EA041983B1 - INDOLE INHIBITORS OF THE ARYL HYDROCARBONIC RECEPTOR (AHR) AND THEIR APPLICATIONS - Google Patents

Description

State of the art

The aryl hydrocarboxylic receptor (AHR) is a transcription factor that, without ligands, exists in an inactive state in the cytoplasm associated with HSP90. After ligand binding, AHR translocates to the nucleus, where it dimerizes with ARNT to form a functional transcription factor. AHR/ARNT binds to dioxin response elements (DRE) in the promoter of many genes, where it modulates gene transcription. The most well-documented genes regulated by AHR are the cytochrome P450 genes Cyp1b1 and Cyp1a1, and activation of AHR significantly increases the expression of these genes. Thus, Cyp1b1 and Cyp1a1 mRNA content is a selective indicator of AHR activation (see Murray et al., 2014 for a review). There are many exogenous and endogenous AHR agonists that activate this receptor. The most well-characterized class of ligands are the dioxins. One of the first classified endogenous ligands is kynurenine, formed by TDO (Opitz 2011) or IDO (Mezrich 2010). Kynurenine is a stable metabolite in the IDO/TDO pathway and is a degradation product of tryptophan. It has been shown that kynurenine activates AHR, which is determined by the increase in the content of Cyp1a1 and/or Cyp1b1 mRNA in multicellular systems, as well as other DRE-regulated genes.

Activation of AHR provides antitumor effects by acting directly on tumor cells and indirectly inducing immunosuppression, thereby preventing the body's own immune system from attacking the tumor. For example, activation of AHR through multiple ligands results in increased FoxP3 expression and polarization of CD4+ T cells relative to a suppressive subsystem called Foxp3+ T regulatory cells (Tregs). These regulatory T cells suppress the proliferation of activated T cells (Funatake 2005, other references). Notably, kynurenine has been shown to induce immunosuppressive Tregs via AHR. Kynurenine does not affect the formation of regulatory T cells in AHR null T cells or when an AHR antagonist (Mezrich) is added. In addition to T-regs, AHR activation also results in an increase in Trl-suppressing T cells (Gandhi 2010). It has also been shown that IDO expression is regulated by AHR activation in both tumor cells and T cells, leading to significant suppression of the immune system (Vogel). It is possible that AHR also has an effect on immunosuppressive myeloid cells (Nguyen 2013). Immunosuppression is often associated with high levels of anti-inflammatory cytokines and there is evidence to suggest that AHR is involved in the activation of many such cytokines such as IL-10 (Gandhi 2010, Wagage 2014). There remains an unmet need for the development of AHR inhibitors for the treatment of AHR-associated diseases, disorders and conditions.

Brief description of the invention

The present invention has found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as AHR inhibitors. Such compounds have the general formula I:

GvU(k ^u )p

I

I or is a pharmaceutically acceptable salt of the specified compound, where each variable is as defined and described herein.

The compounds of the present invention and their pharmaceutically acceptable compositions are suitable for use in the treatment of various diseases, disorders or conditions associated with AHR. Such diseases, disorders, or conditions include the diseases, disorders, or conditions described herein.

The compounds of the present invention are also suitable for use in the study of AHR in biological and pathological events; study of intracellular signal transduction pathways and comparative evaluation of new AHR inhibitors in vitro or in vivo.

Brief description of the drawings

In FIG. 1 is a graph showing the reduction in IL-22 and cyp1a1 RNA expression levels upon inhibition with a compound as described herein.

In FIG. 2 is a graph showing the decrease in IL-22 protein (upper graph) and the increase in IL-2 (lower graph) by treatment of activated T cells with a compound as described herein.

In FIG. 3 is a graph showing the results of an efficacy study on CT26 vehicle, a compound of the present disclosure, anti-PD-1, and combinations thereof.

In FIG. 4 is a graph showing the results of the efficacy study on

- 1 041983

B16-IDO carrier, compounds according to the present description, anti-PD-1 and combinations thereof.

Detailed description of several implementation options

1. General description of the compounds according to the present invention.

In some embodiments of the present invention, AHR inhibitors are provided. In some embodiments, such compounds include compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein ring A is selected from:

each R ¹ is independently selected from R, -C(O)R, -C(O)OR, -SO2R, -C(O)N(R)2 or -SO2RN(R)2;

each R is independently hydrogen, deuterium, or a substituted or unsubstituted group selected from C _1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring; 4-8-membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10-membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R ^x , R ^y and R ^z is independently selected from R, halo, cyano, nitro, -OR, -SR, -N(R) ₂ , -N(R)C(O)R, -C(O) N(R)2, -N(R)C(O)N(R)2, -N(R)C(O)OR, -OC(O)N(R)2, -N(R)SO2R, -SO2RN(R)2, -C(O)R, -C(O)OR, -OC(O)R, -S(O)R or -SO2R, or two R ^x at the same carbon atom combined with the formation of =0 or =S;

or two R ^y at the same carbon atom are combined to form ═O or ═S;

each of m and n is independently 1, 2, 3, 4, or 5;

ring B is phenyl, a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen , oxygen or sulfur;

ring C is phenyl or a 5-6 membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or an 8-10 membered bicyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

L ¹ is a covalent bond or an optionally substituted C1-6 membered straight or branched divalent hydrocarbon chain, where the methylene unit of L ¹ is optionally substituted with -Cy-, -O-, -S-, -NR-, -C(O)- , -C(O)O, -OC(O)-, -C(O)N(R)-, -N(R)C(O)-, -SO2-, -N(R)SO2- or - SO ₂ N(R)-S; and -Cy- is a 3-8 membered divalent saturated, partially unsaturated or aromatic monocyclic ring containing 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered divalent saturated, partially unsaturated or aromatic bicyclic a ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

- 2 041983

In some embodiments of the present invention, AHR inhibitors are provided, such compounds include compounds of formula I':

or their pharmaceutically acceptable salts, where ring A is selected from:

each p is independently 0, 1 or 2 depending on the valency;

each R ¹ is independently selected from R, -C(O)R, -C(O)OR, -SO ₂ R, -C(O)N(R) ₂ or -SO ₂ RN(R) ₂ ;

each R is independently hydrogen, deuterium, or a substituted or unsubstituted group selected from C _1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring; 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10-membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or two R's on the same nitrogen atom are combined with intermediate atoms between them to form a 4-7 membered saturated, partially unsaturated, or aromatic ring containing 1-2 heteroatoms in addition to said nitrogen atom, independently selected from oxygen, nitrogen or sulfur;

each of R ^x , R ^y and R ^z is independently selected from R, halo, cyano, nitro, -OR, -SR, -N(R) ₂ , -N(R)C(O)R, -C(O) N(R)2, -C(O)N(R)OR, -N(R)C(O)N(R)2, -N(R)C(O)OR, -OC(O)N( R)2, -N(R)SO2R, -SO2RN(R)2, -C(O)R, -C(O)OR, -OC(O)R, -S(O)R or -SO2R, or two R ^x at the same carbon atom are combined to form ═O or ═S; or two R ^y at the same carbon atom combined to form ═O or ═S;

each of m and n is independently 1, 2, 3, 4, or 5;

ring B is phenyl, 7-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, 8-10 membered bicyclic heteroaryl a ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 12-15-membered partially unsaturated or aromatic tricyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

ring C is phenyl or a 5-6 membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

L ¹ is a covalent bond or an optionally substituted C1_6-membered straight or branched divalent hydrocarbon chain, where the methylene unit of L ¹ is optionally substituted with -Cy-, -O-, -S-, -NR-, -C(O)-, -C(O)O, -OC(O)-, -C(O)N(R)-, -N(R)C(O)-, -SO2-,

- 3 041983

-N(R)SO2- or -SO2N(R)-S; And

-Cy- is a 3-8 membered divalent saturated, partially unsaturated or aromatic monocyclic ring containing 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered divalent saturated, partially unsaturated or aromatic bicyclic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, the present invention provides a compound of formula I or formula I', provided that when ring A is

^Rz ,

ring B is not

or or or and/or ring C is not and/or R ¹ is not

As generally defined above, Ring A is selected from:

One of skill in the art will readily understand and appreciate that there are many orientations of ring A. By way of example, and for purposes of clarity, when ring A is chosen to be

- 4 041983 may be provided for embodiments of the present invention, in which ring A can be oriented in accordance with formula I or formula I' so

or so

Accordingly, both such orientations are contemplated by the present invention. In some embodiments, the present invention provides a compound of formula I or formula I', provided that L ¹ is not -NHCH2CH2-. In some embodiments, the present invention provides a compound of formula I or formula I', provided that when ring A is

L ¹ is not -NHCH2CH2-.

2. Connections and definitions.

Compounds of the present invention include those generally described above and further illustrated by the classes, subclasses and species disclosed herein. In the context of the present description, the following definitions should be used, unless otherwise indicated. For the purposes of the present invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed. In addition, the general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5 ^th Ed., Ed.: Smith, MB and March, I, John Wiley and Sons , New York: 2001, the entire contents of which are incorporated herein by reference. The term aliphatic or aliphatic group in the context of the present description means a straight (i.e. straight) or branched, substituted or unsubstituted hydrocarbon chain which is fully saturated or which contains one or more units of unsaturation, or a monocyclic hydrocarbon, or a bicyclic hydrocarbon, which are fully saturated, or which contain one or more units of unsaturation, but are not aromatic (also referred to herein as carbocycle, carboaliphatic, or cycloalkyl) that have a single point of attachment to the rest of the molecule. Unless otherwise indicated, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-4 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-3 aliphatic carbon atoms, and in other embodiments, the aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, cycloaliphatic (or carbocycle or cycloalkyl) refers to a C3-C6 monocyclic hydrocarbon that is fully saturated, or that contains one or more units of unsaturation, but is aromatic, and that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

The term lower alkyl refers to a C _1-4 straight or branched alkyl group. Illustrative lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl.

The term lower haloalkyl refers to a C _1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. The term heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form

- 5 041983 nitrogen, sulfur, phosphorus or silicon; the quaternized form of any nitrogen atom of the base or a substituted nitrogen atom of a heterocyclic ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl)).

The term unsaturated in the context of the present description means that the fragment has one or more units of unsaturation.

As used herein, the term bivalent C _1-8 (or C _1-6 ) saturated or unsaturated, straight or branched hydrocarbon chain refers to bivalent alkylene, alkenylene and alkynylene chains that are straight or branched as defined herein.

The term alkylene refers to a divalent alkyl group. The alkylene chain is a polymethylene group, i.e. -(CH ₂ ) _p - where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The substituted alkylene chain is a polymethylene group, in which one or more methylene hydrogen atoms have been replaced by a substituent.

Suitable substituents include those described below for the substituted aliphatic group.

The term alkenylene refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond and in this group one or more hydrogen atoms have been replaced by a substituent. Suitable substituents include those described below for the substituted aliphatic group.

In the context of the present description, the term cyclopropylene refers to a bivalent cyclopropyl group of the following structure:

In the context of the present description, the term cyclobutylene refers to a bivalent cyclobutyl group of the following structure: ++ . In the context of

of the present description, the term oxetanyl refers to a bivalent oxetanyl group of the following structure:

The term halogen means F, Cl, Br or I.

The term aryl, used alone or as part of a larger moiety, as in aralkyl, aralkoxy, or aryloxyalkyl, refers to monocyclic and bicyclic ring systems containing a total of five to fourteen ring members, at least one ring in said system being aromatic, and moreover, each ring in the system contains from 3 to 7 members. The term aryl may be used interchangeably with the term aryl ring. The term aryl, alone or as part of a larger moiety, as in aralkyl, aralkoxy, or aryloxyalkyl, refers to monocyclic and bicyclic ring systems containing a total of five to 10 ring members, where at least one ring in said system is aromatic and each ring in system contains from three to seven members. The term aryl may be used interchangeably with the term aryl ring. In some embodiments of the present invention, aryl refers to an aromatic ring system that includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may contain one or more substituents. Also within the scope of the term aryl as used herein is a group in which an aromatic ring is hybridized to one or more non-aromatic rings such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The terms heteroaryl and heteroar-, used alone or as part of a larger moiety, such as heteroaralkyl or heteroaralkoxy, refer to groups containing 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms, and containing 6, 10 or 14 p -electrons distributed in a cyclic matrix, and also containing, in addition to carbon atoms, from one to five heteroatoms. The term heteroatom refers to nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms heteroaryl and heteroar- as used herein also include groups in which a heteroaromatic ring hybridizes to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherein said radical or attachment site is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,

- 6 041983 phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group may be mono- or bicyclic. The term heteroaryl may be used interchangeably with the terms heteroaryl ring, heteroaryl group, or heteroaromatic, and any of these terms includes rings that are optionally substituted. The term heteroaralkyl refers to an alkyl group substituted with a heteroaryl, said alkyl and heteroaryl moieties independently being optionally substituted.

As used herein, the terms heterocycle, heterocyclyl, heterocyclic radical, and heterocyclic ring are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and contains, in addition to carbon atoms, one or more , preferably one to four heteroatoms as defined above. When used in relation to a heterocycle ring atom, the term nitrogen includes a substituted nitrogen. By way of example, in a saturated or partially unsaturated ring containing 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen can be N (as in 3,4-dihydro-2Hpyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring may be attached to its adjacent group at any heteroatom or carbon atom resulting in a stable structure, and any ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, ohazepinyl, thiazepinyl, quinuclidinyl, and quinuclidinyl. The terms heterocycle, heterocyclyl, heterocyclyl ring, heterocyclic group, heterocyclic moiety, and heterocyclic radical are used interchangeably herein and also include groups in which the heterocyclyl ring is hybridized to one or more aryl, heteroaryl, or cycloaliphatic rings such as indolinyl, 3Nindolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl, wherein the radical or site of attachment is on the heterocyclyl ring. The heterocyclyl group may be mono- or bicyclic. The term heterocyclylalkyl refers to an alkyl group substituted with heterocyclyl, said alkyl and heterocyclyl moieties being independently optionally substituted.

In the context of the present description, the term partially unsaturated refers to a ring fragment that includes at least one double or triple bond. The term partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but does not include aryl or heteroaryl moieties as defined herein.

As described in the present description, the compounds according to the present invention may contain optionally substituted fragments. In general, the term substituted, whether or not preceded by the term optionally, means that one or more hydrogens of the moiety being defined is replaced by a suitable substituent. Unless otherwise indicated, an optionally substituted group may contain a suitable substituent at each substitutable position of the group, and when more than one position in any specified structure may be substituted with more than one substituent selected from the specified group, said substituents may be either the same, or different in each position. The combinations of substituents contemplated by the present invention are preferably those that result in stable or chemically feasible compounds. The term stable in the context of the present description refers to compounds that are essentially unchanged under the conditions that ensure their production, definition and, in some embodiments, their isolation, purification and use for one or more of the purposes disclosed in the present description.

Suitable monovalent substituents on the substituted carbon atom of the optionally substituted group are independently halogen; -(CH ₂ ) o- ₄ R°; -(CH ₂ )o- ₄ OR°; -O(CH ₂ )o- ₄ R°, -O(CH ₂ ) ₀ _ ₄ C(O)OR°; -(CH ₂ ) ₀ _ ₄ CH(OR°) ₂ ; -(CH ₂ ) ₀ _ ₄ SR°; -(CH ₂ ) ₀ _ ₄ Ph, which may be substituted by R°; -(CH ₂ ) ₀ _ ₄ O(CH ₂ ) ₀ _1Ph, which may be substituted by R°; -CH=CHPh, which may be substituted with R°; -(CH ₂ ) ₀ _ ₄ O(CH ₂ ) ₀ _ ₁ -pyridyl which may be substituted by R°; -NO ₂ ; -CN; -N ₃ ; -(CH ₂ ) ₀ _ ₄ N(R°) ₂ ; -(CH2)0-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)0-4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)0-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°; -C(S)R°; -(CH2)0-4C(O)OR°; -(CH2)0-4C(O)SR°; -(CH2)0-4C(O)OSiR° ₃ ; -(CH2)0-4OC(O)R°; -OC(O)(CH2)0-4SR-SC(S)SR°; -(CH2)0-4SC(O)R°; -(CH2)0-4C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2)0-4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)0-4SSR°; -(CH2)0-4S(O)2R°; -(CH2)0-4S(O)2OR°; -(CH2)0-4OS(O)2R°; -S(O)2NR°2; -(CH2)0-4S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; SiR°3; -(C1.4 straight or branched alkylene)O-N(R°) ₂ or -(C1-4 straight or branched alkylene)C(O)O-N(R°) ₂ where each R° may be substituted, as defined below, and is independently hydrogen, a C1-6 aliphatic group, -CH ₂ Ph, -O(CH ₂ ) ₀ _1Ph, -CH ₂ -(5-6 membered heteroaryl ring), or 5-6 membered

- 7 041983 saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definition, two independent R° together with intermediate(s) atom(s) between them form a 3-12 membered saturated, partially unsaturated or aryl mono- or bicyclic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

Suitable monovalent substituents at R° (or a ring formed by two independent R° together with intermediate atoms between them) are independently halogen, -(CH ₂ )o- ₂ R·, -(halo-R·), -(SH ^OH, -(CH ₂ )o- ₂ OR , -(CH2) o-2CH(OR *) 2; -O (halogen-R ), -CN, -N ₃ , -(CH ₂ )0. ₂ C(O)R , -(CH2)o-2C(0)OH, -(CH ₂ ) _o.2 C(0)OR , -(CH ₂ )o- ₂ SR , -(CH2) o-2SH, -(CH2)o-2NH2, -(CH ₂ ) _o _ ₂ NHR , -(CH ₂ ) _o-2 NR\ -NO2, -SiR\ -OSiR^ ₃ , -C(O)SR ·, -(C _1-4 straight or branched alkylene)C(O)OR· or -SSR·, where each R· is unsubstituted or, if preceded by a halogen, substituted with only one or more halogens, and is independently selected from C _{1 -4} aliphatic groups, -CH2Ph, -O(CH2) _0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. saturated carbon atom R° include =O and =S.

Suitable divalent substituents on the saturated carbon of an optionally substituted group include the following: =O, =S, =NNRx ₂ , =NNHC(O)Rx, =NNHC(O)ORx, =NNHS(O) ₂ Rx, =NRx, =NORx , -O(C(Rx ₂ )) _2-3 O- or -S(C(Rx ₂ )) _2-3 S-, where Rx is each independently selected from hydrogen, C _1-6 aliphatic group, which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents that bond to adjacent substitutable carbon atoms of an optionally substituted group include: -O(CRx ₂ ) _2-3 O-, where Rx is each independently selected from hydrogen, C _1-6 aliphatic group which may be substituted, as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable substituents on the aliphatic group Rx include halo, -R·, -(halo-R·), -OH, -OR·, -O(halo-R·), -CN, -C(O)OH, -C( O)OR·, -NH2, -NHR·, -NR\ or -NO2, where each R· is unsubstituted or, if preceded by a halogen, substituted by only one or more halogens, and is independently a C _1-4 aliphatic group, - CH2Ph, -O(CH2) _0-1 Ph or a 56-membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the substituted nitrogen atom of an optionally substituted group include -Rf, -NRf2, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf, -C(O)CH2C(O) Rf, -S(O)2Rf, -S(O) ₂ NRf ₂ , -C(S)NRf2, -C(NH)NRf2 or -N(Rf)S(O) ₂ Rf; where each Rf is independently hydrogen, a C _1-6 aliphatic group which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring containing 0-4 heteroatoms, independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definition, two independent R f together with the intermediate atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated or aryl mono- or bicyclic ring containing 0- 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the aliphatic group Rf are independently halo, -R·, -(halo-R·), -OH, -OR·, -O(halo-R·), -CN, -C(O)OH, - C(O)OR·, -NH2, -NHR·, -NR^ ₂ or -NO2, where each R· is unsubstituted or, if preceded by a halogen, substituted with only one or more halogens, and is independently C _1-4 an aliphatic group, -CH2Ph, -O(CH2) _0-1 Ph, or a 56-membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

As used herein, the term pharmaceutically acceptable salt refers to salts that are medically suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic reaction, and the like, and are adequate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, and said publication is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or using other methods used in the art, such as ion exchange.

- 8 041983

Другие фармацевтически приемлемые соли включают адипатные, альгинатные, аскорбатные, аспартатные, бензолсульфонатные, бензоатные, бисульфатные, боратные, бутиратные, камфоратные, камфорсульфонатные, цитратные, циклопентанпропионатные, диглюконатные, додецилсульфатные, этансульфонатные, формиатные, фумаратные, глюкогептонатные, глицерофосфатные, глюконатные, гемисульфатные, гептаноатные , hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, phosphate, phenyl-pionate, 3-phenylpionate , propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Individual alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium, and amine cation salts prepared using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, (lower alkyl)sulfonate, and arylsulfonate.

Unless otherwise indicated, structures depicted herein are also intended to include all isomeric (eg, enantiomeric, diastereomeric, and geometric (or conformational)) forms of such structures; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and conformational Z and E isomers. Thus, the scope of the present invention includes single stereochemical isomers as well as enantiomeric, diastereomeric mixtures and mixtures of geometric (or conformational) isomers of the compounds of the present invention. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. In addition, unless otherwise indicated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures shown, including replacement of hydrogen with deuterium or tritium, or replacement of carbon with ¹³ C- or ¹⁴ C-rich carbon, are within the scope of the present invention. Such compounds are suitable for use, for example, as assay tools, as probes in biological research, or as therapeutic agents in accordance with the present invention.

3. Description of exemplary embodiments.

In some embodiments of the present invention, AHR inhibitors are provided. In some embodiments, such compounds include compounds of formula I

each R ¹ is independently selected from R, -C(O)R, -C(O)OR, -SO2R, -C(O)N(R)2, or -SO2RN(R)2;

each R is independently hydrogen, deuterium, or a substituted or unsubstituted or pharmaceutically acceptable salt thereof, where ring A is selected from:

- 9 041983 a group selected from C _1-6 aliphatic group, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring; 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10-membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R ^x , R ^y and R ^z is independently selected from R, halo, cyano, nitro, -OR, -SR, -N(R) ₂ , -N(R)C(O)R, -C(O) N(R) ₂ , -N(R)C(O)N(R) ₂ , -N(R)C(O)OR, -OC(O)N(R) ₂ , -N(R)SO ₂ R, -SO ₂ RN(R) ₂ , -C(O)R, -C(O)OR, -OC(O)R, -S(O)R or -SO ₂ R, or two R ^x with one and the same carbon atom are combined to form =0 or =S;

or two R ^y at the same carbon atom combined to form ═O or ═S;

each of m and n is independently 1, 2, 3, 4, or 5;

ring B is phenyl, a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen , oxygen or sulfur;

ring C is phenyl or a 5-6 membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or an 8-10 membered bicyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

L ¹ is a covalent bond or an optionally substituted C _1-6 member straight or branched divalent hydrocarbon chain, where the methylene unit of L ¹ is optionally substituted with -Cy-, -O-, -S-, -NR-, -C(O) -, -C(O)O, -OC(O)-, -C(O)N(R)-, -N(R)C(O)-, -SO2-, -N(R)SO2- or -SO2N(R)-S; And

-Cy- is a 3-8 membered divalent saturated, partially unsaturated or aromatic monocyclic ring containing 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered divalent saturated, partially unsaturated or aromatic bicyclic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments of the present invention, AHR inhibitors are provided, such compounds include compounds of formula I':

or a pharmaceutically acceptable salt thereof, wherein ring A is selected from:

each p is independently 0, 1 or 2 depending on the valency;

each R ¹ is independently selected from R, -C(O)R, -C(O)OR, -SO ₂ R, -C(O)N(R) ₂ or -SO ₂ RN(R) ₂ ;

- 10 041983 each R is independently hydrogen, deuterium, or a substituted or unsubstituted group selected from C _1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring ; 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10-membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or two R's on the same nitrogen atom are combined with intermediate atoms between them to form a 4-7 membered saturated, partially unsaturated, or aromatic ring containing 1-2 heteroatoms in addition to said nitrogen atom, independently selected from oxygen, nitrogen, or sulfur;

each of R ^x , R ^y and R ^z is independently selected from R, halo, cyano, nitro, -OR, -SR, -N(R) ₂ , -N(R)C(O)R, -C(O) N(R)2, -C(O)N(R)OR, -N(R)C(O)N(R)2, -N(R)C(O)OR, -OC(O)N( R)2, -N(R)SO2R, -SO ₂ RN(R) ₂ , -C(O)R, -C(O)OR, -OC(O)R, -S(O)R or -SO2R , or two R ^x at the same carbon atom combined to form =0 or =S; or two R ^y at the same carbon atom combined to form ═O or ═S;

each of m and n is independently 1, 2, 3, 4, or 5;

ring B is phenyl, 7-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, 8-10 membered bicyclic heteroaryl a ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 12-15-membered partially unsaturated or aromatic tricyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

ring C is phenyl or a 5-6 membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

L ¹ is a covalent bond or an optionally substituted C _1-6 member straight or branched divalent hydrocarbon chain, where the methylene unit of L ¹ is optionally substituted with -Cy-, -O-, -S-, -NR-, -C(O) -, -C(O)O, -OC(O)-, -C(O)N(R)-, -N(R)C(O)-, -SO2-, -N(R)SO2- or -SO2N(R)-S; And

-Cy- is a 3-8 membered divalent saturated, partially unsaturated or aromatic monocyclic ring containing 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered divalent saturated, partially unsaturated or aromatic bicyclic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, the present invention provides a compound of formula I or formula I', provided that when ring A is ,

ring B is not

and/or R ¹ is not and/or ring C is not

- 11 041983

In some embodiments, the present invention provides a compound of formula I or formula I', provided that L ¹ is not -NHCH2CH2-. In some embodiments, the present invention provides a compound of formula I or formula I', provided that when ring A is

L ¹ is not -NHCH ₂ CH ₂ -.

In some embodiments, the present invention provides a compound of formula I or formula I', provided that the compound is not:

In some embodiments, the proposed connection is not

In some embodiments, the proposed connection is not

In some embodiments, the proposed connection is not

In some embodiments, the proposed connection is not

- 12 041983

In some embodiments, the proposed connection is not

CI

___

In some embodiments, the proposed connection is not a CI

As generally defined above, R ¹ is R, -C(O)R, -C(O)OR, -SO2R, -C(O)N(R)2 or -SO2RN(R)2. In some embodiments, R ¹ is hydrogen. In some embodiments, R ¹ is R. In some embodiments, R ¹ is -C(O)R. In some embodiments, R ¹ is -C(O)OR. In some embodiments, R ¹ is -SO2R. In some embodiments, R ¹ is -C(O)N(R)2. In some embodiments, R ¹ is -SO2RN(R)2. In some embodiments, R ¹ is hydrogen. In some embodiments, R ¹ is deuterium. In some embodiments, R ¹ is an optionally substituted group selected from a C _1-6 aliphatic group. In some embodiments, R ¹ is selected from the options shown in Table 1 below. 1.

As generally defined above, each R ^x is independently R, halogen, cyano, nitro, -OR, -SR, -N(R)2, -N(R)C(O)R, -C(O)N (R)2, -C(O)N(R)OR, -N(R)C(O)N(R)2, -N(R)C(O)OR, -OC(O)N(R )2, -N(R)SO2R, -SO2RN(R)2, -C(O)R, -C(O)OR, -OC(O)R, -C(O)OR, -S(O) R or -SO2R or two R ^x at the same carbon atom are combined to form ═O or ═S. In some embodiments, each R ^x is the same. In some embodiments, each R ^x is different. In some embodiments, R ^x is hydrogen. In some embodiments, R ^x is R. In some embodiments, R ^x is halogen. In some embodiments, R ^x is cyano. In some embodiments, R ^x is nitro. In some embodiments, R ^x is -OR. In some embodiments, R ^x is -SR. In some embodiments, R ^x is -N(R)2. In some embodiments, R ^x is -N(R)C(O)R. In some embodiments, R ^x is -C(O)N(R)2. In some embodiments, R ^x is -C(O)N(R)OR. In some embodiments, R ^x is -N(R)C(O)N(R)2. In some embodiments, R ^x is -N(R)C(O)OR. In some embodiments, R ^x is -OC(O)N(R)2. In some embodiments, R ^x is -N(R)SO2R. In some embodiments, R ^x is -SO2RN(R)2. In some embodiments, R ^x is -C(O)R. In some embodiments, R ^x is -C(O)OR. In some embodiments, R ^x is -CO(O)R In some embodiments, R ^x is -S(O)R In some embodiments, R ^x is -SO2R In some embodiments, two R ^x at the same carbon atom are combined to form =O or =S. In some embodiments, R ^x is hydrogen. In some embodiments, R ^x is deuterium. In some embodiments, R ^x is an optionally substituted group selected from a C _1-6 aliphatic group. In some embodiments, R ^x is selected from the options shown in Table 1 below. 1.

