as a yellow solid. LCMS (ESI) m / z=307.08 [M+H]+.

[0388] Step-5: Synthesis of (S,Z)-3-(4-((tert-butylsulfinyl)imino)-4,7-dihydropyrano[3,4-c]pyrazol-1(5H)-yl)-2-chlorobenzoic acid isopropyl ester (INT-69.5): The reaction was carried out on a 1.5 g scale according to the experimental procedure of INT-14.3 to give INT-69.5 (1.2 g, 56%) as a yellow solid. LCMS (ESI) m / z=438.07 [M+H]+.

[0389] Step-6: Synthesis of isopropyl 3-(S)-(4-((S)-tert-butylsulfinyl)amino)-4,7-dihydropyrano[3,4-c]pyrazole-1(5H)-yl)-2-chlorobenzoate (1.2 g, 99%): The reaction was carried out on a 1.2 g scale according to the experimental procedure of INT-14.4 to give INT-69.6 as a yellow solid. LCMS (ESI) m / z=440.11 [M+H]+.

[0390] Step-7: Synthesis of isopropyl (S)-3-(4-amino-4,7-dihydropyrano[3,4-c]pyrazol-1(5H)-yl)-2-chlorobenzoate hydrochloride (INT-69.7): The reaction was carried out on a 1.2 g scale according to the experimental procedure of INT-14.5 to give INT-69.7 (0.90 g, 98%) as an off-white solid. LCMS (ESI) m / z=337.05 [M+H]+.

[0391] Step-8: Synthesis of isopropyl (S)-2-chloro-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide)-4,7-dihydropyrano[3,4-c]pyrazole-1(5H)-yl)benzoate (Ex-69): Following the experimental procedure of Ex-14, the reaction with 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid was carried out on a 0.40 g scale to give an enantiomeric mixture [18:22] of EX-69 (70 mg) as an off-white solid compound. Further, Ex-69 was separated and purified by chiral HPLC to give pure Ex-69 (24 mg, 4.1%) as a white solid. [Column name: Chiralpak-IG (4.6X250) 5um; Mobile phase: 0.1% TEA in IPA / ACN = 70:30 (v / v); Flow rate: 1.0 ml / min, Temperature: 25 °C; Flow mode: Isocratic; t R (Peak 1) 5.6 minutes (18%), t R (Peak-2) 7.2 min (82%)]LCMS(ESI)m / z=484.25[M+H]+;Chiral HPLC(peak-2):99.9%(t R 7.25 minutes); UPLC (D method): 99.9% (t R1H NMR (400 MHz, DMSO-d6): 7.88 (dd, J = 11.6 Hz, J = 1.6 Hz, 1H), 7.75 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 7.70 (s, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 5.21-5.15 (m, 1H), 5.07-5.04 (m, 1H), 4.57 (dd, J = 14.8 Hz, J = 14.4 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.83 (td, J = 11.6 Hz, J = 3.6 Hz, 2H), 2.99 (t, J = 6.4 Hz, 2H), 1.88-1.83 (m, 2H), 1.78-1.76 (m, 2H), 1.33 (d, J = 6.4 Hz, 6H).

[0392] Example 70: (S)-N-(1-(2-chloro-3-(dimethylcarbamoyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0393] Step-1: Synthesis of (S)-2-chloro-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamido)-4,7-dihydropyrano[3,4-c]pyrazol-1(5H)-yl)benzoic acid (INT-70.1): To a stirred solution of EX-69 (1.2 g, 2.48 mmol) [Note: for hydrolysis enantiomerically enriched mixture of EX-69 was used] in MeOH (6 mL) and THF (6 mL) was added LiOH.H2O (0.42 g, 9.92 mmol) (solution in DM water (1.2 mL)) at room temperature. The reaction was stirred for 6 hours at room temperature. After completion, the reaction mass was evaporated under reduced pressure and the aq. layer was washed with EtOAc. Adjust pH=1-2 with 1N aqueous hydrochloric acid solution. The layers were distilled completely at room temperature to give INT-70.1 (1.0 g, 91%) as a white solid. LCMS (ESI) m / z=442.07 [M+H].

[0394] Step-2: Synthesis of (S)-N-(1-(2-chloro-3-(dimethylcarbamoyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-70): To a stirred solution of INT-70.1 (0.2 g, 0.45 mmol) and dimethylamine in 2M THF solution (0.08 g, 1.81 mmol) in dry DMF (2 mL) was added HATU (0.26 mg, 0.68 mmol) and DIPEA (0.24 mL, 1.36 mmol) at 0° C. Then the reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mass was poured into ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient of 2-10% MeOH in DCM to give an enantiomeric mixture [22:78] of Ex-70 (170 mg) as an off-white solid compound. Further separation and purification of Ex-70 by chiral HPLC gave pure Ex-70 (90 mg, 42.4%) as a white solid [Column name: Chiralcel-OX-H (4.6X250), 5um; Mobile phase: 0.1% ammonium hydroxide / MeOH = 100%; Flow rate: 1.0 ml / min; Temperature: 25 °C; Flow mode: Isocratic; t R (Peak 1) 11.8 minutes (22%), t R (Peak-2) 13.5 min (78%). LCMS (ESI) m / z = 469.23 [M+H] +; Chiral HPLC (Peak-2): 98.9% (t R 13.50 min); UPLC (C method): 99.8% (t R1H NMR (400 MHz, DMSO-d6): 7.69 (s, 1H), 7.62-7.58 (m, 2H), 7.56 (s, 1H), 7.52 (dd, J = 7.2 Hz, J = 2.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 5.07-5.04 (m, 1H), 4.57 (dd, J = 14.8 Hz, J = 13.6 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.83 (td, J = 11.6 Hz, J = 3.6 Hz, 2H), 3.02 (s, 3H), 2.99 (t, J = 6.4 Hz, 2H), 2.81 (s, 3H), 1.86-1.79 (m, 2H), 1.78-1.76 (m, 2H).

