HK1244787B - 5 OR 8-SUBSTITUTED IMIDAZO [1, 5-a] PYRIDINES AS INDOLEAMINE, TRYPTOPHANE DIOXYGENASE INHIBITOR - Google Patents

Description

5- or 8-substituted imidazo[1,5-a]pyridines as indoleamine and tryptophan dioxygenase inhibitors

Technical Field

The present application discloses 5- or 8-substituted imidazo[1,5-a]pyridines and pharmaceutical compositions comprising at least one such 5- or 8-substituted imidazo[1,5-a]pyridine, methods for their preparation, and their use in therapy. Specifically, the present application discloses certain 5- or 8-substituted imidazo[1,5-a]pyridines that can be used to inhibit indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase and treat diseases or conditions mediated thereby.

Background Art

Indoleamine 2,3-dioxygenase 1 (IDO1, EC 1.13.11.42, also known as indoleamine 2,3-dioxygenase) is the first and rate-limiting enzyme in the tryptophan-kynurenine pathway that degrades the essential amino acid L-tryptophan (L-Trp) to N-formyl-kynurenine, which is then metabolized through a series of steps to form NAD. The IDO1 enzyme is expressed in the placenta, mucosa, and lymphoid tissues, as well as in inflammatory lesions (Yamazaki F, et al., Biochem J. 1985;230:635-8; Blaschitz A, et al., PLoS ONE. 2011;6:e21774). In the latter two, it is primarily expressed by antigen-presenting cells (APCs), dendritic cells (DCs), and macrophages, and in cells exposed to interferon-γ (IFNγ) and other proinflammatory stimuli. In human cells, the depletion of L-Trp and the production of a series of immunomodulatory metabolites (collectively referred to as "kynurenine") caused by IDO1 activity can inhibit the proliferation and differentiation of effector T cells [Frumento G, et al., (2002), Journal of Experimental Medicine 196: 459-468] and significantly enhance the suppressive activity of regulatory T cells [Sharma MD, et al. (2009), Blood 113: 6102-6111]. Thus, IDO1 controls and fine-tunes innate and adaptive immune responses [Grohmann U, et al. (2002), Nature Immunology 3:1097-1101] under various conditions, including pregnancy [Munn DH, et al. (1998), Science 281:1191-1193], transplantation [Palafox D, et al. (2010), Transplantation Reviews 24:160-165], infection [Boasso A, et al. (2009), AminoAcids 37:89-89], chronic inflammation [Romani L, et al. (2008), Nature 451:211-U212], autoimmunity [Platten M, et al. (2005), Science 310:850-855], tumor formation, and depression [Maes M, et.al., Life Sciences]. Sci.20026;71(16):1837-48; Myint AM, et.al., (2012), Journal of NeuralTransmission 119:245-251].

Several lines of evidence suggest that IDO is involved in the induction of immune tolerance. The immunosuppressive effect of IDO1 was first demonstrated in a mouse model of fetal protection against maternal immune rejection. Treatment of pregnant mice with a tryptophan analog that inhibits IDO1 (which is constitutively expressed in the placenta) resulted in T cell-mediated rejection of allogeneic embryos [Munn DH, et al. (1998), Science 281: 1191-1193]. Subsequent studies developed this concept into a mechanism for overcoming immune surveillance in cancer (reviewed in [Prendergast GC (2008), Oncogene 27(28): 3889-3900; Munn DH, et al., (2007), J Clin Invest 117(5): 1147-1154]). Indoleamine 2,3-dioxygenase is widely overexpressed in tumor cells and has been associated with poor prognosis [Uyttenhove C, et al., (2003), Nat Med 9(10): 1269-1274; Liu X, et al., (2009), Curr Cancer Drug Targets 9(8): 938-95]. IDO expression by immunogenic mouse tumor cells prevents rejection by pre-immunized mice [Uyttenhove C. et al., Nat Med. 2003 Oct; 9(10): 1269-74. Epub 2003 Sep 21]. EPUB 2003 Sep 21]. It has been shown that IDO activity inhibits T cells [Fallarino F, et.al., (2002), Cell Death Differ 9: 1069-1077; Frumento G, et.al., (2002), J Exp Med 196(4): 459-468; Terness P, et.al., (2002), J Exp Med 196(4): 447-457] and NK cells [Della Chiesa M, et.al., (2006), Blood 108(13): 4118-4125], and IDO has also been shown to support Tregs [Fallarino F, et.al., (2003), Nat Immunol 4(12): 1206-1212] and myeloid-derived suppressor cells (MDSCs) [Smith C, et.al., (2012), Cancer Discovery 2(8):722-735]. It has been shown that the efficacy of therapeutic vaccination of cancer patients can be improved by the simultaneous administration of IDO inhibitors [Uyttenhove C. et al., Nat Med. 2003 Oct; 9(10):1269-74. Epub 2003 Sep 21]. It has been shown that the IDO inhibitor 1-MT can synergize with chemotherapeutic agents to reduce tumor growth in mice, suggesting that IDO inhibition can also enhance the anti-tumor activity of conventional cytotoxic therapies [Muller AJ, et al., Nat Med. 2005 Mar; 11(3):312-9]. It has been shown that IDO inhibitors can synergize with anti-CTLA-4 antibodies or anti-PDL-1 antibodies to inhibit tumor growth in mouse models [Holmgaard RB, et.al., J Exp Med. 2013 Jul 1; 210(7): 1389-402; Spranger S, et.al., J Immunother Cancer. 2014, 2: 3].

It has been proposed that IDO is chronically induced by HIV infection and further increased by opportunistic infections, and that the long-term loss of Trp initiates mechanisms responsible for cachexia, dementia, and diarrhea, and possibly immunosuppression, in AIDS patients [Brown, et al., 1991, Adv. Exp. Med. Biol., 294:425-35]. To this end, IDO inhibition has recently been shown to enhance the levels of virus-specific T cells and simultaneously reduce the number of virus-infected macrophages in a mouse model of HIV [Portula et al., 2005, Blood, 106:2382-90]. Simian immunodeficiency virus (SIV) is very similar to human immunodeficiency virus (HIV) and is used to study conditions in animal models. In both HIV and SIV, the level of virus in the blood, or "viral load," is important because when the viral load is high, the disease progresses and it depletes the patient's immune system. This ultimately leads to the development of acquired immunodeficiency syndrome (AIDS), in which patients are unable to fight infections that would be harmless in healthy individuals. It has also been reported that treating monkeys with a simian form of HIV with an IDO inhibitor called D-1mT along with antiretroviral therapy (ART) reduced the levels of virus in their blood to undetectable levels, so when combined with ART, IDO inhibitors may in the future help HIV patients who do not respond to treatment [Adriano Boasso, et.al., J. Immunol., Apr 2009;182:4313-4320].

Given that experimental data indicate a role for IDO in immunosuppression, tumor resistance and/or rejection, chronic infection, HIV infection, AIDS (including manifestations thereof such as cachexia, dementia, and diarrhea), autoimmune diseases or conditions (such as rheumatoid arthritis), and depression, therapeutic agents that aim to inhibit tryptophan degradation by inhibiting IDO activity are of interest. IDO inhibitors can be used as effective cancer treatments because they can reverse the immunosuppressive effects of the tumor microenvironment and activate the anti-tumor activity of T cells. IDO inhibitors can also be used to activate the immune response in HIV infection. Inhibition of IDO is also an important therapeutic strategy for patients suffering from neurological or neuropsychiatric diseases or conditions such as depression. The compounds, compositions, and methods of the present application help meet the current need for IDO modulators.

Tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) catalyzes the same tryptophan degradation reaction as IDO1. TDO is primarily expressed in the human liver, where it may function as a major regulator of systemic tryptophan levels. Recently, TDO has also been found to be expressed in the brain, where it may regulate the production of neuroactive tryptophan metabolites such as kynurenic acid and quinolinic acid [Kanai M, et al., Mol Brain 2009;2:8]. Two recent studies [Opitz CA, et al., Nature 2011;478:197-203; Pilotte L, et al., Proc Natl Acad Sci U S A. 2012, 109(7):2497-502] indicate the importance of TDO activity in certain cancers in which TDO is constitutively expressed, particularly malignant gliomas, hepatocellular carcinomas, melanomas, and bladder cancers. Functional studies in human tumors have shown that constitutive TDO enzyme activity is sufficient to maintain biologically relevant tryptophan catabolism that can suppress anti-tumor immune responses [Opitz CA, et al., Nature 2011; 478: 197-203; Pilotte L, et al., Proc Natl Acad Sci U S A. 2012, 109(7): 2497-502]. It has been reported that tumor TDO expression prevents rejection in immunized mice. Specific TDO inhibitors have been shown to restore the ability of mice to reject TDO-expressing tumors without significant toxicity [Pilotte L, et al., Proc Natl Acad Sci U S A. 2012, 109(7): 2497-502]. Therefore, inhibitors of TDO have the potential to be used as single agents or in combination with other anticancer therapies to treat a variety of human cancers.

Small molecule inhibitors of IDO are being developed to treat or prevent IDO-related diseases, such as those described above. For example, PCT publication WO 99/29310 reports methods for altering T cell-mediated immunity, comprising altering the local extracellular concentration of tryptophan and tryptophan metabolites using IDO inhibitors such as 1-methyl-DL-tryptophan, p-(3-benzofuranyl)-DL-alanine, p-[3-benzo(b)thienyl]-DL-alanine, and 6-nitro-L-tryptophan) (Munn, 1999). WO 03/087347 (also published as European Patent 1501918) reports methods for preparing antigen-presenting cells for enhancing or reducing T cell tolerance (Munn, 2003). Compounds with indoleamine-2,3-dioxygenase (IDO) inhibitory activity have also been reported in WO 2004/094409; WO 2006/122150; WO 2009/073620; WO 2009/132238; WO 2011/056652, WO 2012/142237; WO 2013/107164; WO 2014/066834; WO 2014/081689; WO 2014/141110; WO 2014/150646; WO 2014/150677; WO 2015/006520; WO 2015/067782; WO 2015/070007;WO In particular, the compounds of WO 2012/142237 and WO 2014/159248 encompass a series of tricyclic imidazoisoindoles with potent IDO inhibitory activity.

Some substituted imidazo[1,5-a]pyridines are known in the literature. For example, WO 2008110523A1 (published on September 18, 2008) discloses imidazo[1,5-a]pyridines as glutaminyl cyclase inhibitors; GB 2174094A (published on October 29, 1986) discloses imidazo[1,5-a]pyridine derivatives as thromboxane synthase inhibitors; and JP 1997071586A (published on March 18, 1997) discloses imidazo[1,5-a]pyridines as inhibitors of the aldosterone biosynthetic enzyme cytochrome P450C18, for the treatment of primary or secondary aldosteronism, renin hypertension, and the like.

However, there are no reports of imidazo[1,5-a]pyridines as IDO/TDO inhibitors. The present application discloses novel 5- or 8-substituted imidazo[1,5-a]pyridines that exhibit IDO (specifically, IDO1, TDO, or dual IDO/TDO) inhibitory activity. The inventors of the present application unexpectedly discovered that substitution of a hydroxyl group on a chiral α-carbon atom attached to the 5- or 8-position of the imidazo[1,5-a]pyridine structure and/or substitution at the ortho or meta position to the chiral α-carbon atom substituted with a hydroxyl group on the pyridine portion of the imidazo[1,5-a]pyridine structure unexpectedly imparts both enzymatic and cellular activity to the novel 5- or 8-substituted imidazo[1,5-a]pyridines disclosed herein.

Summary of the Invention

The present application provides a compound selected from 5- or 8-substituted imidazo[1,5-a]pyridine of formula (IA) and/or (IB), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

in:

n = 0, 1, 2, 3 or 4;

R ^a and R ^b are each independently selected from hydrogen, halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ¹ is selected from hydrogen, halogen, C _1-8 alkyl and C _1-8 haloalkyl;

R ² and R ³ are each independently selected from hydrogen, halogen, OR ⁷ , NR ⁷ R ⁸ , COR ⁷ , SO ₂ R ⁷ , C(═O)OR ⁷ , C(═O)NR ⁷ R ⁸ , C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with at least one substituent R ⁹ ;

R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, halogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, C _1-8 haloalkyl, aryl, heterocyclyl, heteroaryl, -CN, -OR ⁷ and -SR ⁷ , wherein the C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, C _1-8 haloalkyl, aryl, heterocyclyl and heteroaryl are each independently optionally substituted with at least one substituent R ⁹ ,

Provided that at least one of R ⁴ and R ⁵ is not hydrogen;

^RC is selected from C _3-10 cycloalkyl, heterocyclyl or heteroaryl, each optionally substituted with at least one substituent R ⁹ ;

R ⁷ and R ⁸ are each independently selected from hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl, which are optionally substituted with at least one substituent R ⁹ ; or R ⁷ and R ⁸ , together with the nitrogen atom to which they are attached, form a heterocyclyl ring or a heteroaryl ring, which optionally contains another heteroatom selected from nitrogen, oxygen and sulfur atoms, and is optionally substituted with at least one substituent R ⁹ ;

^R is selected from hydrogen, halogen, C _1-4 haloalkyl, C _1-4 alkyl, C _2-8 alkenyl, C _3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, -C _1-4 alkyl-NR'R", -CN, -OR', -NR'R", -COR', -CO ₂ R', -CONR'R", -C(=NR')NR"R"', nitro, -NR'COR", -NR'CONR'R", -NR'CO 2 R", -SO ₂ R', -SO ₂ aryl, -NR'SO ₂ NR"R"', NR'SO ₂ R", and -NR'SO ₂ aryl, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl _, aryl, heteroaryl, or heterocyclyl is each independently optionally substituted with one, two, or three substituents selected from halogen, hydroxy, C _{C 1-4} alkyl and C _1-4 haloalkyl, wherein R′, R″ and R′″ are each independently selected from H, C _1-4 haloalkyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted by one or more halogen, C _1-4 haloalkyl and C _1-4 alkyl, or (R′ and R″) and/or (R″ and R′″) together with the atoms to which they are attached form a ring selected from the following: a heterocyclyl ring optionally substituted by halogen, C _1-4 haloalkyl and C _1-4 alkyl, and a heteroaryl ring optionally substituted by halogen, C _1-4 haloalkyl and C _1-4 alkyl.

The present application also provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier as described herein and at least one compound selected from the compounds of formula (IA) and/or (IB) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

The present application also provides a method for treating cancers responsive to inhibition of IDO and/or TDO, comprising administering to a subject in need of treatment for the above-mentioned cancer an effective amount of at least one compound selected from the compounds of Formula (IA) and/or (IB) described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for treating the cancer.

The present application also provides the use of a compound selected from the compounds of formula (IA) and/or (IB) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating the above-mentioned conditions or diseases.

The present application also provides use of a compound selected from the compounds of formula (IA) and/or (IB) described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting IDO and/or TDO.

The present application also provides use of a compound selected from the compounds of formula (IA) and/or (IB) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating cancer.

DETAILED DESCRIPTION

The following words, phrases and symbols used in this application are generally intended to have the following meanings unless the context in which they are used indicates otherwise.

The following abbreviations and terms have the designated meanings throughout:

The term "alkyl" herein refers to a hydrocarbon group selected from straight and branched chain saturated hydrocarbon groups containing 1-18, such as 1-12, further such as 1-10, further such as 1-8, or 1-6, or 1-4 carbon atoms. Examples of alkyl groups containing 1 to 6 carbon atoms (i.e., _C1-6 alkyl) include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl _{( n - pentyl} , _{-CH2CH2CH2CH2CH3} ), 2 _- pentyl ( _-CH ( _CH3 ) _CH2CH2CH3 ), 3-pentyl (-CH( _{CH2CH3 ) 2} ), 2-methyl-2-butyl (-C( _CH3 ) _2CH2CH3 ) _, 3-methyl _- 2-butyl (-CH(CH3 ₎₂ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (- CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (- CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (- CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (- CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), and 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ .

The term "alkyloxy" herein refers to an alkyl group as defined above bonded to an oxygen group, represented by -Oalkyl. Examples of alkyloxy groups (e.g., _C1-6 alkyloxy or _C1-4 alkyloxy) include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentyloxy, and hexyloxy groups.

The term "haloalkyl" herein refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms such as fluorine, chlorine, bromine and iodine. Examples of haloalkyl groups include _C1-6 haloalkyl groups or _C1-4 haloalkyl groups, but are not limited to _F3C- , _ClCH2- , _CF3CH2- , _{CF3CCl2- and the} like.

As used herein, the term "alkenyl" refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18, such as 2 to 8, and further such as 2 to 6, carbon atoms. Examples of alkenyl groups (e.g., _C2-6 alkenyl) include, but are not limited to, ethenyl or vinyl (-CH= _CH2 ), prop-1-enyl (-CH= _CHCH3 ), prop-2-enyl (-CH2CH= _{CH2 )} , 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl.

The term "alkynyl" as used herein refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18, such as 2 to 8, and further such as 2 to 6 carbon atoms. Examples of alkynyl groups (e.g., C _2-6 alkynyl) include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡CCH ₃ ), 2-propynyl (propargyl, -CH ₂ C≡CH), 1-butynyl, 2-butynyl, and 3-butynyl.

The term "cycloalkyl" as used herein refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, a cycloalkyl group may contain 3-12, such as 3-10, further such as 3-8, further such as 3-6, 3-5 or 3-4 carbon atoms. For further example, a cycloalkyl group may be selected from a monocyclic ring containing 3-12, such as 3-10, further such as 3-8, 3-6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Specifically, examples of cycloalkyl groups (e.g., C _3-8 cycloalkyl groups) include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of bicyclic cycloalkyl groups include bicyclic cycloalkyl groups having 7-12 carbon atoms arranged as a bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or arranged as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Other examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems, such as and wherein the wavy line indicates the point of attachment. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated and does not have aromaticity as defined herein.

The term "aryl" as used herein refers to a group selected from the group consisting of:

a 5- or 6-membered carbocyclic aromatic ring, for example, phenyl;

Bicyclic ring systems, such as 7-12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, for example selected from naphthalene and indane; and

A tricyclic ring system, such as a 10-15 membered tricyclic ring system, wherein at least one ring is carbocyclic and aromatic, for example fluorene.

For example, the aryl group is selected from 5- and 6-membered carbocyclic aromatic rings fused to a 5- to 7-membered cycloalkyl ring or a heterocyclic ring (optionally containing at least one heteroatom selected from N, O, and S), provided that when the carbocyclic aromatic ring is fused to a heterocyclic ring, the point of attachment is at the carbocyclic aromatic ring, and when the carbocyclic aromatic ring is fused to a cycloalkyl ring, the point of attachment may be at the carbocyclic aromatic ring or the cycloalkyl ring. Divalent radicals formed from substituted benzene derivatives and having free valences at ring atoms are designated as substituted phenylene groups. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals ending in "-" by removing one hydrogen atom from a carbon atom having a free valence are designated as follows: "-" is added to the corresponding monovalent radical; for example, naphthyl with two points of attachment is called naphthylene. However, aryl does not in any way encompass or overlap with heteroaryl, which is defined separately below. Thus, if one or more carbocyclic aromatic rings are fused to a heterocyclic aromatic ring, the resulting ring system is a heteroaryl group, not an aryl group, as defined herein.

The term "halogen" or "halo" herein refers to F, Cl, Br or I.

The term "heteroaryl" as used herein refers to a group selected from the group consisting of:

a 5-7 membered aromatic monocyclic ring containing at least one heteroatom selected from N, O and S, for example 1-4, or in some embodiments 1-3, the remaining ring atoms being carbon;

an 8-12 membered bicyclic ring containing at least one heteroatom selected from N, O and S, e.g., 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

An 11-14 membered tricyclic ring containing at least one heteroatom selected from N, O and S, e.g., 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

For example, the heteroaryl group includes a 5-7 membered heterocyclic aromatic ring fused to a 5-7 membered cycloalkyl ring. For the above fused bicyclic heteroaryl ring systems wherein only one ring contains at least one heteroatom, the point of attachment can be at the heteroaryl ring or at the cycloalkyl ring.

When the total number of S and O atoms in the heteroaryl group exceeds 1, the heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is at most 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is at most 1.

Examples of heteroaryl groups include, but are not limited to, (numbering from the attachment position designated as priority 1), pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furanyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (such as 1H-pyrazolo[3,4- b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazolyl, 1-thia-2,3-oxadiazolyl, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-oxadiazolyl, 1-thia-3,4-oxadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthazinyl, furopyridinyl, benzothiazolyl (such as benzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinolinyl.

As used herein, the term "heterocyclic" or "heterocycle" or "heterocyclyl" refers to a ring selected from 4-12 membered monocyclic, bicyclic, and tricyclic saturated and partially unsaturated rings, which contains at least one carbon atom in addition to at least one (such as 1-4, further such as 1-3, or further such as 1 or 2) heteroatom selected from oxygen, sulfur, and nitrogen. As used herein, "heterocycle" also refers to a 5- to 7-membered heterocycle fused to a 5-, 6-, and/or 7-membered cycloalkyl, carbocyclic aromatic, or heteroaromatic ring, which contains at least one heteroatom selected from N, O, and S, provided that when the heterocycle is fused to a carbocyclic aromatic or heteroaromatic ring, the point of attachment is in the heterocycle, and when the heterocycle is fused to a cycloalkyl, the point of attachment can be in the cycloalkyl or heterocycle. As used herein, "heterocycle" also refers to an aliphatic spirocycle containing at least one heteroatom selected from N, O, and S, provided that the point of attachment is in the heterocycle. The ring may be saturated or have at least one double bond (i.e., partially unsaturated). The heterocycle may be substituted with an oxo group. The site of attachment in the heterocycle may be a carbon or heteroatom. The heterocycle is not a heteroaryl group as defined herein.

Examples of heterocycles include, but are not limited to, (numbering from the attachment position designated as priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxirane, aziridine, thiirane, azetidinyl, oxetanyl, thietanyl, 1, 2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, oxathianyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathianyl, 1,4-oxazepanyl, 1,4-dithianyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolane, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinyl, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]cycloheptyl, and azabicyclo[2.2.2]cyclohexyl. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

As used herein, the term "fused ring" refers to a polycyclic ring system, for example, a bicyclic or tricyclic ring system, in which the two rings share only two ring atoms and one common bond. Examples of fused rings may include fused bicyclic cycloalkyl rings, such as bicyclic cycloalkyl rings having 7-12 ring atoms arranged to form a bicyclic ring selected from the above-mentioned [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems; fused bicyclic aryl rings, such as the above-mentioned 7-12 membered bicyclic aryl ring systems; fused tricyclic aryl rings, such as the above-mentioned 10-15 membered tricyclic aryl ring systems; fused bicyclic heteroaryl rings, such as the above-mentioned 8-12 membered bicyclic heteroaryl rings; fused tricyclic heteroaryl rings, such as the above-mentioned 11-14 membered tricyclic heteroaryl rings; and the above-mentioned fused bicyclic or tricyclic heterocyclyl rings.

The compounds described herein may contain asymmetric centers and thus may exist as enantiomers. When the compounds described herein have two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers fall into a wider category of stereoisomers. The present application is intended to include all possible stereoisomers, such as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. The present application is intended to include all stereoisomers of the compounds described herein and/or their pharmaceutically acceptable salts. Unless otherwise specifically stated, reference to an isomer applies to any possible isomer. Where the isomer composition is not specified, all possible isomers are included.

As used herein, the term "substantially pure" means that the target stereoisomer contains at most 35% by weight, such as at most 30% by weight, further such as at most 25% by weight, further such as at most 20% by weight of any one or more other stereoisomers. In some embodiments, the term "substantially pure" means that the target stereoisomer contains at most 10% by weight, for example, at most 5% by weight, such as at most 1% by weight of any one or more other stereoisomers.

When compounds described herein contain olefinic double bonds, unless specified otherwise, such double bonds are intended to include both E and Z geometric isomers.

Certain compounds described herein can exist with different sites of hydrogen attachment, known as tautomers. For example, a compound comprising a carbonyl group _-CH2C (O)- (keto form) can undergo tautomerism to form a hydroxyl group -CH=C(OH)- (enol form). Where applicable, the present application is intended to include both the keto and enol forms, individually and as mixtures thereof.

The reaction products can be advantageously separated from each other and/or from the starting materials. The desired product of each step or series of steps is separated and/or purified (hereinafter referred to as separation) to the desired degree of homogeneity by conventional techniques in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including, for example: reverse phase and normal phase chromatography; size exclusion chromatography; ion exchange chromatography; high, medium, and low pressure liquid chromatography methods and instruments; small-scale analytical chromatography; simulated moving bed ("SMB") chromatography and preparative thin or thick layer chromatography and small-scale thin layer and flash chromatography techniques. Those skilled in the art should use the technique most likely to achieve the desired separation.

Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and then converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolving the racemic mixture using methods such as diastereoisomer formation with an optically active resolving agent (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3) (1975): pp. 283-302). Racemic mixtures of the chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds followed by separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of the diastereomers, and conversion to pure stereoisomers, or (3) direct separation of the substantially pure or enriched stereoisomers under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

"Pharmaceutically acceptable salts" are salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, or the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid, or by reacting an acidic group with a suitable base.

Furthermore, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt (such as a pharmaceutically acceptable addition salt) can be prepared by dissolving the free base in a suitable organic solvent and then treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will readily appreciate the various synthetic methods available for preparing non-toxic pharmaceutically acceptable addition salts without undue experimentation.

"Pharmaceutically acceptable salts thereof" as defined herein include salts of at least one compound (IA) and/or (IB) and salts of at least one stereoisomer of compound (IA) and/or (IB), such as salts of enantiomers and/or diastereomers.

"Treatment," "treating," "treating," or "alleviation" refers to administering to a subject deemed in need thereof (suffering from, for example, cancer) at least one compound described herein and/or at least one stereoisomer thereof and/or at least one pharmaceutically acceptable salt thereof.

The term "effective amount" refers to an amount of at least one compound and/or at least one stereoisomer thereof and/or at least one pharmaceutically acceptable salt thereof described herein that is effective to "treat" (as defined above) a disease or condition in a subject.

The term "at least one substituent" disclosed herein includes, for example, 1-4, such as 1-3, and further such as 1 or 2 substituents, provided that valence permits. For example, the term "at least one substituent R ⁹ " disclosed herein includes 1-4, such as 1-3, and further such as 1 or 2 substituents selected from the list of R ⁹ described herein.

In a first aspect, the present application provides a compound selected from a 5- or 8-substituted imidazo[1,5-a]pyridine of formula (IA) and/or (IB), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

in:

n = 0, 1, 2, 3 or 4;

R ^a and R ^b are each independently selected from hydrogen, halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ¹ is selected from hydrogen, halogen, C _1-8 alkyl and C _1-8 haloalkyl;

R ² and R ³ are each independently selected from hydrogen, halogen, OR ⁷ , NR ⁷ R ⁸ , COR ⁷ , SO ₂ R ⁷ , C(═O)OR ⁷ , C(═O)NR ⁷ R ⁸ , C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with at least one substituent R ⁹ ;

R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, halogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, C _1-8 haloalkyl, aryl, heterocyclyl, heteroaryl, -CN, -OR ⁷ and -SR ⁷ , wherein the C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, C _1-8 haloalkyl, aryl, heterocyclyl and heteroaryl are each independently optionally substituted with at least one substituent R ⁹ ,

Provided that at least one of R ⁴ and R ⁵ is not hydrogen;

^RC is selected from C _3-10 cycloalkyl, heterocyclyl or heteroaryl, each optionally substituted with at least one substituent R ⁹ ;

R ⁷ and R ⁸ are each independently selected from hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl, which are optionally substituted with at least one substituent R ⁹ ; or R ⁷ and R ⁸ , together with the nitrogen atom to which they are attached, form a heterocyclyl ring or a heteroaryl ring, which optionally contains another heteroatom selected from nitrogen, oxygen and sulfur atoms, and is optionally substituted with at least one substituent R ⁹ ;

^R is selected from hydrogen, halogen, C _1-4 haloalkyl, C _1-4 alkyl, C _2-8 alkenyl, C _3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, -C _1-4 alkyl-NR'R", -CN, -OR', -NR'R", -COR', -CO ₂ R', -CONR'R", -C(=NR')NR"R"', nitro, -NR'COR", -NR'CONR'R", -NR'CO 2 R", -SO ₂ R', -SO ₂ aryl, -NR'SO ₂ NR"R"', NR'SO ₂ R", and -NR'SO ₂ aryl, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl _, aryl, heteroaryl, or heterocyclyl is each independently optionally substituted with one, two, or three substituents selected from halogen, hydroxy, C _{C 1-4} alkyl and C _1-4 haloalkyl, wherein R′, R″ and R′″ are each independently selected from H, C _1-4 haloalkyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted by one or more halogen, C _1-4 haloalkyl and C _1-4 alkyl, or (R′ and R″) and/or (R″ and R′″) together with the atoms to which they are attached form a ring selected from the following: a heterocyclyl ring optionally substituted by halogen, C _1-4 haloalkyl and C _1-4 alkyl, and a heteroaryl ring optionally substituted by halogen, C _1-4 haloalkyl and C _1-4 alkyl.

In a second aspect, the present application provides a 5-substituted imidazo[1,5-a]pyridine of formula (IA) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

in:

n = 0, 1, 2, 3 or 4;

R ^a and R ^b are each independently selected from hydrogen, halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ¹ is selected from hydrogen, halogen, C _1-8 alkyl and C _1-8 haloalkyl;

R ² and R ³ are each independently selected from hydrogen, halogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with at least one substituent R ⁹ ;

R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, halogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, C _1-8 haloalkyl, aryl, heterocyclyl, heteroaryl and -OR ⁷ , wherein said C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, C _1-8 haloalkyl, aryl, heterocyclyl and heteroaryl are each independently optionally substituted with at least one substituent R ⁹ ,

Provided that at least one of R ⁴ and R ⁵ is not hydrogen;

^RC is a C _3-10 cycloalkyl group, optionally substituted with at least one substituent R ⁹ ;

R ⁷ is selected from hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl, which is optionally substituted with at least one substituent R ⁹ ;

R ⁹ is selected from hydrogen, halogen, C _1-4 haloalkyl, C _1-4 alkyl, C _2-8 alkenyl, C _3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, -C _1-4 alkyl-NR'R", -CN, -OR', -NR'R", -COR', -CO ₂ R', -CONR'R", nitro, -NR'COR", -NR'CONR'R", -NR'CO ₂ R", -SO 2 R', -SO ₂ aryl, NR'SO ₂ R", and -NR'SO ₂ aryl, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl _, aryl, heteroaryl, or heterocyclyl is each independently optionally substituted with one, two, or three substituents selected from halogen, hydroxy, C _1-4 alkyl, and C 3-6 cycloalkyl. _1-4 haloalkyl, wherein R′ and R″ are each independently selected from H, C _1-4 haloalkyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted by one or more halogen, C _1-4 haloalkyl and C _1-4 alkyl.

In some embodiments, for compounds of Formula (IA), n is 0. In another embodiment, for compounds of Formula (IA), n is 1. In yet another embodiment, for compounds of Formula (IA), n is 2.

In some embodiments, for the compound of formula (IA), ^Ra and ^Rb are each independently selected from hydrogen, halogen, _C1-6 alkyl or _C1-6 haloalkyl; preferably, each independently selected from hydrogen, halogen, _C1-4 alkyl or _C1-4 haloalkyl; more preferably, each independently hydrogen.

In some embodiments, for the compound of formula (IA), R ¹ is selected from hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl, preferably selected from hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably selected from hydrogen and C _1-6 alkyl.

In some embodiments, for the compound of formula (IA), R ² and R ³ are each independently selected from hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl, preferably each independently selected from hydrogen and C _1-6 alkyl.

In some embodiments, for compounds of formula (IA), R ⁴ is not hydrogen, R ⁵ is hydrogen, and R ⁶ is hydrogen. In another embodiment, for compounds of formula (IA), R ⁴ is not hydrogen, R ⁵ is hydrogen, and R ⁶ is not hydrogen.

In some embodiments, for compounds of formula (IA), R ⁴ is hydrogen, R ⁵ is not hydrogen, and R ⁶ is hydrogen. In another embodiment, for compounds of formula (IA), R ⁴ is hydrogen, R ⁵ is not hydrogen, and R ⁶ is not hydrogen.

In some embodiments, for compounds of formula (IA), R ⁴ is not hydrogen, R ⁵ is not hydrogen, and R ⁶ is hydrogen. In another embodiment, for compounds of formula (IA), R ⁴ is not hydrogen, R ⁵ is not hydrogen, and R ⁶ is not hydrogen.

For compounds of formula (IA), in the case where R ⁴ is not hydrogen, R ⁴ is selected from halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, heterocyclyl, aryl, heteroaryl and -OC _1-6 alkyl, wherein the aryl or heteroaryl is independently optionally substituted with at least one R ⁹ which is independently selected from halogen, C _1-4 haloalkyl and C _1-4 alkyl; preferably, R ⁴ is selected from halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _1-6 haloalkyl (such as fluoro-substituted C _1-6 alkyl), phenyl optionally substituted with halogen, C _1-4 alkyl or C _1-4 haloalkyl, heteroaryl optionally substituted with halogen, C _1-4 alkyl or C _1-4 haloalkyl (such as isoxazolyl) and -OC _1-6 alkyl; more preferably, R ⁴ is selected from F, Cl, Br, I, methyl, isopropyl, propenyl (such as prop-1-en-2-yl), ethynyl, cyclopropyl, CF ₃ , phenyl, dimethylisoxazolyl and methoxy.

For compounds of formula (IA), when R ⁵ is not hydrogen, R ⁵ is selected from halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, heterocyclyl, aryl, heteroaryl and -OC _1-6 alkyl, wherein the aryl or heteroaryl is independently optionally substituted with at least one R ⁹ , which is independently selected from halogen, C _1-4 haloalkyl and C _1-4 alkyl; preferably, R ⁵ is selected from halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _1-6 haloalkyl (such as fluorine-substituted C _1-6 alkyl) and -OC _1-6 alkyl; more preferably, R ⁵ is selected from F, Cl, Br, I, cyclopropyl, CF ₃ and methoxy.

For compounds of formula (IA), when R ⁶ is not hydrogen, R ⁶ is selected from halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, heterocyclyl, aryl, heteroaryl and -OC _1-6 alkyl, wherein the aryl or heteroaryl is independently optionally substituted with at least one R ⁹ , which is independently selected from halogen, C _1-4 haloalkyl and C _1-4 alkyl; preferably, R ⁶ is halogen, C _1-6 alkyl or C _1-6 haloalkyl.

In some embodiments, for compounds of formula (IA), ^RC is C _3-8 cycloalkyl, optionally substituted with at least one substituent R ⁹ . In other embodiments, for compounds of formula (IA), ^RC is C _3-8 cycloalkyl, optionally substituted with phenyl.

In some embodiments, for compounds of formula (IA), ^RC is _C3-10 cycloalkyl, preferably _C3-8 cycloalkyl, which is optionally substituted with halogen, _C1-4 haloalkyl, _C1-4 alkyl and -NR'COR", wherein the _C1-4 haloalkyl and _C1-4 alkyl are optionally substituted with one or more halogen or hydroxy; wherein R' and R" are each independently selected from H, _C1-4 haloalkyl, _C1-4 alkyl, _C3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with one or more halogen, _C1-4 haloalkyl and _C1-4 alkyl; preferably, ^RC is _C3-8 cycloalkyl, which is optionally substituted with _C1-4 alkyl and -NR'COR", wherein the _C1-4 alkyl is optionally substituted with hydroxy; wherein R' is hydrogen, and R" is aryl, which is phenyl optionally substituted with halogen (such as fluorine and chlorine).

In other embodiments, for compounds of formula (IA), ^RC is unsubstituted C _3-10 cycloalkyl; preferably unsubstituted C _3-8 cycloalkyl; more preferably ^RC is unsubstituted cyclohexyl. In yet another embodiment, for compounds of formula (IA), ^RC is cyclopropyl, cyclobutyl, cyclopentyl, or cycloheptyl.

In some embodiments, for compounds of Formula (IA), n is 0 and ^RC is unsubstituted cyclohexyl. In other embodiments, for compounds of Formula (IA), n is 1 and ^RC is unsubstituted cyclohexyl. In another embodiment, for compounds of Formula (IA), n is 2 and ^RC is unsubstituted cyclohexyl.

In some embodiments, for compounds of Formula (IA), n is 0 and ^RC is unsubstituted cyclopentyl. In other embodiments, for compounds of Formula (IA), n is 1 and ^RC is unsubstituted cyclopentyl. In another embodiment, for compounds of Formula (IA), n is 2 and ^RC is unsubstituted cyclopentyl.

In some embodiments, for the compound of Formula (IA), n is 0, and ^RC is unsubstituted bicyclo[2.2.1]hept-2-yl.

In some embodiments, for the compound of Formula (IA), n is 0, and ^RC is 4-phenyl-substituted cyclohexyl.

In some embodiments, for compounds of formula (IA), the chiral α-carbon atom attached to the imidazo[1,5-a]pyridine structure is in S- or R-configuration. Preferably, for compounds of formula (IA), the chiral α-carbon atom attached to the imidazo[1,5-a]pyridine structure is in S-configuration.

In a third aspect, the present application provides an 8-substituted imidazo[1,5-a]pyridine of formula (IB) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

in:

n = 0, 1, 2, 3 or 4;

R ^a and R ^b are each independently selected from hydrogen, halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ¹ is selected from hydrogen, halogen, C _1-8 alkyl and C _1-8 haloalkyl;

R ² and R ³ are each independently selected from hydrogen, halogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with at least one substituent R ⁹ ;

R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, halogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, C _1-8 haloalkyl, aryl, heterocyclyl, heteroaryl and -OR ⁷ , wherein said C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, C _1-8 haloalkyl, aryl, heterocyclyl and heteroaryl are each independently optionally substituted with at least one substituent R ⁹ ,

Provided that R ⁴ is not hydrogen;

^RC is a C _3-10 cycloalkyl group, which is optionally substituted with at least one substituent R ⁹ ;

R ⁷ is selected from hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl, which is optionally substituted with at least one substituent R ⁹ ;

R ⁹ is selected from hydrogen, halogen, C _1-4 haloalkyl, C _1-4 alkyl, C _2-8 alkenyl, C _3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, -C _1-4 alkyl-NR'R", -CN, -OR', -NR'R", -COR', -CO ₂ R', -CONR'R", nitro, -NR'COR", -NR'CONR'R", -NR'CO ₂ R", -SO 2 R', -SO ₂ aryl, NR'SO ₂ R", and -NR'SO ₂ aryl, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl _, aryl, heteroaryl, or heterocyclyl is each independently optionally substituted with one, two, or three substituents selected from halogen, hydroxy, C _1-4 alkyl, and C 3-6 cycloalkyl. _1-4 haloalkyl, wherein R′ and R″ are each independently selected from H, C _1-4 haloalkyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted by one or more halogen, C _1-4 haloalkyl and C _1-4 alkyl.

In some embodiments, for compounds of formula (IB), n is 0. In another embodiment, for compounds of formula (IB), n is 1. In yet another embodiment, for compounds of formula (IB), n is 2.

In some embodiments, for the compound of formula (IB), ^Ra and ^Rb are each independently selected from hydrogen, halogen, _C1-6 alkyl or _C1-6 haloalkyl, preferably each independently selected from hydrogen, halogen, _C1-4 alkyl or _C1-4 haloalkyl; more preferably each independently hydrogen.

In some embodiments, for the compound of formula (IB), R ¹ is selected from hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl, preferably selected from hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably selected from hydrogen and C _1-6 alkyl.

In some embodiments, for the compound of formula (IB), R ² and R ³ are each independently selected from hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl, preferably each independently selected from hydrogen and C _1-6 alkyl.

In some embodiments, for the compound of formula (IB), R ⁴ is selected from halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, heterocyclyl, aryl, heteroaryl and -OC _1-6 alkyl; preferably, R ⁴ is selected from halogen, C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _3-6 cycloalkyl, C _1-6 haloalkyl (such as fluorine-substituted C _1-6 alkyl) and -OC _1-6 alkyl; more preferably, _R ⁴ is selected from F, Cl, Br, I, methyl, isopropyl and cyclopropyl.

In some embodiments, for compounds of formula (IB), R ⁵ is hydrogen and R ⁶ is hydrogen. In another embodiment, for compounds of formula (IB), R ⁵ is hydrogen and R ⁶ is not hydrogen.

In some embodiments, for compounds of formula (IB), R ⁵ is not hydrogen, and R ⁶ is hydrogen. In another embodiment, for compounds of formula (IB), R ⁵ is not hydrogen, and R ⁶ is not hydrogen.

For compounds of formula (IB), in the case where R ⁵ is not hydrogen, R ⁵ is selected from halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, heterocyclyl, aryl, heteroaryl and -OC _1-6 alkyl, wherein the aryl or heteroaryl is independently optionally substituted with at least one R ⁹ , which is independently selected from halogen, C _1-4 haloalkyl and C _1-4 alkyl; preferably, R ⁵ is selected from halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _1-6 haloalkyl (such as fluorine-substituted C _1-6 alkyl) and -OC _1-6 alkyl; more preferably, R ⁵ is selected from F, Cl, Br, I, cyclopropyl, CF ₃ and methoxy.

For compounds of formula (IB), in the case where R ⁶ is not hydrogen, R ⁶ is selected from halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, heterocyclyl, aryl, heteroaryl and -OC _1-6 alkyl, wherein the aryl or heteroaryl is independently optionally substituted with at least one R ⁹ , which is independently selected from halogen, C _1-4 haloalkyl and C _1-4 alkyl; preferably, R ⁶ is halogen, C _1-6 alkyl or C _1-6 haloalkyl; more preferably, R ⁶ is halogen.

In some embodiments, for compounds of formula (IB), ^RC is C _3-8 cycloalkyl, optionally substituted with at least one substituent R ⁹ . In other embodiments, for compounds of formula (IB), ^RC is C _3-8 cycloalkyl, optionally substituted with phenyl.

In some embodiments, for compounds of formula (IB), ^RC is _C3-10 cycloalkyl, preferably _C3-8 cycloalkyl, which is optionally substituted with halogen, _C1-4 haloalkyl, _C1-4 alkyl and -NR'COR", wherein the _C1-4 haloalkyl and _C1-4 alkyl are optionally substituted with one or more halogen or hydroxy; wherein R' and R" are each independently selected from H, _C1-4 haloalkyl, _C1-4 alkyl, _C3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with one or more halogen, _C1-4 haloalkyl and _C1-4 alkyl; preferably, ^RC is _C3-8 cycloalkyl, which is optionally substituted with _C1-4 alkyl and -NR'COR", wherein the _C1-4 alkyl is optionally substituted with hydroxy; wherein R' is hydrogen, and R" is aryl, which is phenyl optionally substituted with halogen (such as fluorine and chlorine).

In other embodiments, for compounds of formula (IB), ^RC is unsubstituted _C3-10 cycloalkyl; preferably, unsubstituted _C3-8 cycloalkyl; more preferably, ^RC is unsubstituted cyclohexyl. In yet another embodiment, for compounds of formula (IB), ^RC is cyclopropyl, cyclobutyl, cyclopentyl, or cycloheptyl.

In some embodiments, for compounds of Formula (IB), n is 0 and ^RC is unsubstituted cyclohexyl. In other embodiments, for compounds of Formula (IB), n is 1 and ^RC is unsubstituted cyclohexyl. In another embodiment, for compounds of Formula (IB), n is 2 and ^RC is unsubstituted cyclohexyl.

In some embodiments, for compounds of Formula (IB), n is 0 and ^RC is unsubstituted cyclopentyl. In other embodiments, for compounds of Formula (IB), n is 1 and ^RC is unsubstituted cyclopentyl. In another embodiment, for compounds of Formula (IB), n is 2 and ^RC is unsubstituted cyclopentyl.

In some embodiments, for the compound of Formula (IB), n is 0, and ^RC is unsubstituted bicyclo[2.2.1]hept-2-yl.

In some embodiments, for the compound of Formula (IB), n is 0, and ^RC is cyclohexyl substituted with 4-phenyl.

In some embodiments, for compounds of formula (IB), the chiral α-carbon atom attached to the imidazo[1,5-a]pyridine structure is in S- or R-configuration. Preferably, for compounds of formula (IB), the chiral α-carbon atom attached to the imidazo[1,5-a]pyridine structure is in S-configuration.

The present application also provides a compound selected from the following compounds or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

The present application also provides a compound or a pharmaceutically acceptable salt thereof selected from the following compounds showing the following stereochemistry:

The results of the "Biological Assays" section of this specification indicate that substitution of a hydroxyl group at the chiral α-carbon atom attached to the 5- or 8-position of the imidazo[1,5-a]pyridine structure and/or substitution at the ortho or meta position of the chiral α-carbon atom substituted with a hydroxyl group on the pyridine portion of the imidazo[1,5-a]pyridine structure unexpectedly imparts both enzymatic and cellular activity to the novel 5- or 8-substituted imidazo[1,5-a]pyridines disclosed herein. For example, each of the compounds in Examples A101 to A165 and Examples B101 to B143 exhibited simultaneous inhibition of IDO1 and TDO with _IC50 values ranging from 0.1 nM to 10 μM, and inhibited HeLa cell-based IDO1 activity with _EC50 values ranging from less than 10,000 nM.

The results also indicate that 5-substituted imidazo[1,5-a]pyridines having a chiral α-carbon atom substituted with a hydroxyl group at the 5-position and further ortho-substituted on the pyridine portion of the imidazo[1,5-a]pyridine structure, and 8-substituted imidazo[1,5-a]pyridines having a chiral α-carbon atom substituted with a hydroxyl group at the 8-position and further ortho-substituted on the pyridine portion of the imidazo[1,5-a]pyridine structure, exhibit selective inhibition of IDO1 relative to TDO. For example, Example A119 exhibited an enzyme IC ₅₀ value of 22 nM for IDO1 and an enzyme IC ₅₀ value of 12,000 nM for TDO; Example A117 exhibited an enzyme IC ₅₀ value of 28 nM for IDO1 and an enzyme IC ₅₀ value of 9,700 nM for TDO; and Example B105 exhibited an enzyme IC ₅₀ value of 33 nM for IDO1 and an enzyme IC ₅₀ value of 4,900 nM for TDO.

In a fourth aspect, the present application provides a method for preparing the compound of formula (IA) or (IB) described herein.

The compounds and/or pharmaceutically acceptable salts thereof disclosed in this application can be synthesized from commercially available starting materials in combination with the contents disclosed in this application.

Compounds of formula (IA and IB) can be prepared by those skilled in the art by the exemplary procedures described in the Examples, as well as by procedures from the relevant published literature. Exemplary reagents and procedures for these reactions appear below and in the Examples. Protection and deprotection in the following procedures can be performed by methods well known in the art (see, for example, Greene, T. W. et al., eds., Protecting Groups in Organic Synthesis, ^3rd Edition, Wiley (1999)). General methods for organic synthesis and functional group transformations can be found in Trost, B. Metal., eds., Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, New York, NY (1991); March, J., Advanced Organic Reactions, Mechanisms, and Structure. ^4th Edition, Wiley & Sons, New York, NY (1992); Katritzky, A. R. et al., eds., Comprehensive Organic Functional Groups Transformations, ^1st Edition, Elsevier Science Inc., Tarrytown, NY (1995); Larock, R. C., Comprehensive Organic Transformations, VCH Publishers, Inc., New York, NY (1989), and references therein.

Compounds of formula (IA) can be prepared according to the following schemes using chemical transformations familiar to those skilled in the art of organic/medicinal chemistry. Literature covering a variety of such transformations can be found in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, edited by Michael B. Smith and Jerry March, Wiley-Interscience, New York, 2001, or other standard texts on the subject of synthetic organic chemistry.

Plan A

Wherein R corresponds to -(CR ² R ³ ) _n -R ^c when R ¹ is hydrogen

In this scheme, compound A-1 (wherein R ⁴ , R ⁵ and R ⁶ are as defined above) is commercially available or can be readily prepared using chemical transformations familiar to those skilled in the art of organic/medicinal chemistry. Compound A-1 is treated with a reducing agent (e.g., sodium borohydride) in an alcoholic solvent to provide compound A-2, which is then converted to chloride A-3 by thionyl chloride. The chloride is treated with a protecting agent (such as potassium phthalimide) in a solvent (such as THF, DMF, NMP or DMSO) to provide compound A-4. The phthalimide protecting group is removed by heating with hydrazine to provide the free base A-5. Formation of the carboxamide of compound A-5 is accomplished by treatment with a mixture of formic acid and acetic acid to provide compound A-6, which is cyclized to imidazo[1,5-a]pyridine ester A-7 by heating with POCl ₃ in an inert solvent (such as toluene). Compound A-7 undergoes hydrolysis using a base such as sodium hydroxide in a solvent such as water or an alcohol or a mixture of the two. The resulting acid A-8 is converted to the Weinreb amide A-9 by reaction with N,O-dimethylhydroxylamine under typical coupling reaction conditions. Typical Grignard reagents for Weinreb amide A-9 provide ketone A-10. Reduction of ketone A-10 with a reducing agent such as sodium borohydride in an alcoholic solvent yields a diastereomeric mixture (IA). Final chiral HPLC separation yields a single enantiomer. It should be noted that single enantiomers or diastereomers can also be prepared using chiral reducing agents. Optical purity can be improved by other typical chiral resolution methods reported in various literature.

Plan B

Wherein R corresponds to -(CR ² R ³ ) _n -R ^c when R ¹ is hydrogen

Compound IA (R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as described above) can also be prepared by a slightly modified procedure. Commercially available compound B-1 is first converted to 2-chloro-6-formate B-2. After replacing the chlorine with a cyano group, the resulting 2-cyano-6-formate pyridine B-3 is hydrogenated to 2-Boc-aminomethyl-6-formate pyridine B-4 in the presence of Boc ₂ O and a platinum catalyst. The Boc is then removed to obtain the free amine B-5, which is converted to the formamide B-6. Further cyclization to imidazo[1,5-a]pyridine ester B-7 is achieved by treatment with POCl _3. Compound B-7 is reduced to obtain alcohol B-8, which undergoes a Dess-Martin or other oxidation reaction to obtain aldehyde B-9. Addition of a Grignard reagent to the aldehyde gives the final alcohol (IA). Alternatively, ketone B-10 is first prepared by treating the aldehyde with a hydrazone in the presence of a base (such as cesium carbonate) under reflux conditions. Reduction of ketone B-10 with a reducing agent gives a racemic mixture of alcohols (IA). Further chiral separation gives a single enantiomer.

Plan C

Wherein R corresponds to -(CR ² R ³ ) _n -R ^c when R ¹ is hydrogen

Compound IB (R ⁴ , R ⁵ and R ⁶ as described above) can be prepared by similar procedures. Commercially available compound C-1 is converted into 2-methyl-3-formate C-2. Free radical-catalyzed bromine substitution at the α position gives bromomethylpyridinium ester C-3. After replacing the bromine atom with bis-(Boc)amide, the resulting 2-bis(Boc)aminomethyl-3-formate pyridine C-4 is treated with TFA to give aminomethylpyridine TFA salt C-5. Formamide C-6 is then prepared and further converted into imidazo[1,5-a]pyridinium ester C-7 by treatment with POCl _3. Compound C-7 is reduced to give alcohol C-8, which undergoes Dess-Martin or other oxidation reactions to give aldehyde C- 9. Grignard reagent is added to the aldehyde to give the final alcohol (IB). Further chiral separation gives a single enantiomer. Alternatively, ketone C-10 is first prepared by treating the aldehyde with a hydrazone under reflux conditions in the presence of a base (such as cesium carbonate). Reduction of ketone C-10 with a reducing agent affords a racemic mixture of alcohol (IIA), which can be further chirally separated to afford a single enantiomer.

Plan D

in

^R7 is a conventional amino protecting group;

Wherein R corresponds to -(CR ² R ³ ) _n -R ^c when R ¹ is hydrogen

Compound IC (R ⁴ , R ⁵ and R ⁶ are as described above) can be prepared by similar procedures. Commercially available compound D-1 is converted to hydroxy-methyl-4-chloro-amide D-2. Acid-catalyzed cyclization of lactone D-3 is performed. After replacing the chlorine atom with an alkyl group or a ring, the resulting lactone D-4 is treated with AlLiH ₄ to provide diol D-5. Displacement of the primary alcohol with a chloride provides D-6, which is treated with sodium diformamide to provide N-formyl formamide compound D-7. Formamide D-7 is then cyclized using formic acid and acetic anhydride solvent to provide D-8. Hydrolysis of the ester with lithium hydroxide provides racemic IC, which is separated using chiral HPLC or chiral acid to provide the individual enantiomers.

Plan E

Specifically, R ^7a and R ^8a may be linked to form a bridged ring such as bicyclo[2.2.1]hept-2-yl

Compound ID ( ^R4 , ^R5 , and ^R6 as described above) can also be prepared by a slightly modified procedure. Commercially available compound E-1 is first converted to 2,5-dichloro-6-carboxylate E-2. After replacing the chlorine atom with a cyano group, the resulting 2-cyano- ₅ -chloro-6-carboxylate pyridine E-3 is hydrogenated to 2-Boc-aminomethyl-6-carboxylate pyridine E-4 under palladium/activated carbon catalysis and the presence of Boc2O to protect the primary amine. Hydrolysis of the ester affords acid E-6, which is coupled with N,O-dimethylhydroxylamine to afford E-7. Addition of a Grignard reagent to the Weinreb amide affords ketone E-8. In the presence of _ZnBr2 catalyst, E-8 forms a new ring with a 1,3-diene. Compound E-9 is hydrogenated over palladium/activated carbon catalyst to afford E-10, which is reduced with _NaBH4 to afford alcohol E-11. Removal of Boc with HCl in EA followed by solvent treatment with formic acid and acetic anhydride affords E-13. Hydrolysis of the ester with lithium hydroxide affords racemic ID, which can be separated by chiral HPLC or chiral acid to afford the individual enantiomers.

In a fifth aspect, the present application also provides a method for treating or preventing a hyperproliferative disorder such as cancer, comprising administering to a subject in need thereof, such as a mammal or a human, a pharmaceutically effective amount of a compound selected from the compounds of formula (IA) and/or (IB) described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

The present application also provides a method for treating or preventing hyperproliferative disorders such as cancer by inhibiting IDO, comprising administering to a subject in need thereof, such as a mammal or a human, a pharmaceutically effective amount of a compound selected from the compounds of formula (IA) and/or (IB) described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

The present application also provides a method for treating or preventing cancer, comprising administering to a subject in need thereof, such as a mammal or a human, a pharmaceutically effective amount of a compound selected from the compounds of formula (IA) and/or (IB) described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the cancer includes, but is not limited to, for example, melanoma, thyroid cancer, Barrett's adenocarcinoma, breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, kidney cancer, head and neck cancer, liver cancer, gastric cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematologic cancer, cancer of the biliary tract, non-small cell lung cancer, endometrial cancer, blood cancer, large intestinal colon carcinoma, histiocytic lymphoma, and lung adenocarcinoma.

The present application also provides a method for treating or preventing HIV/AIDS, comprising administering to a subject in need thereof, such as a mammal or a human, a pharmaceutically effective amount of a compound selected from the compounds of formula (IA) and/or (IB) described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

The present application also provides a method for enhancing the efficacy of antiretroviral therapy, comprising administering to a subject in need thereof, such as a mammal or a human, an antiretroviral drug and a pharmaceutically effective amount of a compound selected from the compounds of formula (IA) and/or (IB) described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

The present application also provides a method for treating cancer that responds to inhibition of IDO and/or TDO, comprising administering a pharmaceutically effective amount of a compound selected from the compounds of formula (IA) and/or (IB) described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a subject in need of cancer treatment, such as a mammal or a human, wherein the cancer includes, but is not limited to, melanoma, thyroid cancer, Barrett's adenocarcinoma, breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, kidney cancer, head and neck cancer, liver cancer, gastric cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, biliary tract cancer, non-small cell lung cancer, endometrial cancer, blood cancer, colorectal cancer, histiocytic lymphoma, and lung adenocarcinoma.