As generally defined above, each R ^y is independently R, halogen, cyano, nitro, -OR, -SR, -N(R)2, -N(R)C(O)R, -C(O)N (R)2, -C(O)N(R)OR, -N(R)C(O)N(R)2, -N(R)C(O)OR, -OC(O)N(R )2, -N(R)SO2R, -SO2RN(R)2, -C(O)R, -C(O)OR, -OC(O)R, -C(O)OR, -S(O) R or -SO2R or two R ^y at the same carbon atom are combined to form ═O or ═S. In some embodiments, each R ^y is the same. In some embodiments, each R ^y is different. In some embodiments, R ^y is hydrogen. In some embodiments, R ^y is R. In some embodiments, R ^y is halogen. In some embodiments, R ^y is cyano. In some embodiments, R ^y is nitro. In some embodiments, R ^y is -OR. In some embodiments, R ^y is -SR. In some embodiments, R ^y is -N(R) ₂ . In some embodiments, R ^y is -C(O)N(R)OR. In some embodiments, R ^y is -N(R)C(O)R. In some embodiments, R ^y is

- 13 041983

-C(O)N(R)2. In some embodiments, R ^y is -N(R)C(O)N(R)2. In some embodiments, R ^y is -N(R)C(O)OR. In some embodiments, R ^y is -OC(O)N(R)2. In some embodiments, R ^y is -N(R)SO2R. In some embodiments, R ^y is -SO2RN(R)2. In some embodiments, R ^y is -C(O)R. In some embodiments, R ^y is -C(O)OR. In some embodiments, R ^y is -CO(O)R. In some embodiments, R ^y is -S(O)R. In some embodiments, R ^y is -SO2R. In some embodiments, two R ^y at the same carbon atom are combined to form ═O or ═S. In some embodiments, R ^y is hydrogen. In some embodiments, R ^y is deuterium. In some embodiments, R ^y is an optionally substituted group selected from a C _1-6 aliphatic group. In some embodiments, R ^y is selected from the options shown in Table 1 below. 1.

As generally defined above, each R ^z is independently R, halogen, cyano, nitro, -OR, -SR, -N(R)2, -N(R)C(O)R, -C(O)N (R)2, -C(O)N(R)OR, -N(R)C(O)N(R)2, -N(R)C(O)OR, -OC(O)N(R )2, -N(R)SO2R, -SO2RN(R)2, -C(O)R, -C(O)OR, -OC(O)R, -C(O)OR, -S(O) R or -SO2R. In some embodiments, R ^z is hydrogen. In some embodiments, R ^z is R. In some embodiments, R ^z is halogen. In some embodiments, R ^z is cyano. In some embodiments, R ^z is nitro. In some embodiments, R ^z is -OR. In some embodiments, R ^z is -SR. In some embodiments, R ^z is -N(R)2. In some embodiments, R ^z is -C(O)N(R)OR. In some embodiments, R ^z is -N(R)C(O)R. In some embodiments, R ^z is -C(O)N(R)2. In some embodiments, R ^z is -N(R)C(O)N(R)2. In some embodiments, R ^z is -N(R)C(O)OR. In some embodiments, R ^z is -OC(O)N(R)2. In some embodiments, R ^z is -N(R)SO2R. In some embodiments, R ^z is -SO2RN(R) ₂ . In some embodiments, R ^z is -C(O)R In some embodiments, R ^z is -C(O)OR. In some embodiments, R ^z is -CO(O)R. In some embodiments, R ^z is -S(O)R. In some embodiments, R ^z is -SO2R. In some embodiments, R ^z is hydrogen. In some embodiments, R ^z is deuterium. In some embodiments, R ^z is an optionally substituted group selected from a C1-6 aliphatic group. In some embodiments, R ^z is selected from the options shown in Table 1 below. 1.

As generally defined above, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is selected from the options below in tab. 1.

As generally defined above, n is 1, 2, 3, 4, or 5. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4. In some embodiments, n is 5. In some embodiments, n is selected from the options shown in Table 1 below. 1.

As generally defined above, m is 1, 2, 3, 4, or 5. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4. In some embodiments, m is 5. In some embodiments, m is selected from the options shown in Table 1 below. 1.

As generally defined above, ring B is a phenyl, 7-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, 8 -10-membered bicyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 12-15-membered partially unsaturated or aromatic tricyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur . In some embodiments, ring B is a 7-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring. In some embodiments, ring B is a 12-15 membered partially unsaturated or aromatic tricyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring B is a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is an 8-10 membered bicyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is phenyl. In some embodiments, Ring B is thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, or pteridinyl, indolyl, isoindolyl, benzothienyl,

- 14 041983 benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, tetrahydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroisoquinolinyl, 4-oxazine-3(4H)-one.

In some embodiments, Ring B is selected from the options shown in Table 1 below. 1.

As generally defined above, Ring C is phenyl, a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl ring containing 1-4 a heteroatom independently selected from nitrogen, oxygen or sulfur. In some embodiments, Ring C is phenyl. In some embodiments, ring C is a 5-6 membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring C is thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, or pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H quinolizinyl, carbazolyl, acridinyl, phenazinyl, tetrahydroquinolinyl, tetrahydroisopyrinolinyl]-1-3-pyrinolinyl[2,3-pyrinolinyl] ,4-oxazine-3(4H)-one. In some embodiments, Ring C is selected from the options shown in Table 1 below. 1. As generally defined above, L ¹ is a covalent bond or an optionally substituted C1-6 member straight or branched divalent hydrocarbon chain, where the methylene unit of L ¹ is optionally substituted with -Cy-, -O-, -S-, -NR -, -C(O)-, -C(O)O, -OC(O)-, -C(O)N(R)-, -N(R)C(O)-, -SO2-, - N(R)SO ₂ - or -SO ₂ N(R)-S. in some embodiments, L ¹ is a covalent bond. In some embodiments, L ¹ is an optionally substituted C1-6 member straight or branched divalent hydrocarbon chain. In some embodiments, L ¹ is -Cy-. In some embodiments, L ¹ is phenylene, heterocyclylene, heteroarylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, or oxetanyl. In some embodiments, L ¹ is -NR-. In some embodiments, L ¹ is -N(CH2) ₂ -. In some embodiments, L ¹ is selected from the options shown in Table 1 below. 1.

In some embodiments, -Cy- is phenylene, heterocyclylene, heteroarylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and oxetanyl. In some embodiments, -Sy- is selected from:

where X is a heteroatom selected from nitrogen, oxygen or sulfur. In some embodiments, -Su- is selected from the options shown in Table 1 below. 1.

In some embodiments, the present invention provides a compound selected from any of formulas I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-l, I-m, I-n, I-o, and I-p:

- 15 041983

or their pharmaceutically acceptable salts; where each variable is as defined herein and described in the embodiments of the present invention for formula I and formula I', above, or described in the embodiments presented herein, either individually or in combination.

In some embodiments, the present invention provides a compound selected from any of formulas II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-i, II-j, II-k, II-l, III-m, II-n, II-o and II-p:

- 16 041983

π-p ;

or their pharmaceutically acceptable salts; where each variable is as defined herein and described in the embodiments of the present invention for formula I and formula I', above, or described in the embodiments presented herein, either individually or in combination. In some embodiments, the present invention provides a compound selected from any of formulas III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i, III-j, III-k, III-l, III-m, III-n, III-o, III-p, III-q, III-r, III-s, III-t, III-u, III- v, III-w, III-x, III-y, III-z, III-aa, III-bb, III-cc, III-dd, III-ee, III-ff, III-gg, III-hh, III-ii, III-jj and III-kk:

- 17 041983

- 18 041983

- 19 041983

or their pharmaceutically acceptable salts; where each variable is as defined herein and described in the embodiments of the present invention for formula I and formula I', above, or described in the embodiments presented herein, either individually or in combination. In some embodiments, the present invention provides a compound selected from any of formulas IV-a, IV-b, IV-c, IV-d, IV-e, IV-f, IV-g, IV-h, IV-i, IV-j, IV-k, IV-l, IV-m, IV-n, IV-o, IV-p and IV-q:

- 20 041983

IV-p IV-q or their pharmaceutically acceptable salts; where each variable is as defined herein and described in the embodiments of the present invention for formula I and formula I', above, or described in the embodiments presented herein, either individually or in combination. In some embodiments, the present invention provides a compound selected from any of formulas V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, and Vl:

- 21 041983

or their pharmaceutically acceptable salts; where each variable is as defined herein and described in the embodiments of the present invention for formula I and formula I', above, or described in the embodiments presented herein, either individually or in combination. In some embodiments, the present invention provides a compound selected from any of formulas VI-a, VI-b, VI-c, VI-d, VI-e, and VI-f:

- 22 041983

or their pharmaceutically acceptable salts, where X represents N or CH; where each variable is as defined herein and described in the embodiments of the present invention for formula I and formula I', above, or described in the embodiments presented herein, either individually or in combination.

In some embodiments, the present invention provides a compound selected from any of formulas VII-a, VII-b, VII-c, VII-d, VII-e, VII-f, and VII-g:

or their pharmaceutically acceptable salts, where X represents N or CH; where each variable is as defined herein and described in the embodiments of the present invention for formula I and formula I', above, or described in the embodiments presented herein, either individually or in combination.

In some embodiments, the present invention provides a compound selected from any of formulas VIII-a, VIII-b, VIII-c, VIII-d, VIII-e, and VIII-f:

- 23 041983

or their pharmaceutically acceptable salts, where X represents N or CH; where each variable is as defined herein and described in the embodiments of the present invention for formula I and formula I', above, or described in the embodiments presented herein, either individually or in combination.

In some embodiments, the present invention provides a compound selected from one of formulas IX-a and IX-b:

or their pharmaceutically acceptable salts, where X represents N or CH; where each variable is as defined herein and described in the embodiments of the present invention for formula I and formula I', above, or described in the embodiments presented herein, either individually or in combination.

In some embodiments, the present invention provides a compound selected from any of the formulas X-a, X-b, X-c, X-d, X-e, X-f, X-g, X-h, and X-i:

or their pharmaceutically acceptable salts, where X represents N or CH; where each variable is as defined herein and described in the embodiments of the present invention for formula I and formula I', above, or described in the embodiments presented herein, either individually or in combination.

In some embodiments, the present invention provides a compound selected from any of formulas XI-a, XI-b, XI-c, XI-d, XI-e, XI-f, XI-g, XI-h, and XI-i:

- 24 041983

or their pharmaceutically acceptable salts, where X represents N or CH; where each variable is as defined herein and described in the embodiments of the present invention for formula I and formula I', above, or described in the embodiments presented herein, either individually or in combination.

In some embodiments, the present invention provides a compound selected from any of formulas XII-a, XII-b, and XII-c:

or their pharmaceutically acceptable salts, where X represents N or CH; where each variable is as defined herein and described in the embodiments of the present invention for formula I and formula I', above, or described in the embodiments presented herein, either individually or in combination.

In some embodiments, the present invention provides a compound of formula I and formula I', provided that when ring A is ring B is not

- 25 041983

and/or ring C is not and/or R ¹ is not

In some embodiments, the present invention provides a compound of formula I and formula I', provided that L ¹ is not -NHCH2CH2-. In some embodiments, the present invention provides a compound of formula I and formula I', provided that when the ring

N

A represents

N ^r1 , L ¹ is not -NHCH2CH2-.

Illustrative compounds according to the present invention are given below in table. 1.

Table 1

Exemplary Compounds of Formula I

- 26 041983

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In some embodiments, the present invention provides a compound selected from those depicted in table. 1, or their pharmaceutically acceptable salts.

. Use, composition, administration and pharmaceutically acceptable compositions.

According to another embodiment, the present invention provides a composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, ester, or ester salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the compositions of the present invention is such as to be effective for measurable inhibition of AHR in a biological sample or patient. In some embodiments, the amount of a compound in a composition of the present invention is such as to be effective for measurable inhibition of AHR in a biological sample or in a patient. In some embodiments, a composition of the present invention is in a form for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is in a form for oral administration to a patient.

The term patient as used herein means an animal, preferably a mammal, and most preferably a human.

The term pharmaceutically acceptable carrier, adjuvant, or vehicle refers to a non-toxic carrier, adjuvant, or vehicle that does not interfere with the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, blood serum proteins such as human serum albumin, buffering agents, such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, sodium hydrogen phosphate, hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone , cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, polyethylene glycol and lanolin (wool fat).

A pharmaceutically acceptable derivative means any non-toxic salt, ester, ester salt or other derivative of a compound of the present invention which, when administered to a patient, is capable of providing, either directly or indirectly, a compound of the present invention or an inhibitory active metabolite or residue thereof.

Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion methods. Preferably the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of the present invention may be in the form of an aqueous or oily suspension. These suspensions can be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenteral acceptable diluent or solvent, such as, for example, a solution in 1,3-butanediol. Acceptable bases and solvents that may be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils have traditionally been used as the solvent or suspending medium.

Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used to make injectables because they are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain long chain alcohol diluents or dispersants such as carboxymethyl cellulose or similar dispersing agents which are widely used in pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spanes, and other emulsifying agents or bioavailability enhancers, which are widely used to prepare pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

Pharmaceutically acceptable compositions of the present invention may be administered orally in any suitable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also commonly added. For oral administration in the form of a capsule, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active substance is combined with emulsifying and suspending agents. Certain sweetening, flavoring or coloring agents may also be added, if desired.

Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of rectal suppositories. They can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

Pharmaceutically acceptable compositions of the present invention may also be

- 58 041983 introduced locally, especially if the target of therapy includes areas or organs that are easily accessible for local application, including diseases of the eyes, skin or lower intestinal tract. A suitable topical dosage form is easily prepared for each of these areas or organs. Topical application to the lower intestinal tract can be done in a rectal suppository dosage form (see above) or in a suitable enema dosage form. Topical transdermal patches may also be used.

For topical use, the present pharmaceutically acceptable compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided may be provided as a suitable lotion or cream containing the active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

For ophthalmic use, the present pharmaceutically acceptable compositions may be prepared as a micronized suspension in pH-adjusted isotonic sterile saline, or preferably as solutions in pH-adjusted isotonic sterile saline, with or without the addition of a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, pharmaceutically acceptable compositions may be prepared in the form of an ointment such as petrolatum. Pharmaceutically acceptable compositions according to the present invention may also be administered as a nasal spray or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical art and may be prepared as solutions in aqueous sodium chloride, including benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of the present invention are in a form for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of the present invention are administered with food.

The number of compounds according to the present invention, which can be combined with substances-carriers to obtain a composition in the form for a single use, may vary depending on the patient receiving treatment, the particular route of administration. Preferably, the compositions of the invention should be formulated such that a dose of 0.01-100 mg/kg body weight/day of the inhibitor can be administered to the patient receiving the compositions.

It should be understood that the specific dosage and treatment regimen for each individual patient will depend on a variety of factors, including the potency of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate of elimination, combination of drugs, and the judgment of the attending physician. and the severity of the particular disease being treated. The amount of the compound of the present invention in the composition will also depend on the particular compound in the composition.

Use of the Compounds and Pharmaceutically Acceptable Compositions The activity of the compound used in the present invention as an AHR inhibitor can be determined in vitro or in vivo. Determination of the effectiveness of the compounds according to the present invention in vivo can be performed using models of obesity or metabolic syndrome in animals, for example, models in rodents or primates. The study on cells can be performed using, for example, cell lines isolated from tissue expressing AHR. Additionally, biochemical or mechanism-based assays can be performed, for example, transcription assays with purified protein, Northern blotting, reverse transcription-PCR (RT-PCR), etc. In vitro assays include assays that determine cell morphology, protein expression and/or cytotoxicity, enzyme inhibition activity, and/or resulting functional consequences of treating cells with compounds of the present invention. Alternative in vitro assay methods quantify the ability of an inhibitor to bind intracellularly to protein or nucleic acid molecules. Inhibitor binding can be measured by radiolabeling inhibitors prior to binding, isolating the inhibitor/target molecular complex, and quantifying radiolabeled bonds. Alternatively, inhibitor binding can be determined by performing a competitive binding experiment in which novel inhibitors are incubated with purified proteins or nucleic acids linked to known radio ligands. Detailed analysis conditions for the compound used in the present invention as an AHR inhibitor are shown in the examples below. The above methods of analysis are illustrative and are not intended to limit the scope of the present invention. The skilled practitioner is able to appreciate that modifications can be made to standard assay methods in order to develop equivalent assay methods that produce the same result.

As used herein, the terms treatment, treat, and treatment refer to regression, alleviation, delaying the onset, or slowing the progression of a disease or disorder, or one or more of its symptoms, as used herein. In some embodiments, therapy may be administered after the development of one or more symptoms. In other embodiments, therapy may be administered in the absence of symptoms. For example, therapy may be administered to a predisposed subject prior to the onset of symptoms (eg, based on history of symptoms and/or genetic or other predisposing factors). Therapy may be continued after the symptoms have been eliminated, for example, in order to prevent or delay the onset of their recurrence.

Compounds and compositions according to the method of the present invention may be administered using any amount and by any route of administration effective to treat or alleviate the severity of a metabolic disorder or condition, cancer, bacterial infection, fungal infection, parasitic infection (e.g., malaria), autoimmune disorder, a neurodegenerative or neurological disorder, schizophrenia, a bone-related disorder, liver disease, or a heart disorder.

In some embodiments, the compounds and compositions according to the method of the present invention may be administered using any amount and by any route of administration effective to treat or alleviate the severity of a disease associated with AHR.

The precise amount required may vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the present invention are preferably prepared in unit dosage form for ease of administration and dose uniformity. The expression unit dosage form in the context of the present description refers to a physically separate unit of an agent suitable for the patient to whom treatment is intended. It should be understood, however, that the total daily use of the compounds and compositions of the present invention will be determined by the attending physician as part of an informed medical decision. Specific effective dose levels for each individual patient or organism will depend on a variety of factors, including the disorder requiring treatment and the severity of that disorder; the activity of the specific compound used, the specific composition used; age, body weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the particular compound used; duration of treatment; drugs used in combination or concurrently with the specific compound used; and the like, well known in the medical arts. The term patient as used herein means an animal, preferably a mammal, and most preferably a human. Pharmaceutically acceptable compositions according to the present invention can be administered to humans and animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In some embodiments, the compounds of the present invention may be administered orally or parenterally at dose levels from about 0.01 mg/kg to about 50 mg/kg, and preferably from about 1 mg/kg to about 25 mg/kg of the subject's body weight per day. , one or more times a day, to achieve the desired therapeutic effect. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents widely used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and flavoring agents.

Injectable forms, for example sterile injectable aqueous or oily suspensions, may be prepared according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable form may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable bases and solvents that may be used include water, USP Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are traditionally used as solvents or suspending media. Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used to make injectables.

Injectable dosage forms can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent into a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a compound of the present invention, it is often necessary to delay the absorption of the compound from subcutaneous or intramuscular injection. This can be done by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of a compound is further dependent on its rate of dissolution, which in turn may be dependent on the size of the crystals and the shape of the crystals. Alternatively, slowing the absorption of a parenterally administered form of a compound is accomplished by dissolving or suspending the compound in an oil base. Depot injectable dosage forms are made by forming microencapsulated matrices with compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable dosage forms are also made by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or wax for a suppository that is solid at ambient temperature but liquid at body temperature and thus melts in the rectum or vaginal cavity and releases the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or calcium diphosphate and/or a) excipients or diluents such as starches, lactose, sucrose, glucose, mannitol and silicic acid. acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants, such as glycerol, d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate e) solution retention agents such as paraffin f) absorption accelerators such as quaternary ammonium compounds g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate h ) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate , solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In capsule, tablet and pill form, the dosage form may also contain buffering agents.

Solid compositions of a similar type can also be used as filler in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutical formulations. They may optionally contain opacifying agents and may also be formulated to release the active ingredient(s) only, or preferably in a specific part of the intestinal tract, optionally with a delayed release. Examples of inclusion compositions that can be used include polymeric materials and waxes. Solid compositions of this kind can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

The active compounds may also be in microencapsulated form with one or more excipients as noted above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be formulated with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compounds may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain, in common practice, additional substances other than inert diluents, for example tabletting lubricants and other tabletting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may also be formulated to release the active ingredient(s) only, or preferably in a specific part of the intestinal tract, optionally with a delayed release. Examples of inclusion compositions that can be used include polymeric materials and waxes.

Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, if necessary. Also intended to be within the scope of the present invention are ophthalmic formulations, ear drops and eye drops. In addition, the present invention contemplates the use of transdermal patches, which have the added benefit of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers may also be used to increase the rate of penetration of the compound through the skin. The rate can be controlled either by using a release rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Application and methods of treatment

According to one embodiment, the present invention relates to a method for inhibiting AHR in a biological sample, comprising the step of contacting said biological sample with a compound of the present invention, or a composition containing said compound.

The term biological sample in the context of the present description includes, without limitation, cell cultures or their extracts; biopsy material obtained from a mammal or its extracts; as well as blood, saliva, urine, feces, semen, tears or other body fluids or their extracts. Inhibition of enzymes in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such goals include, but are not limited to, biological research, gene expression research, and biological target identification.

Another embodiment according to the present invention relates to a method for inhibiting AHR in a patient, comprising the step of administering to said patient a compound of the present invention or a composition containing said compound.

The proposed compounds are inhibitors of AHR and thus can be used to treat one or more disorders associated with AHR activity. Thus, in some embodiments, the present invention provides a method of treating an AHR-mediated disorder, comprising the step of administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition comprising the same.

In the context of the present description, the terms AHR-mediated disorders, diseases and/or conditions used in the present description, mean any disease or other detrimental condition, which is known to be related to AHR or its mutant. Accordingly, another embodiment of the present invention relates to the treatment or alleviation of one or more diseases to which AHR or a mutant thereof is known to be related.

AHR-mediated disorders are well understood in the art. The relationship between AHR and AHR-mediated disorders, diseases and/or conditions described in the present description, is well established in the relevant fields of technology. For example, see:

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Uyttenhove et al., "Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase" Nature Medicine, 2003 vol. 9(10), 1038; Murray et al., "AN RECEPTOR LIGANDS IN CANCER: FRIEND AND FOE" Nat. Rev. CancerDecember 2014, vol. 14(12), pages 801-814; Moon et al., "Targeting the indoleamine 2,3-dioxygenase pathway in cancer" J. ImmunoTherapy of Cancer, 2015 vol 3, page 51; Ishida et al., "Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with c poor prognosis and cigarette smoke" Int. J. Cancer July 2015 vol. 15, no. 137(2), pages 299-310; Ishida et al., "Activation of aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer" Carcinogenesis February 2010 vol. 31(2), pages 287-295. Su et al., "Prognostic value of nuclear translocation of aryl hydrocarbon receptor for non-small cell lung cancer" Anticancer Res. September 2013, vol. 33(9), pages 3953-3961; Peng et al., "Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9" BMC Cell Biol. April 2009 vol. 16; pages 10-27; Jin et al., "Aryl hydrocarbon Receptor Activation Reduces Dendritic Cell Function during Influenza Virus Infection" Toxicol Sci. August 2010, vol. 116(2), pages 514-522; Head et al., "Aryl hydrocarbon receptor is a modulator of anti-viral immunity" Biochem. Pharmacol. February 2009 vol. 15; no. 77(4), pages 642-53; Jin et al., "New insights into the role of aryl hydrocarbon receptor in the function of CDllc ⁺ cells during respiratory viral infection" Eur. J. Immunol. June 2014, vol. 44(6), pages 1685-98; Nguyen et al., "Aryl hydrocarbon receptor and kynurenine: recent advances in autoimmune disease research" Front Immunol. October 2014, vol. 29, no. 5, page 551; Esser et al., "Aryl hydrocarbon receptor in immunity" Trends in Immunology, Vol.30, No.9.

In some embodiments, the present invention provides a method of treating one or more disorders, diseases, and/or conditions, wherein said disorder, disease, or condition is a proliferative disease, such as cancer, an inflammatory disorder, or a viral infection.

In some embodiments, the present invention provides a method of treating cancer or other proliferative disorder, comprising administering a compound or composition of the present invention to a patient with cancer or other proliferative disorder. In some embodiments, a method for treating cancer or other proliferative disorder comprises administering a compound and composition of the present invention to a mammal. In some embodiments, the mammal is a human.

As used herein, the terms inhibition of cancer and inhibition of proliferation of cancer cells refers to the inhibition of growth, division, maturation, or viability of cancer cells and/or the induction of death of cancer cells, either alone or in combination with other cancer cells, due to cytotoxicity, nutrient deficiency, or induction of apoptosis. Examples of tissues containing cancer cells whose proliferation is inhibited by the compounds and compositions described herein and against which the methods described herein can be applied include, but are not limited to, breast, prostate, brain, blood. , bone marrow, liver, pancreas, skin, kidney, colon, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, choroid, conjunctiva, spleen, head, neck, trachea , gallbladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscles, heart and stomach. In some embodiments, the cancer being treated with the compounds or compositions of the present invention is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, or colon cancer. . In some embodiments, said cancer is primary effusion lymphoma (PEL).

The compounds of the present invention can be used to treat a proliferative disease selected from benign or malignant tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate , pancreas, lung, vagina, cervix, testes, urogenital tract, esophagus, larynx, skin, bone, or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, or cancer of the stomach

- 63 041983 of the intestinal tract, in particular colon carcinoma or colorectal adenoma or tumor of the neck and head, epidermal hyperproliferation, psoriasis, prostate enlargement, neoplasia, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, squamous cell carcinoma, large cell carcinoma, non-small cell lung carcinomas, lymphomas, Hodgkin's and non-Hodgkin's, Waldenström's macroglobulinemia, breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, MYD88 disorder, diffuse large B-cell lymphoma (DLBCL), DLBCL type ABC, disorders, caused by IL-1, smoldering or indolent multiple myeloma or leukemia. In some embodiments, cancer includes, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia , chronic lymphocytic leukemia), polycythemia vera, lymphoma (eg, Hodgkin's or non-Hodgkin's lymphoma), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (eg, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leimiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma cynoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonic carcinoma, cervical cancer , uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelioma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma , schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma and retinoblastoma).

In some embodiments, said cancer is a glioma, astrocytoma glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma craniopharyngioma ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma melanoma, neuroblastoma, or retinoblastoma.

In some embodiments, said cancer is acoustic neuroma, astrocytoma (e.g., grade I - piloid astrocytoma, grade II - poorly differentiated astrocytoma, grade III - anaplastic astrocytoma, or grade IV - glioblastoma (GBM)), chordoma, lymphoma CNS, craniopharyngioma, brainstem glioma, ependymoma, mixed glioma, optic nerve glioma, subepidioma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal tumor (PNET), or schwannoma. In some embodiments, said cancer is a type found in most cases more frequently in children than in adults, such as brainstem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal cell tumor, primitive neuroectodermal tumor (PNET) or rhabdoid tumor. In some embodiments, the patient is an adult. In some embodiments, the patient is a child or a pediatric patient.

In another embodiment, the cancer includes, without limitation, mesothelioma, hepatobiliary (hepatic and bile duct) cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer. colon, anal cancer, gastric cancer, gastrointestinal cancer (gastric, colorectal and duodenal), uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, cancer bladder, kidney or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, non-Hodgkin's lymphoma, spinal tumors a, brainstem glioma, pituitary adenoma, adrenocortical cancer, gallbladder cancer, multiple myeloma, scholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or combinations of one or more of the above cancers.

In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, epithelial ovarian cancer, or fallopian tube cancer; sero-papillary cystadenocarcinoma or sero-papillary carcinoma of the uterus (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatoscholangiocarcinoma; sarcomas of soft tissues, bones and synovial sarcoma;

- 64 041983 rhabdomyosarcomas; osteosarcomas; chondrosarcomas; Ewing's sarcomas; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic duct carcinomas or pancreatic adenocarcinomas; gastrointestinal tract/stomach cancer (GIST); lymphomas; squamous cell carcinoma of the head and neck (SCCH); salivary gland cancer; glioma or brain cancer; neurofibromatosis-1 associated with malignant tumors of the membranes of peripheral nerves (MNMF); Waldenström's macroglobulinemia or medulloblastoma.

In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, papillary serous uterine carcinoma (UPSC), hepatoscholangiocarcinoma, soft tissue sarcoma. tissue, bone and synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated with malignant tumors of the peripheral nerve sheaths (NAMN), macroglobulinemia Waldenstrom or medulloblastoma.

In some embodiments, said cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. Solid tumors mainly contain pathological tumor formation of tissues that usually do not have a membrane or areas of fluid. In some embodiments, the cancer is selected from renal cell carcinoma or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma or liver cancer; melanomas; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, epithelial ovarian cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or papillary serous carcinoma of the uterus (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatoscholangiocarcinoma; soft tissue and bone sarcomas and synovial sarcomas; rhabdomyosarcomas; osteosarcomas; chondrosarcomas; Ewing's sarcomas; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic duct carcinomas or pancreatic adenocarcinomas; gastrointestinal tract/stomach cancer (GIST); lymphomas; squamous cell carcinoma of the head and neck (SCCH); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated with malignant tumors of the membranes of peripheral nerves (MNMF); macroglobulinemia Waldenström or medulloblastoma.

In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, epithelial ovarian cancer, ovarian carcinoma, fallopian cancer tubal, papillary serous cystadenocarcinoma, papillary serous uterine carcinoma (UPSC), hepatoscholangiocarcinoma, soft tissue sarcoma, bone and synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, adenocarcinoma gland, glioma, brain cancer, neurofibromatosis-1 associated with malignant tumors of the peripheral nerve sheaths (MPNM), Waldenström's macroglobulinemia or medulloblastoma.

In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatoscholangiocarcinoma , soft tissue, bone and synovial sarcomas, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated with malignant tumors of the peripheral nerve sheaths ), macroglobulinemia Waldenström or medulloblastoma.

In some embodiments, said cancer is hepatocellular carcinoma (HNC). In some embodiments, said cancer is a hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, said cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer or ovarian carcinoma. In some embodiments, said cancer is epithelial ovarian cancer. In some embodiments, said cancer is fallopian tube cancer. In some embodiments, said cancer is papillary serous cystadenocarcinoma. In some embodiments, said cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, said cancer is hepatoscholangiocarcinoma. In some embodiments, said cancer is soft tissue, bone, and synovial sarcoma. In some embodiments, said cancer is rhabdomyosarcoma. In some

- 65 041983 In other embodiments, said cancer is osteosarcoma. In some embodiments, the cancer is aplastic thyroid cancer. In some embodiments, said cancer is an adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer or pancreatic ductal carcinoma. In some embodiments, said cancer is pancreatic adenocarcinoma. In some embodiments, said cancer is a glioma. In some embodiments, said cancer is peripheral nerve sheath malignant tumors (MNMTs). In some embodiments, said cancer is neurofibromatosis-1 associated with MAD. In some embodiments, said cancer is Waldenstrom's macroglobulinemia. In some embodiments, said cancer is a medulloblastoma.