[0395] Example 71: (S)-N-(1-(2-chloro-3-(pyrrolidine-1-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0396] Step-1: Synthesis of (S)-N-(1-(2-chloro-3-(pyrrolidine-1-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-71): Following the experimental procedure of Ex-71, the reaction was carried out on a 0.15 g scale 78 using pyrrolidine (0.1 g, 4.0 equiv.) to obtain 22 of the 60 enantiomeric mixture of EX-71 as an off-white solid compound. Ex-71 was further separated and purified by chiral HPLC to obtain pure Ex-71 (10 mg, 8.3%) as a white solid. [Column name: Chiralcel-OX-H (4.6X250), 5um; Mobile phase: 0.1% ammonium hydroxide / MeOH = 100%; Flow rate: 1.0ml / min; Temperature: 25℃; Flow mode: Isocratic; tR (Peak 1) 15.6 minutes (22%), t R (Peak-2) 18.3 min (78%)] LCMS (ESI) m / z = 495.25 [M+H] +; Chiral HPLC (Peak-2): 99.8% (t R 18.42 min); UPLC (L method): 96.4% (t R 8.50 min); 1H NMR (400 MHz, DMSO-d6): 7.69 (s, 1H), 7.62-7.59 (m, 1H), 7.57-7.54 (m, 3H), 7.42 (d, J = 8.4 Hz, 1H), 5.07-5.04 (m, 1H), 4.57 (dd, J = 14.8 Hz, J = 11.6 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.83 (td, J = 8.0 Hz, J = 0.4 Hz, 2H), 3.49 (t, J = 6.4 Hz, 2H), 3.12 (t, J = 6.4 Hz, 2H), 2.99 (t, J = 6.4 Hz, 2H), 1.90-1.83 (m, 6H), 1.79-1.76 (m, 2H).

[0397] Example 72: (S)-N-(1-(2-chloro-3-(piperidine-1-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0398] Step-1: Synthesis of (S)-N-(1-(2-chloro-3-(piperidine-1-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-72): Following the experimental procedure of Ex-70, reaction with piperidine (0.12 g, 4.0 equiv.) was carried out on a 0.15 g scale to obtain an enantiomeric mixture [22:78] of EX100-72 as an off-white solid compound. Furthermore, Ex-72 was separated and purified by chiral HPLC to obtain pure Ex-72 (26 mg, 15.0%) as a white solid. [Column name: Chiralcel-OX-H (4.6X250), 5um; Mobile phase: 0.1% ammonium hydroxide / MeOH = 100%; Flow rate: 1.0ml / min; Temperature: 25℃; Flow mode: Isocratic; t R (Peak 1) 15.9 minutes (22%), t R (Peak-2) 18.9 min (78%)] LCMS (ESI) m / z = 509.28 [M+H] +; Chiral HPLC (Peak-2): 99.5% (t R 19.24 min); UPLC (C method): 99.5% (t R 1H NMR (400 MHz, DMSO-d6): 7.70 (s, 1H), 7.61-7.56 (m, 3H), 7.51 (dd, J = 7.2 Hz, J = 2.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 5.07-5.04 (m, 1H), 4.62 (d, J = 14.8 Hz, 1H), 4.54 (dd, J = 14.4 Hz, J = 4.0 Hz, 1H), 3.99 (t, J = 5.6 Hz, 2H), 3.84 (td, J = 15.2 Hz, J = 3.6 Hz, 2H), 3.71-3.67 (m, 1H), 3.59-3.55 (m, 1H), 3.13 (t, J = 5.6 Hz, 2H), 2.99 (t, J = 6.4 Hz, 2H), 1.88-1.84 (m, 2H), 1.79-1.76 (m, 2H), 1.60-1.58 (m, 4H), 1.47-1.46 (m, 2H).

[0399] Example 73: (S)-N-(1-(2-chloro-3-(morpholine-4-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0400] Step-1: Synthesis of (S)-N-(1-(2-chloro-3-(morpholine-4-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-73): Following the experimental procedure of Ex-70, the reaction was carried out on a 0.15 g scale using morpholine (0.12 g, 4.0 equiv.) to give a mixture of enantiomers [22:78] of Ex-71 (60 mg) as an off-white solid compound. Further separation and purification of Ex-73 by chiral HPLC gave pure Ex-73 (37 mg, 21.3%) as a white solid. [Column name: Chiralcel-OX-H (4.6X250), 5um; Mobile phase: 0.1% ammonium hydroxide / MeOH = 100%; Flow rate: 1.0ml / min; Temperature: 25℃; Flow mode: Isocratic; t R (Peak 1) 17.3 minutes (22%), t R (Peak-2) 20.3 min (78%)] LCMS (ESI) m / z = 511.26 [M+H] +; Chiral HPLC (Peak-2): 99.5% (t R 20.53 minutes); UPLC (C method): 99.6% (t R1H NMR (400 MHz, DMSO-d6): 7.70 (s, 1H), 7.63-7.56 (m, 4H), 7.42 (dd, J = 4.8 Hz, J = 3.6 Hz, 1H), 5.07-5.05 (m, 1H), 4.58 (dd, J = 14.8 Hz, J = 14.4 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.84 (td, J = 16.0 Hz, J = 3.6 Hz, 2H), 3.71-3.60 (m, 4H), 3.55 (t, J = 4.0 Hz, 2H), 3.17 (s, 2H), 2.99 (t, J = 6.4 Hz, 2H), 1.88-1.83 (m, 2H), 1.79-1.74 (m, 2H).