The present application also provides the use of a compound selected from the compounds of formula (IA) and/or (IB) described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancers responsive to inhibition of IDO and/or TDO, wherein the cancers include, but are not limited to, melanoma, thyroid cancer, Barrett's adenocarcinoma, breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, kidney cancer, head and neck cancer, liver cancer, gastric cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, biliary tract cancer, non-small cell lung cancer, endometrial cancer, blood cancer, colorectal cancer, histiocytic lymphoma, and lung adenocarcinoma.

The present application also provides a compound selected from the compounds of formula (IA) and/or (IB) described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating cancers responsive to inhibition of IDO and/or TDO, wherein the cancers include, but are not limited to, melanoma, thyroid cancer, Barrett's adenocarcinoma, breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, kidney cancer, head and neck cancer, liver cancer, gastric cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, biliary tract cancer, non-small cell lung cancer, endometrial cancer, blood cancer, colorectal cancer, histiocytic lymphoma, and lung adenocarcinoma.

The compound selected from the compound of formula (IA) and/or (IB) or its stereoisomer or its pharmaceutically acceptable salt can be used for treatment alone or in combination with at least one other therapeutic agent. In some embodiments, the compound selected from the compound of formula (IA) and/or (IB) or its stereoisomer or its pharmaceutically acceptable salt can be used in combination with at least one other therapeutic agent. The at least one other therapeutic agent can, for example, be selected from anti-hyperproliferative drugs, anticancer drugs and chemotherapeutic drugs. The at least one compound and/or at least one pharmaceutical salt disclosed in the present application can be administered in a single dose or in a separate dosage form with at least one other therapeutic agent. When administered in a separate dosage form, the at least one other therapeutic agent can be administered before, simultaneously with or after the administration of the at least one compound and/or at least one pharmaceutical salt disclosed in the present application.

"Chemotherapeutic drugs" are chemical compounds used to treat cancer, regardless of the mechanism of action. Chemotherapeutic drugs include compounds used in "targeted therapies" and conventional chemotherapy. Suitable chemotherapeutic drugs can be, for example, selected from: drugs that induce apoptosis; polynucleotides (e.g., ribozymes); polypeptides (e.g., enzymes); drugs; biological mimetics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal antibodies conjugated to anticancer drugs, toxins, and/or radionuclides; biological response modifiers (e.g., interferons, such as IFN-α, and interleukins, such as IL-2); adoptive immunotherapy agents; hematopoietic growth factors; drugs that induce tumor cell differentiation (e.g., all-trans retinoic acid); gene therapy agents; antisense therapy agents and nucleotides; tumor vaccines; and angiogenesis inhibitors.

Examples of chemotherapeutic drugs include erlotinib (Genentech/OSIPharm.); Bortezomib (Millennium Pharm.); Fulvestrant (AstraZeneca); Sunitinib (Pfizer); Letrozole (Novartis); Imatinib mesylate (Novartis); PTK787/ZK 222584 (Novartis); Oxaliplatin (Sanofi); 5-FU (5-fluorouracil); Leucovorin; Rapamycin (Sirolimus, Wyeth); Lapatinib (GSK572016, GlaxoSmithKline); Lonafarnib (SCH 66336); Sorafenib (NEXAVAR, Bayer); Irinotecan (Pfizer) and Gefitinib (AstraZeneca); AG1478, AG1571 (SU 5271, Sugen); Trametinib (GSK1120212); Selumetinib (AZD6244); Binimetinib (MEK162); Pimasertib; Alkylating agents such as thiotepa and cyclophosphamide; Alkyl sulfonates such as busulfan, improsulfan, and piposulfan; Aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethylenimine and methylamelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomelamine; acetogenins such as bullatacin and bullatacinone; camptothecins such as the synthetic analogue topotecan; bryostatin; callystatin; CC-1065 and its synthetic analogues adozelesin, carzelesin, and bizelesin; cryptophycins such as cryptophycin 1 and cryptophycin 2. 8); dolastatin; duocarmycin and its synthetic analogs, such as KW-2189 and CB1-TM1; eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitroureas such as carmustine, chlorozotocin, fotemustine fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as enediyne antibiotics (e.g., calicheamicins such as calicheamicin γ 1I and calicheamicin ω 1I (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186); anthracycline antibiotics (dynemicins such as dynemicin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores). chromophore), aclacinomysin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid acid), nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tuberculin tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azaguanosine, dapoxet ... azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; and androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenal drugs such as aminoglutethimide, mitotane, trilostane; folic acid replenishers such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazine; procarbazine; polysaccharide complex (JHS Natural Products, Eugene, Oreg.; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (such as T-2 toxin, verracurin A, roridin A, and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide (cyclophosphamide); thiotepa; taxoids, such as (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), (cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and (docetaxel; Rhone-Poulenc Rorer, Antony, France); chloranmbucil; (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine ibandronate; CPT-11; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the foregoing.

"Chemotherapeutic drugs" may also be selected, for example, from: (i) antihormonal drugs used to modulate or inhibit the effects of hormones on tumors, such as anti-estrogen drugs and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone and toremifine citrate; (ii) aromatase inhibitors that inhibit the aromatase enzyme (which regulates estrogen production in the adrenal glands), such as 4(5)-imidazole, aminoglutethimide, megestrol acetate, (exemestane; Pfizer), formestanie, fadrozole, vorozole, letrozole, and anastrozole; AstraZeneca; (iii) anti-androgen drugs, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors, such as MEK1/2 inhibitors, for example, trametinib, selumetinib, pimasertib, and GDC- 0973; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, such as antisense oligonucleotides that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, for example, PKC-α, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ) and HER2 expression inhibitors; (viii) antiretroviral protease inhibitors such as lopinavir, indinavir, nelfinavir, amprenavir, darunavir and atazanavir; (ix) vaccines such as gene therapy vaccines, for example, and rIL-2; topoisomerase 1 inhibitors such as rmRH; (x) anti-angiogenic drugs such as bevacizumab (Genentech); and (xi) pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

"Chemotherapeutic drugs" can also be selected, for example, from therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (Genentech); cetuximab (Imclone); panitumumab (Amgen), rituximab (Genentech/Biogen Idec), pertuzumab (2C4, Genentech), trastuzumab (Genentech), tositumomab (Bexxar, Corixia) and the antibody drug conjugate gemtuzumab ozogamicin (Wyeth).

The humanized monoclonal antibodies having therapeutic potential as chemotherapeutic agents and used in combination with a compound selected from the group consisting of compounds of formula (IA) and/or (IB) or (IV), their stereoisomers and pharmaceutically acceptable salts thereof can, for example, be selected from the group consisting of alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, BGB-A317, BGB-A333, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab daclizumab, eculizumab, efalizumab, elotuzumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin), inotuzumabozogamicin, ipilimumab, labetuzumab, lintuzumab, MPDl3280A, matuzumab, medi4736, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, Pembroluzimab, pertuzumab, pexelizumab, ralivizumab, ranibizumab ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tremelizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.

In a sixth aspect, the present application also provides a pharmaceutical composition comprising a compound selected from compound (IA) and/or (IB) described herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or adjuvant.

The present application also provides a composition comprising a compound selected from the compounds of formula (IA) and/or (IB) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

Although the most appropriate route in any given case will depend on the specific subject, the nature and severity of the disease to which the active ingredient is to be administered, compositions comprising a compound selected from a compound of formula (IA) and/or (IB) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof can be administered in a variety of known ways, such as oral administration, topical administration, rectal administration, parenteral administration, administration by inhalation spray or administration via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The compositions disclosed herein can conveniently be in unit dosage form and can be prepared by any method well known in the art.

The compounds selected from the compounds of formula (IA) and/or (IB), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, can be administered in solid dosage forms such as capsules, tablets, lozenges, dragees, granules, and powders, or in liquid dosage forms such as elixirs, syrups, emulsions, dispersions, and suspensions. The compounds selected from the compounds of formula (IA) and/or (IB), or stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein, can also be administered parenterally in sterile liquid dosage forms such as dispersions, suspensions, or solutions. Other dosage forms that can also be used to administer at least one compound selected from the compounds of formula (IA) and/or (IB) disclosed herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, include ointments, creams, drops, transdermal patches, or powders for topical administration; ophthalmic solutions or suspensions, i.e., eye drops, for ophthalmic administration; aerosol sprays or powder compositions for inhalation or intranasal administration; or creams, ointments, sprays, or suppositories for rectal or vaginal administration.

Gelatin capsules can also be used, which contain at least one compound disclosed herein and/or at least one pharmaceutically acceptable salt thereof and a powdered carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be prepared into sustained-release products to provide sustained-release of medicine over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect tablets from atmospheric destruction, or enteric-coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration may further comprise at least one agent selected from coloring agents and flavoring agents to increase patient acceptance.

Typically, water, suitable oil, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycol can be examples of suitable carriers for parenteral solutions. Solutions for parenteral administration can include a water-soluble salt of at least one compound described herein, at least one suitable stabilizer, and, if necessary, at least one buffer substance. Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, alone or in combination, can be examples of suitable stabilizers. Citric acid and its salts and sodium EDTA can also be used as examples of suitable stabilizers. In addition, parenteral solutions can also include at least one preservative, which is, for example, selected from benzalkonium chloride, methyl parahydroxybenzoate and ethyl parahydroxybenzoate and chlorobutanol.

Pharmaceutical carriers are, for example, selected from carriers that are compatible with the active ingredient of the composition (and, in some embodiments, capable of stabilizing the active ingredient) and are harmless to the subject to be treated. For example, solubilizers, such as cyclodextrins (which can form specific, more soluble complexes with at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein), can be used as pharmaceutical excipients for delivering the active ingredient. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

The effectiveness of a compound selected from the compounds of formula (IA) and/or (IB) disclosed herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in treating cancer can also be examined by in vivo assays. For example, at least one compound disclosed herein and/or at least one pharmaceutically acceptable salt thereof can be administered to an animal (e.g., a mouse model) suffering from cancer and a therapeutic effect thereof can be obtained. A positive result in one or more of the above tests is sufficient to increase the scientific knowledge base and thus to illustrate the practical utility of the tested compound and/or salt. Based on the results, an appropriate dosage range and route of administration for an animal (such as a human) can also be determined.

For administration by inhalation, the compounds selected from the compounds of formula (IA) and/or (IB) disclosed herein, or their stereoisomers, or their pharmaceutically acceptable salts, can be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer. The compounds selected from the compounds of formula (IA) and/or (IB) disclosed herein, or their stereoisomers, or their pharmaceutically acceptable salts, can also be delivered in the form of a powder, which can be formulated and then inhaled using an insufflation powder inhaler device. An exemplary delivery system for inhalation can be a metered dose inhalation (MDI) aerosol, which can be formulated as a suspension or solvent of the compounds selected from the compounds of formula (IA) and/or (IB) disclosed herein, or their stereoisomers, or their pharmaceutically acceptable salts, in at least one suitable propellant (e.g., selected from a fluorocarbon and a hydrocarbon).

For ocular administration, ophthalmic preparations can be formulated with a solution or suspension of a compound selected from the compounds of formula (IA) and/or (IB) disclosed herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in an appropriate weight percentage in an appropriate ophthalmic vehicle, such that the compound selected from the compounds of formula (IA) and/or (IB), its stereoisomers, and at least one pharmaceutically acceptable salt thereof disclosed herein remain in contact with the ocular surface for a sufficient period of time to allow the compound to penetrate the cornea and internal areas of the eye.

Useful pharmaceutical dosage forms for administering a compound selected from the compounds of formula (IA) and/or (IB) disclosed herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections, and oral suspensions.

The dosage will depend on a variety of factors, such as the age, health and weight of the recipient, the extent of the disease, the type of concurrent treatment, the frequency of treatment (if any), and the nature of the desired effect. In general, the daily dose of the active ingredient may vary, for example, from 0.1 to 2000 mg per day. For example, 10-500 mg once or more per day may be effective in achieving the desired result.

In some embodiments, a number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules with, for example, 100 mg of a compound selected from the compounds of formula (IA) and/or (IB), stereoisomers thereof, and pharmaceutically acceptable salts thereof disclosed herein in powder form, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate each.

In some embodiments, a mixture of at least one compound selected from the compounds of Formula (IA) and/or (IB) disclosed herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and an edible oil (such as soybean oil, cottonseed oil, or olive oil) can be prepared and then injected into gelatin using a positive displacement pump to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and then dried.

In some embodiments, various tablets can be prepared by conventional procedures such that the dosage unit comprises, for example, 100 mg of at least one compound selected from the group consisting of compounds of formula (IA) and/or (IB) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate coatings may be used to improve palatability or delay absorption.

In some embodiments, a parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of at least one compound disclosed herein and/or at least one enantiomer, diastereomer, or pharmaceutically acceptable salt thereof in 10% by volume of propylene glycol. The solution is adjusted to the desired volume with water for injection and then sterilized.

In some embodiments, an aqueous suspension for oral administration can be prepared. For example, the following aqueous suspension can be used: 100 mg of finely divided compound selected from the compound of formula (IA) and/or (IB) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, 100 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution U.S.P., and 0.025 ml of vanillin can be used per 5 ml of aqueous suspension.

When a compound selected from the group consisting of a compound of formula (IA) and/or (IB) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is administered in steps or in combination with at least one other therapeutic agent, the same dosage form is generally used. When the drugs are administered in a physical combination, the dosage form and route of administration are selected based on the compatibility of the drugs being combined. Thus, the term "co-administration" is understood to include the administration of at least two drugs simultaneously or sequentially or in the form of a fixed dose combination of at least two active ingredients.

The compounds selected from the compounds of formula (IA) and/or (IB), their stereoisomers and pharmaceutically acceptable salts thereof disclosed herein can be administered as the sole active ingredient or with at least one second active ingredient, for example, selected from other active ingredients known to be useful in treating cancer in a patient.

Example

The following examples are intended to be purely illustrative and should not be construed as limiting in any way. While every effort has been made to ensure the accuracy of the numbers/quantities used (e.g., amounts, temperatures, etc.), some experimental errors and deviations should be considered. Unless otherwise stated, temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and were used without further purification unless otherwise stated.

Unless otherwise noted, the reactions described below were carried out under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents; reaction flasks were equipped with rubber gaskets for introduction of substrates and reagents via syringe; and glassware was oven-dried and/or heat-dried.

Unless otherwise stated, column chromatography purifications were performed on a Biotage system (manufacturer: Dyax Corporation) with silica gel columns or on silica SepPak columns (Waters), or on a Teledyne Isco Combifilash purification system using prepacked silica gel columns.

^1H NMR spectra were recorded on a Varian instrument operating at 400 MHz. 1H NMR spectra were obtained using CDCl ₃ , CD ₂ Cl ₂ , CD ₃ OD, D ₂ O, d ₆ -DMSO, d ₆ -acetone, or (CD ₃ ) ₂ CO as solvents and tetramethylsilane (0.00 ppm) or residual solvent (CDCl ₃ : 7.25 ppm; CD ₃ OD: 3.31 ppm; D ₂ O: 4.79 ppm; d ₆ -DMSO: 2.50 ppm; d ₆ -acetone: ^2.05 ; (CD ₃ ) ₂ CO: 2.05) as reference standards. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Where given, coupling constants are reported in Hertz (Hz). All compound names except for reagents were generated by ChemDraw version 12.0.

In the following examples, the following abbreviations are used:

AcOH acetic acid

Aq Aqueous/aqueous solution

Brine saturated sodium chloride aqueous solution

Bn benzyl

BnBr benzyl bromide

_{CH2Cl2 dichloromethane}

DMF N,N-dimethylformamide

Dppf 1,1″-bis(diphenylphosphino)ferrocene

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DIEA or DIPEA N,N-diisopropylethylamine

DMAP 4-N,N-dimethylaminopyridine

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

EtOAc

EtOH

Et ₂ O or ether

g grams

H or hr hours

HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphorus

acid salt

HCl

HPLC high-performance liquid chromatography

IPA 2-Propanol

i-PrOH isopropyl alcohol

mg milligrams

mL milliliters

Mmol millimole

MeCN Acetonitrile

MeOH methanol

Min minutes

ms or MS mass spectrometry

Na ₂ SO ₄ sodium sulfate

PE petroleum ether

PPA polyphosphoric acid

Rt retention time

Rt or rt room temperature

TBAF Tetrabutylammonium fluoride

TBSCl tert-Butyldimethylsilyl chloride

TFA trifluoroacetic acid

THF Tetrahydrofuran

TLC thin layer chromatography

μL microliter

Example A: Synthesis of 5-substituted imidazo[1,5-a]pyridine

Example A001: Cyclohexyl(imidazo[1,5-a]pyridin-5-yl)methanol

Step 1: Ethyl 6-(hydroxymethyl)pyridine-2-carboxylate

Diethyl 2,6-pyridinedicarboxylate (27.9 g, 0.125 mol) and NaBH ₄ (3.8 g, 0.1 mol) were dissolved in anhydrous THF (250 mL) and refluxed for 2 h under moisture-proof conditions. The solvent was removed and water (50 mL) was added. After stirring for 10 min, the mixture was extracted with EA (200 mL*2). The organic phases were combined and dried over MgSO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel with PE/EA=1:1 to obtain the product as a colorless solid (28 g, 41% yield). ¹ H NMR (DMSO-d ₆ ) 8.00 (t, 1H, J = 7.6Hz), 7.91 (d, 1H, J = 7.2Hz), 7.71 (d, 1H, J = 7.6Hz), 5.56 (t, 1H , J=6.0Hz), 4.62 (d, 2H, J=6.0Hz), 4.34 (q, 2H, J=7.2Hz), 1.33 (d, 3H, J=7.2Hz).

Step 2: Ethyl 6-(chloromethyl)pyridine-2-carboxylate

Thoroughly dried ethyl 6-(hydroxymethyl)pyridine-2-carboxylate (28 g, 154 mmol) was dissolved in DCM (400 mL) and _8OCl2 (56 mL) was added dropwise at 0°C. After 90 min, the solution was allowed to return to room temperature and excess _8OCl2 was removed under reduced pressure without heating. DCM (500 mL) was added to the oily residue, and the solution was washed with saturated aqueous _NaHCO3 and dried _{over Na2SO4} . The solvent was evaporated to give ethyl 2-(chloromethyl)pyridine-6-carboxylate (31 g, 100% yield) as an orange oil. ¹ H NMR (DMSO-d ₆ ) 8.01-8.08 (m, 2H), 7.81 (d, 1H, J=7.2Hz), 4.86 (s, 2H), 4.37 (q, 2H, J=6.0Hz), 1.34 (t, 3H, J=7.2Hz).

Step 3: Ethyl 6-((1,3-dioxoisoindole-2-yl)methyl)pyridine-2-carboxylate

To a solution of ethyl 2-(chloromethyl)pyridine-6-carboxylate (59 g, 270 mmol) in anhydrous DMF (210 mL) was slowly added sodium phthalimide (54 g, 320 mmol) at room temperature and the mixture was stirred overnight. The reaction mixture was then centrifuged, the solvent removed under reduced pressure, and the residue suspended in H ₂ O (200 mL) and [EA (300 mL)] and filtered to give the crude product as a white solid (74 g, 88% yield). ¹ H NMR (DMSO-d ₆ ) δ 7.88-7.96 (m, 6H), 7.64 (dd, 1H, J=7.2 Hz), 4.98 (s, 2H), 4.24 (q, 2H, J=6.4 Hz), 1.17 (t, 3H, J=7.2 Hz).

Step 4: Ethyl 6-(aminomethyl)pyridine-2-carboxylate

To a solution of ethyl 6-((1,3-dioxoisoindol-2-yl)methyl)pyridine-2-carboxylate (80 g, 258 mmol) in EtOH (1000 mL) was added hydrazine hydrate (13 mL, 98%) at room temperature and the mixture was heated at 80° C. for 2 h. The mixture was then cooled to room temperature, the white precipitate was removed by filtration and HCOOH (400 mL) was added to the filtrate, the white precipitate was removed by filtration again and the filtrate was evaporated under reduced pressure to give a crude product as an oil containing HCOOH, which was used in the next step without further purification.

Step 5: Ethyl 6-(formylaminomethyl)pyridine-2-carboxylate

A solution of crude ethyl 6-(aminomethyl)pyridine-2-carboxylate (258 mmol) in HCOOH (500 mL) was heated at 80°C for 4 hours. The mixture was then cooled to room temperature and the solvent evaporated under reduced pressure. HCl (500 mL, 1 N) was then added to the residue. The mixture was then extracted with EA (200 mL), and the pH of the aqueous layer was adjusted to 7-8 with saturated aqueous NaOH solution. The mixture was then extracted with EA (500 mL* ₂ ). The organic layers were combined, dried over _Na2SO4 , filtered to remove _Na2SO4 , _and the solvent evaporated under reduced pressure to give the crude product as a yellow oil (23 g, 40% yield over the last two steps). The crude product was then used in the next step without further purification.

Step 6: Ethyl imidazo[1,5-a]pyridine-5-carboxylate

To a solution of ethyl 6-(formylaminomethyl)pyridine-2-carboxylate (23 g, 110 mmol) in toluene (400 mL) was added POCl ₃ (23 mL) at room temperature, and the mixture was heated at 80° C. for 2 hours. The mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. HCl (400 mL, 1 N) was added to the residue, and the mixture was extracted with EA (200 mL*2). The aqueous layer was separated, and the pH was adjusted to 7-8 with saturated aqueous NaOH solution, and then extracted with EA (400 mL*2). The organic layers were combined, and the solvent was evaporated under reduced pressure to give a crude solid (13 g, 62% yield) as a brown solid. ¹ H NMR (DMSO-d ₆ ) δ 9.13 (s, 1H), 7.98 (d, 1H, J=8.8Hz), 7.67 (s, 1H), 7.64 (dd, 1H, J=6.8Hz), 4.24 (q, 2H, J=6.4Hz), 1.39 (t, 3H, J=7.2 Hz).

Step 7: Imidazo[1,5-a]pyridin-5-ylmethanol

To a solution of ethyl imidazo[1,5-a]pyridine-5-carboxylate (36 g, 189 mmol) in EtOH (1 L) was added NaBH ₄ (14.3 g, 379 mmol) portionwise at 80° C., and the mixture was stirred at 80° C. for 1 h. The solvent was then evaporated under reduced pressure, and water (100 mL) was added to the residue, which was extracted with EA (400 mL*2). The organic layers were combined and dried over Na ₂ SO ₄ , the solid was removed by filtration, and the filtrate was evaporated under reduced pressure to give a crude product (27.9 g) which was used in the next step without further purification. ¹ H NMR (DMSO-d ₆ ) δ 8.33 (s, 1H), 7.53 (d, 1H, J=8.8Hz), 7.79-6.83 (m, 1H), 6.68 (dd, 1H, J=6.4 Hz), 5.73 (s, 1H), 4.76 (s, 2H).

Step 8: Imidazolo[1,5-a]pyridin-5-ylcarboxaldehyde

To a solution of imidazo[1,5-a]pyridin-5-ylmethanol (17 g, 115 mmol) in DCM (1 L) was added portionwise Dess-Martin (59 g, 1.2 eq) at room temperature and the mixture was stirred for 5 hours. Then saturated aqueous _NaHCO₃ was slowly added to adjust the pH to 6-7. The organic layer was separated, _H₂O (500 mL) was added, followed by concentrated HCl to adjust the pH to _2-3 . The aqueous layer was separated, and _Na₂CO₃ was added to adjust the pH to 7-8. The product was extracted with EA (500 mL*2). The organic layers were combined and the solvent was evaporated under reduced pressure to give the crude product (10 g, 60% yield). ¹ H NMR (DMSO-d ₆ ) δ 9.95 (s, 1H), 9.32 (s, 1H), 8.11 (d, 1H, J=9.2Hz), 7.78 (dd, 1H, J=6.4Hz), 7.75 (s, 1H), 7.10 (dd, 1H, J=8.8Hz).

Step 9: Cyclohexyl(imidazo[1,5-a]pyridin-5-yl)methanol

To a solution of imidazo[1,5-a]pyridine-5-carbaldehyde (1.46 g, 10 mmol) in anhydrous THF (200 mL) was added cyclohexylmagnesium chloride (10 mL, 2 M) dropwise at 0°C under _N₂ balloon protection. The mixture was then slowly stirred and warmed to room temperature for 2 hours. Water (100 mL) was added to the mixture and extracted with EA (100 mL*2). The organic layers were combined and dried over _{Na₂SO₄ .} The _Na₂SO₄ was removed by filtration, and the filtrate was concentrated. The crude product was purified by column chromatography (PE/EA = 3: ₂ as eluent) to give 1.4 g, 61% yield. ¹ H NMR (DMSO-d ₆ ) δ 8.48 (s, 1H), 7.48 (d, 1H, J=6.8Hz), 7.40 (s, 1H), 6.78 (dd, 1H, J=8.8Hz), 6.60 (d, 1H, J=6.4Hz), 5.71 (d, 1H, J=4.4Hz), 4.61 (dd, 1H, J=6.8Hz), 1.87(m, 2H), 1.70(m, 1H), 1.60(m, 2H), 1.87(m, 2H), 1.31(m, 1H), 1.11(m, 5H).

Examples A001a and A001b: (S)-cyclohexyl(imidazo[1.5-a]pyridin-5-yl)methanol and (R)- Cyclohexyl(imidazo[1,5-a]pyridin-5-yl)methanol

The individual enantiomers of racemic A001a and A001b were separated using preparative HPLC on a Chiralpak AD using 25% methanol/carbon dioxide as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak AD using 25% methanol/carbon dioxide as the eluent at a flow rate of 2.0 mL/min. The first enantiomer eluted at a retention time of 4.8 minutes, while the other enantiomer eluted at a retention time of 6.9 minutes. The spectroscopic properties of the title compound were identical to those of 1.1. Based on the assumption that the binding mode of the more potent isomer, A001a, is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A001a and A001b were tentatively assigned as (S) and (R), respectively.

Examples A002 to A008 were synthesized from imidazo[1,5-a]pyridine-5-carbaldehyde and the corresponding Grignard reagents following procedures similar to those described in Example A001.

Example A002: Cyclopentyl(imidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (DMSO-d ₆ ) δ 8.52 (s, 1H), 7.51 (d, 1H, J=9.2Hz), 7.43 (s, 1H), 6.82 (m, 1 H), 6.67 (d, 1H, J=6.4Hz), 5.75 (d, 1H, J=5.2Hz), 4.64 (dd, 1H, J=5.2Hz), 1.02-1.73 (m, 9H).

Example A003: Cyclopropyl(imidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (DMSO-d ₆ ) δ 8.52 (s, 1H), 7.55 (d, 1H, J=8.8Hz), 7.44 (s, 1H), 6.81 (m, 2 H), 5.73 (d, 1H, J=5.6Hz), 4.33 (dd, 1H, J=6.0Hz), 1.42 (m, 1H), 0.61 (m, 1H), 0.48 (m, 2H), 0.36 (m, 1H).

Example A004: 1-(Imidazolo[1,5-a]pyridin-5-yl)-2,2-dimethylpropan-1-ol

¹ H NMR (DMSO-d ₆ )δ8.68 (s, 1H), 7.46-7.48 (m, 1H), 7.37 (s, 1H), 6.78-6.81 (m, 1H), 6.59-6.61 (m, 1H), 5.73-5.74 (m, 1H), 4.81-4.82 (m, 1H), 0.93 (s, 9H). MS(ESI)m/e [M+1] ⁺ 205.

Example A005: 1-(Imidazolo[1,5-a]pyridin-5-yl)-2-methylpropan-1-ol

¹ H NMR (DMSO-d ₆ )δ8.53(s, 1H), 7.48-7.50(m, 1H), 7.41(s, 1H), 6.77-6.79(m, 1H), 6.63-6.64(m, 1H), 5.82-5.83(m, 1H), 4.65-4.68(m, 1H), 3.75-3.80(m, 2H), 3.17-3.20(m, 1H), 2.10-2.12(m, 1H), 1.68-1.72(m, 1H), 1.32-1.38(m, 1H), 1.12-1.16(m, 1H). MS(ESI)m/e [M+1] ⁺ 233.

Example A006: 1-(Imidazolo[1,5-a]pyridin-5-yl)prop-2-yn-1-ol

¹ H NMR (DMSO-d ₆ ) δ 8.45 (s, 1H), 7.60 (d, 1H, J=8.8Hz), 7.48 (s, 1H), 6.88 (m, 2H), 6.59 (d, 1H, J=6.0Hz), 5.82 (m, 1H), 3.68 (s, 1H).

Example A007: Imidazo[1,5-a]pyridin-5-yl(phenyl)methanol

¹ H NMR (DMSO-d ₆ )δ8.27 (s, 1H), 7.49-7.55 (m, 3H), 7.30-7.39 (m, 5H), 6.85 (t, 1H, J=7.2Hz), 6.69 (d, 1H, J=6.0Hz), 6.48 (d, 1H, J=4.4Hz), 6.08 (d, 1H, J=4.4Hz).

Example A008: (4-Fluorophenyl)(imidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (DMSO-d ₆ )δ8.29(s, 1H), 7.52-7.56(m, 3H), 7.41(s, 1H), 7.19(t, 2H, J=8.8Hz), 6.84( dd, 1H, J=8.8Hz), 6.66 (d, 1H, J=6.4Hz), 6.57 (m, 1H), 6.09 (d, 1H, J=4.4Hz).

Example A009: Cycloheptyl(imidazo[1,5-a]pyridin-5-yl)methanol

Under _N2 atmosphere, Mg (2.4 g, 10 mmol) and _I2 (100 mg) were suspended in THF and bromocycloheptane (1.0 mmol) was added dropwise. When the reaction was initiated, bromocycloheptane (9.0 mmol) was added dropwise below 50°C. The mixture was stirred at room temperature (RT) for 2 hours to obtain cycloheptylmagnesium bromide.

To a solution of imidazo[1,5-a]pyridine-5-carbaldehyde (146 mg, 1 mmol) in THF (20 mL) was added cycloheptylmagnesium bromide (4 mmol) dropwise at 0° C. over 10 minutes. The mixture was quenched with aqueous NH ₄ Cl (50 mL) and EA (50 mL), washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by preparative-TLC to give a yellow solid (w=20 mg). ¹ H NMR (DMSO-d ₆ ) δ8.46 (s, 1H), 7.48-7.50 (m, 1H), 7.41 (s, 1H), 6.78- 6.82 (m, 1H), 6.63-6.65 (m, 1H), 5.71-5.72 (m, 1H), 4.63-4.66 (m, 1H), 1.98-2.02 (m, 1H), 1.32- 1.79 (m, 13H). MS(ESI)m/e[M+1] ⁺ 245.

Example A010: Imidazo[1,5-a]pyridin-5-yl(tetrahydro-2H-pyran-4-yl)methanol

Example A010 was synthesized from imidazo[1,5-a]pyridine-5-carbaldehyde and 4-bromotetrahydro-2H-pyran following procedures similar to those described in Example A009. ¹ H NMR (DMSO-d ₆ ) δ 8.46 (s, 1H), 7.48-7.50 (m, 1H), 7.41 (s, 1H), 6.78-6.82 (m, 1H), 6.63-6.64 (m, 1H), 5.71-5.72 (m, 1H), 4.59-4.61 (m, 1H), 2.14-2.19 (m, 1H), 0.95 (d, 3H, J=6.4 Hz), 0.84 (d, 3H, J=6.4 Hz). MS (ESI) m/e [M+1] ⁺ 191.

Example A013: Imidazo[1,5-a]pyridin-5-yl(piperidin-4-yl)methanol hydrochloride

Step 1. tert-Butyl 4-(2-p-Tolylsulfonylhydrazono)piperidine-1-carboxylate

Tert-butyl 4-oxopiperidine-1-carboxylate (3.98 g, 20 mmol) and 4-methylbenzenesulfonylhydrazide (3.92 g, 20 mmol) were suspended in MeOH (50 mL) and the mixture was stirred at room temperature overnight. The solvent was then removed under reduced pressure to give a white solid, which was the unpurified product (W = 7.4 g). MS (ESI) m / e [M + 1] ⁺ 368

Step 2. tert-Butyl 4-(imidazo[1,5-a]pyridine-5-carbonyl)piperidine-1-carboxylate

1-(Imidazolo[1,5-a]pyridin-5-yl)-2-methylpropan-1-ol (146 mg, 1 mmol), tert-butyl 4-(2-p-tolylsulfonylhydrazono)piperidine-1-carboxylate (367 mg, 1 mmol) and Cs ₂ CO ₃ (487.5, 1.5 mmol) were suspended in 1,4-dioxane (10 mL). The mixture was refluxed for 5 hours, then quenched with EA (100 mL) and brine (50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography (eluted with EA/petroleum ether = 1:10 to 1:0) to give Example A011 (yellow oil, w = 80 mg). ¹ H NMR (DMSO-d ₆ ) δ9.42 (s, 1H), 8.05-8.08 (m, 2H), 7.69 (s, 1H), 6.98-7.01 (m, 1H), 4.00-4.04 (m, 2H), 3.74-3.77 (m, 1H), 2.93 (m, 2H), 1.81-1.84 (m, 2H), 1.38- 1.50 (m, 12H). MS(ESI)m/e[M+1] ⁺ 330

Step 3. tert-Butyl 4-(hydroxy(imidazo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(imidazo[1,5-a]pyridine-5-carbonyl)piperidine-1-carboxylate (75.80 mg, 0.23 mmol) in MeOH (5 mL) was added _NaBH4 (44 mg, 1.15 mmol), and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was purified by preparative-TLC to give Example A012 (W = 60 mg). ¹ H NMR(DMSO-d ₆ )δ 8.51(s, 1H), 7.48-7.50(m, 1H), 741(s, 1H), 6.77-6.79(m, 1H), 6.63-6.64(m, 1H), 4.66-4.69(m, 1H), 3.90-4.02(m, 2H), 2.50-2.51(m, 2H), 1.99-2.04(m, 1H), 1.75(m, 1H), 1.20-1.38(m., 12H). MS(ESI)m/e[M+1] ⁺ 332

Step 4. Imidazo[1,5-a]pyridin-5-yl(piperidin-4-yl)methanol hydrochloride

Tert-butyl 4-(hydroxy(imidazo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate (50 mg) was suspended in HCl(g)/EtOH and stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure to afford Example A013 (w=41 mg). ¹ H NMR (CD ₃ OD-d ₄ ) δ 9.69 (s, 1H), 8.09 (s, 1H), 7.08 (m, 1H), 7.17-7.29 (m, 2H), 4.8 (m, 1H), 3.28-3.31 (m, 2H), 2.87-2.95 (m, 2H), 2.18-2.33 (m, 2H), 1.63-1.67 (m., 3H). MS (ESI) m/e [M+1] ⁺ 232.

Example A014: Imidazo[1,5-a]pyridin-5-yl(1-methylpiperidin-4-yl)methanol

Imidazolo[1,5-a]pyridin-5-yl(piperidin-4-yl)methanol hydrochloride (30 mg, 0.13 mmol) and 40% aqueous HCHO solution (0.1 mL) were suspended in THF/ _Et3N (5 mL/0.1 mL), and the mixture was stirred at room temperature overnight. Sodium triacetoxyborohydride (49 mg, 0.26 mmol) was then added, and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with EA/ _H2O (50 mL/50 mL), _dried over _Na2SO4 , and concentrated. The residue was purified by preparative-TLC to give Example A014 (w = 6.0 mg). ¹ H NMR (CD ₃ OD-d ₄ )δ8.77(s, 1H), 7.48-7.49(m, 2H), 6.73-6.88(m, 2H)), 4.8(m, 1H), 3.20-3.35( m, 2H), 2.73-2.89 (m, 2H), 2.45 (s, 3H), 1.92-2.08 (m, 2H), 0.81-1.75 (m., 4H). MS(ESI)m/e[M+1] ⁺ 246.

Example A015: 5-(cyclohexylmethyl)imidazo[1,5-a]pyridine

Step 1: Imidazo[1,5-a]pyridine-5-carboxylic acid

To a solution of ethyl imidazo[1,5-a]pyridine-5-carboxylate (2.0 g, 10.5 mmol, compound from Step 6 of Example A001) in a mixture of THF (20 mL) and water (5 mL) was added lithium hydroxide hydrate (881 mg, 2 equivalents) at room temperature, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, and water (80 mL) was added to the residue. The pH was adjusted to 6-7 with HCl (4 N), and the yellow precipitate was collected by filtration to give 1.1 g, 65% yield. ^1H NMR (DMSO- _d6 ) δ 9.20 (s, 1H), 7.90 (d, 1H, J = 9.2 Hz), 7.61 (s, 1H), 7.57 (dd, 1H, J = 6.8 Hz), 6.90 (dd, 1H, J = 9.2 Hz).

Step 2: N-methoxy-N-methylimidazo[1,5-a]pyridine-5-carboxamide

To a solution of imidazo[1,5-a]pyridine-5-carboxylic acid (0.5 g, 3.1 mmol) in EA (250 mL) was added Et ₃ N (1.26 g, 4 eq), HATU (2.4 g, 2 eq) and the mixture was stirred for 15 min, then N,O-dimethylhydroxylamine (302 mg, 1 eq) was added and the mixture was stirred overnight. Water (50 mL) was added and the organic layer was separated, washed with brine (50 mL*3), dried over Na ₂ SO ₄ , filtered to remove Na ₂ SO ₄ and the filtrate was evaporated under reduced pressure to give a crude product which was used in the next step without further purification. ¹ H NMR (DMSO-d ₆ ) δ 8.35 (s, 1H), 7.71 (d, 1H, J=9.2Hz), 7.50 (s, 1H), 7.01 (dd, 1H, J=6.8Hz), 6.85 (d, 1H, J=9.2Hz), 3.62 (s, 3H), 3.38 (s, 3H).

Step 3: Cyclohexyl(imidazo[1,5-a]pyridin-5-yl)methanone

To a solution of N-methoxy-N-methylimidazo[1,5-a]pyridine-5-carboxamide (150 mg, 0.73 mmol) in anhydrous THF (20 mL) was added dropwise cyclohexylmagnesium chloride (1.5 mL, 2 M) at -70 _° C under N2 balloon protection, and the mixture was stirred for 2 hours. Water (20 mL) was then added and extracted with EA (20 mL*2). The organic layers were combined and dried over _{Na2SO4 . Na2SO4} was removed by filtration and the filtrate was _evaporated under reduced pressure to give the crude product, which was further purified by preparative-TLC (PE/EA=3:1) to give compound 4 (30 mg, 18% yield). ¹ H NMR (DMSO-d ₆ ) δ 9.44 (s, 1H), 8.00-8.05 (m, 2H), 7.68 (s, 1H), 6.97-7.00 (m, 1H), 3.53 (s, 1H), 1.69-1.86 (m, 5.5H), 1.43-1.51 (m, 4.5H).

Step 4: 5-(cyclohexylmethyl)imidazo[1,5-a]pyridine

To a solution of cyclohexyl(imidazo[1,5-a]pyridin-5-yl)methanone (30 mg, 0.13 mmol) in ethane-1,2-diol (10 mL) was added hydrazine hydrate (1 mL) and KOH (30 mg, 1.0 eq) and the mixture was heated at 130° C. for 4 hours. Water (20 mL) was then added and extracted with EA (20 mL*3), the organic layers were combined, dried over Na ₂ SO ₄ , filtered to remove Na ₂ SO ₄ and the filtrate was evaporated under reduced pressure to give a crude product, which was further purified by preparative-HPLC to give 5.06 mg, 18% yield. ¹ H NMR (DMSO-d ₆ )δ8.39 (s, 1H), 7.45 (d, 1H, J = 9.2Hz), 7.40 (s, 1H), 6.76 (dd, 1H, J = 9.2Hz), 6.4 6 (d, 1H, J=6.4Hz), 2.82 (d, 2H, J=7.2Hz), 1.62-1.81 (m, 4H), 1.02-1.23 (m, 5H).

Example A016: 1-cyclohexyl-1-(imidazo[1,5-a]pyridin-5-yl)ethan-1-ol

To a solution of cyclohexyl(imidazo[1,5-a]pyridin-5-yl)methanone (50 mg, 0.22 mmol) in anhydrous THF (15 mL) was added methyllithium (0.3 mL, 1.6 M) dropwise at -70°C, and the mixture was stirred for 15 minutes. Saturated aqueous _NH4Cl solution (15 mL) was then added, and the mixture was extracted with EA (20 mL*3). The organic layers were combined, _dried over _Na2SO4 , filtered to remove _Na2SO4 , and the _filtrate was evaporated under reduced pressure to give a crude product, which was further purified by preparative-TLC to give 4.36 mg, 8% yield. ¹ H NMR (DMSO-d ₆ ) δ 8.86 (s, 1H), 7.49 (d, 1H, J=8.8Hz), 7.43 (s, 1H), 6.78 (dd, 1H, J=8Hz), 6.57 (d, 1H, J=6.8Hz), 5.64 (s, 1H), 2.03-2.09 (m, 1H), 1.91-1.94 (m, 4H), 1.72-1.76 (m, 1H), 1.53-1.58 (m, 5H), 0.93-1.23 (m, 6H).

Examples A017 to A019 were synthesized from imidazo[1,5-a]pyridine-5-carbaldehyde and the corresponding Grignard reagents following procedures similar to those described in Example A001.

Example A017: 1-(Imidazolo[1,5-a]pyridin-5-yl)ethan-1-ol

¹ H NMR (DMSO-d ₆ ) δ8.47 (s, 1H), 7.50 (d, 1H, J = 8.8Hz), 7.43 (s, 1H), 6.81 (dd, 1H, J = 8.4Hz), 6. 67 (d, 1H, J=6.8Hz), 5.85 (d, 1H, J=5.6Hz), 5.08 (m, 1H), 1.52 (d, 3H, J=6.8Hz).

Example A018: Cyclobutyl(imidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (DMSO-d ₆ ) δ8.48 (s, 1H), 7.48 (d, 1H, J = 9.2Hz), 7.40 (s, 1H), 6.76 (dd, 1H, J = 8.8Hz), 6.5 5(d, 1H, J=6.8Hz), 5.79 (m, 1H), 4.80 (t, 1H, J=6.8Hz), 2.87-2.93 (m, 1H), 1.97- 2.06 (m, 2H), 1.78-1.87 (m, 4H).

Example A019: 1-(Imidazolo[1,5-a]pyridin-5-yl)-2-phenylethan-1-ol

¹ H NMR (DMSO-d ₆ )δ8.53(s, 1H), 7.49(d, 1H, J=9.2Hz), 7.43(s, 1H), 7.18-7.23(m, 5H), 6.75(d, 1H, J=8.8Hz), 6.59 (d, 1H, J=6.4Hz), 5.94 (s, 1H), 5.11-5.13 (m, 1H), 3.09-3.21 (m,2H).

Example A020: 7-chloro-5-((4,4-difluorocyclohexyl)fluoromethyl)imidazo[1,5-a]pyridine

To a solution of 4-((7-chloroimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)cyclohexan-1-one (30 mg, 0.1 mmol) in DCM (10 mL) was added DAST (32 mg, 2 eq) at 0°C and the mixture was stirred for 4 hours. Saturated aqueous _NaHCO₃ was then added and extracted with DCM (20 mL*3). The organic layers were combined and dried over _{Na₂SO₄ . Na₂SO₄} was removed by filtration and the _filtrate was evaporated under reduced pressure to give a crude product, which was then purified by preparative HPLC to give 4.2 mg, 14% yield. ¹ HNMR (DMSO-d ₆ ) δ8.52 (s, 1H), 7.83 (s, 1H), 7.48 (s, 1H), 6.86 (s, 1H), 5.78-5.91 (m, 1H), 2.00-2.07 (m, 4H), 1.81-1.90 (m, 2H), 1.43-1.51 (m, 3H).

Example A021: 7-chloro-5-(cyclohexylfluoromethyl)imidazo[1,5-a]pyridine

¹ H NMR (DMSO-d ₆ ) δ 8.52 (s, 1H), 7.82 (s, 1H), 7.47 (s, 1H), 6.82 (s, 1H), 5.70 (dd, 1H, J=8.0Hz), 1.90-1.92 (m, 1H), 1.73-1.76 (m.1H), 1.60-1.67 (s, 2H), 1.09-1.34 (m, 7H).

Example A022: Cyclohexyl(8-fluoroimidazo[1,5-a]pyridin-5-yl)methanol

Step 1: 6-Bromo-2-(bromomethyl ) -3-fluoropyridine

To a suspension of 6-bromo-3-fluoro-2-methylpyridine (1.9 g, 10 mmol) and N-bromosuccinimide (NBS, 1.98 g, 11.15 mmol) in CCl ₄ (40 mL) was added benzoyl peroxide (BPO, 0.12 g, 0.5 mmol). The resulting mixture was stirred under reflux for 4 hours. The mixture was cooled to room temperature. A precipitate formed and the solid was filtered. The filtrate was concentrated to give a brown solid (3 g, 100%), which was used directly in the next step without further purification. MS: M/e 270 (M+2) ⁺

Step 2: 2-((6-bromo-3-fluoropyridin-2-yl)methyl)dihydroisoindole-1,3-dione

To a solution of the product of step 1 (3 g, 10 mmol) in DMF (20 mL) was added potassium 1,3-dioxoisoindolin-2-ide (1.85 g, 10 mmol). The reaction mixture was stirred at room temperature for 1 hour. Water (40 mL) was added to the mixture, and a white precipitate formed. The solid was then filtered, washed with water (20 ml) and PE (20 mL), and dried to give the desired product (2.2 g, 65% over 2 steps) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93-7.88 (m, 2H), 7.78-7.74 (m, 2H), 7.36 (dd, J=8.4, 3.6 Hz, 1H), 7.29-7.23 (m, 1H), 5.05 (d, J=1.6 Hz, 2H). ppm.MS: M/e 335(M+1) ⁺

Step 3: (6-Bromo-3-fluoropyridin-2-yl)methylamine

To a solution of the product of step 2 (2.2 g, 6.59 mmol) in EtOH (20 mL) was added a solution of hydrazine hydrate (0.3 g, 6.59 mmol). The solution was refluxed and stirred for 3 hours. The mixture was cooled to room temperature. The solid was filtered and the filtrate was concentrated. A solution of EA/PE (20 mL/20 mL) was added to the residue. The resulting residue was filtered and the filtrate was concentrated to give the desired product (1.2 g, crude yield 89%) as a yellow oil. MS: M/e 205 (M+1) ⁺

Step 4: N-((6-bromo-3-fluoropyridin-2-yl)methyl)formamide

A solution of the product from step 3 (1.2 g, 5.88 mmol) in formic acid (10 mL) was stirred at 100°C for 56 hours. The reaction mixture was quenched with water (40 mL) and extracted with EA (40 mL x 2). The organic layer was washed with saturated aqueous _NaHCO₃ and then brine, dried _{over Na₂SO₄} , filtered, and concentrated to afford the crude product (0.7 g, 51%) as a solid, which was used directly in the next step. MS: M/e 233 (M+1) ⁺

Step 5: 5-Bromo-8-fluoroimidazo[1,5-a]pyridine

To a solution of the product of step 4 (0.7 g, 3 mmol) in toluene (10 mL) was added POCl ₃ (450 mg, 3 mmol). The mixture was stirred at 90° C. for 30 min. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO ₃ solution, and extracted with EA (30 mL x 2). The organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE:EA=3:1 to give the desired product (0.4 g, 62%) as a yellow solid. MS: M/e 215 (M+1) ⁺

Step 6: Ethyl 8-fluoroimidazo[1,5-a]pyridine-5-carboxylate

To a solution of the product from step 5 (0.3 g, 1.4 mmol) in EtOH (8 mL) and toluene (1 mL) was added TEA (0.28 g, 2.8 mmol) and Pd(dppf)Cl ₂ (0.1 g, 0.14 mmol). The resulting mixture was stirred at 100° C. under CO (approximately 0.5 MPa) for 8 hours. The resulting solution was concentrated. The residue was purified by silica gel column chromatography eluting with PE:EA = 3:1 to give the desired product (0.2 g, 69%) as a yellow solid. MS: M/e 209 (M+1) ⁺

Step 7: (8-Fluoroimidazo[1,5-a]pyridin-5-yl)methanol

To a mixture of the product of step 6 (0.2 g, 1 mmol) in EtOH (5 mL) was added NaBH ₄ (76 mg, 2 mmol). The resulting mixture was stirred at 80 ° C for 2 hours. The reaction mixture was quenched with acetone (2 mL). The resulting solution was concentrated. The residue was washed with water and extracted with EA (30 mL * 2). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated to give the desired product (160 mg, crude product) as a white solid. MS: M / e 167 (M + 1) ⁺

Step 8: 8-Fluoroimidazolo[1,5-a]pyridine-5-carbaldehyde

To the product of step 7 (160 mg, crude) was added Dess-Martin reagent (424 mg, 1 mmol) in CH ₂ Cl ₂ (10 mL). The solution was stirred at room temperature for 0.5 h. The solution was washed with water and extracted with CH ₂ Cl ₂ (30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography eluting with PE:EA = 3:1 to give the desired product (150 mg, 100%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 9.41 (d, J = 3.2 Hz, 1H), 7.90-7.85 (m, 2H), 7.04 (dd, J = 10.0, 7.6 Hz, 1H). ppm. MS: M/e 165 (M+1) ⁺

Step 9: Cyclohexyl(8-fluoroimidazo[1,5-a]pyridin-5-yl)methanol

To a solution of the product of step H (33 mg, 0.2 mmol) in THF (3 mL) was added a solution of cyclohexylmagnesium chloride in THF (0.17 mL, 1.3 mol/L). The solution was stirred at room temperature for 0.5 h. The solution was washed with water and extracted with EA (30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, then concentrated and purified by preparative TLC (EA: PE = 1: 1) to obtain the desired product (1.7 mg) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ8.63 (d, J=3.2Hz, 1H), 7.56 (s, 1H), 6.70-6.55 (m, 2H), 5.75 (d, J=4.0Hz, 1H), 4.62 (dd, J=7.2, 3.6Hz, 1H), 1.91-1.58 (m, 5H), 1.35-1.03 (m, 6H)ppm. MS：M/e 249 (M+1) ⁺

Example A023: (8-Bromoimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

Example A023 was prepared by a procedure similar to that described for Example A118, using ethyl 5-bromo-6-(hydroxymethyl)pyridine-2-carboxylate (a byproduct of Step 4 in the synthesis of Example A118) as the starting material and under appropriate conditions recognized by one of ordinary skill in the art. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 7.68 (s, 1H), 7.26 (d, J=7.2 Hz, 1H), 6.68 (d, J=7.2 Hz, 1H), 4.66 (d, J=6.8 Hz, 1H), 1.86 (m, 2H), 1.65 (m, 4H), 1.32 (d, J=8.8 Hz, 1H), 1.11 (m, 6H) ppm. MS: M/e 309/311 (M+1) ⁺ .

Example A024: (8-chloroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

Step 1: 5-chloro-6-(hydroxymethyl)pyridine-2-carbonitrile

To a stirred solution of ethyl 3-chloro-6-cyanopyridine-2-carboxylate (6 g, 28.6 mmol) in EtOH:THF=2:1 (30 mL) was added NaBH ₄ (1.13 g, 30 mmol) and stirred at room temperature under moisture-proof conditions for 1.5 h. The solvent was removed and water (50 mL) was added. After stirring for 10 min, the mixture was extracted with EA (20 ml×3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography (PE:EA=20:1-4:1) to give the product (2 g, 20%) as a yellow solid. ¹ H NMR (400 MHz, DMSO) δ 8.20 (d, J=8.2 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 4.67 (s, 2H). LC-MS (M+H) ⁺ =169

Step 2: 5-Chloro-6-(chloromethyl)pyridine-2-carbonitrile

To a stirred solution of 5-chloro-6-(hydroxymethyl)pyridine-2-carbonitrile (4.5 g, 26.6 mmol) in DCM (40 mL) at 0°C was added _SOCl₂ (6.37 g) dropwise. After 90 min, the solution was allowed to reach room temperature and the excess _SOCl₂ was removed under reduced pressure without heating. DCM (50 mL) was added to the oily residue, and the solution was washed with saturated aqueous _NaHCO₃ and dried over _Na₂SO₄ . The solvent was evaporated to give the product (5.1 g, 98%) as _an orange oil. LC-MS (M+H) ^⁺ = 187.

Step 3: 5-chloro-6-((1,3-dioxoisoindole-2-yl)methyl)pyridine-2-carbonitrile

To a mixture of 5-chloro-6-(chloromethyl)pyridine-2-carbonitrile (4.3 g, 23 mmol) in anhydrous DMF (40 mL) was slowly added sodium phthalimide (4.04 g, 21.85 mmol) at room temperature and the mixture was stirred overnight. The reaction mixture was then centrifuged, the solvent removed under reduced pressure, and the residue suspended in H ₂ O (20 mL) and EA (30 mL) and filtered to give the product (6.8 g, 86%) as a white solid. ¹ H NMR (400 MHz, DMSO) δ 8.30 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.98-7.88 (m, 4H), 5.06 (s, 2H). LC-MS (M+H) ⁺ = 298

Step 4: 6-(Aminomethyl)-5-chloropyridine-2-carbonitrile

To a solution of 5-chloro-6-((1,3-dioxoisoindol-2-yl)methyl)pyridine-2-carbonitrile (6.8 g, 23 mmol) in EtOH (40 mL) was added hydrazine hydrate (4.04 g, 98%) at room temperature and the mixture was heated at 80° C. for 2 h. The mixture was then cooled to room temperature, the white precipitate was removed by filtration, and HCOOH (100 mL) was added to the filtrate, which was again filtered to remove the white precipitate and evaporated to give the crude product as an oil containing HCOOH, which was then used in the next step without further purification. LC-MS (M+H) ⁺ = 168.

Step 5: N-((3-chloro-6-cyanopyridin-2-yl)methyl)formamide

A mixture of 6-(aminomethyl)-5-chloropyridine-2-carbonitrile (3.0 g, 17.86 mmol) in HCOOH (40 mL) was heated at 80° C. for 4 hours. The mixture was cooled to room temperature and the solvent was evaporated, and then HCl (50 mL, 1 N) was added to the residue. The pH of the aqueous layer was adjusted to 7-8 with saturated aqueous NaOH solution, and the mixture was extracted with EA (20 ml×3). The organic layers were combined, dried over Na ₂ SO ₄ , and then filtered to remove Na ₂ SO _4. The solvent was evaporated to give the crude product as a yellow oil (1.5 g). The crude product was then used in the next step without further purification. LC-MS (M+H) ⁺ = 196.

Step 6: 8-chloroimidazo[1,5-a]pyridine-5-carbonitrile

To a stirred solution of N-((3-chloro-6-cyanopyridin-2-yl)methyl)formamide (1.8 g, 9.2 mmol) in toluene (20 mL) was added _POCl₃ (28 g) at room temperature, and the mixture was heated at 80°C for 2 hours. The mixture was then cooled to room temperature and the solvent evaporated. HCl (40 mL, 1 N) was added to the residue, and the mixture was extracted with EA (20 mL x 3). The aqueous layer was separated, and the pH was adjusted to 7-8 with saturated aqueous NaOH solution, followed by extraction with EA (20 mL x 3). The organic layers were combined, and the solvent was evaporated to give the product (1.1 g, 67.9%) as a brown solid. ¹ H NMR (400 MHz, DMSO) δ 8.72 (s, 1H), 7.78 (s, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H). LC-MS (M+H) ⁺ =178.