In some embodiments, said cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, atypical teratoid rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer , bone cancer, brain tumor, astrocytoma, tumor of the brain and spinal cord, brain stem glioma, atypical teratoid-rhabdoid tumor of the central nervous system, embryonic tumors of the central nervous system, breast cancer, bronchial tumors, Burkitt's lymphoma, carcinoid tumor, carcinoma of unknown primary site, central nervous system cancer, cervical cancer, childhood cancers, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, skin T-cell lymphoma, encapsulated mollo carcinoma ductal carcinoma (DCIS), embryonic tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer , gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, germ cell tumor of the ovaries, gestational trophoblastic tumor, glioma, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, histiocytosis, Langerhans cell cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, larynx cancer, leukemia, lip and mouth cancer, liver cancer, non-invasive lobular carcinoma (LCIS), lung cancer, lymphoma, AIDS-associated lymphoma , macroglobulinemia, breast cancer in men, medulla loblastoma, medulloepithelioma, melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic squamous cell carcinoma of the neck, undetected primary site, NUT median carcinoma, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell tumor, mycosis fungoides, myelodysplastic syndrome , myelodysplastic/myeloproliferative neoplasia, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), myeloma, multiple myeloma, chronic myeloproliferative disorder, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus cancer, nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, parenchymal tumors shishkovi intermediate differentiation, pineoblastoma, pituitary tumor, plasma cell tumor, pleuropulmonary blastoma, breast cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, clear cell carcinoma of the kidney, renal pelvis cancer, ureteral cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Cesari's syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer of unclear primary site, squamous cell carcinoma of the head and neck (SCCHN), gastric cancer, supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer, throat cancer, thymoma, thymus carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, triple negative breast cancer (TNBC) ), gestational trophoblastic tumor, tumor of unknown primary site atypical childhood cancer, urethral cancer, uterine cancer, uterine sarcoma, Waldenström macroglobulinemia, or Wilms tumor. The compounds of the present invention can be used to treat inflammatory or obstructive airway diseases, resulting in, for example, reduced tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression. Inflammatory or obstructive airway diseases to which the present invention is applicable include asthma of any type or genesis, including both endogenous (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, bronchial physical stress asthma, occupational bronchial

- 66 041983 chial asthma and asthma caused by the following bacterial infections. It should be understood that the treatment of asthma also includes the treatment of subjects, e.g., less than 4 or 5 years of age, who have symptoms of wheezing and who have or may be diagnosed with wheezy infants, a designated category of patients with serious health problems. and now often referred to as an asthmatic of the initial or early stages.

Prophylactic efficacy in the treatment of asthma is evidenced by reduction in the frequency or severity of a symptomatic attack, such as an acute asthmatic or bronchoconstrictor attack, improvement in lung function, or improved airway hyperresponsiveness. It can be further supported by reducing the need for other symptomatic therapy, such as therapy for or aimed at limiting or stopping a symptomatic attack when it occurs, such as anti-inflammatory or bronchodilator.

The prophylactic benefit in asthma may in particular be evident in subjects prone to morning dipping. Morning attack is a well-recognized asthmatic syndrome, which is characteristic of a significant percentage of asthmatics and is characterized by an asthma attack, for example, between about 4 and 6 o'clock in the morning, i.e. at a time significantly remote in time under normal conditions from any previously introduced symptomatic therapy against asthma. The compounds of the present invention may be useful in other inflammatory or obstructive airway diseases and conditions for which the present invention is applicable, and include acute lung injury (ALI), acute respiratory distress syndrome/adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease lung, airway, or lung disease (COPD, COPD, or COLD), including associated chronic bronchitis or dyspnea, emphysema, and exacerbation of airway hyperactivity due to other drug therapy, in particular other inhaled drug therapy. The present invention can also be applied to the treatment of bronchitis of any type or genesis, including, but not limited to, acute, arachidic (arachidic), catarrhal, croupous, chronic or purulent tuberculous bronchitis. Additionally, inflammatory or obstructive airway diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, usually occupational, lung disease often accompanied by airway obstruction, either chronic or acute, and caused by repeated dust inhalation) of any type and genesis, including eg aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and bassinosis.

With regard to anti-inflammatory activity, in particular associated with the inhibition of eosinophil activation, the compounds of the present invention can also be used to treat eosinophilia-associated disorders, for example, eosinophilia, in particular eosinophilia-associated airway disorders (for example, with the occurrence of pathological eosinophilic infiltration lung tissue), including hypereosinophilia, as it affects the airways and/or lungs, as well as, for example, eosinophilia-associated airway disorders following or accompanied by Loeffler's syndrome, eosinophilic pneumonia, parasitic (particularly multicellular) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, and eosinophilia-associated disorders affecting the airways caused by a drug reaction.

The compounds of the present invention can also be used to treat inflammatory or allergic skin conditions, for example, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus stratus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne vulgaris, and other inflammatory or allergic skin conditions.

The compounds of the present invention may also be used in the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, in the treatment of diseases and conditions of the eye, such as allergic eye diseases, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, diseases affecting nose, including allergic rhinitis and inflammatory disease that may involve autoimmune reactions or have an autoimmune component or etiology, including autoimmune hematopoietic disorders (eg, hemolytic anemia, hypoplastic anemia, aplastic congenital anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus , rheumatoid arthritis, polychondria, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic celiac disease, autoimmune inflammatory bowel disease (eg, ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease,

- 67 041983 glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine orbitopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis , interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerol nephritis (with and without nephrotic syndrome, e.g., including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle loss, catabolism disorders, obesity, fetal growth retardation, hypercholesterol Mia, heart disease, chronic heart failure, mesothelioma, anhydrous ectodermal dysplasia, Behçet's disease, pigment incontinence syndrome, Paget's disease, pancreatitis, hereditary intermittent fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis and exercise) , acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, nasal sinusitis, eye allergy, silica inhalation disease, COPD (reduction of damage, airway inflammation, bronchial hyperresponsiveness, disease remodeling or progression), lung disease , cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation with systemic sclerosis, dermatomyositis, polymyositis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus ah, type 1 diabetes or type 2 diabetes.

In some embodiments, the inflammatory disease that may be treated according to the methods of the present invention is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SIIA) , cryopyrin-associated periodic syndromes (CAPS) or osteoarthritis. In some embodiments, the inflammatory disease that can be treated according to the methods of the present invention is selected from a TH17 mediated disease. In some embodiments, the TH17 mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease including Crohn's disease, or ulcerative colitis.

In some embodiments, the inflammatory disease that can be treated in accordance with the methods of the present invention is selected from allergic disorders related to Sjögren's syndrome, osteoarthritis, eye conditions such as allergic eye diseases, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis.

In some embodiments, the inflammatory disease that can be treated according to the methods of the present invention is selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, vulgaris pemphigus, pemphigus stratus, paraneoplastic pemphigus, acquired epidermolysis bullosa, and other inflammatory or allergic skin conditions. In some embodiments, the proposed connection can be used to treat viral infections, diseases or conditions. In some embodiments, the present invention provides a method of treating a viral disease selected from retroviral diseases such as HIV-1, HIV-2, human T-cell leukemia virus type 1 (HTLV-I), HTLV-II, HTLV-III, virus simian immunodeficiency virus (SIV), lymphadenopathy-associated virus (LAV-2), simian T-lymphotropic virus-I (STLV-I), STLV-II, sTlV-III, simian B-lymphotropic virus (SbL), gibbon leukemia virus ( GALV), bovine leukemia virus (BLV), equine infectious anemia virus (EIAV), feline leukemia virus (FELV), murine leukemia virus (MuLV), avian leukemia virus (ALV); other viral infections such as Hepadnaviridae (hepatitis B); Herpesviridae (herpes simplex virus type I, herpes simplex virus type II, Varicella-Zoster, Epstein-Barr virus and cytomegalovirus); Parvoviridae (human parvovirus B19); Papovaviridae (human papillomaviruses type 1-60, JC and BK); poxvirus (variola, smallpox, vaccinia, monkeypox, vaccinia, pseudocowpox or bovine pseudopox virus, parapox or Orff virus, molluscum contagiosum) and cancers, lymphomas and other leukemias.

Combination Therapy

Depending on the particular condition or disease requiring treatment, additional therapeutic agents that are typically administered to treat that condition may be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents that are typically administered to treat a particular disease or condition are known to be appropriate for the disease or condition being treated.

- 68 041983 treatment.

In some embodiments, the present compound or composition thereof is administered in combination with other anticancer, cytotoxic, or chemotherapeutic agents to a patient in need thereof.

In some embodiments, anti-cancer or chemotherapeutic agents used in combination with the compounds or compositions of the present invention include, but are not limited to, metformin, phenformin, buformin, imatinib, nilotinib, gefinitib, sunitinib, carfilzomib, salinosporamide A, retinoic acid, cisplatin , carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, azathioprine, mercaptopurine, doxifluridine, fluorouracil, gemcitabine, methotrexate, thioguanine, vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, etoposide, teniposide, taflucan, tocanselinotec , amsacrine, actinomycin, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, plicamycin, mitomycin, mitoxantrone, melphalan, busulfan, capecitabine, pemetrexed, epothilones, 13-cis-retinoic acid, 2-CdA, 2-chlordeoxyadenosine, 5-azacytidine, 5-fluorouracil, 5-FU, 6-mercaptopurine, 6-MP, 6-TG, 6-thioguanine, abraxane, Accutane®, Actin omycin-D, Adriamycin®, Adrucil®, Afinitor®, Agrilin®, Ala-Cort®, Aldesleukin, Alemtuzumab, ALIMTA, Alitretinoin, Alkaban-AQ®, Alkeran®, all-trans retinoic acid, Interferon-Alpha, Altretamine, Amethopterin , Amifostine, Aminoglutethimide, Anagrelide, Anandron®, Anastrozole, Arabinosylcytosine, Ara-C, Aranesp ®, Aredia®, Arimidex®, Aromasin®, Arranone®, Arsenic Trioxide, Arzerra®, Asparginase, ATRA, Avastin®, Azacitidine, BCG, BHNM, Bendamustine, Bevacizumab, Bexarotene, BEXXAR®, Bicalutamide, BiKNU, Blenoxan®, Bleomycin, Bortesonib, Busulfan, Busulfex®, C225, Calcium Leucovorin, Campat®, Camptosar®, Camptothecin-11, Capecitabine, Carac®, Carboplatin, Carmustine , Carmustine Implant Capsule, Casodex®, CC-5013, CCI-779, CCNU, CDDP, Cerubidin®, Cetuximab, Chlorambucil, Citrovorum Factor, Cladribine, Cortisone, Comegen®, CPT-11, Cytadren®, Cytosar-U® , Cytoxan®, Dacarbazine, Dacogen, Dactinomycin, Darbepoetin Alpha, Dasatinib, Daunomycin, Daunorubicin Hydrochloride, Daunorubicin Liposomal ny, DaunoXom®, Decadron, Decitabin, Delta-Cortef®, Deltason®, Denileukin, Diftitox, Depocit®, Dexamethasone, Dexamethasone acetate, Dexamethasone sodium phosphate, Dexazon, Dexrazoxane, DHAD, DIC, Diodex, Docetaxel, Doxil®, Doxorubicin, Doxorubicin Liposomal, Droxia®, DTIC, DTIC-Dome®, Duralon®, Efudex®, Eltgard®, Ellens®, Eloxatin®, Elspar®, Emcit®, Epirubicin, Epoetin Alfa, Erbitux, Erlotinib, Ervinia L-asparaginase, Estramustine, Etiol, Etopophos®, Etoposide Phosphate, Eulexin®, Everolimus, Evista®, Exemestane, Fareston®, Faslodex®, Femara®, Filgrastim, Floxuridin, Fludara®, Fludarabine, Fluoroplex®, Fluorouracil, Fluorouracil (cream), Fluoxymesterone, Flutamide, Folinic Acid, FUDR®, Fulvestrant, G-CSF, Gefinitib, Gemcitabine, Gemtuzumab, Ozogamycin, Gemzar Glivec®, Gliadel® Implant Capsule, GM-CSF, Goserelin, Granulocyte Colony Stimulating Factor, Granulocyte Macrophage Colony Stimulating Factor, Halogentestin®, Herceptin ®, Hexadrol, Hexalene®, Hexamethi Melamine, NMM, Hycamtin®, Hydrea®, Hydrocort Acetate®, Hydrocortisone, Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate, Hydrocorton Phosphate, Hydroxyurea, Ibritumomab, Ibritumomab, Tiuxetan, Idamycin®, Idarubicin Ifex®, IF-alpha, Ifosfamide, IL- 11, IL-2, Imatinib mesylate, Imidazole Carboxamide, Interferon alfa, Interferon alfa-2b (PEG conjugate), Interleukin-2, Interleukin-11, Intron A® (interferon alfa-2b), Iressa®, Irinotecan, Isotretinoin, Ixabepilone , Ixempra®, Kidrolase®, Lanacort®, Lapatinib, Lasparaginase, LCR, Lenalidomide, Letrozole, Leucovorin, Leukeran, Leukin®, Leuporide, Leurocristin, Leustatin®, Liposomal Ara-C, Liquid Pred®, Lomustine, L-PAM, L - Sarcolysin, Lupron®, Lupron Depot®, Matulan®, Maxidex, Mechlorethamine, Mechlorethamine Hydrochloride, Medralon®, Medrol®, Megas®, Megestrol, Megestrol Acetate, Melphalan, Mercaptopurine, Mesna, Mesnex®, Methotrexate, Sodium Methotrexate, Methylprednisolone, Meticorten®, Mitomycin, Mitomycin-C, Mitoxantrone, MPrednisol®, MTS, MTX, Mustargen®, Mustine, Mutamycin®, Myleran®, Mylocel®, Mylotarg®, Navelbin®, Nelarabine, Neosar®, Neulasta®, Niymega®, Neupogen®, Nexavar®, Niladron®, Nilotinib, Nilutamide, Nipent®, Chlormethine , Novaldex®, Novantron®, Enplate, Octreotide, Octreotide acetate, Ofatumumab, Oncospar®, Onkovin®, Ontak®, Onxal®, Oprelvekin, Oprapred®, Orazon®, Oxaliplatin, Paclitaxel, Paclitaxel, protein-bound, Pamidronate, Panitumumab, Panretin®, Paraplatin®, Pazopanib, Pediapred®, PEG Interferon, Pegaspargasa, PEG filgarstim, PEG-INTRON®, PEG-Asparaginase, PEMETREXED, Pentostatin, Phenylalanine Mustard, Paltinol®, PaltinolAQ®, Prednisolone, Prednisone, Prelon®, Procarbazine, PROCRIT®, Proleukin®, Prolifeprospan 20 Implant with Carmustine, Purintol®, Raloxifene, Revlimid®, Reumatrex®, Rituxan®, Rituximab, Roferon-A® (Interferon alfa-2a), Romiplostim, Rubex®, Rubidomycin Hydrochloride, Sandostatin®, Sandostatin LAR®, Sargramostim, Solu-Cortef®, Solu-Medrol®, Sorafenib, Sprycel®, STI-571, Streptozo cin, SU11248, Sunitinib, Sutent®, Tamoxifen, Tarceva®, Targretin®, Tasigna®,

- 69 041983

Taxol®, Taxotere®, Temodar®, Temozolomide, Temsirolimus, Teniposide, TESPA, Thalidomide, Thalomid®, TeraCis®, Thioguanine, Thioguanine Tabloid®, Thiophosphoamide, Thioplex®, Thiopepa, TICE®, Toposar®, Topotecan, Toremifene, Torisel® , Tositumomab, Trastuzumab, Treanda®, Tretinoin, Trexall®, Trizenox®, TSPA, TYKERB®, VCR, Vectibix®, Velban®, Velkad®, Vepezid®, Vesanoid®, Viadur®, Vidaza®, Vinblastine, Vinblastine sulfate, Vinkasar PFS®, Vincristine, Vinorelbine, Vinorelbine tartrate, VLB, VM-26, Vorinostat, Votrient, VP-16, Vumon®, Xeloda®, Zanosar®, Zevalin®, Zinecard®, Zoladex®, Zoledronic acid, Zolinza, Zometa® or combinations of any of the above. In some embodiments, an immuno-oncological agent may be administered together with a compound as described herein to treat a proliferative disorder as described herein. As used herein, the term immuno-oncological agent refers to an agent that is effective in improving, stimulating and/or activating an immune response in a subject. In some embodiments, administration of an immuno-oncological agent together with a compound of the present disclosure has a synergistic effect in the treatment of cancer. In some embodiments, a compound as described herein is administered sequentially prior to administration of the immuno-oncological agent. In some embodiments, a compound of the present disclosure is administered concurrently with an immuno-oncological agent. In some embodiments, a compound as described herein is administered sequentially after administration of an immuno-oncological agent.

In some embodiments, a compound as described herein may be co-formulated with an immuno-oncological agent. The immunooncological agent may be, for example, a small molecule drug, an antibody, or a biological agent, or a small molecule. Examples of biological immuno-oncological agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody.

In some embodiments, the monoclonal antibody is humanized or human.

In some embodiments, the immuno-oncological agent is (i) an agonist of a stimulatory (including co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal in T cells, both of which lead to an increase in an antigen-specific T cell response. Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA) and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the TNF family of molecules that bind to recognized members of the TNF receptor family, which include CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL , BCMA, LTeR, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α/TNFe , TNFR2, TNFa, LTeR, lymphotoxin α1β2, FAS, FASL, RELT, DR6 , TROY, NGFR.

In some embodiments, the immuno-oncological agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate immune response.

In some embodiments, the combination of compounds of the present disclosure and an immuno-oncological agent may stimulate T-cell immune responses. In some embodiments, the immuno-oncological agent is: (i) a protein antagonist that inhibits T cell activation (e.g., immune checkpoint inhibitors), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG- 3, TIM-3, galectin 9, SEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1 and TIM-4; or (ii) a protein agonist that inhibits T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL , CD70, CD27, CD40, DR3 and CD28H. In some embodiments, the immuno-oncological agent is an inhibitory receptor antagonist on NK cells or an activating receptor agonist on NK cells. In some embodiments, the immuno-oncological agent is an immunoglobulin-like killer cell receptor (KIR) antagonist, such as lirilumab.

In some embodiments, the immuno-oncological agent is an agent that inhibits or reduces the number of macrophages or monocytes, including, but not limited to, colony stimulating factor 1 receptor (CSF-1R) antagonists, such as CSF1R antagonist antibodies, including RG7155 (WO11/70024 , WO11/107553, WO11/131407, WO13/87699, WO13/119716,

- 70 041983

WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).

In some embodiments, the immuno-oncological agent is selected from antagonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signal through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of antitumor T cells, agents that bypass certain immunosuppressive pathways within the tumor or microenvironment (eg, blocking inhibitory receptor binding (eg, PD-L1/PD-1 interactions), depleting or inhibiting regulatory T cells (eg, using anti-CD25 monoclonal antibodies (eg, daclizumab) or by depleting associated anti-CD25 antibody microbeads), inhibit metabolic enzymes such as IDO, or restore/prevent T cell energy or depletion), and agents that trigger innate immune activation and/or inflammation at tumor sites.

In some embodiments, the immuno-oncological agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is a CTLA-4 antibody antagonist. In some embodiments, the CTLA-4 antagonist antibody is EPBOI (ipilimumab) or tremelimumab.

In some embodiments, the immuno-oncological agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the immuno-oncological agent is an antibody, or an antigen-binding portion thereof, that specifically binds to programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is a PD-1 antibody antagonist. In some embodiments, the PD-1 antagonist antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In some embodiments, the immuno-oncological agent may be pidilizumab (CT011). In some embodiments, the immuno-oncological agent is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, referred to as AMP-224.

In some embodiments, the immuno-oncological agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is a PD-L1 antagonist antibody. In some embodiments, the anti-PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMC-936559 (WO2007/005874) and MCB0010718C (WO2013/79174).

In some embodiments, the immuno-oncological agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is a LAG-3 antagonist antibody. In some embodiments, the anti-LAG3 antibody is BMC-986016 (WO10/19570, WO14/08218), or IMP-731, or IMP-321 (WO08/132601, WO009/44273).

In some embodiments, the immuno-oncological agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is a CD137 agonist antibody. In some embodiments, the anti-CD137 antibody is urelumab or PF-05082566 (WO12/32433).

In some embodiments, the immuno-oncological agent is a GITR agonist. In some embodiments, the GITR agonist is a GITR agonist antibody. In some embodiments, the GITR antibody is BMC-986153, BMC-986156, TRX518 (WO006/105021, WO009/009116) or MK-4166 (WO11/028683).

In some embodiments, the immuno-oncological agent is an IDO antagonist. In some embodiments, the IDO antagonist is INCB-024360 (WO2006/122150, WO07/75598, WO08/36653, WO08/36642), indoxymod, or NLG-919 (WO09/73620, WO009/1156652, WO11/56652, WO12/142237 ).

In some embodiments, the immuno-oncological agent is an OX40 agonist. In some embodiments, the OX40 agonist is an OX40 agonist antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, the immuno-oncological agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an OX40 antagonist antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06/029879).

In some embodiments, the immuno-oncological agent is a CD40 agonist. In some embodiments, the CD40 agonist is a CD40 agonist antibody. In some embodiments, the immuno-oncological agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is a CD40 antagonist antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

In some embodiments, the immuno-oncological agent is a CD27 agonist. In some embodiments, the CD27 agonist is a CD27 agonist anti-body. In some embodiments, the CD27 antibody is varlilumab.

In some embodiments, the immuno-oncological agent is MGA271 (to

B7H3) (WO11/109400).

In some embodiments, the immuno-oncological agent is abagovomab, adecatumumab; афутузумаб, алемтузумаб, анатумомаб мафенатокс, аполизумаб, атезолимаб, авелумаб, блинатумомаб, ВМС-936559, катумаксомаб, дурвалумаб, эпакадостат, эпратузумаб, индоксимод, инотузумаба озогамицин, интелумумаб, ипилимумаб, изатуксимаб, ламбролизумаб, MED14736, MPDL3280A, ниволумаб, обинутузумаб, окаратузумаб, ofatumumab, olatatumab, pembrolizumab, pidyliz, rituximab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, the immuno-oncological agent is an immunostimulatory agent. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis can trigger activated tumor-reactive T cells, and have also been shown in clinical studies to induce a robust antitumor response in an increasing number of histological sections of tumors, including some types of tumors that traditionally not considered susceptible to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sc. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMC-936558) has shown the potential to improve overall survival in patients with renal cell carcinoma (RCC) who have disease progression occurred during, after, or before anti-angiogenic therapy.

In some embodiments, the immunomodulatory drug specifically induces apoptosis of tumor cells. Approved immunomodulatory drugs that may be used in the present invention include pomalidomide (Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenol mebutate (Picato®, LEO Pharma).

In some embodiments, the immuno-oncological agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-t (Provenge®, Dendreon/Valeant Pharmaceuticals), which is approved for the treatment of symptomatic or minimally symptomatic metastatic castration resistant prostate cancer (hormone refractory); and talimogen lagerparepvec (Imlidjik®, BioVex/Amgen, formerly known as T-VEC), a genetically engineered oncolytic viral therapy approved for the treatment of inoperable cutaneous, subcutaneous, and nodular lesions in melanomas. In some embodiments, the immuno-oncological agent is selected from an oncolytic viral therapy such as pexastimogen devacirevec (PexaBek/JX-594, SillaJen/formerly Jennerex Biotherapeutics), a vaccinia virus lacking thymidine kinase (TK) engineered to express GM-CSF in hepatocellular carcinoma (NCT02562755 ) and melanoma (NCT00429312); pelareoprep (Rheolizin®, Oncolytics Biotech), a respiratory enteric orphan virus (reovirus) variant that does not replicate in cells that are not activated by RAS in a variety of cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); squamous cell carcinoma of the head and neck (NCT01166542); pancreatic adenocarcinoma (NCT00998322) and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineered to express full-length CD80 and antibody fragments specific for the CD3 T-cell receptor protein in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirus engineered to express GM-CSF in melanoma (NCT03003676); and peritoneal disease, colorectal or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68/GLV-1h153, Genelux GmbH), vaccinia viruses engineered to express beta-galactosidase (beta-gal)/beta-glucuronidase or beta-gal/human sodium iodide symporter (hNIS), respectively, were studied with peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, in bladder cancer (NCT02365818).

In some embodiments, the immuno-oncological agent is selected from JX-929 (SillaJen/formerly Jennerex Biotherapeutics), a vaccinia virus lacking TK- and vaccinia growth factor, engineered to express a cytosine deaminase that is capable of converting the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos), protein-based immunotherapeutic agents targeting refractory RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5/3E2F-delta24-hTNFa-IRES-hIL20; and VSV-GP (ViraTherapeutics) vesicular stomatitis virus (VSV) engineered to express lymphocytic choriomeningitis virus (LCM virus) glycoprotein (GP), which can be further engineered to express antigens designed to enhance the antigen-specific response of CD8+ T cells.

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In some embodiments, the immuno-oncological agent is a T cell engineered to express a chimeric antigen receptor, or CAR. T cells engineered to express such a chimeric antigen receptor are referred to as CAR-T cells.

CARs have been designed to consist of binding domains that can be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell membrane antigens, fused to endodomains that represent the functional end of the T cell receptor (TCR), such as the CD3-zeta signaling domain from TCR, which are capable of generating an activation signal in T lymphocytes. When bound to an antigen, these CARs are inserted into endogenous signaling pathways in the effector cell and generate activating signals similar to those initiated by the TCR complex.

For example, in some embodiments, the CAR-T cell is one of those described in US Pat. a domain (such as a domain that binds to CD19) fused to an intracellular signaling domain of the T-cell zeta chain receptor complex (such as CD3 zeta) for antigen recognition. When expressed in T cells, CAR is able to redirect antigen recognition based on specificity for antigen binding. In the case of CD19, the antigen is expressed in malignant B cells. There are over 200 clinical trials currently underway using CAR-T for a wide range of indications.

[https://clinicaltrials.gov/ct2/resvrkts?term=chimeric+antigen+receptors&pg=1].

In some embodiments, the immunostimulatory agent is a retinoic orphan receptor γ (RORyt) activator. RORyt is a transcription factor with a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as the differentiation of natural subsets of immune cells that secrete IL-17, such as NK cells. In some embodiments, the RORYt activator is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

In some embodiments, the immunostimulatory agent is a toll-like receptor (TLR) agonist or activator. Suitable TLR activators include a TLR9 agonist or activator such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that is being studied in B-cell, follicular and other lymphomas (NCT02254772). TLR8 agonists or activators that may be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which is being studied in head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

Other immuno-oncological agents that may be used in the present invention include urelumab (BMC-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), anti-CD27 monoclonal antibody; BMC-986178 (Bristol-Myers Squibb), anti-OX40 monoclonal antibody; lirilumab (IPH2102/BMC-986015, Innate Pharma, BristolMyers Squibb), anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) anti-NKG2A monoclonal antibody; and ecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), anti-GITR monoclonal antibody.

In some embodiments, the immunostimulatory agent is selected from elotuzumab, mifamurtide, a toll-like receptor agonist or activator, and a RORYt activator.

In some embodiments, the immunostimulatory drug is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been clinically investigated as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, the IL-15 immunotherapeutic agent is heterodimeric IL-15 (hetIL-15, Novartis/Admune), a fusion complex consisting of a synthetic form of endogenous IL-15 complexed with a soluble IL-15 protein-binding alpha chain. IL-15 receptor (IL15:sIL15RA), which was studied in phase 1 clinical trials in melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Ne consumedicines, Inc.), NCT02544724 or NCT02542124. In some embodiments, the immuno-oncological agent is selected from those described in Jerry L. Adams ET. AL., Big opportunities for small molecules in immuno-oncology, Cancer Therapy 2015, Vol. 14, pages 603-622, the entire content of which is incorporated herein by reference. In some embodiments, the immuno-oncological agent is selected from the examples described in Table 1. 1 at Jerry L. Adams ET. AL. In some embodiments, the immuno-oncological agent is

- 73 041983 is a small molecule aimed at immuno-oncological target, selected from those shown in table. 2 at Jerry L. Adams ET. AL. In some embodiments, the immuno-oncological agent is a small molecular weight agent selected from those shown in Table. 2 in

Jerry L. Adams ET. AL.

In some embodiments, the immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, Small molecule immuno-oncology therapeutic agents, Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the entire content of which is incorporated herein by reference. In some embodiments, the immuno-oncological agent is an agent that targets pathways as described in Peter L. Toogood. In some embodiments, the immuno-oncological agent is selected from those described in Sandra L. Ross et al., Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing, PLoS ONE 12(8): e0183390, full content which is included in the present description by reference. In some embodiments, the immuno-oncological agent is a bispecific T cell recruiter (BiTE®) antibody construct. In some embodiments, the bispecific T cell recruiter (BiTE®) antibody construct is a CD19/CD3 bispecific antibody construct. In some embodiments, the bispecific T cell recruiter (BiTE®) antibody construct is an EGFR/CD3 bispecific antibody construct. In some embodiments, a bispecific T cell recruiter (BiTE®) antibody construct activates T cells. In some embodiments, the bispecific T cell recruiter (BiTE®) antibody construct activates T cells that secrete cytokines that induce increased expression of intercellular adhesion molecule 1 (ICAM-1) and FAS on neighboring cells (bystander cells). In some embodiments, a bispecific T cell recruiter (BiTE®) antibody construct activates T cells, resulting in induction of lysis of neighboring cells. In some embodiments, neighbor cells are located in solid tumors. In some embodiments, neighbor cells to be lysed are in proximity to BATE®-activated T cells. In some embodiments, the neighbor cells contain tumor-associated antigen (TAA) negative cancer cells. In some embodiments, the neighboring cells contain epidermal growth factor receptor (EGFR) negative cancer cells. In some embodiments, the immuno-oncological agent is an antibody that blocks the PD-L1/PD1 and/or CTLA4 axis. In some embodiments, the immuno-oncological agent is ex-vivo expanded tumor infiltrating T cells. In some embodiments, the immuno-oncological agent is a bispecific antibody construct or chimeric antigen receptor (CAR) that directly binds T cells to tumor-associated surface antigens (TAAs).