[0401] Example 74: (S)-N-(1-(2-chloro-3-(diethylcarbamoyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide [ka]

[0402] Step-1: Synthesis of (S)-N-(1-(2-chloro-3-(diethylcarbamoyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (Ex-74): Following the experimental procedure of Ex-74, the reaction was carried out on 0.15 g scale 75 using diethylamine (0.10 g, 4.0 equiv.) to give a mixture of enantiomers [22:78] of Ex-72 (100 mg) as an off-white solid compound. Furthermore, Ex-74 was separated and purified by chiral HPLC to obtain pure Ex-74 (12 mg, 7.11%) as a white solid [Column name: Chiralcel-OX-H (4.6X250), 5um; Mobile phase: 0.1% ammonium hydroxide / MeOH = 100%; Flow rate: 1.0 ml / min; Temperature: 25°C; Flow mode: Isocratic; tR (Peak 1) 12.5 minutes (20%), t R (Peak-2) 14.2 min (75%). LCMS (ESI) m / z = 497.27 [M+H] +; Chiral HPLC (Peak-2): 98.1% (t R 14.23 min); UPLC (Method K): 99.9%(t R 1H NMR (400 MHz, DMSO-d6): 7.70 (s, 1H), 7.61-7.56 (m, 3H), 7.52 (dd, J = 7.2 Hz, J = 2.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 5.07-5.04 (m, 1H), 4.62 (d, J = 15.2 Hz, 1H), 4.54 (dd, J = 14.4 Hz, J = 5.6 Hz, 1H), 3.99 (t, J = 5.6 Hz, 2H), 3.84 (td, J = 11.6 Hz, J = 3.6 Hz, 2H), 3.66-3.57 (m, 1H), 3.39-3.35 (m, 1H), 3.19-3.11 (m, 1H), 3.08-3.03 (m, 1H), 2.99 (t, J = 6.4 Hz, 2H), 1.88-1.84 (m, 2H), 1.79-1.75 (m, 2H), 1.61 (t, J = 7.2 Hz, 3H), 1.02 (t, J = 7.2 Hz, 3H).

[0403] biological example Biological Example 1: Inhibition of Human Dihydrorotate Dehydrogenase (DHODH)

[0404] Inhibition of human dihydrorotate dehydrogenase (DHODH) by the exemplary compounds described herein was determined using one of the two assays described below.

[0405] Assay A DHODH enzyme assays were performed with 6 nM recombinant human DHODH (purified essentially as described by Wale et al., Biochemistry, 47, 8929-8936 (2008)). The reaction mixture consisted of 1 mM DL-dihydrorotonic acid (#D7003, Sigma-Aldrich), 100 μM 3,4-dimethoxy-5-methyl-p-benzoquinone (#D9150, Sigma-Aldrich), and 100 μM 2,6-dichlorophenol indophenol sodium salt (DCIP) (#D1878, Sigma-Aldrich) in enzyme buffer (50 mM Tris-HCl pH 8.0, 0.1% Triton X-100, 150 mM KCl). A stock solution of 20 mM DCIP was prepared in enzyme buffer and filtered through Whatman paper immediately before use. Reactions were carried out in a total volume of 100 μL consisting of 1 μL compound, 49 μL enzyme and 50 μL reaction mix. Absorbance loss due to the chromogen DCIP was measured at 595 nm after incubation at 32° C. for 70 min. [Table 3]

[0406] Biological Example 2: Inhibition of MOLM Assay B

[0407] MOLM-13 cells (acute myeloid leukemia cell line) were plated at 1,000 cells per well in 384-well plates in RPMI supplemented with 10% FBS and 1% Pen / Strep on day 0. Treatment of cells with compounds (concentration range 10E-5 and 6E-12M) was initiated on day 1 in the presence or absence of 100 μM uridine. After incubating cells for 72 hours in the presence or absence of test compounds, the number of viable cells per well was assessed by CellTiter-GloLuminescent CellViabilityAssay (Promega, Madison, WI, USA). IC50 was calculated using DMSO control as 100% cell viability and wells without cells (medium only) as 0% cell viability. Each condition was tested in duplicate and the potency of the test compounds was determined from two independent experiments.

[0408] Using the assay described in Biological Example 2, the following IC 50 values ​​were obtained. [Table 4]

[0409] FIG. 2 shows the data obtained for Ex-6, Ex-9, Ex-11 and Ex-13 on the viability of MOLM13 cells in the presence and absence of uridine.

[0410] Biological example 3: Antiviral activity Materials and Methods

[0411] cell The lung cancer epithelial cell line A549 was obtained from the American Type Culture Collection (ATCC; Rockville, MD, USA) and cultured in MEM medium (GibcoBRL, Gaithersburg, MD, USA) containing 10% fetal calf serum (FCS; GibcoBRL), 2 mM L-glutamine (GibcoBRL), and 0.075% sodium bicarbonate (GibcoBRL).