Step 7: 8-chloroimidazo[1,5-a]pyridine-5-carboxylic acid

A mixture of compound 6 (0.2 g, 1.13 mmol) and KOH (0.19 g, 3.39 mmol) in EtOH (20 ml) was stirred at 90 ° C for 2 h. TLC (DCM: MeOH = 5: 1, R _f = 0.2) showed that the reaction was complete. Cooled to room temperature and the solvent was evaporated, and then HCl (20 mL, 1 N) was added to the residue. The pH of the aqueous layer was adjusted to 7-8, and the solvent was removed under reduced pressure to give crude compound 7 (0.3 g, 90%) as a yellow solid. The crude product was then used in the next step without further purification. LC-MS (M+H) ⁺ = 197

Step 8: 8-Chloro-N-methoxy-N-methylimidazo[1,5-a]pyridine-5-carboxamide

A stirred solution of compound 7 (0.2 g, 1.02 mmol), HOBT (0.165 g, 1.22 mmol), EDCI (0.234 g, 1.22 mmol), _Et₃N (0.2 g, 2.04 mmol), and N,O-dimethylhydroxylamine (0.12 g, 1.22 mmol) was reacted at room temperature for 4 h. TLC (PE:EA=1:1, _Rf =0.2) indicated the reaction was complete. The solvent was evaporated under reduced pressure. Saturated _NH₄Cl (20 ml) was added to the mixture, and the mixture was extracted with EA (20 ml x 3). The combined organic layers were dried _{over Na₂SO₄} , filtered, and concentrated to afford compound 8 (0.29 g, 90%) as a gray solid. LC-MS (M+H) ^⁺ = 240.

Step 9: 8-chloroimidazo[1,5-a]pyridine-5-carbaldehyde

To a stirred solution of compound 8 (0.29 g, 1.2 mmol) in EtOH (10 mL) was added _NaBH₄ (68 mg, 1.8 mmol) under moisture-proof conditions and stirred at room temperature for 2 h. The solvent was removed and water (10 mL) was added. After stirring for 10 min, the mixture was extracted with EA (20 ml x ₃ ). The combined organic layers were dried over _Na₂SO₄ , filtered, and concentrated to afford compound 9 (92 mg, 42%) as a yellow solid. LC-MS (M+H) ^⁺ = 183.

Step 10: 8-chloroimidazo[1,5-a]pyridine-5-carbaldehyde

To a solution of compound 9 (92 mg, 0.52 mmol) in DCM (10 ml) was added portionwise Dess-Martin (424 mg, 1 mmol) at room temperature and the mixture was stirred for 2 hours. Saturated aqueous _NaHCO₃ was then slowly added to adjust the pH to 6-7. The organic layer was separated, _H₂O (50 mL) was added, followed by concentrated HCl to adjust the pH to 2-3. The aqueous layer was separated, _{and Na₂CO₃} was added to adjust the pH to 7-8. The mixture was extracted with EA (10 mL×2). The organic layers were combined and the solvent was evaporated to give the product (50 mg, 50%) as a yellow solid. LC-MS (M+H) ^⁺ = 181.

Step 11: (8-chloroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

To a solution of 8-chloroimidazo[1,5-a]pyridine-5-carbaldehyde (146 mg, 1.0 mmol) in anhydrous THF (15 mL) was added phenylmagnesium chloride (1.0 mL, 2 M) dropwise at 0°C under _N2 balloon protection. The mixture was slowly stirred and warmed to room temperature for 2 hours. Water (20 mL) was added to the mixture and extracted with EA (20 mL x 3). The organic layers were combined and dried over _{Na2SO4 . Na2SO4} was removed by filtration and the filtrate _was concentrated. The crude product was purified by preparative-TLC (DCM/MeOH = 9:1 as eluent) to give 5.25 mg, 4% yield. ¹ H NMR (400MHz, CD ₃ OD) δ 8.53 (s, 1H), 7.42 (s, 2H), 6.80 (d, J = 7.2Hz, 1H), 6.51 (d, J = 7.2Hz, 1H), 4.51 (d, J = 7.8Hz, 1H), 1.96 (d, J = 12.8Hz, 1H), 1.90-1.78 (m, 1H), 1.69 (dd, J=12.9, 2.4Hz, 1H), 1.60-1.49 (m, 3H), 1.29-1.01 (m, 4H), 0.86-0.68 (m, 2H).

Example A025: 1-(8-chloroimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylethanol-1-ol

Example A025 was prepared according to the procedure described for Example A024 using 8-chloroimidazo[1,5-a]pyridine-5-carbaldehyde and (cyclohexylmethyl)magnesium chloride as starting materials under appropriate conditions recognized by one of ordinary skill in the art. ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.45 (d, J = 0.8 Hz, 1H), 7.43 (d, J = 0.8 Hz, 1H), 6.32 (d, J = 7.2 Hz, 1H), 6.57 (d, J = 7.2 Hz, 1H), 4.95 (dd, J = 8.8, 4.8 Hz, 1H), 1.38-1.62 (m, 7H), 1.09-1.21 (m, 4H), 0.89-0.96 (m, 2H). MS: M/e 309/311(M+1) ⁺ .

Example A026: 7-chloro-5-(cyclohexylmethyl)imidazo[1,5-a]pyridine

Step 1: 7-chloroimidazo[1,5-a]pyridine-5-carboxylic acid

To a solution of ethyl 7-chloroimidazo[1,5-a]pyridine-5-carboxylate (0.5 g, 2.2 mmol) in a mixture of THF (15 mL) and water (5 mL) was added lithium hydroxide hydrate (370 mg, 4 equivalents) at room temperature and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, water (10 mL) was added to the residue, the pH was adjusted to 6-7 with HCl (4 N), and the yellow precipitate was collected by filtration to give 256 mg, 59% yield. [M+H] ⁺ = 197.

Step 2: 7-Chloro-N-methoxy-N-methylimidazo[1,5-a]pyridine-5-carboxamide

To a solution of 7-chloroimidazo[1,5-a]pyridine-5-carboxylic acid (256 mg, 1.3 mmol) in DMF (15 mL) was added _Et₃N (265 mg, 2 eq) and HATU (494 mg, 1 eq) and the mixture was stirred for 15 minutes. N,O-dimethylhydroxylamine (127 mg, 1 eq) was then added and the mixture was stirred overnight. Water (35 mL) was added and the organic layer was separated, washed with brine (20 mL* ₃ ), dried over _Na₂SO₄ , filtered to remove _{Na₂SO₄ ,} and the filtrate was evaporated under reduced pressure to give a crude product that was used in the next step without further purification. [M+H] ^⁺ = 240.

Step 3: (7-chloroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanone

To a solution of 7 _- chloro-N-methoxy-N-methylimidazo[1,5-a]pyridine-5-carboxamide (311 mg, 1.3 mmol) in anhydrous THF (20 mL) was added cyclohexylmagnesium chloride (2.6 mL, 2 M) dropwise at -70°C under N2 balloon protection, and the mixture was stirred for 2 hours. Water (20 mL) was then added and extracted with EA (20 mL*2). The organic layers were combined and dried over _{Na2SO4 . Na2SO4} was removed by filtration, and the filtrate was _evaporated under reduced pressure to give a crude product, which was further purified by preparative-TLC (PE/EA=1:1) to give 30 mg, 18% yield. [M+H] ⁺ = 263.

Step 4: 7-chloro-5-(cyclohexylmethyl)imidazo[1,5-a]pyridine

To a solution of (7-chloroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanone (30 mg, 0.13 mmol) in ethane-1,2-diol (10 mL) was added hydrazine hydrate (1 mL) and KOH (30 mg, 1.0 eq) and the mixture was heated at 130° C. for 4 hours. Water (20 mL) was then added and extracted with EA (20 mL*3), the organic layers were combined, dried over Na ₂ SO ₄ , filtered to remove Na ₂ SO ₄ and the filtrate was evaporated under reduced pressure to give a crude product, which was further purified by preparative-HPLC to give 4.6 mg, 18% yield. ¹ H NMR (DMSO-d ₆ ) δ 8.46 (s, 1H), 7.64 (d, 1H, J=2.0Hz), 7.39 (s, 1H), 6.55 (d, 1H, J=2.0Hz), 2.84 (d, 2H, J=7.2Hz), 1.78-1.79 (m, 1H), 1.62-1.81 (m, 5H), 1.02-1.23 (m, 5H).

Example A101: (7-chloroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

Step 1: Ethyl 4-chloro-6-(hydroxymethyl)pyridine-2-carboxylate

To diethyl 4-chloropyridine-2,6-dicarboxylate (32 g, 123 mmol) and NaBH ₄ (2.4 g, 62 mmol) was added EtOH (100 mL) and refluxed under moisture-proof conditions for 2 h. The solvent was removed and water (100 mL) was added. After stirring for 10 min, the mixture was extracted with EA (100 mL*3). The organic phases were combined and dried over Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel with PE/EA=1:1 to obtain the product as a white solid (11 g, 41% yield).

Step 2: Ethyl 4-chloro-6-(chloromethyl)pyridine-2-carboxylate

To a solution of ethyl 4-chloro-6-(hydroxymethyl)pyridine-2-carboxylate (11 g, 51 mmol) in DCM (80 mL) was added SOCl₂ ₍ 11 mL ₎ dropwise at room temperature. After 3 h, the solution was allowed to reach room temperature and the excess SOCl₂ was removed under reduced pressure without heating. The pH was adjusted to >7 with saturated aqueous _NaHCO₃ and extracted with EtOAc (100 mL x ₂ ). The organic layer was dried over _Na₂SO₄ . The solvent was evaporated to afford ethyl 2-(chloromethyl)pyridine-6-carboxylate (12.3 g) as a brown oil, which was used in the next step without further purification. MS (ESI) m/e[M+1] ^⁺ 234.

Step 3: Ethyl 4-chloro-6-((1,3-dioxoisoindol-2-yl)methyl)pyridine-2-carboxylate

To a solution of ethyl 4-chloro-6-(chloromethyl)pyridine-2-carboxylate (12.3 g, 53 mmol) in DMF (80 mL) was slowly added sodium phthalimide (12 g, 63.6 mmol) at room temperature and the mixture was stirred overnight. The solid was filtered and washed with H ₂ O (200 mL). The residual solid was suspended in Et ₂ O, filtered and dried in vacuo to give the product (10 g, 56%) as a white solid. ¹ H NMR (CDCl ₃ ) δ7.99 (d, J=1.6Hz, 1H), 7.9-7.94 (m, 2H), 7.76- 7.81 (m, 2H), 7.34 (d, J=1.6Hz), 5.11 (s, 2H), 4.42 (q, J=7.2Hz, 2H), 1.34 (t, J=7.2Hz, 3H). MS(ESI)m/e[M+1] ⁺ 345.

Step 4: Ethyl 6-(aminomethyl)-4-chloropyridine-2-carboxylate

To a solution of ethyl 4-chloro-6-((1,3-dioxoisoindol-2-yl)methyl)pyridine-2-carboxylate (10 g, 29 mmol) in EtOH (60 mL) was added hydrazine hydrate (1.5 g, 29 mmol) at room temperature and the mixture was heated at 90° C. for 2 h. The mixture was then cooled to room temperature, the white precipitate was removed by filtration, and HCOOH (70 mL) was added to the filtrate, which was again removed by filtration and evaporated to give a crude product (9 g) containing HCOOH as a brown oil, which was used in the next step without further purification. MS (ESI) m/e[M+1] ⁺ 215.

Step 5: Ethyl 4-chloro-6-(formylaminomethyl)pyridine-2-carboxylate

A solution of ethyl 6-(aminomethyl)-4-chloropyridine-2-carboxylate (9 g, 42 mmol) in HCOOH (100 mL) was heated at 90° C. for 2 hours. The mixture was cooled to room temperature and the solvent was evaporated, and then HCl (500 mL, 1 mmol/mL) was added to the residue. It was then extracted with EA (80 mL*3). The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated to give a mixture of solid and liquid. EtOAc (30 ml) was added to the mixture, the solid was filtered, and the filtrate was concentrated to give the product (4.7 g, 47%) as a brown liquid, which was used in the next step without further purification.

Step 6: Ethyl 7-chloroimidazo[1,5-a]pyridine-5-carboxylate

To a solution of ethyl 4-chloro-6-(formylaminomethyl)pyridine-2-carboxylate (4.7 g, 19.3 mmol) in toluene (30 mL) was added _POCl₃ (4.7 mL) at room temperature, and the mixture was heated at 80°C for 2 hours. The mixture was then cooled to room temperature and the solvent evaporated. HCl (10 mL, con.) and _H₂O (20 mL) were then added to the residue, followed by extraction with EA (50 mL*2). The aqueous layer was separated, adjusted to pH 7-8 with saturated aqueous NaOH, and then extracted with EA (100*2). The organic layers were combined and the solvent evaporated to give a crude solid, which was further purified by silica gel (100 g) column chromatography eluting with EtOAc (500 mL) to give the product (2.25 g, 52%) as a yellow solid. MS (ESI) m/e [M+1] ^⁺ 225.

Step 7: (7-chloroimidazo[1,5-a]pyridin-5-yl)methanol

To a solution of ethyl 7-chloroimidazo[1,5-a]pyridine-5-carboxylate (2.25 g, 10 mmol) in EtOH (50 mL) was added portionwise _NaBH₄ (0.5 g, 12 mmol) at room temperature and the mixture was stirred at 90°C for 2 h. The solvent was then evaporated and _H₂O (100 mL) was added to the residue. The solid was filtered and dried to give the product (2.1 g, 117%) as a yellow solid, which was used in the next step without further purification. MS (ESI) m/e [M+1] ⁺ 183.

Step 8: 7-chloroimidazo[1,5-a]pyridine-5-carbaldehyde

To a solution of imidazo[1,5-a]pyridin-5-ylmethanol (2 g, 11 mmol) in DCM (60 mL) and THF (40 mL) was added portionwise Dess-Martin (9.3 g, 22 mmol) at room temperature, and the mixture was stirred overnight. _H₂O (30 mL) and HCl (6 mL) were added to the resulting mixture. The aqueous layer was extracted with EtOAc (20 mL*2) and the pH was adjusted to > ₈ with _Na₂CO₃ . The aqueous layer was extracted with EtOAc (50 mL*3). The organic layer was dried _{over Na₂SO₄} , filtered, and concentrated to afford the product (770 mg, 39%) as a brown solid, which was used in the next step without further purification. MS (ESI) m/e [M+1] ⁺ 181.

Step 9: (7-chloroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

To a solution of 7-chloroimidazo[1,5-a]pyridine-5-carbaldehyde in anhydrous THF (15 mL) was added cyclohexylmagnesium chloride (1.3 mL, 1.3 M) dropwise at 0°C under _N2 balloon protection. The mixture was then slowly warmed to room temperature and maintained for 30 minutes. Water (10 mL) was added to the mixture and extracted with EA (20 mL*2). The organic layers were combined and dried over _{Na2SO4 . Na2SO4} was removed by filtration and the filtrate _was concentrated. The crude product was purified by preparative HPLC (PE/EA = 1:1 as eluent) to give the compound of Example A101 (Compound 2.1) (18 mg, 12% yield). ¹ H NMR (DMSO-d ₆ ) δ8.53 (s, 1H), 7.67 (s, 1H), 7.40 (s, 1H), 6.64 (s, 1H), 5.85 (d, 1H, J=4.0Hz), 4.65-4.68 (m, 1H), 3.07-3.10 (m, 3H), 1.57-1.83 (m, 5H) and 1.11-1.40 (m, 2H). MS(ESI)m/e[M+1] ⁺ 265.

Examples A101a and A101b: (S)-(7-chloroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol and (R)-(7-chloroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

Each enantiomer of racemic A101a and A101b was separated using preparative HPLC on a Chiralpak IC using 25% methanol/carbon dioxide as eluent. Enantiomeric excess was determined using HPLC on a Chiralpak AD using 25% methanol/carbon dioxide as eluent at a flow rate of 2.0 mL/min. The first enantiomer eluted at a retention time of 4.1 min, while the other enantiomer eluted at a retention time of 6.2 min. The spectral properties of the title compound were identical to those of A101.

Based on its co-crystal structure with IDO1 enzyme, the absolute stereochemistry of the more potent isomer A101a in both enzymatic and cellular assays was assigned to the (S)-configuration at the chiral α-carbon.

A101a/IDO1 eutectic

Example A102: 1-(7-chloroimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylethanol-1-ol

Example A012 was synthesized from 7-chloroimidazo[1,5-a]pyridine-5-carbaldehyde and (cyclohexylmethyl)magnesium bromide as described in Example A101. ^1H NMR (DMSO- _d6 ) δ 8.42 (s, 1H), 7.68 (d, 1H, J = 2.0 Hz), 7.41 (s, 1H), 6.67 (s, 1H), 5.96 (d, 1H, J = 3.2 Hz), 4.97-5.02 (m, 1H), 1.87-1.90 (m, 1H), 1.55-1.73 (m, 7H), 1.11-1.23 (m, 3H), 0.91-0.99 (m, 2H).

Examples A102a and A102b: (S)-1-(7-chloroimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylethanol-1-ol Compound and (R)-1-(7-chloroimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylethanol-1-ol

The individual enantiomers of racemic A102a and A102b were separated using preparative HPLC on a Chiralpak AD using 100% methanol as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak AD using 100% methanol as the eluent at a flow rate of 2.0 mL/min. The first enantiomer eluted at a retention time of 3.15 min, while the other enantiomer eluted at a retention time of 4.85 min. The spectroscopic properties of the title compound were identical to those of A102. Based on the assumption that the binding mode of the more potent isomer, A102a, is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A102a and A102b were tentatively assigned as (S) and (R), respectively.

Example A103: (7-chloroimidazo[1,5-a]pyridin-5-yl)(cyclopentyl)methanol

Example A103 was synthesized from 7-chloroimidazo[1,5-a]pyridine-5-carbaldehyde and cyclopentylmagnesium bromide as described in Example A101. ^1H NMR (DMSO-d ₆ ) δ 8.55 (s, 1H), 7.67 (s, 1H), 7.40 (s, 1H), 6.68 (s, 1H), 5.88 (d, 1H, J=5.2 Hz), 4.68-4.72 (m, 1H), 3.30 (s, 1H), 2.45-2.51 (m, 1H), and 1.15-1.68 (m, 7H). MS (ESI) m/e [M+1] ⁺ 251.

Example A104: (7-chloroimidazo[1,5-a]pyridin-5-yl)(4-methylcyclohexyl)methanol

Step 1: 4-Methyl-N′-(4-methylcyclohexylidene)benzenesulfonylhydrazide

To a solution of 4-methylcyclohexan-1-one (2.0 g, 17.85 mmol) in MeOH (10 mL) was added 4-methylbenzenesulfonylhydrazide (3.32 g, 17.85 mmol) at room temperature and the mixture was stirred overnight. After concentration to dryness, 5 mL of MeOH was added to the crude product and sonicated for 5 minutes. Some white solid separated, which was filtered and concentrated to dryness to give 2.99 g of a white solid, 60.69% yield. ¹ H NMR (CDCl ₃ ) δ7.85 (d, 2H, J=8.0Hz), 7.44 (s, 1H, NH), 7.30 (d, 2H, J = 8.0Hz), 2.64 (m, 1H), 2.42 (m, 4H), 2.11 (m, 1H), 1.83 (m, 3H), 1.62 (m, 1H), 1.12 (m, 1H), 0.92 (d, 2H, J = 8.0Hz).

Step 2: (7-chloroimidazo[1,5-a]pyridin-5-yl)(4-methylcyclohexyl)methanone

To a solution of (E)-N′-(dihydro-2H-pyran-3(4H)-ylidene)-4-methylbenzenesulfonylhydrazide (181 mg, 1.00 mmol) in 1,4-dioxane (15 mL) was added 4-methyl-N′-(4-methylcyclohexylidene)benzenesulfonylhydrazide (276 mg, 1.00 mmol) and Cs ₂ CO ₃ (487 mg, 1.50 mmol) at room temperature, and the mixture was stirred at 110° C. under N 2 balloon protection overnight. After concentration to dryness, 20 mL of water was added to the crude product and extracted with EA (20 mL*3). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by preparative-TLC (DCM/MeOH=15:1 as eluent) to give 56 mg, 20.2% yield. ESI-MS m/z 277.1 ([M+H] ⁺ ).

Step 3: (7-chloroimidazo[1,5-a]pyridin-5-yl)(4-methylcyclohexyl)methanol

To a solution of (7-chloroimidazo[1,5-a]pyridin-5-yl)(4-methylcyclohexyl)methanone (56 mg, 0.2 mmol) in MeOH (5 mL) was added NaBH ₄ (15 mg, 0.4 mmol) at room temperature, and the mixture was sonicated for 5 minutes. After quenching with water (0.5 mL) and concentrating to dryness, the crude product was purified by preparative-TLC (EA/PE=1:1 as eluent) to give 9.78 mg of a light yellow solid in a 17.6% yield. ¹ H NMR (DMSO-d ₆ ) δ8.53 (s, 1H), 7.67 (d, 1H, J=1.6Hz), 7.40 (s, 1H), 6.63 (d, 1H, J=1.6Hz), 5.85 (d, 1H, J=1.6Hz), 4.67 (m, 1H), 1.59-1.84 (m, 4H), 1.12-1.34 (m, 4H), 0.81-0.94 (m, 5H).

Example A105: 3-chloro-N-(3-((7-chloroimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)cyclohexyl) Benzamide

Step 1: Synthesis of tert-butyl (E)-(3-(2-p-tolylsulfonylhydrazono)cyclohexyl)carbamate

To a solution of tert-butyl (3-oxocyclohexyl)carbamate (8.4 g, 39 mmol) in MeOH (50 mL) was added 4-methylbenzenesulfonylhydrazide (7.3 g, 39 mmol). The mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was removed in vacuo to give the product (15.7 g, 100%) as a white solid, which was used in the next step without further purification.

Step 2: Synthesis of tert-butyl (3-(7-chloroimidazo[1,5-a]pyridine-5-carbonyl)cyclohexyl)carbamate

To a solution of 7-chloroimidazo[1,5-a]pyridine-5-carbaldehyde (1.5 g, 8.2 mmol) in 1,4- _dioxane (50 mL) were added _CsCO (5.3 g, 16.4 mmol) and tert-butyl (E)-(3-(2-p-tolylsulfonylhydrazono)cyclohexyl)carbamate (6.2 g, 16.4 mmol). The mixture was stirred at 110°C under _N2 overnight. The solid was filtered and the filtrate was concentrated to dryness to give the crude product, which was further purified by column chromatography on silica gel (100 g) eluting with EA:PE = 1:1 to give the product (1.2 g, 39%) as a brown oil. MS (ESI) m/e [M+1] ⁺ 378.

Step 3: Synthesis of 3-chloro-N-(3-(7-chloroimidazo[1,5-a]pyridine-5-carbonyl)cyclohexyl)-benzamide

To a solution of tert-butyl (3-(7-chloroimidazo[1,5-a]pyridine-5-carbonyl)cyclohexyl)-carbamate (500 mg, 1.3 mmol) in DCM (50 ml) was added _CF3COOH (3 ml). The mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated to give (3-aminocyclohexyl)(7-chloroimidazo[1,5-a]pyridin-5-yl)methanone, which was used in the next step without further purification.

To a solution of (3-aminocyclohexyl)(7-chloroimidazo[1,5-a]pyridin-5-yl)methanone in THF (30 ml) was added _Et₃N (3 ml) and 3-chlorobenzoyl chloride (0.2 ml). The mixture was stirred at room temperature for 5 h. After completion of the reaction, _NaHCO₃ (saturated, 20 ml) was added to the mixture and extracted with EtOAc (50 ml x 3). The organic layer was dried _{over Na₂SO₄} , filtered, and concentrated to give the product (500 mg, 92%) as a brown oil, which was used in the next step without further purification. MS (ESI) m/e [M+1] ⁺ 416.

Step 4: 3-Chloro-N-(3-((7-chloroimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)-cyclohexyl)benzene Synthesis of amides

To a solution of 3-chloro-N-(3-(7-chloroimidazo[1,5-a]pyridine-5-carbonyl)cyclohexyl)-benzamide (500 mg, 1.2 mmol) in EtOH (30 ml) was added NaBH ₄ (91 mg, 2.4 mmol). The mixture was stirred at room temperature for 30 min. The mixture was concentrated and H ₂ O (30 ml) was added to the residue and extracted with EA (30 ml×3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified by preparative HPLC to give the product (3 mg, 0.6%) as a white solid. ¹ H NMR (DMSO-d ₆ )δ8.71(s, 1H), 8.37-8.42(m, 1H), 7.71-7.88(m, 3H), 7.46-7.60(m, 3H) , 6.72(s, 1H), 5.98(s, 1H), 4.74-4.84(m, 2H), 3.76-3.79(m, 2H), 1.94- 2.03 (m, 3H), and 1.31-1.78 (m, 4H). MS(ESI)m/e[M+1] ⁺ 418.

Example A106: (7-chloroimidazo[1,5-a]pyridin-5-yl)(1-(hydroxymethyl)cyclohexyl)methanol

To a solution of ethyl 1-((7-chloroimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)cyclohexane-1-carboxylate (50 mg, 0.15 mmol) in diethyl ether (5 mL) was added lithium aluminum hydride (11 mg, 0.3 mmol) and the mixture was stirred at room temperature for 24 hours. After the reaction mixture was concentrated to dryness, 20 mL of water was added to the crude product and extracted with EA (20 mL * 3), the aqueous layer was concentrated to dryness, and the crude product was purified by preparative-TLC (EA/PE=1:1 as eluent) to give 5 mg, 11.3% yield. ¹ HNMR (DMSO-d ₆ ) δ 8.68 (s, 1H), 7.54 (d, 1H, J=1.6Hz), 7.36 (d, 1H, J=0.4Hz), 6.68 (d, 1H, J=1.6Hz), 5.10 (s, 1H), 4.84 (s, 1H), 3.83 (d, 1H, J=11.2Hz), 3.58 (d, 1H, J=11.2Hz), 1.0-1.71 (m, 10H).

Example A107: Cyclohexyl(7-iodoimidazo[1,5-a]pyridin-5-yl)methanol 2,2,2-trifluoroacetate

¹ H NMR (DMSO-d ₆ ) δ 9.08 (s, 1H), 8.17 (s, 1H), 7.71 (s, 1H), 7.04 (s, 1H), 4.67 (m, 1H), 4.40 (s, 1H), 1.60-1.82 (m, 5H), 1.10-1.31 (m, 6H). MS(ESI)m/e[M+1] ⁺ 357.

Example A108: Cyclohexyl(7-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol 2,2,2-trifluoroacetate

Step 1: Ethyl 7-cyclopropylimidazo[1,5-a]pyridine-5-carboxylate

Ethyl 7-iodoimidazo[1,5-a]pyridine-5-carboxylate (948 mg, 3 mmol), cyclopropylboronic acid (387 mg, 5 mmol), 4,5-bis-diphenylphosphino-9,9-dimethyl-9H-xanthene (174 mg, 0.3 mmol), tris(dibenzylideneacetone)dipalladium (275 mg, 0.3 mmol), and _{K2CO3 (} 1251 mg, 9.0 mmol) were suspended in toluene (50 mL). The mixture was heated to 110°C under an _N2 atmosphere for 5 hours. The mixture was quenched with _H2O (150 mL) and EA (150 mL), washed with brine (150 _mL ), dried over _Na2SO4 , and concentrated. The residue was purified by silica gel chromatography (eluted with EA/petroleum ether = 1:5-1:1) to give a yellow solid (w = 600 mg). MS (ESI) m/e [M+1] ⁺ 231.

Step 2: (7-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol

At room temperature, ethyl 7-cyclopropylimidazo[1,5-a]pyridine-5-carboxylate (400 mg, 1.74 mmol) was suspended in EtOH (20 mL), and then NaBH ₄ (198 mg, 5.22 mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was quenched with EA (100 mL) and H ₂ O (100 mL), and the organic layer was washed with brine (100 mL), dried over Na ₂ SO ₄ , and concentrated. The residue was purified by silica gel chromatography (eluted with EA/petroleum ether = 1:5-1:0) to give a yellow oil (w = 280 mg). MS (ESI) m/e [M+1] ⁺ 189

Step 3: 7-cyclopropylimidazo[1,5-a]pyridine-5-carbaldehyde

To a solution of (7-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol (140 mg, 0.76 mmol) in DCM (10 mL) was added Dess-Martin reagent (647 mg, 1.53 mmol) at room temperature. The mixture was stirred at room temperature for 4 hours. The mixture was quenched with EA (100 mL) and _H₂O (50 mL), and the organic layer was washed with brine (100 _mL ), dried over _Na₂SO₄ , and concentrated. The residue was purified by silica gel chromatography (eluting with EA/petroleum ether = 1:10 to 1:1) to give a yellow solid (w = 60 mg). MS (ESI) m/e [M+1] ⁺ 187.

Step 4: Cyclohexyl(7-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol 2,2,2-trifluoroacetate

To a solution of 7-cyclopropylimidazo[1,5-a]pyridine-5-carbaldehyde (60 mg, 0.32 mmol) in THF (6 mL) was added cyclohexylmagnesium chloride (0.5 mmol, 1.3 N in toluene) dropwise under _N₂ atmosphere at room temperature over 0.5 h. The mixture was stirred at room temperature for 0.5 h. The mixture was quenched with aqueous _NH₄Cl (50 mL) and EA (50 mL), washed with brine (50 mL), _dried over _Na₂SO₄ , and concentrated. The residue was purified by preparative HPLC to give a white solid (W = 3.0 mg). ¹ H NMR (DMSO-d ₆ ) δ 9.50 (s, 1H), 7.81 (s, 1H), 7.42 (s, 1H), 6.80 (s, 1H), 4.67 (m, 1H), 4.40 (s, 1H), 1.67-2.01 (m, 5H), 0.81-0.88 (m, 10H). MS(ESI)m/e[M+1] ⁺ 271.

Example A109: Cyclohexyl(7-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)methanol

Step 1: Synthesis of diethyl 4-iodopyridine-2,6-dicarboxylate

To a solution of diethyl 4-chloropyridine-2,6-dicarboxylate (70 g, 266 mmol) in CH ₃ CN (570 mL) was added acetyl chloride (56 mL) and NaI (280 g, 1862 mmol) at room temperature. The mixture was then stirred at 65° C. overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was adjusted to pH >7 by addition of Na ₂ CO ₃ (aq.) and extracted with EtOAc (500 mL*3). The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated to give the crude product, which was further purified by column chromatography eluting with EA:PE = 1:1 to give the product (59.5 g, 64%) as a brown solid. ¹ H NMR (DMSO-d ₆ ) δ 8.56 (s, 2H), 4.40 (q, 4H, J = 7.2 Hz), 1.35 (t, 6H, J = 7.2 Hz). MS (ESI) m/e [M+1] ⁺ 350.

Step 2: Synthesis of diethyl 4-(trifluoromethyl)pyridine-2,6-dicarboxylate

To a solution of diethyl 4-iodopyridine-2,6-dicarboxylate (6.5 g, 19 mmol) in DMF (50 mL) _was added Cu (7.3 g, 38 mmol), Pd(dppf) _Cl₂ (0.7 g, 0.95 mmol), and _{FSO₂CF₂CO₂CH₃} (9.1 _g , 47.5 mmol). The mixture was stirred at 100° C. under _N₂ overnight. The solid was filtered and the filtrate was poured into _H₂O (150 mL) and extracted with EtOAc (50 _mL *3). _The organic layer was dried over _Na₂SO₄ , filtered, and concentrated to give the crude product, which was further purified by column chromatography eluting with EA:PE=1:1 to give the product (2.8 g, 51%) as a brown solid.

Step 3: Synthesis of ethyl 6-(hydroxymethyl)-4-(trifluoromethyl)pyridine-2-carboxylate

To a solution of diethyl 4-(trifluoromethyl)pyridine-2,6-dicarboxylate (2.8 g, 9.6 mmol) in EtOH (20 mL) was added _NaBH₄ (182 mg, 4.8 mmol). The mixture was stirred at 90°C for 1 h. The solvent was removed in vacuo. _H₂O (50 mL) was added to the residue and extracted with EtOAc (50 _mL *3). The organic layer was dried over _Na₂SO₄ , filtered, and concentrated to afford the product (1.6 g, 67%) as a brown solid, which was used in the next step without further purification.

Step 4: Synthesis of ethyl 6-(chloromethyl)-4-(trifluoromethyl)pyridine-2-carboxylate

To a solution of ethyl 6-(hydroxymethyl)-4-(trifluoromethyl)pyridine-2-carboxylate (1.6 g, 6.4 mmol) in DCM (20 mL) was added SOCl₂ ( ₂ mL) dropwise at room temperature. After 3 h at room temperature, the excess _SOCl₂ was removed under reduced pressure without heating. The residue was adjusted to pH > 7 with saturated aqueous _NaHCO₃ and extracted with EtOAc (30 mL x 2). The organic layer was dried over _Na₂SO₄ . The solvent was evaporated to afford ethyl _6- (chloromethyl)-4-(trifluoromethyl)pyridine-2-carboxylate (1.8 g), which was used in the next step without further purification.

Step 5: Ethyl 6-((1,3-dioxoisoindol-2-yl)methyl)-4-(trifluoromethyl)pyridine-2-carboxylate

To a solution of ethyl 6-(chloromethyl)-4-(trifluoromethyl)pyridine-2-carboxylate (1.8 g, 6.7 mmol) in DMF (30 mL) was added sodium phthalimide (1.5 g, 8.04 mmol) at room temperature, and the mixture was stirred at room temperature overnight. The solid was then filtered, and the filtrate was poured into water (50 mL) and extracted with EtOAc (50 mL*3). The organic layer was purified by silica gel column chromatography eluting with EA:PE = 1:1 to give the product (1.4 g). MS (ESI) m/e [M+1] ⁺ 379.

Steps 6 and 7: Ethyl 6-(formylaminomethyl)-4-(trifluoromethyl)pyridine-2-carboxylate

To a solution of ethyl 6-((1,3-dioxoisoindol-2-yl)methyl)-4-(trifluoromethyl)pyridine-2-carboxylate (1.4 g, 3.7 mmol) in EtOH (80 mL) was added hydrazine hydrate (222 mg). The mixture was stirred at 90° C. for 3.5 h. It was then cooled to room temperature, the white precipitate was filtered off, and HCOOH (20 mL) was added to the filtrate, which was filtered again and evaporated to give a crude product containing HCOOH as a brown oil. The crude product, ethyl 6-(aminomethyl)-4-(trifluoromethyl)pyridine-2-carboxylate, was used in the next step without further purification. The crude product, ethyl 6-(aminomethyl)-4-(trifluoromethyl)pyridine-2-carboxylate, was dissolved in HCOOH (60 mL) and Ac ₂ O (20 mL) and stirred at 50° C. for 2 h. After cooling to room temperature and evaporating the solvent, HCl (30 mL, 0.5 N) was added to the residue. Extraction was then performed with EA (30 mL x 3). The organic layer was dried _{over Na₂SO₄} , filtered, and concentrated to afford the product (880 mg, 86% over two steps), which was used in the next step without further purification. MS (ESI) m/e [M+1] ^⁺ 277.

Step 8: Ethyl 7-(trifluoromethyl)imidazo[1,5-a]pyridine-5-carboxylate

To a solution of ethyl 6-(formamidomethyl)-4-(trifluoromethyl)pyridine-2-carboxylate (0.88 g, 3.2 mmol) in toluene (30 mL) was added _POCl₃ (1.5 mL) at room temperature, and the mixture was heated at 80°C for 2 hours. The mixture was then cooled to room temperature and the solvent evaporated. HCl (5 mL, con.) and _H₂O (20 mL) were then added to the residue, followed by extraction with EA (20 mL*2). The aqueous layer was separated, adjusted to pH 7-8 with saturated aqueous NaOH, and then extracted with EA (100 mL*2). The organic layers were combined, and the solvent evaporated to give the product (480 mg, 58%) as a brown oil. MS (ESI) m/e [M+1] ^⁺ 259.

Step 9: (7-(Trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)methanol

To a solution of ethyl 7-(trifluoromethyl)imidazo[1,5-a]pyridine-5-carboxylate (480 mg, 1.9 mmol) in EtOH (50 mL) was added _NaBH₄ (144 mg, 3.8 mmol) in portions at room temperature, and the mixture was stirred at 90°C for 2 h. The solvent was removed in vacuo. _H₂O (20 mL) and HCl (37%, 5 mL) were added to the residue, followed by extraction with EtOAc (30 _mL *2). The aqueous layer was adjusted to pH > 8 with _Na₂CO₃ (solid) and extracted with EtOAc ( ₃₀ mL*3). The organic layer was dried over _Na₂SO₄ , filtered, and concentrated to afford the product (230 mg, 56%) as a brown solid.

Step 10: 7-(Trifluoromethyl)imidazo[1,5-a]pyridine-5-carbaldehyde

To a solution of (7-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)methanol (230 mg, 1.1 mmol) in DCM (50 mL) was added portionwise Dess-Martin (932 mg, 2.2 mmol) at room temperature, and the mixture was stirred overnight. _H₂O (20 mL) and HCl (5 mL) were added to the resulting mixture. The aqueous layer was extracted with DCM (20 ml*2) and the pH was adjusted to > ₈ with _Na₂CO₃ . The aqueous layer was extracted with EtOAc (50 mL*3). The organic layer was dried _{over Na₂SO₄} , filtered, and concentrated to give the product (130 mg, 55%) as a brown solid, which was used in the next step without further purification. MS (ESI) m/e [M+1] ⁺ 215.

Step 11: Cyclohexyl(7-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)methanol

To a solution of 7-(trifluoromethyl)imidazo[1,5-a]pyridine-5-carbaldehyde (50 mg, 0.23 mmol) in anhydrous THF (20 mL) was added cyclohexylmagnesium chloride (0.29 mL, 1.6 M) dropwise at ₀ °C under N2 balloon protection. The mixture was then slowly stirred and warmed to room temperature for 30 min. Water (20 mL) was added to the mixture and extracted with EA (30 mL*3). The organic layers were combined and dried over _{Na2SO4 . Na2SO4} was removed by filtration and the filtrate was concentrated. The crude product was purified by preparative TLC (PE/EA = 1:1 as eluent) _to give 20 mg, 28% yield. ¹ H NMR (DMSO-d ₆ ) δ 8.70 (s, 1H), 8.08 (s, 1H), 7.73 (s, 1H), 6.80 (s, 1H), 5.89 (d, 1H, J=4.0Hz), 4.76 (q, 1H, J=4.8Hz), 1.59-1.81 (m, 5H), 1.23-1.32(m, 1H) and 1.11-1.16(m, 6H). MS(ESI)m/e[M+1] ⁺ 299.

Examples A109a and A109b: (S)-cyclohexyl(7-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)methanol and (R)-cyclohexyl(7-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)methanol

Each enantiomer of racemic A109a and A109b was separated using preparative HPLC on a Chiralpak IC using hexane/IPA = 90/10 (v/v) as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak IC using hexane/IPA = 90/10 (v/v) as the eluent at a flow rate of 2.0 mL/min. The first enantiomer eluted at a retention time of 4.17 min, while the other enantiomer eluted at a retention time of 5.84 min. The spectroscopic properties of the title compound were identical to those of A109. Based on the assumption that the binding mode of the more potent isomer, A109a, is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A109a and A109b were tentatively assigned as (S) and (R), respectively.

Example A110: Cyclopentyl(7-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)methanol

Example A110 was synthesized from 7-(trifluoromethyl)imidazo[1,5-a]pyridine-5-carbaldehyde and cyclopentylmagnesium chloride by following a procedure similar to that described in Example A109. ^1H NMR (DMSO-d ₆ ) δ 8.72 (s, 1H), 8.09 (s, 1H), 7.73 (s, 1H), 6.84 (s, 1H), 5.92 (d, 1H, J=6.0 Hz), 4.80 (q, 1H, J=4.8 Hz), and 1.44-1.63 (m, 9H). MS (ESI) m/e [M+1] ⁺ 285.

Examples A111 and A112 were synthesized following similar procedures under appropriate conditions that would be recognized by one of ordinary skill in the art.

Example A111: (7-bromoimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

¹ H NMR (400MHz, CDCl ₃ )δ9.64 (t, J=3.6Hz, 1H), 7.80 (s, 1H), 7.76 (s, 1H), 6.98 (s, 2H), 4.75 (d, J=2.0Hz, 1H), 2.31-1.65 (m, 5H), 1.41-1.02 (m, 6H)ppm. MS：M/e 309 (M+1) ⁺

Example A112: (7-bromoimidazo[1,5-a]pyridin-5-yl)(cyclopentyl)methanol

¹ H NMR (400MHz, CD ₃ OD) δ 8.68 (s, 1H), 7.74 (s, 1H), 7.45 (s, 1H), 6.80 (s, 1H), 4.63 (d, J=8.4Hz, 1H), 2.60-2.40 (m, 1H), 2.16-1.75 (m, 2H), 1.71-1.40 (m, 6H)ppm. MS：M/e 295(M+1) ⁺

Examples A113 and A114 were synthesized following procedures similar to those described in Example A109 using the corresponding aldehydes and Grignard reagents.

Example A113: 1-(7-chloroimidazo[1,5-a]pyridin-5-yl)-3-cyclohexylpropan-1-ol

¹ H NMR (DMSO-d ₆ )δ8.47 (s, 1H), 7.67 (d, J=2.0Hz, 1H), 7.41 (s, 1H), 6.66 (d, J=2.0Hz, 1H), 5. 83(d, J=4.2Hz, 1H), 4.86-4.90(m, 1H), 2.49-2.51(m, 2H), 1.74-1.75(m, 5H), 1.12-1.20 (m, 6H), 0.81-0.85 (m, 2H).

Example A114: 2-cyclohexyl-1-(7-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)ethan-1-ol

¹ H NMR (DMSO-d ₆ )δ8.5δ(s, 1H), 8.10(s, 1H), 7.74(s, 1H), 6.84(s, 1H), 5.86(d, 1H, J=5.6Hz), 5.05-5.10(m, 1H), 1.59-1.91(m, 7H), 0.89-1.23(m, 6H).

Examples A114a and A114b: (R)-2-cyclohexyl-1-(7-(trifluoromethyl)imidazo[1,5-a]pyridine-5- (S)-2-cyclohexyl-1-(7-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)ethan-1-ol

Each enantiomer of racemic A114a and A114b was separated using preparative HPLC on Chiralpak AD using an elution agent (hexane/IPA = 90/10 (V/V)). Enantiomeric excess was determined using HPLC on Chiralpak AD using hexane/IPA = 90/10 (V/V) as the eluent at a flow rate of 2.0 mL/min. The first enantiomer eluted at a retention time of 3.81 min, ¹ H NMR (DMSO-d ₆ ) δ 8.56 (s, 1H), 8.10 (s, 1H), 7.74 (s, 1H), 6.84 (s, 1H), 5.86 (d, 1H, J=5.6 Hz), 5.05-5.10 (m, 1H), 1.59-1.91 (m, 7H), 0.89-1.23 (m, 6H). MS (ESI) m/e [M+1] ⁺ 313; the other enantiomer eluted at a retention time of 4.54 ^min . H NMR (DMSO-d ₆ ) δ 8.56 (s, 1H), 8.10 (s, 1H), 7.74 (s, 1H), 6.84 (s, 1H), 5.86 (d, 1H, J = 5.6 Hz), 5.05-5.10 (m, 1H), 1.59-1.91 (m, 7H), 0.89-1.23 (m, 6H). MS (ESI) m/e [M+1] ⁺ 313. Based on the assumption that the binding model of the more potent isomer A114b is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A114a and A114b are tentatively assigned to (R) and (S), respectively.

Example A115: Cycloheptyl(7-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)methanol

Example A115 was synthesized using the corresponding aldehyde and Grignard reagent following procedures similar to those described in Example A109. ^1H NMR (DMSO- _d6 ) 8.67 (s, 1H), 8.08 (s, 1H), 7.73 (s, 1H), 6.82 (s, 1H), 5.90 (d, J = 4.8 Hz, 1H), 4.68 (dd, J = 4.8, 10.2 Hz, 1H), 1.99-2.01 (m, 1H), 1.02-1.67 (m, 12H). LC-MS (M+H) ⁺ = 313.

Example A116: (6-chloroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

Step 1: Ethyl 3,6-dichloropyridine-2-carboxylate

To a solution of compound 1 (100 g, 520.8 mmol) in EtOH (400 mL) was added _SOCl₂ (155 g, 1.3 mol) dropwise at 0°C. The mixture was then stirred at 90°C for 2 h. TLC (PE:EA=3:1, Rf=0.5) indicated the reaction was complete. The solvent was evaporated under reduced pressure. _Saturated NaHCO₃ was added to the mixture to adjust pH to 7 and the mixture was extracted with EA (200 ml*3). _The combined organic layers were dried over _Na₂SO₄ , filtered, and concentrated to afford compound 1 (120 g, 100%) as a yellow oil. LC-MS (M+H) ^⁺ = 220.

Step 2: Ethyl 3-chloro-6-cyanopyridine-2-carboxylate

To a mixture of compound 2 (50 g, 90.816 mmol) in DMF (300 mL) were added ZnCN (20 g, 170.45 mmol) and Pd(pph ₃ ) ₄ (26 g, 227.3 mol), and the mixture was stirred at 95° C. under N ₂ for 2 hours. TLC (PE:EA=3:1, Rf=0.5) showed the reaction was complete. H ₂ O (100 mL) was added to the solution, and the white precipitate was removed by filtration and extracted with EA (200 mL*3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated to give a crude product. The crude product was purified by silica gel chromatography (PE:EA=20:1-8:1) to give compound 3 (22 g, 47%) as a yellow oil.

Step 3: Ethyl 6-(((tert-Butoxycarbonyl)amino)methyl)-3-chloropyridine-2-carboxylate

To a solution of compound 3 (3.6 g, 17.1 mmol) and (Boc) _2O (5.95 g, 34.2 mmol) in EtOH (30 mL) was added Raney-Ni (3.6 g) and stirred at room temperature under 60 psi _H2 for 16 h. The mixture was then filtered and the solvent removed in vacuo. The residue was purified by silica gel chromatography (PE:EA=5:1) to afford compound 4 (4.6 g, 85.4%) as a colorless solid. LC-MS (M+H) ⁺ = 259, 315.

Step 4: Ethyl 6-(aminomethyl)-3-chloropyridine-2-carboxylate

To a stirred solution of compound 4 (5.35 g, 16.98 mmol) in DCM (30 mL) was added CF ₃ COOH (15 mL) and stirred at room temperature for 3 h. The solvent was then removed under reduced pressure in vacuo to give the product, which was used in the next step without further purification. LC-MS (M+H) ⁺ = 215.

Step 5: Ethyl 3-chloro-6-(formylaminomethyl)pyridine-2-carboxylate

A mixture of compound 5 (4.3 g) in HCOOH (30 mL) was stirred at 50° C. for 30 min. (AcO) ₂ O (10 mL) was then added and stirred at 50° C. for another 2 h. After cooling to room temperature, the solvent was removed in vacuo to give the crude product (3.5 g), which was used in the next step without further purification. LC-MS (M+H) ⁺ = 243.1

Step 6: Ethyl 6-chloroimidazo[1,5-a]pyridine-5-carboxylate

To a mixture of compound 6 (3.5 g, 14.5 mmol) in toluene (20 mL) was added _POCl₃ (2 mL) and the mixture was heated at 80°C for 2 h. The mixture was then cooled to room temperature, the solvent was removed in vacuo, and a saturated aqueous _NaHCO₃ solution (100 mL) was added to the residue, which was extracted with DCM (100 mL*2), dried over _Na₂SO₄ , and evaporated in vacuo. The residue was purified on silica gel (PE:EA=1: ₅ then DCM:MEOH=100:1) to give the product as a yellow solid (2.0 g, 62%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.63 (s, 1H), 7.84-7.86 (d, J=9.2Hz, 1H), 7.62 (s, 1H), 6.91-6.93 (d, J =9.2Hz, 1H), 4.49-4.55(m, 1H), 1.37-1.41(m, 3H). LC-MS (M+H) ⁺ =225.

Step 7: (6-chloroimidazo[1,5-a]pyridin-5-yl)methanol

To a solution of compound 7 (2.0 g, 8.93 mmol) in EtOH (60 mL) was added LiBH ₄ (0.45 g, 22.3 mmol) and stirred at room temperature for 4 hours. Water (100 mL) was then added, and the mixture was extracted with DCM (100 mL*2), dried over Na ₂ SO ₄ , filtered to remove Na ₂ SO ₄ , and the solvent was evaporated to give the crude product as a yellow oil (1.9 g). The crude product was then used in the next step without further purification. LC-MS (M+H) ⁺ = 183.0.

Step 8: 6-chloroimidazo[1,5-a]pyridine-5-carbaldehyde

To a solution of compound 8 (1.9 g, 10.43 mmol) in DCM (50 mL) was added Dess-Martin (6.64 g, 15.65 mmol) at room temperature, and the mixture was stirred at room temperature for 12 hours. Water (80 mL) was then added, and the mixture was extracted with DCM (75 mL*2), dried over Na ₂ SO ₄ , filtered to remove Na ₂ SO ₄ , and the solvent was evaporated. The residue was purified by silica gel (PE: EA = 1: 5 then to = 1: 1) to give the product as a yellow solid (1.5 g, 83%). LC-MS (M+H) ⁺ = 181.

Step 9: (6-chloroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol (Example A116)

To a solution of compound 9 (0.1 g, 0.56 mmol) in THF (10 mL) was added cyclohexyl-magnesium bromide (0.6 mL, 1.12 mmol) at -60°C, and the mixture was stirred for 2 hours at -60°C. Water (20 mL) was then added, extracted with DCM (20 mL _{x 2} ), dried over _Na2SO4 , filtered to remove _Na2SO4 , the solvent was evaporated, and the residue was purified by prep-HPLC to give the product as a white solid (25 mg, 21%). ¹ H NMR (400MHz, CD ₃ OD) δ9.58 (s, 1H), 7.93 (s, 1H), 7.65 (d, J=10Hz, 1H), 7.11 (d, J=10Hz, 1H), 5.19 (d, J=9.6Hz, 1H), 2.16-2.19 (m, 1H), 1.98-2.03(m, 1H), 1.72-1.76(m, 1H). 1.57-1.61 (m, 2H), 1.03-1.24 (m, 7H). LC-MS (M+H)+=265.1.

Examples A116a and A116b: (S)-(6-chloroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol and (R)-(6-chloroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

Each enantiomer of racemic A116a and A116b was separated using preparative HPLC on a Chiralpak OD using hexane/IPA/TEA = 70/30/0.1 as the eluent. The enantiomeric excess was determined using HPLC on a Chiralpak OD using hexane/IPA/TEA = 70/30/0.1 as the eluent at a flow rate of 1.0 mL/min. The first enantiomer eluted at a retention time of 3.42 min, while the other enantiomer eluted at a retention time of 4.65 min. The spectral properties of the title compound were identical to those of A116. Based on the assumption that the binding model of the more potent isomer A116a is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A116a and A116b are tentatively assigned to (S) and (R), respectively.

Example A117 was synthesized from 6-chloroimidazo[1,5-a]pyridine-5-carbaldehyde and the corresponding Grant reagent following procedures similar to those described in Example A116.

Example A117: 1-(6-chloroimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylethanol-1-ol

¹ HNMR (400MHz, DMSO-d ₆ ) δ 8.71 (s, 1H), 7.54 (d, J = 10Hz, 1H), 7.47 (s, 1H), 6.79 (d, J ⁼ 10Hz, 1H), 6.03 (d, J=4Hz, 1H), 5.48-5.52 (m, 1H), 1.96-2.01 (m, 1H), 1.47-1.77 (m, 7H), 0.88-1.25 (m, 5H). LC-MS (M+H) ⁺ =279.1.

Examples A117a and A117b: (S)-1-(6-chloroimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylethanol-1-ol and (R)-1-(6-chloroimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylethanol-1-ol

Each enantiomer of racemic A117a and A117b was separated using preparative HPLC on a Chiralpak AS using hexane/EtOH/TEA = 90/10/0.1 as the eluent. The enantiomeric excess was determined using HPLC on a Chiralpak AS using hexane/EtOH/TEA = 90/10/0.1 as the eluent at a flow rate of 1.0 mL/min. The first enantiomer eluted at a retention time of 5.15 min, while the other enantiomer eluted at a retention time of 7.99 min. The spectral properties of the title compound were identical to those of A117. Based on the assumption that the binding model of the more potent isomer A117a is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A117a and A117b were tentatively assigned as (S) and (R), respectively.

Example A118: (6-bromoimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

Step 1: 3-Bromopyridine-2,6-dicarboxylic acid

To a solution of 3-bromo-2,6-dimethylpyridine (20 g, 0.107 mol) in _H₂O (300 mL) was added _KMnO₄ (85 g, 0.537 mol) in ten portions. The first five portions were added over 5 hours at 70°C, and the second five portions were added over 5 hours at 90°C. After the addition was complete, the mixture was stirred at 90°C for 12 hours. The reaction mixture was hot filtered and the residue was washed with hot _H₂O (100 mL). The filtrate was concentrated and concentrated HCl (60 mL) was added, heated to 100°C to dissolve the precipitated white solid. The mixture was cooled to room temperature and filtered. The filter cake was collected and dried to afford the title compound (12 g, 45.6%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.82 (s, 2H), 8.36 (t, J = 18.8Hz, 1H), 8.02 (d, J = 8.4Hz, 1H) ppm. MS: M/e 246(M+1) ⁺ .

Step 2: 3-Bromopyridine-2,6-dicarbonyl chloride

A mixture of the product of step 1 (12 g, 48.8 mmol) in SOCl ₂ (20 mL) was stirred at 100° C. for 2 hours until the solvent was complete, and then concentrated to give the title compound, which was used in the next step without further purification.

Step 3: Diethyl 3-bromopyridine-2,6-dicarboxylate

A mixture of the product from step 2 (48.8 mmol) in EtOH (50 mL) was refluxed for 4 hours. The reaction mixture was then concentrated to afford the title compound (14.7 g, 100%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 4.58-4.43 (m, 4H), 1.44 (m, 6H). MS: M/e 302 (M+1) ⁺ .

Step 4: Ethyl 3-bromo-6-(hydroxymethyl)pyridine-2-carboxylate

To a stirred mixture of the product from step 3 (14.7 g, 48.8 mmol) in EtOH (100 mL) was added portionwise _NaBH₄ (0.92 g, 24.4 mmol). After addition, the reaction mixture was stirred at 50°C for 4 hours. _NaBH₄ (0.2 g) was then added in four portions until the product from step 3 was consumed. The reaction mixture was quenched with acetone and concentrated to give a residue, which was treated with EtOAc/ _H₂O (100 mL/100 mL). The organic layer was separated, concentrated, and purified by column chromatography (petroleum ether/EtOAc = 6:1 to 2:1) to give the title compound (4 g, 31.5%) and a by-product (2 g, 15.7%) as a colorless oil. Target compound (5b): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.77 (s, 2H), 4.48 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H) ppm. MS: M/e 260/262 (M+1) ⁺ . 5a (byproduct): ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (d, J = 8.2 Hz, 1H), 7.96-7.91 (d, J = 8.2 Hz, 1H), 4.81 (s, 2H), 4.48-4.42 (q, J = 7.2 Hz, 2H), 4.32 (s, 1H), 1.45-1.41 (t, J = 7.2 Hz, 3H) ppm. MS: M/e 260/262 (M+1) ⁺ .