In some embodiments, a combination of 2 or more therapeutic agents may be co-administered with the compounds of the present invention. In some embodiments, a combination of 3 or more therapeutic agents may be co-administered with the compounds of the present invention. Other illustrative inhibitor agents of the present invention may also be combined and include, but are not limited to: vitamins and dietary supplements, cancer vaccines, neutropenia therapy (e.g., G-CSF, filgrastim, lenograstim), thrombocytopenia therapy (e.g., blood transfusion, erythropoietin), PI3 kinase (PI3K) inhibitors, MEK inhibitors, mTOR inhibitors, CPT1 inhibitors, AMPK activators, PCSK9 inhibitors, SREBP site 1 protease inhibitors, HMG CoA reductase inhibitors, antiemetics (eg, 5-HT3 receptor antagonists, antagonists dopamine, NK1 receptor antagonists, histamine receptor antagonists, cannabinoids, benzodiazepines or anticholinergics), Alzheimer's therapy such as Aricept® and Exelon®; therapies for Parkinson's disease such as LDOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexefendil and amantadine; agents for the treatment of multiple sclerosis (PC) such as interferon-beta (eg Avonex® and Rebif®), Copaxone® and mitoxantrone; asthma therapy such as albuterol and Singulair®; agents for the treatment of schizophrenia such as zyprexa, risperdal, seroquel and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, interleukin 1 receptor (IL-1 RA) antagonist, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalase; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinson's agents; agents for the treatment of cardiovascular diseases such as beta blockers, angiotensin converting enzyme (ACE) inhibitors, diuretics, nitrates, calcium channel blockers and statins, fibrates, cholesterol absorption inhibitors, bile acid sequestrants and niacin; agents for the treatment of liver diseases such as corticosteroids, cholestyramine, interferons and antiviral agents; agents for the treatment of blood disorders such as corticosteroids, antileukemic agents and growth factors; agents for treatment

- 74 041983 immunodeficiency disorders such as gamma globulin; and anti-diabetic agents such as biguanides (metformin, phenformin, buformin), thiazolidinediones (rosiglitazone, pioglitazone, troglitazone), sulfonylurea derivatives (tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide), meglitinides (repaglinide, nateglinide) , alphaglucosidase inhibitors (miglitol, acarbose), incretin mimetics (exenatide, liraglutide, taspoglutide), gastroinhibitory peptide analogs, DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin), amylin analogs (pramlintide), insulin and insulin analogs.

In some embodiments, the compounds of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with desensitizing agents, monoclonal or polyclonal antibodies, or siRNA-based drugs.

In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a compound of the present invention and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac (Lodin®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex ®), gold salts such as aurothioglucose (Solganal®), aurothiomalate (Myocrisin®) and auranofin (Ridaura®), D-penicillamine (Depen® or Kuprimin®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmun®), leflunomide (Arava®), and anti-TNF agents such as etanercept (Enbrel®), infliximab (Remicad®), golimumab (Simponi®), certolizumab regol (Cimzia®), and adalimumab (Humira®), anti-IL-G agents such as anakinra (Kineret®) and rilonacept (Arcalist®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®) , anti-T cell agents such as abatacept (Orencia®), anti-IL-6 agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezzmab, anticoagulants such as heparin (Calcinparin® or Liquemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron ( Lotronex®), lubiprostone (Amitiza®), laxatives such as magnesium suspension, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senekot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singular®, beta agonists -2 such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopen ex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanseril®), triamcinolone acetonide (Azmacort®), momentazone (Astmanex®), budesonide (Pulmocort®) and flunisolide (Aerobid®), Afviar ®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (TeoDur®, Theolair®, Slo-bid®, Unifil®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab ( Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine (Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva ®), lamivudine (Epivir®), lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Givid®), non-nucleoside agents reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramun®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir ( Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir ( Fortovase® or Invirase®) and tipranavir (Aptivus®), cell entry inhibitors such as enfuvirtide (Fuseon®) and maraviroc (Selzentri®), integrase inhibitors such as raltegravir (Izentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velkad®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®), or any combination(s) thereof. In some embodiments, the present compound is administered in combination with an antiviral agent, including, for example, acyclovir, penciclovir, cidofovir, idoxuridine, zidovudine, ribavirin, amantadine, foscarnet, didanosine, acyclovir, ganciclovir, cidofovir, zalcitabine, rimantadine, calaciclovir, famciclovir , abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine, zidovudine lamivudine, TRIZIVIR (zidovudine, lamivudine, abacavir), EPZICOM (abacavir-lamivudine), TRUVA

- 75 041983

YES (tenofovir-emtricitabine), efavirenz, nevirapine and delavirdine, amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir-ritonavir, nelfinavir, ritonavir, saquinavir and tipranavir. In some embodiments, the antiviral agents are an anti-influenza agent, including, for example, rimantadine, amantadine, oseltamivir, and zanamivir. These additional agents may be administered separately from the composition containing the compounds of the present invention, as part of a multiple dosing regimen. Alternatively, these agents may be part of a unit dosage form, combined together with the connection according to the present invention in a single composition. When administered as part of a multiple dosing regimen, the two active agents may be administered simultaneously, sequentially, or timed apart from each other, typically five hours apart from each other.

In the context of the present description, the terms combination, combined and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with the present invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a unit dosage form. Accordingly, the present invention provides a unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of both the proposed compound and the additional therapeutic agent (in those compositions containing the additional therapeutic agent as described above) that can be combined with carriers to form a unit dosage form may vary depending on the subject receiving treatment and the specific mode of administration. . Preferably, the compositions of the present invention should be formulated so that a dose of the invention of 0.01-100 mg/kg body weight/day can be administered.

In said compositions which contain an additional therapeutic agent, said additional therapeutic agent and the compound of the present invention may act synergistically. Thus, the amount of additional therapeutic agent in such a composition will be less than what would be needed for monotherapy using that therapeutic agent alone. In such a composition, a dose of 0.01-100 μg/kg body weight/day of the additional therapeutic agent may be administered.

The amount of additional therapeutic agent present in a composition according to the present invention will be no more than the amount that is usually administered in compositions containing this therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the composition disclosed in the present invention will be in the range from about 50% to 100% of the amount normally present in a composition containing this agent as the sole therapeutic active agent.

In one embodiment, the present invention provides a composition comprising a compound of the present invention and one or more additional therapeutic agents. The therapeutic agent may be co-administered with a compound of the present invention, or may be administered before or after administration of a compound of the present invention. Suitable therapeutic agents are described in more detail below. In some embodiments, a compound of the present invention may be administered within 5, 10, 15, 30 minutes, 1 hour, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, or 18 hours before the therapeutic agent. In other embodiments, a compound of formula I' may be administered within 5, 10, 15, 30 minutes, 1 hour, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17 or 18 hours after the therapeutic agent.

In some embodiments, the present invention provides a medicament comprising at least one compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Examples

As shown in the examples below, in some exemplary embodiments, compounds are prepared according to the following general procedures. It should be understood that although the general methods reflect the synthesis of certain compounds according to the present invention, the following general methods and other methods known to the person skilled in the art can be applied to all compounds, as well as subclasses and forms of each of these compounds described in this description.

Example 1A.

DRE analysis of the luciferase reporter gene.

AHR binds to dioxin responsive elements (DRE) upstream of the genes it activates. One measure of AHR activity is the activation of a reporter gene, such as the luciferase gene, downstream of one or more DRE elements. Luciferase activity will reflect the activation and inhibition of AHR in cells expressing its reporter.

- 76 041983

A mouse cell line, Hepa1-6 or Hepa-1c1c7, or another mouse cell line with a DRE-luciferase reporter, either stably or transiently transfected, was plated in media in plates (96-well, 384-well, or other plates) and incubated overnight at 37 °C in a CO ₂ incubator. Similarly, a human cell line HepG2 or another human cell line with a DRE-luciferase reporter, stably or transiently transfected, was plated in medium in plates (96-well, 384-well or other plates) and incubated overnight at 37°C in CO ₂ - incubator.

The next day, an AHR activating ligand such as TCDD, kynurenine, ITE (2(1H-indol-3-ylcarbonyl)-4-thiazolecarboxy methyl ester), VAF347, BNF (betanaphthoflavone), FICZ (6-formylindolo(3, 2-b) carbazole) or other AHR ligands, with or without an AHR antagonist.

Cells were incubated for 4, 15, or 24 hours, or other times, and then lysed to determine luciferase activity as a measure of AHR activation or inhibition. Luciferase was determined using a commercial kit, such as the Promega Luciferase kit, or any kit or reagents that provide a luciferin substrate for determining luciferase activity. The level of luciferase with the addition of only the activating ligand corresponded to the maximum signal, while the luciferase without the ligand corresponded to the minimum signal. IC ₅₀ values were defined as the concentration that inhibits half of the luciferase activity. The analyzed compounds and their IC ₅₀ values are shown in Table 1. 2 below.

In some embodiments, the compounds have IC ₅₀ values in the range of 5-20 μM. In some embodiments, the compounds have IC ₅₀ values < 5 μM. In some embodiments, the compounds have IC ₅₀ values < 1 μM. In some embodiments, the compounds have IC50 values < 0.1 μM. In some embodiments, the compounds have IC50 values < 0.01 μM. In some embodiments, the compounds have IC50 values < 0.001 μM.

The activity of certain compounds according to the present invention, obtained as a result of the analysis of the above method, is presented in table. 2 below. in table. 2 IC ₅₀ values are presented as A, B, C and D, where A is IC ₅₀ < 0.5 μM; B represents the range of IC ₅₀ from 0.5 to 1.0 μm; and C is an IC ₅₀ range of 1.0 to 1.5 μM; and D is IC ₅₀ >1.5 μM.

table 2

IC ₅₀ values for selected compounds analyzed according to example 1A

Example 1B.

DRE analysis of the luciferase reporter gene (alternative method).

AHR binds to dioxin-responsive elements (DREs) located upstream of the genes it activates. One measure of AHR activity is the activation of a reporter gene, such as the luciferase gene, downstream of one or more DRE elements. Luciferase activity will reflect the activation and inhibition of AHR in cells expressing its reporter. A mouse cell line, Hepa1-6 or Hepa-1c1c7, or another mouse cell line with a DRE-luciferase reporter, stably or transiently transfected, was plated in medium in plates (96-well, 384-well or other plates) and incubated overnight at 37°C. in a CO2 incubator, or the compound and agonist were added at the time of inoculation. Similarly, a human HepG2 cell line or another human cell line with a DRE-luciferase reporter, stably or transiently transfected, was plated in medium in plates (96-well, 384-well or other plates) and incubated overnight at 37°C in CO ₂ incubator, or compound and agonist were added at the time of inoculation.

An AHR activating ligand such as TCDD, kynurenine, ITE (2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxy methyl ester), VAF347, BNF was added at the time the cells were seeded or after overnight incubation. (beta-naphthoflavone), FICZ (6-formylindolo(3,2-b)carbazole), or other AHR ligands, with or without an AHR antagonist.

Cells were incubated for 4, 15, or 24 hours or other time and then lysed

- 77 041983 to determine the activity of luciferase as a registered indicator of activation or inhibition of AHR. Luciferase was determined using a commercial kit, such as the Promega Luciferase kit, or any kit or reagents that provide a luciferin substrate for determining luciferase activity. The level of luciferase with the addition of only the activating ligand corresponded to the maximum signal, while the luciferase without the ligand corresponded to the minimum signal. IC ₅₀ values were defined as the concentration that inhibits half of the luciferase activity. The studied compounds and their IC ₅₀ values are shown in Table 1. 3 below.

In some embodiments, the compounds have IC ₅₀ values of 5-20 μM. In some embodiments, the compounds have IC ₅₀ values < 5 μM. In some embodiments, the compounds have IC ₅₀ values < 1 μM. In some embodiments, the compounds have IC ₅₀ values < 0.1 μM. In some embodiments, the compounds have IC ₅₀ values < 0.01 μM. In some embodiments, the compounds have IC ₅₀ values < 0.001 μM.

The activity of certain compounds according to the present invention, obtained as a result of the analysis of the above method, is presented in table. 3 below. In table. 3 IC ₅₀ values are presented as A, B, C and D, where A is IC ₅₀ < 0.5 μM; B represents the range of IC ₅₀ from 0.5 to 1.0 μm; and C is an IC ₅₀ range of 1.0 to 1.5 μM; and D is IC ₅₀ >1.5 μM.

Table 3

IC ₅₀ values for selected compounds analyzed according to Example 1B

Compound 1C ₅₀ Compound 1С ₅ 0 1-1 A 1-58 D 1-2 A 1-59 A 1-3 A 1-60 IN 1-4 A 1-61 A 1-5 A 1-62 A 1-6 A 1-63 A 1-7 D 1-64 A 1-8 D 1-65 A 1-9 IN 1-66 A 1-10 D 1-67 A 1-11 A 1-68 IN 1-13 D 1-69 A 1-14 D 1-70 A 1-15 A 1-71 A 1-16 A 1-72 A 1-19 A 1-73 A 1-20 A 1-74 IN 1-21 A 1-75a D 1-22 A 1-75b D 1-23 A 1-77 A 1-24 D 1-78 A 1-25 D 1-79 A 1-26 D 1-80 IN 1-27a IN 1-81 A 1-28a D 1-82b D 1-29 D 1-83 A 1-30 A 1-84 D 1-31 D 1-85 IN 1-32a D 1-86 A 1-33 A 1-87 A 1-34 D 1-88 IN 1-35 D 1-89 A 1-36 D 1-90 A 1-37a D 1-91 A 1-38 D 1-92 A 1-39 A 1-93 A 1-40 A 1-94a D 1-41 D 1-95 D 1-42a D 1-96 A 1-43 IN 1-97a D 1-44 D 1-98a D 1-45 A 1-99 A 1-46 A 1-100 D

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1-47 A 1-101 A 1-48 A 1-102 A 1-49 A 1-103 A 1-50 D 1-104 IN 1-51 A 1-105 A 1-52 IN 1-106 A 1-53 A 1-107 A 1-54 A 1-108 A 1-55 A 1-109 A 1-56 A 1-110 IN 1-57 A 1-111 A 1-120 D 1-185 D 1-121 D 1-186 IN 1-122 D I-187a D 1-123 C I-187b D 1-124 D 1-125 D 1-189 D 1-126 A I-190a D I-128a D I-190b D I-128b D 1-192 IN 1-129 A 1-193 D 1-130 A 1-194 D 1-131 A 1-195 D 1-132 IN 1-196 A 1-133 A 1-197 A 1-134 D I-198a A 1-135 A I-198b IN 1-136 A 1-200 A I-137a A 1-201 A I-137b A 1-202 A I-139a A 1-203 A I-139b A I-204a A 1-141 A I-204b A 1-142 D 1-206 D 1-143 D 1-207 D I-144a C 1-208 D I-144b A 1-209 IN I-146a D 1-210 C I-146b D 1-211 D 1-148 D 1-212 D 1-149 D 1-213 A I-150a A 1-214 A I-150b C 1-215 D I-152a D I-216a IN I-152b A I-216b D

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1-154 A 1-218 A 1-155 IN 1-219 A 1-156 D 1-220 A 1-157 D 1-221 D 1-158a D 1-222a A 1-158b D 1-222b A 1-160a D 1-224 A 1-160b D 1-225 A 1-162 A 1-226 A 1-163 A 1-227 A 1-164 A 1-228 D 1-165 A 1-229 D 1-166 A 1-230 A 1-167 D 1-231 D 1-168 D 1-232 A 1-169 IN 1-233 IN 1-170 D 1-234 IN 1-171 WITH 1-235 A 1-172 WITH 1-236 D 1-173 D 1-237 A 1-174 D 1-238 D 1-175 D 1-239 D 1-176 D 1-240 D 1-177 A 1-241 A 1-178 D 1-242 A 1-179 A 1-243a D 1-180 IN 1-243b D 1-181 D 1-245 D 1-182 D 1-246 WITH 1-183 D 1-247 D 1-184 D 1-248 D 1-249a A 1-249b A 1-250 D 1-251 D 1-252a A 1-252b A 1-253 A 1-254 D 1-255 A 1-256 A 1-257 A 1-258 D 1-259a A 1-259b A 1-260 D 1-261 D 1-262 A 1-263a WITH 1-263b WITH 1-264 D 1-265 A 1-266 D 1-267 A 1-268 D 1-269 D 1-270 A 1-271 D 1-272 D 1-273 WITH 1-274 A 1-275 A 1-276 A 1-277 A 1-278 A 1-279 D 1-280 D 1-281 A 1-282 A 1-283 D 1-284 IN 1-285 D 1-286 A 1-287 D 1-288 A 1-289 A

Example 1C.

Pharmacokinetic study in mice.

The compositions of the compounds presented in table. 4 was administered intravenously or orally via gavage to CD-I mice. Typically, at 0.167, 0.5, 1, 2, 4, 6, 12, and 24 hours post-dose, blood was collected and processed to plasma by centrifugation and stored at -80°C until analysis.

An internal standard was added to each sample, followed by protein precipitation with acetonitrile. The precipitates were filtered through a Phree phospholipid removal filter plate and the resulting samples were analyzed by LC/MS/MS. Standard curve solutions were prepared in plasma, typically from 1.0 ng/mL to 3000 ng/mL, and processed in the same manner as the samples. Sample analysis was typically performed on a suitable LC/MS/MS system equipped with an analytical column for UPLC, and compounds were eluted from the analytical column with a gradient of 30-95% 0.1% formic acid (v/v) in ACN: 0. 1% formic acid (v/v) in water. Mass spectrometric detection of the test compound and internal standard was carried out using MRM in the mode of detecting positively charged ions. The pharmacokinetics of each compound was analyzed using Phoenix WinNonlin software (Pharsight, St. Louis, MO, USA) using non-compartmental analysis. The results are presented in table. 4 below.

Table 4

Pharmacokinetic data in mice according to example 1C

Connection Dose (mg/kg) Route of entry Compound Stax (ng/ml) Ttah (h) J1/2 (h) Vdss (l/kg) C1 (ml/mi n/kg) last (h) end tration/time AUC O-last AUC 0-inf (ng*h/ml) Biodo step (%) (ng*h/ml) 1-137a 3 i/v 1.5 mg/ml in dmsoleg 400:water=5:75:20, solution 8.2 6.6 25 24 1921 2008 1-137a thirty By 3 mg/ml in 0.5% methylcellulose and 0.2% Tween 80, suspension 953 0.5 3.5 24 3782 3835 19 1-137b 3 i/v 1.5 mg/ml in dmsoleg 400:water=5:75:20, solution 11.2 16.6 37 24 1220 1352 1-137b thirty By 3 mg/ml in 0.5% methylcellulose and 0.2% Tween 80, suspension 476 2 5.9 24 3630 3828 28 1-144b thirty By 1.5 mg/ml in dmsoleg 400:water=5:75:20, solution 1.3 0.8 44 6 1140 1145 1-144b thirty By 3 mg/ml in 0.5% methylcellulose and 0.2% Tween 80, suspension 599 0.2 2 6 613 727 6 1-154 3 i/v 1.5 mg/ml in dmsoleg 400:water=5:75:20, solution 12 13.7 16.5 24 2414 3034 1-154 thirty By 3 mg/ml in 0.5% methylcellulose and 0.2% Tween 80, suspension 840 2 9.6 24 9358 11207 39 1-198a 3 i/v 1.5 mg/ml in dmsoleg 400:water=5:75:20, solution 4.3 12.1 64.8 24 765 772 1-198a thirty By 3.00 mg/ml in 0.5% methylcellulose, suspension 721 1 4.2 24 3961 4048 52 1-201 3 i/v 1.5 mg/ml in dmsoleg 8.52 19.6 37.5 24 1203 1334

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400:water=5:75:20, solution 1-201 thirty n/o 3.0θ mg/mL in 0.5% methylcellulose, suspension 1413 1 7.16 24 9653 10558 79 1-203 3 b/b 1.5 mg/ml in dmsoleg 400:water=5:75:20, solution 2.3 5.8 88.5 12 555 565 1-203 thirty n/o 3.00 mg/ml in 0.5% methylcellulose, suspension 604 0.2 0.7 6 656 657 12 I-204b 3 b/b 1.5 mg/ml in DMSOLEG 400: water=5: 75:20, solution 0.9 4 110 6 454 455 I-204b thirty n/o 3.00 mg/ml in 0.5% methylcellulose, suspension 55 0.2 3.2 12 63 67 2 1-219 3 b/b 1.5 mg/ml in dmsoleg 400:water=5:75:20, solution 0.7 2.4 73.3 6 678 682 1-219 thirty n/o 3.00 mg/mL in 30% PEG400/10% Solutol/60% water, suspension 48.9 0.2 12 132 215 2 I-222a 3 b/b 1.5 mg/ml in dmsoleg 400:water=5:75:20, solution 2.4 1.5 36.9 6 1329 1329 I-222a thirty n/o 3.00 mg/mL in 30% PEG40 0/10% Solutol/60% water, solution 2873 0.2 1.7 12 2231 2239 16 I-222b 3 b/b 1.5 mg/ml in dmsoleg 400:water=5:75:20, solution 1.8 2 88.1 6 564 567 I-222b thirty n/o 3.00 mg/mL in 30% PEG40 0/10% Solutol/60% water, solution 2167 0.2 3.3 24 2865 2870 51 1-39 3 b/b 1.5 mg/ml in dmsoleg 400:water=5: 1.31 3.5 53.7 6 908 931

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75:20, solution 1-39 thirty n/o 3.00 mg/ml in dmsoleg 400:water=5:75:20 solution 799 3.35 24 1597 1609 17 1-40 3 b/b 1.5 mg/ml in DMSOLEG 400: water=5: 75:20, solution 8.4 24 41.2 24 1066 1213 1-40 thirty n/o 3.00 mg/mL in 30% PEG40 0/10% Solutol/60% water, solution 853 2 8.8 24 7560 9142 75 1-65 3 b/b 1.5 mg/ml in dmsoleg 400:water=5:75:20, solution 0.7 2.7 93.1 4 522 537 1-65 thirty n/o 3.00 mg/ml in DMSOLEG 400:water=5:75:20 solution 574 0.2 0.8 6 370 373 7 1-70 3 b/b 1.5 mg/ml in dmsoleg 400:water=5:75:20, solution 1.08 3.2 54.9 6 862 872 1-70 thirty n/o 10.0 mg/ml in 30% PEG/70% (20% hp-?-CD) solution, clear solution 900 0.5 2.26 12 1944 1993 26 1-73 3 b/b 1.5 mg/ml in dmsoleg 400:water=5:75:20, solution 2 7.7 90 12 553 556 1-73 thirty n/o 3.00 mg/ml in 0.5% methylcellulose, suspension 37.5 1 2.1 6 24 96 108 2 I-75a 3 b/b 1.5 mg/ml in dmsoleg 400:water=5:75:20, solution 13.8 13.7 14.4 24 2666 2265 I-75a thirty n/o 3.0 mg/ml in dmsoleg 400:water=5:75:20, solution 969 2 9.8 24 13579 936 51 1-103 3 b/b 3.00 mg/ml in 40% PEG40 0.62 1.4 43.9 6 1137 1140

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0/10% SOLUTOL /50% water, solution 1-103 thirty n/o 6.00 mg/ml in 40% PEG40 0/10% SOLUTOL /50% water, solution 713 0.2 2.15 12 649 671 6 1-107 3 b/b 3.00 mg/ml in DMSO: solyutol: water = 5:10:85, solution 2.18 43.2 540 6 88 92 1-107 15 n/o 3.00 mg/ml in DMSO: solyutol: water = 5:10:85, solution 0 0 0 0 0 0 1-2 3 b/b 3.00 mg/ml in DMSO PEG 400:water=5:75:20 solution 1.99 9.6 82 6 554 610 1-2 thirty n/o 6.00 mg/ml in DMSO PEG 400:water=5:75:20 solution 182 0.2 3.9 24 730 743 12 I-259a 3 b/b 1.5 mg/ml in DMSO PEG 400:water=5:75:20, clear solution 1.2 4.7 59 6 825 842 I-259a thirty n/o 3.0 mg/ml in 0.5% methylcellulose, homogeneous opaque suspension 82 0.5 1.2 6 237 249 3 1-118 3 b/b 1.5 mg/ml in DMSO PEG 400:water=5:75:20, clear solution 0.6 4.9 136 4 364 368 1-118 thirty n/o 3.0 mg/ml in 0.5% methylcellulose, homogeneous opaque suspension 41 1 1.9 6 107 121 3 1-126 3 b/b 1.5 mg/ml in DMSO PEG 400:water=5:75:20, 8.8 17 thirty 24 1463 1651

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clear solution 1-126 thirty By 3.0 mg/ml in 0.5% yulose methylcell, homogeneous opaque suspension 1870 1 6.1 24 13748 14741 100 1-129 3 i/v 1.5 mg/ml in DMSO PEG 400:water=5:75:20, clear solution 14 22 31 24 1339 1615 1-129 thirty By 3.0 mg/ml in 0.5% yulose methylcell, homogeneous opaque suspension 1043 2 6.4 24 7034 7532 53 1-130 3 i/v 1.5 mg/ml in DMSO PEG 400:water=5:75:20, clear solution 2.6 7.5 39 12 1223 1272 1-130 thirty By 3.0 mg/ml in 0.5% yulose methylcell, homogeneous opaque suspension 936 2 3.5 24 6624 6689 53 1-59 3 i/v 1.5 mg/ml in DMSO PEG 400:water=5:75:20, clear solution 6.6 11.2 53 24 925 949 1-59 thirty By 3.0 mg/ml in 0.5% methylcellulose, homogeneous opaque suspension 719 0.5 4.3 24 2110 2130 22

Example 1D.

Metabolic stability analysis in S9 mouse liver in vitro.

CD-1 mouse liver S9 were purchased from Corning, or XenoTech LLC, or BioreclamationIVT, LLC, or obtained from WuXi. Until use, the cells were stored at -80°C in a freezer. β-Nicotinamide adenine dinucleotide phosphate (NADP), glucose-6-phosphate (G6P), glucose-6-phosphate dehydrogenase from yeast (G6PDH), uridine-5'-diphosphoglucuronic acid trisodium salt (UDPGA), and adenosine-3'-phosphate-5'-phosphosulfate lithium salt hydrate (PAPS) were commercially available from Sigma. Compounds were diluted in DMSO to give a 10 mM stock solution. 5 µl of this stock solution (10 mM, DMSO) was diluted with 45 µl DMSO and 450 µl 50% methanol/water to give an intermediate solution (100 µM, 45% MeOH, 10% DMSO). 50 μl of the intermediate solution was diluted with 450 μl of 100 mM phosphate buffer to obtain the final solution (10 μm, 4.5% MeOH, 1% DMSO). 10 μl of the final solution was added to 90 μl of liver S9 system (1 μM final concentration, 0.45% MeOH, 0.1% DMSO).

Test compounds were incubated at 37°C with liver S9 (combined from multiple donors) at 1 μM in the presence of NADPH, UDPGA and PAPS regeneration system at 1 mg/mL S9 protein. Samples corresponding to time points (0 and 60 minutes) were taken and immediately mixed with cold acetonitrile containing an internal standard (from the English internal standard, BC). The samples were analyzed by LC/MS/MS and the disappearance of the test compounds was estimated based on the ratios of the peak areas of the analyzed compound/BC (no calibration curve). All samples were injected and analyzed using LC-MS/MS. The analyte/internal standard peak area ratios were converted to the percentage remaining (% remaining) using the following equation: % remaining at 60 min = (analyte to BC peak area ratio at 60 min / analyte to BC peak area ratio at t = 0)x100%. The results are presented in table. 5 below.

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Table 5

Mouse Stability Data According to Example 1D

Compound Stability in S9 mouse: % remaining after 60 minutes Compound Stability in S9 mouse: % remaining after 60 minutes 1-6 0 1-40 87 1-2 13 1-39 thirty 1-4 0 1-36 29 1-21 26 1-30 AND 1-16 2 1-235 2 1-109 10 1-224 0 1-107 0 1-222b 0 1-106 1 1-222a 1 1-105 8 1-219 5 1-103 7 1-214 0 1-101 1 1-209 0 1-98b 0 1-208 0 1-96 36 1-204b 0 1-92 0 1-203 0 1-90 And 1-202 0 1-81 2 1-201 34 1-78 1 1-200 0 1-75a 65 1-198a thirty 1-73 eleven 1-196 0 1-72 3 1-177 2 1-70 0 1-166 4 1-68 4 1-165 3 1-67 5 1-164 0 1-67 1 1-162 54 1-65 0 1-156 28 1-59 AND 1-154 13 1-47 50 1-152b 3 1-45 19 1-152a 2

Example 1E.

Cyp1a1 modulation analysis of mouse liver and spleen in vivo.

C57BL/6 mice, female, 6-8 weeks old, weighing approximately 18-20 g, were purchased from Shanghai Lingchang Biological Technology Co., Ltd or other certified suppliers and used in the studies. The conditions of keeping, food and state of health comply with the rules for keeping animals. VAG539 (30 mg/kg, po) was used as the AHR agonist and test compounds were formulated in suitable vehicles, typically 0.5% methylcellulose.