[0412] virus The ZIKVMR766 prototype strain and the DENV-2 laboratory-adapted New Guinea C strain were obtained from ATCC, and strains were propagated in the C6 / 36 mosquito cell line (ATCC). Viral stock titers were determined using a plaque assay in BHK-21 cells (ATCC).

[0413] Antiviral assay Anti-ZIKV and anti-DENV-2 activities in A549 cells were measured using a tetrazolium-based colorimetric cytopathic effect (CPE) reduction assay. This assay has been described in detail previously (Virology. 2021; doi.org / 10.1016 / j.virol.2021.07.003). A549 cells (1.5 × 10 in 100 μL of cell culture medium) were cultured at 4 °C for 1 h. 4Cells) were seeded in 96-well flat-bottom plates (TPP, Trasadingen, Switzerland) and incubated overnight to allow cells to grow to confluence. Drug dilutions were prepared in medium with reduced FCS concentration to 2% and diluted 3-fold in the plate (in duplicate). Finally, 100 μL of virus was added, with ZIKV at an MOI of 1 and DENV-2 at an MOI of 5, to a final volume of 200 μL. Virus-induced cytopathic effects were checked periodically by microscopy. Three days after infection with ZIKV and four days after infection with DENV-2, when a strong cytopathic effect was observed in the positive control (i.e., untreated infected cells), cell viability was assessed spectrophotometrically via in situ reduction of the tetrazolium compound 3-(4·5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS / PES) using a CellTiter96 aqueous one-part cell proliferation assay (Promega, Fitchburg, WI, USA). After 3 h of MTS incubation, virus was inactivated using 0.5% TritonX-100 (ThermoFisherScientific, Waltham, MA, USA), and then absorbance was recorded at 490 nm using a 96-well plate reader and compared to four cell control replicates (cells without virus and drug) and four virus control wells (cells with virus but without drug). Each assay was performed in duplicate. Median inhibitory concentrations (IC 50 The cytotoxic concentration of compound 50 (CC), or the concentration that inhibits 50% of virus-induced cell death, was calculated from each dose-response curve by performing nonlinear regression. The absorbance was recorded using a VersaMax ELISA™ microplate reader (Molecular Devices) and analyzed using SoftmaxPro software (Molecular Devices version 4.0). Mock-infected cells were used to determine the cytotoxic concentration of compound 50 (CC 50 ) were examined in parallel.

[0414] Results and Discussion The antiviral activity of Ex-9 against ZIKV and DENV-2 was evaluated. In parallel, the cytotoxicity against A549 cells was also examined. The results of the compounds that showed antiviral activity against ZIKV and DENV-2 are shown in the table below. [Table 5] I C 50 = concentration required to inhibit ZIKV / DENV-induced CPE by 50% in A549 cells. CC 50 = concentration required to reduce viability of mock-infected A549 cells by 50%. Head-to-head Example 1: Better stability of O analogues (examples 3-69) compared to C analogues (compounds A-X)

[0415] Human liver microsomal metabolic stability: Microsomal metabolic stability assays were performed using pooled human liver microsomes (mixed gender, BD Gentest) supplemented with cofactors NADPH and UDPGA (SolaBio S&T Co., Ltd.) in two separate experiments as follows.

[0416] a) With cofactors (NADPH and UDPGA): 25 μL of 10 mM NADPH and 25 μL of 20 mM UDPGA were added to 197.5 μL of reaction solution (phosphate buffer (final concentration in assay 100 mM), MgCl2 (final concentration in assay (5 mM)), alamethacin (final concentration in assay 0.025 mg / mL) and microsomes (final concentration in assay 0.5 mg / mL). b) No cofactors (NADPH and UDPGA): 50 μL of water was added to 197.5 μL of reaction solution.

[0417] The mixture was preheated at 37°C for 10 min. The reaction was initiated by adding 2.5 μL of 100 μM control or test compound solution. Diclofenac was used as a positive control in this study. The final concentrations of the control and test compounds were 1 μM. Aliquots of 25 μL were taken from the reaction solution after 0.5, 5, 15, 30, and 60 min. The reaction was stopped by adding 5 volumes of cold acetonitrile containing an internal standard. The samples were centrifuged at 3,220 g for 40 min. An aliquot of 100 μL of the supernatant was mixed with 100 μL of ultrapure water and used for LC-MS / MS analysis. Peak areas were measured from the extracted ion chromatograms. The parent compound remaining rate was calculated from the area ratio of the test compound. The slope value was determined by linear regression of the natural logarithm of the parent compound remaining rate versus incubation time curve.