Step 5: Ethyl 3-bromo-6-(chloromethyl)pyridine-2-carboxylate

To a stirred solution of the product from step 4 (4 g, 15.4 mmol) in _CH₂Cl₂ (4 _mL ) at 0°C was added _SOCl₂ (3.6 g, 30.8 mmol) dropwise. After addition, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with _H₂O (20 mL). The organic layer was separated, dried _{over Na₂SO₄} , and concentrated to afford the title compound (3.75 g, 87.7%) as a yellow oil. MS: M/e 278/280 (M+1) ^⁺ .

Step 6: Ethyl 3-hydroxy-6-((1,3-dioxoisoindol-2-yl)methyl)pyridine-2-carboxylate

To a stirred solution of the product of step 5 (3.75 g, 13.5 mmol) in DMF (10 mL) was added potassium phthalimide (2.5 g, 13.5 mmol). After the addition, the reaction mixture was stirred overnight. The reaction mixture was poured into _H₂O (50 mL) and stirred for 30 minutes, then filtered. The filter cake was collected and dried to give the title compound (4.59 g, 87.6%) as a white solid. ^1H NMR (400 MHz, DMSO- _d₆ ) δ 8.19 (d, J = 8.4 Hz, 1H), 7.91 (m, 4H), 7.55 (d, J = 8.4 Hz, 1H), 4.91 (s, 2H), 4.29 (q, J = 7.2 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H) ppm. MS: M/e 389/391(M+1) ⁺ .

Step 7: Ethyl 6-(aminomethyl)-3-bromopyridine-2-carboxylate

To a stirred suspension of the product from step 6 (4.59 g, 11.82 mmol) in EtOH (100 mL) was added N ₂ H ₄ .H ₂ O (0.59 _g , 11.82 mmol). After addition, the reaction mixture was stirred at 90° C. for 5 hours. The reaction mixture was cooled to room temperature, and HCOOH (1 mL) was added and stirred for 30 minutes and filtered. The filtrate was concentrated to give a residue, which was treated with EtOAc (100 mL) and filtered. The filtrate was concentrated to give the title compound (3 g, 100%) as a yellow oil, which was used directly in the next step. MS: M/e 259/261 (M+1) ⁺ .

Step 8. Ethyl 3-[3-(6-(formylaminomethyl)pyridine-2-carboxylate

A solution of the product from Step 7 (3 g, 11.82 mmol) in HCOOH (10 mL) was stirred at 100°C overnight. The reaction mixture was poured into _H₂O (60 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over _Na₂SO₄ , and concentrated in vacuo to afford the title compound (3.1 g, 91.3%), which was used in the next step. _MS : M/e 287/289 (M+1) ^⁺ .

Step 9: Ethyl 6-bromoimidazo[1,5-a]pyridine-5-carboxylate

To a stirred solution of the product of step 8 (3.1 g, 10.8 mmol) in toluene (20 mL) was added POCl₃ ( ₃ mL), and the reaction mixture was stirred at 90°C for 3 hours. The reaction mixture was poured into _H₂O (20 mL) and basified with _{aqueous K₂CO₃} to pH = 9-11, and then extracted with EtOAc (20 mL x ₃ ). The combined organic layers were washed with brine, dried over _Na₂SO₄ , and concentrated to give the title compound (1.95 g, 67.1%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 7.74 (d, J=9.6Hz, 1H), 7.60 (s, 1H), 7.02 (d, J=9.6Hz, 1H), 4.52 (q, J=7.2Hz, 3H), 1.39 (t, J=7.2Hz, 4H) ppm. MS: M/e 269/271(M+1) ⁺ .

Step 10: (6-Bromoimidazo[1,5-a]pyridin-5-yl)methanol

To a stirred solution of the product from step 9 (1.95 g, 7.5 mmol) in EtOH (20 mL) was added _NaBH₄ (0.285 g, 7.5 mmol). The reaction mixture was then stirred at 60°C for 2 hours. The reaction mixture was quenched with acetone (2 mL) and concentrated to give a residue, which was treated with EtOAc/ _H₂O (50 mL/50 mL). The organic layer was separated, washed with brine, dried over _Na₂SO₄ , and concentrated to give the title compound (1.2 g, 70.4%) as a yellow oil. _MS : M/e 227/229 (M+1) ^⁺ .

Step 11: 6-Bromoimidazo[1,5-a]pyridine-5-carbaldehyde

To a stirred solution of the product from step 10 (1.2 g, 5.28 mmol) in _CH₂Cl₂ (10 _mL ) was added Dess-Martin periodinane (2.2 g, 5.28 mmol). After addition, the reaction mixture was stirred for 2 hours. The reaction mixture was washed with _{aqueous K₂CO₃} and brine, dried over _Na₂SO₄ , concentrated, and purified by column chromatography (petroleum ether/EtOAc = 4 _: 1 to 2:1) to afford the title compound (500 mg, 42%) as a yellow solid. MS: M/e 225/257 (M+1) ^⁺ .

Step 12: (6-Bromoimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

To a stirred solution of the product from step 11 (200 mg, 0.89 mmol) in anhydrous THF (10 mL) at 0°C was added cyclohexylmagnesium chloride (0.67 mL, 1.34 mmol) dropwise. After addition, the reaction mixture was stirred at room _temperature for 2 hours. The reaction mixture was quenched with _H₂O and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over _Na₂SO₄ , concentrated, and purified by preparative HPLC to afford the title compound. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.16 (s, 1H), 7.81 (s, 1H), 7.61 (d, J=9.6Hz, 1H), 7.11 (d, J=9.6Hz, 1H), 6.23 (s, 1H), 5.10 (d, J=9.6Hz, 1H), 2.14 (m, 2H), 1.76 (d, J=13.6Hz, 1H), 1.59 (d, J=8.2Hz, 2H), 1.32~0.91 (m, 6H)ppm. MS: M/e309/311(M+1) ⁺ .

Examples A118a and A118b: (S)-(6-bromoimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol and (R)- (6-Bromoimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

The racemic enantiomers of A118a and A118b were separated using preparative HPLC on a Chiralpak OD using hexane/EtOH = 80/20 as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak OD using hexane/EtOH = 80/20 as the eluent at a flow rate of 1.0 mL/min. The first enantiomer eluted at a retention time of 2.32 min, while the other enantiomer eluted at a retention time of 3.15 min. The spectroscopic properties of the title compound were identical to those of A118. Based on the assumption that the binding mode of the more potent isomer A118a is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A118a and A118b were tentatively assigned as (S) and (R), respectively.

Example A119: 1-(6-Bromoimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylethanol-1-ol

To a stirred solution of 6-bromoimidazo[1,5-a]pyridine-5-carbaldehyde (product of Step 11 in the synthesis of compound A118, 200 mg, 0.89 mmol) in anhydrous THF (10 mL) at 0°C was added (cyclohexylmethyl)magnesium bromide (7 mL, 3.56 mmol) dropwise. After addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with _H₂O and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine, dried _{over Na₂SO₄} , concentrated, and purified by preparative HPLC to yield the title compound. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 7.74 (s, 1H), 7.57 (d, J = 9.6Hz, 1H), 7.06 (d, J = 9.6Hz, 1H), 6.20 (s, 1H), 5.51 (dd, J = 9.6, 4.4Hz, 1H), 1.98 (m 1H), 1.79 (t, J=12.8Hz, 2H), 1.67 (m, 2H), 1.52-1.43 (m, 2H), 1.30-1.08 (m, 4H), 0.94 (m, 2H)ppm. MS: M/e323/325(M+1) ⁺ .

Examples A119a and A119b: (S)-1-(6-Bromoimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylethanol-1-ol Compound and (R)-1-(6-bromoimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylethanol-1-ol

Each enantiomer of racemic A119a and A119b was separated using preparative HPLC on a Chiralpak OD using hexane/EtOH = 80/20 (v/v) as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak OD using hexane/EtOH = 80/20 (v/v) as the eluent at a flow rate of 2.0 mL/min. The first enantiomer eluted at a retention time of 2.28 min, while the other enantiomer eluted at a retention time of 3.28 min. The spectroscopic properties of the title compound were identical to those of Example A119. Based on the assumption that the binding mode of the more potent isomer A119a is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A119a and A119b were tentatively assigned as (S) and (R), respectively.

Example A120: (6-bromoimidazo[1,5-a]pyridin-5-yl)(cyclopentyl)methanol

Example A120 was synthesized from 6-bromoimidazo[1,5-a]pyridine-5-carbaldehyde and cyclopentylmagnesium chloride following procedures analogous to those described in Example A118. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.18 (s, 1H), 7.80 (s, 1H), 7.60 (d, J = 9.6 Hz, 1H), 7.11 (d, J = 9.6 Hz, 1H), 6.28 (br. s, 1H), 5.15 (d, J = 10.4 Hz, 1H), 2.69-2.66 (m, 1H), 2.03-1.88 (m, 1H), 1.63-1.56 (m, 6H), 1.30-1.22 (m, 2H) ppm. MS: M/e 295/297 (M+1) ⁺ .

Example A121: 1-(6-chloroimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylpropan-1-ol

Step 1: (E)-N′-(1-cyclohexylethylidene)-4-methylbenzenesulfonylhydrazide

A solution of 4-methylbenzenesulfonylhydrazide (Compound 1, 2.95 g, 15.85 mmol) and 1-cyclohexylethyl-1-one (Compound 2, 2.0 g, 15.85 mmol) in 30 mL of MeOH was stirred at room temperature for 4 h. LC-MS showed that the reaction was complete. The solvent was concentrated to give the crude product, which was filtered and washed with PE/EA = (2: 1) to give Compound 3 (4.5 g, 96.5%) as a white solid. LC-MS (M+H) ⁺ = 295.1.

Step 2: 1-(6-chloroimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylpropan-1-one

A mixture of compound 3 (0.3 g, 1.68 mmol), 6-chloroimidazo[1,5-a]pyridine-5-carbaldehyde (0.49 g, 1.68 mmol), and Cs ₂ CO ₃ (0.81 g, 2.50 mmol) in dioxane (30 mL) was stirred at 110° C. under N ₂ for 4 h, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (PE:EA=5:1) to give compound 4 (20 mg, 4.7%) as a yellow solid. LC-MS (M+H) ⁺ = 291.1.

Step 3: 1-(6-chloroimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylpropan-1-ol

To a solution of compound 4 (20 mg, 0.07 mmol) in EtOH (10 mL) was added LiBH ₄ (4.0 mg, 0.18 mmol) and stirred at room temperature for 4 hours. Water (20 mL) was then added, extracted with DCM (20 mL*2), dried over Na ₂ SO ₄ , then filtered to remove Na ₂ SO ₄ , and the solvent was evaporated to give a crude product as a yellow oil (1.9 g). The crude product was then purified by preparative HPLC to give the product (5 mg, 25%) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ8.63 (s, 1H), 7.38 (d, J=9.6Hz, 1H), 7.35 (s, 1H), 6.68-6.70 (d, J=9.6Hz, 1H), 5.34- 5.37 (d, J=10.4Hz, 1H), 1.92-2.21 (m, 2H), 1.61-1.75 (m, 4H), 1.01-1.26 (m, 6H), 0.47-0.49 (d, J=7.2Hz, 3H). LC-MS (M+H) ⁺ =293.1.

Example A122: Cyclohexyl(6-methylimidazo[1,5-a]pyridin-5-yl)methanol

Step 1: (6-bromoimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanone

To a stirred solution of (6-bromoimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol (225 mg, 0.75 mmol) in _CH₂Cl₂ (10 _mL ) was added Dess-Martin periodinane (636 mg, 1.5 mmol). After addition, the reaction mixture was stirred for 2 hours. The reaction mixture was quenched with _{aqueous K₂CO₃} (30 mL), and the organic layer was separated and concentrated to give a residue, which was purified by column chromatography (petroleum ether/EtOAc = 5:1) to give the title compound (120 mg) as a yellow oil. MS: M/e 307/309 (M+1) ^⁺ .

Step 2: Cyclohexyl(6-methylimidazo[1,5-a]pyridin-5-yl)methanone

To a stirred solution of the product from step 1 (120 mg, 0.39 mmol) in anhydrous THF (10 mL) was added MeMgBr (1 mL, 1.6 mmol). After addition, the reaction mixture was stirred at 45°C for 2 hours. The reaction mixture was extracted with _H₂O (10 mL) and EtOAc (5 mL x ₂ ). The combined organic layers were washed with brine, dried over _Na₂SO₄ , and concentrated to give a residue, which was used directly in the next step. MS: M/e 243 (M+1) ⁺ .

Step 3: Cyclohexyl(6-methylimidazo[1,5-a]pyridin-5-yl)methanol

To a stirred solution of the product of step 2 (0.39 mmol) in MeOH (2 mL) was added _NaBH4 (15 mg, 0.39 mmol). After 10 minutes, the reaction mixture was quenched with acetone (2 mL) and concentrated to give a residue which was purified by prep-HPLC to afford the title compound as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.48 (s, 1H), 7.99 (s, 1H), 7.65 (d, J=9.6Hz, 1H), 7.01 (d, J=9.6Hz, 1H), 4.88 (d, J=9.6Hz, 1H), 2.30 (s, 3H), 2.19 (d, J=11.6Hz, 1H), 2.02-1.99 (m, 1H), 1.74-1.71 (m, 1H), 1.57-1.51 (m, 2H), 1.21-0.94 (m, 7H)ppm. MS: M/e 245(M+1) ⁺ .

Example A123: Cyclohexyl(6-ethynylimidazo[1,5-a]pyridin-5-yl)methanol

Step 1: 6-((Trimethylsilyl)ethynyl)imidazo[1,5-a]pyridine-5-carbaldehyde

To a stirred solution of 6-bromoimidazo[1,5-a]pyridine-5-carbaldehyde (100 mg, 0.44 mmol) and ethynyltrimethylsilane (52 mg, 0.53 mmol) in DMF (5 mL) were added CuI (8.4 mg, 0.044 mmol), Pd(PPh) _{2Cl2 (} 31 mg, 0.044 mmol), and _Et3N (90 mg, 0.88 mmol). After the addition, the reaction mixture was stirred for 2 hours. The reaction mixture was poured into _H2O (20 mL) and extracted with EtOAc (15 mL x ₃ ). The combined organic layers were washed with brine, dried over _Na2SO4 , concentrated, and purified by column chromatography (petroleum ether/EtOAc = 5:1 to 2:1) to give the title compound (60 mg, 56.3%) as a yellow solid. MS: M/e 243 (M+1) ⁺ .

Step 2: Cyclohexyl(6-((trimethylsilyl)ethynyl)imidazo[1,5-a]pyridin-5-yl)methanol

To a stirred solution of the product from Step 1 (60 mg, 0.248 mmol) in THF (10 mL) at room temperature was added cyclohexylmagnesium bromide (2 M, 0.25 mL). After stirring for half an hour, the reaction mixture was quenched with _H₂O (10 mL) and extracted with EtOAc (10 mL x ₃ ). The combined organic layers were washed with brine, dried over _Na₂SO₄ , and concentrated to afford the title compound without further purification. MS: M/e 327 (M+1) ^⁺ .

Step 3: Cyclohexyl(6-ethynylimidazo[1,5-a]pyridin-5-yl)methanol

To a stirred solution of the product from step 2 (0.248 mmol) in DMF (5 mL) was added CsF (38 mg, 0.248 mmol). After addition, the reaction mixture was stirred overnight. The reaction mixture was poured into _H₂O (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried _{over Na₂SO₄} , concentrated, and purified by preparative HPLC to afford the title compound (32 mg, 50%) as a white solid. ¹ HNMR (400MHz, DMSO-d ₆ ) δ9.26 (s, 1H), 7.82 (s, 1H), 7.68 (d, J = 9.2Hz, 1H), 7.00 (d, J = 9.2Hz, 1H), 5.14 (d, J = 9.6Hz, 1H), 4.64 (s, 1H), 2.23 (d, J=12.4Hz, 1H), 2.05 (s, 1H), 1.76 (d, J=12.6Hz, 1H), 1.58 (s, 2H), 1.11 (m, 7H)ppm. MS: M/e 255(M+1) ⁺ .

Example A124: 2-Cyclohexyl-1-(6-iodoimidazo[1,5-a]pyridin-5-yl)ethan-1-ol

Step 1: 6-iodoimidazo[1,5-a]pyridine-5-carbaldehyde

To a stirred solution of 6-chloroimidazo[1,5-a]pyridine-5-carbaldehyde (2.0 g, 11.1 mmol) in NMP (25 mL) was added NaI (12.0 g, 80.0 mmol) at room temperature, and the resulting mixture was stirred at 130° C. for 10 hours. 50 mL of EA was added to the mixture, and the resulting mixture was filtered through a celite pad and the filtrate was washed with brine (50 mL×3), dried over Na ₂ SO ₄ , concentrated, and the resulting residue was purified by column chromatography to give the title compound (320 mg, 11%) as an orange solid. ¹ H NMR (400 MHz, DMSO-d 6 ) δ 10.09 (s, 1H), 9.43 (s, 1H), 7.80 (d, J=9.2 Hz, 1H), 7.74 (s, 1H), 7.37 (d, J=9.2 Hz, 1H). MS: M/e 273(M+1) ⁺ .

Step 2: 2-cyclohexyl-1-(6-iodoimidazo[1,5-a]pyridin-5-yl)ethan-1-ol

To a stirred solution of 6-iodoimidazo[ _1,5 -a]pyridine-5-carbaldehyde (100 mg, 0.37 mmol) in THF (5 mL) was added dropwise a solution of (cyclohexylmethyl)magnesium bromide in THF (0.5 M, 1.5 mL) under N₂ at room temperature. The resulting mixture was stirred for 2 hours. 5 mL of _H₂O was added, and the mixture was extracted with EA (5 mL*3). The combined extracts were washed with brine (10 mL* ₂ ), dried over _Na₂SO₄ , and concentrated. The resulting residue was purified by preparative HPLC to give the title compound (35 mg, 11%) as a light yellow solid. ¹ H NMR (400MHz, DMSO-d6) δ9.21 (s, 1H), 7.78 (s, 1H), 7.40 (d, J=9.6Hz, 1H), 7.24 (d, J=9.6Hz, 1H), 6.24 (s, 1H), 5.43 (dd, J=10.0, 4.0Hz, 1H), 1.91-1.74(m, 2H), 1.74-1.55(m, 5H), 1.32-1.11(m, 4H), 1.06-0.87(m, 2H). MS: M/e 371(M+1) ⁺ .

Examples A124a and A124b: (S)-2-Cyclohexyl-1-(6-iodoimidazo[1,5-a]pyridin-5-yl)ethan-1-ol and (R)-2-cyclohexyl-1-(6-iodoimidazo[1,5-a]pyridin-5-yl)ethan-1-ol

The individual enantiomers of racemic A124a and A124b were separated using preparative HPLC on a Chiralpak OD using _CO₂ /MeOH = 80/20 (/V/V) as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak OD using _CO₂ /MeOH = 80/20 (/V/V) as the eluent at a flow rate of 2.0 mL/min. The first enantiomer eluted at a retention time of 6.94 min, while the other enantiomer eluted at a retention time of 8.62 min. The spectroscopic properties of the title compound were identical to those of compound A124. Based on the assumption that the binding mode of the more potent isomer, A124a, is the same as that of A101a for the 1DO1 enzyme, the absolute configurations of A124a and A124b were tentatively assigned as (S) and (R), respectively.

Example A125: Cyclohexyl(6-iodoimidazo[1,5 -a]pyridin-5-yl)methanol

Example 125 was prepared according to the procedures described for Example A124 under appropriate conditions recognized by one of ordinary skill in the art. ¹ H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 7.85 (s, 1H), 7.45 (d, J = 9.6 Hz, 1H), 7.31 (d, J = 9.6 Hz, 1H), 6.30 (br s, 1H), 5.07 (d, J = 9.2 Hz, 1H), 2.28-2.08 (m, 2H), 1.83-1.75 (m, 1H), 1.67-1.57 (m, 2H), 1.35-1.00 (m, 6H). MS: M/e 357 (M+1) ⁺

Examples A125a and 125b: (S)-cyclohexyl(6-iodoimidazo[1,5-a]pyridin-5-yl)methanol and (R)-cyclohexyl Hexyl(6-iodoimidazo[1,5-a]pyridin-5-yl)methanol

The individual enantiomers of racemic A125a and A125b were separated using preparative HPLC on a Chiralpak IC using ACN/MeOH/DEA = 90/10/0.1 (v/v/v) as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak IC using ACN/MeOH/DEA = 90/10/0.1 (v/v/v) as the eluent at a flow rate of 1.0 mL/min. The first enantiomer eluted at a retention time of 3.07 min, while the other enantiomer eluted at a retention time of 4.16 min. The spectroscopic properties of the title compound were identical to those of compound A125. Based on the assumption that the binding mode of the more potent isomer, A125a, is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A125a and A125b were tentatively assigned as (S) and (R), respectively.

Example A126: Cyclohexyl(6-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)methanol

Step 1: Ethyl 3-(trifluoromethyl)pyridine-2-carboxylate

To a solution of 3-(trifluoromethyl)pyridine-2-carboxylic acid (3.8 g, 20 mmol) in EtOH (50 mL) was added concentrated H ₂ SO ₄ (3 mL). The resulting mixture was refluxed overnight. The mixture was concentrated, poured into water (40 mL) and treated with 1N NaOH to pH = 8. The mixture was extracted with EA (40 mL x 3), washed with saturated brine solution, dried over Na ₂ SO ₄ , filtered and concentrated to give the desired product (2.5 g, 57%). It was an oil. MS: M/e 220 (M+1) ⁺

Step 2: 2-(Ethoxycarbonyl)-3-(trifluoromethyl)pyridine 1-oxide

To a solution of the product of step 1 (2.5 g, 11.4 mmol) in DCM (30 mL) was added m-CPBA (3.9 g, 22.8 mmol). The reaction mixture was stirred at room temperature overnight. The suspension was filtered and the solid was washed with DCM (30 ml). The filtrate was diluted with saturated NaHCO ₃ solution and extracted with DCM (40 mLx2). The organic layer was washed with 10% NaHSO ₃ solution, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography eluted with PE: EA = 1: 1 to give the desired product (1.6 g, 59%) as an oil. MS: M / e 236 (M + 1)

Step 3: Ethyl 6-cyano-3-(trifluoromethyl)pyridine-2-carboxylate

To a solution of the product of step 2 (1.6 g, 6.77 mmol) and TEA (2.7 g, 27 mmol) in CH ₃ CN (40 mL) were added TMSCN (0.8 g, 8.12 mmol) and dimethylcarbamoyl chloride (0.8 g, 7.45 mmol). The solution was stirred at reflux overnight. Another portion of TMSCN (0.8 g, 8.12 mmol) and dimethylcarbamoyl chloride (0.8 g, 7.45 mmol) were added. The solution was then stirred at reflux for another 16 hours. The mixture was cooled to room temperature, quenched with water (50 mL), extracted with EA (40 mL x 3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography eluting with PE:EA=10:1 to give the desired product (1.3 g, 78%) as an oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.25 (d, J=8.4Hz, 1H), 7.94 (dd, J=8.0, 0.8Hz, 1H), 4.51 (q, J=14.4, 7.2Hz, 2H), 1.43 (t, J=7.2Hz, 3H). ppm.MS：M/e245(M+1) ⁺

Step 4: Ethyl 6-(aminomethyl)-3-(trifluoromethyl)pyridine-2-carboxylate

To a solution of the product of step 3 (1.3 g, 5.32 mmol) in EtOH (20 mL) and formic acid (3 mL) was added Pd/C (0.13 g, 10%). The reaction mixture was stirred at room temperature under a _H2 atmosphere (balloon) overnight. The solution was filtered, washed with EtOH (20 ml), and the filtrate was concentrated to give the desired product as a black oil. MS: M/e 249 (M+1)

Step 5: Ethyl 6-(formylaminomethyl)-3-(trifluoromethyl)pyridine-2-carboxylate

A solution of the product from step 4 (crude) in formic acid (12 mL) and acetic anhydride (4 mL) was stirred at 50°C for 5 hours. The reaction mixture was quenched with water (30 mL) and extracted with EA (40 mL x 3). The organic layer was washed with saturated aqueous NaHCO ₃ solution and then with saturated brine solution, dried over Na ₂ SO ₄ , filtered, and concentrated to give the crude product (0.6 g) as an oil, which was used directly in the next step. MS: M/e 277 (M+1) ⁺

Step 6: Ethyl 6-(trifluoromethyl)imidazo[1,5-a]pyridine-5-carboxylate

To a solution of the product of step 5 (0.6 g, crude product) in toluene (10 mL) was added POCl ₃ (0.8 g, 5.32 mmol). The mixture was stirred at 90° C. for 2 hours. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO ₃ solution, and extracted with EA (40 mL×2). The organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE:EA=3:1 to give the desired product (0.24 g, 17.5% over 3 steps) as a yellow solid. MS: M/e 259

Step 7: (6-(Trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)methanol

To a mixture of the product of step 6 (0.24 g, 0.93 mmol) in EtOH (10 mL) was added NaBH ₄ (70 mg, 1.86 mmol). The resulting mixture was stirred at 80 ° C for 2 hours. The reaction mixture was cooled to room temperature and 2/3 of the EtOH was removed under reduced pressure. Water (20 mL) was added to the residue to form a suspension. The solid was collected by filtration to give the desired product (120 mg, 60%) as a light yellow solid. MS: M / e 217 (M + 1) ⁺

Step 8: 6-(Trifluoromethyl)imidazo[1,5-a]pyridine-5-carbaldehyde

To a solution of the product from step 7 (120 mg, 0.55 mmol) in _CH₂Cl₂ (20 _mL ) was added Dess-Martin reagent (280 mg, 0.66 mmol). The solution was stirred at room temperature for 0.5 h. An additional portion of Dess-Martin reagent (100 mg, 0.23 mmol) was then added, and the reaction mixture was stirred at room temperature for 20 min. The solution was washed with water and extracted with _CH₂Cl₂ (50 _mL ). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, then concentrated and purified by silica gel column chromatography eluting with PE:EA = 2:1 to give the desired product (90 mg, 75%) as a yellow solid. MS: M/e 215 (M+1) ⁺

Step 9: Cyclohexyl(6-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)methanol

To the solution of the product (45mg, 0.2mmol) of step 8 in THF (4mL), a solution of cyclohexylmagnesium chloride in THF (0.15mL, 2mol/L) is added. The solution is stirred at room temperature for 0.5h. The solution is washed with water and extracted with EA (30mL). The organic layer is washed with salt water, dried over anhydrous sodium sulfate, then concentrated and purified by preparative TLC (EA: PE=1: 1) to obtain the desired product (15mg) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ 8.84 (s, 1H), 7.70 (d, J = 9.2Hz, 1H), 7.55 (s, 1H), 6.97 (d, J = 9.2Hz, 1H), 6.34 (d, J = 4.0Hz, 1H), 4.83 (dd, J=9.2, 4.0Hz, 1H), 2.36-2.26 (m, 1H), 2.24-2.12 (m, 1H), 1.85-1.70 (m, 1H), 1.65- 1.45 (m, 2H), 1.32-0.74 (m, 6H)ppm. MS：M/e 299(M+1) ⁺

Examples 126a and 126b: (S)-cyclohexyl(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol and (R)- Cyclohexyl(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol

Each enantiomer of racemic A126a and A126b was separated using preparative HPLC on a Chiralpak IC using ACN (0.1% DEA) as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak IC using ACN (0.1% DEA) as the eluent at a flow rate of 1.0 mL/min. The first enantiomer eluted at a retention time of 4.76 min, while the other enantiomer eluted at a retention time of 7.33 min. The spectroscopic properties of the title compound were identical to those of Example A126. Based on the assumption that the binding mode of the more potent isomer, A126a, is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A126a and A126b were tentatively assigned as (S) and (R), respectively.

Example A127: 2-Cyclohexyl-1-(6-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)ethan-1-ol

Example A127 was prepared according to the procedures described for Example A126 under appropriate conditions recognized by one of ordinary skill in the art. ¹ H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 4.8 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 4.0 Hz, 1H), 7.02 (dd, J = 10.0, 2.8 Hz, 1H), 6.35 (br. s, 1H), 5.38 (d, J = 10.0 Hz, 1H), 2.25-2.14 (m, 1H), 1.95-1.80 (m, 1H), 1.75-1.55 (m, 5H), 1.40-0.78 (m, 6H) ppm. MS: M/e 313 (M+1) ⁺

Examples A127a and A127b: (S)-2-cyclohexyl-1-(6-(trifluoromethyl)imidazo[1,5-a]pyridine-5- (R)-2-cyclohexyl-1-(6-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)ethan-1-ol

Each enantiomer of racemic A127a and A127b was separated using preparative HPLC on a Chiralpak OD using _CO₂ /MeOH = 85/15 (/V/V) as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak OD using _CO₂ /MeOH = 85/15 (/V/V) as the eluent at a flow rate of 2.0 mL/min. The first enantiomer eluted at a retention time of 4.86 min, while the other enantiomer eluted at a retention time of 5.53 min. The spectroscopic properties of the title compound were identical to those of compound A127. Based on the assumption that the binding mode of the more potent isomer, A127a, is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A127a and A127b were tentatively assigned as (S) and (R), respectively.

Example A128: 1-(6-chloroimidazo[1,5-a]pyridin-5-yl)-3-cyclohexylpropan-1-ol

Example A128 was prepared by following procedures similar to those described for Example A116 using 6-chloroimidazo[1,5-a]pyridine-5-carbaldehyde (the intermediate in Step 8 of the synthesis of Example A116) as the starting material and under appropriate conditions recognized by one of ordinary skill in the art.

¹ H NMR (400MHz, DMSO-d ₆ ): δ _H 8.69(s, 1H), 7.47-7.57(m, 2H), 6.78-6.80(m, 1H), 6.05-6.06(m, 1H), 5. 35-5.40(m, 1H), 1.83-1.86(m, 2H), 1.58-1.59(m, 5H), 1.03-1.18(m, 7H), 0.77-0.83(m,2H). MS(ESI)m/e[M+1] ⁺ 293.

Example A129: Cyclohexyl(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol

Step 1: 6-cyclopropylimidazo[1,5-a]pyridine-5-carbaldehyde

A stirred solution of 6-chloroimidazo[1,5-a]pyridine-5-carbaldehyde (50 mg, 0.29 mmol), tricyclohexylphosphine (24.5 mg, 0.087 mmol), Pd(OAc) ₂ (6.5 mg, 0.029 mmol), and cyclopropylboronic acid (74.7 mg, 0.87 mmol) in toluene/ _H2O (5 mL)/(2 mL) was stirred at 100°C under _N2 for 4 hours. The reaction mixture was concentrated to give a residue, which was treated with EtOAc/ _H2O (10 mL/5 mL). The organic layer was separated, washed with brine, dried _{over Na2SO4} , concentrated, and purified by column chromatography (petroleum ether/EtOAc = 4:1 to 1:1) _to give the title compound (40 mg, 74.1%) as a yellow solid. MS: M/e 187 (M+1) ⁺ .

Step 2: Cyclohexyl(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol

To a stirred solution of the product of step 1 (40 mg, 0.215 mmol) in THF (5 mL) was added a solution of cyclohexylmagnesium bromide in THF (2 M, 0.2 mL) at room temperature. After stirring for half an hour, the reaction mixture was quenched with H ₂ O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated, and purified by preparative HPLC to afford the title compound (15 mg) as a TFA salt. ¹ H NMR (400MHz, DMSO-d6) δ 9.56 (s, 1H), 8.02 (s, 1H), 7.68 (d, J = 9.6Hz, 1H), 6.81 (d, J = 9.6Hz, 1H), 6.12 (s, 1H), 5.27 (d, J=9.6Hz, 1H), 2.26 (d, J=11.2Hz, 1H), 2.18-2.00 (m, 2H), 1.78 (m, 1H), 1.61 (m, 2H), 1.31-0.94 (m, 8H), 0.89-0.66 (m, 2H)ppm. MS: M/e 271(M+1) ⁺ .

Examples A129a and A129b: (S)-cyclohexyl(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol and (R)-Cyclohexyl(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol

The individual enantiomers of racemic A129a and A129b were separated using preparative HPLC on a Chiralpak IC using ACN/MeOH/DEA = 90/10/0.1 (v/v/v) as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak IC using ACN/MeOH/DEA = 90/10/0.1 (v/v/v) as the eluent at a flow rate of 1.0 mL/min. The first enantiomer eluted at a retention time of 3.02 min, while the other enantiomer eluted at a retention time of 4.33 min. The spectroscopic properties of the title compound were identical to those of Example A129. Based on the assumption that the binding mode of the more potent isomer, A129a, is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A129a and A129b were tentatively assigned as (S) and (R), respectively.

Example A130: Cyclohexyl(6-phenylimidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (400MHz, DMSO-d6) δ9.48 (s, 1H), 8.03 (s, 1H), 7.78 (d, J = 9.2Hz, 1H), 7.59-7.41 (m, 5H), 7.00 (d, J = 9.2Hz, 1H), 6.18 (s, 1H), 4 .68 (d, J=10.0Hz, 1H), 2.09 (m, 2H), 1.78-1.57 (m, 2H), 1.42 (m, 2H), 1.27-1.10 (m, 1H), 0.94 (m, 2H), 0.71 (m, 1H), 0.41 (m, 1H)ppm. MS: M/e 307(M+1) ⁺ .

Example 131: Cyclohexyl(6-methoxyimidazo[1,5-a]pyridin-5-yl)methanol

Step 1: 6-methoxyimidazo[1,5-a]pyridine-5-carbaldehyde

To a stirred solution of 6-chloroimidazo[1,5-a]pyridine-5-carbaldehyde (50 mg, 0.29 mmol) in MeOH (5 mL) was added MeONa (5.4 M, 0.5 mL). After 4 hours at 70°C, the reaction mixture was quenched with aqueous HCl (2.0 M, 5 mL). Most of the MeOH was removed to afford a residue, which was extracted with EtOAc (10 mL x ₃ ). The combined organic layers were washed with brine, dried over _Na₂SO₄ , and concentrated to afford the title compound (50 mg, 100%), which was used directly in the next step. MS: M/e 177 (M+1) ⁺ .

Step 2: Cyclohexyl(6-methoxyimidazo[1,5-a]pyridin-5-yl)methanol

To a stirred solution of the product of step 1 (50 mg, 0.29 mmol) in THF (5 mL) was added a solution of cyclohexylmagnesium bromide in THF (2 M, 0.3 mL) at room temperature. After stirring for half an hour, the reaction mixture was quenched with H ₂ O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated, and purified by preparative HPLC to give the title compound (12 mg) as a TFA salt. ¹ H NMR (400MHz, DMSO-d6) δ 9.35 (s, 1H), 7.98 (s, 1H), 7.80 (d, J=10.0Hz, 1H), 7.36 (d, J=10.0Hz, 1H), 5.90 (s, 1H), 5.05 (d, J=9.6Hz, 1H), 3.88 (s, 3H), 2.18 (d, J=12.4Hz, 1H), 2.00 (m, 1H), 1.75 (m, 1H), 1.57 (m, 2H), 1.22-0.86 (m, 6H)ppm. MS: M/e 261(M+1) ⁺ .

Examples A132 to A142 were prepared according to the procedure described for A126 under appropriate conditions as would be recognized by one of ordinary skill in the art.

Example A132: Cyclopropyl(6-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (400MHz, DMSO-d6) δ9.11 (s, 1H), 7.77 (d, J = 9.6Hz, 1H), 7.69 (s, 1H), 7.05 (d, J = 9.6Hz, 1H), 4.5 8(d, J=8.4Hz, 1H), 1.66-1.54(m, 1H), 0.80-0.60(m, 2H), 0.51-0.38(m, 1H), 0.32-0.18(m, 1H)ppm. MS：M/e 257(M+1) ⁺

Example A133: Cyclopentyl(6-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (400MHz, DMSO-d6) δ8.99 (s, 1H), 7.74 (d, J=10.0Hz, 1H), 7.63 (s, 1H), 7.02 (dd, J=10.0, 1.6Hz, 1H), 6.42 (br .s, 1H), 4.94 (d, J=10.0Hz, 1H), 2.80-2.69 (m, 1H), 2.08-1.98 (m, 1H), 1.70-1.35 (m, 5H), 1.12-0.94 (m, 2H)ppm. MS: M/e 285(M+1) ⁺ .

Example A134: Cyclopropyl(6-iodoimidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (400MHz, DMSO-d6) δ9.22 (s, 1H), 7.78 (s, 1H), 7.42 (d, J=7.6Hz, 1H), 7.25 (d, J=7.6Hz, 1H), 4.76 (d, J=10.0Hz, 1H), 1.57-1.60 (m, 1H), 0.41-0.67 (m, 4H) ppm.

Example A135: Cyclohexyl(6-isopropylimidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (400MHz, DMSO-d6) δ9.09 (s, 1H), 7.66 (s, 1H), 7.58 (d, J=7.6Hz, 1H), 7.04 (d, J =7.6Hz, 1H), 5.91 (s, 1H), 4.99 (d, J = 6.0Hz, 1H), 2.22-2.23 (m, 1H), 2.02-2.04 (m, 1H), 1.58-1.75(m, 3H), 1.01-1.19(m, 13H)ppm. MS: M/e 273(M+1) ⁺ .

Example A136: Cyclohexyl(6-(prop-1-en-2-yl)imidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (400MHz, DMSO-d6) δ9.31 (s, 1H), 7.88 (s, 1H), 7.67 (d, J=9.2Hz, 1H), 6.90 (d, J=9.2Hz, 1H), 6.03 (s, 1H), 5.35 (s, 1H), 5.05 (s, 1H), 4.82 (d, J=9.6Hz, 1H), 2.22- 2.23 (m, 1H), 2.05 (s, 3H), 1.58-1.75 (m, 3H), 0.78-1.19 (m, 7H)ppm. MS: M/e 271(M+1) ⁺ .

Example A137: Cyclopropyl(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (400MHz, DMSO-d6) δ9.49 (s, 1H), 7.91 (s, 1H), 7.64 (d, J = 9.6Hz, 1H), 6.76 (d, J = 9.6Hz, 1H), 6.07 (s, 1H), 4 .95 (d, J=8.4Hz, 1H), 2.08 (m, 1H), 1.69-1.49 (m, 1H), 0.98 (m, 2H), 0.80 (m, 1H), 0.68 (m, 3H), 0.39 (m, 2H)ppm. MS: M/e 229(M+1) ⁺ .

Example A138: Cyclopentyl(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (400MHz, DMSO-d6) δ9.52 (s, 1H), 7.95 (s, 1H), 7.65 (d, J = 9.6Hz, 1H), 6.78 (d, J = 9.6Hz, 1H), 6.08 (s, 1H), 5.32 (d, J = 10.4Hz, 1H), 2.67 (m, 1H), 2.14 (m, 1H), 1.99 (m, 1H), 1.78-1.52 (m, 4H), 1.44 (m, 1H), 1.19 (m, 2H), 1.10-0.94 (m, 2H), 0.85 (m, 1H), 0.73 (m, 1H)ppm. MS: M/e 257(M+1) ⁺ .

Example A139: 2-Cyclohexyl-1-(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)ethan-1-ol

¹ H NMR (400MHz, DMSO-d6) δ9.37 (s, 1H), 7.86 (s, 1H), 7.61 (d, J=9.6Hz, 1H), 6.80 (d , J=9.6Hz, 1H), 5.98 (s, 1H), 5.82-5.66 (m, 1H), 2.06-1.94 (m, 2H), 1.78 (m, 2H), 1.65 (m, 3H), 1.56-1.47 (m, 2H), 1.25 (m, 8H), 0.81 (m, 1H), 0.69 (m, 1H)ppm. MS: M/e 285 (M+1) ⁺ .

Examples A139a and A139b: (S)-cyclohexyl(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol and (R)-Cyclohexyl(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol

Each enantiomer of racemic A139a and A139b was separated by preparative HPLC using ACN/MeOH/DEA=90/10/0.1 (V/V/V) as eluent on a Chiralpak AD-H. Enantiomeric excess was determined by HPLC using ACN/MeOH/DEA=90/10/0.1 (V/V/V) as eluent at a flow rate of 1.0 mL/min on a Chiralpak AD-H. The first enantiomer eluted when the retention time was 3.02 min, while the other enantiomer eluted when the retention time was 4.33 min. The spectral properties of the title compound were identical to those of compound A139. Based on the assumption that the binding model of the more efficient isomer A139a is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A139a and A139b are tentatively assigned to (S) and (R), respectively.

Example A140: Cyclohexyl(6-(3,5-dimethylisoxazol-4-yl)imidazo[1,5-a]pyridin-5-yl)methane alcohol

¹ H NMR (400MHz, DMSO-d6) δ9.24 (d, J=14.4Hz, 1H), 7.84 (s, 1H), 7.73 (d, J=9.2Hz, 1H ), 6.82 (dd, J=20.8, 9.2Hz, 1H), 6.24 (s, 1H), 4.38 (dd, J=52.0, 9.6Hz, 1H), 2.39- 2.23 (d, J=36Hz, 3H), 2.12 (d, J=14.4Hz, 3H), 2.00 (m, 1H), 1.69 (m, 1H), 1.48 (m, 2H), 1.24-0.77 (m, 6H), 0.50 (m, 1H)ppm. MS: M/e 326(M+1) ⁺ .

Example A141: 2-((6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)cyclohexan-1-ol

¹ H NMR (DMSO-d ₆ ) δ 8.64 (s, 1H), 7.42 (d, 1H, J = 9.6Hz), 7.32 (s, 1H) 6.44 (d, 1H, J = 9.6Hz), 6.35 (s, 1H), 5.65 (d, 1H, J = 8.0Hz), 5.52 (d, 1H, J = 3.2Hz), 3.70-3.74 (m, 1H), 2.17-2.20 (m, 1H), 1.99- 2.07(m, 1H), 1.88-1.91(m, 1H), 1.59-1.62(m, 1H), 1.42-1.45(m, 1H), 1.17-1.33(m, 2H), 0.88-1.04(m, 5H), 0.73-0.77(m, 1H), 0.61-0.65(m, 1H).

Example A142: 4-((6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)cyclohexan-1-ol

Step 1: ((4-bromocyclohexyl)oxy)trimethylsilane

At room temperature, TMSBr (54 g, 1.2 equivalents) was added dropwise to a solution of 7-oxabicyclo[2.2.1]heptane (32.8 g, 334 mmol) in anhydrous DCM (500 mL). After the dropwise addition, the resulting mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was distilled to give the desired product (50 g, 60% yield).

Steps 2 and 3: 4-((6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)cyclohexan-1-ol

To a suspension of Mg (1.0 g) in anhydrous THF (20 mL) were added ((4-bromocyclohexyl)oxy)trimethylsilane (1.0 g) and a catalytic amount of I ₂ , and the mixture was heated at 50° C. for 0.5 h. To the mixture was then added ((4-bromocyclohexyl)oxy)trimethylsilane (6.0 g), and the reaction was continued for 0.5 h until the Grignard reagent was formed, cooled to room temperature, and added dropwise to a solution of 6-cyclopropylimidazo[1,5-a]pyridine-5-carbaldehyde (1.0 g) in anhydrous THF (10 mL) at 0° C. The mixture was stirred for 0.5 h, and then saturated aqueous NH ₄ Cl was added, extracted with EA (20 mL*3), dried over Na ₂ SO ₄ , filtered, and the filtrate was evaporated and purified by CC (D:M=10:1) to give the desired product 1.0 g in 70% yield. ¹ H NMR (DMSO-d ₆ ) 8.57 (s, 1H), 7.39 (d, 1H, J=9.6Hz), 7.29 (s, 1H), 6.46 (d, 1H, J=9.6Hz), 5.73 (d, 1H, J=4.0Hz), 5.26 (dd, 1H, J=9.6, 3.6Hz), 4.26 (d, 1H, J=3.2Hz), 3.74 (s, 1H), 2.08-2.13 (m, 1H), 1.91-1.95 (m, 2 H), 1.62-1.71(m, 5H), 1.18-1.24(m, 1H), 0.89-0.98(m, 2H), 0.73-0.81(m, 2H), 0.62-0.67(m, 1H).

Examples A142a, A142b, A142c and A142d: (1R,4s)-4-((S)-(6-cyclopropylimidazo[1,5-a] Pyridin-5-yl)(hydroxy)methyl)cyclohexan-1-ol, (1S,4r)-4-((S)-(6-cyclopropylimidazo[1,5-a]pyridine-5- (1R,4s)-4-((R)-(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy) methyl)cyclohexan-1-ol and (1S,4r)-4-((R)-(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)cyclohexan-1-ol Hexan-1-ol.

Each enantiomer was separated using preparative HPLC on a Chiralpak AD-H using 30% propan-2-ol/carbon dioxide as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak AD-H using 30% propan-2-ol/carbon dioxide as the eluent at a flow rate of 2.0 mL/min. The first enantiomer eluted at a retention time of 9.137 min, ¹ H NMR (DMSO-d ₆ ) 8.57 (s, 1H), 7.39 (d, 1H, J=9.6 Hz), 7.29 (s, 1H), 6.46 (d, 1H, J=9.6 Hz), 5.73 (d, 1H, J=4.0 Hz), 5.26 (dd, 1H, J=9.6, 3.6 Hz), 4.26 (d, 1H, J=3.2 Hz), 3.74 (s, 1H), 2.09-2.13 (m, 1H), 1.91-1.95 (m, 2H), 1.62-1.71 (m, 5H), 1.18-1.24 (m, 1H), 0.89-0.98 (m, 2H), 0.73-0.81 (m, 2H), 0.63-0.67 (m, 1H); the second enantiomer eluted at a retention time of 12.750 min, ^1H NMR (DMSO-d ₆ ) 8.57 (s, 1H), 7.39 (d, 1H, J=9.6 Hz), 7.29 (s, 1H), 6.45 (d, 1H, J=9.6 Hz), 5.74 (d, 1H, J=4.0 Hz), 5.17 (dd, 1H, J=9.6, 3.6 Hz), 4.45 (d, 1H, J=3.2 Hz), 2.25-2.27 (m, 1H), 1.89-2.03 (m, 3H), 1.66-1.69 (m, 1H), 0.89-0.98 (m, 2H), 0.73-0.81 (m, 7H), 0.63-0.73 (m, 3H); the third enantiomer eluted at a retention time of 15.375 min, ¹ H NMR (DMSO-d ₆ ) 8.57 (s, 1H), 7.38 (d, 1H, J=9.6 Hz), 7.29 (s, 1H), 6.45 (d, 1H, J=9.6 Hz), 5.72 (d, 1H, J=4.0 Hz), 5.27 (dd, 1H, J = 9.6, 4.0 Hz), 4.26 (d, 1H, J = 4.0 Hz), 3.74 (s, 1H), 2.10-2.13 (m, 1H), 1.91-1.95 (m, 2H), 1.21-1.70 (m, 7H), 0.91-0.98 (m, 2H), 0.74-0.81 (m, 2H), 0.63-0.65 (m, 1H); and the fourth enantiomer eluted at a retention time of 17.955 min, ^1H NMR (DMSO-d ₆ ) 8.57 (s, 1H), 7.38 (d, 1H, J = 9.6 Hz), 7.30 (s, 1H), 6.45 (d, 1H, J=9.6Hz), 5.75 (d, 1H, J=4.0Hz), 5.17 (dd, 1H, J=9.6, 4.0Hz), 4.46 (d, 1H, J = 4.0Hz), 2.25-2.27 (m, 1H), 1.89-2.03 (m, 3H), 1.6-1.70 (m, 1H), 0.89-1.23 (m, 2H), 0.74-0.81 (m, 5H), 0.63-0.75 (m, 2H). Based on the assumption that the binding model of the more potent isomers A142a and A142b is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A142a, A142b, A142c, and A142d are tentatively assigned as (S), (S), (R), and (R), respectively, but the relative configurations in cyclohexane are uncertain.

Example A143: Cyclohexyl(6,7-dichloroimidazo[1,5-a]pyridin-5-yl)methanol

Step 1: Diethyl 4-hydroxypyridine-2,6-dicarboxylate

To a solution of 4-hydroxypyridine-2,6-dicarboxylic acid (183 g, 1.0 mol) in EtOH (1500 ml) at room temperature was added thionyl chloride (200 ml, 2.0 mol), and the mixture was heated at 90°C for 3 h. The mixture was cooled to room temperature and concentrated to dryness. 1 L of water was added to the crude product, stirred at room temperature, and neutralized with sodium carbonate. After filtration and washing with water (200 ml x 3), a white solid (201 g, yield: 83.92%) was obtained. ¹ H NMR (CD3OD-d4) δ 7.45 (s, 1H), 4.40 (dd, 4H, J = 7.2 Hz), 1.40 (t, 3H, J = 6.8 Hz).

Step 2: Diethyl 3,4-dichloropyridine-2,6-dicarboxylate

To a solution of diethyl 4-hydroxypyridine-2,6-dicarboxylate (140 g, 0.585 mol) in DCM (1400 ml) were added triethylamine (47 ml, 0.703 mol) and N-chlorosuccinimide (N-chloropyrrolidine-2,5-dione) (86.3 g, 0.644 mol). The reaction mixture was then stirred at room temperature for 1 h and concentrated to dryness. The crude product was dissolved in 500 mL of neutral EA and extracted with 6N HCl (500 ml*3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was dissolved in 800 ml of acetonitrile, phosphorus oxychloride (80 ml) was added, and the mixture was stirred at 75° C. for 1 h and then concentrated to dryness. The crude product was purified by column chromatography on silica gel (400 g) using PE:EA=20:1 as the eluent to give a white solid (30.0 g, 17.56% yield). ¹ H NMR (DMSO-d ₆ ) δ 8.40 (s, 1H), 4.42 (m, 4H), 1.35 (m, 6H).

Step 3: 3,4-dichloro-6-(hydroxymethyl)pyridine-2-carboxylic acid ethyl ester and 4,5-dichloro-6-(hydroxymethyl)pyridine Ethyl pyridine-2-carboxylate

To a solution of diethyl 3,4-dichloropyridine-2,6-dicarboxylate (30 g, 103.09 mmol) in ethanol (1000 ml) was added sodium borohydride (1.96 g, 51.55 mmol), and the mixture was stirred at 50°C for 2 h, cooled to room temperature, quenched with 5 ml of water, and concentrated to dryness. To the crude product was added 500 ml of water, extracted with EA (500 ml * 3), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel (50 g) column chromatography (PE:EA = 1:1) to give a light yellow oil (mixture, 9.00 g, 35.06% yield). ESI-MS m/z 250.0 ([M+H] ⁺ ).

Step 4: 3,4-dichloro-6-(chloromethyl)pyridine-2-carboxylic acid ethyl ester and 4,5-dichloro-6-(chloromethyl)pyridine-2-carboxylic acid ethyl ester Ethyl formate

To a solution of ethyl 3,4-dichloro-6-(hydroxymethyl)pyridine-2-carboxylate and ethyl 4,5-dichloro-6-(hydroxymethyl)pyridine-2-carboxylate (9.00 g, 36.14 mmol) in dichloromethane (100 ml) was added thionyl chloride (6.6 ml, 90.36 mmol) dropwise, and the mixture was stirred at 45°C for 2 h, cooled to room temperature, quenched with 2 ml of water, and concentrated to dryness. Saturated aqueous sodium bicarbonate (50 ml) was added to the crude product, which was extracted with EA (50 ml * 3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product (11.19 g) was used in the next step without further purification.

Step 5: ethyl 3,4-dichloro-6-((1,3-dioxoisoindole-2-yl)methyl)pyridine-2-carboxylate and 4, Ethyl 5-dichloro-6-((1,3-dioxoisoindol-2-yl)methyl)pyridine-2-carboxylate.

Ethyl 3,4-dichloro-6-(chloromethyl)pyridine-2-carboxylate and ethyl 4,5-dichloro-6-(chloromethyl)pyridine-2-carboxylate (11.19 g, 41.95 mmol) were dissolved in anhydrous DMF (100 ml), and potassium phthalimide (9.26 g, 50.10 mmol) was slowly added at room temperature, and the mixture was stirred overnight. Water (100 ml) was then added to the reaction mixture, which was then extracted with EA (150 ml x 3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was recrystallized from PE:EA = 10:1 (50 ml) to give a pale yellow solid (mixture, 9.50 g, 59.91% yield). One isomer: ¹ H NMR (DMSO-d ₆ ) δ 8.11 (s, 1H), 7.86-7.97 (m, 4H), 5.11 (s, 2H), 4.08 (dd, 3H, J=7.2 Hz), 0.93 (t, 2H, J=7.2 Hz). Another isomer: ¹ H NMR (DMSO-d ₆ ) 8.08 (s, 1H), 7.86-7.97 (m, 4H), 4.92 (s, 2H), 4.34 (dd, 3H, J=7.2 Hz), 1.19 (t, 2H, J=7.2 Hz).

Steps 6 and 7: 6-(aminomethyl)-3,4-dichloropyridine-2-carboxylic acid ethyl ester and 6-(aminomethyl)-4,5-dichloro- Ethyl pyridine-2-carboxylate

To a solution of ethyl 3,4-dichloro-6-((1,3-dioxoisoindol-2-yl)methyl)pyridine-2-carboxylate and ethyl 4,5-dichloro-6-((1,3-dioxoisoindol-2-yl)methyl)pyridine-2-carboxylate (9.50 g, 25.13 mmol) in EtOH (100 ml) was added hydrazine hydrate (1.25 ml, 98%) at room temperature, and the mixture was heated to 80° C. for 2 h. It was then cooled to room temperature, HCOOH (5 ml) was added, filtered and washed with EtOH, and the filtrate was evaporated to give the crude product as an oil. The crude product was dissolved in HCOOH (40 ml) and acetic anhydride (8 ml), and the mixture was stirred at 90° C. for 2 h, then cooled to room temperature and concentrated to dryness. Saturated sodium bicarbonate (100 ml) was added to the crude product, extracted with EA (80 ml*3), the organic layers were combined, washed with saturated NaHCO ₃ (200 ml*2), dried over sodium sulfate, filtered and concentrated under vacuum to give yellow oil (mixture, 6.84 g). ESI-MS m/z 277.0 ([M+H] ⁺ ).

Step 7: Ethyl 6,7-dichloroimidazo[1,5-a]pyridine-5-carboxylate and 7,8-dichloroimidazo[1,5-a]pyridine Ethyl 5-pyridinecarboxylate

To a solution of ethyl 6-(aminomethyl)-3,4-dichloropyridine-2-carboxylate and ethyl 6-(aminomethyl)-4,5-dichloropyridine-2-carboxylate (6.84 g, 24.78 mmol) in acetonitrile (50 ml) was added POCl ₃ (4.54 ml, 49.56 mmol) at room temperature and the mixture was heated at 80° C. for 2 h, then cooled to room temperature and concentrated in vacuo to give a crude product, which was dissolved in HCl (400 ml, 1 N) and extracted with EA (200 ml*3). The aqueous layer was separated, adjusted to pH=7-8 with sodium carbonate, and extracted with EA (400 ml*3). The organic layers were combined and the solvent was evaporated to give a crude product, which was purified by column chromatography on silica gel (50 g) using PE:EA=1:1 as eluent to give a pale yellow solid (2.8 g, ethyl 6,7-dichloroimidazo[1,5-a]pyridine-5-carboxylate): ¹ HNMR (DMSO-d ₆ ) δ 9.15 (d, 1H, J = 6.4 Hz), 7.75 (d, 1H, J = 0.8 Hz), 7.66 (s, 1H), 4.44 (q, 2H, J = 7.2 Hz), 1.39 (t, 3H, J = 7.2 Hz). And another isomer (ethyl 7,8-dichloroimidazo[1,5-a]pyridine-5-carboxylate): ¹ H NMR (DMSO-d ₆ ) δ 8.44 (s, 1H), 7.72 (s, 1H), 7.52 (s, 1H), 4.59 (m, 2H, J = 7.2 Hz), 1.49 (m, 3H, J = 7.2 Hz).