C57BL/6 mice (n=3 per group) were treated with AHR agonist or AHR agonist alone and test compounds. Animals were sacrificed 4 or 10 hours after administration, after which their livers and spleens were collected and then analyzed by qPCR. The normalized fold of Cyp1a1 induction was determined by comparing the amount (ct) of mCYP1A1 and mGAPDH according to: normalized fold = 2' ^ΔΔα . Percent inhibition was calculated according to:

mean normalized fold for agonist administration | AHR and connections $। ~ ....................................... । $ s % inhibition | mean normalized fold for agonist administration | ⁴ AHR

The results are shown in table. 6 below.

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Table 6

Cyplal inhibition data according to example 1E

Compound Dose Inhibition of Cvplai Liver Spleen 4h 10 h 4 h 1-2 30 mg/kg 50% 1-103 30 mg/kg 94% 0% 1-75a 30 mg/kg 55% 1-57 30 mg/kg 77% 66% 1-46 30 mg/kg 96% 94% 1-39 30 mg/kg 90% 69% 1-70 30 mg/kg 98% 10 mg/kg 99% 81% 10 mg/kg 98% 98% 88% 5 mg/kg 93% 96% 79% 2 mg/kg 83% 63% 65% 1 mg/kg 52% 34% 38% 1-40 25 mg/kg 98% 97% 96% 10 mg/kg 93% 75% 74% 5 mg/kg 77% 48% 34% 1-201 25 mg/kg 86% 97% 72% 10 mg/kg 72% 59% 46% 5 mg/kg 58% 44% 40%

Example 1F.

T cell study using I-70.

Human T cells were isolated by CD3-negative selection after isolation of PBMCs from blood of human donors by Ficoll density gradient centrifugation. One million T cells were activated with 25 μl of CD3/CD28 tetramer (Stemcell) in the presence or absence of I70 for 24 h, after which the medium was removed and stored at -80°C for subsequent cytokine analysis. The cells were then washed twice with PBS before RNA isolation according to the manufacturer's instructions for the RNAeasy mini kit (Qiagen).

Based on RNA, cDNA was prepared using a VTLO-IV RT mastermix (Thermofisher) and a quantitative reverse transcription polymerase chain reaction (q-RT-PCR) was performed to determine the levels of IL-22 (Hs01574154_m1), Cyp1a1 (Hs01054797_g1) and GAPDH (Hs00266705_g1) . The data were analyzed using the ddCT method, whereby each sample is first normalized to the constitutive GAPDH gene and then normalized to a control sample. IL-22 and cyp1a1 RNA expression levels are reduced by treatment with I-70 as shown in FIG. 1. Cytokine levels were determined using a mesoscale discovery platform (MSD) (K15067L-2) and MSD analysis software according to the manufacturer's instructions. Upon treatment with I-70, IL-22 protein levels decrease and pro-inflammatory IL-2 protein levels increase, as shown in FIG. 2.

CD3/CD28-activated T cells are activated by AHR, as determined by gene expression and cytokine production. Treatment with an AHR inhibitor leads to inhibition of the expression of the cyp1a1 and IL-22 genes and the production of the cytokine IL-22. Inhibition of AHR also increases the production of the pro-inflammatory cytokine IL-2.

Example 1G.

Study of the efficacy of I-70 and an anti-PD-1 checkpoint inhibitor in the CT26 mouse colorectal cancer model in Balb/c mice.

CT26 is a mouse colon carcinoma cell line derived from ATCC. CT26 cells were cultured in RPMI supplemented with 10% FBS. 5x10 5 CT26 cells in 100 μl PBS were subcutaneously implanted in Balb/c female mice aged 6-8 weeks. The introduction for the study of efficacy begins 4 days after implantation: AHR antagonist was administered orally every day (QD) at a dose of 10 mg/kg for 3 weeks. Anti-PD-I (BioXcell RMP1-14) was administered twice a week, intraperitoneally (ip) at a dose of 10 mg/kg, in a total of five doses. Tumors were monitored by measuring with a caliper every 2-3 days, and body weight was measured three times a week. Tumor growth is inhibited by AHR I-70 antagonist alone or in combination with anti-PD-1, as shown in FIG. 3. Tumor growth inhibition is statistically significant for I-70 alone versus vehicle with a p-value of 0.0166. In addition, tumor growth inhibition in the combined group was significant compared to anti-PD-1 alone, p-value = 0.0420. p-values were determined by analysis with Student's t-test.

Example 1H.

Efficacy Study of I-70 and Anti-PD-1 Checkpoint Inhibitor in a Melanoma Model

- 87 041983 B16-IDO mice in C57BL/6 mice.

B16-IDO is a mouse melanoma cell line that has been designed to overexpress IDO1 (Holmgaard, 2015 Cell Reports). B16-IDO cells were cultured in DMEM supplemented with 10% FBS. 2x105 B16-IDO cells in 50 µl PBS were intradermally implanted in female C57BL/6 mice aged 6-8 weeks. Administration for efficacy studies was started 7 days after implantation: AHR antagonist I-70 was administered orally every day (QD) at a dose of 10 mg/kg for 2 weeks. Anti-PD-I (BioXcell RMP1-14) was administered every 3 days, intraperitoneally (ip) at a dose of 250 μg/mouse, in a total of five doses. Tumors were monitored by measuring with a caliper every 2-3 days, and body weight was measured three times a week.

Tumor growth was inhibited by the AHR I-70 antagonist alone or in combination with anti-PD-1, as shown in FIG. 4. Tumor growth inhibition was statistically significant for I-70 alone versus vehicle with a p-value of <0.001. In addition, tumor growth inhibition in the combined group was significant compared to anti-PD-1 alone, p-value <0.03. p-values were determined by analysis with Student's t-test.

Example 2

AHR-dependent gene expression.

Mouse Hepa1-6 or Hepa-1e1c7 or another mouse cell line is plated on medium in plates (6-well, 12-well or other plates) and incubated overnight at 37° C. in a CO ₂ incubator; or a human HepG2 or other human cell line is plated on medium in plates (6-well, 12-well or other plates) and incubated overnight at 37° C. in a CO ₂ incubator. The next day, an AHR activating ligand such as TCDD, kynurenine, ITE (2-(1Nindol-3-ylcarbonyl)-4-thiazolecarboxy methyl ester), VAF347, BNF (betanaphthoflavone), ICZ (6-formylindolo(3,2 -b) carbazole) or other AHR ligands, with or without an AHR antagonist. Cells are incubated for 4, 15, or 24 hours, or other length of time, and then the cells are lysed to obtain RNA. RNA can be obtained using an RNA isolation kit such as Qiagen or any other RNA isolation method. Gene expression is determined by quantitative RT-PCR using probes for specific genes, including constitutive genes such as Gapdh, β-actin, or other constitutively expressed genes for normalization. AHR dependent genes to be investigated include, but are not limited to: cyp1a1, cyp1b1, AHRR, IDO1, IDO2, cox2, IL6, VEGFA, cyelinD1, cdc2, MMP-9, c-myc.

Example 3

AHR-dependent gene expression is determined in tissue samples such as tumor or liver. The RNA is extracted from the tissue using methods such as an RNA isolation kit such as Qiagen or any other RNA isolation method known to one of skill in the art. RNA extraction can be performed from total cells or cells after sorting for specific cell populations such as tumor cells, tumor-associated T cells, tumor-associated myeloid cells, or others. Gene expression is determined by quantitative RT-PCR using probes for specific genes, including constitutive genes such as Gapdh, β-actin, or other constitutively expressed genes for normalization. AHR dependent genes to be investigated include, but are not limited to: cyp1a1, cyp1b1, AHRR, IDO1, IDO2, cox2, IL6, VEGFA, cyclinD1, cdc2, MMP-9, c-myc.

Example 4

Synthesis I-5

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Step 1: N-(2-(1H-indol-3-yl)ethyl)-2-chlorothieno[2,3-d]pyrimidin-4-amine

DIPEA (630.24 mg, 4.88 mmol, 849, 38 µl, 5.0 eq.) and 2-(1H-indol-3-yl)ethanamine (203.14 mg, 1.27 mmol, 1.3 eq.). The mixture was stirred at 50° C. for 3 hours. LC-MS indicated that the starting material had been completely consumed and one major peak with the desired MS was found. The reaction mixture was diluted with H ₂ O (15 ml) and extracted with DCM (15 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: gradient 20-30 % EtOAc/PE at a flow rate of 50 ml/min) to give 2-chloro-N-[2-(1H-indol-3-yl)ethyl]thieno[2,3-d]pyrimidin-4-amine (260 mg , 774.90 µmol, 79.4% yield) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 7.67 (d, J=7.9 Hz, 1H), 7.40-7.35 (m, 2H), 7.31 (d, J=8.2 Hz, 1H), 7.10-7.05 (m, 2H), 7.00-6.93 (m, 1H), 3.86-3.79 (m, 2H), 3.11 (t, J=7.4 Hz, 2H); ER-LCMS m/z 329.0, 331.0 [M+H]+.

Step 2: N-(2-(1H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)thieno[2,3-d]pyrimidin-4-amine (I-5)

To a solution of 2-chloro-N-[2-(1H-indol-3-yl)ethyl]thieno[2,3-d]pyrimidin-4-amine (100 mg, 298.04 µmol, 1 eq.) in 1 ,4-dioxane (3 ml) and H ₂ O (1 ml) was added (5-fluoro-3-pyridyl)boronic acid (75.59 mg, 536.47 μmol, 1.8 eq.), Cs ₂ CO ₃ (291.32 mg, 894.11 µmol, 3.0 eq.) and Pd(dppf)Cl ₂ (32.71 mg, 44.71 µmol, 0.15 eq.). The mixture was stirred at 120° C. while microwaved for 1 hour. LC-MS showed that the starting material had been completely consumed and one major peak with the desired MS was found. The reaction mixture was filtered. The filtrate was diluted with H ₂ O (15 ml) and extracted with EtOAc (15 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenomenex Kinetex XB-C18 150 mm x 30 mm, 5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 50%-75%, 12 min) and the desired fraction was lyophilized to give 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indole -3-yl)ethyl]thieno[2,3-d]pyrimidin-4-amine (54.40 mg, 109.05 µmol, 36.59% yield, 100% purity, 3HCl salt) as yellow solid .

1H NMR (400 MHz, CD3OD) δ ppm 9.19 (s, 1H), 8.84 (s, 1H), 8.58 (d, J=9.3 Hz, 1H), 7.63-7, 57 (m, 2H), 7.54 (d, J=5.7 Hz, 1H), 7.19 (d, J=7.7 Hz, 1H), 7.02-6.90 (m, 3H ), 4.08 (t, J=6.8 Hz, 2H), 3.19 (t, J=6.7 Hz, 2H); ER-LCMS m/z 390.0 [M+H] ⁺ .

Example 5

Synthesis I-4

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Synthesis scheme:

Stage 1: 2,4-dichloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine

A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 5.32 mmol, 1 eq.), 2-bromopropane (3.27 g, 26.59 mmol, 2.50 ml , 5.0 eq.) and K ₂ CO ₃ (3.68 g, 26.59 mmol, 5 eq.) in DMSO (20 ml) were degassed and purged with N ₂ 3 times, then the mixture was stirred at 10-20 ° C for 48 hours under N ₂ atmosphere. TLC (PE/EA = 3/1, Rf = 0.50) indicated that the starting material had been consumed and one major new spot with greater polarity was found. The reaction mixture was diluted with H ₂ O (50 ml) and extracted with EtOAc (50 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 4/1, TLC: PE/EtOAc = 3 /1, Rf = 0.50) to give the title product 2,4-dichloro-7-isopropyl-pyrrolo[2,3-d]pyrimidine (650 mg, 2.71 mmol, 50.99% yield, 96% purity ) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.33 (d, J=3.7 Hz, 1H), 6.62 (d, J=3.5 Hz, 1H), 5.20-5.01 (m, 1H), 1.53 (d, J=6.8 Hz, 6H); ER-LCMS m/z 230.0, 232.0 [M+H] ⁺ .

Step 2: 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-isopropylpyrrolo[2,3-d]pyrimidin-4-amine

A mixture of 2,4-dichloro-7-isopropyl-pyrrolo[2,3-d]pyrimidine (100 mg, 417.22 µmol, 1 eq.), 2-(1Hindol-3-yl)ethanamine (100 mg, 620 µmol , 1.2 eq.) and DIEA (161.77 mg, 1.25 mmol, 218.02 μl, 3 eq.) in i-PrOH (5 ml) were degassed and flushed with N ₂ 3 times. The mixture was then stirred at 50° C. for 11 hours under N ₂ atmosphere. LC-MS showed that 15% of the starting material remained. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc=1/0 to 1/1, TLC: PE/EtOAc=3/1, Rf=0.28) to give the indicated product 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-isopropyl-pyrrolo[2,3-d]pyrimidin-4-amine (120 mg, 315.39 µmol, yield 75.59%, 93% pure as a light red oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.06 (s, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H ), 7.26-7.20 (m, 1H), 7.18-7.13 (m, 1H), 7.09 (d, J=2.4 Hz, 1H), 6.96 (d, J=3.5 Hz, 1H), 6.23 (s, 1H), 5.22 (s, 1H), 5.03 (d, J=6.8, 13.5 Hz, 1H), 3, 99 (q, J=6.6 Hz, 2H), 3.17 (t, J=6.6 Hz, 2H), 1.46 (d, J=6.8 Hz, 6H); ER-LCMS m/z 353.8, 354.9 [M+H]+.

Step 3: 2-(5-fluoro-3-pyridyl)-N-[2-( 1 H-indol-3 -yl)ethyl]-7-isopropylpyrrolo[2,3-d]pyrimidine4-amine (I -4)

2-Chloro-N-[2-(1H-indol-3-yl)ethyl]-7-isopropyl-pyrrolo[2,3-d]pyrimidin-4-amine (80 mg, 210.26

- 90 041983 µmol, 1 eq.), (5-fluoro-3-pyridyl)boronic acid (44.44 mg, 315.39 µmol, 1.5 eq.), Pd (dppf) Cl ₂ (15.38 mg , 21.03 µmol, 0.1 eq.) and Cs ₂ CO ₃ (205.52 mg, 630.78 µmol, 3 eq.) in 1,4-dioxane (2 ml) and H2O (0.5 ml) placed in a tube with microwave radiation. The reaction mixture was purged with N2 for 3 min, then sealed tightly and heated at 110° C. for 30 min while being treated with microwave radiation. LC-MS indicated that 90% of the desired compound was found. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (MeCN/H2O as eluents, acidic conditions, instrument: DC/Phenomenex Kinetex XB-C18 150 mm x 30 mm, 5 µm/Mobile phase: water (0. 05% HCl)-ACN/Gradient: B 47% to 77% over 10 min/Flow rate: 25 ml/min) followed by lyophilization to give 2-(5-fluoro-3-pyridyl)-N-[2-( 1H-indol-3-yl)ethyl]-7-isopropyl-pyrrolo[2,3-d]pyrimidin-4-amine (51.57 mg, 120.95 µmol, 57.52% yield, 97.21% purity , salt 3HCl) as a yellow solid.

1H NMR (400 MHz, DMSOCH) δ ppm 9.41 (s, 1H), 8.72 (s, 1H), 8.50 (d, J=8.6 Hz, 1H), 8.09 (s, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.23 (s, 1H), 7.07 (t, J=7.4 Hz, 1H), 7.02-6.93 (m, 1H), 6.69 (s, 1H), 5.06 (s, 1H), 3.89 (s, 1H), 3.80-3.77 (m, 2H), 3.20-3.00 (m, 2H), 1.48 (d, J=6.6Hz, 6H) ; ERLCMS m/z 414.9 [M+H]+.

Example 6

Synthesis I-3

1-3

Synthesis scheme:

Br

Step 1: N-(2-(1H-indol-3-yl)ethyl)-7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine

Br

To a solution of 7-bromo-2,4-dichloro-thieno[3,2-d]pyrimidine (100 mg, 352.16 µmol, 1 eq.) and 2-(1Hindol-3-yl)ethanamine (84.63 mg , 528.24 µmol, 1.5 eq.) in i-PrOH (3 ml) was added DIEA (136.54 mg, 1.06 mmol, 184.02 µl, 3 eq.). The mixture was stirred at 50° C. for 3 hours. LC-MS indicated that no starting material remained and 93% of the desired compound was found. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (DCM/MeOH = 1/0 to 100/1, TLC: PE/EtOAc = 3/1, R _f = 0.42), giving 7-bromo-2chloro-N-[2-(1H-indol-3-yl)ethyl]thieno[3,2-d]pyrimidin-4-amine (140 mg, 339.94 µmol, 96.53% yield , 99% pure) as a gray solid.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm 8.11 (s, 1H), 7.69-7.66 (m, 2H), 7.43 (d, J=8.2 Hz, 1H), 7 .25-7.23 (m, 1H), 7.18-7.14 (m, 1H), 7.09 (d, J=2.2 Hz, 1H), 5.25 (s, 1H), 4.01 (q, J=6.4 Hz, 2H), 3.18 (t, J=6.5 Hz, 2H); ERLCMS m/z 406.9, 408.9 [M+H]+.

- 91 041983

Step 2: N-(2-(1H-indol-3-yl)ethyl)-2-chloro-7-(prop-1-en-2-yl)thieno[3,2-d]pyrimidin-4-amine

-NH

GD _N A _r s ^w A Di SG Ν ξ

7-Bromo-2-chloro-N-[2-(1H-indol-3-yl)ethyl]thieno[3,2-d]pyrimidin-4-amine (120 mg, 291.38 µmol, 1 eq.) , 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (39.17 mg, 233.10 µmol, 0.8 eq.), Pd(dppf)Cl ₂ (42.64 mg, 58.28 µmol, 0.2 eq.) and Cs ₂ CO ₃ (284.81 mg, 874.14 µmol, 3.0 eq.) in 1,4-dioxane (5 ml) and H ₂ O ( 1 ml) was placed in a tube with microwave radiation. The tube was purged with N ₂ for 3 min, then tightly capped and heated at 80° C. for 10 min while being treated with microwave radiation. LC-MS indicated that most of the starting material had been consumed and 68% of the desired compound was found. The combined reaction mixture was diluted with H ₂ O (20 ml) and extracted with EtOAc (20 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC: PE/EtOAc = 3 /1, R _f = 0.45), obtaining the specified product N-(2-(1H-indol-3-yl)ethyl)-2-chloro-7-(prop-1-en-2-yl)thieno[ 3,2d]pyrimidine-4-amine (95 mg, 73.85% yield, 98% purity) as a light yellow oil.

1H NMR (400 MHz, CDCI3) δ ppm 8.10 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J=8.0Hz, 1H), 7.26-7.22(m, 1H), 7.20-7.13(m, 1H), 7.09(d, J=2.3Hz, 1H ), 6.37 (s, 1H), 5.38 (s, 1H), 5.11 (s, 1H), 4.00 (q, J=6.4 Hz, 2H), 3.18 (t , J=6.7 Hz, 2H), 2.21 (s, 3H); ER-LCMS m/z 369.0, 371.0 [M+H] ⁺ .

Step 3: N-(2-(1H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-7-(prop-1-en-2-yl)thieno[3,2d ]pyrimidine-4-amine

-NH ££

A> ^N7

2-Chloro-N-[2-(1H-indol-3-yl)ethyl]-7-isopropenyl-thieno[3,2-d]pyrimidin-4-amine (95 mg, 252.38 µmol, 1 eq. ), (5-fluoro-3-pyridyl)boronic acid (53.34 mg, 378.58 µmol, 1.5 eq.), Pd(dppf)Cl ₂ (18.47 mg, 25.24 µmol, 0, 1 eq.) and Cs ₂ CO ₃ (246.69 mg, 757.15 µmol, 3 eq.) in 1,4-dioxane (2 ml) and H ₂ O (0.5 ml) were placed in a tube with microwave radiation . The sealed tube was purged with N ₂ for 3 minutes, then heated at 110° C. for 30 minutes while being treated with microwave radiation. LC-MS showed that most of the starting material had been consumed and 85% of the desired compound was found. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC: PE/EtOAc = 3/1, R _f = 0.44), obtaining the indicated product 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-isopropenyl-thieno[3,2-d]pyrimidin-4-amine (85 mg , 188.00 µmol, 74.49% yield, 95% purity) as an oil.

'H NMR (400 MHz, CDCI3) δ ppm 9.59 (s, 1H), 8.55 (d, J=2.6 Hz, 1H), 8.48 (d, J=10.1 Hz, 1H ), 8.07 (s, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.56 (s, 1H), 7.42 (d, J=7.9 Hz, 1H ), 7.26-7.22 (m, 1H), 7.20-7.15 (m, 1H), 7.11 (s, 1H), 6.70 (s, 1H), 5.46 ( s, 1H), 5.06 (s, 1H), 4.14 (q, J=6.5 Hz, 2H), 3.26 (t, J=6.5 Hz, 2H), 2.30 ( s, 3H); ERJHMS m/z 430.0 [M+H] ⁺ .

Stage 4: N-(2-(1H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-7-isopropylthieno[3,2-d]pyrimidin4-amine (I-3)

To a solution of 2-(5-fluoro-3-pyridyl)-N-[2-( 1 H-indol-3 -yl)ethyl]-7-isopropenyl-thieno[3,2d]pyrimidine-4-amine (50 mg , 110.59 µmol, 1 eq.) in MeOH (20 ml) and THF (2 ml) was added Pd/C (10%, 50 mg) under N ₂ atmosphere. The suspension was degassed under vacuum and purged with H ₂ 3 times. The mixture was stirred in H ₂ (15 psi) at 10-15° C. for 0.5 h. LC-MS indicated that no starting material remained and 95% of the desired compound was found. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC.

- 92 041983 (MeCN/H ₂ O as eluents, acid conditions, instrument: DC/Phenomenex Kinetex XB-C18 150 mm x 30 mm, 5 µm/Mobile phase: water (0.05% HCl)-ACN/Gradient: V from 62% to 92% in 10 min/Flow rate: 25 ml/min) followed by lyophilization to give 2-(5-fluoro-3-pyridyl)-N-[2(1H-indol-3-yl)ethyl] -7-isopropyl-thieno[3,2-d]pyrimidin-4-amine (40.32 mg, 74.05 µmol, yield

66.96%, 99.34% purity, 3HCl salt) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, 1H), 9.46 (s, 1H), 8.69 (d, J=2.8 Hz, 1H), 8.42 ( d, J=10.0 Hz, 1H), 8.19 (t, J=5.6 Hz, 1H), 7.77 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.07 (t, J=7.4 Hz, 1H) , 6.99-6.95 (m, 1H), 3.93-3.87 (m, 2H), 3.46-3.41 (m, 1H), 3.12 (t, J=7, 4 Hz, 2H), 1.37 (d, J=6.8 Hz, 6H); ER-LCMS m/z 432.0 [M+H] ⁺ .

Example 7

Synthesis I-2

Synthesis scheme:

Stage 1: 2-formyl-3-methylbutanenitrile

To a mixture of diisopropylamine (2.43 g, 24.06 mmol, 3.40 ml, 1 eq.) in THF (20 ml) was added dropwise n-BuLi (2.5 M, 10.10 ml, 1.05 eq. .) at -78°C under N2 atmosphere. The mixture was stirred at -78°C for 10 min, then warmed to 0°C and stirred for 1 h. The mixture was cooled to -78°C, 3-methylbutanenitrile (2 g, 24.06 mmol, 2.53 ml, 1 eq) and stirred at -78°C for 10 min. A solution of ethyl formate (1.87 g, 25.26 mmol, 2.03 ml, 1.05 equiv.) in THF (15 ml, anhydrous) was added dropwise and stirred at -78°C for 40 min, then the mixture was heated to 5-14°C for 16 hours. TLC (PE/EA=3/1, _Rf =0.34) indicated that one major new spot was detected. The reaction mixture was quenched by adding 1 N. HCl solution (50 ml) at -78°C and extracted with EtOAc (50 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 1/4, TLC: PE/EtOAc = 3 /1, R _f = 0.34) to give 2-formyl-3-methyl-butanenitrile (2 g, 16.20 mmol, 67.32% yield, 90% purity) as a light yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.57 (s, 1H), 3.43 (d, J=4.4 Hz, 1H), 2.56-2.40 (m, 1H), 1 .20 (d, J=6.8 Hz, 3H), 1.12 (d, J=6.8 Hz, 3H).

- 93 041983

Stage 2: 4-isopropyl-1H-pyrazole-5-amine

A mixture of 2-formyl-3-methyl-butanenitrile (500 mg, 4.05 mmol, 1 eq.), hydrazine hydrate (168.67 mg, 5.26 mmol, 190.37 µl, 1.3 eq.) and AcOH (425.50 mg, 7.09 mmol, 405.24 μl, 1.75 eq.) in EtOH (20 ml) was degassed and flushed with N2 3 times. The mixture was stirred at 80-90°C (reflux) for 16 h under N ₂ then concentrated under reduced pressure. The rest watered us down. NaHCO ₃ solution (20 ml) and extracted with DCM (20 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product 4-isopropyl-1H-pyrazole-5-amine (420 mg, 3.02 mmol, 74.58% yield, 90% purity ) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.13 (s, 1H), 2.69 (t, J=6.9 Hz, 1H), 1.21 (d, J=6.8 Hz, 6H ).

Stage 3: methyl 3-(5-fluoropyridin-3-yl)-3-oxopropanoate

To a solution of 5-fluoropyridine-3-carboxylic acid (500 mg, 3.54 mmol, 1 eq.) in THF (20 ml) was added CDI (689.51 mg, 4.25 mmol, 1.2 eq.). The mixture was stirred at 5-14°C for 2 hours. (3Methoxy-3-oxo-propanoyl)hydroxypotassium (553.43 mg, 3.54 mmol, 1 eq) and _MgCl 54 mmol, 1 eq.) and the reaction mixture was stirred at 5-14°C for 16 h. TLC (PE/EA=1/1, Rf=0.58) indicated that the starting material was consumed and one major a new spot with greater polarity. The reaction mixture was diluted with 3 N HCl solution (20 ml) and extracted with EtOAc (20 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 1/4, TLC: PE/EtOAc = 1/1, Rf = 0.58) to give methyl 3-(5-fluoro3-pyridyl )-3-oxo-propanoate (175 mg, 843.21 µmol, 23.80% yield, 95% purity) as white solid and methyl 3-(5-fluoro-3-pyridyl)-3-oxo -propanoate (175 mg, 843.21 µmol, 23.80% yield, 95% purity) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 12.48 (s, 1H), 8.97 (s, 1H), 8.82 (s, 1H), 8.70 (d, J=2.6 Hz , 1H), 8.56 (d, J=2.6 Hz, 1H), 7.96 (d, J=2.2, 8.6 Hz, 1H), 7.86-7.73 (m, 1H), 5.75 (s, 1H), 4.04 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H); ER-LCMS m/z 198.1 [M+H]+.

Step 4: 5-(5-fluoropyridin-3-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-o l

To a solution of methyl 3-(5-fluoro-3-pyridyl)-3-oxo-propanoate (200 mg, 963.67 µmol, 1 eq.) in AcOH (5 ml) -amine (134.03 mg, 963.67 µmol, 1 eq.). The mixture was stirred at 120° C. for 0.5 h. LCMS showed that the starting material had been completely consumed and one major peak was found with the desired MS. The reaction mixture was concentrated under reduced pressure to give the crude product 5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5a]pyrimidin-7-ol (300 mg, 639.05 µmol, yield 66.31 %, purity 58%) as a yellow oil, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 8.79 (m, 1H), 8.63-8.67 (m, 1H), 8.09-8.06 (m, 1H), 7.87 (m , 1H), 6.06 (m, 1H), 3.26-3.25 (m, 1H), 2.75-2.70 (m, 1H), 1.30 (d, J=6.8 Hz, 3H), 1.15-1.09 (m, 3H); ER-LCMS m/z 567.0 [2M+Na]+.

Step 5: 7-chloro-5-(5-fluoropyridin-3-yl)-3-isopropylpyrazolo[1,5-a]pyrimidine

A solution of 5-(5-fluoropyridin-3-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-ol (300 mg, 639.05 µmol, 1 eq.) in POCl ₃ (4.95 g, 32.28 mmol, 3 ml, 50.52 eq) was stirred at 110°C for 3 hours.

- 94 041983

LC-MS showed that no starting material remained and 67% of the desired compound was found. The reaction mixture was concentrated under reduced pressure, then diluted with DCM (20 ml x 2), concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 2/5, TLC: PE/EtOAc = 1/1, Rf = 0.64) to give the title product 7-chloro-5-(5-fluoropyridin-3-yl)-3-isopropylpyrazolo[1,5-a]pyrimidine (140 mg, 385.25 µmol , yield 60.28%, purity 80%) as a yellow solid.

1H NMR (400 MHz, CDCI3) δ ppm 9.10 (s, 1H), 8.61-8.60 (m, 1H), 8.22-8.14 (m, 2H), 7.41-7 .27 (m, 1H), 3.47-3.38 (m, 1H), 1.48-1.44 (m, 6H); ER-LCMS m/z 291.0, 293.0 [M+H]+.