[0418] Human hepatocyte metabolic stability: Human hepatocytes (X008000, BioIVT) were freshly thawed prior to incubation with test compounds. Hepatocytes were transferred to a 50 mL conical tube and centrifuged at 100 g for 10 min. The thawing medium was removed and replaced with pre-warmed (37 °C) incubation medium (William's E medium supplemented with GlutaMAX) to achieve a hepatocyte density of ~1.5 × 10 6 Cell viability was measured using AO / PI staining, and hepatocytes were cultured in incubation medium at 0.5 × 10 6 The cells were diluted to a working density of viable cells / mL. 198 μL of hepatocytes were added to each well of the 96-well plate and placed in an incubator to warm the hepatocytes for 10 minutes. 2 μL of test compound or positive control was added to each well of the 96-well plate (final concentration of test compound 1 μM) to initiate the reaction. The plate was returned to the incubator and 25 μL aliquots of well contents were removed at 0, 15, 30, 60, 90, and 120 minutes. The reaction was terminated by mixing the aliquots with 6 volumes (150 μL) of acetonitrile containing internal standards (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide). The plate was centrifuged at 3,200 g for 20 minutes. A 150 μL aliquot of the supernatant was used for LC / MS / MS analysis. All incubations were performed in duplicate. Peak areas were measured from the extracted ion chromatograms, and the in vitro half-life (t1 / 2) of the parent compound was determined by regression analysis of the parent compound disappearance rate vs. time curve. The in vitro half-life (invitrot1 / 2) was calculated from the slope value (invitrot1 / 2=-0.693 / k). All calculations were performed using Microsoft Excel. Table 3 below summarizes the results and shows the improved stability of the compounds of the present invention when compared to the corresponding C-analogues.

[0419] [Table 6] [Table 7] [Table 8]

[0420] Head-to-head Example 2: O-Analog Ex-9 does not inhibit human CYPs compared to Compound C.

[0421] CYP Inhibition: Pooled human liver microsomes (cat. Xenotech, H0610) were used to determine the potential for drug-drug interactions by co-incubation of compounds with P450 enzyme-selective substrates. Assays were performed in duplicate. The formation of acetaminophen, 7'-hydroxycoumarin, hydrobupropion, N-desethylamodiaquine, 4'-hydroxydiclofenac, 4'-hydroxymephenytoin, 1'-hydroxybufuralol, and 6'-hydroxychlorzoxazone were quantified as markers for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1, respectively. CYP3A4 inhibition was measured using two substrates measuring the formation of 6β-hydroxytestosterone (3A4-T) and 1'-hydroxymidazolam (3A4-M). Incubations were performed in 96 deep-well plates containing 179 μL of master solution (0.2 mg / mL microsomes and CYP substrate (see below for final substrate concentrations and incubation times for the different CYP assays)) in 100 mM phosphate buffer and 1 μL of compound working solution or solvent. Final concentrations were 30 μM for single doses and 0.1, 0.3, 1, 3, 10 and 30 μM for dose responses.

[0422] [Table 9]

[0423] The incubation plate was placed in a water bath and preheated to 37°C for 5 min, after which 20 μL of 10 mM NADPH solution was added to initiate the reaction and incubated at 37°C for the above times. The reaction was stopped by adding 1.5 volumes (300 μL) of cold ACN, 200 nM aprozolam, and 200 nM lavalol containing 3% formic acid and 200 nM tolbutamide. The plate was centrifuged at 3,220 g for 50 min, after which 200 μL of the supernatant was transferred to an analytical plate for LC / MS / MS analysis. The formation of the respective metabolites from each probe substrate was compared to that observed in the solvent control incubations.

[0424] [Table 10]

[0425] Abbreviation The abbreviations used herein are well known to those of skill in the art, and in particular the following abbreviations may be used herein: Aq. Water-based ACN Acetonitrile AcOH Acetic acid DCM Dichloromethane DEA Diethylamine DIPEA N,N-Diisopropylethylamine DMF Dimethylformamide DMF-DMA Dimethylformamide Dimethylacetal DMSO Dimethyl sulfoxide EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOH Ethanol HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3 triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HCl Hydrochloric acid HOBt Hydroxybenzotriazole HPLC High Performance Liquid Chromatography HRMS high resolution mass spectrometry MeOH Methanol NaBH3CN Sodium Borofyde Cyanide NaNO2 Sodium nitrite NH4Cl Ammonium chloride NMR nuclear magnetic resonance SnCl2 Tin(II) chloride T3P Propanephosphonic anhydride TBTU O-(benzotriazol 1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate TFA Trifluoroacetic acid THF Tetrahydrofuran Ti(OiPr)4 Titanium(IV) Tetraisopropoxide TLC Thin Layer Chromatography UPLC Ultra High Performance Liquid Chromatography