Step 8: (6,7-Dichloroimidazo[1,5-a]pyridin-5-yl)methanol

To a solution of ethyl 6,7-dichloroimidazo[1,5-a]pyridine-5-carboxylate (2.80 g, 10.85 mmol) in EtOH (100 ml) was added _NaBH₄ (1.23 g, 32.56 mmol) at room temperature, and the mixture was stirred at room temperature for 2 h, then quenched with _H₂O (5 ml). After concentration to dryness, 100 ml of water was added to the residue, which was filtered and concentrated to dryness to give a white solid (1.85 g, 78.62% yield). ^⁻¹H NMR (DMSO- _d₆ ) δ 8.49 (s, 1H), 8.02 (s, 1H), 7.49 (s, 1H), 5.84 (t, 1H, J = 5.6 Hz), 5.03 (d, 2H, J = 5.6 Hz).

Step 9: 6,7-Dichloroimidazo[1,5-a]pyridine-5-carbaldehyde

To a solution of (6,7-dichloroimidazo[1,5-a]pyridin-5-yl)methanol (1.85 g, 8.53 mmol) in DCM (15 ml) at room temperature was added Dess-Martin reagent (5.42 g, 12.79 mmol), and the mixture was stirred overnight. Water (40 ml) was then added and extracted with DCM (100 ml * 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel (50 g) column chromatography using PE:EA = 1:1 as the eluent to give a pale yellow solid (1.01 g, 55.07% yield). ¹ H NMR (DMSO-d ₆ ) δ 10.62 (s, 1H), 9.64 (s, 1H), 7.99 (s, 1H), 7.70 (s, 1H).

Step 10: Cyclohexyl(6,7-dichloroimidazo[1,5-a]pyridin-5-yl)methanol

At 0 ° C, under N ₂ , cyclohexylmagnesium chloride (5.35 ml, 1.3 mmol/ml) was added dropwise to a solution of 6,7-dichloroimidazo[1,5-a]pyridine-5-carboxaldehyde (500 mg, 2.32 mmol) in anhydrous THF (10 ml). The mixture was then stirred at room temperature for 1 h. Water (30 ml) was added to the mixture and extracted with EA (30 ml * 3). The organic layers were combined and dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by preparative-TLC (PE: EA = 1: 1 as eluent) to give the product as a solid (52 mg, 7.23% yield). ¹ H NMR (DMSO-d ₆ ) δ 8.82 (s, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 5.40 (d, 1H, J=9.6Hz), 3.06 (s, 1H), 1.67-2.27 (m, 5H), 1.07-1.33 (m, 6H).

Examples A143a and A143b: (S)-cyclohexyl(6,7-dichloroimidazo[1,5-a]pyridin-5-yl)methanol and (R)-cyclohexyl(6,7-dichloroimidazo[1,5-a]pyridin-5-yl)methanol

Each enantiomer of racemic A143a and A143b was separated using preparative HPLC on Chiralpak OZ-H with hexane/IPA=80/20 (V/V) as eluent. Enantiomeric excess was determined using HPLC on Chiralpak OZ-H with hexane/IPA=80/20 (V/V) as eluent at a flow rate of 1.0 mL/min. The first enantiomer eluted at a retention time of 5.98 min, while the other enantiomer eluted at a retention time of 7.68 min. The spectral properties of the title compound were identical to those of Example A143. Based on the assumption that the binding model of the more potent isomer A143a is the same as that of A101a for the 1D01 enzyme, the absolute configurations of A143a and A143b are tentatively assigned to (S) and (R), respectively.

Examples A144 to A146 were synthesized from the corresponding aldehydes and Grignard reagents following procedures similar to those described in Example A143.

Example A144: 2-Cyclohexyl-1-(6,7-dichloroimidazo[1,5-a]pyridin-5-yl)ethan-1-ol

¹ H NMR (DMSO-d ₆ ) δ 8.87 (s, 1H), 7.57 (s, 1H), 7.53 (s, 1H), 5.83 (dd, 1H, J=4.0Hz), 1.59-2.14 (m, 7H), 0.97-1.35 (m, 6H).

Examples A144a and A144b: (R)-2-cyclohexyl-1-(6,7-dichloroimidazo[1,5-a]pyridin-5-yl)ethyl 1-ol and (S)-2-cyclohexyl-1-(6,7-dichloroimidazo[1,5-a]pyridin-5-yl)ethan-1-ol

Each enantiomer of racemic A144a and A144b was separated using preparative HPLC on a Chiralpak AS-H with hexane/EtOH = 90/10 (v/v) as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak AS-H with hexane/EtOH = 90/10 (v/v) as the eluent at a flow rate of 1.0 mL/min. The first enantiomer eluted at a retention time of 4.45 min, while the other enantiomer eluted at a retention time of 7.21 min. The spectroscopic properties of the title compound were identical to those of Example A144. Based on the assumption that the binding mode of the more potent isomer A144b is the same as that of A101a for the IDO1 enzyme, the absolute configurations of A144a and A144b were tentatively assigned as (R) and (S), respectively.

Example A145: Imidazo[1,5-a]pyridin-5-yl(phenyl)methanol

¹ H NMR (DMSO-d ₆ ) δ 8.45 (s, 1H), 7.52 (s, 1H), 6.70 (s, 1H), 5.02 (dd, 2H, J=3.2Hz), 1.59-1.91 (m, 8H), 0.96-1.30 (m, 6H).

Example A146: Cyclohexyl(7,8-dichloroimidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (DMSO-d ₆ ) δ 8.94 (s, 1H), 7.62 (s, 1H), 6.70 (s, 1H), 4.68 (d, 2H, J=7.6Hz), 1.70-2.05 (m, 5H), 1.10-1.40 (m, 6H).

Example A147: 1-(7-bromo-8-chloroimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylethanol-1-ol

Step 1: Diethyl 4-bromo-3-chloropyridine-2,6-dicarboxylate

A solution of diethyl 4-hydroxypyridine-2,6-dicarboxylate (200 g, 0.837 mol) in DCM (1400 ml) was stirred at room temperature, and triethylamine (101 g, 1 mol) and N-chlorosuccinimide (N-chloropyrrolidine-2,5-dione) (65.13 g, 0.488 mol) were added portionwise. The reaction mixture was then stirred at room temperature for 1 hour and concentrated to dryness. 500L of EA was added to the crude product, and the mixture was extracted with 6N HCl (500 ml x 3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was dissolved in 800 ml of acetonitrile, and _POBr₃ (219 g, 0.7664 mol) was added. The mixture was stirred at 75°C for 1 hour and then concentrated to dryness. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to give a white solid (50.0 g, 32% yield). ¹ H NMR (DMSO-d6) δ 8.50 (s, 1H), 4.40-4.42 (m, 4H), 1.28-1.34 (m, 6H).

Step 2: 4-bromo-3-chloro-6-(hydroxymethyl)pyridine-2-carboxylic acid ethyl ester and 4-bromo-5-chloro-6-(hydroxymethyl)pyridine Ethyl pyridine-2-carboxylate

To a solution of compound 2 (21 g, 62.7 mmol) in ethanol (200 ml) was added _NaBH₄ (1.54 g, 40.47 mmol), and the mixture was stirred at 50°C for 2 h, cooled to room temperature, quenched with 5 ml of water, and concentrated to dryness. The crude product was added with 500 ml of water and extracted with EA (100 ml x 3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel (50 g) column chromatography (PE:EA = 1:1) to yield a light yellow oil (7 g, 38%). One isomer: ¹ H NMR (400 MHz, DMSO) δ 9.21 (dd, J = 11.6, 6.7 Hz, 1H), 7.93-7.75 (m, 1H), 7.73-7.58 (m, 1H), 4.76-4.32 (m, 3H), 1.57-1.32 (m, 4H). Another isomer: ¹ H NMR (400 MHz, DMSO) δ 8.71-8.47 (m, 1H), 8.45-8.32 (m, 0H), 8.32-8.18 (m, 1H), 7.58 (dd, J = 8.8, 1.6 Hz, 1H), 4.68-4.41 (m, 3H), 1.50-1.28 (m, 4H).

Step 3: 4-bromo-3-chloro-6-((tosyloxy)methyl)pyridine-2-carboxylic acid ethyl ester and 4-bromo-5-chloro-6- Ethyl ((Tosyloxy)methyl)pyridine-2-carboxylate

To a solution of compounds 3a and 3b (14 g, 48 mmol), _Et3N (9.7 g, 96 mol), and DMAP (0.5 g, 4.8 mol) in dichloromethane (150 ml) was added TosCl (11 g, 57.6 mmol) and stirred at room temperature for 2 h. LCMS indicated the reaction was complete. _Aqueous NHCl4 was added to the crude product and extracted with EA (100 ml*3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product (23 g, >99.9%) was used in the next step without further purification.

Step 4: ethyl 4-bromo-3-chloro-6-((1,3-dioxodiioxyisoindol-2-yl)methyl)pyridine-2-carboxylate and Ethyl 4-bromo-5-chloro-6-((1,3-dioxoisoindol-2-yl)methyl)pyridine-2-carboxylate

A mixture of compounds 4a and 4b (23 g, 51.54 mmol) and potassium phthalimide (9.54 g, 51.54 mmol) in anhydrous DMF (200 ml) was stirred at room temperature for 2 h. 100 ml of water was then added to the reaction mixture, which was then extracted with EA (150 ml x 3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was recrystallized from PE:EA (10:1) (50 ml) to obtain a light yellow oil (17 g of both compounds, 78.3% yield).

Steps 5 and 6: 4-bromo-3-chloro-6-(formylaminomethyl)pyridine-2-carboxylic acid ethyl ester and 4-bromo-5-chloro-6-(formylaminomethyl)pyridine-2-carboxylic acid ethyl ester Ethyl aminomethyl pyridine-2-carboxylate

At room temperature, to a solution of compounds 5a and 5b (17 g, 40.28 mmol) in EtOH (100 ml) was added hydrazine hydrate (2 g, 98%) and the mixture was heated at 80 ° C for 2 h. It was then cooled to room temperature, HCOOH (10 ml) was added, filtered and washed to remove the white precipitate and the filtrate was evaporated to give a crude product as an oil. To this crude product was added HCOOH 100 ml and acetic anhydride 8 ml and the mixture was stirred at 90 ° C for 2 h. After cooling to room temperature, it was concentrated to dryness. Saturated sodium bicarbonate 100 ml was added to the crude product, extracted with (80 ml * 3) EA, the organic layer was washed with saturated brine (200 ml * 2), dried over sodium sulfate, filtered and concentrated to dryness to give a yellow oil (11.5 g, impure, 91.3%).

Step 7: 7-bromo-6-chloroimidazo[1,5-a]pyridine-5-carboxylic acid ethyl ester and 7-bromo-8-chloroimidazo[1,5-a]pyridine Ethyl 5-pyridinecarboxylate

To a solution of compounds 7a and 7b (11.5 g, 36 mmol) in toluene (150 ml) was added POBr ₃ (15.4 g, 54 mmol) at room temperature, and the mixture was heated at 80°C for 2 h. The mixture was then cooled to room temperature and the solvent evaporated. HCl (400 ml, 1 N) was added to the residue, and the mixture was extracted with EA (200 ml * 3). The aqueous layer was separated, the pH was adjusted to 7-8 with sodium carbonate, and then extracted with EA (200 ml * 3). The organic layers were combined, and the solvent was evaporated to give a crude product. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to give compound 8a (3.6 g). ¹ H NMR (400MHz, DMSO) δ 8.57 (s, 1H), 8.39 (d, J=0.4 Hz, 1H), 7.59 (s, 1H), 4.56 (q, J=7.1Hz, 2H), 1.40 (t, J=7.1Hz, 4H).

Step 8: (7-bromo-6-chloroimidazo[1,5-a]pyridin-5-yl)methanol

To a solution of compound 9 (3.6 g, 12 mmol) in EtOH (10 ml) was added NaBH ₄ (0.67 g, 18 mmol) in portions at room temperature and the mixture was stirred at room temperature for 2 h and then quenched with H ₂ O (1 ml). After concentration to dryness, 10 ml of water was added to the residue, filtered and concentrated to dryness to give a yellow oil (3.1 g, 99.3% yield).

Step 9: 7-Bromo-6-chloroimidazo[1,5-a]pyridine-5-carbaldehyde

To a solution of compound 10 (3.1 g, 11.9 mmol) in DCM (30 ml) was added portionwise Dess-Martin (7.58 g, 17.88 mmol) at room temperature and the mixture was stirred for 5 h. 20 ml of water was then added and extracted with DCM (20 ml * 3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (PE:EA=1:1) to give compound 11 (1.8 g, 58%) as a yellow solid. ¹ H NMR (400 MHz, DMSO) δ 10.53-10.38 (m, 1H), 9.41 (d, J=26.4 Hz, 1H), 8.65 (d, J=18.0 Hz, 1H), 7.83-7.67 (m, 2H).

Step 10: 1-(7-bromo-6-chloroimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylethanol-1-ol

To a solution of compound 11 (1 g, 3.78 mmol) in anhydrous THF (20 ml) was added dropwise cyclohexylmagnesium chloride (5 ml, 1.3 mmol/ml, 1.50 mmol) at 0°C under _N2 balloon protection. The mixture was then slowly stirred and warmed to room temperature for 1 h. Water (10 ml) was added to the mixture and extracted with EA (10 ml * 3). The organic layers were combined and dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by preparative-TLC (PE: EA = 1: 2 as eluent) to give 5 mg, 4% yield. ¹ HNMR (400MHz, cdcl ₃ ) δ8.81 (s, 1H), 7.71 (s, 1H), 7.38 (s, 1H), 7.29 (d, J=26.9 Hz, 2H), 5.81 (dd, J=9.6, 3.9Hz, 1H), 4.53-4.40 (m, 1H), 1.70-1.53 (m, 1H), 1.31-1.17 (m, 8H), 0.93-0.78 (m, 2H).

Examples A148 to A150 were synthesized from the corresponding aldehydes and Grignard reagents following procedures analogous to those described in Example A147.

Example A148: (7-bromo-6-chloroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

¹ H NMR (400MHz, DMSO-d ₆ )δ8.70 (s, 1H), 8.13 (s, 1H), 7.45 (s, 1H), 6.19 (d, J = 4.4Hz, 1H), 5.17 (dd, J =9.6, 4.4Hz, 1H), 2.07-2.19(m, 2H), 1.61-1.72(m, 3H), 1.04-1.25(m, 6H).

Example A149: (7-bromo-6-chloroimidazo[1,5-a]pyridin-5-yl)(cyclopentyl)methanol

¹ H NMR (400MHz, DMSO-d ₆ )δ8.74 (s, 1H), 8.14 (s, 1H), 7.46 (s, 1H), 6.21 (d, J=4.0Hz, 1H), 5.22 (dd, J =9.6, 4.0Hz, 1H), 1.93-1.95 (m, 1H), 1.45-1.58 (m, 5H), 1.20-1.23 (m, 3H).

Example A150: (7-bromo-6-chloroimidazo[1,5-a]pyridin-5-yl)(cyclopropyl)methanol

¹ H NMR (400MHz, DMSO-d ₆ )δ8.82 (s, 1H), 8.14 (s, 1H), 7.47 (s, 1H), 6.25 (d, J=4.0Hz, 1H), 4.87 (dd, J =8.8, 4.0Hz, 1H), 1.51-1.59(m, 1H), 0.51-0.68(m, 2H), 0.39-0.43(m, 2H).

Example A151: (6-chloro-7-fluoroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

Step 1: Ethyl 3-chloro-4-fluoro-6-(formylaminomethyl)pyridine-2-carboxylate

A mixture of ethyl 3,4-dichloro-6-(formylaminomethyl)pyridine-2-carboxylate (4.3 g, 15.5 mmol, 1.0 eq) and CsF (6.1 g, 40.1 mmol, 2.6 eq) in DMSO (100 mL) was heated to 120° C. overnight. After cooling, the mixture was poured into water and extracted with EA. The organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated, and purified on silica gel to give a crude product (2.5 g). ESI-MS m/z 261 ([M+H] ⁺ ).

Step 2: Ethyl 6-chloro-7-fluoroimidazo[1,5-a]pyridine-5-carboxylate

A solution of ethyl 3-chloro-4-fluoro-6-(formylaminomethyl)picolinate (2.5 g, <9.6 mmol) and _POCl₃ (1 mL) in ACN (100 mL) was heated to 70°C for 2 h. After cooling, the mixture was concentrated, saturated aqueous _NaHCO₃ was added, and the mixture was extracted with EA _. The EA layer was washed with brine, dried over _Na₂SO₄ , concentrated, and purified on silica gel to give the product (1.6 g). ESI-MS m/z 243 ([M+H] ^⁺ ).

Step 3: (6-chloro-7-fluoroimidazo[1,5-a]pyridin-5-yl)methanol

Ethyl 6-chloro-7-fluoroimidazo[1,5-a]pyridine-5-carboxylate (1.6 g, 6.6 mmol, 1.0 eq) and NaBH ₄ (500 mg, 13.2 mmol, 2.0 eq) in EtOH (50 mL) were heated to 80° C. for 2 hours. After cooling, 100 mL of water was added and the mixture was concentrated to remove EtOH. The yellow solid was collected and air-dried to give the product (780 mg). ESI-MS m/z 201 ([M+H] ⁺ ).

Step 4: 6-chloro-7-fluoroimidazo[1,5-a]pyridine-5-carbaldehyde

To a solution of compound 1 (0.3 g, 1.5 mmol) in DCM (20 mL) was added Dess-Martin (1.23 g, 3.0 mmol) at room temperature, and the mixture was stirred at room temperature for 12 hours. Water (80 mL) was then added, extracted with DCM (75 mL x 2), dried over Na ₂ SO ₄ , filtered to remove Na ₂ SO ₄ , the solvent was evaporated, and the residue was purified by silica gel (PE: EA = 1: 5 then to = 1: 1) to give the product as a yellow solid (0.21 g, 70%). LC-MS (M+H) ⁺ = 199.1

Step 5: (6-chloro-7-fluoroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

To a solution of compound 2 (0.1 g, 0.51 mmol) in THF (10 mL) was added cyclohexylmagnesium bromide (0.6 mL, 0.77 mmol) at 0° C., and the mixture was stirred at 0° C. for 2 hours. Then water (20 mL) was added, extracted with DCM (20 mL×2), dried over Na ₂ SO ₄ , filtered to remove Na ₂ SO ₄ , evaporated the solvent, and purified the residue by prep-HPLC to give the product as a white solid (25 mg, 21%). ¹ H NMR (400MHz, DMSO-d6) δ 8.70 (s, 1H), 7.63 (d, J = 8.8Hz, 1H), 7.44 (s, 1H), 6.02 (s, 1H), 5.07-5.10 (d, J = 9.2Hz, 1H), 2.18-2.22 (m, 1H), 2.07- 2.10 (m, 1H), 1.74-1.77 (m, 1H), 1.58-1.60 (m, 1H), 1.02-1.26 (m, 7H).

Example A152: 1-(6-chloro-7-fluoroimidazo[1,5-a]pyridin-5-yl)-2-cyclohexylethanol-1-ol

Example A152 was synthesized from the corresponding aldehyde and Grignard reagent following procedures similar to those described in Example A151. ¹ H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.61-7.63 (d, J = 8.8 Hz, 1H), 7.44 (s, 1H), 6.19 (s, 1H), 5.50-5.53 (d, J = 8.8 Hz, 1H), 0.83-2.0 (m, 13H). LC-MS (M+H) ⁺ = 297.1.

Example A153: (8-chloro-7-methoxyimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

Step 1: Diethyl 3-chloro-4-methoxypyridine-2,6-dicarboxylate

A mixture of diethyl 3-chloro-4-hydroxypyridine-2,6-dicarboxylate (11 g, 40 mmol, 1.0 eq), MeI (10 g, 70 mmol, 1.75 eq), and K ₂ CO ₃ (11 g, 80 mmol, 2.0 eq) in DMF (100 mL) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with EA. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , concentrated, and purified on silica gel to give 6.6 g (57% yield). ¹ H NMR (DMSO-d ₆ ) δ 7.83 (s, 1H), 4.35-4.44 (m, 4H), 4.09 (s, 3H), 1.31-1.36 (m, 6H). ESI-MS m/z 288 ([M+H] ⁺ ).

Step 2: Ethyl 5-chloro-6-(hydroxymethyl)-4-methoxypyridine-2-carboxylate

To a solution of diethyl 3-chloro-4-methoxypyridine-2,6-dicarboxylate (6.6 g, 23 mmol, 1.0 eq) in EtOH (100 mL) was slowly added NaBH ₄ (400 mg, 10.5 mmol, 0.46 eq) at 50° C., then heated to 80° C. and maintained for 1 h. After cooling down, the mixture was concentrated, added with water, extracted with EA, and the organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated, and purified on silica gel to give 750 mg of a white solid (13% yield). ¹ H NMR (DMSO-d ₆ ) δ 7.69 (s, 1H), 4.64 (s, 2H), 4.37 (q, J=7.2 Hz, 2H), 4.04 (s, 3H), 1.34 (t, J=7.2 Hz, 3H).

Step 3: Ethyl 5-chloro-6-(chloromethyl)-4-methoxypyridine-2-carboxylate

A solution of ethyl 5-chloro-6-(hydroxymethyl)-4-methoxypicolinate (750 mg, 3.05 mmol, 1.0 eq) and _SOCl2 (0.3 mL) in DCM (10 mL) was stirred at rt for 1 h, concentrated in vacuo, added EA, washed with aqueous _NaHCO3 and brine, dried _{over Na2SO4} , and concentrated to give the crude product (700 mg) which was used in the next step without further purification.

Step 4: Ethyl 5-chloro-6-((1,3-dioxoindolin-2-yl)methyl)-4-methoxypyridine-2-carboxylate ester

A mixture of ethyl 5-chloro-6-(chloromethyl)-4-methoxypyridine-2-carboxylate (700 mg, 2.65 mmol, 1.0 eq) and potassium phthalimide (740 mg, 4.0 mmol, 1.3 eq) in DMF (15 mL) was stirred overnight. The mixture was poured onto ice, and the white solid was collected and air-dried to give 960 mg (84% yield over 2 steps). ¹ H NMR (DMSO-d ₆ ) δ 7.88-7.96 (m, 4H), 7.64 (s, 1H), 5.01 (s, 1H), 4.03-4.09 (m, 5H), 0.87-0.91 (t, J=7.2 Hz, 3H). ESI-MS m/z 375 ([M+H] ⁺ ).

Step 5: Ethyl 6-(aminomethyl)-5-chloro-4-methoxypyridine-2-carboxylate

A solution of ethyl 5-chloro-6-((1,3-dioxoisoindolin-2-yl)methyl ₎ -4-methoxypicolinate (960 mg, 2.56 mmol, 1.0 eq) and _N2H4 · _H2O (128 mg, 2.56 mmol, 1.0 eq) in EtOH (30 mL) was heated to 90°C for 2 hours. After cooling down, the mixture was filtered and 5 mL of HCOOH was added to the filtrate. The mixture was concentrated to give a crude product (1.3 g) which was used in the next step without further purification.

Step 6: Ethyl 5-chloro-6-(formylaminomethyl)-4-methoxypyridine-2-carboxylate

A solution of ethyl 6-(aminomethyl)-5-chloro-4-methoxypicolinate (1.3 g, 5.3 mmol, 1.0 eq) in HCOOH (30 mL) and _Ac2O (10 mL) was heated to 50°C for 2 h, EA was added, washed with saturated aqueous _NaHCO3 , water and brine, dried _{over Na2SO4} and concentrated to give the crude product (605 mg) which was used in the next step without further purification.

Step 7: Ethyl 8-chloro-7-methoxyimidazo[1,5-a]pyridine-5-carboxylate

To a solution of ethyl 5-chloro-6-(formamidomethyl)-4-methoxypicolinate (600 mg, 2.2 mmol, 1.0 eq) in ACN was added _POCl3 (0.3 mL), the reaction mixture was heated to 70 °C for 2 h, after cooling down, the mixture was concentrated, saturated aqueous _NaHCO3 solution was added, extracted with EA, the EA layer was washed with brine, dried over _Na2SO4 , concentrated and purified _on silica gel to give the product as a yellow solid (350 mg, 54% yield over 3 steps). ¹ H NMR (DMSO-d ₆ ) δ9.02 (d, J=0.8Hz, 1H), 7.64 (s, 1H), 7.48 (d, J=0.8Hz, 1H), 4.43-4.49 (q, J=7.2Hz, 2H), 3.99 (s, 3H), 1.38-1.42 (t, J=7.2Hz, 3H). ESI-MS m/z 255([M+H] ⁺ ).

Step 8: (8-chloro-7-methoxyimidazo[1,5-a]pyridin-5-yl)methanol

To a solution of ethyl 8-chloro-7-methoxyimidazo[1,5-a]pyridine-5-carboxylate (0.5 g, 1.98 mmol) in EtOH (30 mL) was added LiBH ₄ (0.15 g, 6.25 mmol) and stirred at room temperature for 4 hours. Water (100 mL) was then added, the mixture was extracted with DCM (50 mL*2), dried over Na ₂ SO ₄ , filtered to remove Na ₂ SO ₄ , and the solvent was evaporated to give the crude product as a white solid (1.9 g), which was used in the next step without further purification. LC-MS (M+H) ⁺ = 213.1

Step 9: 8-chloro-7-methoxyimidazo[1,5-a]pyridine-5-carbaldehyde

To a solution of the compound (8-chloro-7-methoxyimidazo[1,5-a]pyridin-5-yl)methanol (0.31 g, 1.46 mmol) in DCM (20 mL) was added Dess-Martin (1.24 g, 2.92 mmol) at room temperature, and the mixture was stirred at room temperature for 12 hours. Water (40 mL) was then added, extracted with DCM (30 mL x 2), dried over Na ₂ SO ₄ , filtered to remove Na ₂ SO ₄ , the solvent was evaporated, and the residue was purified by silica gel (PE: EA = 1: 5 then to = 1: 1) to give the product as a yellow solid (0.11 g, 35.6%). LC-MS (M+H) ⁺ = 211.1

Step 10: (8-chloro-7-methoxyimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

To a solution of compound 8-chloro-7-methoxyimidazo[1,5-a]pyridine-5-carbaldehyde (0.05 g, 0.24 mmol) in THF (10 mL) was added cyclohexylmagnesium bromide (0.3 mL, 0.36 mmol) at 0° C., and the mixture was stirred at 0° C. for 2 hours. Then water (20 mL) was added, extracted with DCM (20 mL×2), dried over Na ₂ SO ₄ , filtered to remove Na ₂ SO ₄ , evaporated the solvent, and purified the residue by prep-HPLC to give the product as a white solid (6.5 mg, 10.3%). ¹ H NMR (400MHz, DMSO) δ9.44 (s, 1H), 7.78 (s, 1H), 7.16 (s, 1H), 3.96 (s, 3H), 1.97-1.99 (m, 1H), 1.82-1.89 (m, 1H), 1.71-1.74 (m, 1H), 1.58-1.60 (m, 3H), 1.03-1.29 (m, 5H). LC-MS(M+H) ⁺ =295.1

Example A154: Cyclohexyl(6,7,8-trichloroimidazo[1,5-a]pyridin-5-yl)methanol

Step 1: Diethyl 4-hydroxypyridine-2,6-dicarboxylate

To a solution of 4-hydroxypyridine-2,6-dicarboxylic acid (183 g, 1.0 mol) in EtOH (1500 ml) was added thionyl chloride (200 ml, 2.0 mol) at room temperature, and the mixture was heated at 90°C for 3 h. The mixture was cooled to room temperature and concentrated to dryness. 1 L of water was added to the crude product, stirred at room temperature, and neutralized with sodium carbonate. After filtration and washing with water (200 ml x 3), a white solid (201 g, 83.92% yield) was obtained. ¹ H NMR (CD ₃ OD-d ₄ ) δ 7.45 (s, 1H), 4.40 (d, J = 7.2 Hz, 4H), 1.40 (t, J = 7.2 Hz, 6H).

Step 2: Diethyl 3,4,5-trichloropyridine-2,6-dicarboxylate

To a solution of diethyl 4-hydroxypyridine-2,6-dicarboxylate (24 g, 100 mmol) in acetonitrile was added N-chlorosuccinimide (N-chloropyrrolidine-2,5-dione) (33 g, 250 mmol). The reaction mixture was then stirred at 70°C overnight. 100 ml of water was added to the mixture, and the mixture was extracted with EA (200 ml * 3). The organic layers were then combined, washed with 500 ml of saturated brine, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product (14.1 g) was dissolved in 200 ml of acetonitrile, 25 ml of phosphorus oxychloride was added, and the mixture was stirred at 70°C for 2 h. After concentration to dryness, 500 ml of EA was added to the crude product, and the mixture was extracted with saturated brine (500 ml * 3). The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by column chromatography on silica gel (200 g) using PE as eluent to give a clear yellow oil (28 g, 63.62%). ¹ H NMR (DMSO-d6) δ 4.42 (m, 4H), 1.34 (m, 6H).

Step 3: Ethyl 3,4,5-trichloro-6-(hydroxymethyl)pyridine-2-carboxylate

To a solution of diethyl 3,4,5-trichloropyridine-2,6-dicarboxylate (28 g, 85.89 mmol) in ethanol (200 mL) was added sodium borohydride (1.66 g, 42.95 mmol), and the mixture was stirred at 70°C for 2 h, cooled to room temperature, quenched with 5 mL of water, and concentrated to dryness. The crude product was added with 200 mL of water and extracted with EA (200 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by column chromatography on silica gel (80 g) (PE:EA = 2:1) to afford a pale yellow oil (3.31 g, 13.57% yield). ¹ H NMR (DMSO-d6) δ 4.67 (s, 2H), 4.42 (q, J = 8.8 Hz, 4H), 1.34 (t, J = 8.8 Hz, 3H).

Step 4: Ethyl 3,4,5-trichloro-6-(chloromethyl)pyridine-2-carboxylate

To a solution of ethyl 3,4,5-trichloro-6-(hydroxymethyl)pyridine-2-carboxylate (3.31 g, 11.65 mmol) in DMF (40 ml) were added p-toluenesulfonyl chloride (2.66 g, 14.00 mmol), triethylamine (2.35 g, 23.30 mmol), and dimethylaminopyridine (141 mg, 1.16 mmol). The mixture was then stirred at room temperature overnight. Water (80 ml) was then added, and some light yellow solid separated. The solution was filtered, washed with 5 ml of water, and concentrated to dryness to give a light yellow solid (2.50 g, 71.05% yield). ^1H NMR (DMSO- _d6 ) δ 4.92 (s, 2H), 4.43 (q, J = 8.0 Hz, 2H), 1.34 (t, J = 8.0 Hz, 3H).

Step 5: Ethyl 3,4,5-trichloro-6-((1,3-dioxoisoindol-2-yl)methyl)pyridine-2-carboxylate

To a solution of ethyl 3,4,5-trichloro-6-(chloromethyl)pyridine-2-carboxylate (11.19 g, 8.28 mmol) in anhydrous DMF (20 ml) was slowly added potassium phthalimide (5.21 g, 28.16 mmol) at room temperature, and the mixture was stirred overnight. Then, 30 ml of water was added to the reaction mixture, which was filtered and washed with 10 ml of water to give a yellow solid (3.97 g, 116.37% yield). ¹ H NMR (DMSO-d ₆ ) δ 7.96-7.89 (m, 4H), 5.07 (s, 2H), 4.16 (q, J=7.2 Hz, 2H), 0.95 (t, J=7.2 Hz, 3H).

Step 6: Ethyl 3,4,5-trichloro-6-(formylaminomethyl)pyridine-2-carboxylate

To a solution of ethyl 3,4,5-trichloro-6-((1,3-dioxoisoindol-2-yl)methyl)pyridine-2-carboxylate (3.93 g, 8.28 mmol) in EtOH (20 ml) was added hydrazine hydrate (0.5 ml, 9.94 ml) at room temperature, and the mixture was heated at 80°C for 2 h. The mixture was then cooled to room temperature, HCOOH (5 ml) was added, filtered and washed to remove the white precipitate, and then evaporated to give the crude product as an oil (2.41 g). To this crude product were added 25 ml of HCOOH and 5 ml of acetic anhydride, and the mixture was stirred at 50°C for 3 h. After cooling to room temperature, it was concentrated to dryness. The crude product (2.30 g, 89.31%) was used in the next step without further purification. ESI-MS m/z 312.8 ([M+H] ⁺ ).

Step 7: Ethyl 6,7,8-trichloroimidazo[1,5-a]pyridine-5-carboxylate

To a solution of ethyl 3,4,5-trichloro-6-(formylaminomethyl)pyridine-2-carboxylate (2.30 g, 7.39 mmol) in acetonitrile (20 ml) was added _POCl₃ (4.0 ml) at room temperature, and the mixture was heated at 80°C for 2 h. The mixture was then cooled to room temperature and the solvent evaporated. HCl (400 ml, 1 N) was added to the residue, and the mixture was extracted with EA (200 ml * 3). The aqueous layer was separated, the pH was adjusted to 7-8 with sodium carbonate, and then extracted with EA (400 ml * 3). The organic layers were combined, and the solvent was evaporated to give a crude product. The crude product was purified by silica gel (50 g) column chromatography (PE:EA = 1:1) to give a pale yellow solid (1.03 g, 47.73%). ¹ H NMR (DMSO- d ₆ ) δ 8.69 (s, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 4.54 (q, J=7.2Hz, 2H), 1.39 (t, J=7.2Hz, 3H).

Step 8: (6,7,8-Trichloroimidazo[1,5-a]pyridin-5-yl)methanol

To a solution of ethyl 6,7,8-trichloroimidazo[1,5-a]pyridine-5-carboxylate (1.03 g, 3.53 mmol) in EtOH/THF = 2/1 (14 ml) was added portionwise NaBH4 (268 mg, 7.05 mmol) at room temperature. The mixture was stirred at 40°C for 1 hour and then quenched with water (1 ml). After concentration to dryness, 10 ml of water was added to the residue, which was then filtered and concentrated to dryness to give a pale yellow solid (0.70 g, 78.69% yield). ESI-MS m/z 250.8 ([M+H] ⁺ ).

Step 9: 6,7,8-Trichloroimidazo[1,5-a]pyridine-5-carbaldehyde

To a solution of (6,7,8-trichloroimidazo[1,5-a]pyridin-5-yl)methanol (0.70 g, 2.78 mmol) in DCM (20 ml) at room temperature was added portionwise Dess-Martin (2.35 g, 5.56 mmol). The mixture was stirred, filtered, and concentrated to dryness. The crude product was purified by silica gel (50 g) column chromatography (PE:EA = 1:1) to give 593 mg of a pale yellow solid, 87.55% yield. ¹ H NMR (DMSO-d ₆ ) δ 10.42 (s, 1H), 9.49 (s, 1H), 7.89 (s, 1H).

Step 10: Cyclohexyl(6,7,8-trichloroimidazo[1,5-a]pyridin-5-yl)methanol

To a solution of 6,7,8-trichloroimidazo[1,5-a]pyridine-5-carbaldehyde (100 mg, 0.4 mmol) in anhydrous THF (10 ml) at 0°C was slowly added cyclohexylmagnesium chloride (1.54 ml, 1.3 mmol/ml, 2.0 mmol) dropwise. The mixture was stirred and allowed to warm to room temperature for 1 hour. Water (10 ml) was added to the mixture, and the mixture was extracted with EA (10 ml x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by HPLC to yield the product (27.50 mg) in a 15.38% yield. ^H NMR (DMSO-d ₆ ) δ 8.84 (s, 1H), 7.63 (s, 1H), 6.29 (s, 1H), 5.13 (d, J=7.6 Hz, 1H), 1.07-2.08 (m, 11H).

Example A155: (6-chloro-7-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

Example A155 was synthesized from the corresponding aldehyde and Grignard reagent following procedures similar to those described in Example A151. ¹ H NMR (DMSO-d ₆ ) δ 8.85 (s, 1H), 8.30 (s, 1H), 7.79 (s, 1H), 5.90 (d, 1H, J=4.0 Hz), 4.80 (m, 1H), 2.10-2.21 (m, 2H), 1.72-1.77 (m, 1H), and 1.03-1.26 (m, 6H). MS (ESI) m/e [M+1] ⁺ 333.

Example A156: (7-chloro-6-fluoroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

Step 1: 2-Carboxy-5-fluoropyridine 1-oxide

At room temperature, 3-chloroperoxybenzoic acid (77.85 g, 0.45 mol) was added to a solution of 5-fluoropyridine-2-carboxylic acid (42.3 g, 0.3 mol) in DCM (500 mL). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EA=100: 1-5: 1) to obtain a white solid, which was 2-carboxyl-5-fluoropyridine 1-oxide (w=38.0 g, yield=81%). MS (ESI) m/e[M+1] ⁺ 158.

Step 2: 6-Chloro-5-fluoropyridine-2-carboxylic acid

2-Carboxy-5-fluoropyridine 1-oxide (37.5 g, 238.8 mmol) was slowly added to _POCl₃ (300 mL) at room temperature. The mixture was heated to 60°C for 6 hours, and the solvent was removed under reduced pressure. The residue was quenched with ice/ _H₂O and EA (500 g/1000 mL). The organic layer was washed with brine ( ₅₀₀ mL*2), dried over _Na₂SO₄ , and concentrated to give crude 6-chloro-5-fluoropyridine-2-carboxylic acid (w=30 g, 71%). MS (ESI) m/e [M+1] ^⁺ 176.

Step 3: 2-Chloro-3-fluoro-6-(methoxycarbonyl)pyridine 1-oxide

To a solution of 6-chloro-5-fluoropyridine-2-carboxylic acid (25.0 g, 141.3 mmol) in TFA (200 mL) was added H ₂ O ₂ (35 mL, 30% solution in water) at 80° C. The mixture was stirred at 80° C. for 4 hours. The solvent was removed. The residue was crude 6-carboxy-2-chloro-3-fluoropyridine 1-oxide. The crude 6-carboxy-2-chloro-3-fluoropyridine 1-oxide was suspended in MeOH (500 mL), and then SOCl ₂ (33.5 g, 282 mmol) was added at 0° C. and maintained for 5 hours. The solvent was removed under reduced pressure. The residue was quenched with brine (200 mL*2) and EA (500 mL), and the organic layer was dried over Na ₂ SO ₄ and concentrated to give crude 2-chloro-3-fluoro-6-(methoxycarbonyl)pyridine 1-oxide (w=24 g, 83%). MS (ESI) m/e [M+1] ⁺ 206.

Step 4: (4,6-Dichloro-5-fluoropyridin-2-yl)methanol

2-Chloro-3-fluoro-6-(methoxycarbonyl)pyridine 1-oxide (24.0 g, 117 mmol) was slowly added to _POCl₃ (150 mL) at room temperature. The mixture was heated to 60°C for 6 hours, and the solvent was removed under reduced pressure. The residue was quenched with brine and EA (500 g/500 mL), and _the organic layer was dried over _Na₂SO₄ and concentrated to give crude (4,6-dichloro-5-fluoropyridin-2-yl)methanol. (4,6-dichloro-5-fluoropyridin-2-yl)methanol was suspended in MeOH (150 mL), and _NaBH₄ (13.3 g, 351 mmol) was slowly added over 2 hours. The residue was quenched with _H₂O (500 mL) and EA (500 mL), _dried over _Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EA=100:1-5:1) to give a white solid, (4,6-dichloro-5-fluoropyridin-2-yl)methanol (w=13.0 g, yield=56%). MS (ESI) m/e[M+1] ⁺ 197.

Step 5: Ethyl 4-chloro-3-fluoro-6-(hydroxymethyl)pyridine-2-carboxylate

(4,6-Dichloro-5-fluoropyridin-2-yl)methanol (12.0 g, 61 mmol), _Et3N (18.5 g, 183 mmol), and Pd(dppf) _{2Cl2 (} 2.23 g, 3.05 mmol) were suspended in EtOH (150 mL). Under a 60 psi CO atmosphere, the mixture was heated to 80°C for 6 hours, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EA = 100:1-1:1) to give a yellow solid, ethyl 4-chloro-3-fluoro-6-(hydroxymethyl)pyridine-2-carboxylate (w = 8.0 g, yield = 56%). MS (ESI) m/e [M+1] ⁺ 234. ¹ H NMR (DMSO-d ₆ ) δ 7.88 (d, 1H, J=5.2Hz), 5.73 (s, 1H), 4.57 (s, 2H), 4.35-4.41 (m, 2H), 1.30-1.35 (m, 3H).

Step 6: Ethyl 4-chloro-6-((1,3-dioxoisoindol-2-yl)methyl)-3-fluoropicolinate

At room temperature, _SOCl2 (10 mL) was added to a solution of 4-chloro-3-fluoro-6-(hydroxymethyl)pyridine-2-carboxylic acid ethyl ester (7.5 g, 32 mmol) in DCM (200 mL), and the mixture was stirred at room temperature overnight. The solvent was removed to give crude 4-chloro-6-(chloromethyl)-3-fluoropyridine-2-carboxylic acid ethyl ester. Crude 4-chloro-6-(chloromethyl)-3-fluoropyridine-2-carboxylic acid ethyl ester and potassium phthalimide (8.88 g, 48 mmol) were suspended in DMF (100 mL) and the mixture was stirred at room temperature overnight. The mixture was quenched with _H2O (500 mL) and EA (500 mL), and the organic layer was dried _{over Na2SO4} and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EA = 100: 1-1: 2) to give a white solid, ethyl 4-chloro-6-((1,3-dioxoisoindol-2-yl)methyl)-3-fluoropicolinate (w = 6.3 g, yield = 54%). MS (ESI) m/e [M+1] ⁺ 363. ¹ H NMR (DMSO-d ₆ ) δ 8.1 (d, 1 H, J = 4.8 Hz), 7.86-7.94 (m, 4 H), 4.93 (s, 2 H), 4.25-4.30 (m, 2 H), 1.15-1.18 (m, 3 H).

Step 7: Ethyl 6-(aminomethyl)-4-chloro-3-fluoropicolinate

To a solution of ethyl 4-chloro-6-((1,3-dioxoisoindol-2-yl)methyl)-3-fluoropyridine-2-carboxylate (2.1 g, 5.7 mmol) in EtOH (50 mL) was added hydrazine hydrate (570 mg, 11.4 mmol) at 80° C. over 0.5 hours. The mixture was stirred at 80° C. for 4 hours, quenched with 10 mL of HCOOH at room temperature, and then the solvent (approximately 80% EtOH) was removed. The precipitate was filtered and the filtrate was concentrated to give crude ethyl 6-(aminomethyl)-4-chloro-3-fluoropyridine-2-carboxylate (w=1.28 g). MS (ESI) m/e[M+1] ⁺ 233.

Step 8: Ethyl 4-chloro-3-fluoro-6-(formylaminomethyl)pyridine-2-carboxylate

Ethyl 6-(aminomethyl)-4-chloro-3-fluoropicolinate (1.28 g, 5.4 mmol) was suspended in HCOOH/CH ₃ CN (12 mL/4 mL), and the mixture was heated to 60° C. for 4 hours, and the solvent was removed under reduced pressure. The mixture was quenched with H ₂ O (150 mL) and EA (150 mL), and the organic layer was washed with brine (150 mL), dried over Na ₂ SO ₄ , and concentrated to give ethyl 4-chloro-3-fluoro-6-(formylaminomethyl)picolinate (w=800 mg). MS (ESI) m/e [M+1] ⁺ 261

Step 9: Ethyl 7-chloro-6-fluoroimidazo[1,5-a]pyridine-5-carboxylate

To a solution of ethyl 4-chloro-3-fluoro-6-(formamidomethyl)pyridine-2-carboxylate (800 mg, 3.07 mmol) in CH ₃ CN (50 mL) was added POCl ₃ (939 mg, 6.14 mmol) at room temperature. The mixture was stirred at 80° C. for 2 hours, and the solvent was removed under reduced pressure. The mixture was quenched with H ₂ O (100 mL) and EA (100 mL), and the organic layer was dried over Na ₂ SO ₄ and concentrated to give ethyl 7-chloro-6-fluoroimidazo[1,5-a]pyridine-5-carboxylate (w=650 mg).

Step 10: (7-Chloro-6-fluoroimidazo[1,5-a]pyridin-5-yl)methanol

To a solution of ethyl 7-chloro-6-fluoroimidazo[1,5-a]pyridine-5-carboxylate (650 mg, 2.67 mmol) in EtOH/THF (8 mL/4 mL) was added NaBH ₄ (203 mg, 5.34 mmol), and the mixture was stirred at room temperature for 4 hours. The mixture was quenched with H ₂ O (100 mL) and EA (100 mL), and the organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ , and concentrated to give a yellow solid as crude (7-chloro-6-fluoroimidazo[1,5-a]pyridin-5-yl)methanol (w=400 mg). MS (ESI) m/e[M+1] ⁺ 201.

Step 11: 7-Chloro-6-fluoroimidazo[1,5-a]pyridine-5-carbaldehyde

(7-chloro-6-fluoroimidazo[1,5-a]pyridine-5-yl)methanol (400 mg, 2 mmol) and Dess-Martin periodinane (1.27 g, 3 mmol) were suspended in DCM (50 mL) and the mixture was stirred at room temperature for 4 hours, and then the solvent was removed. The residue was purified by silica gel chromatography (petroleum ether/EA=100: 1-1: 2) to give a yellow solid, which was 7-chloro-6-fluoroimidazo[1,5-a]pyridine-5-carboxaldehyde (w=240 mg). MS (ESI) m/e[M+1] ⁺ 199.

Step 12: (7-chloro-6-fluoroimidazo[1,5-a]pyridin-5-yl)(cyclohexyl)methanol

To a solution of 7-chloro-6-fluoroimidazo[1,5-a]pyridine-5-carbaldehyde (60 mg, 0.3 mmol) in THF (20 mL) was added cyclohexylmagnesium bromide (3 mmol) dropwise at 0°C over 10 minutes. The mixture was quenched with aqueous _NH4Cl (50 mL) and EA (50 mL), washed with brine (50 _mL ), dried over _Na2SO4 and concentrated. The residue was purified by preparative-TLC to give a yellow solid (W = 20 mg). ¹ H NMR (DMSO-d ₆ ) δ8.61 (s, 1H), 7.94 (d, J=6.8Hz, 1H), 7.47 (s, 1H), 6.05 (d, J=4.4Hz, 1H), 4.87-4.89 (m, 1H), 1.98-2.20 (m, 3H), 1.57-1.59 (m, 2H), 0.97- 1.19 (m, 6H). MS(ESI)m/e[M+1] ⁺ 283.

Examples A157 to A158 were prepared according to the procedure described for A126 under appropriate conditions as would be recognized by one of ordinary skill in the art.

Example A157: Cyclohexyl(6-(cyclopent-1-en-1-yl)imidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (DMSO-d ₆ ). δ8.58 (s, 1H), 7.34-7.44 (m, 2H), 6.58-6.61 (m, 1H), 5.73-5.77 (m, 2H), 4.77-4.81(m, 1H), 2.67-2.71(m, 1H), 1.93-24(m, 4H), 1.48-1.57(m, 4H), 0.76-1.17(m, 7H) MS(ESI)m/e[M+1] ⁺ 297.0.

Example A158: Cyclohexyl(6-cyclopentylimidazo[1,5-a]pyridin-5-yl)methanol

¹ H NMR (DMSO-d ₆ ). δ8.58 (s, 1H), 8.13 (s, 1H), 7.27-7.47 (m, 2H), 6.73-6.75 (m, 1H), 5.70-5.71 (m, 2H), 4.95 (m, 1H), 1.56-1.77 (m, 10H), 0.97-1.10 (m, 8H). MS(ESI)m/e [M+1] ⁺ 299.0.

Example A159: 3-((6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)benzoic acid

Step 1: Methyl 3-((6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)benzoate

A solution of methyl 3-iodobenzoate (1.15 g, 4.4 mmol, 1.0 eq) in anhydrous THF (20 mL) was cooled to -30°C and i-PrMgCl (1.3 M solution in THF, 3.7 mL, 4.8 mmol, 1.1 eq) was added dropwise, maintaining the internal temperature at -20°C to -30°C and stirring for 30 min. A solution of 6-cyclopropylimidazo[1,5-a]pyridine-5-carbaldehyde in anhydrous THF (20 mL) was added dropwise. The reaction mixture was stirred at -20°C to -30°C for 30 and allowed to warm to room temperature. It was quenched with MeOH (10 mL), poured into water, extracted with EA, and the organic layer was washed with water and brine, dried over _Na2SO4 , concentrated, and purified _on silica gel to afford 220 mg, with a yield of 63%. ¹ H NMR (DMSO-d ₆ ) δ 8.08-8.10 (m, 1H), 7.60-7.64 (m, 1H), 7.45-7.51 (m, 2H), 7.28 (s, 1H), 6.86-6.87 (d, 1H, J=4.4Hz), 6.74-6.75 (d, 1H, J=4.0Hz), 6.61-6.63 (d, 1H, J=9.2Hz) , 3.84 (s, 3H), 2.21-2.29 (m, 1H), 0.97-1.03 (m, 2H), 0.86-0.93 (m, 1H), 0.73-0.78 (m, 1H).

Step 2: N-cyclopropyl-3-((6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)-benzoyl amine

A mixture of methyl 3-((6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy)-methyl)benzoate and LiOH·H ₂ O in MeOH/THF/H ₂ O was stirred at room temperature overnight and concentrated. The pH of the residue was adjusted to 6 with 1N aqueous HCl solution. The white solid was collected and air-dried to give 130 mg of the product. Yield: 62%. ¹ H NMR (DMSO-d ₆ ) δ 8.57 (s, 1H), 8.05 (s, 1H), 7.84-7.86 (d, 1H, J=7.6Hz), 7.59-7.63 (m, 3H), 7.45-7.50 (t, 1H, J=7.6Hz), 6.90 (s, 2H), 6.78-6.81 (d, 1H, J=9.6Hz), 2.26-2.36 (m, 1H), 1.00-1.09 (m, 2H), 0.90-0.96 (m, 1H), 0.77-0.85 (m, 1H).

Example A160: N-cyclopropyl-3-((6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)benzene Formamide

A mixture of 3-((6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy) _methyl )-benzoic acid, cyclopropylamine, HATU and _Et3N in DMF was stirred at room temperature for 2 hours, the reaction mixture was poured into water, extracted with EA, the organic layer was washed with water and brine, dried over _Na2SO4 , concentrated and purified on silica gel to give Example A160 (40 mg) as a white solid in 59% yield. ¹ H NMR (DMSO-d ₆ ) δ 8.51 (d, 1H, J=3.6Hz), 8.15 (s, 1H), 7.98 (s, 1H), 7.71 (d, 1H, J=7.6Hz), 7.35-7.50 (m, 3H), 7.28 (s, 1H), 6.83 (d, 1H, J=3.6Hz), 6.60-6.65 (m, 2H), 2 .76-2.85(m, 1H), 2.20-2.28(m, 1H), 0.98-1.02(m, 2H), 0.73-0.93(m, 3H), 0.65-0.70(m, 2H), 0.53-0.58(m,2H).

Example A161: 3-((6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)bicyclo[2.2.1] Heptan-2-one

At -70 ° C, under N ₂ atmosphere, LDA (1.0 M solution in THF) was added to a solution of (1S, 4R)-bicyclo[2.2.1]heptan-2-one (440mg 4mmol) in THF. The mixture was stirred at this temperature for 0.5 hours. A solution of 6-cyclopropylimidazo[1,5-a]pyridine-5-carboxaldehyde (362mg 2mmol) in THF was then added dropwise. The mixture was stirred at this temperature for 0.5 hours. The reaction mixture was quenched with EA (50mL) and saturated NH ₄ Cl solution (50mL), the organic layer was washed with brine (50mL*2), dried over Na ₂ SO ₄ and concentrated. The residue was purified by preparative-TLC to obtain 3-((6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)bicyclo[2.2.1]heptan-2-one as a yellow solid. ^1HNMR (DMSO- _d6 ) _δH 7.30-7.32(m, 2H), 6.22-6.24(m, 1H), 5.73-5.76(m, 1H), 5.53(s, 1H), 5.13-5.17(m, 1H), 2.96- 2.98(m, 1H), 2.51-2.53(m, 1H), 2.04-2.09(m, 2H), 1.41-1.52(m, 3H), 0.85-0.86(m, 3H), 0.58- 0.84 (m, 2H), 0.38-0.41 (m, 1H). MS(ESI)m/e[M+1] ⁺ 297.0.

Example A162: (Bicyclo[2.2.1]hept-2-yl)(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol

Step 1: Ethyl 6-(((tert-Butoxycarbonyl)amino)methyl)-3-cyclopropylpyridine-2-carboxylate

Ethyl 6-(((tert-butoxycarbonyl)amino)methyl)-3-chloropyridine-2-carboxylate (37.8 g, 120 mmol), Pd(dppf) _Cl₂ (13.16 g, 18 mmol), cyclopropylboronic acid (12.38 g, 144 mmol) _, and _Cs₂CO₃ (46.8 g, 144 mmol) were suspended in toluene (750 mL). The resulting mixture was stirred at 90° C. under an _N₂ atmosphere for 4 hours. After cooling to room temperature, EA (200 mL) was added to the residue, which was filtered through celite and concentrated to afford ethyl 6-(((tert-butoxycarbonyl)amino)methyl)-3-cyclopropylpyridine-2-carboxylate (26.0 g) as a yellow solid. ^ℓ NMR (DMSO- _dℓ ). δ _H 7.45-7.47(m, 2H), 7.28-7.31(m, 1H), 4.34-4.38(m, 2H), 4.17-4.19(m, 2H), 2.09-2.14(m, 1H), 1.23-1.40(m, 12H), 0.95(m, 2H), 0.67-0.70(m, 2H).

Step 2: 6-(((tert-Butoxycarbonyl)amino)methyl)-3-cyclopropylpyridine-2-carboxylic acid

Ethyl 6-(((tert-butoxycarbonyl)amino)methyl)-3-cyclopropylpyridine-2-carboxylate (28.0 g, 87.5 mmol) and LiOH (7.0 g, 1750 mmol) were suspended in MeOH/ _H₂O (200 mL/20 mL), and the resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the mixture was acidified with 1N HCl to pH 6-7. The mixture was extracted with EA (500 mL), washed with brine (200 _mL ), dried over _Na₂SO₄ , and concentrated to give crude 6-(((tert-butoxycarbonyl)amino)methyl)-3-cyclopropylpyridine-2-carboxylic acid (25.0 g) as a yellow oil. MS (ESI) m/e [M+1] ^⁺ 293.0.