Step 6: N-(2-(1H-indol-3-yl)ethyl)-5-(5-fluoropyridin-3-yl)-3-isopropylpyrazolo[1,5a]pyrimidin-7-amine (I-2 )

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (80 mg, 220.14 µmol, 1 eq.) and 2-(1H- indol-3-yl)ethanamine (52.90 mg, 330.21 µmol, 1.5 eq.) in i-PrOH (3 ml) was added DIEA (85.36 mg, 660.42 µmol, 115.03 µl, 3.0 eq.). The mixture was stirred at 50° C. for 3 hours. LCMS indicated that no starting material remained and 92% of the desired compound was found. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (MeCN/H ₂ O as eluents, acidic conditions, instrument: DC/Phenomenex Kinetex XB-C18 150 mm x 30 mm, 5 µm/Mobile phase: water (0.05 % HCl)-ACN/Gradient: B 47% to 57% over 10 min/Flow rate: 25 ml/min) followed by lyophilization to give 5-(5-fluoro-3-pyridyl)-N-[2-(1H -indol-3-yl)ethyl]-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-amine (88.45 mg, 168.66 µmol, 76.61% yield, 99.89% purity, salt 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.73 (d, J=2.2 Hz, 1H), 8.34 (s, 1H), 8.15 (s, 1H), 7.55 (d, J=8.6Hz, 1H), 7.43(d, J=7.9Hz, 1H), 7.07(d, J=8.2Hz, 1H), 6.94(s, 1H) , 6.86 (t, J=7.2 Hz, 1H), 6.72 (t, J=7.4 Hz, 1H), 5.71 (s, 1H), 3.95 (t, J= 5.7 Hz, 2H), 3.17-3.12 (m, 3H), 1.26 (d, J=6.8 Hz, 6H); ER-LCMS m/z 415.2 [M+H] ⁺ .

Example 8 Synthesis of I-10 o. HN Lj ^N V 1-10 Synthesis scheme: Г NO ₂ /L ^.F /. .NHBoc IH (j ^NHB» 0 HN—γ Aa ----- FL F-/ Pd(dppf)CI ₂ , Cs ₂ CO ₃ , ^{Cl N} 1,4-dioxane, H2O _—NH nh ₂ Pd/C, H ₂ 1 J c -------► < NHBoc FA Cl HN—γ Ϊ J > F^nh _; ° / DIEA O ₄ ^_-ΝΗ HN γ \\ _F ^NN \ A 1-10 '

- 95 041983

Stage 1: tert-butyl N-[2-(2-nitroanilino)ethyl]carbamate no ₂

ΛΑ/-K NHBoc

To a solution of 1-fluoro-2-nitrobenzene (10 g, 70.87 mmol, 7.46 ml, 1 eq.) and tert-butyl N-(2-aminoethyl) carbamate (11.35 g, 70.87 mmol, 11.13 ml, 1 eq.) in DMF (50 ml) was added K ₂ CO ₃ (15.67 g,

113.39 mmol, 1.6 eq.). The mixture was stirred at 70° C. for 18 hours. TLC (PE/EtOAc = 5/1, Rf = 0.69) indicated that most of the starting material had been consumed. The mixture was diluted with H2O (100 ml), extracted with EtOAc (100 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 5/4, TLC: PE/EtOAc = 5/1, Rf = 0.69) to give tert-butyl N-[2-( 2-nitroanilino)ethyl]carbamate (19 g, 67.54 mmol, 95.3% yield, 100% purity) as an orange solid.

'and NMR (400 MHz, CDCl ₃ ) δ ppm 8.19 (d, J=8.8 Hz, 1H), 7.47-7.43 (m, 1H), 6.95 (d, J=8 .4 Hz, 1H), 6.696.65 (m, 1H), 3.50-3.43 (m, 4H), 1.46 (s, 9H); ER-LCMS m/z 304.0 [M+Na]+.

Stage 2: tert-butyl N-[2-(2-aminoanilino)ethyl]carbamate

To a solution of tert-butyl N-[2-(2-nitroanilino)ethyl]carbamate (5 g, 17.77 mmol, 1 eq.) in MeOH (50 ml) was added Pd/C (10%, 500 mg) under atmosphere _N2 . The suspension was degassed and purged with H ₂ 3 times. The mixture was stirred in H ₂ (15 Psi) at 2-9° C. for 18 hours. LC-MS indicated that the starting material had been completely consumed and one major peak was found with the desired MS. The mixture was filtered and concentrated under reduced pressure to give crude tert-butyl N-[2-(2aminoanilino)ethyl]carbamate (4.4 g, 17.51 mmol, 98.50% yield, crude) as a dark red oil, which was used in the next step without further purification.

'H NMR (400 MHz, CD3OD) δ ppm 6.70-6.67 (m, 2H), 6.62 (d, J=7.6 Hz, 1H), 6.56 (t, J=7, 2 Hz, 1H), 3.29-3.26 (m, 2H), 3.18-3.17 (m, 2H), 1.42 (s, 9H); ER-LCMS m/z 252.2 [M+H] ⁺ .

Stage 3: tert-butyl N-[2-(2-oxo-3H-benzimidazol-1-yl)ethyl]carbamate

CDI (1.55 g, 9.55 mmol, 1.2 eq.). The mixture was stirred at 80° C. for 2 hours. LC-MS indicated that the starting material had been completely consumed and one major peak was found with the desired MS. The mixture was diluted with EtOAc (50 ml), washed with citric acid solution (aq., 20 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (from PE/ EtOAc = 1/0 to 5/4, TLC: PE/EtOAc = 1/1, Rf = 0.31). The resulting slightly yellowish oil was diluted with 1 N. HCl solution (5 ml), filtered and the solid was collected. The solid was triturated with isopropyl ether (20 ml), filtered and the resulting product was collected tert-butyl N-[2-(2-oxo-3H-benzimidazol-1yl)ethyl]carbamate (1.63 g, 5.73 mmol, yield 72.0%, 97.52% pure) as a white solid.

'H NMR (400 MHz, CD ₃ OD) δ ppm 7.13-7.01 (m, 4H), 3.93 (t, J=6.0 Hz, 2H), 3.35-3.31 ( m, 2H), 1.29, 1.17 (s, 9H); ER-LCMS m/z 300.1 [M+H] ⁺ .

Step 4: 3-(2-aminoethyl)-1H-benzimidazol-2-one

HCl/ 1,4-dioxane (4M, 5.00 ml, 8.80 eq.) dropwise at 0°C. After the addition, the mixture was stirred at 4-12°C for 1 hour. LC-MS showed that most of the starting material had been consumed. The reaction mixture was concentrated under reduced pressure to give crude 3-(2-aminoethyl)-1H-benzimidazol-2-one (400 mg, 1.87 mmol, 82.4% yield, HCl salt) as a white solid which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 7.18-7.17 (m, 1H), 7.11-7.08 (m, 3H), 4.19-4.16 (m, 2H), 3 .31-3.28 (m, 2H); ER-LCMS m/z 178.1 [M+H] ⁺ .

- 96 041983

Step 5: 3-[2-[(2-chloro-9-isopropyl-purin-6-yl)amino]ethyl]-1H-benzimidazol-2-one

DIEA (427.65 mg, 3.31 mmol, 576.35 µl, 4.0 eq.) and 3-(2-aminoethyl)-1H-benzimidazol-2-one (265.13 mg, 1.24 mmol, 1.5 eq., HCl). The mixture was stirred at 50° C. for 5 hours. LC-MS showed that most of the starting material had been consumed. The reaction mixture was concentrated under reduced pressure to remove isopropanol. The residue was diluted with H ₂ O (20 ml) and extracted with DCM/isopropanol (20 mlx3, v/v=3/1). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (DCM/MeOH=1/0 to 10/1, TLC: DCM/MeOH=10/1, Rf=0.15) to give 3-[2-[(2-chloro -9-isopropyl-purin-6-yl)amino]ethyl]-1H-benzimidazol-2-one (280 mg, 730.45 µmol, 88.3% yield, 97% purity) as a white solid;

1H NMR (400 MHz, CD3OD) δ ppm 8.14 (s, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.06-6.97 (m, 3H), 4, 78-4.75 (m, 1H), 4.22 (t, J=6.0 Hz, 2H), 3.97 (t, J=6.0 Hz, 2H), 1.62 (d, J =6.4 Hz, 6H); ER-LCMS m/z 372.1, 374.0 [M+H]+.

Step 6: 3-[2-[[2-(5-Fluoro-3-pyridyl)-9-isopropyl-purin-6-yl]amino]ethyl]-1 H-benzimidazol-2-one (I-10)

To a solution of 3-[2-[(2-chloro-9-isopropyl-purin-6-yl)amino]ethyl]-1H-benzimidazol-2-one (100 mg, 260.88 µmol, 1 eq.) and ( 5-fluoro-3-pyridyl)boronic acid (73.52 mg, 521.75 µmol, 2 eq.) in 1,4dioxane (2 ml) and H ₂ O (0.5 ml) was added Pd(dppf)Cl ₂ (9.54 mg, 13.04 µmol, 0.05 eq.) and Cs ₂ CO ₃ (255.00 mg, 782.63 µmol, 3 eq.). The mixture was purged with N ₂ for 3 min and stirred at 120° C. for 0.5 h while being treated with microwave radiation. LC-MS indicated that most of the starting material had been consumed and the desired compound was found. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc/MeOH/THF (10 ml/10 ml/10 ml) and stirred for 5 min, filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (MeCN/H ₂ O as eluents, acidic conditions, instrument: DC/Phenomenex Kinetex XB-C18 150 mm x 30 mm, 5 µm/Mobile phase: water (0 05% HCl)-ACN/Gradient: B 20% to 50% over 12 min/flow rate: 25 ml/min) followed by lyophilization to give 3-[2-[[2-(5-fluoro-3 -pyridyl)-9-isopropyl-purin-6-yl]amino]ethyl]-1Hbenzimidazol-2-one (11.08 mg, 21.29 µmol, 8.16% yield, 97.1% purity, 2HCl salt, 10.85 mg remained) as a light yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.51-9.27 (m, 2H), 9.15-8.90 (m, 2H), 7.23 (d, J=7.8 Hz, 1H ), 6.92 (t, J=7.8 Hz, 1H), 6.75 (t, J=7.5 Hz, 1H), 6.63 (d, J=7.8 Hz, 1H), 5.19-4.97 (m, 1H), 4.30-4.15 (m, 4H), 1.67 (d, J=6.8 Hz, 6H); ER-LCMS m/z 433.1 [M+H]+.

Example 9

Synthesis I-19

- 97 041983

Synthesis scheme:

Step 1: N-(2-(1H-indol-3-yl)ethyl)-7-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazine-4-amine

DIEA ( 242.10 mg, 1.87 mmol, 326.29 µl, 5.0 eq.) and 2-(1H-indol-3-yl)ethanamine (78.03 mg, 487.06 µmol, 1.3 eq. ). The mixture was stirred at 50° C. for 1.5 hours. LC-MS indicated that the starting material had been completely consumed and one major peak was found with the desired MS. The reaction mixture was diluted with H2O (15 ml) and extracted with DCM (15 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent: gradient 20 ~25% ethyl acetate/petroleum ether at a flow rate of 55 ml/min) to give 7-bromo-2-chloro^-[2-(1H-indol-3yl)ethyl]pyrrolo[2,1-f][1,2 ,4]triazine-4-amine (140 mg, 354.78 µmol, 94.7% yield) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.08 (s, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H ), 7.26-7.23 (m, 1H), 7.19-7.14 (m, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.59 (d, J=4.6 Hz, 1H), 6.40 (br s, 1H), 5.55 (m, 1H), 3.99 (q, J=6.2 Hz, 2H), 3.17 ( t, J=6.6 Hz, 2H); ER-LCMS m/z 389.9, 392.0 [M+H]+.

Step 2: N-(2-(1H-indol-3-yl)ethyl)-2-chloro-7-(prop-1-en-2-yl)pyrrolo [2,1-f][1,2 ,4]triazine-4-amine

To a solution of 7-bromo-2-chloro-N-[2-(1H-indol-3-yl)ethyl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (90 mg, 228.07 µmol, 1 eq.) in 1,4-dioxane (2 ml) and H2O (0.5 ml) was added 2-isopropenyl-4,4,5,5-tetramethyl1,3,2-dioxaborolane (38. 33 mg, 228.07 µmol, 1.0 eq.), Pd(dppf)Cl ₂ (33.38 mg, 45.61 µmol, 0.2 eq.) and Cs ₂ CO ₃ (222.93 mg, 684 .22 µmol, 3.0 eq.). The mixture was stirred under microwave radiation at 80° C. for 30 minutes. LCMS showed that 67% of the desired product was found. The reaction mixture was filtered and the filtrate was diluted with H2O (15 ml) then extracted with EtOAc (15 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: gradient 10 ~13% ethyl acetate/petroleum ether at a flow rate of 50 ml/min) giving 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7isopropenyl-pyrrolo[2,1-f][1 ,2,4]triazine-4-amine (65 mg, 144.10 µmol, 63.2% yield) as a colorless oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.08 (broad s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.41 (d, J=8.2 Hz , 1H), 7.26-7.23 (m, 1H), 7.20-7.14 (m, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.58 ( d, J=4.6 Hz, 1H), 6.36 (br. s, 1H), 6.25 (s, 1H), 5.50 (br. s, 1H), 5.35 (s, 1H ), 4.02-3.96 (m, 2H), 3.16 (t, J=6.5 Hz, 2H), 2.20 (s, 3H); ER-LCMS m/z 352.0, 354.0 [M+H] ⁺ .

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Step 3: N-(2-(1 H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-7-(prop-1-en-2-yl)pyrrolo [2, 1f][1,2,4]triazine-4-amine

To a solution of 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-isopropenyl-pyrrolo[2,1-f][1,2,4]triαzine-4-amineα (65 mg , 144.10 µmol, 1 eq.) in 1,4-dioxane (3 ml) and H2O (1 ml) was added (5-fluoro-3-pyridyl)boronic acid (30.46 mg, 216.15 µmol, 1.5 eq.), Pd(dppf)Cl ₂ (15.82 mg, 21.62 µmol, 0.15 eq.) and Cs ₂ CO ₃ (140.85 mg, 432.31 µmol, 3.0 eq.). The mixture was stirred at 110° C. while microwaved for 0.5 h. LCMS indicated that approximately 72% of the desired product was found. The reaction mixture was filtered and the filtrate was diluted with H2O (15 ml) then extracted with EtOAc (15 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative TLC (PE/EtOAc = 1.5/1, R _f = 0.6) to give 2-(5 -fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-isopropenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (40 mg , 76.61 µmol, 53.2% yield) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm 9.29 (s, 1H), 8.38 (d, J=2.9 Hz, 1H), 8.23-8.16 (m, 1H), 8, 05 (broad s, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.30-7.27 (m, 1H), 7.30-7.24 (m, 1H) , 7.14-7.09 (m, 1H), 7.07-7.02 (m, 1H), 6.95 (d, J=2.2 Hz, 1H), 6.54 (d, J =4.6 Hz, 1H), 6.34-6.23 (m, 2H), 5.45 (t, J=5.6 Hz, 1H), 5.27 (s, 1H), 3.95 (q, J=6.5 Hz, 2H), 3.09 (t, J=6.6 Hz, 2H), 2.15 (s, 3H); ER-LCMS m/z 413.1 [M+H]+.

Step 4: N-(2-(1H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-7-isopropylpyrrolo[2,1-f]

[1,2,4]triazine-4-amine (I-19)

To a solution of 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-isopropenyl-pyrrolo[2,1f][1,2,4]triazine- 4-amine (30 mg, 57.46 µmol, 1 eq.) in MeOH (8 ml) was added with Pd/C (10%, 40 mg). The slurry was degassed under vacuum and purged with H2 several times, then the mixture was stirred at H ₂ (15 psi) at 20°C for 0.5 h. with the desired MS. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenomenex Kinetex XB-C18 150 mm x 30 mm, 5 µm; mobile phase: [water (0.05% HCl)- ACN]; B%: 75%-95%, 12 min) and the desired fraction was lyophilized to give 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]- 7-isopropyl-pyrrolo[2,1-f][1,2,4]triazine-4-amine (6.75 mg, 12.89 µmol, 17.72% yield, 100% purity, 3HCl salt) as white solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.05 (s, 1H), 8.76 (broad s, 1H), 8.42 (d, J=8.8 Hz, 1H), 7.63 ( d, J=7.3 Hz, 1H), 7.23 (d, J=7.7 Hz, 1H), 7.06-6.97 (m, 3H), 6.92 (d, J=4 .0 Hz, 1H), 6.54 (d, J=4.0 Hz, 1H), 4.01 (t, J=7.1 Hz, 2H), 3.55 (d, J=7.0 , 14.1 Hz, 1H), 3.17 (t, J=6.8 Hz, 2H); ER-LCMS m/z 415.1 [M+H]+.

Example 10

Synthesis I-22

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Step 1: 2-(chloromethyl)imidazo[1,2-a]pyridine

To a solution of pyridin-2-amine (5 g, 53.13 mmol, 1 eq.) in DME (10 ml) was added 1,3-dichloropropan2-one (13.49 g, 106.25 mmol, 2 eq.). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOH (50 ml), then stirred at 90° C. for 16 h. LC-MS indicated that the starting material had been completely consumed and the desired MS was found. The reaction mixture was concentrated and the residue was hydrolysed with saturated sodium carbonate solution (100 ml). The reaction mixture was subjected to extraction with DCM (60 mlx3), combined, dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure, obtaining 2-(chloromethyl)imidazo[1,2-a]pyridine (8.85 g, crude) , which was used in the next step without further purification.

1H NMR (400 MHz, CDCI3) δ ppm 8.14 (d, J=6.8 Hz, 1H), 7.70-7.59 (m, 2H), 7.26-7.20 (m, 1H ), 6.85 (t, J=6.8 Hz, 1H), 4.79 (s, 2H); ER-LCMS m/z 167.2, 169.5 [M+H] ⁺ .

Step 2: 2-imidazo[1,2-a]pyridin-2-ylacetonitrile

A mixture of 2-(chloromethyl)imidazo[1,2-a]pyridine (3 g, 18.01 mmol, 1 eq.) and KCN (1.52 g, 23.41 mmol, 1.3 eq.) in DMSO ( 50 ml) was degassed and purged with N ₂ 3 times. The mixture was then stirred at 80°C for 16 hours under N2. LC-MS showed that 27% of the starting material remained and 17% of the desired compound was found. The reaction mixture was quenched with water (200 ml) then extracted with EtOAc (100 mlx3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (DCM/MeOH = 1/0 to 10/1 , TLC: DCM/MeOH = 10/1, R _f = 0.49) to give 2-imidazo[1,2-a]pyridin-2-ylacetonitrile (200 mg, 890.75 µmol, 5.0% yield, 70% pure as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.59-8.49 (m, 1H), 7.92 (s, 1H), 7.55-7.49 (m, 1H), 7, 28-7.11 (m, 1H), 6.92-6.85 (m, 1H), 4.12 (s, 3H); ER-LCMS m/z 158.1 [M+H]+.

Step 3: 2-imidazo[1,2-a]pyridin-2-yl-ethanamine

BH ₃ -Me ₂ S (10 M, 445.37 µl , 10 equiv.). The mixture was stirred at 80° C. for 2 hours when the LCMS indicated that the starting material had been completely consumed and the desired MS was found. The reaction mixture was quenched with MeOH at 10°C, then stirred at 80°C for 1 hour. The resulting mixture was concentrated under reduced pressure to give 2-imidazo[1,2-a]pyridin-2-yl-ethanamine (71.8 mg, crude ) as a white solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 8.82-8.61 (m, 1H), 8.21-8.06 (m, 1H), 8.02-7.61 (m, 2H), 7 .52-7.21 (m, 1H), 3.61-3.38 (m, 2H), 3.35-3.28 (m, 2H); ER-LCMS m/z 162.1 [M+H] ⁺ .

Step 4: 2-(5-fluoro-3-pyridyl)-N-(2-imidazo[1,2-a]pyridin-2-ylethyl)-9-isopropyl-purine-6-amine (I-22)

DIEA (106.33 mg, 822.73 µmol, 143.31 µl, 5 eq.) and 2-imidazo[1,2-a]pyridin-2ylethanamine (71.8 mg, 445.40 µmol, 2.71 eq.). The mixture was stirred at 90° C. for 16 hours. LC-MS indicated that the starting material had been completely consumed and one major peak was found with the desired MS. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Kinetex XB-C18 150 mm x 30 mm, 5 µm; mobile phase: [water (0.05% HCl)-ACN] ; B%: 10%-38%, 12 min) and the desired fraction was lyophilized to give 2-(5-fluoro-3-pyridyl)-N-(2-imidazo[1,2-a]pyridin-2-ylethyl) -9-isopropyl-purine-6amine (22.38 mg, 41.71 µmol, 25.4% yield, 98% purity, 3HC1) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.62 (s, 1H), 9.36 (s, 1H), 9.18-8.90 (m, 2H), 8.71 (d, J=6 .2 Hz, 1H), 8.17 (s, 1H), 7.96-7.76 (m, 2H), 7.43 (t, J=6.8 Hz, 1H), 5.16 (s , 1H), 4.30 (s, 2H), 3.43 (t, J=6.4 Hz, 2H), 1.75 (d, J=6.8 Hz, 6H); ER-LCMS m/z 417.1 [M+H] ⁺ .

Example 11.

Synthesis of I-20

Stage 1: 4,6-dichloro-2-iodo-pyrimidine

CH2I2 (8.98 g, 33.54 mmol, 2.71 ml, 1, 1 eq.) and isopentyl nitrite (17.86 g, 152.45 mmol, 20.53 ml, 5.0 eq.). The mixture was stirred at 80° C. for 3.5 hours. LCMS indicated that the starting material had been completely consumed and one major peak was detected. The reaction mixture was concentrated under reduced pressure to remove acetonitrile. The residue was diluted with EtOAc (50 ml), washed with Na ₂ SO ₃ solution (50 mlx2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (from PE/EtOAc = 100/1 to 10/1, TLC: PE/EtOAc = 3/1, R _f = 0.90) to give 4,6-dichloro-2-iodo-pyrimidine (6.32 g, 22.60 mmol, yield 74.1%, purity 98.3%) as a white solid.

1H NMR (400 MHz, CD3OD) δ ppm 7.79-7.76 (m, 1H); ER-LCMS m/z 274.7, 276.8 [M+H]+.

Stage 2: 4,6-dichloro-2-(5-fluoro-3-pyridyl)pyrimidine

4,6-Dichloro-2-iodo-pyrimidine (500 mg, 1.79 mmol, 1 eq.), (5-fluoro-3-pyridyl)boronic acid (251.96 mg, 1.79 mmol, 1 eq. ), Na ₂ CO ₃ (568.55 mg, 5.36 mmol, 3.0 eq.) and Pd(dppf)C1 ₂ (130.84 mg, 178.81 μmol, 0.1 eq.) in 1, 4-dioxane (6 ml) and water (1.2 ml) were placed in a microwave tube. The sealed tube was heated at 80° C. for 30 minutes while being treated with microwave radiation. LCMS indicated that 53% of the desired compound was found. The reaction mixture was diluted with EtOAc (30 ml) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 10/3, TLC: PE/EtOAc = 3/1, R _f = 0.80), affording 4,6-dichloro-2-(5-fluoro-3-pyridyl)pyrimidine (165 mg, 676.08 µmol, 37.8% yield, 100% purity) as a white solid.

- 101 041983

1H NMR (400 MHz, CD3OD) δ ppm 9.36 (s, 1H), 8.67 (d, J=2.9 Hz, 1H), 8.52-8.44 (m, 1H), 7, 76(s, 1H);

ER-LCMS m/z 243.9, 245.9 [M+H] ⁺ .

Stage 3: 6-chloro-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine

DIEA (262.13 mg , 2.03 mmol, 353.28 μl, 3.0 eq.) and 2-(1H-indol-3-yl)ethanamine (108.32 mg, 676.08 μmol, 1.0 eq.). The mixture was stirred at 50° C. for 3 hours. LCMS showed that 88% of the desired compound was found. The reaction mixture was concentrated to give 6-chloro-2(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine (240 mg, crude) as an oil brown, which was used in the next step without further purification.

Ή NMR (400 MHz, DMSOCH) δ ppm 9.31-9.23 (m, 1H), 8.86-8.20 (m, 2H), 8.11 (s, 1H), 7.92 (s , 1H), 7.57 (dd, J=7.8, 11.8 Hz, 1H), 7.42-7.29 (m, 1H), 7.26-7.17 (m, 1H), 7.13-6.93 (m, 2H), 6.55 (s, 1H), 3.83-3.70 (m, 2H), 3.04-2.95 (m, 2H); ER-LCMS m/z 368.0, 369.0 [M+H]+.

Step 4: 2-(5-fluoro-3-pyridyl)-N6-[2-(1H-indol-3-yl)ethyl]-N4-isopropyl-pyrimidine-4,6-diamine (I-20)

6-Chloro-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine (60 mg, 140.62 µmol, 1.0 eq .), propane-2-amine (1.03 g, 17.46 mmol, 1.5 ml, 124.16 eq.) and DIEA (90.87 mg, 703.10 µmol, 122.46 µl, 5, 0 eq.) was placed in a microwave tube in i-PrOH (3 ml). The sealed tube was heated at 125° C. for 6 hours while being treated with microwave radiation. LCMS indicated that 66% of the desired compound was found. The reaction mixture was concentrated under reduced pressure to remove i-PrOH. The residue was purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 25%55%, 10 min) and the desired fraction was lyophilized , giving 2-(5-fluoro-3-pyridyl)-N6-[2-(1H-indol-3yl)ethyl]-N4-isopropyl-pyrimidine-4,6-diamine (19.11 mg, 38.19 µmol , yield 27.16%, purity 99.90%, salt 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.99 (s, 1H), 8.75 (d, J=2.6 Hz, 1H), 8.18 (s, 1H), 7.62 (d, J=7.9Hz, 1H), 7.31(s, 1H), 7.17-6.98(m, 4H), 3.73(s, 2H), 3.13(t, J=6 .4 Hz, 3H), 1.21 (s, 6H); ER-LCMS m/z 391.3 [M+H] ⁺ .

Example 12.

Synthesis I-15

- 102 041983

Synthesis scheme:

,__Ν h ₂ n

Pd(dppf)Cl2, _{Cs2CO3 :}

1,4-dioxane, HgO

Step 1: 1-imidazo[1,2-a]niridin-3-yl-N,N-gumethylmethanamine

A mixture of imidazo[1,2-a]pyridine (500 mg, 4.23 mmol, 1 eq.), N-methylmethanamine (414.16 mg, 5.08 mmol, 1.2 eq., HCl), and HCHO ( 412.16 mg, 5.08 mmol, 378.13 μl, 37% in water, 1.2 eq) in n-BuOH (5 ml) was degassed and flushed with N2 3 times. The mixture was then stirred at 120° C. for 3 hours under N ₂ atmosphere. LCMS indicated that the starting material had been completely consumed and one major peak was found with the desired MS. The reaction mixture was concentrated under reduced pressure to give 1-imidazo[1,2-a]pyridin-3-yl-N,N-dimethylmethanamine (742 mg, crude) as a yellow solid, which was used in the next step without additional cleaning.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.85 (d, J=6.8 Hz, 1H), 8.27 (d, J=6.8 Hz, 1H), 7.85-7, 73 (m, 2H), 7.68 (s, 1H), 4.41 (s, 2H), 2.64 (s, 6H); ER-LCMS m/z 176.2 [M+H] ⁺ .

Step 2: 2-imidazo[1,2-a]pyridin-3-ylacetonitrile

Dimethyl sulfate was added dropwise (534.10 mg, 4.23 mmol, 401.58 µl, 1 eq). The resulting mixture was heated at 70° C. for 30 minutes. The solvent was removed and the residue was dissolved in H ₂ O (5 ml). KCN (303.30 mg, 4.66 mmol, 1.1 eq.) was added to the mixture and the mixture was heated at 110°C for 3 hours. LC-MS indicated that 27% of the original mixture remained and 33% of the desired connections. The reaction mixture was quenched by adding NaHCO ₃ (30 ml), then was extracted with EtOAc (20 mlx3). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography (DCM/MeOH = 1/0 to 10/1, TLC: DCM/MeOH = 10/1, Rf = 0.48) to give 2-imidazo[1,2-a ]pyridin-3-ylacetonitrile (900 mg, 50.4% yield, 87.6% purity) as a yellow solid.

Ή NMR (400 MHz, CDCl ₃ ) δ ppm 8.39 (d, J=6.8 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.58 (s, 1H ), 7.32 (ddd, J=1.1, 6.7, 9.0 Hz, 1H), 7.06 (dt, J=0.9, 6.8 Hz, 1H), 4.47 ( s, 2H); ER-LCMS m/z 158.1 [M+H]+.

Step 3: 2-imidazo[1,2-a]pyridin-3-yl-ethanamine

BH 3 -Me ₂ S ( ₁₀ M, 421 .70 µl, 10 eq.). The mixture was stirred at 70° C. for 2 hours. LC-MS showed that the starting material had been completely consumed and the desired MS was found. The reaction mixture was slowly quenched by adding MeOH (20 ml) and HCl/MeOH (4 M, 0.1 ml), then stirred at 70° C. for 3 hours. The mixture was concentrated under reduced pressure to give 2-imidazo[1,2 -a]pyridin-3-yl-ethanamine (68 mg, crude) as a colorless oil, which was used in the next step without further purification.

- 103 041983

1H NMR (400 MHz, CD3OD) δ ppm 8.48-8.43 (m, 1H), 7.89-7.65 (m, 1H), 7.69-7.44 (m, 1H), 7 .46 (s, 1H),

7.26-7.17 (m, 1H), 3.17-3.10 (m, 2H), 3.09-3.01 (m, 2H); ER-LCMS m/z 162.1 [M+H]+.

Stage 4: 6-chloro-9-isopropyl-purine-2-amine

To a solution of 6-chloro-9H-purine-2-amine (27 g, 159.22 mmol, 1 eq.) in DMSO (220 ml) was added K ₂ CO ₃ (66.02 g, 477.67 mmol, 3 eq. .) and 2-bromopropane (97.92 g, 796.12 mmol, 74.75 ml, 5 eq.). The mixture was stirred at 15° C. for 88 hours. LC-MS indicated that the starting material had been completely consumed and one major peak was found with the desired MS. The reaction mixture was quenched by adding water (1000 ml), then extracted with EtOAc (500 mlx3). The combined organic layers were washed with water (100 ml x 2), brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue as a yellow solid, PE/EtOAc (5/ 1, 500 ml), then stirred at 15° C. for 2 hours. The suspension was filtered and the filter residue was rinsed with PE (30 mlx2). The solid was collected and dried in vacuo to give crude 6-chloro-9-isopropyl-purine-2-amine (28 g, 130.97 mmol, 82.2% yield, 99% purity) as a light yellow solid , which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.84 (s, 1H), 5.20 (s, 2H), 4.74-4.64 (m, 1H), 1.57 (d, J= 6.8 Hz, 6H); ER-LCMS m/z 212.0, 214.0 [M+H] ⁺ .