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 where: A １ is a 9-membered bicyclic heteroaryl, a 6-membered heteroaryl, or a 5-membered heteroaryl optionally substituted with one or more groups independently selected from G 2 ; A ２ is a phenyl group optionally substituted with one or more groups independently selected from G 3 ; L １ represents —C(O)—; R １ represents H; Each G 2 independently represents halo, R a2 , -CN, -A a2 -C(Q a2 )R b2 -A b2 -C(Q b2 )N(R c2 )R d2, -A c2 -C(Q c2 )OR e2 , -A d2 -S(O) p R f2 , -A e2 -S(O) q N(R g2 )R h2 , -A f2 -S(O) p OR i2 , -N 3 , -N(R j2 )R k2, -N(H)CN, -NO 2, -ONO 2 , -OR l2 or -SR m2; each Q a2 to Q c2 independently represents =O, =S, =NR n2 or =N(OR o2 ); each A a2 to A f2 independently represents a single bond, —N(R p2 )—, or —O—; each G 3 independently represents halo, R a3 , —CN, -A a3 -C(Q a3 )R b3 , -A b3 -C(Q b3 )N(R c3 )R d3 , -A c3 -C(Q c3 )OR e3 , -A d3 -S(O) p R f3 , -A e3 -S(O) q N(R g3 )R h3 , -A f3 -S(O) p OR i3 , -N 3 , -N(R j3 )R k3 , -N(H)CN, —NO 2 , —ONO 2 , —OR l3 or —SR m3 ; each Q a3 to Q c3 independently represents =O, =S, =NR n3 or =N(OR o3 ); each A a3 to A f3 independently represents a single bond, —N(R p3 )—, or —O—; each R a2 and R f2 independently represents C 1-6 alkyl optionally substituted with one or more groups independently selected from G 6a , heterocycloalkyl optionally substituted with one or more groups independently selected from G 6b , aryl optionally substituted with one or more groups independently selected from G 6c , or heteroaryl optionally substituted with one or more groups independently selected from G 6d ; each R p2 independently represents H or C 1-6 alkyl optionally substituted with one or more F; each R b2 , R c2 , R d2 , R e2 , R g2 , R h2 , R i2 , R j2 , R k2 , R l2 , R m2 , R n2 and R o2 independently represent H, C 1-6 alkyl optionally substituted by one or more groups independently selected from G 6a , heterocycloalkyl optionally substituted by one or more groups independently selected from G 6b , aryl optionally substituted by one or more groups independently selected from G 6c , or heteroaryl optionally substituted by one or more groups independently selected from G 6d ; or Alternatively, any of R c2 and R d2 , R g2 and R h2 , and / or R j2 and R k2 are linked to each other and together with the nitrogen atom to which they are attached form a 3- to 6-membered ring, which may optionally further contain one heteroatom, and which may be substituted by one or more groups selected from halo, C 1-3 alkyl optionally substituted by halo, and ═O; each R a3 and R f3 independently represents C 1-6 alkyl optionally substituted with one or more groups independently selected from G 7a , heterocycloalkyl optionally substituted with one or more groups independently selected from G 7b , aryl optionally substituted with one or more groups independently selected from G 7c , or heteroaryl optionally substituted with one or more groups independently selected from G 7d ; each R p3 independently represents H or C 1-6 alkyl optionally substituted with one or more F; each R b3 , R c3 , R d3 , R e3 , R g3 , R h3 , R i3 , R j3 , R k3 , R l3 , R m3 , R n3 and R o3 independently represent H, C 1-6 alkyl optionally substituted by one or more groups independently selected from G 7a , heterocycloalkyl optionally substituted by one or more groups independently selected from G 7b , aryl optionally substituted by one or more groups independently selected from G 7c , or heteroaryl optionally substituted by one or more groups independently selected from G 7d ; or Alternatively, any of R c3 and R d3 , R g3 and R h3 , and / or R j3 and R k3 are linked to each other and together with the nitrogen atom to which they are attached form a 3- to 6-membered ring, which may optionally further contain one heteroatom, and which may be substituted by one or more groups selected from halo, C 1-3 alkyl optionally substituted by halo, and ═O; each G 6a , G 6b , G 7a , and G 7b independently represents halo, —CN, —N(R b5 )R c5 , —OR d5 , —SR e5 , or ═O; each G 6c , G 6d , G 7c , and G 7d independently represents halo, R a5 , —CN, —N(R b5 )R c5 , —OR d5 , —SR e5 , or ═O; each R a5 independently represents C 1-6 alkyl optionally substituted with one or more F; each R b5, R c5 , R d5 and Re5 independently represents H or C 1-6 alkyl optionally substituted with one or more F or ═O; or R b5 and R c5 are joined to each other and together with the nitrogen atom to which they are attached form a 3- to 6-membered ring, which may optionally further contain one heteroatom, and which may be substituted by one or more groups selected from F, C 1-3 alkyl optionally substituted by F, and ═O; and each p and q independently represents 1 or 2; compound.

2. Each G ２ are independently -CN, -A ａ２ -C(Q ａ２ ) R ｂ２ , -A ｂ２ -C(Q ｂ２ ) N (R ｃ２ ) R ｄ２ , -A ｃ２ -C(Q ｃ２ ) OR ｅ２ , -A ｄ２ -S(O) ｐ R ｆ２ , -A ｅ２ -S(O) ｑ N (R ｇ２ ) R ｈ２ , -A ｆ２ -S(O) ｐ OR ｉ２ , -N ３ , -N(R ｊ２ ) R ｋ２ , -N(H)CN, -NO ２ , -ONO ２ , Haro, R ａ２ , -OR ｌ２ , or -SR m2 ; each Q ａ２ ~Q ｃ２ are independently ═O, ═S, or ═NR ｎ２ , or = N (OR ｏ２ ) and / or each A ａ２ ~A ｆ２ are independently a single bond, —N(R ｐ２ )-, or -O-; and / or Each G ３ are independently -CN, -A ａ３ -C(Q ａ３ ) R ｂ３ , -A ｂ３ -C(Q ｂ３ ) N (R ｃ３ ) R ｄ３ , -A ｃ３ -C(Q ｃ３ ) OR ｅ３ , -A ｄ３ -S(O) ｐ R ｆ３ , -A ｅ３ -S(O) ｑ N (R ｇ３ ) R ｈ３ , -A ｆ３ -S(O) ｐ OR ｉ３ , -N ３ , -N(R ｊ３ ) R ｋ３ , -N(H)CN, -NO ２ , -ONO ２ , Haro, R ａ３ , -OR ｌ３ , or -SR m3 ; each Q ａ３ ~Q ｃ３ are independently ═O, ═S, or ═NR ｎ３ , or = N (OR ｏ３ ) and / or each A ａ３ ~A ｆ３ are independently a single bond, —N(R ｐ３ )- or -O-; The compound of claim 1.