Step 3: tert-Butyl ((5-cyclopropyl-6-(methoxy(methyl)carbamoyl)pyridin-2-yl)methyl)carbamate ester

6-(((tert-Butoxycarbonyl)amino)methyl)-3-cyclopropylpyridine-2-carboxylic acid (25.0 g, 87 mmol), HATU (33.0 g, 87 mmol), Et _N (26.0 g, 262 mmol) and N, O-dimethylhydroxylamine hydrochloride (9.8 g, 100 mmol) were suspended in DCM (350 mL). The resulting mixture was stirred at room temperature under an _N atmosphere for 4 hours. DCM (200 mL) was added to the mixture, washed with brine (200 mL*2), dried _over Na _SO and concentrated. The residue was purified by chromatography to give tert-butyl ((5-cyclopropyl-6-(methoxy-(methyl)carbamoyl)pyridin-2-yl)methyl)carbamate (27 g) as a yellow oil. ¹ HNMR(DMSO-d6).δ _H 7.35-7.43(m, 2H), 7.18-7.21(m, 1H), 4.21-4.22(m, 2H), 3.53(s, 3H), 3.29 (s, 1H), 1.79 (m, 1H), 1.19 (s, 9H), 0.93 (m, 2H), and 0.67-0.70 (m, 2H).

Step 4: tert-Butyl ((6-acryloyl-5-cyclopropylpyridin-2-yl)methyl)carbamate

To _a solution of tert-butyl ((5-cyclopropyl-6-(methoxy(methyl)carbamoyl)pyridin-2-yl)methyl)carbamate (26.0 g, 77 mmol) in anhydrous THF (500 mL) was added vinylmagnesium bromide (194 mL, a 1.0 M solution in THF) dropwise at 0°C under an _N atmosphere. The resulting mixture was stirred at 0°C under an N atmosphere for 1 hour. The reaction mixture was quenched with 0.5N HCl (50 mL) and extracted with EA (200 mL*2), washed with brine (200 mL*2), dried over _NaSO and concentrated. The residue was purified by chromatography to give tert-butyl (( ₆ -acryloyl-5-cyclopropylpyridin-2-yl)methyl)carbamate (15.2 g) as a yellow solid. ¹ H NMR(DMSO-d ₆ )δ _H 7.44-7.49(m, 2H), 7.27-7.34(m, 2H), 6.23-6.27(m, 1H), 6.03-6.06(m, 1H), 4.21-4.22(m, 1H), 2.39-2.43(m, 1H), 1.40(s, 9H), 0.94-0.98(m, 2H), and 0.68-0.71(m, 2H).

Step 5: ((6-(bicyclo[2.2.1]hept-5-ene-2-carbonyl)-5-cyclopropylpyridin-2-yl)methyl)carbamic acid tert-Butyl ester

To a solution of ZnBr (2.0 _g ) in DCM was added cyclopenta-1,3-diene (3 mL) at -78°C under _N atmosphere. The resulting mixture was stirred at -78°C under _N atmosphere for 0.5 h, followed by the dropwise addition of a solution of tert-butyl ((6-acryloyl-5-cyclopropylpyridin-2-yl)methyl)carbamate (2.1 g, 7 mmol) in DCM at -78°C under _N atmosphere. The mixture was stirred at -78°C under _N atmosphere for an additional 0.5 h. The reaction mixture was then quenched with saturated _NaHCO solution (150 mL) and DCM (200 mL), washed with brine (200 mL), _dried over _NaSO , and concentrated. The residue was purified by chromatography to give tert-butyl ((6-(bicyclo[2.2.1]hept-5-ene-2-carbonyl)-5-cyclopropylpyridin-2-yl)methyl)carbamate (2.2 g) as an oil. ¹ HNMR(DMSO-d ₆ )δ _H 7.26-7.46(m, 3H), 6.15-6.18(m, 1H), 5.75-5.78(m, 1H), 4.13-4.24(m, 3H), 3.10(s, 1H), 2.91(s, 1H), 2.18-2.21(m, 1H), 1.81-1.85(m, 1H), 1.15- 1.30 (m, 12H), 0.91-0.96 (m, 2H), and 0.61-0.66 (m.2H). MS(ESI)m/e[M+1] ⁺ 369.0.

Step 6: tert-Butyl ((6-(bicyclo[2.2.1]hept-2-carbonyl)-5-cyclopropylpyridin-2-yl)methyl)carbamate ester

The reaction mixture of tert-butyl ((6-(bicyclo[2.2.1]hept-5-ene-2-carbonyl)-5-cyclopropylpyridin-2-yl)methyl)carbamate (9.2 g, 25 mmol) and Pd/carbon (920 mg) in MeOH (100 mL) was stirred at ambient temperature under _H2 (4 atm) for 2 hours. The resulting solution was filtered through celite and concentrated to give tert-butyl ((6-(bicyclo[2.2.1]heptane-2-carbonyl)-5-cyclopropylpyridin-2-yl)methyl)carbamate (W = 9.2 g) as a yellow oil.

Step 7: ((6-((bicyclo[2.2.1]hept-2-yl)(hydroxy)methyl)-5-cyclopropylpyridin-2-yl)methyl)amino tert-Butyl formate

To a solution of tert-butyl ((6-(bicyclo[2.2.1]hept-2-carbonyl)-5-cyclopropylpyridin-2-yl)methyl)carbamate (9.2 g, 25 mmol) in anhydrous THF (100 mL) was added (S)-3,3-diphenyl-1-methylpyrrolidino[1,2-c]-1,3,2-oxazaborolane (5 mL, 1.0 M solution in toluene) and borane-dimethyl sulfide complex (25 mL, 2.0 M solution in THF) in portions at room temperature. The resulting mixture was stirred at this temperature for 5 hours, then quenched with 6N HCl (5 mL) for 2 hours, extracted with EA (200 mL*2), washed with brine (200 mL*2), _dried over _Na2SO4 and concentrated. The residue was purified by chromatography to give tert-butyl ((6-((bicyclo[2.2.1]hept-2-yl)(hydroxy)methyl)-5-cyclopropylpyridin-2-yl)methyl)carbamate (4.2 g, 45%) as an oil. ¹ H NMR (DMSO-d ₆ )δ _H 7.26-7.35 (m, 2H), 6.99-7.01 (m, 1H), 4.80-4.86 (m, 2H), 4.14-4.16 (m, 2H), 2.51-2.53 (m, 1H), 2.43 (m, 1H), 2.21-2.25 (m, 1H), 2.07(m, 1H), 1.77-1.82(m, 1H), 1.05-1.50(m, 14H), 0.90-0.97(m, 2H), 0.70-0.73(m, 2H), and 0.38-0.43(m, 2H).

Step 8: (6-(Aminomethyl)-3-cyclopropylpyridin-2-yl)((1R,4S)-bicyclo[2.2.1]hept-2-yl)methane Alcohol hydrochloride:

tert-Butyl ((6-((bicyclo[2.2.1]hept-2-yl)(hydroxy)methyl)-5-cyclopropyl-pyridin-2-yl)methyl)carbamate (1.2 g, 3.2 mmol) was suspended in HCl(gas)/EA (20 mL, 4.0 M solution in EA) and the resulting mixture was stirred at this temperature for 5 hours. The solvent was removed under reduced pressure to give (6-(aminomethyl)-3-cyclopropylpyridin-2-yl)((1R,4S)-bicyclo[2.2.1]hept-2-yl)methanol hydrochloride (0.96 g, 97%) as a white solid. MS (ESI) m/e[M+1] ⁺ 273.0.

Step 9: (Bicyclo[2.2.1]hept-2-yl)(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol

HCOOH/ _Ac₂O (6 mL/20 mL) was heated to 55°C for 2 hours. (6-(Aminomethyl)-3-cyclopropylpyridin-2-yl)(bicyclo[2.2.1]hept-2-yl)methanol hydrochloride (0.95 g, 3.0 mmol) was then added to the HCOOH/ _Ac₂O solution. The resulting mixture was stirred at 55°C overnight. The solvent was removed under reduced pressure, and the residue was quenched with saturated _NaHCO₃ solution (100 mL) and EA (150 mL), washed with brine (200 mL*2), _dried over _Na₂SO₄ , and concentrated. The residue was dissolved in MeOH (15 mL), and LiOH· _H₂O (0.95 g, 24 mmol) was added. The mixture was stirred at room temperature for 1 hour. The residue was quenched with saturated _NaHCO₃ solution (50 mL) and EA (50 mL), washed with brine (20 mL* ₂ ), dried over _Na₂SO₄ , and concentrated. The residue was purified with MTBE/petroleum ether and recrystallized to give ((bicyclo[2.2.1]hept-2-yl)(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol as a yellow solid. MS (ESI) m/e [M+1] ⁺ 283.0.

Examples A162a and A162b: (1S)-(Bicyclo[2.2.1]hept-2-yl)(6-cyclopropylimidazo[1,5-a]pyrrolidone pyridin-5-yl)methanol and (1R)-(bicyclo[2.2.1]hept-2-yl)(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)methanol

At 85 ° C, bicyclo [2.2.1] hept-2-yl (6-cyclopropylimidazo [1, 5-a] pyridin-5-yl) methanol (1.9 g, 6.7 mmol) was dissolved in CH 3 CN (90 ml), and then a solution of L- (-) -dibenzoyl-L-tartaric acid (2.78 g, 7.38 mmol) in 10 mL of CH ₃ CN was added. The mixture was slowly cooled to room temperature and stirred at room temperature overnight. A white solid was obtained by filtration. The white solid was dissolved in EA (100 mL), washed with saturated NaHCO ₃ solution (100 mL), and the organic layer was washed with brine (50 mL * 2), dried over Na ₂ SO ₄ and concentrated. The residue was recrystallized from EA / petroleum ether to give bicyclo [2.2.1] hept-2-yl (6-cyclopropylimidazo [1, 5-a] pyridin-5-yl) methanol (590 mg) as a white solid. ¹ H NMR (DMSO-d ₆ ) δ _H 8.62 (s, 1H), 7.38 (d, 1H, J=9.6Hz), 7.30 (s, 1H), 6.48 (d, 1H, J=9.6Hz), 5.63 (d, 1H, J=3.2Hz), 5.41- 5.45(m, 1H), 2.67-2.74(m, 1H), 2.51-2.53(m, 1H), 1.99-2.08(m, 2H), 1.80-1.82(m, 1H), 4-(4-(4-(4-oxo-2-nitro-1-yl)-2-nitro-2-nitro-3-nitro-4-oxo-2-nitro-5-nitro-6-oxo-2-nitro-7-oxo-2-nitro-6-oxo-2-nitro-7-oxo-2-nitro-7-oxo-2-nitro ^- 8 ... ¹ H NMR (DMSO-d ₆ ). δ _H 8.61 (s, 1H), 7.38 (d, 1H, J=9.6Hz), 7.30 (s, 1H), 6.48 (d, 1H, J=9.6Hz), 5.63 (d, 1H, J=3.2Hz), 5.43 (dd, 1H, J=11.2, 3.2Hz), 2.68-2.74 (m, 1H), 2.51-2.53 (m, 1H), 1.99-2.08 (m, 2H), 1.80-1.82 (m, 1H), 1.45-1.50 (m, 2H), 1.32 (m, 2H), 1.09-1.16 (m, 2H), 0.95-0.99 (m, 1H), 0.85-0.86 (m, 1H), 0.61-0.65 (m, 2H). MS (ESI) m/e[M+1] ⁺ 283.0. Based on the assumption that the binding model of the more potent isomer A162a is the same as that of A101a for the 1DO1 enzyme, the absolute configuration of A162a is tentatively assigned to (S).

Examples A163 and A164 were prepared according to the procedure described for A129 under appropriate conditions as would be recognized by one of ordinary skill in the art.

Example A163: 2-(Adamantane-1-yl)-1-(6-cyclopropylimidazo[1,5-a]pyridin-5-yl)ethan-1-ol

¹ H NMR (DMSO-d ₆ )δ8.65 (s, 1H), 7.38 (d, J=9.2Hz, 1H), 7.32 (s, 1H), 6.51 (d, J=9.2Hz, 1H), 5.83-5.77 (m, 1H), 5.55 (d, J=3. 6Hz, 1H), 2.08-1.88(m, 4H), 1.70-1.33(m, 14H), 1.00-0.90(m, 2H), 0.88-0.75(m, 1H), 0.65-0.57(m, 1H). MS(ESI)m/e[M+1] ⁺ 337.2.

Example A164: 3-((6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)cyclohexan-1-ol

Following procedures similar to those described in Example A126, the desired product was prepared.Separation by prep-HPLC gave A164a (35 mg, including two racemic isomers) as an off-white solid. ¹ H NMR (DMSO-d ₆ ) δ _H 8.59 (s, 1H), 7.41 (d, J=9.4Hz, 1H), 7.32 (s, 1H), 6.59 (d, J=9.4Hz, 1H), 5.79 (d, J=3.6 Hz, 1H), 5.23 (dd, J=3.6, 9.6Hz, 1H), 4.42 (br s, 1H), 3.20-3.08 (m, 1H), 2.24-2.10 (m, 2H), 2.04-1.92 (m, 1H), 1.90- 1.70 (m, 2H), 1.30-1.12 (m, 3H), 1.06-0.82 (m, 4H), 0.77-0.62 (m, 2H). MS (ESI) m/e [M+1] ⁺ 287.2. A164b (135 mg, including four isomers) was obtained as a yellow solid. ¹ H NMR (DMSO-d ₆ ) δ 8.57 (s, 1H), 7.39 (d, J = 9.2Hz, 1H), 7.30 (s, 1H), 6.45 (d, J = 9.2Hz, 1 H), 5.79 (d, J=4.0Hz, 0.65H), 5.70 (d, J=3.6Hz, 0.35H), 5.25-5.17 (m, 1H), 4.63-4.53 (m, 0.65H), 4.20-4.14(m, 0.35H), 3.80-3.73(m, 0.35), 2.48-2.38(m, 1H), 2.20-2.10(m, 1H), δ 2.04-1.90 (m, 1H), 1.80-1.70 (m, 1H), 1.65-1.42 (m, 2H), 1.20-0.80 (m, 6H), 0.79-0.69 (m, 1H), 0.68-0.58 (m, 1H). MS (ESI) m/e [M+1] ⁺ 287.2. A164c (40 mg, including two racemic isomers) was obtained as a light yellow solid. ¹ H NMR (DMSO-d ₆ ) δ 8.57 (s, 1H), 7.39 (d, J=9.6Hz, 1H), 7.30 (s, 1H), 6.45 (d, J=9.6Hz, 1H), 5.70 (d, J=2.6Hz, 1H), 5.20 (dd, J=2.6, 9.2Hz, 1H), 4.35 (br s, 1H), 3.97 (brs, 1H), 2.24-2.14 (m, 1H), 2.24-1.92 (m, 1H), 1.85-1.20 (m, 6H), 1.10-0.85 (m, 4H), 0.80-0.70 (m, 1H), 0.68-0.58 (m, 1H). MS (ESI) m/e [M+1] ⁺ 287.2.

Example A165: 5-((6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)bicyclo[2.2.1] Heptan-2-ol

Step 1: (Cyclopenta-1,4-dien-1-yloxy)trimethylsilane

To a solution of cyclopent-2-en-1-one (2 g, 24.4 mmol) and _Et3N (3.7 g, 36.6 mmol) was added triethylsilyl trifluoromethanesulfonate (5.42 g, 24.4 mmol) at 0°C. After 15 min, the reaction mixture was esterified with trifluoromethanesulfonic acid via syringe and concentrated under reduced pressure. The residue was used in the next step without further purification.

Step 2: ((5-cyclopropyl-6-(5-oxobicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-yl)methyl)amino tert-Butyl formate

At -78 ° C, under _N2 atmosphere, to a solution of _ZnBr2 (1.3g) in DCM, (cyclopenta-1,4-diene-1-yloxy) trimethylsilane (1.3g, 4.3mmol) is added. The resulting mixture is stirred at -78 ° C under _N2 atmosphere for 0.5 hour. At -78 ° C, under _N2 atmosphere, a solution of tert-butyl ((6-acryloyl-5-cyclopropylpyridin-2-yl) methyl) carbamate (0.99g, 6.45mmol) in DCM is added dropwise, and the mixture is stirred at -78 ° C for 0.5 hour. The reaction mixture is quenched with saturated _NaHCO3 solution (150mL) and DCM (200mL), and washed with brine ( _20mL ), dried over _Na2SO4 and concentrated. The residue is purified by chromatography to obtain product (80mg), which is a yellow oil. MS (ESI) m/e [M+1] ⁺ 384.7.

Step 3: 5-(6-(Aminomethyl)-3-cyclopropylpyridine-2-carboxyl)bicyclo[2.2.1]heptan-2-one

To a mixture of tert-butyl ((5-cyclopropyl-6-(5-oxobicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-yl)methyl)carbamate (80 mg, 0.2 mmol) in DCM (10 ml) was added TFA (1 ml) dropwise, and the mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The solvent was then removed in vacuo to give a crude product (60 mg, 99%, yellow oil) which was used in the next step without further purification.

Step 4: 5-(6-cyclopropylimidazo[1,5-a]pyridine-5-carbonyl)bicyclo[2.2.1]heptan-2-one

HCOOH/ _Ac₂O (6 mL/20 mL) was heated to 55°C for 2 hours, followed by the addition of 5-(6-(aminomethyl)-3-cyclopropylpyridine-2-carbonyl)bicyclo[2.2.1]heptan-2-one (60 mg, 0.2 mmol), and the mixture was stirred at 55°C overnight. The solvent was removed under reduced pressure, and the residue was quenched with saturated _NaHCO₃ solution (100 mL) and EA (20 mL), washed with brine (20 _mL *2), dried over _Na₂SO₄ , filtered, and concentrated to afford the crude product. The crude product was purified by silica gel chromatography (PE:EA = 20:1 to 1:1) to afford the product (40 mg, 68%) as a yellow solid. MS (ESI) m/e [M+1] ^⁺ 294.7.

Step 5: 5-((6-cyclopropylimidazo[1,5-a]pyridin-5-yl)(hydroxy)methyl)bicyclo[2.2.1]hept-2-yl alcohol

To a solution of 5-(6-cyclopropylimidazo[1,5-a]pyridine-5-carbonyl)bicyclo[2.2.1]heptan-2-one (20 mg, 0.068 mmol) in MeOH (10 ml) was added NaBH ₄ (5.2 mg, 0.136 mmol) dropwise and stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The solvent was removed in vacuo and the crude product was purified by preparative HPLC to give the product (15 mg, 75%) as a white solid. ¹ H NMR (DMSO-d6) δ9.70 (s, 1H), 8.07 (s, 1H), 7.71 (d, J=9.6Hz, 1H), 6.86 (d, J=9.6H z, 1H), 5.23 (d, J=10.4Hz, 1H), 4.01 (d, J=10.4Hz, 1H), 2.51 (m, 3H), 2.31 (dd, J= 13.8, 9.6Hz, 1H), 2.10 (d, J=16.3Hz, 2H), 2.03-1.86 (m, 1H), 1.50 (d, J=5.8Hz, 2H), 1.28 (d, J=9.8 Hz, 1H), 1.05 (d, J=8.4Hz, 2H), 0.95-0.82 (m, 2H), 0.72 (d, J=5.0Hz, 1H). [M+1] ⁺ 298.7.

Example B: Synthesis of 8-substituted imidazo[1,5-a]pyridine

Example B001: Cyclohexyl(imidazo[1,5-a]pyridin-8-yl)methanol

Step 1: N-methoxy-N-methylimidazo[1,5-a]pyridine-8-carboxamide

To a solution of imidazo[1,5-a]pyridine-8-carboxylic acid (50 mg, 0.31 mmol) in DMF (5 mL) was added TEA (94 mg, 0.37 mmol), N,O-dimethylhydroxylamine hydrochloride (36 mg, 0.37 mmol), and HATU (140 mg, 0.37 mmol). The reaction mixture was stirred at ambient temperature for approximately 2 hours. The solvent was removed by concentration under reduced pressure, and water (5 mL) was added to the residue. _The mixture was extracted with _CH₂Cl₂ (3*10 mL), and the combined organic phases were washed with saturated NaCl ( ₅ mL), dried over anhydrous _Na₂SO₄ , filtered, concentrated, and purified by silica gel column chromatography to afford approximately 100 mg (>95%, crude) of the product as a light yellow oil. MS (ESI) m/e [M+1] ^⁺ 206.1.

Step 2: Cyclohexyl(imidazo[1,5-a]pyridin-8-yl)methanone

To a solution of N-methoxy-N-methylimidazo[1,5-a]pyridine-8-carboxamide (100 mg, 0.30 mmol) in THF (10 mL) was added cyclohexylmagnesium chloride (2 M, 0.45 mL, 0.9 mmol), and the reaction mixture was stirred at ambient temperature for approximately 2 hours. The reaction mixture was quenched by the addition of saturated _NH₄Cl (5 mL). The mixture was then extracted with EA (3*10 mL), and the combined organic phases were washed with saturated NaCl ( ₅ mL), dried over anhydrous _Na₂SO₄ , filtered, and concentrated to give the crude product (approximately 100 mg) as a yellow solid. MS (ESI) m/e[M+1] ^⁺ 229.1.

Step 3: Cyclohexyl(imidazo[1,5-a]pyridin-8-yl)methanol

To a solution of cyclohexyl(imidazo[1,5-a]pyridin-8-yl)methanone (100 mg, 0.30 mmol) in EtOH (5 mL) was added NaBH ₄ (23 mg, 0.60 mmol), and the reaction mixture was stirred at ambient temperature for about 3 hours. Saturated NH ₄ Cl (3 mL) was added to the reaction mixture, which was then concentrated under reduced pressure to remove the organic solvent and extracted with CH ₂ Cl ₂ (3*10 mL). The combined organic phases were washed with saturated NaCl (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated, and the crude product was purified by preparative-TLC (DCM:MeOH=15:1) to give the product (5.0 mg, 7.2%) as a light yellow solid. ¹ H NMR (DMSO-d ₆ ) δ 8.34 (s, 1H), 8.21 (d, J = 6.8Hz, 1H), 7.39 (s, 1H), 6.68 (d, J = 6.8Hz, 1H), 6.62 (dd, J=6.8, 6.8Hz, 1H), 5.24 (d, J=4.4Hz, 1H), 4.47 (dd, J=4.4, 6.0Hz, 1H), 1.82-1.52 (m, 5H), 1.40-1.00 (m, 6H). MS(ESI)m/e[M+1] ⁺ 231.1.

Example B002: Cyclopentyl(imidazo[1,5-a]pyridin-8-yl)methanol

Using procedures similar to those described for Example B001 (Steps 2 to 3), the desired product was prepared from N-methoxy-N-methylimidazo[1,5-a]pyridine-8-carboxamide and cyclopentylmagnesium bromide under appropriate conditions recognized by one of ordinary skill in the art. ¹ H NMR (DMSO-d ₆ ) δ 8.40 (s, 1H), 8.23 (d, J=6.8 Hz, 1H), 7.44 (s, 1H), 6.73 (d, J=6.4 Hz, 1H), 6.63 (dd, J=6.4, 6.8 Hz, 1H), 5.33 (d, J=3.6 Hz, 1H), 4.51 (dd, J=3.6, 4.8 Hz, 1H), 2.37-2.28 (m, 1H), 1.65-1.20 (m, 8H). MS (ESI) m/e [M+1] ⁺ 217.1.

Example B003: Imidazo[1,5-a]pyridin-8-yl(phenyl)methanone

Using a procedure similar to that described for Example B001 (Step 2), the desired product was prepared from N-methoxy-N-methylimidazo[1,5-a]pyridine-8-carboxamide and phenylmagnesium bromide under appropriate conditions recognized by one of ordinary skill in the art. ¹ H NMR (DMSO-d ₆ ) δ 8.67-8.63 (m, 1H), 8.54 (d, J=0.8 Hz, 1H), 8.78-8.74 (m, 2H), 7.72-7.66 (m, 2H), 7.61-7.55 (m, 2H), 7.23 (dd, J=0.8, 6.8 Hz, 1H), 6.82 (dd, J=6.8, 6.8 Hz, 1H). MS (ESI) m/e[M+1] ⁺ 223.1.

Example B004: Imidazo[1,5-a]pyridin-8-yl(phenyl)methanol

The desired product was prepared from Example B003 using a procedure similar to that for Example B001 (Step 3) under appropriate conditions recognized by one of ordinary skill in the art. ¹ H NMR (DMSO-d ₆ ) δ 8.43 (s, 1H), 8.23 (d, J=6.8 Hz, 1H), 7.47 (d, J=7.6 Hz, 2H), 7.32-7.27 (m, 3H), 7.24-7.18 (m, 1H), 6.93 (d, J=6.8 Hz, 1H), 6.68 (dd, J=6.8, 6.8 Hz, 1H), 6.05 (d, J=4.2 Hz, 1H), 5.85 (d, J=4.2 Hz, 1H). MS (ESI) m/e [M+1] ⁺ 225.1.

Example B005: Cycloheptyl(imidazo[1,5-a]pyridin-8-yl)methanol

Using a similar procedure to Example B001 (steps 2 to 3), the desired product was prepared from N-methoxy-N-methylimidazo[1,5-a]pyridine-8-carboxamide and cycloheptylmagnesium bromide under appropriate conditions recognized by one of ordinary skill in the art. The product (20 mg, 15%) was obtained as an off-white solid. ¹ H NMR (DMSO-d ₆ ) δ 8.37 (s, 1H), 8.22 (d, J=7.2 Hz, 1H), 7.38 (s, 1H), 6.72 (d, J=6.4 Hz, 1H), 6.63 (dd, J=6.4, 7.2 Hz, 1H), 5.28 (d, J=4.0 Hz, 1H), 4.53 (dd, J=4.0, 5.2 Hz, 1H), 2.00-1.20 (m, 13H). MS (ESI) m/e [M+1] ⁺ 245.2.

Example B006: 2-cyclohexyl-1-(imidazo[1,5-a]pyridin-8-yl)ethan-1-ol

Step 1: Imidazo[1,5-a]pyridine-8-carbaldehyde

To a solution of N-methoxy-N-methylimidazo[1,5-a]pyridine-8-carboxamide (4.2 g, 20.5 mmol) in 60 mL of anhydrous THF was added portionwise _LiAlH₄ (3.9 g, 102.5 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h. 50 mL of saturated aqueous _NH₄Cl and 150 mL of saturated brine were added. 300 mL of ethyl acetate was then added. The organic layer was separated from the aqueous layer. The mixture was washed with saturated brine (200 mL x 2) and dried over sodium sulfate. Purification by silica gel chromatography (eluting with DCM/MeOH) afforded 0.9 g (30%) of imidazo[1,5-a]pyridine-8-carboxaldehyde as a yellow solid. MS (ESI) m/e [M+1] ⁺ 147.1.

Step 2: 2-cyclohexyl-1-(imidazo[1,5-a]pyridin-8-yl)ethan-1-ol

To a solution of imidazo[1,5-a]pyridine-8-carbaldehyde (50 mg, 0.34 mmol) in THF (5 mL) was added (cyclohexylmethyl)magnesium chloride (2.0 mL, 0.5 M, 1.0 mmol), and the reaction mixture was stirred at ambient temperature for about 1 hour. The reaction mixture was quenched by the addition of saturated _NH4Cl (5 mL), then extracted with EA (3*10 mL), and the combined organic phases were washed with saturated NaCl (5 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated. The crude product was purified by preparative-TLC (DCM:MeOH=15:1) to give the product (45 mg, 53.6%) as a white solid. ¹ H NMR (DMSO-d ₆ ) δ 8.42 (s, 1H), 8.24 (d, J=7.0Hz, 1H), 7.34 (s, 1H), 6.77 (d, J=6.8Hz, 1H), 6.66 (dd, J=6.8, 7.0Hz, 1H), 5.31 (d, J=4.4Hz, 1H), 4.84-4.80 (m, 1H), 1.99-0.79 (m, 13H). MS(ESI)m/e[M+1] ⁺ 245.2.

Example B007: 2-Cyclopropyl-1-(imidazo[1,5-a]pyridin-8-yl)ethan-1-ol

Using a procedure similar to that described for Example B006 (Step 2), the desired product was prepared from imidazo[1,5-a]pyridine-8-carbaldehyde and (cyclopropylmethyl)magnesium bromide under appropriate conditions recognized by one of ordinary skill in the art. The product (50 mg, 60.2%) was obtained as a brown oil. ¹ H NMR (DMSO-d ₆ )δ8.40 (s, 1H), 8.24 (d, J=6.8Hz, 1H), 7.39 (s, 1H), 6.76 (d, J=6.6Hz, 1H), 6.65 (dd, J=6.6, 6.8Hz, 1H), 5.89-5 .78 (m, 1H), 5.41 (d, J=4.4Hz, 1H), 5.03-4.92 (m, 2H), 4.79-4.74 (m, 1H), 2.15-2.07 (m, 2H), 1.88-1.70 (m, 2H). MS(ESI)m/e[M+1] ⁺ 203.1.

Example B008: 3-cyclohexyl-1-(imidazo[1,5-a]pyridin-8-yl)propan-1-ol

Using a procedure similar to that described for Example B006 (Step 2), the desired product was prepared from imidazo[1,5-a]pyridine-8-carbaldehyde and (2-cyclohexylethyl)magnesium bromide under appropriate conditions recognized by one of ordinary skill in the art. The product (45 mg, 42.4%) was obtained as a white solid. ^1H NMR (DMSO- _d ) δ 8.42 (s, 1H), 8.24 (d, J=6.8 Hz, 1H), 7.34 (s, 1H), 6.75 (d, J=6.6 Hz, 1H), 6.66 (dd, J=6.6, 6.8 Hz, 1H), 5.33 (d, J=4.0 Hz, 1H), 4.72-4.68 (m, 1H), 1.77-1.53 (m, 8H), 1.38-1.00 (m, 7H). MS (ESI) m/e [M+1] ⁺ 259.2.

Example B009: 1-cyclohexyl-2-(imidazo[1,5 -a]pyridin-8-yl)propan-2-ol

Step 1: 2-cyclohexyl-1-(imidazo[1,5-a]pyridin-8-yl)ethan-1-one

To a solution of 2-cyclohexyl-1-(imidazo[1,5-a]pyridin-8-yl)ethan-1-ol (40 mg, 0.16 mmol) in _CH₂Cl₂ (5 _mL ) was added Dess-Martin (204 mg, 0.48 mmol), and the reaction mixture was stirred at ambient temperature for approximately 3 hours. Saturated _NH₄Cl (5 mL) was added to the reaction mixture, followed by extraction with _CH₂Cl₂ (3*10 mL) _. The combined organic phases were washed with saturated NaCl (5 mL), dried _over anhydrous _Na₂SO₄ , filtered, and concentrated. The crude product was purified by preparative TLC (DCM:MeOH = 15:1) to afford the product (30 mg, 75.6%) as a yellow solid. MS (ESI) m/e [M+1] ^⁺ 243.2.

Step 2: 1-cyclohexyl-2-(imidazo[1,5-a]pyridin-8-yl)propan-2-ol

To a solution of 2-cyclohexyl-1-(imidazo[1,5-a]pyridin-8-yl)ethan-1-one (30 mg, 0.12 mmol) in THF (5 mL) was added methylmagnesium bromide (0.5 mL, 2.0 M, 1.0 mmol), and the reaction mixture was stirred at ambient temperature for about 1 hour. Saturated _NH4Cl (5 mL) was added to the reaction mixture, followed by extraction with EA (3*10 mL), and the combined organic phases were washed with saturated NaCl ( ₅ mL), dried over anhydrous _Na2SO4 , filtered, and concentrated. The crude product was purified by preparative-TLC (DCM:MeOH=15:1) to give the product (15 mg, 46.9%) as a brown oil. ¹ H NMR (DMSO-d ₆ ) δ8.33 (s, 1H), 8.20 (d, J=6.8Hz, 1H), 7.43 (s, 1H), 6.81 (d, J=6.8Hz, 1H), 6.63 (dd, J=6.8, 6.8Hz, 1H), 5.03 (s, 1H), 1.73-1.63 (m, 2H), 1.53 (s, 3H), 1.52-0.80 (m, 11H). MS(ESI)m/e[M+1] ⁺ 259.2.

Example B010: 1-cyclohexyl-3-(imidazo[1,5-a]pyridin-8-yl)propan-1-ol

Step 1: (E)-1-cyclohexyl-3-(imidazo[1,5-a]pyridin-8-yl)prop-2-en-1-one

To a solution of imidazo[1,5-a]pyridine-8-carbaldehyde (60 mg, 0.41 mmol) in _H₂O (10 mL) was added 1-cyclohexylethan-1-one (52 mg, 0.41 mmol) and _NaHCO₃ (18 mg, 0.21 mmol). The reaction mixture was warmed to reflux and stirred for approximately 40 hours. The mixture was extracted with _{CH₂Cl₂ (} 3*10 mL), and the combined organic phases were washed with saturated NaCl (5 mL), dried _over anhydrous _Na₂SO₄ , filtered, and concentrated. The crude product was purified by preparative TLC (DCM:MeOH=15:1) to give the product (10 mg, 9.6%) as a light yellow solid. MS (ESI) m/e [M+1] ^⁺ 255.1.

Step 2: (E)-1-cyclohexyl-3-(imidazo[1,5-a]pyridin-8-yl)prop-2-en-1-ol

To a solution of (E)-1-cyclohexyl-3-(imidazo[1,5-a]pyridin-8-yl)prop-2-en-1-one (10 mg, 0.039 mmol) in EtOH (5 mL) was added _NaBH4 (4.5 mg, 0.12 mmol), and the reaction mixture was stirred at ambient temperature for about 3 hours. Saturated _NH4Cl (3 mL) was added to the reaction mixture, which was then concentrated under reduced pressure to remove the solvent and extracted with _CH2Cl2 (3*10 mL) _. The combined organic phases were washed with saturated NaCl (5 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated. The crude product was purified by preparative-TLC (DCM:MeOH=15:1) to give the product (5.0 mg, 49.6%) as a light yellow solid. ¹ H NMR (CDCl ₃ -d) δ 8.59 (s, 1H), 7.97 (d, J=6.8Hz, 1H), 7.75 (s, 1H), 6.90 (d, J= 6.8Hz, 1H), 6.76 (dd, J=6.8, 6.8Hz, 1H), 6.70 (d, J=16.0Hz, 1H), 6.48 (dd, J=6.2, 16.0 Hz, 1H), 4.14 (dd, J=5.8, 6.2Hz, 1H), 2.20-1.00 (m, 11H). MS(ESI)m/e[M+1] ⁺ 257.2.

Step 3: 1-cyclohexyl-3-(imidazo[1,5-a]pyridin-8-yl)propan-1-ol

To a solution of (E)-1-cyclohexyl-3-(imidazo[1,5-a]pyridin-8-yl)prop-2-en-1-ol (3.0 mg, 0.012 mmol) in EtOH (5 mL) was added Pd/C (3 mg), the reaction mixture was purged with H ₂ three times, and then stirred at ambient temperature under H ₂ atmosphere for about 3 hours. Filtered, washed with EtOH (5 mL), the filtrate was concentrated and purified by preparative-TLC (DCM: MeOH = 15: 1) to give the product (1.0 mg, 33.1%) as an off-white solid. ¹ H NMR (CDCl ₃ -d) δ 8.42 (s, 1H), 7.92 (d, J=4.8Hz, 1H), 7.56 (s, 1H), 6.65-6.61 (m, 2H), 5.39-5.30 (m, 2H), 2.00-1.00 (m, 15H). MS(ESI)m/e[M+1] ⁺ 259.2.

Example B011: Cyclohexyl(6-methylimidazo[1,5-a]pyridin-8-yl)methanol

Step 1: Ethyl 2,5-dimethylpyridine-3-carboxylate

A mixture of ethyl 2-chloro-3-oxobutanoate (10.0 g, 61.0 mmol), methacrolein (5.12 g, 73.2 mmol) and _NH₄OAc (11.74 g, 152.5 mmol) in AcOH (150 mL) was heated to reflux for 1.0 hour, and then the mixture was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated to give a residue. The residue was partitioned between DCM (200 mL) and _H₂O (200 mL). The organic layer was washed with aqueous _NaHCO₃ (200 mL) and brine (200 mL), dried _{over Na₂SO₄} , and concentrated to give ethyl 2,5-dimethylpyridine-3-carboxylate (6.2 g, 56.8%) as a yellow solid. MS (ESI, m/e) [M+1] ⁺ 179.9.

Step 2: Ethyl 2-(chloromethyl)-5-methylpyridine-3-carboxylate

A mixture of ethyl 2,5-dimethylpyridine-3-carboxylate (6.0 g, 33.52 mmol) and 1,3,5-trichloro-1,3,5-hexahydrotriazine-2,4,6-trione (11.3 g, 50.3 mmol) in DCM (200 mL) was stirred at room temperature for 16 hours. The mixture was poured into aqueous _NaHCO₃ (100 mL), and the organic layer was dried _{over Na₂SO₄} , concentrated, and purified by silica gel column chromatography using 20% EA/PE as the eluent to give ethyl 2-(chloromethyl)-5-methylpyridine-3-carboxylate (4.5 g, 63.0%) as a yellow oil. MS (ESI, m/e) [M+1] ^⁺ 214.0.

Step 3: Ethyl 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-methylpyridine-3-carboxylate

To a solution of di-tert-butyl iminodicarbonate (6.87 g, 31.6 mmol) in DMF (40 mL) was added t-BuOK (3.54 g, 31.6 mmol). After 2 hours, a solution of ethyl 2-(chloromethyl)-5-methylpyridine-3-carboxylate (4.5 g, 21.1 mmol) in DMF (10 mL) was added to the mixture, which was then stirred at 50°C for 16 hours. The mixture was poured into _H₂O (200 mL) and extracted with EA (100 mL* ₃ ). The combined organic layers were dried over _Na₂SO₄ , concentrated, and purified by silica gel column chromatography using 10% EA/PE as the eluent to yield ethyl 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-methylpyridine-3-carboxylate (6.5 g, 78.3%) as a yellow solid. MS (ESI, m/e) [M+1] ^⁺ 394.9.

Step 4: Ethyl 2-(aminomethyl)-5-methylpyridine-3-carboxylate TFA salt

A solution of ethyl 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-methylpyridine-3-carboxylate (6.5 g, 16.50 mmol) in DCM/TFA (50 mL/5 mL) was stirred at room temperature for 16 h. The mixture was concentrated to afford ethyl 2-(aminomethyl)-5-methylpyridine-3-carboxylate (2.6 g, 81.3%) as a yellow solid. MS (ESI, m/e) [M+1] ⁺ 194.9.

Step 5: Ethyl 6-methylimidazo[1,5-a]pyridine-8-carboxylate

A mixture of _Ac2O (2.0 mL) and HCOOH (4 mL) was heated to 60°C and maintained for 3.0 hours. The mixture was then cooled to room temperature and 2-(aminomethyl)-5-methylpyridine-3-ethyl formate (2.0 g, 10.3 mmol) was added to the mixture. The mixture solution was stirred at room temperature for 16 hours, but LCMS showed no reaction, so the mixture was heated to reflux and maintained for 16 hours. The concentrated mixture obtained a residue and purified by silica gel column chromatography using 10% MeOH/DCM as eluent to obtain 6-methylimidazo[1,5-a]pyridine-8-ethyl formate (1.0 g, 47.7%) as a yellow solid. MS (ESI, m/e) [M+1] ⁺ 204.9.

Step 6: 6-Methylimidazo[1,5-a]pyridine-8-carboxylic acid

A mixture of ethyl 6-methylimidazo[1,5-a]pyridine-8-carboxylate (800 mg, 3.92 mmol), LiOH (330 mg, 7.84 mmol) in THF (15 mL) and _H₂O (2.0 mL) was stirred at room temperature for 16 hours. The mixture was adjusted to a pH of approximately 1-2 and concentrated to afford 6-methylimidazo[1,5-a]pyridine-8-carboxylic acid (1.2 g, crude). MS (ESI, m/e) [M+1] ^⁺ 176.9.

Step 7: N-methoxy-N,6-dimethylimidazo[1,5 -a]pyridine-8-carboxamide

A mixture of 6-methylimidazo[1,5-a]pyridine-8-carboxylic acid (1.2 g, 6.8 mmol), O,N-dimethylhydroxylamine HCl salt (6.6 mg, 6.8 mmol), HATU (2.58 g, 6.80 mmol), and _Et₃N ( _1.38 g, 13.6 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours. The mixture was poured into _H₂O (50 mL) and extracted with EA (50 mL*3). The combined organic layers were dried over _Na₂SO₄ , concentrated, and purified by silica gel column chromatography using 5% MeOH/DCM as the eluent to provide N-methoxy-N,6-dimethylimidazo[1,5-a]pyridine-8-carboxamide (320 mg, 20%) as a yellow solid. MS (ESI, m/e) [M+1] ^⁺ 219.9.

Step 8: Cyclohexyl(6-methylimidazo[1,5-a]pyridin-8-yl)methanone

To a solution of N-methoxy-N,6-dimethylimidazo[1,5-a]pyridine-8-carboxamide (100 mg, 0.46 mmol) in THF (5 mL) at room temperature was added cyclohexylmagnesium chloride (2.0 M in _Et2O , 0.35 mL). After 5 min, the reaction mixture was quenched with aqueous _NH4Cl (5 mL) and extracted with EA (5 mL*3). The combined organic layers were dried over _{Na2SO4 and} concentrated to afford cyclohexyl(6-methylimidazo[1,5-a]pyridin-8-yl)methanone (60 mg, 54.0%) as a yellow solid. MS (ESI, m/e) [M+1] ⁺ 242.9.

Step 9: Cyclohexyl(6-methylimidazo[1,5-a]pyridin-8-yl)methanol

To a solution of cyclohexyl(6-methylimidazo[1,5-a]pyridin-8-yl)methanone (60 mg, 0.25 mmol) in MeOH (5 mL) was added _NaBH₄ (38 mg, 1.0 mmol) at room temperature. After 5 min, the reaction mixture was quenched with _H₂O (5 mL) and extracted with EA (5 mL*3). _The combined organic layers were dried over _Na₂SO₄ , concentrated, and purified by preparative-TLC (MeOH/DCM=1/10) to give cyclohexyl(6-methylimidazo[1,5-a]pyridin-8-yl)methanol (5.0 mg, 8.2%) as a yellow solid. ¹ HNMR (400MHz, DMSO-d ₆ ) δ9.28 (s, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 6.91 (s, 1H), 5.50 (br s, 1H), 4.51 (d, J=6.4Hz, 1H), 2.27 (s, 3H), 1.8-1.08 (m, 13H). MS (ESI, m/e)[M+1] ⁺ 244.9.

Example B012: 2-cyclohexyl-1-(6-methylimidazo[1,5-a]pyridin-8-yl)ethanol

Step 1: 6-Methylimidazo[1,5-a]pyridine-8-carbaldehyde

To a solution of N-methoxy-N,6-dimethylimidazo[1,5-a]pyridine-8-carboxamide (200 mg, 0.91 mmol) in THF (5 mL) was added _LiAlH₄ (64 mg, 1.82 mmol) at room temperature. After 5 min, the reaction mixture was quenched with _H₂O (5 mL) and extracted with EA (10 mL*3). The combined organic layers were washed with brine (10 mL*3), dried _{over Na₂SO₄} , and concentrated to afford 6-methylimidazo[1,5-a]pyridine-8-carboxaldehyde (40 mg, 27.4%) as a yellow solid. MS (ESI, m/e) [M+1] ^⁺ 160.9.

Step 2: 2-cyclohexyl-1-(6-methylimidazo[1,5-a]pyridin-8-yl)ethanol

To a solution of 6-methylimidazo[1,5-a]pyridine-8-carbaldehyde (40 mg, 0.25 mmol) in THF (10 ml) was added (cyclohexylmethyl)magnesium bromide (1.0 M in THF, 0.5 mL) at room temperature. After 5 min, the mixture was quenched with aqueous _NH4Cl (5 ml) and extracted with EA ( ₁₀ mL*3). The combined organic layers were dried over _Na2SO4 , concentrated, and purified by preparative TLC (MeOH/DCM = 1/10) to give 2-cyclohexyl-1-(6-methylimidazo[1,5-a]pyridin-8-yl)ethanol (25 mg, 38.5%) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.26 (s, 1H), 8.01 (s, 1H), 7.26 (s, 1H), 6.63 (s, 1H), 5.30 (d, J=4.6Hz, 1H), 4.81 (m, 1H), 2.20 (s, 3H), 1.89-0.95 (m, 13H). MS(ESI,m/e)[M+1] ⁺ 258.9.

Example B013: 1-(6-chloroimidazo[1,5-a]pyridin-8-yl)-2-cyclohexylethanol-1-ol

Step 1: Ethyl 5-chloro-2-methylpyridine-3-carboxylate

A solution of ethyl 3-oxobutanoate (6.5 g, 50 mmol) and t-BuOK (5.85 g, 52.5 mmol) in THF (100 mL) was stirred at 0-5°C for 1 h. DABCO (5.85 g, 52.5 mmol) and 2-chloro-1,3-bis(dimethylamino)trimethyleneium hexafluorophosphate (16.2 g, 53 mmol) were then added and stirred at room temperature for 3 h. _NH₄OAc (10.8 g, 140 mmol) was added and stirred at room temperature for 16 h. The mixture was then concentrated and the residue was purified by silica gel column chromatography (EA/PE = 1/5) to give the product (7.85 g, 78.9%) as a white solid. MS (ESI, m/e) [M+1] ^⁺ 200.0, 202.0.

Step 2: Ethyl 2-(bromomethyl)-5-chloropyridine-3-carboxylate

A mixture of ethyl 5-chloro-2-methylpyridine-3-carboxylate (4.6 g, 23 mmol), NBS (4.52 g, 25 mmol), and BPO (556 mg, 2.3 mmol) in _CCl₄ (100 mL) was stirred at 65°C for 24 h. The mixture was then cooled to room temperature, poured into water (200 mL), and extracted with _DCM (100 mL*3). The combined organic layers were dried over _Na₂SO₄ , filtered, and concentrated to afford the product (6.4 g, 99.2%) as a yellow oil. MS (ESI, m/e) [M+1] ^⁺ 277.9, 279.9.

Step 3: Ethyl 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-chloropyridine-3-carboxylate

A solution of t-BuOK (5.13 g, 45.8 mmol) and di-tert-butyl iminodicarboxylate (7.4 g, 34.4 mmol) in THF (100 mL) was stirred at room temperature for 1 h. Ethyl 2-(bromomethyl)-5-chloropyridine-3-carboxylate (6.4 g, 22.9 mmol) was then added and heated to 65°C for 16 h. The mixture was added to brine (200 mL) and extracted with EA (200 mL x 2). The combined organic layers _were dried over _Na₂SO₄ , filtered, and concentrated to give the crude product (9.47 g, 100%), which was used in the next step without further purification. MS (ESI, m/e) [M+1] ^⁺ 415.1, 417.1.

Step 4: Ethyl 6-chloroimidazo[1,5-a]pyridine-8-carboxylate

A solution of ethyl 2-((bis(tert-butoxycarbonyl)amino)methyl)-5-chloropyridine-3-carboxylate (9.0 g, 21.7 mmol) in a mixture of TFA (5 mL) and trimethoxymethane (100 mL) was stirred at 100° C. for 5 h. The resulting solution was then concentrated and the residue was purified by silica gel chromatography (eluting with a gradient of EA/PE = 1/5 to MeOH/DCM = 1/10) to give the product as a yellow solid (2.82 g, 57.7%). MS (ESI, m/e) [M+1] ⁺ 225.1, 227.1.

Step 5: 6-chloroimidazo[1,5-a]pyridine-8-carboxylic acid

To a solution of ethyl 6-chloroimidazo[1,5-a]pyridine-8-carboxylate (2.82 g, 12.5 mmol) in THF (20 mL) and water (20 mL) was added LiOH (1.05 g, 25 mmol). The mixture was stirred at room temperature for 16 h. The THF was then removed in vacuo, the residue was adjusted to pH 5, and concentrated. The residue (2.4 g, 100%) was used in the next step without further purification. MS (ESI, m/e) [M+1] ⁺ 197.1, 199.0.

Step 6: 6-Chloro-N-methoxy-N-methylimidazo[1,5-a]pyridine-8-carboxamide

A mixture of 6-chloroimidazo[1,5-a]pyridine-8-carboxylic acid (2.4 g, 12.5 mmol), N,O-dimethylhydroxylamine hydrochloride (1.46 g, 15 mmol), HATU (5.7 g, 25 mmol), and TEA (2.5 g, 25 mmol) in DMF (30 mL) was stirred at room temperature for 16 h. The mixture was then quenched with water (150 mL) and extracted with EA (70 mL*3). The combined organic layers were dried _{over Na₂SO₄} , filtered, and concentrated to afford the desired compound as an oil (2.4 g, 81.6%). MS (ESI, m/e) [M+1] ^⁺ 240.1, 242.0.

Step 7: 6-chloroimidazo[1,5-a]pyridine-8-carbaldehyde

A solution of 6-chloro-N-methoxy-N-methylimidazo[1,5-a]pyridine-8-carboxamide (367 mg, 1.6 mmol) in THF (20 mL) was cooled to -78°C. DIBAL-H (1.2 M, 1.5 mL, 1.8 mmol) was added and stirred at -78°C for 1 h. The mixture was then quenched with MeOH (2 mL) and concentrated. The residue was dissolved in EA (100 mL), washed with brine (50 mL*2), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product as a yellow solid (115 mg, 40.5%). MS (ESI, m/e) [M+1] ⁺ 181.1, 183.0.

Step 8: 1-(6-chloroimidazo[1,5-a]pyridin-8-yl)-2-cyclohexylethanol-1-ol

(Cyclohexylmethyl)magnesium bromide (1 M, 1.5 mL) was added to a solution of 6-chloroimidazo[1,5-a]pyridine-8-carbaldehyde (115 mg, 0.64 mmol) in THF (10 mL) at 0°C and stirred for 1 h. The reaction mixture was then quenched with saturated _NH4Cl and extracted with EA (10 _mL *3). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated to give the crude product, which was purified by preparative HPLC to give the product as a yellow solid (7 mg, 3.9%). ¹ H NMR (400MHz, CD ₃ OD) δ 9.15 (s, 1H), 8.43 (s, 1H), 7.90 (s, 1H), 7.06 (s, 1H), 4.90 (dd, J=9.6, 3.2Hz, 1H), 1.84 (d, J=12.4Hz, 1H), 1.71-1.42 (m, 6H), 1.27-1.06 (m, 4H), 0.99-0.84 (m, 2H). MS(ESI,m/e)[M+1] ⁺ 279.1, 281.1.

Example B014: (6-chloroimidazo[1,5-a]pyridin-8-yl)(cyclohexyl)methanol

Example B014 was synthesized following procedures similar to those described in Example B012, under appropriate conditions that would be recognized by one of ordinary skill in the art.

¹ H NMR (400MHz, CD ₃ OD) δ9.09 (s, 1H), 8.45 (s, 1H), 7.96 (s, 1H), 7.00 (s, 1H), 4.52 (d, J=6.6Hz, 1H ), 1.85-1.77(m, 1H), 1.74-1.51(m, 4H), 1.40-1.31(m, 1H), 1.17-0.99(m, 5H). MS(ESI,m/e)[M+1] ⁺ 265.1, 267.1.

Example B101: 2-cyclohexyl-1-(7-methylimidazo[1,5-a]pyridin-8-yl)ethan-1-ol

Example B101 was synthesized following procedures similar to those described in Example B006, under appropriate conditions that would be recognized by one of ordinary skill in the art. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.23 (s, 1H), 8.11 (d, J = 7.1Hz, 1H), 7.41 (s, 1H), 6.42 (d, J = 7.1Hz, 1H), 5.24-5.18 (m, 1H), 5.08-5.01 (m, 1H), 2.20 (s, 3H), 1.83-1.71 (m, 2H), 1.67-1.59 (m, 4H), 1.48-1.42 (m, 1H), 1.36-1.32 (m, 1H), 1.23-1.11 (m, 3H), 0.97-0.86 (m, 2H). MS(ESI,m/e)[M+1] ⁺ 259.1.

Examples B102 to B105 were synthesized following procedures similar to those described in Example B012, under appropriate conditions that would be recognized by one of ordinary skill in the art.

Example B102: Cyclohexyl(7-methylimidazo[1,5-a]pyridin-8-yl)methanol

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.21 (s, 1H), 8.11 (d, J = 7.2Hz, 1H), 7.37 (s, 1H), 6.42 (d, J=7.2Hz, 1H), 5.18 (d, J=3.6Hz, 1H), 4.62 (dd, J=8.4, 3.6Hz, 1H), 2.22 (s, 3H), 2.1 6-2.13 (m, 1H), 1.85-1.80 (m, 1H), 1.74-1.71 (m, 1H), 1.59-1.54 (m, 2H), 1.19-0.92 (m, 6H). MS(ESI,m/e)[M+1] ⁺ 245.1.

Examples B102a and B102b: (S)-cyclohexyl(7-methylimidazo[1,5-a]pyridin-8-yl)methanol and (R)- Cyclohexyl(7-methylimidazo[1,5-a]pyridin-8-yl)methanol

Each enantiomer of racemic B102a and B102b was separated using preparative HPLC on Chiralpak AS with _CO2 /MeOH 0.1% DEA = 80/20 (/V/V) as eluent. Enantiomeric excess was determined using HPLC on Chiralpak AS with _CO2 /MeOH 0.1% DEA = 80/20 (/V/V) as eluent at a flow rate of 2.0 mL/min. The first enantiomer eluted at a retention time of 6.73 min, ¹ H NMR (DMSO-d ₆ ) δ 8.21 (s, 1 H), 8.11 (d, J=6.8 Hz, 1 H), 7.36 (s, 1 H), 6.41 (d, J=6.8 Hz, 1 H), 5.18 (d, J=3.2 Hz, 1 H), 4.60 (dd, J=8.4, 3.2 Hz, 1 H), 2.20 (s, 3 H), 2.13-2.16 (m, 1 H), 1.54-1.91 (m, 4 H), 0.91-1.19 (m, 6 H). MS (ESI) m/e [M+1] ⁺ 245; while the other enantiomer eluted at a retention time of 9.31 min, ¹ H NMR (DMSO-d ₆ ) δ 8.21 (s, 1H), 8.11 (d, J = 6.8 Hz, 1H), 7.36 (s, 1H), 6.41 (d, J = 6.8 Hz, 1H), 5.18 (d, J = 3.2 Hz, 1H), 4.60 (dd, J = 8.4, 3.2 Hz, 1H), 2.20 (s, 3H), 2.13-2.16 (m, 1H), 1.54-1.91 (m, 4H), 0.91-1.19 (m, 6H). MS (ESI) m/e [M+1] ⁺ 245. Based on the assumption that the binding model of the more efficient isomer B102a is the same as that of A101a for the IDO1 enzyme, the absolute configurations of B102a and B102b are tentatively assigned to (S) and (R), respectively.

Example B103: Cyclohexyl(7-iodoimidazo[1,5-a]pyridin-8-yl)methanol

¹ H NMR (400MHz, CD ₃ OD-d ₄ ) δ9.36 (s, 1H), 8.09 (d, J = 7.2Hz, 2H), 7.40 (d, J = 7.6Hz, 1H), 4.82 (d, J = 7.2, 1H), 1.64-1.99 (m, 5H), 1.16-1.37 (m, 5H). MS(ESI,m/e)[M+1] ⁺ 357.1.

Example B104: (7-chloroimidazo[1,5-a]pyridin-8-yl)(cyclohexyl)methanol

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.34 (s, 1H), 8.25 (d, J = 7.2Hz, 1H), 7.54 (s, 1H), 6.62 (d, J=7.2Hz, 1H), 5.53 (d, J=3.6Hz, 1H), 4.62 (dd, J=8.4, 3.6Hz, 1H), 2.06-2.09 (m, 1H), 1.57-1.87 (m, 4H), 1.03-1.23 (m, 6H). MS(ESI,m/e)[M+1] ⁺ 265.1.