Stage 5: 6-chloro-2-iodo-9-isopropyl-purine

To a mixture of 6-chloro-9-isopropyl-purine-2-amine (10 g, 46.78 mmol, 1 eq.), I2 (11.87 g, 46.78 mmol, 1 eq.), CuI (8, 91 g, 46.78 mmol, 1 eq.), and CH2I2 (125.28 g, 467.75 mmol, 37.73 ml, 10 eq.) in THF (400 ml) was added isopentyl nitrite (16.44 g, .33 mmol, 18.89 ml, 3 eq.). The mixture was stirred at 70° C. for 3 hours. LC-MS indicated that the starting material had been completely consumed and the desired MS was found. The reaction mixture was filtered through celite and the filter residue was rinsed with EtOAc (100 mlx2). The filtrate was concentrated under reduced pressure and the residue was diluted with EtOAc (300 ml), washed with Na ₂ SO ₃ (100 ml), brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.58) to give 6-chloro-2-iodo-9-isopropyl -purine (12.5 g, 31.39 mmol, 67.1% yield, 81% purity) as a yellow solid.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm 8.09 (s, 1H), 4.98-4.82 (m, 1H), 1.63 (d, J=7.0 Hz, 6H); ER-LCMS m/z 322.8, 324.8 [M+H] ⁺ .

Stage 6: 6-chloro-2-(5-fluoro-3-pyridyl)-9-isopropyl-purine

6-Chloro-2-iodo-9-isopropyl-purine (3 g, 8.28 mmol, 1 eq.), (5-fluoro-3-pyridyl)boronic acid (1.17 g, 8.28 mmol, 1 eq.), Pd(dppf)Cl ₂ (302.86 mg, 413.91 µmol, 0.05 eq.) and Cs ₂ CO ₃ (2.70 g, 8.28 mmol, 1 eq.) in 1, 4-dioxane (50 ml) and H2O (10 ml) were degassed and then heated at 80° C. for 16 h under N2 atmosphere. LCMS indicated that the starting material had been completely consumed. The reaction mixture was poured into H2O (100 ml) then extracted with EtOAc (80 mlx3). The organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 1/1, TLC : PE/EtOAc = 1/1, R _f = 0.58) to give 6-chloro-2-(5-fluoro-3-pyridyl)-9-isopropyl-purine (1.71 g, 5.63 mmol, yield 68.0%, purity 96%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.54 (s, 1H), 8.58 (d, J=2.8 Hz, 1H), 8.48 (td, J=2.1, 9, 5 Hz, 1H), 8.21 (s, 1H), 5.10-4.93 (m, 1H), 1.73 (d, J=6.8 Hz, 6H); ER-LCMS m/z 292.0, 294.0 [M+H] ⁺ .

- 104 041983

Step 7: 2-(5-fluoro-3-pyridyl)-X-(2-imidazo[1,2-a]pyridin-3-ylethyl)-9-isopropyl-purine-6-amine (N5)

To a solution of 6-chloro-2-(5-fluoro-3-pyridyl)-9-isopropyl-purine (50 mg, 164.55 µmol, 1 eq.), and 2-imidazo[1,2-a]pyridine-3- ylethanamine (68 mg, 421.83 µmol, 2.56 eq.) in i-PrOH (5 ml) was added DIEA (106.33 mg, 822.73 µmol, 143.31 µl, 5 eq.). The mixture was stirred at 95° C. for 16 hours. LC-MS indicated that the starting material had been completely consumed and the desired MS was found (m/z=M/2+H). The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Phenomenex Kinetex XB-C18 150 mmx30 mm, 5 µm; mobile phase: [water (0.05% HC1)-ACN]; V%: 7%- 37%, 12 min) and the desired fraction was lyophilized to give 2-(5fluoro-3-pyridyl)-X-(2-imidazo[1,2-a]pyridin-3-ylethyl)-9-isopropyl-purine-6- amine (34.09 mg, 63.53 µmol, 38.6% yield, 98% purity, 3HC1 salt) as a yellow solid.

Ή NMR (400 MHz, CD ₃ OD) δ ppm 9.50 (s, 1H), 9.33 (s, 1H), 9.03-8.88 (m, 3H), 8.00 (s, 1H ), 7.96-7.88 (m, 1H), 7.86-7.79 (m, 1H), 7.54 (t, J=6.8 Hz, 1H), 5.21-5, 07 (m, 1H), 4.32 (t, J=6.2 Hz, 2H), 3.58 (t, J=6.3 Hz, 2H), 1.74 (d, J=6.6 Hz, 6H); ER-LCMS m/z 416.9 [M+H] ⁺ .

Example 13.

Synthesis 1-1

Synthesis scheme:

Stage 1: 3-isopropyl-4-nitro-1H-pyrazole-5-carboxylic acid

To an ice bath and a stirred solution of fuming HNO3 (700.00 mg, 11.11 mmol, 0.5 ml, 1.71 eq.) and fuming H2SO4 (1.88 g, 18.76 mmol, 1.02 ml, purity 98%, 2.89 eq) 3isopropyl-1H-pyrazole-5-carboxylic acid (1 g, 6.49 mmol, 1 eq) was added portionwise at 0°C over 5 min. After

- 105041983 addition, the mixture was stirred at this temperature for 1 hour then at 100°C for 6 hours.

LC-MS showed that the starting material was completely consumed and one main peak with the desired MS was found. The mixture was poured into ice water (30 g), the white precipitate was filtered and dried to give 3-isopropyl-4-nitro-1H-pyrazole-5-carboxylic acid (700 mg, 3.20 mmol, 49.36% yield, 91 purity .1%) as a white solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 3.56 (spt, J=7.0 Hz, 1H), 1.35 (d J=7.1 Hz, 6H); ER-LCMS m/z 200.1 [M+H]+.

Stage 2: 3-isopropyl-4-nitro-1H-pyrazole-5-carboxamide

Oxalyl chloride ( 1.22 g, 9.61 mmol, 840.83 µl, 3 eq) for 5 min. After the addition, the mixture was stirred at 15° C. for 1 h, then the resulting mixture was concentrated. The residue was dissolved in THF (10 ml) and cooled to 0°C. NH3-H2O (9.75 g, 77.90 mmol, 10.71 mL, 28% purity, 24.33 eq.) was added dropwise. After the addition, the mixture was stirred at 15° C. for 1 hour. LC-MS indicated that the starting material had been completely consumed and one major peak with the desired MS was found. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (50 ml) and extracted with EtOAc (50 mlx2).

The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 3-isopropyl-4-nitro-1H-pyrazole5-carboxamide (0.6 g, 2.91 mmol, yield 90.96%, purity 96.2%) as a white solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 3.68-3.60 (m, 1H), 1.34 (d, J=6.8 Hz, 6H); ER-LCMS m/z 199.1 [M+H] ⁺ .

Stage 3: 4-amino-3-isopropyl-1H-pyrazole-5-carboxamide o

To a mixture of 3-isopropyl-4-nitro-1H-pyrazole-5-carboxamide (600 mg, 2.91 mmol, 1 eq.) in MeOH (20 ml) N2 atmosphere. The suspension was degassed under vacuum and purged several times with H ₂ . The mixture was stirred in H ₂ (15 psi) at 15° C. for 3 h. TLC (PE/EA = 1/1, Rf = 0.1) indicated that the starting material had been completely consumed. The reaction mixture was filtered and the filtrate was concentrated to give 4-amino-3-isopropyl-1H-pyrazole-5-carboxamide (500 mg, 2.68 mmol, 91.86% yield, 90% purity) as an off-white solid .

1 H NMR (400 MHz, CD ₃ OD) δ ppm 3.02 (spt, J=7.0 Hz, 1H), 1.27 (d, J=7.1 Hz, 6H); ER-LCMS m/z 169.1 [M+H] ⁺ .

Step 4: 3-isopropyl-1,4-dihydropyrazolo[4,3-d]pyrimidine-5,7-dione

ABOUT

CDI (477.20 mg, 2.94 mmol, 1 1 eq.) and the mixture was stirred at 80° C. for 12 hours. LC-MS indicated that the starting material had been completely consumed and one major peak with the desired MS was found. The reaction mixture was concentrated to give 3-isopropyl-1,4-dihydropyrazolo[4,3-d]pyrimidine-5,7-dione (550 mg, crude) as a brown solid.

1H NMR (400 MHz, CD3OD) δ ppm 3.22-3.13 (m, 1H), 1.30 (d, J=6.8 Hz, 6H); ER-LCMS m/z 195.1 [M+H] ⁺ .

- 106 041983

Stage 5: 5,7-dichloro-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidine ci

A solution of 3-isopropyl-1,4-dihydropyrazolo[4,3-d]pyrimidine-5,7-dione (500 mg, 2.57 mmol, 1 eq.) in POCl ₃ (10 ml) was stirred at 100°C in within 2 h. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (50 ml), adjusted to pH 8 and extracted with EtOAc (50 ml x 2). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (ISCO®; 4 g SepaFlash® flash chromatography column with silica, eluent: gradient 0-30% ethyl acetate/petroleum ether at a flow rate of 15 ml/min) to give 5,7-dichloro-3isopropyl-1H-pyrazolo[4,3-d]pyrimidine (110 mg, 442, 22 µmol, 17.18% yield, 92.9% purity) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 10.39 (broad s, 1H), 3.51 (spt, J=6.9 Hz, 1H), 1.47 (d, J=6.8 Hz , 6H); ER-LCMS m/z 231.3, 233.3 [M+H] ⁺ .

Step 6: 5-chloro-N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine

To a solution of 5,7-dichloro-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidine (110 mg, 442.22 µmol, 1 eq.), 2-(1H-indol-3-yl)ethanamine ( 85.02 mg, 530.67 µmol, 1.2 eq.) in i-PrOH (5 ml) was added DIEA (171.46 mg, 1.33 mmol, 231.08 µl, 3 eq.). The mixture was stirred at 8° C. for 16 hours. LC-MS indicated that the starting material had been completely consumed and one major peak was found with the desired MS. The reaction mixture was concentrated under reduced pressure to give 5-chloro-N-[2-(1H-indol-3yl)ethyl]-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine (160 mg, 392.29 µmol, 88.71% yield, 87% purity) as a brown solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 7.67 (br s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.14-7.08 (m, 2H) , 7.046.98 (m, 1H), 3.94 (q, J=6.2 Hz, 2H), 3.43 (broad s, 1H), 3.17 (t, J=7.2 Hz, 2H), 1.39 (s, 6H); ER-LCMS m/z 355.2, 357.1 [M+H]+.

Step 7: 5-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-1H-pyrazolo[4,3d]pyrimidin-7-amine ( I-1)

To a mixture of 5-chloro-N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine (80 mg, 196.15 µmol , 1 eq.), (5-fluoro-3-pyridyl)boronic acid (33.17 mg, 235.38 µmol, 1.2 eq.), Cs ₂ CO ₃ (159.77 mg, 490.37 µmol, 2.5 eq.) in 1,4-dioxane (2 ml) and water (0.5 ml) was added Pd(dppf)Cl ₂ (7.18 mg, 9.81 μmol, 0.05 eq.) in an atmosphere N2. The mixture was stirred in N2 at 120° C. for 30 min while being treated with microwave radiation. LCMS indicated that 82.5% of the product was detected. The reaction mixture was concentrated under reduced pressure and the residue was diluted with DCM (20 ml) and extracted with DCM (20 mlx2). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0 .05% HCl)-ACN]; B%: 40%-70%, 10 min). The desired fraction was lyophilized to give 5-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-1H-pyrazolo[4,3d]pyrimidin-7- amine (66.84 mg, 123.15 µmol, 62.78% yield, 96.7% purity, 3HCl salt) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.93 (s, 1H), 8.74 (d, J=2.6 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H ), 7.55 (d,

- 107 041983

J=7.9Hz, 1H), 7.16(d, J=7.9Hz, 1H), 7.04(s, 1H), 6.94(t, J=7.7Hz, 1H) , 6.88-6.81 (m, 1H), 4.18 (t, J=6.6 Hz,

2H), 3.57 (d, J=7.0, 13.9 Hz, 1H), 3.21 (t, J=6.6 Hz, 2H), 1.44 (d, J=7.1 Hz, 6H); ER-LCMS m/z 415.9 [M+H] ⁺ .

Example 14

Synthesis I-9

HCHO (680.06 mg, 8.38 mmol, 623.91 µl, 37% in water, 1.1 eq.) and N-methylmethanamine hydrochloride (695.78 mg, 8.53 mmol, 1.12 eq.). The mixture was stirred at 120° C. for 3 hours. TLC (DCM/MeOH = 10/1, R _f = 0.06) indicated that the starting material had been completely consumed and one major new spot was detected. The reaction mixture was concentrated under reduced pressure to give N,Ndimethyl-1-(1H-pyrrolo[2,3-c]pyridin-3-yl)methanamine (1.85 g, crude) as a yellow oil which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 8.83 (d, J=7.7 Hz, 1H), 8.22 (d, J=5.7 Hz, 1H), 7.97 (s, 1H) , 7.91 (d, J=0.7 Hz, 1H), 4.56 (s, 2H), 2.87 (s, 6H); ER-LCMS m/z 176.2 [M+H] ⁺ .

Step 2: 2-(1H-pyrrolo[2,3-c]pyridin-3-yl)acetonitrile

To a solution of N,N-dimethyl-1-(1H-pyrrolo[2,3-c]pyridin-3-yl)methanamine (2.75 g, 8.55 mmol, 1 eq.) in THF (20 ml) in dimethyl sulfate (1.08 g, 8.55 mmol, 810.81 µl, 1.0 eq.) was added dropwise. The resulting mixture was stirred at 70° C. for 30 minutes. THF was removed and the residue was dissolved in water (15 ml). KCN (612.44 mg, 9.40 mmol, 1.1 eq.) was added to the mixture and the mixture was stirred at 110° C. for 3 hours. desired MS. The reaction mixture was diluted with water (40 ml) and extracted with EtOAc (45 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 2-(1H-pyrrolo[2,3-c]pyridin-3-yl)acetonitrile (417.0 mg, crude) as a solid yellow, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 8.70 (s, 1H), 8.13 (d, J=5.8 Hz, 1H), 7.67 (d, J=5.8 Hz, 1H) , 7.58 (s, 1H), 4.01 (s, 2H); ER-LCMS m/z 158.1 [M+H]+.

- 108 041983

Step 3: 2-(1H-pyrrolo[2,3-c]pyridin-3-yl)ethanamine

BH ₃ -Me ₂ S (10 M, 2.65 ml, 10 eq.). The mixture was stirred at 70° C. for 2 hours. LCMS indicated that the starting material had been completely consumed and one major peak was detected. MeOH (50 ml) was added dropwise to the reaction mixture and it was stirred at 70°C for 2 hours. The mixture was concentrated under reduced pressure to give 2-(III-pyrrolo[2,3-c]pyridin-3yl)ethanamine (423 .9 mg, crude) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 8.71-8.59 (m, 1H), 8.08-8.00 (m, 1H), 7.73-7.64 (m, 1H), 7 .63-7.53 (m, 1H), 3.09-2.92 (m, 4H); ER-LCMS m/z 162.1 [M+H]+.

Stage 4: 2-(5-fluoro-3-pyridyl)-9-isopropyl-N-[2-(1 H-pyrrolo[2,3-c]pyridin-3-yl)ethyl]purine-6amine (I- 9)

DIEA (57 .72 mg, 446.64 µmol, 77.79 µl, 3.0 eq.) and 2-(III-pyrrolo[2,3c]pyridin-3-yl)ethanamine (72.00 mg, 446.64 µmol, 3.0 equiv.). The mixture was stirred at 50° C. for 15 hours. LCMS showed that 71% of the desired compound was found. The reaction mixture was concentrated under reduced pressure to remove i-PrOH. The residue was purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; V%: 30%-60%, 10 min) and the desired fraction lyophilized to give 2-(5-fluoro-3-pyridyl)-9-isopropyl-N-[2-(1H-pyrrolo[2,3-c]pyridin-3-yl)ethyl]purine-6-amine (11.84 mg, 21.76 µmol, 14.62% yield, 96.66% purity, 3HCl salt) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.54 (s, 1H), 9.36 (s, 1H), 9.05-8.98 (m, 2H), 8.96 (s, 1H), 8.27-8.22 (m, 1H), 8.21-8.16 (m, 2H), 5.15 (td, J=6.7, 13.6 Hz, 1H), 4.21 ( t, J=6.4 Hz, 2H), 3.39 (t, J=6.7 Hz, 2H), 1.74 (d, J=6.8 Hz, 6H); ER-LCMS m/z 417.0 [M+H] ⁺ .

Example 15

Synthesis I-11

- 109 041983

Step 1: N-(2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-9-isopropyl-9Hpurine-6- amine (I-11)

DIEA (97.47 mg, 754.17 µmol, 131.36 µl, 5 eq.) and 2-(5,7-difluoro-2-methyl-1Hindol-3-yl)ethanamine (45.29 mg, 150.83 µmol, 1 eq., oxalic acid). The mixture was stirred at 50° C. for 16 hours. LCMS showed that 65% of the desired compound was found. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 50%-80%, 10 min) and the desired fraction was lyophilized to give N-(2-(5,7-difluoro-2methyl-1H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-9-isopropyl- 9H-purine-6-amine (53.81 mg, 36.8% yield, 100% purity, 3HCl salt) as a light yellow solid.

Ή NMR (400 MHz, CD3OD) δ ppm 9.36 (s, 1H), 8.85 (s, 1H), 8.76 (s, 1H), 8.61 (d, J=8.8 Hz, 1H), 6.95 (d, J=7.3 Hz, 1H), 6.49 (t, J=10.2 Hz, 1H), 5.11-4.99 (m, 1H), 4, 03 (s, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.31 (s, 3H), 1.70 (d, J=6.8 Hz, 6H); ER-LCMS m/z 466.0 [M+H]+.

Example 16

Synthesis I-14

TEA (5.31 g, 52.44 mmol, 7 .30 ml, 3 eq.) and (Boc) ₂ O (4.58 g, 20.98 mmol, 4.82 ml, 1.2 eq.). The mixture was stirred at 15°C for 3 hours. LCMS indicated that the starting material had been completely consumed and one major peak was found with the desired MS. H2O (20 ml) was added and the mixture was subjected to extraction with DCM (20 mlx3). The combined organic layers were washed with brine (20

- 110 041983 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure, obtaining a residue, which was purified using silica gel column chromatography (from PE/EtOAc =

1/0 to 3/1, TLC: PE/EtOAc=2/1, Rf=0.45) to give t-butyl (2-(1H-indol-3-yl)ethyl)carbamate (3.55 g,

13.50 mmol, 77.2% yield, 99% purity) as a yellow solid.

1H NMR (400 MHz, CDC13) δ ppm 8.13 (broad s, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.24-7.16 (m, 1H), 7.16-7.08 (m, 1H), 7.00 (s, 1H), 4.59 (br s, 1H), 3 .47 (q, J=6.4 Hz, 2H), 2.96 (t, J=6.8 Hz, 2H), 1.46 (s, 9H); ER-LCMS m/z 283.0 [M+Na]+.

Stage 2: tert-butyl (2-(1-methyl-1H-indol-3-yl)ethyl)carbamate

I

-—N Gu.

NaH (456.30 mg , 11.41 mmol, 60% purity, 2.0 eq.) at 0°C for 5 min. After the addition, the mixture was stirred at this temperature for 20 minutes, then MeI (809.67 mg, 5.70 mmol, 355.12 μl, 1.0 eq.) was added dropwise at 0°C. The resulting mixture was stirred at 10°C for 2 hours. TLC (PE/EtOAc = 3/1, Rf = 0.49) showed that the starting material was completely consumed and two new spots formed. The reaction mixture was quenched by adding water (50 ml) at 10°C then extracted with EtOAc (30 mlx3). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EA = 1/0 to 3/1, TLC : PE/EA=3/1, Rf=0.49) to give tert-butyl N-[2-(1-methylindol-3-yl)ethyl]carbamate (900 mg, 50.4% yield, 87 purity, 6%) as a colorless oil.

1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J=7.8 Hz, 1H), 7.74-7.57 (m, 2H), 7.55-7.43 (m, 1H ), 4.99 (br s, 1H), 4.13 (s, 3H), 3.89-3.81 (m, 2H), 3.32 (t, J=6.4 Hz, 2H) , 1.82 (s, 9H); ER-LCMS m/z 219.0 [M-tBu+H] ⁺ .

Stage 3: 2-(1-methyl-1H-indol-3-yl)ethanamine

I r- ^N Gu.

HCl/MeOH (4 M, 5 ml, 8.95 eq.). The mixture was stirred at 10° C. for 4 hours. TLC (EtOAc, R _f = 0.0) indicated that the starting material had been completely consumed. The reaction mixture was concentrated under reduced pressure to give crude 2-(1-methylindol-3-yl)ethanamine (500 mg, crude, 2HCl) as a white solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 7.58 (d, J=7.8 Hz, 1H), 7.36 (d, J=8.3 Hz, 1H), 7.20 (t, J= 7.5 Hz, 1H), 7.14-7.04 (m, 2H), 3.78 (s, 3H), 3.27-3.19 (m, 2H), 3.15-3.07 (m, 2H); ER-LCMS m/z 175.1 [M+H] ⁺ .

Step 4: 2-chloro-9-isopropyl-N-(2-(1-methyl-1H-indol-3-yl)ethyl)-9H-purine-6-amine

DIEA (855.30 mg, 6.62 mmol, 1.15 ml, 8 eq.) and 2-(1-methylindol-3-yl)ethanamine (306.70 mg, 992.69 µmol, 1.2 eq., 2HC1). The mixture was stirred at 50° C. for 14 hours. LC-MS showed that the starting material was completely consumed and one major peak was found with the desired MS. The reaction mixture was concentrated under reduced pressure to remove i-PrOH (10 ml) and the residue was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/2, Rf = 0.62) to give 2-chloro-9-isopropyl-N-[2-(1-methylindol-3-yl)ethyl]purine-6-amine (250 mg, 81.9% yield, 100% purity) as a colorless oil.

1H NMR (400 MHz, CD3OD) δ ppm 8.48-8.19 (m, 2H), 7.73 (d, J=7.5 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.25-6.94 (m, 3H), 4.70-4.58 (m, 1H), 3.77-3.64 (m, 5H), 3.06-2, 91 (m, 2H), 1.50 (d, J=6.5 Hz, 6H); ER-LCMS m/z 369.1, 371.1 [M+H] ⁺ .

- 111 041983

Step 5: 2-(5-fluoropyridin-3-yl)-9-isopropyl-N-(2-(1-methyl-1H-indol-3-yl)ethyl)-9H-purine-6amine (I-14)

2-Chloro-9-isopropyl-N-[2-(1-methylindol-3-yl)ethyl]purine-6-amine (100 mg, 271.10 µmol, 1 eq), (5-fluoro-3- pyridyl)boronic acid (95.50 mg, 677.76 µmol, 2.5 eq.), Pd(dppf)Cl ₂ (19.84 mg, 27.11 µmol, 0.1 eq.) and Cs ₂ CO ₃ (264.99 mg, 813.31 µmol, 3.0 eq.) were placed in a microwave tube in 1,4-dioxane (3 ml) and H2O (0.6 ml). The sealed tube was heated at 120° C. for 30 minutes while being treated with microwave radiation. LC-MS showed that the starting material was completely consumed and one main peak with the desired MS was found. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 ml), filtered through SiO ₂ . The filter residue was washed with EtOAc (10 mlx2). The combined organic layers were concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)ACN]; B%: 55%-85%, 10 min). The desired fraction was lyophilized to give 2-(5-fluoro-3-pyridyl)-9isopropyl-N-[2-(1-methylindol-3-yl)ethyl]purine-6-amine (53.81 mg, yield 36.8 %, purity 100%, salt 3HCl) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.36 (s, 1H), 9.11 (broad s, 1H), 8.84 (s, 1H), 8.75 (d, J=8, 8 Hz, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.20 (d, J=7.9 Hz, 1H), 7.07 (t, J=7.5 Hz , 1H), 7.02-6.93 (m, 2H), 5.09 (td, J=6.8, 13.6 Hz, 1H), 4.16-4.10 (m, 2H), 3.61 (s, 3H), 3.20 (t, J=6.6 Hz, 2H), 1.72 (d, J=6.8 Hz, 6H); ER-LCMS m/z 430.2 [M+H]+.

Example 17. Synthesis of I-7 h N' TU N ———- g Ν HCHO, l-BuOH \ . Ν H Ν ^7 ^with bh ₃ /dms №\ -----------► 1 νη __ η ₂ ν ^/ ^ ^/ F^^H (OH) ₂ TU Ν Pd (dppf) CI ₂ , CS2CO3, 1,4-dioxane, H2O || ^-nh X^N 1-7 _ CN _/ dimethyl sulfate G-< \ KCN ^H -NH Ϊ IX AU-m 1 _N y-% l X> * SG N ^N , DIEA \___ --NH HN ^-- -U Xn Tx> 1-7 /

- 112 041983

Step 1: N,N-dimethyl-1-(1H-pyrrolo[3,2-b]pyridin-3-yl)methanamine \ N—

MJ

Η

HCHO (377.65 mg, 4.65 mmol, 346.47 µl, 37% in water, 1.1 eq) and N-methylmethanamine (379.43 mg, 4.65 mmol, 1.1 eq, HCl salt). The mixture was stirred at 120° C. for 3 hours. LC-MS indicated that the starting material had been completely consumed and one major peak was found with the desired MS. The reaction mixture was concentrated under reduced pressure to give N,N-dimethyl-1-(1H-pyrrolo[3,2b]pyridin-3-yl)methanamine (559.7 mg, crude) as a yellow solid which was used on next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 8.32 (dd, J=1.1, 4.6 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.56 ( s, 1H), 7.16 (dd, J=4.8, 8.3 Hz, 1H), 3.80 (s, 2H), 2.28 (s, 6H); ER-LCMS m/z 176.1 [M+H]+.

Step 2: 2-(1H-pyrrolo[3,2-b]pyridin-3-yl)acetonitrile

CN

V / ^N u ny

H

To a solution of N,N-dimethyl-1-(1H-pyrrolo[3,2-b]pyridin-3-yl)methanamine (200.00 mg, 1.14 mmol, 1 eq.) in THF (1.5 ml ) dimethyl sulfate (143.96 mg, 1.14 mmol, 108.24 µl, 1.0 eq.) was added dropwise. The resulting mixture was stirred at 70° C. for 30 minutes. The solvent was removed and the residue was dissolved in water (1.2 ml). KCN (81.76 mg, 1.26 mmol, 1.1 eq.) was added to the mixture and the mixture was stirred at 110°C for 3 h. LC-MS indicated that the starting material had been completely consumed and one major peak with the desired MS. The reaction mixture was diluted with water (5 ml) and extracted with EtOAc (15 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 2-(1H-pyrrolo[3,2-b]pyridin-3-yl)acetonitrile (131.7 mg, 662.72 µmol, yield 58.1%, 79.1% pure) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 8.37-8.29 (m, 1H), 7.87-7.78 (m, 1H), 7.64-7.51 (m, 1H), 7 .25-7.14 (m, 1H), 4.01 (d, J=0.9 Hz, 2H); ER-LCMS m/z 158.1 [M+H]+.

Step 3: 2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethanamine

BH ₃ -Me ₂ S (1 ml, 10 M in Me ₂ S). The reaction mixture was stirred at 70° C. for 2 hours. LC-MS indicated that the starting material had been completely consumed and one major peak was detected. MeOH (30 ml) was added dropwise and the mixture was stirred at 70° C. for 2 hours. The mixture was concentrated under reduced pressure to give 2-(1H-pyrrolo[3,2-b]pyridin-3yl)ethanamine (50.00 mg , crude) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 8.30 (d, J=4.6 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.44 (s, 1H) , 7.16 (dd, J=4.6, 8.2 Hz, 1H), 3.35 (s, 2H), 3.03 (s, 2H); ER-LCMS m/z 162.2 [M+H]+.

Stage 4: 2-chloro-9-isopropyl-N-[2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]purine-6-amine

DIEA (172.57 mg, 1.34 mmol , 232.57 µl, 5.0 eq.) and 2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethanamine (50.00 mg, 267.05 µmol, 1 eq.). The mixture was stirred at 50° C. for 12 hours. LC-MS indicated that the starting material had been completely consumed and 55% of the desired compound was found. The reaction mixture was concentrated and the residue was purified by preparative TLC (SiO ₂ , DCM/MeOH=10/1, Rf=0.65) to give 2-chloro-9-isopropyl-N-[2-(1H-pyrrolo[3, 2-b]pyridin-3-113 041983 yl)ethyl]purine-6-amine (25.00 mg, 70.26 µmol, 26.3% yield, 100% purity) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.30 (dd, J=1.3, 4.8 Hz, 1H), 8.08 (s, 1H), 7.77 (dd, J=1.1 , 8.2 Hz, 1H), 7.44 (s, 1H), 7.14 (dd, J=4.8, 8.3 Hz, 1H), 4.79-4.68 (m, 1H) , 3.96-3.87 (m, 2H), 3.20 (t, J=6.8 Hz, 2H), 1.56 (d, J=6.8 Hz, 6H); ER-LCMS m/z 356.1, 358.1 [M+H]+.