3. A 1 is halo, R ａ２ , -C(O)OR ｅ２ , -OR ｌ２ and -SR ｍ２ or one or more fluoro, —C(O)OH, —C(O)OC １－３ Alkyl, —OH, —OC １－３ Alkyl, —SH and —SC １－３ substituted by C 1-3 alkyl optionally substituted by alkyl; The compound of claim 1.

4. A １ is selected from tetrahydro 2,1-benzisoxazolyl, benzoxazolyl, pyrazinyl, indazolyl, 5H,6H,7H,8H-imidazo[1,5-a]pyridin-3-yl, 5H,6H,7H,8H-imidazo[1,5-a]pyridin-1-yl, imidazo[1,5-a]pyridin-3-yl, pyridinyl, thiazolyl, isoxazolyl, and tetrahydro 1,2-benzisoxazolyl; The compound of claim 1.

5. A2 is halo, -A ａ３ -C(Q ａ３ ) R ｂ３ , -A ｃ３ -C(Q ｃ３ ) OR ｅ３、 R ａ３ and -OR ｌ３ or A ２ is halo, —C(O)-morpholinyl, —C(O)OC １－３ Alkyl, and C １－４ substituted by one or more groups independently selected from alkyl; The compound of claim 1.

6. A 1 is 5H,6H,7H,8H-imidazo[1,5-a]pyridin-3-yl, 5H,6H,7H,8H-imidazo[1,5-a]pyridin-1-yl, 4H,5H,6H,7H-1,2-benzisoxazol-3-yl, 4H,5H,6H,7H-2,1-benzisoxazol-3-yl, or 4H,5H,6H,7H-indazol-3-yl, pyridinyl, pyrazolyl, or imidazolyl. The compound of claim 1.

7. Each G ２ independently represents R a2 ; and / or Each G ３ are independently halo, R ａ３ , -A ｂ３ -C(Q ｂ３ ) N (R ｃ３ ) R ｄ３ , -A ｃ３ -C(Q ｃ３ ) OR ｅ３ , -A ｄ３ -S(O) ｐ R ｆ３ , -OR ｌ３ represents; Optionally, where: Halo is fluoro or chloro; R ａ３ is CH ３ or CF ３ and 、 A ｂ３、 A ｃ３ and A ｄ３ is a single bond, and Q ｂ３ and Q ｃ３ is =O, p is 2, R ｃ３ and R ｄ３ is CH ３ or are joined together with the nitrogen atom to which they are attached to form a 5- or 6-membered ring, which ring optionally contains one further heteroatom; R ｅ３ is C １－３ alkyl, and R ｆ３ is CH ３ and R ｌ３ is CH ３ , C.F. ３ , N(CH ３ ) ２ , OH, OCH ３ or N(C=O)CH ３ C substituted with ２ alkyl, and / or C(=O)N(CH ３ ) ２ C substituted with １ is alkyl, The compound of claim 1.

8. 10. The compound of claim 1, which is a compound of formula Ia, or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 In the formula, A １ , A ２ , L １ and R １ is as defined in claim 1, The compound of claim 1.