Example B105: 1-(7-chloroimidazo[1,5-a]pyridin-8-yl)-2-cyclohexylethanol-1-ol

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.36 (s, 1H), 8.25 (d, J=7.2Hz, 1H), 7.59 (s, 1H), 6.62 (d, J=7.2Hz, 1H), 5.55 (d, J=4.0Hz, 1H), 5.18 (dd, J=7.2, 4.0Hz, 1H), 1.40-1.82 (m, 9H), 0.87-1.23 (m, 4H). MS(ESI,m/e)[M+1] ⁺ 279.1.

Example B106: Cyclohexyl(7-isopropylimidazo[1,5-a]pyridin-8-yl)methanol

Step 1: Cyclohexyl(7-(prop-1-en-2-yl)imidazo[1,5-a]pyridin-8-yl)methanol

Using a procedure similar to that described in Example A136, the desired product was prepared from 7-(prop-1-en-2-yl)imidazo[1,5-a]pyridine-8-carbaldehyde under appropriate conditions recognized by one of ordinary skill in the art to afford the product (150 mg crude) as a pale yellow oil. MS (ESI) m/e[M+1] ⁺ 271.0.

Step 2: Cyclohexyl(7-isopropylimidazo[1,5-a]pyridin-8-yl)methanol

To a solution of cyclohexyl(7-(prop-1-en-2-yl)imidazo[1,5-a]pyridin-8-yl)methanol (100 mg, 0.37 mmol) in MeOH (20 mL) was added wet Pd/C (50 mg, 50% m/m). The mixture was exchanged with H ₂ three times and stirred under a H ₂ atmosphere for approximately 16 hours. The mixture was filtered and washed with MeOH (20 mL), and the filtrate was concentrated under reduced pressure to obtain a crude product of approximately 150 mg. This was purified by silica gel column chromatography (200-300 mesh, DCM/MeOH = 50/1) to obtain a product of approximately 40 mg. This was further purified by preparative TLC (DCM/MeOH = 15/1) to obtain the product as a light yellow solid (15 mg, 14.9%). ¹ H NMR (CD ₃ OD-d ₄ ) δ 8.18 (s, 1H), 8.01 (d, J = 7.6Hz, 1H), 7.44 (s, 1H), 6.61 (d, J = 7.6Hz, 1H), 4.73 (d, J=9.2Hz, 1H), 3.37-3.27 (m, 1H), 2.20-0.80 (m, 17H). MS(ESI)m/e[M+1] ⁺ 273.0.

Examples B106a and B106b: (S)-cyclohexyl(7-isopropylimidazo[1,5-a]pyridin-8-yl)methanol and (R)-Cyclohexyl(7-isopropylimidazo[1,5-a]pyridin-8-yl)methanol

The individual enantiomers of racemic B106a and B106b were separated using preparative HPLC on a Chiralpak AS-H using _CO₂ /MeOH 0.1% DEA = 80/20 (v/v) as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak AS-H using _CO₂ /MeOH 0.1% DEA = 80/20 (v/v) as the eluent at a flow rate of 2.0 mL/min. The first enantiomer eluted at a retention time of 6.45 min, while the other enantiomer eluted at a retention time of 10.76 min. Based on the assumption that the binding mode of the more potent isomer, B106a, is the same as that of A101a for the IDO1 enzyme, the absolute configurations of B106a and B106b were tentatively assigned as (S) and (R), respectively.

Example B107: Cyclohexyl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol

Step 1: Methyl 7-cyclopropylimidazo[1,5-a]pyridine-8-carboxylate

To a solution of methyl 7-chloroimidazo[1,5-a]pyridine-8-carboxylate (7.0 g, 33.3 mmol) in 1,4-dioxane (250 mL) was added cyclopropylboronic acid (5.72 g, 66.6 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (2.34 g, 3.33 mol) and K ₃ PO ₄ (17.65 g, 83.3 mmol). The mixture was exchanged with N ₂ three times and then warmed to 100° C. and maintained for about 16 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure to remove the solvent. The residue was partitioned between _CH2Cl2 (200 _mL ) and water (100 _mL ). The aqueous phase was extracted with _CH2Cl2 (3*100 mL). The combined organic phases were washed with saturated NaCl (20 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to give about 9.0 g of a crude product, which was purified by silica gel column chromatography (200-300 mesh, DCM/MeOH=50/1) to give the product (5.1 g, 71.5%) as a light yellow solid. ¹ H NMR (DMSO-d ₆ ) δ 8.38 (d, J=7.4Hz, 1H), 8.34 (s, 1H), 7.35 (s, 1H), 6.21 (d, J=7.4Hz, 1H), 3.93 (s, 3H), 2.69-2.60 (m, 1H), 1.07-0.98 (m, 2H), 0.86-0.79 (m, 2H). MS(ESI)m/e[M+1] ⁺ 217.0.

Step 2: (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol

To a solution of methyl 7-cyclopropylimidazo[1,5-a]pyridine-8-carboxylate (1.1 g, 5.09 mmol) in THF (40 mL) was added _LiAlH₄ (580 mg, 15.28 mmol) at -40°C, then slowly warmed to 0°C and stirred for approximately 30 min. The mixture was cooled to -40°C, and _{Na₂SO₄.10H₂O} was added. _{The mixture} was warmed to ambient temperature, filtered, and concentrated to afford the crude product (850 mg) as a pale yellow solid, which was used directly in the next step without purification. MS (ESI) m/e [M+1] ^⁺ 189.0.

Step 3: 7-cyclopropylimidazo[1,5-a]pyridine-8-carbaldehyde

To a solution of (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol (850 mg, 4.52 mmol) in _CH₂Cl₂ (40 _mL ) was added Dess-Martin (2.30 g, 5.43 mmol ₎ at ambient temperature, and the reaction mixture was stirred for approximately 30 min. Saturated _{Na₂S₂O₃} (10 _mL ) was added, and the aqueous _phase was extracted with _CH₂Cl₂ (3*100 mL). The combined organic phases were washed with saturated NaCl (10 mL), dried _over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to afford the crude product (1.0 g). The product was purified by silica gel column chromatography (200-300 mesh, DCM/MeOH = 50/1) to afford the product (500 mg, 59.4%) as a yellow solid. MS (ESI) m/e [M+1] ^⁺ 187.0.

Step 4: Cyclohexyl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol

To a solution of 7-cyclopropylimidazo[1,5-a]pyridine-8-carbaldehyde (500 mg, 2.69 mmol) in THF (40 mL) was added cyclohexylmagnesium chloride (6.2 mL, 1.3 M, 8.07 mmol), and the reaction mixture was stirred at 0° C. for about 30 min. Saturated NH ₄ Cl (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with EA (3*100 mL). The combined organic phase was washed with saturated NaCl (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a crude product (about 600 mg), which was purified by silica gel column chromatography (100-200 mesh, DCM/MeOH=50/1) to give the product (300 mg, 41.1%) as a light yellow solid. ¹ H NMR (DMSO-d ₆ ) δ 8.19 (s, 1H), 8.10 (d, J=7.2Hz, 1H), 7.38 (s, 1H), 6.14 (d, J= 7.2Hz, 1H), 5.24 (d, J=3.6Hz, 1H), 4.91 (dd, J=3.6, 8.4Hz, 1H), 2.23-2.08 (m, 2H), 1.98- 1.85 (m, 1H), 1.77-1.68 (m, 1H), 1.62-1.51 (m, 2H), 1.25-0.85 (m, 8H), 0.75-0.60 (m, 2H). MS(ESI)m/e[M+1] ⁺ 271.0.

Examples B107a and B107b: (S)-cyclohexyl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol and (R)-Cyclohexyl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol

Each enantiomer of racemic B107a and B107b was separated using preparative HPLC on a Chiralpak AY using _CO₂ /EtOH 0.1% DEA = 75/25 (/V/V) as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak AY using _CO₂ /EtOH 0.1% DEA = 75/25 (/V/V) as the eluent at a flow rate of 2.0 mL/min. The first enantiomer eluted at a retention time of 5.01 min, while the other enantiomer eluted at a retention time of 7.35 min. Based on the assumption that the binding mode of the more potent isomer, B107a, is the same as that of A101a for the IDO1 enzyme, the absolute configurations of B107a and B107b were tentatively assigned as (S) and (R), respectively.

Examples B108 to B114 were synthesized following procedures similar to those described in Example B107 under appropriate conditions as would be recognized by one of ordinary skill in the art.

Example B108: 2-cyclohexyl-1-(7-isopropylimidazo[1,5-a]pyridin-8-yl)ethan-1-ol

¹ H NMR (CD ₃ OD-d ₄ ) δ9.25 (s, 1H), 8.26 (d, J = 7.6Hz, 1H), 7.99 (s, 1H), 7.06 (d, J = 7.6Hz, 1H), 5.30 (dd, J = 4.4, 9.6Hz, 1H), 3.30-3.20 (m, 1H), 1.90-0.70 (m, 19H). MS(ESI)m/e[M+1] ⁺ 287.0.

Example B109: 2-cyclohexyl-1-(7-isopropylimidazo[1,5-a]pyridin-8-yl)ethan-1-ol

¹ H NMR (DMSO-d ₆ )δ8.19 (s, 1H), 8.09 (d, J = 7.6Hz, 1H), 7.41 (s, 1H), 6.13 (d, J = 7.6Hz, 1H), 5.29 (d, J=3.6Hz, 1H), 4.97 (dd, J=3.6, 9.2Hz, 1H), 2.50-2.51 (m, 1H), 1.90-0.64 (m, 13H).

Example B110: 2-cyclohexyl-1-(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)ethan-1-ol

¹ H NMR (DMSO-d ₆ )δ8.21 (s, 1H), 8.09 (d, J = 7.2Hz, 1H), 7.43 (s, 1H), 6.18 (d, J = 7.2Hz, 1H), 5.2 4-5.40 (m, 1H), 5.25 (d, J=3.6Hz, 1H), 1.98-2.09 (m, 1H), 1.85-0.64 (m, 17H).

Examples B110a and B110b: (S)-cyclohexyl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol and (R)-Cyclohexyl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol

The individual enantiomers of racemic B110a and B110b were separated using preparative HPLC on a Chiralpak AS-H using _CO₂ /MeOH = 80/20 (/V/V) as the eluent. Enantiomeric excess was determined using HPLC on a Chiralpak AS-H using _CO₂ /MeOH = 80/20 (/V/V) as the eluent at a flow rate of 2.0 mL/min. The first enantiomer eluted at a retention time of 5.04 min, while the other enantiomer eluted at a retention time of 8.87 min. Based on the assumption that the binding mode of the more potent isomer, B110a, is the same as that of A101a for the IDO1 enzyme, the absolute configurations of B110a and B110b were tentatively assigned as (S) and (R), respectively.

Example B111: Cyclohexyl(7-(trifluoromethyl)imidazo[1,5-a]pyridin-8-yl)methanol

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.51 (s, 1H), 8.38 (d, J = 7.4Hz, 1H), 7.85 (s, 1H), 6.80 (d, J=7.4Hz, 1H), 5.77-5.75 (m, 1H), 4.66 (d, J=8.6Hz, 1H), 2.25-2.22 (m, 1 H), 1.97-1.94 (m, 1H), 1.75-1.72 (m, 1H), 1.61-1.55 (m, 2H), 1.28-0.84 (m, 6H). MS(ESI,m/e)[M+1] ⁺ 298.9.

Example B112: (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(tetrahydro-2H-pyran-4-yl)methanol

¹ H NMR (DMSO-d ₆ )δ8.21 (s, 1H), 8.12 (d, J = 7.2Hz, 1H), 7.42 (s, 1H), 6.15 (d, J = 7.2Hz, 1H), 5. 38 (d, J=3.6Hz, 1H), 4.96 (dd, J=8.7, 3.6Hz, 1H), 3.93-3.87 (dd, J=11.2, 3.0 Hz, 1H), 3.73 (dd, J=11.2, 3.0Hz, 1H), 3.29-3.24 (m, 1H), 3.12-3.06 (m, 1H), 2.23-2.08 (m, 2H), 2.01-1.96(m, 1H), 1.44-1.24(m, 2H), 0.97-0.88(m, 3H), 0.73-0.63(m, 2H). MS(ESI, m/e)[M+1] ⁺ 273.1.

Example B113: (7-(tert-Butyl)imidazo[1,5-a]pyridin-8-yl)(cyclohexyl)methanol

¹ H NMR (DMSO-d ₆ )δ8.20 (s, 1H), 8.11 (d, J = 7.2Hz, 1H), 7.48 (s, 1H), 6.68 (d, J = 7.2Hz, 1H), 5.19 (d, J = 4.0Hz, 1H), 5.02 (dd, J = 8.8, 4.0Hz, 1H), 2.34 (br d, J=10.8Hz, 1H), 2.12 (m, 1H), 1.76 (m, 1H), 1.64-1.53 (m, 1H), 1.49 (m, 1H), 1.38 (s, 9H), 1.31-1.14 (m, 2H), 1.14-0.72 (m, 4H). MS (ESI) m/e [M+1] ⁺ 287.2.

Example B114: (7-cyclobutylimidazo[1,5-a]pyridin-8-yl)(cyclohexyl)methanol

¹ H NMR (CD ₃ OD) δ 9.30 (s, 1H), 8.36 (d, J=7.5Hz, 1H), 8.01 (s, 1H), 7.33 (d, J=7.5Hz, 1H), 4.01-3.84 (m, 1H), 2.37-0.99 (m, 18H). MS(ESI)m/e[M+1] ⁺ 285.2.

Example B115: 1-(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)prop-2-en-1-ol

To a solution of 7-cyclopropylimidazo[1,5-a]pyridine-8-carbaldehyde (500 mg, 2.74 mmol) in THF (20 mL) was added vinylmagnesium bromide (1.0 M in THF, 4.12 mL, 4.12 mmol) at -78°C. The reaction mixture was stirred at -78°C for 45 min and then quenched with saturated aqueous _NH4Cl (10 mL). The mixture was diluted with DCM (50 mL) and the organic phase was separated and washed with brine (20 _mL ), dried over _Na2SO4 , and purified on silica gel chromatography (DCM/MeOH = 30:1) to give 1-(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)prop-2-en-1-ol (301 mg, 51%) as a yellow solid. ¹ H NMR (CDCl ₃ ) δ7.93 (s, 1H), 7.71 (d, J=7.2Hz, 1H), 7.51 (s, 1H), 6.27-6.14 (m, 2H), 5.96 (m, 1H), 5.43 (d, J=11.2Hz, 1H), 5.20 (d, J=10.4Hz, 1H), 2.12-1.98 (m, 1H), 1.01-0.91 (m, 2H), 0.74-0.62 (m, 2H). MS(ESI)m/e 215.1.

Example B116: (7-chloroimidazo[1,5-a]pyridin-8-yl)(cyclohex-3-en-1-yl)methanol

Example B116 was synthesized following procedures similar to those described in Example B115 under appropriate conditions recognized by one of ordinary skill in the art. ¹ H NMR (DMSO-d6) δ 8.36 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 7.56 (s, 1H), 6.64 (d, J = 7.2 Hz, 1H), 5.67 (dd, J = 17.9, 4.0 Hz, 1H), 5.65 (dd, J = 17.9, 4.0 Hz, 1H), 5.58-53 (m, 1H), 4.92-4.87 (m, 1H), 2.32-1.24 (m, 7H). MS (ESI, m/e) [M+1]+ 263.1, 265.1.

Example B117: (Adamantane-2-yl)(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol

¹ H NMR (DMSO-d ₆ ) δ 8.23 (s, 1H), 8.10 (d, J=6.6Hz, 1H), 7.38 (s, 1H), 6.14 (d, J=6.6Hz, 1H), 5.51 (br s, 1H), 5.14 (br s, 1H), 2.45-2.30 (m, 2H), 2.15-1.15 (m, 15H), 1.00-0.80 (m, 2H), 0.65-0.50 (m, 1H). MS(ESI)m/e[M+1] ⁺ 323.2.

Example B118: 2-(Adamantane-1-yl)-1-(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)ethan-1-ol

¹ H NMR (DMSO-d ₆ )δ8.31 (s, 1H), 8.11 (d, J = 7.6Hz, 1H), 7.47 (s, 1H), 6.22 (d, J = 7.6Hz, 1H), 5.50 (d, J =8.8Hz, 1H), 5.15-5.05(m, 1H), 2.13-2.03(m, 1H), 1.96-1.82(m, 3H), 1.71-1.55(m 12H), 1.34-1.20(m, 2H), 0.97-0.90(m 2H), 0.75-0.62(m, 2H). MS(ESI)m/e[M+1] ⁺ 337.2.

Example B119: 4-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)cyclohexan-1-ol

Step 1: 4-((tert-Butyldimethylsilyl)oxy)cyclohexan-1-ol

To a solution of cyclohexane-1,4-diol (100 g, 862 mol) in THF (1000 mL) was added imidazole (58.6 g, 862 mmol) and TBSCl (130 g, 862 mmol), and the reaction mixture was stirred at ambient temperature for approximately 16 hours. The solid was filtered, washed with THF (100 mL), and the filtrate was concentrated under reduced pressure. The crude product (approximately 60 g) was purified by Al ₂ O ₃ column to obtain the product as a colorless oil (172 g, 86.7%). MS (ESI) m/e [M+1] ⁺ 231.0.

Step 2: ((4-bromocyclohexyl)oxy)(tert-butyl)dimethylsilane

To a solution of 4-((tert-butyldimethylsilyl)oxy)cyclohexan-1-ol (80 g, 348 mmol) in THF (800 mL) were added CBr ₄ (138 g, 417 mmol) and PPh ₃ (108 g, 417 mmol) at 0° C., and the reaction mixture was stirred at 0° C. for about 6 hours. Water (200 mL) was added to the reaction mixture, and the aqueous phase was extracted with EA (3*200 mL). The combined organic phases were washed with saturated NaCl (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated, and the crude product was extracted with PE (3*500 mL). The combined organic phases were purified by silica gel column chromatography (200-300 mesh, PE) to give the product as a colorless oil (73.0 g, 71.6%).

Step 3: (4-((tert-Butyldimethylsilyl)oxy)cyclohexyl)magnesium bromide

To a solution of ((4-bromocyclohexyl)oxy)(tert-butyl)dimethylsilane (2.5 g, 8.53 mmol) in THF (5.0 mL) was added Mg (1.03 g, 43.0 mmol) and _I ( ₁₀ mg) at ambient temperature under N2 atmosphere. The reaction mixture was warmed until the reaction occurred. A solution of ((4-bromocyclohexyl)oxy)(tert-butyl)dimethylsilane (8.0 g, 27.3 mmol) in THF (35 mL) was added dropwise to the reaction mixture. After the addition, the reaction mixture was warmed to 50°C, stirred for about 3 hours, cooled to ambient temperature and used directly in the next step.

Step 4: (4-((tert-Butyldimethylsilyl)oxy)cyclohexyl)(7-cyclopropylimidazo[1,5-a]pyrrolidone pyridin-8-yl)methanol

To a solution of (4-((tert-butyldimethylsilyl)oxy)cyclohexyl)magnesium bromide (40 mL, 35.8 mmol in THF) at ambient temperature was added a solution of 7-cyclopropylimidazo[1,5-a]pyridine-8-carbaldehyde (1.2 g, 6.45 mmol) in THF (30 mL). The reaction mixture was stirred at ambient temperature for approximately 1 hour. Saturated _NH₄Cl (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with EA (15 mL*3). The combined organic phases were washed with saturated NaCl (10 mL), dried over _{anhydrous Na₂SO₄} , filtered, and concentrated. The crude product was purified by silica gel column chromatography (200-300 mesh, eluent: DCM:MeOH = 50:1) to afford the product as a white solid (1.5 g, 58.1%). MS (ESI) m/e [M+1] ^⁺ 401.2.

Step 5: 4-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)cyclohexan-1-ol

(4-((tert-Butyldimethylsilyl)oxy)cyclohexyl)(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol (2.5 g, 6.25 mmol) was added to HCl (gas in dioxane, 30 mL), and the reaction mixture was stirred at ambient temperature for approximately 1 hour. The solvent was removed by concentration under reduced pressure to provide approximately 2.0 g of crude product. MS (ESI) m/e [M+1] ⁺ 287.1.

Step 6: (trans)-4-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)cyclohexan-1-ol and (cis)-4-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)cyclohexan-1-ol

4-((7-Cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)cyclohexan-1-ol (2.0 g, 6.25 mmol) was separated by prep-HPLC to give the trans isomer 750 mg as a white solid. ¹ H NMR (DMSO-d ₆ )δ8.20 (s, 1H), 8.10 (d, J = 7.2Hz, 1H), 7.38 (s, 1H), 6.14 (d, J = 7.2Hz, 1H), 5.27 (d, J = 3.2Hz, 1H), 4.88 (dd, J = 3.2, 8.8Hz, 1H), 4.43 ( d, J=4.0Hz, 1H), 3.34-3.24 (m, 1H), 2.20-2.08 (m, 2H), 1.90-1.78 (m, 2H), 1.75-1.65 (m, 1H), 1.20-0.85 (m, 7H), 0.72-0.62 (m, 2H). MS (ESI) m/e [M+1] ⁺ 287.1, 300 mg of cis isomer as a white solid. ¹ H NMR (DMSO-d ₆ ) δ 8.20 (s, 1 H), 8.10 (d, J=7.2Hz, 1H), 7.38 (s, 1H), 6.14 (d, J=7.6Hz, 1H), 5.24 (d, J=3.6Hz, 1H), 4.97 (dd, J=3.6, 9.0Hz, 1H), 4.22 (d, J=2.8Hz, 1H), 2.20-2.08 (m, 1H), 2.00-1.90 (m, 1H), 1.88-1.80(m, 1H), 1.70-1.45(m, 3H), 1.45-1.29(m, 2H), 1.25-1.15(m, 2H), 0.96-0.85(m, 3 H), 0.75-0.62(m, 2H). MS(ESI)m/e[M+1] ⁺ 287.1.

The trans isomers were then separated using preparative HPLC on a CHIRALCEL OJ-H column using EtOH (100%) as the eluent. The enantiomeric excess was determined using HPLC on a CHIRALCEL OJ-H column using EtOH (100%) as the eluent at a flow rate of 1.0 mL/min. The first enantiomer (B119a) eluted at a retention time of 7.02 min, while the other enantiomer (B119b) eluted at a retention time of 9.45 min. The cis isomers were then separated using preparative HPLC on a CHIRALCEL AD-H column using EtOH/DEA = 100/0.1 (v/v) as the eluent. Enantiomeric excess was determined using HPLC on a CHIRALCEL AD-H column with EtOH/DEA = 100/0.1 (v/v) as the eluent at a flow rate of 0.4 mL/min. The first enantiomer (B119c) eluted at a retention time of 5.27 min, while the other enantiomer (B119d) eluted at a retention time of 6.85 min. Based on the assumption that the binding mode of the more potent isomers B119a and B119d is the same as that of A101a for the IDO1 enzyme, the absolute configurations of B119a, B119b, B119c, and B119d were tentatively assigned as (S), (R), (R), and (S), respectively.

Example B120: (4-((tert-Butyldimethylsilyl)oxy)cyclohexyl)(7-isopropylimidazo[1,5- a]pyridin-8-yl)methanol

Following a procedure similar to that described in Example B119, the desired product was prepared as a white solid. ¹ H NMR (DMSO-d ₆ ) δ 8.24 (s, 1H), 8.18 (d, J=7.4 Hz, 1H), 7.40 (s, 1H), 6.62 (d, J=7.4 Hz, 1H), 5.35-5.25 (m, 1H), 4.73-4.63 (m, 1H), 3.60-3.45 (m, 1H), 2.20-2.12 (m, 1H), 1.90-1.40 (m, 4H), 1.30-1.10 (m, 11H), 0.90-0.78 (m, 9H), 0.06-0.04 (m, 6H). MS (ESI) m/e [M+1] ⁺ 403.3.

Example B121 (trans)-4-(hydroxy(7-isopropylimidazo[1,5-a]pyridin-8-yl)methyl)cyclohexane-1- Alcohol (Examples B121a and B121b) and (cis)-4-(hydroxy(7-isopropylimidazo[1,5-a]pyridin-8-yl)methyl)cyclohexane Hexan-1-ol (two isomers: Examples B121c and B121d)

The desired product was prepared by procedures similar to those described in Example B119. The trans form was a white solid. ¹ H NMR (DMSO-d ₆ ) δ 8.21 (s, 1H), 8.17 (d, J=7.2 Hz, 1H), 7.38 (s, 1H), 6.60 (d, J=7.4 Hz, 1H), 5.30 (br s, 1H), 4.65 (d, J=7.2 Hz, 1H), 4.45 (br s, 1H), 3.50-3.30 (m, 1H), 2.21-2.14 (m, 1H), 1.90-1.84 (m, 1H), 1.78-1.55 (m, 2H), 1.17-0.85 (m, 12H). MS (ESI) m/e [M+1] ⁺ 289.2. The cis form is also a white solid. ¹ H NMR (DMSO-d ₆ ) δ 8.20 (s, 1H), 8.17 (d, J = 7.2 Hz, 1H), 7.37 (s, 1H), 6.61 (d, J = 7.2 Hz, 1H), 5.23 (d, J = 3.2 Hz, 1H), 4.73 (dd, J = 3.2, 8.8 Hz, 1H), 4.22 (d, J = 3.6 Hz, 1H), 1.92-1.82 (m, 2H), 1.72-1.66 (m, 1H), 1.60-1.33 (m, 3H), 1.30-1.10 (m, 9H), 0.88-0.78 (m, 1H). MS (ESI) m/e [M+1] ⁺ 289.2. The trans isomers were then separated using preparative HPLC on a CHIRALCEL AD-H column using _CO₂ /MeOH = 80/20 (/V/V) as the eluent. The enantiomeric excess was determined using HPLC on a CHIRALCEL AD-H column using _CO₂ /MeOH = 80/20 (/V/V) as the eluent at a flow rate of 2.0 mL/min. The first enantiomer (B121a) eluted at a retention time of 6.68 min, while the other enantiomer (B121b) eluted at a retention time of 7.60 min. The cis isomers were then separated using preparative HPLC on a CHIRALCEL AS-H column using _CO₂ /MeOH 0.1% DEA = 75/25 (V/V) as the eluent. Enantiomeric excess was determined using HPLC on a CHIRALCELAS-H column with _CO₂ /MeOH 0.1% DEA = 75/25 (v/v) as the eluent at a flow rate of 2.0 mL/min. The first enantiomer (B121c) eluted at a retention time of 6.93 min, while the other enantiomer (B121d) eluted at a retention time of 11.18 min. Based on the assumption that the binding mode of the more potent isomers B121a and B121c is the same as that of A101a for the IDO1 enzyme, the absolute configurations of B121a, B121b, B121c, and B121d were tentatively assigned as (S), (R), (S), and (R), respectively.

Example B122: Bicyclo[2.2.1]hept-2-yl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol

Step 1: Bicyclo[2.2.1]hept-5-ene-2-carbaldehyde

To a suspension of ZnBr ₂ (83 g, 0.37 mol) in anhydrous DCM (1.5 L) was added acrolein (208 g, 3.7 mol) at -70°C, followed by the slow addition of cyclopenta-1,3-diene (320 g, 3.7 mol) at -70°C. The mixture was then stirred for 0.5 h when the addition was complete. The solid was removed by filtration and the filtrate was evaporated to give the crude product. ¹ H NMR (DMSO-d ₆ )9.42 (m, 1H), 6.21-6.23 (m, 1H), 5.99-6.01 (m, 1H), 3.26 (s, 1H), 2.99 (s, 1H), 2.91-2.95 (m, 1H), 1.89-1.95 (m, 1H), 1.42-1.50 (m, 2H), 1.31-1.33 (m, 1H).

Step 2: Bicyclo[2.2.1]heptane-2-carbaldehyde

To a suspension of (1S,2S,4S)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (300 g, 2.5 mol) in a mixture of MeOH (1.1 L) and EA (1.1 L) was added Pd/C (25 g) at room temperature, and the mixture was stirred under H ₂ (0.4 MPa) overnight. The Pd/C was removed by filtration, and the filtrate was evaporated to give the crude product. ¹ H NMR (DMSO-d ₆ ) 9.78 (s, 1H), 2.71-2.75 (m, 2H), 2.33 (m, 1H), 1.34-1.70 (m, 11H).

Step 3: N-Benzyl-3-((bicyclo[2.2.1]hept-2-yl)(hydroxy)methyl)-4-chloropyridine-2-carboxamide

At -70 ° C, to a solution of ⁿ Bu-Li (0.3 L, 2.4 M) in anhydrous THF (1.1 L), a solution of N-benzyl-4-chloropyridine-2-carboxamide (70 g, 0.28 mol) in anhydrous THF (0.4 L) was slowly added. Then, at -70 ° C, bicyclo [2.2.1] heptane-2-carboxaldehyde (174 g, 1.4 mol) was slowly added and the mixture was stirred for 2 hours. Then EA (0.3 L) and water (0.3 L) were added, the organic layer was separated, the solvent was evaporated and the residue was poured into PE (3.0 L) with vigorous stirring and filtered to obtain a crude product. The crude product was first recrystallized from EtOH and then recrystallized from EA to obtain 38 g as a white solid. ¹ H NMR (DMSO-d ₆ ) 8.41-8.43 (dd, 1H, J=5.2Hz), 8.29 (s, 1H), 8.24-8.25 (dd, 1H, J=2.0Hz), 7.42-7.11 (m, 1H), 7.28-7.36 (m, 5H), 4.67 (d, 2H, J=6.0Hz).

Step 4: 5-(Bicyclo[2.2.1]hept-2-yl)-4-chlorofuro[3,4-b]pyridin-7(5H)-one

A mixture of N-benzyl-3-((bicyclo[2.2.1]hept-2-yl)(hydroxy)methyl)-4-chloropicolinamide (38 g, 0.1 mol) in AcOH (0.5 L) was heated at 50° C. overnight. The solvent was evaporated, then EA (0.5 L) was added and washed with saturated aqueous NaHCO ₃ solution, the organic layer was separated and the solvent was evaporated to give 27 g as a white solid. ¹ H NMR (DMSO-d ₆ ) 8.88 (d, 1H, J=5.2Hz), 7.98 (d, 1H, J=5.2Hz), 5.90 (d, 1H, J=8.0Hz), 2.49-2.50 (m, 1H), 2.34 (s, 1H), 2.19 (s, 1H), 1.89-1.95 (m, 1H), 1.54-1.58 (m, 2H), 1.26-1.42 (m, 5H).

Step 5: 5-((Bicyclo[2.2.1]hept-2-yl)-4-cyclopropylfuro[3,4-b]pyridin-7(5H)-one

To a solution of 5-(bicyclo[2.2.1]hept-2-yl)-4-chlorofuro[3,4-b]pyridin-7(5H)-one (27 g, 102 mmol) in 1,4-dioxane (0.6 L) was added cyclopropylboronic acid (17.5 g, 204 mmol), Pd(dppf) _Cl2 (7.5 g, 10.2 mmol) and _K2CO3 (56 g, 408 _mmol ) and the mixture was heated at 90°C for 3 hours. Cooled to room temperature and filtered to remove solids, the filtrate was evaporated, then EA (1.0 L) was added and filtered through a silicone pad, the filtrate was evaporated to give 24 g of crude product as a brown solid. ¹ H NMR (DMSO-d ₆ )8.65(s, 1H), 7.22(d, 1H, J=5.2Hz), 5.96(d, 1H, J=6.8Hz), 2.45-2.48(m, 2H), 2.26-2.28(m, 1H), 2.02-2.13(m, 2H), 1.80-1.88(m, 1H), 1.45- 1.52 (m, 2H), 1.07-1.34 (m, 8H), 0.78-0.84 (m, 1H).

Step 6: (Bicyclo[2.2.1]hept-2-yl)(4-cyclopropyl-2-(hydroxymethyl)pyridin-3-yl)methanol

To a suspension of LAH (5.1 g, 135 mmol) in anhydrous THF (0.5 L) was added dropwise a solution of 5-(bicyclo[2.2.1]hept-2-yl)-4-cyclopropylfuro[3,4-b]pyridin-7(5H)-one (12 g, 45 mmol) in anhydrous THF (120 mL) at 0° C. and the mixture was stirred for 2 h after the addition was complete. Water (5.1 mL) was then slowly added, followed by NaOH (10.2 mL, 10%) and water (15.3 mL) and the mixture was stirred for 1 h before filtration and evaporation of the filtrate to give 12 g as a crude product.

Step 7: (Bicyclo[2.2.1]hept-2-yl)(2-(chloromethyl)-4-cyclopropylpyridin-3-yl)methanol

To a solution of (bicyclo[2.2.1]hept-2-yl)(4-cyclopropyl-2-(hydroxymethyl)pyridin-3-yl)methanol (32 g, 117 mmol) in anhydrous DCM (1.4 L) was added Et ₃ N (36.5 g, 351 mmol), TsCl (44.8 g, 234 mmol) and 4-DMAP (1.5 g, 11.7 mmol) at room temperature, and the mixture was stirred and filtered. The mixture was washed with water and purified by column chromatography (DCM:MeOH=95:5) to give 27 g as a brown solid.

Step 8: N-((3-((bicyclo[2.2.1]hept-2-yl)(hydroxy)methyl)-4-cyclopropylpyridin-2-yl)methyl)- N-Formylformamide

To a solution of (bicyclo[2.2.1]hept-2-yl)(2-(chloromethyl)-4-cyclopropylpyridin-3-yl)methanol (27 g, 93 mmol) in anhydrous DMF (0.5 L) was added sodium diformamide (17.7 g, 186 mmol) at room temperature and the mixture was heated at 80° C. for 2 hours. The solvent was evaporated, then EA (0.5 L) was added and washed with brine, the organic layer was separated and evaporated to give the crude product as a brown solid.

Step 9: (Bicyclo[2.2.1]hept-2-yl)(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methyl formate

To a solution of crude N-((3-((bicyclo[2.2.1]hept-2-yl)(hydroxy)methyl)-4-cyclopropylpyridin-2-yl)methyl)-N-formylcarboxamide (93 mmol) in Ac ₂ O (0.4 L) was added HCOOH (0.2 L) at room temperature, and the mixture was heated at 60° C. for 3 hours. The solvent was evaporated, and then EA (0.6 L) was added and washed with saturated aqueous NaHCO ₃ solution, the organic layer was separated, the solvent was evaporated and purified by column chromatography (PE:EA=1:1 to EA) to give 15 g as a light brown solid.

Step 10: (Bicyclo[2.2.1]hept-2-yl)(7-cyclopropylimidazo[1,5-a]pyridin-R-yl)methanol

To a solution of (bicyclo[2.2.1]hept-2-yl)(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methyl formate (15 g, 48 mmol) in a mixture of THF (0.4 L) and water (0.1 L) was added LiOH H ₂ O (4.0 g, 96 mmol) at room temperature, and the mixture was stirred for 1 hour. EA (0.2 L) was added, the organic layer was separated, the solvent was evaporated, and the mixture was washed with EA/PE = 1:1 to give 13 g of a white solid. ¹ H NMR (DMSO-d ₆ ) δ8.24-8.21 (m, 1H), 8.13-8.08 (m, 1H), 7.44-7.38 (m, 1H), 6.20-6.13 (m, 1H), 5.35-5.15 (m, 1H), 5.10-4.80 (m, 1H), 2.70-2.50 (m, 1H), 2.30-2.00 (m, 3 H), 1.72-0.60 (m, 12H). MS(ESI)m/e[M+1] ⁺ 283.2.

Example B122a: (S)-((1R,2S,4S)-bicyclo[2.2.1]hept-2-yl)(7-cyclopropylimidazo[1,5-a] pyridin-8-yl)methanol

To a suspension of (bicyclo[2.2.1]hept-2-yl)(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol (0.9 g, 3.2 mmol) in CH ₃ CN (100 mL) at 60° C., a solution of L-DBTA (1.26 g, 1.1 equiv) in CH ₃ CN (36 mL) was added dropwise until the mixture was completely dissolved. The mixture was then slowly cooled to room temperature and filtered to afford 0.7 g as a white solid. This was then recrystallized from CH ₃ CN (70 mL) to afford 490 mg as a white solid. The solid was then dispersed in DCM (50 mL) and aqueous K ₂ CO ₃ solution (5 mL) was added with stirring. The organic layer was separated and the solvent evaporated to afford 230 mg as a white solid. ¹ HNMR (DMSO-d ₆ ) 8.20 (s, 1H), 8.09 (d, 1H, J=7.2Hz), 7.40 (s, 1H), 6.14 (d, 1H, J=7.2Hz), 5.13-5.19 (m, 2H), 2.59 (s, 1H), 2.06-2.17 (m, 2H), 1.81-1.85 (m, 1H), 1.38-1.54 (m, 2H), 0.58-1.29 (m, 1OH).

The absolute stereochemistry of the compound of Example B122a, which was more potent in both enzyme and cellular assays, was assigned to the (S),(S)-configuration at the chiral α-carbon based on its co-crystal structure with IDO1 enzyme.

Example B122b: (1S)-Bicyclo[2.2.1]hept-2-yl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methane Alcohol (exo-enantiomer)

Step 1: Bicyclo[2.2.1]hept-2-yl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanone

To a solution of bicyclo[2.2.1]hept-2-yl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol (2.0 g, 7.09 mol) in EA (150 mL) was added IBX (6.0 g, 21.3 mmol). The reaction mixture was warmed to 60° C. and stirred for approximately 6 hours. The mixture was cooled to ambient temperature, filtered, and the solid was washed with EA (20 mL). The filtrate was concentrated and the crude product was purified by silica gel column chromatography (200-300 mesh, eluent: DCM:MeOH=100:1) to give the product as a yellow oil (1.8 g, 90.6%). MS (ESI) m/e[M+1] ⁺ 281.1.

Step 2: (1S)-Bicyclo[2.2.1]hept-2-yl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol

To a solution of bicyclo[2.2.1]hept-2-yl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanone (1.8 g, 6.43 mol) in THF (100 mL) was added (S)-ME CBS (CAS: 112022-81-8, 1 M, 1.65 mL, 0.064 mmol). After stirring for approximately 15 minutes, borane-methyl sulfide complex (2.0 M, 6.5 mL, 13.0 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at ambient temperature for approximately 16 hours. Concentrated HCl (5.0 mL) was added to the reaction mixture, and the solid was filtered, washed with THF (10 mL), and dissolved in _CH₂Cl₂ (20 _mL ). Saturated _Na₂CO₃ was added to the solution to adjust the pH to _8-9 , _and the aqueous solution was extracted with _CH₂Cl₂ (20 mL*3). The combined organic phases were washed with saturated NaCl (10 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated to give the product as a light brown solid (1.3 g, 71.7%).

The solid (1.3 g, 4.61 mmol) was added to CH ₃ CN (65 mL), warmed to 56° C., and stirred until all the solid was dissolved. L-DBTA (1.65 g, 4.61 mmol) was added to the solution, and the reaction mixture was slowly cooled to ambient temperature and stirred for approximately 16 h. The solid was filtered, washed with CH ₃ CN (15 mL), and added to CH ₂ Cl ₂ (20 mL). Saturated Na ₂ CO ₃ was added to the solution to adjust the pH to 8-9. The aqueous phase was extracted with CH ₂ Cl ₂ (3*10 mL), and the combined organic phases were washed with saturated NaCl (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to afford the product as a light yellow solid (900 mg, 69.2%).

Step 3: (1S)-Bicyclo[2.2.1]hept-2-yl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol ( exo -enantiomer )

The pale yellow solid (100 mg) was separated by preparative HPLC on a CHIRALCEL IC-H column using CO ₂ /IPA = 50/50 (/V/V) as the eluent. The enantiomeric excess was determined by HPLC on a CHIRALCEL AC-H column using hexane/EtOH 0.1% DEA = 70/30 (/V/V) as the eluent at a flow rate of 1.0 mL/min. The enantiomer (20 mg, 20%) eluted at a retention time of 4.59 min. ¹ H NMR (DMSO-d ₆ ) δ 8.30 (s, 1H), 8.12 (d, J=7.4Hz, 1H), 7.46 (s, 1H), 6.19 (d, J=7.4Hz, 1H), 5.34 (br s, 1H), 4.85 (d, J=8.8 Hz, 1H), 2.57-2.52(m, 1H), 2.22-2.07(m, 3H), 1.59-1.37(m, 3H), 1.27-0.60(m, 9H). MS(ESI)m/e[M+1] ⁺ 283.2.

Example B123: Bicyclo[2.2.2]oct-5-en-2-yl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methane alcohol

The desired product was prepared following procedures similar to those described in Example B122. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.12 (s, 1H), 8.00 (s, 1H), 7.97 (s, 1H), 6.51-6.27 (m, 4H), 4.98 (d, J=9.7 Hz, 1H), 3.04-3.02 (m, 1H), 2.49-2.30 (m, 2H), 2.03-1.98 (m, 1H), 1.58-1.55 (m, 1H), 1.41-1.36 (m, 2H), 1.29-1.23 (m, 2H), 1.11-1.08 (m, 2H), 0.77-0.74 (m, 3H).

Example B124: Bicyclo[2.2.2]octan-2-yl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol

The desired product was reduced following procedures similar to those described in Example B122. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.08 (s, 1H), 8.02 (d, J = 7.4 Hz, 1H), 7.95 (s, 1H), 6.51 (d, J = 7.4 Hz, 1H), 5.44 (d, J = 10.3 Hz, 1H), 2.30-0.75 (m, 18H). MS (ESI) m/e [M+1] ⁺ 297.2.

Example B125: N-cyclopropyl-3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)benzene Formamide

Step 1: tert-Butyl 3-((2-(Benzylcarbamoyl)-4-chloropyridin-3-yl)(hydroxy)methyl)-benzoate

To a solution of ^nBu -Li (40 mL, 2.4 M) in anhydrous THF (40 mL) at -70°C under nitrogen, a solution of N-benzyl-4-chloropyridine-2-carboxamide (12 g, 48 mmol) in anhydrous THF (50 mL) was slowly added and the mixture was stirred for 30 min, and then tert-butyl 3-formylbenzoate (20 g, 120 mmol) was added dropwise at -70°C and the mixture was stirred for 1 h, then quenched with water (0.2 L), extracted with EA (40 mL*3), combined and dried over _Na2SO4 , _the solid was removed by filtration and the filtrate was evaporated to give the crude product, which was then used in the next step without further purification.

Step 2: tert-Butyl 3-(4-chloro-7-oxo-5,7-dihydrofuro[3,4-b]pyridin-5-yl)benzoate

A mixture of tert-butyl 3-((2-(benzylcarbamoyl)-4-chloropyridin-3-yl)(hydroxy)methyl)benzoate (crude, 48 mmol) in AcOH (0.2 L) was stirred at room temperature overnight. The solvent was evaporated, and then EA (0.4 L) was added. The mixture was washed with water, saturated aqueous NaHCO ₃ solution, and brine. The organic layer was evaporated to give a crude product, which was further purified by column chromatography (PE:EA=5:1 to PE:EA=1:1) to give 11 g of a light-colored solid.

Step 3: tert-Butyl 3-(4-cyclopropyl-7-oxo-5,7-dihydrofuro[3,4-b]pyridin-5-yl)benzoate

To a solution of tert-butyl 3-(4-chloro-7-oxo-5,7-dihydrofuro[3,4-b]pyridin-5-yl)benzoate (3.5 g, 10 mmol) in 1,4-dioxane (0.1 L) were added cyclopropylboronic acid (1.7 g, 20 mmol), Pd(dppf)Cl ₂ (0.8 g, 1.0 mmol) and K ₂ CO ₃ (5.5 g, 40 mmol), and the mixture was heated at 90° C. for 6 hours. The mixture was cooled to room temperature and filtered to remove the solid, and the filtrate was evaporated, followed by the addition of EA (1.0 L), filtered through a pad of silica gel, and the filtrate was evaporated and purified by column chromatography (PE:EA=1:1) to give 3.3 g of a brown solid.

Step 4: tert-Butyl 3-((4-cyclopropyl-2-(hydroxymethyl)pyridin-3-yl)(hydroxy)methyl)benzoate

To a solution of tert-butyl 3-(4-cyclopropyl-7-oxo-5,7-dihydrofuro[3,4-b]pyridin-5-yl)benzoate (12 g, 34 mmol) in EtOH (0.3 L) was added portionwise NaBH ₄ (2.6 g, 68 mmol) at room temperature and the mixture was heated at 50° C. for 2 hours. The solvent was evaporated and water (0.1 L) was added, extracted with EA (0.2 L*3), the organic layers were combined, dried over Na ₂ SO ₄ , filtered and the filtrate was evaporated to give a crude product, which was then used in the next step without further purification.

Step 5: 3-((4-cyclopropyl-2-((tosyloxy)methyl)pyridin-3-yl)(hydroxy)methyl)benzyl Tert-butyl ester

To a solution of tert-butyl 3-((4-cyclopropyl-2-(hydroxymethyl)pyridin-3-yl)(hydroxy)-methyl)benzoate (crude, 34 mmol) in anhydrous DCM (0.3 L) was added Et N ( _7.0 g, 68 mmol) and TsCl (7.8 g, 41 mmol) at room temperature, and the mixture was stirred for 4 hours. Water (0.2 L) was added, the organic layer was separated and dried _over Na _SO , filtered, and the filtrate was evaporated to give the crude product. The crude product was then used in the next step without further purification.

Step 6: 3-((4-cyclopropyl-2-((N-formylformamido)methyl)pyridin-3-yl)(hydroxy)methyl)benzene tert-Butyl formate

To a solution of tert-butyl 3-((4-cyclopropyl-2-((tosyloxy)methyl)pyridin-3-yl)(hydroxy)methyl)benzoate (crude, 34 mmol) in anhydrous DMF (0.3 L) was added sodium diformamide (6.4 g, 68 mmol) at room temperature and the mixture was heated at 80° C. for 2 hours. The solvent was evaporated, then EA (0.5 L) was added and washed with brine, the organic layer was separated and evaporated to give the crude product as a brown solid. The crude product was then used in the next step without further purification.

Step 7: tert-Butyl 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(formyloxy)methyl)benzoate ester

To a solution of tert-butyl 3-((4-cyclopropyl-2-((N-formylformamido)methyl)pyridin-3-yl)(hydroxy)methyl)benzoate (crude, 34 mmol) in Ac ₂ O (0.2 L) was added HCOOH (0.1 L) at room temperature and the mixture was heated at 50° C. for 4 hours. The solvent was evaporated and EA (0.2 L) was added, washed with saturated aqueous NaHCO ₃ solution and brine, and the solvent was evaporated to give a crude product, which was then used in the next step without further purification.

Step 8: tert-Butyl 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)benzoate

To a solution of tert-butyl 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(formyloxy)methyl)benzoate (crude, 34 mmol) in MeOH (60 mL) was added LiOH H ₂ O (3.0 g, 68 mmol) at room temperature, and the mixture was stirred for 4 hours. The solvent was evaporated, water (0.1 L) was added, and the mixture was extracted with EA (40 mL*3). The organic layers were combined, the solvent was evaporated, and the mixture was purified by column chromatography (EA/PE=1:1 to EA) to give 2.0 g as a white solid. ¹ H NMR (DMSO-d ₆ )8.18 (s, 1H), 8.14 (d, 1H, J=7.2Hz), 8.00 (s, 1H), 7.67-7.72 (m, 2H), 7.40 (t, 1H, J=7.6Hz), 7.20 (s, 1H) , 6.18-6.23 (m, 2H), 2.30-2.31 (m, 1H), 1.50 (s, 9H), 0.90-0.98 (m, 2H), 0.70-0.80 (m, 2H).

Step 9: 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)benzoic acid

To a solution of tert-butyl 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)benzoate (2.0 g, 5.5 mmol) in anhydrous DCM (50 mL) was added TFA (10 mL) at room temperature and the mixture was stirred overnight. The solvent was evaporated to give the crude product, which was then used in the next step without further purification.

Step 10: N-cyclopropyl-3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)benzoyl Amine (Example B125)

To a solution of 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)benzoic acid (0.1 g, 0.32 mmol) in anhydrous DMF (10 mL) was added HATU (243 mg, 0.64 mmol) and DIEA (165 mg, 1.28 mmol) at room temperature, and the mixture was stirred for 0.5 h. Cyclopropylamine (37 mg, 0.64 mmol) was then added, and the mixture was stirred for 6 hours. Water (20 mL) was added and extracted with EA (20 mL * 3), the combined extracts were washed with brine, and the solvent was evaporated to give a crude product, which was further purified by preparative HPLC to give 15 mg, 14% yield. ¹ H NMR (DMSO-d ₆ ) 8.43 (d, 1H, J=4.0Hz), 8.21 (s, 1H), 8.16 (d, 1H, J=6.8Hz), 7.95 (s, 1H), 7.63 (d, 1H, J=7.6Hz), 7.53 (d, 1H, J=7.6Hz), 7.33 (t, 1H, J=7.6Hz), 7.23 (s, 1H), 6.49 (d, 1H, J=3.2Hz), 6.25 (d, 1H, J=7.2Hz), 6.15(s, 1H), 2.79-2.81(m, 1H), 2.29-2.32(m, 1H), 0.92-0.96(m, 2H), 0.74-0.76(m, 2H), 0.65-0.69(m, 2H), 0.55-0.57(m, 2H).

Example B126: Cyclohexyl(7-(cis-2-fluorocyclopropyl)imidazo[1,5-a]pyridin-8-yl)methanol

Step 1: (cis-2-fluorocyclopropyl)ethan-1-one

MeLi (1.6 M in _Et2O , 44 mL, 70 mmol) was slowly added to a cooled solution of cis-2-fluorocyclopropane-1-carboxylic acid (3.63 g, 35 mmol) in anhydrous _Et2O (60 mL) at -78°C over _1.5 h. The resulting mixture was stirred at -78°C for 15 min and slowly warmed to 0°C and stirred for 2 h. The reaction mixture was carefully treated with water (100 mL), extracted with MeOt-Bu (100 mL*2), dried over _Na2SO4 , and concentrated to afford (cis-2-fluorocyclopropyl)ethan-1-one (2.8 g, 77%) as a colorless oil. ¹ H NMR (DMSO-d ₆ ) δ 5.01-4.82 (m, 1H), 2.27 (m, 1H), 2.23 (s, 3H), 1.69-1.59 (m, 1H), 1.12-1.06 (m, 1H).

Steps 2 and 3: 4-((cis-2-fluorocyclopropyl)-2-methylpyridine-3-carbonitrile

Accompanying stirring to the β-aminobutene nitrile (3.4g, 42mmol) and NEt ₃ (10.7mL, 77mmol) solution in DCM (50mL) of ice bath cooling, slowly add TiCl ₄ solution (1M solution in DCM, 21mL, 21mmol). Subsequently, press a solution of (cis-2-fluorocyclopropyl) second-1-ketone (2.8g, 27.5mmol) in DCM (20mL). After 4h, concentrated reaction mixture also adds MeOt-Bu (300mL). With the gained slurries stirred at room temperature for 1h, then filtered and washed with MeOt-Bu (200mL). Evaporating solvent, obtains crude product, which is directly used in next step.

To a solution of β-enaminonitrile in DCM (200 mL) was added an imine salt (11 g, 52.5 mmol) in one portion. The reaction mixture was stirred at room temperature for 20 h and 2N NaOH (200 mL) was added. After stirring for 15 min, the organic phase was separated and the aqueous phase was extracted with DCM (100 mL*2). The combined organic phases were washed with brine (200 mL), dried over Na ₂ SO ₄ , and purified by silica gel chromatography (petroleum ether/ethyl acetate = 10:1) to give 4-((cis-2-fluorocyclopropyl)-2-methylpyridine-3-carbonitrile (1.92 g, 40%) as a colorless oil. ¹ H NMR (DMSO-d ₆ ) δ 8.58 (d, J = 5.2 Hz, 1H), 7.26 (d, J = 5.2 Hz, 1H), 5.16 (m, 1H), 2.68 (s, 3H), 2.46-2.34 (m, 1H), 1.69 (dtd, J = 23.2, 7.7, 3.0 Hz, 1H), 1.51-1.38 (m, 1H). MS (ESI) m/e [M+1] ⁺ 177.1.

Step 4: 4-(cis-2-fluorocyclopropyl)-2-methylpyridine-3-carbaldehyde

To a stirred solution of 4-((cis-2-fluorocyclopropyl)-2-methylpyridine-3-carbonitrile (1.76 g, 10 mmol) in DCM (25 mL) was added DIBAL-H (1.0 M solution in PhMe, 25 mL, 25 mmol) dropwise at -78°C and stirred at the same temperature for 1 h. The reaction mixture was poured into 2N HCl (100 mL) at 0°C and then neutralized with NaOH. The mixture was then extracted with EA (100 mL*3), washed with brine (100 mL), dried over Na ₂ SO ₄ , and purified on silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give 4-(cis-2-fluorocyclopropyl)-2-methylpyridine-3-carbaldehyde (1.42 g, 79%) as a light yellow solid. ¹ H NMR (DMSO-d ₆ ) δ10.67 (s, 1H), 8.55 (d, J = 5.2Hz, 1H), 7.33 (d, J = 5.2Hz, 1H), 5.17-4.96 (m, 1H), 2.72 (s, 3H), 2.69 (m, 1H), 1.54-1.47 (m, 1H), 1.40-1.27 (m, 1H). MS(ESI) m/e[M+1] ⁺ 180.1.

Step 5: 2-(Chloromethyl)-4-(cis-2-fluorocyclopropyl)pyridine-3-carbaldehyde

At room temperature, 1,3,5-trichloro-1,3,5-hexahydrotriazine-2,4,6-trione (2.21 g, 9.5 mmol) was added to a stirred solution of 4-(cis-2-fluorocyclopropyl)-2-methylpyridine- ₃ -carboxaldehyde (1.42 g, 7.9 mmol) in DCM (40 mL). After stirring for 20 h, the mixture was filtered and the filtrate was washed with a NaHCO aqueous solution (50 mL). The mixture was dried over _Na SO and concentrated to give 2-(chloromethyl) _-4- (cis-2-fluorocyclopropyl)pyridine-3-carboxaldehyde (1.7 g, quantitative) as a white solid. ¹ H NMR (DMSO-d ₆ ) δ10.69 (s, 1H), 8.66 (d, J = 5.2Hz, 1H), 7.51 (d, J = 5.2Hz, 1H), 5.17-5.00 (m, 3H), 2.73 (m, 1H), 1.60-1.54 (m, 1H), 1.40-1.34 (m, 1H). MS(ESI)m/e[M+1] ⁺ 214.0.