9. N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (R)—N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)—N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (R)—N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)—N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; N-1-[3,4-c]-5-1,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-((4S)-1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-((4R)-1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-1-[3,4-c]-5-1,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-((4S)-1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-((4R)-1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; N-(1-(2,6-dichlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2,6-dichlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2,6-dichlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (R)—N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (S)—N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (R)—N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)—N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydro-1H-indazole 3-carboxamide; (R)—N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydro-1H-indazole 3-carboxamide; (S)—N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (R)—N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)—N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4-ethyl-5-methyl-1H-pyrazole 3-carboxamide; (R)—N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4-ethyl-5-methyl-1H-pyrazole 3-carboxamide; (S)—N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (R)—N-(1-(2-chloro-3-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)—N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (R)—N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (S)—N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (R)—N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)—N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5,6,7-tetrahydro; (R) indazole 3-carboxamido-N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydro; (S)—N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (R)—N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)—N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4-ethyl-5-methyl-1H-pyrazole 3-carboxamide; (R)—N-(1-(2-chloro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4-ethyl-5-methyl-1H-pyrazole 3-carboxamide; (S)—N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (R)—N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5-dimethylpicolinamide; (S)—N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (R)—N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (S)—N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (R)—N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)—N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydro-1H-indazole 3-carboxamide; (R)—N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydro1H-indazole 3-carboxamide; (S)—N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (R)—N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)—N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4-ethyl-5-methyl-1H-pyrazole 3-carboxamide; (R)—N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4-ethyl-5-methyl-1H-pyrazole 3-carboxamide; (S)—N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (R)—N-(1-(2-chloro-6-fluoro-3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5-dimethylpicolinamide; (S)—N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (R)—N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-5-ethyl-1-methyl-1H-imidazole 4-carboxamide; (S)—N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (R)—N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)—N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydro-1H-indazole 3-carboxamide; (R)—N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydro1H-indazole 3-carboxamide; (S)—N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (R)—N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)—N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4-ethyl-5-methyl-1H-pyrazole 3-carboxamide; (R)—N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4-ethyl-5-methyl-1H-pyrazole 3-carboxamide; (S)—N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (R)—N-(1-(2-chloro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)-5-ethyl-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-1-methyl-1H-imidazole 4-carboxamide; (R)-5-ethyl-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-1-methyl-1H-imidazole 4-carboxamide; (S)—N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydro-1H-indazole 3-carboxamide; (R)—N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydro-1H-indazole 3-carboxamide; (S)—N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (R)—N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole 3-carboxamide; (S)-4-ethyl-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5-methyl-1H-pyrazole 3-carboxamide; (R)-4-ethyl-N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-5-methyl-1H-pyrazole 3-carboxamide; (S)—N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (R)—N-(1-(2-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)—N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydro-1H-indazole 3-carboxamide; (R)—N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol 4-yl)-4,5,6,7-tetrahydro-1H-indazole 3-carboxamide; (S)—N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (R)—N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; (S)—N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (R)—N-(1-(2-chloro-6-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-4,5-dimethylpicolinamide; (S)—N-(1-(3-(methylsulfonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(3-(methylsulfonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-3-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-3-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(o-tolyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(o-tolyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-5-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-5-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(3-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(3-(trifluoromethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(3-(trifluoromethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-fluoro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-fluoro-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2,6-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2,6-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-6-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-6-methoxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-methoxy-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-methoxy-6-methylphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-3-hydroxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-3-hydroxyphenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-3-(2-(dimethylamino)ethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-3-(2-(dimethylamino)ethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-3-(2-(dimethylamino)-2-oxoethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-3-(2-(dimethylamino)-2-oxoethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-3-(2-(methylamino)-2-oxoethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-3-(2-(methylamino)-2-oxoethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(3-(2-acetamidoethoxy)-2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(3-(2-acetamidoethoxy)-2-chlorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-3-(2-methoxyethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-3-(2-methoxyethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-3-(2-hydroxyethoxy)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; Isopropyl (S)-2-chloro-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamido)-4,7-dihydropyrano[3,4-c]pyrazol-1(5H)-yl)benzoate; Isopropyl (R)-2-chloro-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamido)-4,7-dihydropyrano[3,4-c]pyrazol-1(5H)-yl)benzoate; (S)—N-(1-(2-chloro-3-(dimethylcarbamoyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-3-(dimethylcarbamoyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-3-(pyrrolidine-1-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-3-(pyrrolidine-1-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-3-(piperidine-1-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-3-(piperidine-1-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-3-(morpholine-4-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-3-(morpholine-4-carbonyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)—N-(1-(2-chloro-3-(diethylcarbamoyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)—N-(1-(2-chloro-3-(diethylcarbamoyl)phenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; or a pharmaceutically acceptable salt thereof; The compound of claim 1.

10. 10. A composition comprising a compound according to any one of claims 1 to 9 and optionally one or more pharmaceutically acceptable adjuvants, diluents and / or carriers. Pharmaceutical compositions.

11. For use in medicine, The compound according to any one of claims 1 to 9.

12. For use in the treatment of cancer and / or the treatment or prevention of viral infections, The compound according to any one of claims 1 to 9. (A) a compound according to any one of claims 1 to 9; and (B) one or more additional therapeutic agents for the treatment of cancer or the treatment or prevention of a viral infection; Each of components (A) and (B) is optionally formulated in admixture with one or more pharmaceutically acceptable adjuvants, diluents or carriers; Combination products. (a) a compound according to any one of claims 1 to 9; and (b) one or more additional therapeutic agents for the treatment of cancer or the treatment or prevention of a viral infection, optionally mixed with one or more pharmaceutically acceptable adjuvants, diluents, or carriers; Each of components (a) and (b) is provided in a form suitable for administration in combination with the other component; Parts kit.

15. A process for the preparation of a compound according to any one of claims 1 to 9, comprising: (i) reacting a compound of formula II with a compound of formula III in the presence of a suitable solvent, optionally in the presence of a suitable base and / or a suitable catalyst; 【Transformation 3】 In the formula, R １ and A ２ is as defined in claim 1, 【Chemistry 4】 In the formula, A １ and L １ is as defined in claim 1, LG １ represents a suitable leaving group; (ii) where L １ is -C(O)N(R ２ ) and R ２ represents H, reaction of a compound of formula II with a compound of formula IV in the presence of a suitable solvent and optionally in the presence of a suitable base and / or a suitable catalyst under conditions known to those skilled in the art, 【Transformation 5】 In the formula, A １ is as defined in claim 1; or (iii) reaction of a compound of formula (V) with a compound of formula (VI) in the presence of a suitable solvent and optionally in the presence of a suitable base and / or a suitable catalyst, 【Transformation 6】 In the formula, R １ , A １ and L １ is as defined in claim 1, 【Transformation 7】 In the formula, A ２ is as defined in claim 1, LG ２ represents a suitable leaving group, including process.

16. For use in medicine, The pharmaceutical composition of claim 10.

17. For use in the treatment of cancer and / or the treatment or prevention of viral infections, The pharmaceutical composition of claim 10.

18. (a) the pharmaceutical composition of claim 10; and (b) one or more additional therapeutic agents for the treatment of cancer or the treatment or prevention of a viral infection, optionally mixed with one or more pharmaceutically acceptable adjuvants, diluents, or carriers; Each of components (a) and (b) is provided in a form suitable for administration in combination with the other component; Parts kit.

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