Steps 6 and 7: 7-(cis-2-fluorocyclopropyl)imidazo[1,5-a]pyridine-8-carbaldehyde

Sodium diformamide (1.5 g, 15.8 mmol) was added to a stirred solution of 2-(chloromethyl)-4-(cis-2-fluorocyclopropyl)pyridine-3-carbaldehyde (1.69 g, 7.9 mmol) in DMF (30 mL). The reaction mixture was stirred at room temperature for 5.5 h. The mixture was then concentrated and EA/water (100 mL/100 mL) was added. The organic phase was separated and the aqueous phase was extracted with EA (100 mL*3). The combined organic phases were washed with brine (100 _mL ), dried over _Na₂SO₄ , and concentrated to yield N-((4-(cis-2-fluorocyclopropyl)-3-formylpyridin-2-yl)methyl)formamide. MS (ESI) m/e [M+1] ^⁺ 223.1; a 1:1 mixture of HCOOH and _Ac₂O (20 mL) was stirred at 50°C for 1.5 h. After cooling to room temperature, the mixture was added to N-((4-(cis-2-fluorocyclopropyl)-3-formylpyridin-2-yl)methyl)formamide at the same temperature. After 20 h, the reaction mixture was concentrated and saturated aqueous _NaHCO₃ (50 mL) was carefully added. 2N NaOH was then added to maintain the pH > 12. The aqueous phase was extracted with EA (3*50 mL), _dried over _Na₂SO₄ , and purified by silica gel chromatography (DCM/MeOH = 50:1) to give 7-(cis-2-fluorocyclopropyl)imidazo[1,5-a]pyridine-8-carbaldehyde (1.32 g, 82%) as a waxy solid. ¹ H NMR (DMSO-d ₆ ) δ 10.62 (s, 1H), 8.62 (d, J=7.2Hz, 1H), 8.43 (s, 1H), 7.84 (s, 1H), 6.79 (d, J=7.2Hz, 1H), 5.25-4.98 (m, 1H), 2.80- 2.73 (m, 1H), 1.55-1.37 (m, 2H). MS(ESI)m/e[M+1] ⁺ 205.1.

Step 8: Cyclohexyl(7-(cis-2-fluorocyclopropyl)imidazo[1,5-a]pyridin-8-yl)methanol

To a solution of 7-(cis-2-fluorocyclopropyl)imidazo[1,5-a]pyridine-8-carbaldehyde (114 mg, 0.56 mmol) in THF (2 mL) was added cyclohexylmagnesium chloride (1.3 M solution in PhMe/THF, 0.64 mL, 0.84 mmol) at 0°C. The reaction mixture was stirred at 0°C for 40 min and then quenched with saturated aqueous _NH4Cl (10 mL). The mixture was diluted with DCM (50 mL) and the organic phase was separated and washed with brine (20 _mL ), dried over _Na2SO4 , and purified on silica gel chromatography (DCM/MeOH = 100:3) to give cyclohexyl(7-(cis-2-fluorocyclopropyl)imidazo[1,5-a]pyridin-8-yl)methanol as two diastereomers (95 mg, 59%). Major (Example B126a): pale yellow solid, ¹ H NMR (CDCl ₃ ) δ 8.09 (s, 1H), 7.82 (d, J=7.2 Hz, 1H), 7.67 (s, 1H), 6.51 (d, J=7.2 Hz, 1H), 5.02-4.82 (m, 1H), 4.94 (d, J=9.2 Hz, 1H), 2.37 (br d, J=12.4 Hz, 1H), 2.20-2.06 (m, 2H), 1.83 (br d, J=12.4 Hz, 1H), 1.65-1.58 (m, 2H), 1.28-1.06 (m, 7H), 0.95-0.86 (m, 1H). MS (ESI) m/e [M+1] ⁺ 289.1; minor (Example B126b): pale yellow solid, ¹ H NMR (CDCl ₃ ) δ 8.05 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.63 (s, 1H), 6.46 (d, J = 7.2 Hz, 1H), 5.04 (d, J = 9.0 Hz, 1H), 4.94-4.74 (m, 1H), 2.30-2.27 (m, 1H), 2.14-2.05 (m, 1H), 1.89-1.60 (m, 3H), 1.38-1.06 (m, 7H), 0.97-0.88 (m, 1H). MS (ESI) m/e [M+1] ⁺ 289.1.

Examples B127a and B127b: 2-cyclohexyl-1-(7-(cis-2-fluorocyclopropyl)imidazo[1,5-a]pyridine- 8-amino)ethanol-1-ol

To a solution of 7-(cis-2-fluorocyclopropyl)imidazo[1,5-a]pyridine-8-carbaldehyde (52 mg, 0.25 mmol) in THF (2 mL) was slowly added methylmagnesium bromide (0.5 M in THF, 0.76 mL, 0.38 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1.5 h and then quenched with saturated aqueous _NH4Cl (10 mL). The mixture was diluted with DCM (50 mL) and the organic phase was separated and washed with brine (20 _mL ), dried over _Na2SO4 , and purified on preparative TLC (DCM/MeOH = 100:5) to give 2-cyclohexyl-1-(7-(cis-2-fluorocyclopropyl)imidazo[1,5-a]pyridin-8-yl)ethan-1-ol (12 mg, 16%) as two diastereomers. Major (Example B127a: pale yellow solid, ^1H NMR (DMSO- _d6 ) δ 8.30 (s, 1H), 8.15 (d, J = 7.2 Hz, 1H), 7.51 (s, 1H), 6.51 (d, J = 7.2 Hz, 1H), 5.31 (br d, J = 3.6 Hz, 1H), 5.27-5.24 (m, 1H), 5.10-4.91 (m, 1H), 2.16-2.08 (m, 1H), 1.94-1.81 (m, 2H), 1.77-1.49 (m, 4H), 1.45-1.03 (m, 7H), 0.96-0.85 (m, 2H). MS (ESI) m/e [M+1] ⁺ 303.2; minor (Example B127b: pale yellow solid, ^1H NMR (DMSO- _d6 ) δ 8.29 (s, 1H), 8.14 (d, J = 7.2 Hz, 1H), 7.50 (s, 1H), 6.49 (d, J = 7.2 Hz, 1H), 5.46-5.33 (m, 1H), 5.26 (d, J = 3.2 Hz, 1H), 5.06-4.71 (m, 1H), 2.24-2.10 (m, 1H), 1.93-1.82 (m, 2H), 1.76-1.45 (m, 5H), 1.45-1.05 (m, 6H), 0.96-0.87 (m, 2H). MS (ESI) m/e [M+1] ⁺ 303.1.

Example B128: Cyclohexyl(7-((trans)-2-fluorocyclopropyl)imidazo[1,5-a]pyridin-8-yl)methanol

This compound was prepared by following a procedure similar to Example B126, which includes four isomers. ¹ H NMR (CDCl ₃ ) δ 8.04 (s, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.62 (s, 1H), 6.11 (d, J = 7.2 Hz, 0.5H), 6.06 (d, J = 7.2 Hz, 0.5H), 5.08 (d, J = 8.8 Hz, 0.5H), 5.02 (d, J = 7.2 Hz, 0.5H), 4.79-4.71 (m, 0.5H). H), 4.63-4.55(m, 0.5H), 3.75-3.62(m, 0.5H), 3.43-3.35(m, 0.5H), 2.60-2.42(m, 1H), 2.35-1.95(m, 2H), 1.90-0.80(m, 11H). MS(ESI)m/e[M+1] ⁺ 289.1.

Examples B128a, B128b and B128c: Cyclohexyl(7-((trans)-2-fluorocyclopropyl)imidazo[1,5-a]pyrrolidone pyridin-8-yl)methanol

This compound, comprising four isomers, was separated by preparative HPLC on a CHIRALCEL AS-H column using CO ₂ /EtOH 0.1% DEA = 60/40 (/V/V) as the eluent. The enantiomeric excess was determined by HPLC on a CHIRALCEL AS-H column using CO ₂ /EtOH 0.1% DEA = 60/40 (/V/V) as the eluent at a flow rate of 2.0 mL/min. Peak 1 (B128a), comprising two isomers, eluted at a retention time of 4.60 min as an off-white solid (20 mg, two isomers). ^1H NMR (DMSO-d ₆ ) δ 8.35 (s, 1H), 8.13 (d, J=7.2 Hz, 1H), 7.43 (s, 1H), 5.38-5.28 (m, 1H), 5.04-4.80 (m, 2H), 2.25-2.13 (m, 1H), 2.04-1.85 (m, 2H), 1.81-1.41 (m, 3H), 1.30-0.80 (m, 8H). MS (ESI) m/e [M+1] ⁺ 289.1; Peak 2 (B128b) as a single isomer eluted at a retention time of 5.60 min as an off-white solid (6.0 mg, single isomer). ¹ H NMR (CDCl ₃ -d ₁ ) δ8.06 (s, 1H), 7.76 (d, J=7.0Hz, 1H), 7.62 (s, 1H), 6.06 (d, J=7.0Hz, 1H), 5.08 (d, J=8.8Hz, 1 H), 4.77-4.55 (m, 1H), 3.10-2.90 (m, 1H), 2.62-2.48 (m, 1H), 2.38-1.96 (m, 3H), 1.90-1.45 (m, 4H), 1.40-0.80 (m, 6H). MS (ESI) m/e [M+1] ⁺ 289.1.; and peak 3 (B128c) as a single isomer eluted at a retention time of 7.14 min as an off-white solid (6.0 mg, single isomer). ¹ H NMR (CDCl ₃ -d ₁ ) δ 8.07 (s, 1H), 7.77 (d, J=7.0Hz, 1H), 7.63 (s, 1H), 6.11 (d, J=7.0Hz, 1H), 5.03 (d, J=8.8Hz, 1H), 4.90-4.57 (m, 1H), 3.10-2.95 (m, 1H), 2.62-2.48 (m, 1H), 2.38-1.96 (m, 3H), 1.90-1.50 (m, 4H), 1.40-0.80 (m, 6H). MS(ESI)m/e[M+1] ⁺ 289.1.

Example B129: 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)piperidine-1-carboxylic acid Benzyl ester

Example B129 was synthesized following procedures similar to those described in Example B107 under appropriate conditions that would be recognized by one of ordinary skill in the art. ¹ H NMR (DMSO-d ₆ )δ8.27-8.25(m, 1H), 8.20-8.10(m, 1H), 7.42-7.29(m, 5H), 6.17(d, J=7.4Hz, 1H), 5.52-5.49(m, 1H), 5.08-5.05( m, 1H), 4.99-4.93 (m, 1H), 4.49-4.47 (m, 0.5H), 3.94-3.91 (m, 1H), 3.60-3.57 (m, 0.5H), 2.88-2.62 (m, 2H), 2.28- 1.98 (m, 2H), 1.71-0.68 (m, 8H). MS (ESI, m/e) [M+1] ⁺ 406.2.

Examples B130a and B130b: (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(1-(methylsulfonyl)piperidin- pyridin-3-yl)methanol

Step 1: (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(piperidin-3-yl)methanol

A mixture of benzyl 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)piperidine-1-carboxylate (1.0 g, 2.47 mmol) and Pd/C (50 mg) in EtOH (10 ml) was stirred at room temperature for 16 hours, then the mixture was filtered and the filtrate was concentrated to give 500 mg (74.6%) of (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(piperidin-3-yl)methanol as a yellow solid. MS (ESI, m/e) [M+1] ⁺ 272.2.

Step 2: (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(1-(methylsulfonyl)piperidin-3-yl)methanol

To a solution of (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(piperidin-3-yl)methanol (100 mg, 0.37 mmol) and _Et3N (56 mg, 0.56 mmol) in DCM (10 mL) was added methanesulfonyl chloride (42 mg, 0.37 mmol). The mixture was stirred at room temperature for 30 min, then quenched with aqueous _NH4Cl (10 ml) and extracted with EA (10 mL*3). The organic layer was concentrated to give the crude product, which was purified by preparative HPLC to give two diastereomers: 2.6 mg (2.0%) as an off-white solid (B130a). ^1H NMR (CD ₃ OD) δ 8.09 (s, 1H), 7.94 (d, J = 7.4 Hz, 1H), 7.42 (s, 1H), 6.18 (d, J = 7.4 Hz, 1H), 5.18 (d, J = 8.4 Hz, 1H), 3.49-3.36 (m, 1H), 3.19-3.12 (m, 1H), 2.72-2.63 (m, 1H), 2.60 (s, 3H), 2.57-0.60 (m, 11H). MS (ESI) m/e [M+1] ⁺ 350.2, ^and 3.5 mg (2.7%) as an off-white solid (B130b). ¹ H NMR (CD ₃ OD) δ8.09 (s, 1H), 7.95 (d, J=7.4Hz, 1H), 7.42 (s, 1H), 6.17 (d, J=7.4Hz, 1H), 5.12 (d, J=9.4Hz, 1H), 4.10-3.99 (m, 1H), 3.53-3.49 (m, 1H), 2.76 (s, 3H), 2.69-0.60 (m, 12H). MS(ESI)m/e[M+1] ⁺ 350.2.

Example B131: (2-(3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)piperidin-1-yl) tert-Butyl)-2-oxoethyl)carbamate

A solution of (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(piperidin-3-yl)methanol (150 mg, 0.55 mmol), (tert-butoxycarbonyl)glycine (96 mg, 0.55 mmol), HATU (210 mg, 0.55 mmol), and Et3N (56 mg, 0.56 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours, and then the mixture was quenched with _H2O (10 ml) and extracted with EA (10 mL*3). The organic layer was concentrated to give a crude product, which was then purified by preparative-TLC to give 120 mg (51.1%) of tert-butyl (2-(3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)piperidin-1-yl)-2-oxoethyl)carbamate as a yellow solid. ¹ H NMR (CDCl ₃ ) δ8.29-8.16 (m, 1H), 7.82-7.80 (m, 1H), 7.55-7.54 (m, 1H), 6.19-6.16(m, 1H), 5.56-5.43(m, 1H), 5.20-5.17(m, 1H), 4.43-0.72(m, 25H). MS(ESI, m/e)[M+1] ⁺ 429.2.

Example B132: 2-amino-1-(3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)piperidin- pyridin-1-yl)ethan-1-one

A solution of tert-butyl (2-(3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)piperidin-1-yl)-2-oxoethyl)carbamate (100 mg, 0.23 mmol) and TFA (1 mL) in DCM (5 mL) was stirred at room temperature for 2 hours, and then the mixture was quenched with aqueous NaHCO ₃ solution and extracted with DCM (10 mL*3). The organic layer was concentrated to give a crude product, which was then purified by preparative-TLC to give 35 mg (46.7%) of tert-butyl (2-(3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)piperidin-1-yl)-2-oxoethyl)carbamate as a yellow solid. ¹ H NMR (DMSO-d ₆ ) δ 8.24-8.22 (m, 1H), 8.15-8.13 (m, 1H), 7.47 (s, 1H), 7.37-7.35 (m, 1H), 7.20 (br s, 2H), 6.18- 6.15 (m, 1H), 5.58-4.85 (m, 1H), 4.14-0.73 (m, 16H). MS(ESI,m/e)[M+1] ⁺ 329.2.

Examples B133a and B133b: 1-(3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl) Piperidin-1-yl)ethan-1-one

Following procedures similar to those described in Example B107, under appropriate conditions recognized by one of ordinary skill in the art, the desired compound was synthesized and purified by preparative HPLC to yield two diastereomers. (B133a is a rotamer): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.23 (s, 0.4H), 8.22 (s, 0.5H), 8.15 (d, J=7.2 Hz, 0.4H), 8.13 (d, J=7.2 Hz, 0.5H), 7.44 (s, 0.4H), 7.37 (s, 0.5H), 6.17 (d, J=7.2 Hz, 1H), 5.52 (d, J = 3.7 Hz, 0.4H), 5.43 (d, J = 3.7 Hz, 0.5H), 5.11-5.02 (m, 0.4H), 5.02-4.94 (m, 0.5H), 4.21-0.64 (m, 14H), 1.89 (s, 1.7), 1.59 (s, 1.3H). MS (ESI, m/e) [M+1] ⁺ 314.2; (B133b is a rotamer): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.23 (s, 0.5H), 8.22 (s, 0.5H), 8.14 (d, J=7.2Hz, 0.5H), 8.12 (d, J=7.2Hz, 0.5H), 7.43 (s, 0.5H), 7.37 (s, 0.5H), 6.17 (d, J=7.2Hz, 0.5H), 6.15 (d, J=7.2Hz, 0.5H), 5.54 ( d, J=3.0Hz, 0.5H), 5.46 (d, J=3.0Hz, 0.5H), 5.08-4.75 (m, 1H), 4.17-3.99 (m, 1H), 3.71-0.64 (m, 14H), 2.05 (s, 1.5H), 1.98 (s, 1.5H). MS(ESI,m/e)[M+1] ⁺ 314.2.

Example B134: (3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)piperidin-1-yl) (Phenyl) ketone

The desired compound was synthesized by following procedures similar to those described in Example B107 under appropriate conditions recognized by one of ordinary skill in the art. ¹ H NMR (DMSO-d ₆ ) δ 8.43-8.39 (m, 1H), 8.15 (s, 1H), 7.40-7.33 (m, 6H), 6.21 (s, 1H), 5.61-3.98 (m, 3H), 2.92-0.70 (m, 14H). MS (ESI, m/e) [M+1] ⁺ 376.2.

Examples B135a and B135b: 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)piperidin- Pyridine-1-sulfonamide

Step 1: ((3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)piperidin-1-yl)sulfonyl tert-Butyl)carbamate

A solution of (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(piperidin-3-yl)methanol (50 mg, 0.19 mmol), sulfurisocyanatidic chloride (26 mg, 0.19 mmol), t-BuOH (14 mg, 0.19 mmol), and _Et₃N (37 mg, 0.37 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours, then quenched with _H₂O (5 ml) and extracted with DCM (5 mL*3). The organic layer was concentrated to give the crude product, which was then purified by column chromatography using 5% MeOH/DCM to give 45 mg (54.2%) of tert-butyl (3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)piperidin-1-yl)sulfonyl)carbamate as a yellow solid. MS (ESI) m/e [M+1] ^⁺ 450.2.

Step 2: 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)piperidine-1-sulfonamide

A solution of tert-butyl ((3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)piperidin-1-yl)sulfonyl)carbamate (45 mg, 0.10 mmol), TFA (2 mL) in DCM (10 mL) was stirred at room temperature for 16 hours, then the mixture was quenched with aqueous NaHCO ₃ solution and extracted with DCM (10 mL * 3). The organic layer was concentrated to give the crude product, which was then purified by preparative HPLC to give two diastereomers. (5.5 mg, 15.7%, B135a): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.22 (s, 1H), 8.13 (d, J=7.2Hz, 1H), 7.40 (s, 1H), 6.61 (s, 2H), 6.22 (d, J= 7.2Hz, 1H), 5.46 (d, J=3.4Hz, 1H), 5.11-4.99 (m, 1H), 3.06-2.97 (m, 1H), 2.55-0.63 (m, 13H). MS (ESI, m/e) [M+1] ⁺ 351.1; (9.0 mg, 25.7%, B135b): ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.23 (s, 1H), 8.13 (d, J = 7.2Hz, 1H), 7.40 (s, 1H), 6.72 (s, 2H), 6.17 (d, J = 7.2Hz, 1H), 5.5 2(d, J=2.8Hz, 1H), 5.07-4.91(m, 1H), 2.47-2.36(m, 2H), 2.28-2.09(m, 2H), 1.70-1.55(m, 1H), 1.37-0.64(m, 9H). MS (ESI, m/e) [M+1] ⁺ 351.1.

Example B137: (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(1-((2,2-diethoxyethoxy)methyl (4-(2-Methyl)cyclohexyl)methanol

Step 1: Methyl 1-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)cyclohexane-1-carboxylate

To a solution of (i-Pr) ₂ NH (518 mg, 5.13 mmol) in THF (20 mL) was added n-BuLi (3.2 mL, 1.6 mol/L) at -30°C under N _2. The mixture was stirred for 30 min. A solution of methyl cyclohexanecarboxylate (767 mg, 5.4 mmol) in THF (5 mL) was added at -70°C and stirred for 1 h. A solution of 7-cyclopropylimidazo[1,5-a]pyridine-8-carbaldehyde (500 mg, 2.7 mmol) in THF (10 mL) was then added at -70°C. The mixture was then slowly warmed to room temperature and stirred overnight. The reaction mixture was quenched with water (30 mL) and extracted with DCM (50 mL*2). The combined organic layers were washed with brine (80 mL*3), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by preparative HPLC to give the desired product as a light green solid (61 mg, 7%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.37 (d, J=7.4 Hz, 1H), 7.82 (s, 1H), 6.53 (d, J=7.4 Hz, 1H), 6.13 (br s, 1H), 5.39 (s, 1H), 3.47 (s, 3H), 2.28- 0.75 (m, 15H). MS (ESI) m/e [M+1] ⁺ 329.2.

Step 2: (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(1-(hydroxymethyl)cyclohexyl)methanol (Example B136)

To a mixture of LiAlH ₄ (13 mg, 0.33 mmol) in THF (5 mL) was added dropwise a solution of methyl 1-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)cyclohexane-1-carboxylate (36 mg, mmol) in THF (1 mL) at 5° C. The mixture was then stirred for 3 h and quenched with 4N NaOH (5 mL). The resulting mixture was extracted with DCM (15 mL*2). The combined organic layers were washed with brine (20 mL*2), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by preparative HPLC to give the desired product as a white solid (61 mg, 7%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.14 (s, 1H), 8.10 (d, J = 7.2Hz, 1H), 7.46 (s, 1H), 6.05 (d, J = 7.2Hz, 1H), 5.47 (d, J=8.8Hz, 1H), 5.24 (d, J=8.8Hz, 1H), 4.52-4.49 (m, 1H), 3.85-3.55 (m, 2H), 2.08-0.76 (m, 13H). MS(ESI)m/e[M+1] ⁺ 301.2.

Step 3: (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(1-((2,2-diethoxyethoxy)methyl)cyclo (hexyl)methanol (Example B137)

To a solution of (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(1-(hydroxymethyl)cyclohexyl)methanol (300 mL, 1 mmol) in DMF (1 mL) with an ice-water bath was added 60% NaH (120 mg). It was then stirred at room temperature for 30 min. 2-Bromo-1,1-diethoxyethane (1.18 g, 6 mmol) was added and heated to 60 ° C and stirred overnight. The reaction mixture was cooled to room temperature and water (10 mL) was added. The resulting mixture was extracted with EA (20 mL*2). The combined organic layers were washed with brine (20 mL*2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC to give the desired product (81 mg, 19%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.19 (s, 1H), 8.10 (d, J=7.3Hz, 1H), 7.44 (s, 1H), 6.04 (d, J = 7.3Hz, 1H), 5.39 (s, 1H), 5.19 (s, 1H), 4.52 (t, J = 5.1Hz, 1H), 3.62- 3.32 (m, 8H), 2.06-1.99 (m, 1H), 1.74-0.73 (m, 20H). MS(ESI)m/e[M+1] ⁺ 417.3.

Example B138: 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)cyclohexane-1-carboxylic acid acid

Step 1: Dimethyl cyclohexane-1,3-dicarboxylate

To a solution of cyclohexane-1,3-dicarboxylic acid (10.32 g, 60 mmol) in MeOH (130 mL) was added concentrated _H₂SO₄ (2.5 _mL ) and stirred at reflux for 16 hours. The mixture was concentrated and the pH of the residue was adjusted to 7 with saturated aqueous _NaHCO₃ . The residue was extracted with EA (200 mL*3). The organic layers were combined and dried over _Na₂SO₄ , filtered, and concentrated to afford the desired compound as a colorless oil ( ^{12 g, 100%). 1H} _NMR (400 MHz, DMSO- _d₆ ) δ 3.61 (s, 6H), 2.69-1.13 (m, 10H). MS (ESI) m/e [M+1] ^⁺ 201.1.

Step 2: 3-(Methoxycarbonyl)cyclohexane-1-carboxylic acid

Over 20 min, at 0 ° C, 1 N NaOH (10 mL) was added dropwise to a solution of dimethyl cyclohexane-1,3-dicarboxylate (2 g, 10 mmol) in MeOH (20 mL). The resulting mixture was stirred at 0 ° C for 30 min and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was distributed between EA and water. The aqueous phase was separated, acidified with concentrated HCl, saturated with NaCl, and then extracted with EA. The extract was dried over Na ₂ SO ₄ , filtered and concentrated to obtain the desired compound as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.12 (br s, 1H), 3.60 (s, 3H), 2.40-1.15 (m, 10H).

Step 3: Methyl 3-(hydroxymethyl)cyclohexane-1-carboxylate

A solution of 3-(methoxycarbonyl)cyclohexane-1-carboxylic acid (30 g, 160 mmol) in THF (300 mL) was cooled to -78°C. _BH3 ·S( _CH3 ) ₂ (81 mL, 2.0 M) was then added dropwise over 2 h. The mixture was then stirred at -78°C for 2 hours and at room temperature for 16 hours, quenched with 2N HCl (20 mL) and water (200 mL), and extracted with EA (200 mL*3). The organic layers were combined, washed with saturated _NaCO3 (200 mL*2), dried _{over Na2SO4} , filtered, and concentrated to give the desired compound as a colorless oil. MS (ESI) m/e[M+1] ⁺ 173.1.

Step 4: Methyl 3-formylcyclohexane-1-carboxylate

To a solution of methyl 3-(hydroxymethyl)cyclohexane-1-carboxylate (8.7 g, 50.6 mmol) and triethylamine (30.3 g, 300 mmol) in DMSO (100 mL) was added pyridine sulfur trioxide (24.1 g, 150 mmol) and stirred at room temperature for 16 hours. The solution was then poured into water (300 mL) and EA (300 mL) and separated. The aqueous phase was extracted with EA (200 mL*2), and _the combined organic layers were dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with EA/PE = 1/10) to give the desired compound as an oil. MS (ESI) m/e [M+1] ⁺ 171.1.

Step 5: Methyl 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)cyclohexane-1-carboxylate

Methyl 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)cyclohexane-1-carboxylate was prepared following procedures similar to those described in Example B122.

Step 6: 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)cyclohexane-1-carboxylic acid

To a solution of methyl 3-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)cyclohexane-1-carboxylate (126 mg, 0.38 mmol) in THF (1 mL) and H ₂ O (1 mL) was added LiOH (18 mg, 0.76 mmol) and stirred at room temperature for 16 hours. The THF was then removed in vacuo, the residue was extracted with DCM (2 mL*3), the organic layers were combined, dried over Na ₂ SO ₄ , filtered and concentrated, and the residue was purified by preparative HPLC to give the desired compound (mixed isomers) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.30 (s, 1H), 8.34 (d, J=7.4Hz, 1H), 7.96 (s, 1H), 6.57 (d, J=7.4Hz, 1H), 5.58-5.55 (m, 1H), 5.01 (d, J=8.1Hz, 1H), 2.46-2.19 (m, 3H), 1.91-1.65(m, 3H), 1.24-1.15(m, 3H), 1.10-1.00(m, 4H), 0.80-0.77(m, 2H). MS(ESI)m/e [M+1] ⁺ 315.1.

Examples B139 to B141 were synthesized following procedures similar to those described in Example B107 under appropriate conditions as would be recognized by one of ordinary skill in the art.

Example B139: Bicyclo[3.1.0]hexan-3-yl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol

¹ H NMR (CDCl ₃ -d ₁ ) δ9.08 (s, 1H), 7.96 (s, 2H), 6.52-6.40 (m, 1H), 5.33-5.12 (m, 1H), 2.20-1.99 (m, 3H), 1.80-1.76 (m, 1H), 1.64-1.58 (m, 1H), 1.40-0.80 (m, 10H) and 0.31-0.07 (m, 2H). MS(ESI)m/e[M+1]+269.

Example B140: Bicyclo[4.1.0]hept-3-yl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol

¹ H NMR (DMSO-d ₆ )δ9.22 (s, 1H), 8.31 (d, 1H, J=7.6Hz), 7.90 (d, 1H, J=7.6Hz), 6.51-6.55 (m, 1H ), 5.57-5.59 (m, 1H), 4.81-4.98 (m, 1H), 1.15-2.37 (m, 7H) and 0.42-0.89 (m, 9H). MS(ESI)m/e[M+1] ⁺ 283.

Example B141: Cyclohex-2-en-1-yl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methanol

¹ H NMR (DMSO-d ₆ )δ8.14 (d, 1H, J=7.6Hz), 7.40 (s, 1H), 6.81-6.85 (m, 1H), 6.36-6.43 (m, 1H), 6 .25(d, 1H, J=7.6Hz), 4.77-4.79(m, 1H), 3.87-3.89(m, 1H), 1.45-2.05(m, 7H), 0.96-0.97 (m, 2H), 0.79-0.85 (m, 1H) and 0.68-0.70 (m, 2H). MS(ESI)m/e[M+1] ⁺ 269.

Example B142: 5-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)bicyclo[2.2.1] Heptan-2-ol

Step 1: Acetic acid 5-(acetoxy(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methyl)bicyclo[2.2.1] Heptyl 2-yl ester

To a solution of bicyclo[2.2.1]hept-5-en-2-yl(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methyl acetate (Compound 1, synthesized according to the same procedure as described in Example B122, 140 mg, 0.43 mmol) in AcOH (10 mL) was slowly added _BF₃ · _Et₂O (5 drops) at room temperature. The mixture was then stirred at 80°C under _N₂ for 2 h. The reaction mixture was quenched _{with Na₂CO₃} solution and extracted with EtOAc (30 ml*3). The organic layer was dried _{over Na₂SO₄} , filtered, and concentrated to give a crude product, which was further purified by preparative HPLC to give the product, 5-(acetoxy(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methyl)bicyclo[2.2.1]hept-2-yl acetate (20 mg). MS (ESI) m/e [M+1] ⁺ 382.7.

Step 2: 5-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)bicyclo[2.2.1]hept-2-yl alcohol

To a solution of 5-(acetoxy(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)methyl)bicyclo[2.2.1]hept-2-yl acetate (20 mg, 0.052 mmol) in MeOH (10 mL) and H ₂ O (2 ml) was added LiOH (6.24 mg, 0.26 mmol) at room temperature under N ₂ and stirred for 0.5 h. The solvent was removed in vacuo, H ₂ O (20 mL) was added to the mixture, and extracted with EtOAc (25 ml×3). The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated to give a crude product, which was further purified by preparative HPLC to give the product, 5-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)bicyclo[2.2.1]hept-2-ol (5 mg). ¹ H NMR (CD ₃ OD) δ8.11 (s, 1H), 7.96-7.91 (m, 1H), 7.41-7.35 (m, 1H), 7.26-7.23(m, 1H), 6.23-6.18(m, 1H), 3.63-3.52(m, 2H), 2.50-2.47(m, 1H), 2.11-2.01(m, 3H), 1.64-1.21 (m, 4H), 0.95-0.92 (m, 3H), 0.64-0.60 (m, 1H) and 0.45-0.35 (m, 1H). MS(ESI)m/e [M+1] ⁺ 299.

Example B143: 5-((7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(hydroxy)methyl)bicyclo[2.2.1] Heptan-2-ol

Step 1: Synthesis of 4-methyl-N′-(4-phenylcyclohexylene)benzenesulfonylhydrazide

To a solution of 4-phenylcyclohexan-1-one (5.00 g, 28.74 mmol) in methanol (50 mL) was added p-toluenesulfonyl hydrazide (5.34 g, 28.74 mmol). The mixture was then stirred at 70° C. for 3 hours, cooled to room temperature, added with water (50 mL) and sonicated for 3 minutes, filtered, and the filter cake was washed with methanol to give a white solid (4.81 g, yield: 48.94%). ¹ H NMR (DMSO-d ₆ ) δ 10.17 (s, 1H), 7.73 (d, J=8.0Hz, 2H), 7.39 (d, J=8.0Hz, 2H), 7.15-7.29 (m, 5H), 3.77(s, 1H), 2.92(m, 1H), 2.78(m, 1H), 2.38(s, 3H), 2.25(m, 2H), 19.3(m, 2H), 1.51(m, 2H).

Step 2: Synthesis of (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(4-phenylcyclohexyl)methanone

To a solution of 4-methyl-N′-(4-phenylcyclohexylidene)benzenesulfonylhydrazide (3.40 g, 10 mmol) and 7-cyclopropylimidazo[1,5-a]pyridine-8-carbaldehyde (1.90 g, 10 mmol) in 1,4-dioxane (200 mL) was added cesium carbonate (4.90 g, 15 mmol). The mixture was then stirred at 110° C. for 8 hours, cooled to room temperature, and concentrated to dryness. The crude product was purified by silica gel (150 g) column chromatography (PE/EA=1:2 as eluent) to give 1.01 g, 29.07% yield. ¹ H NMR (DMSO-d6) δ8.29 (m, 2H), 7.20 (m, 6H), 6.24 (m, 1H), 3.18 (m, 1H), 2.64 (m, 1H), 2.36 (m, 1H), 2.01 (m, 1H), 1.79 (m, 4H), 1.53 (m, 2H), 0.91 (m, 2H), 0.78 (m, 2H).

Step 3: Synthesis of (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(4-phenylcyclohexyl)methanol

To a solution of (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(4-phenylcyclohexyl)methanone (1.01 g, 2.9 mmol) in ethanol (100 mL) was added sodium borohydride (220 mg, 5.8 mmol). The mixture was then stirred at room temperature overnight, quenched with water (5 mL), and concentrated to dryness. The crude product was purified by silica gel (150 g) column chromatography (DCM/MeOH=40:1 as eluent) to give 0.88 g, 87.70% yield. ¹ H NMR (DMSO-d6) δ 8.14 (m, 2H), 7.20 (m, 6H), 6.15 (m, 1H), 5.32 (m, 1H), 4.96 (m, 1H), 6.15 (m, 1H), 1.15-2.67 (m, 11H), 0.92 (m, 2 H), 0.70(m, 2H).

Examples B143a and B143b: (S)-(7-cyclopropylimidazo[1,5-a]pyridin-8-yl) (trans or cis-4- phenylcyclohexyl)methanol and (S)-(7-cyclopropylimidazo[1,5-a]pyridin-8-yl) (cis or trans-4-phenylcyclohexyl) Methanol

B143 (a mixture of four diastereomers) was separated by preparative HPLC on Chiralpak OD-H using _CO2 /EtOH (0.1% DEA) = 70/30 (V/V) as eluent. The enantiomeric excess was determined by HPLC on Chiralpak OD-H using _CO2 /IPA (0.1% DEA) = 60/40 (V/V) as eluent at a flow rate of 1.0 mL/min. The first enantiomer (first peak) eluted at a retention time of 7.077 min (B143a), ¹ H NMR (DMSO-d ₆ ) δ 8.20 (s, 1H), 8.12 (d, 1H, J=7.2 Hz), 7.43 (s, 1H), 7.11-7.26 (m, 5H), 6.15 (d, 1H, J=7.2 Hz), 5.30 (m, 1H), 4.96 (d, 1H, J = 8.4 Hz), 1.15-2.45 (m, 11H), 0.92 (m, 2H), 0.70 (m, 2H); a possible mixture of two isomers (second peak) coeluted at a retention time of 9.332 min, but the mixture decomposed when the solution was concentrated in vacuo; the third enantiomer (third peak) eluted at a retention time of 12.13 min (B143b), ¹ H NMR (DMSO-d ₆ ) δ 8.20 (m, 1H), 8.12 (m, 1H), 7.55 (s, 1H), 7.16-7.29 (m, 5H), 6.15 (m, 1H), 4.60 (m, 1H), 4.24 (d, 2 H, J = 5.6 Hz), 1.65-2.81 (m, 11H), 0.94 (m, 2H), 0.77 (m, 2H). Based on the assumption that the binding model of the more potent isomer B143a is the same as that of A101a for the IDO1 enzyme, the absolute configurations of B143a and B143b are tentatively assigned to (S) and (S), respectively.

Example C: Biological Assay

IDO1 enzyme assay

Recombinant IDO1 was overexpressed and purified from E. coli cells using an N-terminal His tag. An IDO1 enzyme assay was performed using a method similar to that described in the literature (J. Biol. Chem. (1980), 255, 1339-1345). The reaction mixture contained 50 nM IDO1, 1.3 mM D-tryptophan, 5 mM L-ascorbic acid, 6.25 μM methylene blue, 0.4 mg/mL hydrogen peroxide (catalase), and compound (or DMSO) in a buffer containing 50 mM potassium phosphate, pH 7.5, and 0.1% BSA. After incubation for 1.5 hours at 24°C, the absorbance of the reaction mixture was read continuously at 321 nm for 1 hour using a FULOstar OMEGA microplate reader (BMG LABTECH) to monitor the formation of N'-formylkynurenine. Enzyme activity was determined by measuring the slope of the linear absorbance increase as a function of time. The _IC50 was calculated based on the residual enzyme activity in the presence of increasing concentrations of compound.

TDO enzyme assay

Recombinant TDO was overexpressed and purified from E. coli cells using a C-terminal His tag. The TDO enzyme assay was performed using the same method as the IDO1 enzyme assay, except that 100 nM TDO and 0.5 mM L-tryptophan (Km concentration) were used in the TDO assay.

Hela cell-based IDO1 Kyn (kynurenine) production assay:

The inhibitory activity of IDO1 inhibitors was determined using a colorimetric reaction that measures Kyn produced by oxidation of L-Trp (L-tryptophan) by cellular IDO1 in HeLa cells following induction of IDO1 by IFN-γ.

HeLa cells were obtained from the American Type Tissue Culture Collection and recovered in phenol red-free DMEM medium containing 10% FBS supplemented with 0.4mM L-Trp. Cells were seeded in 96-well plates at 8,000 cells per well (100 μl/well). Human recombinant IFN-γ (8901SC, CST) was added to the cells (final concentration 100 ng/mL) to stimulate endogenous IDO1. Compounds of varying concentrations diluted in dimethyl sulfoxide (DMSO) were added simultaneously with IFN-γ. The cells were maintained at 37°C in a humidified incubator supplemented with 5% _CO2 . After incubation for 48 hours, 100 μl of supernatant was removed from each well and placed on a new plate. 8 μl of 6N trichloroacetic acid was added to precipitate the protein in the culture medium. The plate was incubated at 60°C for 45 minutes and then centrifuged at 2500 rpm for 10 minutes to remove the sediment. Carefully remove 80 μl of the supernatant to a new clean plate and add an equal volume of 2% 4-(dimethylamino)benzaldehyde (D2004, Sigma) dissolved in glacial acetic acid. The absorbance at 480 nm from Kyn was measured using a FULOstar OMEGA microplate reader (BMGLABTECH). Dose-response data were fitted to a four-parameter logistic model using Graphpad Prism software to derive the _IC50 for each compound.

Protein purification and co-crystallization (A101a)

IDO1 protein was expressed and purified following a protocol similar to that described in the literature (Biochimica et Biophysica Acta 1814 (2011) 1947-1954). IDO1 protein was concentrated to 40 mg/ml in a buffer containing 10 mM MES pH 6.5, 25 mM NaCl, and 0.5 mM TCEP. The protein solution was incubated with A101a at a molar ratio of 1:5 at 20°C for 1 h and then mixed with a stock solution containing 0.1 M HEPES pH 6.5 and 10% PEG 6000. Cocrystals of IDO1 and A101a were obtained by sitting-drop vapor diffusion at 20°C.

X-ray data collection and structure determination (A101a)

A nylon loop was used to harvest IDO1 crystals, which were then immersed in a mother liquor supplemented with 30% xylitol for 1 min. Synchronous data were collected on an ADSC Q315 CCD detector at the Shanghai Synchrotron Radiation Facility. Diffraction images were processed using the program HKL2000. The preliminary structure of IDO1 was solved by molecular replacement using the program PHASER. The IDO1 crystal structure (PDB code 2D0T) was used as a search model. REFMAC5 was used to perform rigid body, TLS, and restricted refinement of the X-ray data, followed by manual adjustments in the COOT program and further refinement in the REFMAC5 program.

Data collection and refinement statistics (A101a).

^a R _merage = ∑∑ _i |I(h) _i - <I(h)>|/∑∑ _i |I(h) _i |, where <I(h)> is the average equivalent intensity

^b R = ∑|Fo-Fc|/∑|Fo|, where Fo and Fc are the measured and calculated values of the result factor amplitude, respectively.

^c R _free ∑|Fo-Fc|/∑|Fo|, calculated using a test data set randomly selected from 5% of the total data of measured reflections.

Protein purification and co-crystallization (B122a)

IDO1 protein was expressed and purified following a protocol similar to that described in the literature (Biochimica et Biophysica Acta 1814 (2011) 1947-1954). IDO1 protein was concentrated to 40 mg/ml in a buffer containing 10 mM MES pH 6.5, 25 mM NaCl, and 0.5 mM TCEP. The protein solution was incubated with B122a at a molar ratio of 1:4 at 20°C for 1 h and then mixed with a stock solution containing 0.1 M HEPES pH 7.5 and 10% PEG 8000. Cocrystals of IDO1 and B122a were obtained by sitting-drop vapor diffusion at 20°C.

X-ray data collection and structure determination (B122a)

A nylon loop was used to harvest IDO1 crystals, which were then immersed in a mother liquor supplemented with 20% ethylene glycol for 1 min. Synchronous data were collected on an ADSC Q315 CCD detector at the Shanghai Synchrotron Radiation Facility. Diffraction images were processed using the program HKL2000. The preliminary structure of IDO1 was solved by molecular replacement using the program PHASER. The IDO1 crystal structure (PDB code 2D0T) was used as a search model. REFMAC5 was used to perform rigid body, TLS, and restricted refinement of the X-ray data, followed by manual adjustments in the COOT program and further refinement in the REFMAC5 program.

Data collection and refinement statistics (B122a).

^a R _merage = ∑∑ _i |I(h) _i - <I(h)>|/∑∑ _i |I(h) _i |, where <I(h)> is the average equivalent intensity

^b R = ∑|Fo-Fc|/∑|Fo|, where Fo and Fc are the measured and calculated values of the result factor amplitude, respectively.

^c R _free =∑|Fo-Fc|/∑|Fo|, calculated using a test data set randomly selected from 5% of the total data of measured reflections.

Table 1: Enzyme activity data of 5-substituted imidazo[1,5-a]pyridines IC ₅₀ s (IDO1 and TDO) and cell viability According to EC ₅₀ (based on IDO1 in Hela cells)

Table 1a: Chiral α-carbon atoms not further substituted or substituted with hydroxyl groups in the ortho and/or meta positions Activity data of 5-substituted imidazo[1,5-a]pyridines

Table 1b: Activity data of 5-substituted imidazo[1,5-a]pyridines further substituted in the ortho and/or meta positions

Table 2: Enzyme activity data _IC50 (IDO1 and TDO) and cell activity data of 8-substituted imidazo[1,5-a]pyridines _EC50 (based on IDO1 in Hela cells)

Table 2a: 8-substituted α-carbon atoms not further substituted in the ortho position or having a chiral α-carbon atom substituted with a hydroxyl group Activity data of imidazo[1,5-a]pyridine

Table 2b: Activity data of 5-substituted imidazo[1,5-a]pyridines further substituted in the ortho position

Examples A101 to A165 and Examples B101 to B143 exhibited the activity of simultaneously inhibiting both IDO1 and TDO with _IC50 values ranging from 0.1 nM to 10 μM, and inhibiting the activity of Hela cell-based IDO1 with _EC50 values ranging from less than 10000 nM.

It will be appreciated that, if any prior art publication is referred to herein, this citation does not constitute an admission that the publication forms part of the common general knowledge in the art in any country.

In the following claims and in the foregoing description of the invention, except where required by context, due to language expression or necessary implication, the word "comprise" or variations such as "include" or "comprising" are used in a broad sense, i.e. to specify the presence of recited features, but not to exclude the presence or addition of further features in various embodiments of the invention.

All publications, patents, patent applications, and published patent applications mentioned herein are incorporated by reference in their entirety by acknowledging citation.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to one skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims (30)

1. A compound or its stereoisomer or pharmaceutical salt thereof, said compound being selected from 5- or 8-substituted imidazo[1,5-a]pyridine of formula (IA) and/or (IB): in: n = 0, 1, or 2; Ra and Rb are each independently selected from hydrogen, halogen, C1-8 alkyl, C1-8 haloalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, heterocyclic, phenyl and heteroaryl; R1 is selected from hydrogen; R2 and R3 are each independently selected from hydrogen, halogen, OR7 , NR7R8 , COR7 , SO2R7 , C(=O) OR7 , C(=O) NR7R8 , C1-8 alkyl , C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, heterocyclic, phenyl, and heteroaryl, wherein each of the C1-8 alkyl , C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl , heterocyclic, phenyl, and heteroaryl is independently optionally substituted with at least one substituent R9 ; R4 is selected from hydrogen, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, phenyl, -OR7 , heteroaryl, wherein the C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl and heteroaryl are independently optionally substituted with at least one substituent R9 ; R5 is selected from hydrogen, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, phenyl, and -OR7 , wherein the C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, and phenyl are each optionally substituted with at least one substituent R9 . R6 is selected from hydrogen or halogen; The condition is that at least one of R4 and R5 is not hydrogen; R C is selected from C3-10 cycloalkyl groups, with optional substitution having at least one substituent R9 ; R7 and R8 are each independently selected from hydrogen and C1-8 alkyl groups, wherein the C1-8 alkyl groups are optionally substituted with at least one substituent R9 ; R 9 is selected from hydrogen, halogen, C1-4 alkyl, C2-8 alkenyl, C3-6 cycloalkyl, phenyl, heteroaryl, heterocyclic, C2-8 alkynyl, oxo, -C1-4 alkyl-NR'R", -CN, -OR', -NR'R", -COR', -CO 2 R', -CONR'R", -C(＝NR')NR”R”', nitro, -NR'COR", -NR'CONR'R", -NR'CO 2 R', -SO 2 R ', -SO 2phenyl , -NR'SO 2 NR”R”', NR'SO 2 R” and -NR'SO 2phenyl , wherein each of the C1-4 alkyl, C3-6 cycloalkyl, phenyl, heteroaryl or heterocyclic is independently substituted by one, two or three of the following substituents optionally: halogen, hydroxyl, C1-4 alkyl and C3-6 cycloalkyl. 1-4 haloalkyl, wherein R', R” and R”’ are each independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, heterocyclic, phenyl and heteroaryl, wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, heterocyclic, phenyl and heteroaryl are each optionally substituted by one or more halogens, C1-4 haloalkyl and C1-4 alkyl, or (R' and R”) and/or (R” and R”’) together with the atoms to which they are attached form a ring selected from: a heterocyclic ring optionally substituted by halogens, C1-4 haloalkyl and C1-4 alkyl and a heteroaryl ring optionally substituted by halogens, C1-4 haloalkyl and C1-4 alkyl; The heteroaryl group is a 5-7 membered aromatic monocyclic heteroaryl group containing at least one heteroatom selected from N, O and S; the heterocyclic group is a 4-12 membered monocyclic, bicyclic and tricyclic saturated and partially unsaturated ring, wherein the ring contains at least one carbon atom in addition to at least one heteroatom selected from oxygen, sulfur and nitrogen. 2. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutical salt thereof, wherein the compound is a 5-substituted imidazo[1,5-a]pyridine of formula (IA): in: n = 0, 1, or 2; Ra and Rb are each independently selected from hydrogen, halogen, C1-8 alkyl, C1-8 haloalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, heterocyclic, phenyl and heteroaryl; R1 is selected from hydrogen; R2 and R3 are each independently selected from hydrogen, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, heterocyclic, phenyl, and heteroaryl, wherein each of the C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, heterocyclic, phenyl, and heteroaryl is optionally substituted with at least one substituent R9 ; R4 is selected from hydrogen, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, phenyl, -OR7 , heteroaryl, wherein the C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, and heteroaryl are independently optionally substituted with at least one substituent R9 ; R5 is selected from hydrogen, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, phenyl, and -OR7 , wherein the C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, and phenyl are each optionally substituted with at least one substituent R9 . R6 is selected from hydrogen or halogen; The condition is that at least one of R4 and R5 is not hydrogen; R C  is a C 3-10  cycloalkyl group, which may optionally have at least one substituent R 9 . R7 is selected from hydrogen and C1-8 alkyl, wherein the C1-8 alkyl is optionally substituted with at least one substituent R9 ; R9 is selected from hydrogen, halogen, C1-4 alkyl, C2-8 alkenyl, C3-6 cycloalkyl, phenyl, heteroaryl, heterocyclic, C2-8 ynyl, oxo, -C1-4 alkyl-NR'R", -CN, -OR', -NR'R", -COR', -CO2R ', -CONR'R", nitro, -NR'COR", -NR'CONR'R", -NR'CO2R", -SO2R ', -SO2phenyl , NR'SO2R ", and -NR'SO2phenyl , wherein each of the C1-4 alkyl, C3-6 cycloalkyl, phenyl, heteroaryl, or heterocyclic groups is independently substituted by one, two, or three of the following substituents: halogen, hydroxyl, C1-4 alkyl, and C1-4 haloalkyl, wherein R' and R" are each independently selected from H, C1-4 alkyl, C2-4 alkenyl, C3-6 cycloalkyl, C4-6 cycloalkyl ... 2-4 alkynyl, C3-6 cycloalkyl, heterocyclic, phenyl, and heteroaryl, wherein each of the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl , heterocyclic, phenyl, and heteroaryl is optionally substituted by one or more halogens, C1-4 haloalkyl, and C1-4 alkyl groups. 3. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutical salt thereof, wherein the compound is an 8-substituted imidazo[1,5-a]pyridine of formula (IB): in: n = 0, 1, or 2; Ra and Rb are each independently selected from hydrogen, halogen, C1-8 alkyl, C1-8 haloalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, heterocyclic, phenyl and heteroaryl; R1 is selected from hydrogen; R2 and R3 are each independently selected from hydrogen, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, heterocyclic, phenyl, and heteroaryl, wherein each of the C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, heterocyclic, phenyl, and heteroaryl is optionally substituted with at least one substituent R9 ; R4 is selected from hydrogen, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, phenyl, -OR7 , heteroaryl, wherein the C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, heteroaryl are independently optionally substituted with at least one substituent R9 ; R5 is selected from hydrogen, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, phenyl, and -OR7 , wherein the C1-8 alkyl, C2-8 alkenyl, C2-8 ynyl, C3-8 cycloalkyl, and phenyl are each optionally substituted with at least one substituent R9 . R6 is selected from hydrogen or halogen; The condition is that R4 is not hydrogen; R C  is a C 3-10  cycloalkyl group, which may optionally have at least one substituent R 9 . R7 is selected from hydrogen and C1-8 alkyl, wherein the C1-8 alkyl is optionally substituted with at least one substituent R9 ; R9 is selected from hydrogen, halogen, C1-4 alkyl, C2-8 alkenyl, C3-6 cycloalkyl, phenyl, heteroaryl, heterocyclic, C2-8 ynyl, oxo, -C1-4 alkyl-NR'R", -CN, -OR', -NR'R", -COR', -CO2R ', -CONR'R", nitro, -NR'COR", -NR'CONR'R", -NR'CO2R", -SO2R ', -SO2phenyl , NR'SO2R ", and -NR'SO2phenyl , wherein each of the C1-4 alkyl, C3-6 cycloalkyl, phenyl, heteroaryl, or heterocyclic groups is independently substituted by one, two, or three of the following substituents: halogen, hydroxyl, C1-4 alkyl, and C1-4 haloalkyl, wherein R' and R" are each independently selected from H, C1-4 alkyl, C2-4 alkenyl, C3-6 cycloalkyl, C4-6 cycloalkyl ... 2-4 alkynyl, C3-6 cycloalkyl, heterocyclic, phenyl, and heteroaryl, wherein each of the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl , heterocyclic, phenyl, and heteroaryl is optionally substituted by one or more halogens, C1-4 haloalkyl, and C1-4 alkyl groups. 4. The compound of claim 2 or 3, wherein Ra and Rb are hydrogen. 5. The compound of claim 2 or 3, wherein R2 and R3 are each independently selected from hydrogen, halogens and C1-6 alkyl groups. 6. The compound of any one of claims 1-3, wherein, when R4 is not hydrogen, R4 is selected from halogens, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl, heteroaryl, phenyl and -OC1-6 alkyl, wherein the heteroaryl is optionally substituted with at least one R9 , and R9 is independently selected from halogens, C1-4 haloalkyl and C1-4 alkyl. 7. The compound of claim 6, wherein R4 is selected from F, Cl, Br, I, methyl, isopropyl, propenyl, ethynyl, cyclopropyl, CF3 , phenyl, dimethylisoxazolyl, and methoxy. 8. The compound of any one of claims 1-3, wherein, when R5 is not hydrogen, R5 is selected from halogens, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl, phenyl and -OC1-6 alkyl, wherein the phenyl is optionally substituted with at least one R9 , which is independently selected from halogens, C1-4 haloalkyl and C1-4 alkyl. 9. The compound of claim 8, wherein R5 is selected from halogens, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl and -OC1-6 alkyl. 10. The compound of claim 6, wherein R 6 is selected from halogens. 11. The compound of claim 8, wherein R6 is selected from halogens. 12. The compound of claim 2 or 3, wherein R C is a C3-8 cycloalkyl group, optionally substituted with at least one substituent R9 . 13. The compound of claim 2 or 3, wherein R C is a C3-8 cycloalkyl group, optionally substituted with a phenyl group. 14. The compound of claim 2 or 3, wherein RC is a C 3-8  cycloalkyl group, optionally substituted with a halogen, a C 1-4 alkyl group, and -NR'COR", wherein the C 1-4  alkyl group is optionally substituted with one, two, or three halogens or hydroxyl groups; wherein R' and R" are each independently selected from H, C 1-4  alkyl, C 3-6  cycloalkyl, heterocyclic, phenyl, and heteroaryl groups, wherein the C 1-4  alkyl, C 3-6  cycloalkyl, heterocyclic, phenyl, and heteroaryl groups are each optionally substituted with one or more halogens, C 1-4  haloalkyl groups, and C 1-4  alkyl groups. 15. The compound of claim 2 or 3, wherein R C is an unsubstituted cyclohexyl group. 16. The compound of claim 2 or 3, wherein n is 0, and R C is unsubstituted cyclohexyl or unsubstituted cyclopentyl. 17. The compound of claim 2 or 3, wherein n is 1, and R C is unsubstituted cyclohexyl or unsubstituted cyclopentyl. 18. The compound of claim 2 or 3, wherein n is 2 and R C is unsubstituted cyclohexyl or unsubstituted cyclopentyl. 19. The compound of claim 2 or 3, wherein n is 0 and R C is an unsubstituted bicyclic [2.2.1]hept-2-yl. 20. The compound of claim 2 or 3, wherein n is 0 and RC is a 4-phenyl-substituted cyclohexyl group. 21. The compound of claim 2 or 3, wherein the chiral α-carbon atom attached to the imidazo[1,5-a]pyridine structure is in the S-configuration. 22. A compound or its stereoisomer or its pharmaceutical salt, wherein the compound is selected from: 23. A compound or a pharmaceutical salt thereof, said compound being selected from the following compounds exhibiting the following stereochemistry: 24. A pharmaceutical composition comprising at least one pharmaceutical carrier and a therapeutically effective amount of the compound of any one of claims 1-23, or a stereoisomer thereof, or a pharmaceutical salt thereof, as an active ingredient. 25. Use of any compound of claims 1-23, or a stereoisomer thereof, or a pharmaceutical salt thereof, in the preparation of a medicament for treating or preventing hyperproliferative disorders in response to inhibition of IDO and/or TDO. 26. The application of claim 25, wherein the hyperproliferative condition is cancer. 27. The application of claim 25, wherein the hyperproliferative disease is selected from melanoma and thyroid cancer, Barrett's adenocarcinoma, breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, kidney cancer, head and neck cancer, liver cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, biliary tract cancer, endometrial cancer, leukemia, colon cancer, histiocytic lymphoma, and lung adenocarcinoma. 28. The application of claim 27, wherein the lung cancer is non-small cell lung cancer. 29. Use of any compound of claims 1-23, or its stereoisomer, or its pharmaceutical salt, in the preparation of a medicament for the treatment or prevention of HIV/AIDS. 30. Use of any compound of claims 1-23, or its stereoisomer, or its pharmaceutical salt, in the preparation of a medicament for enhancing the efficacy of antiretroviral therapy.