Step 5: 2-(5-fluoro-3-pyridyl)-9-isopropyl-N-[2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]purine-6amine (I-7 )

2-chloro-9-isopropyl-N-[2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]purine-6-amine (25.00 mg, 70.26 µmol, 1 eq .), (5-fluoro-3-pyridyl)boronic acid (24.75 mg, 175.65 µmol, 2.5 eq.), Cs ₂ CO ₃ (68.68 mg, 210.78 µmol, 3.0 equiv.) and Pd(dppf)Cl ₂ (5.14 mg, 7.03 µmol, 0.1 equiv.) were placed in a tube with microwave radiation in 1,4-dioxane (2 ml) and water (0.4 ml ). The sealed tube was heated at 120° C. for 30 minutes while being treated with microwave radiation. LC-MS showed that the starting material was completely consumed and 60% of the desired compound was found. The reaction mixture was diluted with EtOAc (10 ml) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions, column: Phenomenex Kinetex XB-C18 150 mm x 30 mm, 5 µm; mobile phase: [water (0.05% HCl)ACN]; B %: 5%-35%, 12 min) and the desired fraction was lyophilized to give 2-(5-fluoro-3-pyridyl)-9isopropyl-N-[2-(1H-pyrrolo[3,2-b]pyridine-3 -yl)ethyl]purine-6-amine (8.83 mg, 16.14 µmol, 23.0% yield, 96.1% purity, 3HCl salt) as a white solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.37 (s, 1H), 8.92 (s, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 8.51 (s, 1H), 8.43 (d, J=7.3 Hz, 1H), 8.05 (s, 1H), 7.59 (s, 1H), 5.06 (td, J=6, 8, 13.6 Hz, 1H), 4.22 (t, J=6.4 Hz, 2H), 3.38 (t, J=6.8 Hz, 2H), 1.70 (d, J= 6.8 Hz, 6H); ER-LCMS m/z 417.2 [M+H] ⁺ .

Example 18.

Synthesis I-13

Synthesis scheme:

Cl

1-13

Pd(dppf)CI ₂ , Cs ₂ CO ₃

1,4-dioxane, H ₂ O

- 114 041983

Step 1: N-(2-(1H-benzo[d]imidazol-1-yl)ethyl)-2-chloro-9-isopropyl-9H-purine-6-amine

DIEA (106.91 mg, 827.24 µmol, 144.09 µl, 1 eq.) and 2-(benzimidazol-1-yl)ethanamine (160.02 mg, 992.69 µmol, 1.2 eq.). The mixture was stirred at 50° C. for 16 hours. LC-MS showed that the starting material was completely consumed and one major peak was found with the desired MS. The reaction mixture was concentrated under reduced pressure to remove i-PrOH to give a residue which was purified by silica gel flash column chromatography (DCM/MeOH = 1/0 to 10/1, TLC: DCM/MeOH = 10/1, R _f =0.33) to give N-[2-(benzimidazol-1-yl)ethyl]-2-chloro-9-isopropyl-purine6-amine (275 mg, 93.4% yield, 100% purity) as white solid.

1H NMR (400 MHz, CD3OD) δ ppm 7.98-7.71 (m, 2H), 7.54 (d, J=7.5 Hz, 2H), 7.38-7.18 (m, 2H ), 6.77 (br. s, 1H), 4.86-4.67 (m, 1H), 4.53 (t, J=6.0 Hz, 2H), 4.02 (br. s, 2H), 1.69-1.46 (m, 6H); ER-LCMS m/z 356.1, 357.1 [M+H]+.

Step 2: N-(2-(1H-benzo[d]imidazol-1-yl)ethyl)-2-(5-fluoropyridin-3-yl)-9-isopropyl-9H-purine-6amine (I-13)

N-[2-(benzimidazol-1-yl)ethyl]-2-chloro-9-isopropyl-purine-6-amine (120 mg, 337.24 µmol, 1 eq), (5-fluoro-3-pyridyl )boronic acid (95.04 mg, 674.49 µmol, 2 eq.), Cs ₂ CO ₃ (329.64 mg, 1.01 mmol, 3.0 eq.) and Pd(dppf)Cl ₂ (12, 34 mg, 16.86 μmol, 0.05 eq.) in 1,4-dioxane (5 ml) and H ₂ O (1 ml) was degassed and refilled with N ₂ . The mixture was heated to 80° C. for 12 hours. LC-MS showed 58% of the desired compound. The reaction mixture was poured into H ₂ O (30 ml) then extracted with EtOAc (20 mlx3). The organic phase was combined, washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 38%-68%, 10 min), giving N-[2-(benzimidazol-1-yl)ethyl]-2-(5-fluoro-3pyridyl)-9-isopropyl-purine-6-amine (31.40 mg, 22.4% yield, 100% purity ) as a white solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.08 (broad s, 1H), 8.43 (d, J=2.6 Hz, 1H), 8.17 (s, 1H), 8.15- 7.95 (m, 2H), 7.67 (d, J=8.2 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.26 (t, J=7 .7 Hz, 1H), 7.17-7.00 (m, 1H), 4.88-4.83 (m, 1H), 4.62 (t, J=5.4 Hz, 2H), 4 .20 (br s, 2H), 1.63 (d, J=6.8 Hz, 6H); ER-LCMS m/z 417.1 [M+H] ⁺ .

Example 19.

Synthesis I-8

- 115 041983

Synthesis scheme:

1-8

Stage 1: 2,6-dichloro-9-isopropyl-purine

CI

To a solution of 2,6-dichloro-9H-purine (20 g, 105.82 mmol, 1 eq.) in DMSO (160 ml) was added K ₂ CO ₃ (73.13 g, 529.09 mmol, 5 eq.) and 2-bromopropane (65.07 g, 529.09 mmol, 49.67 ml, 5 eq.). The mixture was stirred at 25° C. for 12 hours. TLC (PE/EtOAc = 1/1, R _f = 0.45) indicated that the starting material had been completely consumed and one major new spot was detected. The reaction mixture was diluted with water (200 ml) and extracted with EtOAc (100 mlx3). The combined organic layers were washed with water (80 mlx3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash column chromatography (PE/EtOAc = 5/1 to 2/1 , TLC: PE/EtOAc = 1/1, R _f = 0.45) to give 2,6-dichloro-9-isopropyl-purine (3.52 g, 14.75 mmol, 13.9% yield, 96 purity .8%) as a white solid.

1 H NMR (400 MHz, CD3OD) δ ppm 8.66 (s, 1H), 4.97-4.89 (m, 1H), 1.65 (d, J=6.8 Hz, 6H); ER-LCMS m/z 231.0, 232.9 [M+H]+.

Stage 2: 2-chloro-9-isopropyl-N-[2-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethyl]purine-6-amine

DIEA (400.86 mg, 3.10 mmol, 540 .24 µl, 5.0 eq.) and 2-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethanamine (100 mg, 620.33 µmol, 1 eq.). The mixture was stirred at 50° C. for 12 hours. LC-MS indicated that the starting material had been completely consumed and 33% of the desired compound was found. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel flash chromatography (DCM/MeOH = 100/1 to 5/1, TLC: DCM/MeOH = 10/1, R _f = 0.68) to give 2-chloro-9-isopropyl- N-[2-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethyl]purine-6-amine (74.5 mg, 33.8% yield, crude) as yellow solid; ER-LCMS m/z 356.0, 357.0 [M+H] ⁺ .

Step 3: 2-(5-fluoro-3-pyridyl)-9-isopropyl-N-[2-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethyl]purine-6amine (I-8 )

2-chloro-9-isopropyl-N-[2-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethyl]purine-6-amine (74.5 mg, 104.69 µmol, 1 eq .), (5-fluoro-3-pyridyl)boronic acid (36.88 mg, 261.72 µmol, 2.5 eq.), Cs ₂ CO ₃ (102.33 mg, 314.06 µmol, 3.0 eq.) and Pd(dppf)Cl ₂ (7.66 mg, 10.47 µmol, 0.1 eq.) were placed in a tube with

- 116 041983 microwave radiation in 1,4-dioxane (3 ml) and water (0.6 ml). The sealed tube was heated at 120° C. for 30 minutes while being treated with microwave radiation. LC-MS showed that the starting material was completely consumed, 56% of the desired compound was found. The reaction mixture was diluted with EtOAc (15 ml) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions, column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%- 45%, 10 min) and the desired fraction was lyophilized to give 2-(5-fluoro-3-pyridyl)-9-isopropylN-[2-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethyl] purine-6-amine (22.19 mg, 42.20 µmol, 40.3% yield, 100% purity, 3HCl salt) as a white solid.

Ή NMR (400 MHz, CD ₃ OD) δ ppm 9.53 (s, 1H), 9.31 (s, 2H), 9.00-8.94 (m, 2H), 8.28 (d, J =6.5Hz, 1H), 7.85(d, J=6.8Hz, 1H), 7.79(s, 1H), 5.14(d, J=6.7, 13.5Hz , 1H), 4.23 (s, 2H), 3.41 (t, J=6.7 Hz, 2H), 1.74 (d, J=6.8 Hz, 6H); ER-LCMS m/z 417.2[M+H]+.

Example 20.

Synthesis I-21

Step 1: 4,6-dichloro-2-(5-fluoro-3-pyridyl)pyrimidine

Cl

4,6-Dichloro-2-iodo-pyrimidine (1 g, 3.58 mmol, 1 eq.), (5-fluoro-3-pyridyl)boronic acid (503.91 mg, 3.58 mmol, 1 eq. ), Na ₂ CO ₃ (1.14 g, 10.73 mmol, 3.0 eq.) and Pd(dppf)Cl ₂ (261.67 mg, 357.62 μmol, 0.1 eq.) were placed in a tube with microwave radiation in 1,4 dioxane (14 ml) and water (2.4 ml). The sealed tube was heated at 80° C. for 30 minutes while being treated with microwave radiation. LCMS indicated that 58% of the desired compound was found. The reaction mixture was diluted with EtOAc (50 ml) and filtered] through a Celite pad. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 5/1, TLC: PE/EtOAc = 3/1, R _f = 0.80), affording 4,6-dichloro-2-(5-fluoro-3-pyridyl)pyrimidi] (275 mg, 1.13 mmol, 37.8% yield, 100% purity) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.34 (t, J=1.4 Hz, 1H), 8.66 (d, J=2.9 Hz, 1H), 8.51-8.4 ( m, 1H), 7.75 (s, 1H); ER-LCMS m/z 243.9, 245.9 [M+H] ⁺ .

- 117 041983

Stage 2: 4-chloro-2-(5-fluoro-3-pyridyl)-6-isopropoxy-pyrimidine

NaH (11.80 mg, 295.02 µmol, 60% in mineral oil, 1.2 eq.). The mixture was stirred at 0° C. for 30 minutes. 4,6-Dichloro-2-(5-fluoro-3-pyridyl)pyrimidine (60 mg, 245.85 µmol, 1.0 eq) was added to the above solution and the mixture was stirred at 15°C for 12 hours. LCMS indicated that 83% of the desired compound was found. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with water (30 ml) and extracted with EtOAc (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 4chloro-2-(5-fluoro-3-pyridyl)-6-isopropoxy-pyrimidine (50 mg, 167.92 µmol, 68.3 yield %, purity 89.9%) as a brown solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 9.39-9.28 (m, 1H), 8.68-8.58 (m, 1H), 8.50-8.39 (m, 1H), 6 .85 (s, 1H), 5.57 (m, 1H), 1.44 (d, J=6.2 Hz, 6H); ER-LCMS m/z 268.0, 270.0 [M+H]+.

Stage 3: 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-isopropoxy-pyrimidin-4-amine (I-21)

DIEA (65 .11 mg, 503.76 µmol, 87.74 µl, 3.0 eq.) and 2-(1H-indol-3yl)ethanamine (134.52 mg, 839.60 µmol, 5 eq.). The mixture was stirred at 70° C. for 12 hours. LCMS showed starting materials remained and the desired compound was absent. The reaction mixture was added to a microwave tube and heated at 125° C. for 3 hours while being treated with microwave radiation. LCMS indicated that the starting material had been completely consumed and 28% of the desired compound was found. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 55% -85%, 10 min) and the desired fraction was lyophilized to give 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]6-isopropoxy-pyrimidin-4-amine (26.35 mg, 52.45 µmol, 31.2% yield, 99.7% purity, 3HCl salt) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.15 (s, 1H), 8.66 (d, J=2.4 Hz, 1H), 8.32 (d, J=8.8 Hz, 1H) , 7.60 (d, J=7.7 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.13-6.95 (m, 3H), 5.69 ( m, 1H), 5.04 (m, 1H), 3.78 (m, 2H), 3.09 (t, J=6.8 Hz, 2H), 1.40-1.33 (m, 6H ); ER-LCMS m/z 392.1 [M+H] ⁺ .

Example 21.

Synthesis I-23

- 118 041983

Synthesis scheme:

Stage 1: tert-butyl N-(2-bromo-4,6-difluoro-phenyl) carbamate

A mixture of 2-bromo-4,6-difluoroaniline (5 g, 24.04 mmol, 1 eq.), Boc ₂ O (15.74 g, 72.11 mmol, 16.57 ml, 3 eq.), DMAP (293.67 mg, 2.40 mmol, 0.1 eq.) in THF (50 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 70° C. for 16 h under N2 atmosphere. LC-MS showed that the starting material had been completely consumed and the di-BOC intermediate was found. The reaction mixture was concentrated under reduced pressure to give a residue which was dissolved in MeOH (50 mL) and K2CO3 (9.97 g, 72.11 mmol, 3 eq) was added. The mixture was stirred at 70° C. for 4 hours. LC-MS indicated that the intermediate was completely consumed and one major peak was found with the desired MS. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, water (100 ml) was added to the residue, extracted with EtOAc (60 mlx3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue, n-heptane (100 ml) was added to the residue, then stirred for 1 h at 15°C. The suspension was filtered, the filter residue was rinsed with n-heptane (30 ml x 2), dried under vacuum, obtaining tert-butyl N-(2-bromo-4,6-difluorophenyl)carbamate (4.15 g, 13.47 mmol, yield 56.0%, purity 100%) as a white solid, which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCI3) δ ppm 7.18 (td, J=2.3, 7.7 Hz, 1H), 6.89 (dt, J=2.8, 8.9 Hz, 1H) , 5.91 (s, 1H), 1.51 (s, 9H); ER-LCMS m/z 251.9, 253.9 [Mt-Bu+H]+.

Stage 2: tert-butyl N-[2,4-difluoro-6-(2-trimethylsilylethynyl)phenyl]carbamate

A mixture of tert-butyl N-(2-bromo-4,6-difluorophenyl)carbamate (4 g, 12.98 mmol, 1 eq.), ethynyl(trimethyl)silane (2.55 g, 25.96 mmol, 3.60 ml, 2.0 eq.), TEA (3.94 g, 38.95 mmol, 5.42 ml, 3.0 eq.), CUI (247.24 mg, 1.30 mmol, 0, 1 eq.) and Pd(PPh3hCb (455.60 mg, 649.10 µmol, 0.05 eq.) in DMF (80 ml) were degassed and purged with N2 3 times, and then the mixture was stirred at 100°C for 16 h under N2 LC-MS showed that the starting material was completely consumed and the desired MS was found The reaction mixture was quenched by adding water (300 ml), extracted with EtOAc (200 ml x 3) The combined organic layers were washed with brine (50 ml ), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 10/1, TLC: PE/EtOAc = 20 /1, R _f = 0.31) to give tert-butyl N-[2,4-difluoro-6-(2-trimethylsilylethynyl)phenyl]carbamate (2.05 g, 5.04 mmol, 38.8% yield , 80% pure) as a black-brown solid.

1H NMR (400 MHz, CDC13) δ ppm 7.00-6.94 (m, 1H), 6.90-6.81 (m, 1H), 6.10 (s, 1H), 1.51 (s , 9H), 0.27 (m, 9H); ER-LCMS m/z 270.0 [M-t-Bu+H]+.

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Stage 3: 5,7-difluoro-III-indole r--NH._

GA xj

F

Na (791.23 mg, 34.42 mmol, 8 eq.) was added slowly to EtOH (100 ml). After stirring for 1 hour at 15°C, tert-butyl N-[2,4-difluoro-6-(2trimethylsilylethynyl)phenyl]carbamate (1.75 g, 4.30 mmol, 1 eq.) was added to the above solution. ). The mixture was stirred at 85° C. for 16 hours. LC-MS showed that the starting material had been completely consumed and the desired MS was found. The reaction mixture was concentrated under reduced pressure to remove EtOH. water (100 ml) was added to the residue and extracted with EtOAc (60 mlx3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 10/1 , TLC: PE/EtOAc = 20/1, Rf = 0.17) to give 5,7-difluoro-III-indole (410 mg, 1.87 mmol, 43.5% yield, 70% purity) as black oils.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.31 (s, 1H), 7.29-7.22 (m, 1H), 7.09 (dd, J=2.1, 9.2 Hz, 1H), 6.73 (ddd, J=2.2, 9.4, 11.1 Hz, 1H), 6.59-6.51 (m, 1H); ER-LCMS: The correct mass was not found.

Stage 4: 5,7-difluoro-1H-indole-3-carbaldehyde

To a solution of DMF (10 ml) was added POCl ₃ (350.46 mg, 2.29 mmol, 212.40 μl, 2.0 eq.) dropwise at -20°C over a period of 10 min under N2 atmosphere. After stirring for 1 hour, 5,7-difluoro-III-indole (250 mg, 1.14 mmol, 1 eq.) in DMF (2 ml) was added to the above solution while the temperature was maintained below -20°C. . The reaction mixture was heated to 15° C. and stirred for 1 h. LC-MS indicated that the starting material had been completely consumed and the desired MS was detected. The reaction mixture was quenched by adding NaHCO3 (30 ml), extracted with EtOAc (20 mlx3). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 1/1, TLC : PE/EtOAc=1/1, Rf=0.40) to give 5,7-difluoro-1H-indole-3-carbaldehyde (200 mg, 993.71 µmol, 86.9% yield, 90% purity) in form of a yellow solid.

1H NMR (400 MHz, Acetone) δ ppm 11.74 (s, 1H), 10.06 (d, J=0.8 Hz, 1H), 8.38 (s, 1H), 7.74 (dd, J=2.3, 9.0 Hz, 1H), 7.03 (ddd, J=2.3, 9.5, 11.3 Hz, 1H); ER-LCMS m/z 182.1 [M+H]+.

Step 5: 5,7-difluoro-3-[(E)-2-nitrovinyl]-1H-indole r-NH c

F

NH ₄ OAc (229.79 mg, 2.98 mmol, 3 0 equiv.). The mixture was stirred at 110° C. for 16 hours. LC-MS showed that the starting material had been completely consumed and the desired MS was found. The reaction mixture was concentrated under reduced pressure to remove nitromethane. The residue was diluted with EtOAc (50 ml), washed with water (10 ml), brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure, obtaining 5,7-difluoro-3-[(E)- 2nitrovinyl]-1H-indole (160 mg, 599.56 µmol, 60.3% yield, 84% purity) as a brown solid, which was used in the next step without further purification.

1H NMR (400 MHz, CDCI3) δ ppm 8.23 (d, J=13.6 Hz, 1H), 7.74-7.58 (m, 2H), 7.26-7.11 (m, 1H ), 6.916.75 (m, 1H); ER-LCMS m/z 225.0 [M+H] ⁺ .

Stage 6: 2-(5,7-difluoro-1H-indol-3-yl)ethanamine r-NH c Ty/ η ₂ ν^^Α^Α Λ

F

LAH (1 M, 936.82 µl, 5 equiv.) at 0°C. After the addition, the mixture was stirred at

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80° C. for 2 hours. LC-MS showed that the starting material was completely consumed and one major peak with the desired MS was found. The reaction mixture was diluted with THF (50 ml), quenched by adding water (0.05 ml), then successively 10% NaOH (0.05 ml) and water (0.15 ml) at 0°C. After stirring for 30 minutes, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give 2-(5,7-difluoro-1H-indol-3-yl)ethanamine (36 mg, crude) as a yellow oil, which was used in the next step without further purification.

1H NMR (400 MHz, CD ₃ OD) δ ppm 7.18 (s, 1H), 7.13-7.01 (m, 1H), 6.73-6.67 (m, 1H), 2.97 -2.79 (m, 4H); ER-LCMS m/z 197.2 [M+H]+.

Stage 7: N-[2-(5,7-difluoro-1H-indol-3-yl)ethyl]-2-(5-fluoro-3-pyridyl)-9-isopropyl-purine-6-amine (I- 23)

DIEA (106.33 mg, 822.73 µmol, 143.30 µl, 5 eq.) and 2-(5,7-difluoro-III-indol-3yl)ethanamine (35.51 mg, 181.00 µmol, 1.1 eq.). The mixture was stirred at 60° C. for 16 hours. LC-MS indicated that 21% of the starting material remained and 66% of the desired compound was found. The reaction mixture was concentrated under reduced pressure to remove i-PrOH to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 46 %-76%, 10 min). The desired fraction was lyophilized to give N-[2-(5,7-difluoro-1H-indol-3-yl)ethyl]-2-(5-fluoro-3-pyridyl)-9-isopropyl-purine-6-amine ( 20.82 mg, 36.75 µmol, 22.3% yield, 99% purity, 3HCl salt) as a yellow solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 9.45 (s, 1H), 9.20 (s, 1H), 8.90 (s, 1H), 8.83 (d, J=9.0 Hz, 1H), 7.24 (s, 1H), 7.11 (d, J=8.8 Hz, 1H), 6.67-6.58 (m, 1H), 5.11 (m, 1H ), 4.13 (s, 2H), 3.17 (t, J=6.6 Hz, 2H), 1.73 (d, J=6.8 Hz, 6H); ER-LCMS m/z 452.2 [M+H] ⁺ .

Example ₂₂ Synthesis of ^I -16 ^F r— NH g Υ ΗΝ^Υ^^Χ Λ ΧτΎ Ν ⁷ 1-16 0 0 γ- Ύ'he νη ₂ ηνΥχ Sr / / ^ΝΗ ι γυ "γγ ) η ₂ ν^ύλ χ _Ν ^ζ __γ γγ S - _D |EA X Mb

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Stage 1: 5-fluoropyridine-3-carbonyl chloride

DMF ( 0.1 ml) at 0°C. After the addition, the mixture was stirred at 50° C. for 2 hours. TLC (PE/EA = 1/1, R _f = 0.75, MeOH was added) indicated that the starting material had been completely consumed. The mixture was concentrated to give 5-fluoropyridine-3-carbonyl chloride (7 g, crude) as a light yellow oil, which was used in the next step without further purification.

Stage 2: 5-fluoropyridine-3-carboxamide

To a solution of ΝΗ ₃ Η ₂ Ο (31.85 g, 254.47 mmol, 35.00 ml, 28% purity, 5.80 eq.) in THF (10 ml) was added a solution of 5-fluoropyridine-3-carbonyl chloride ( 7 g, 43.87 mmol, 1 eq.) in THF (30 ml) dropwise at 0°C under N2 atmosphere. The mixture was stirred at 15° C. for 1 hour. LCMS indicated that the starting material had been completely consumed and one major peak was found with the desired MS. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with EtOAc (50 ml) and extracted with EtOAc (50 mlx2). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 5-fluoropyridine-3-carboxamide (6 g, 42.39 mmol, 96.6% yield, 99 purity .0%) as an off-white solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.87 (s, 1H), 8.62 (d, J=2.6 Hz, 1H), 8.06-8.01 (m, 1H); ER-LCMS m/z 141.1 [M+H]+.

Stage 3: 5-fluoropyridine-3-carbonitrile

XY N

To a mixture of 5-fluoropyridine-3-carboxamide (6 g, 42.39 mmol, 1 eq.) and TEA (6.43 g, 63.59 mmol, 8.85 ml, 1.5 eq.) in DCM (60 ml) TFUA (13.36 g, 63.59 mmol, 8.85 ml, 1.5 eq.) was added dropwise at 15° C. under N2 atmosphere. The mixture was stirred at 15° C. for 12 hours. TLC (PE/EA = 1/1, R _f = 0.89) showed that the starting material had been completely consumed and one new spot had formed. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (ISCO®; 24 g SepaFlash® silica flash column, eluent: gradient 0~20% ethyl acetate/petroleum ether at flow rate 30 ml/min) to give 5-fluoropyridine-3-carbonitrile (4.7 g, 36.57 mmol, 86.3% yield, 95.0% purity) as a white solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.82-8.71 (m, 2H), 8.14-8.06 (m, 1H); ER-LCMS: The correct mass was not found.

Step 4: 5-fluoro-N-(4-isopropyl-1H-pyrazol-5-yl)pyridine-3-carboxamidine

A mixture of 5-fluoropyridine-3-carbonitrile (1.02 g, 7.91 mmol, 1 eq.) and 4-isopropyl-1H-pyrazole-5-amine (880.27 mg, 6.33 mmol, 0.8 eq.) in xylene (20 ml) was stirred for 30 min at 70°C. AlMe ₃ (2 M, 4.75 mL, 1.2 eq.) was then added to the above mixture in one portion at 70° C. under N2 atmosphere. The mixture was stirred at 100° C. for 15 hours. LC-MS indicated that 16% of the desired MS was found. The mixture was quenched with MeOH (20 ml), concentrated to give a residue which was purified by silica gel flash chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: gradient 0~10% MeOH/DCM at speed flow 30 ml/min) to give 5-fluoro-N-(4-isopropyl-1H-pyrazol-5-yl)pyridine-3-carboxamidine (600 mg, 1.94 mmol, 24.5% yield, 80% purity ) as a yellow solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 8.96 (s, 1H), 8.54 (d, J=2.6 Hz, 1H), 8.11 (d, J=9.5 Hz, 1H), 7.34 (s, 1H), 3.06 (m, 1H), 1.25 (d, J=6.8 Hz, 6H); ER-LCMS m/z 248.1 [M+H]+.

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Step 5: 2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4-ol one

To a mixture of 5-fluoro-N-(4-isopropyl-1H-pyrazol-5-yl)pyridine-3-carboxamidine (100 mg, 323.53 µmol, 1 eq.) in 1,4-dioxane (10 ml) and THF (5 ml) was added triphosgene (33.60 mg, 113.24 μmol, 0.35 eq.) and then the mixture was stirred for 15 h at 80°C. LC-MS showed that 57.5% of the desired MS was found. The reaction mixture was concentrated under reduced pressure to give 2-(5fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4-ol (88 mg, crude) as a brown solid which was used in the next step without further purification.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.90-8.85 (m, 2H), 8.18 (d, J=2.3, 8.6 Hz, 1H), 7.66 (s, 1H), 3.04 (d, J=6.9, 13.7 Hz, 1H), 1.26 (d, J=6.8 Hz, 6H); ER-LCMS m/z 274.3 [M+H]+.

Stage 6: 4-chloro-2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine

Cl

2-(5-Fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4-ol mixture (88 mg, 322.03 µmol, 1 eq.) in POCl ₃ (8.1 g, 52.83 mmol, 4.91 ml, 164.04 eq.) was stirred for 2 h at 100°C. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue, then diluted with DCM (20 ml) and extracted with DCM (20 mlx2). The combined organic layers were washed with brine (15 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (ISCO®; 12 g SepaFlash® dioxide flash chromatography column silicon, eluent: gradient 0~15% ethyl acetate/petroleum ether at a flow rate of 30 ml/min), obtaining 4-chloro-2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a ][1,3,5]triazine (15 mg, 49.78 µmol, 15.5% yield, 96.8% purity) as a white solid.

1H NMR (400 MHz, CDCl3) δ ppm 9.49 (s, 1H), 8.60 (d, J=2.6 Hz, 1H), 8.42 (d, J=9.5 Hz, 1H) , 8.17 (s, 1H), 3.35 (d, J=6.7, 13.9 Hz, 1H), 1.43 (d, J=6.8 Hz, 6H); ER-LCMS m/z 292.0, 294.0 [M+H] ⁺ .

Stage 7: 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-8-isopropyl-pyrazolo[1,5-a]

[1,3,5]triazine-4-amine (I-16)

4-Chloro-2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine mixture (15 mg, 49.78 µmol, 1 eq.) , DIEA (19.30 mg, 149.33 µmol, 26.01 µl, 3 eq.) and 2-(1H-indol-3-yl)ethanamine (9.57 mg, 59.73 µmol, 1.2 eq. .) in i-PrOH (3 ml) was stirred for 3 h at 50°C. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenomenex Kinetex XB-C18 150 mm x 30 mm, 5 µm; mobile phase: [water (0.05% HCl)-ACN] ; B%: 55%-85%, 17 min) and the desired fraction was lyophilized to give 2-(5-fluoro-3-pyridyl)-N-[2-(1Hindol-3-yl)ethyl]-8-isopropyl- pyrazolo[1,5-a][1,3,5]triazine-4-amine (6.17 mg, 11.70 µmol, 23.5% yield, 99.5% purity, 3HCl) as white solid colors.

1H NMR (400 MHz, CD3OD) δ ppm 9.14 (s, 1H), 8.81 (broad s, 1H), 8.56 (d, J=9.0 Hz, 1H), 7.97 ( s, 1H), 7.69-7.63 (m, 1H), 7.18-7.12 (m, 1H), 7.00-6.94 (m, 3H), 4.04 (t, J=6.7 Hz, 2H), 3.27-3.20 (m, 1H), 3.17 (t, J=6.7 Hz, 2H), 1.37 (d, J=6.8 Hz, 6H); ER-LCMS m/z 416.2 [M+H] ⁺ .

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Example 23.

Synthesis I-24

Step 1: [5-(5-fluoro-3-pyridyl)-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1,5a] pyrimidin-3-yl]morpholino-methanone (I-24)

To a solution of 5-(5-fluoro-3-pyridyl)-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1,5a]pyrimidine- 3-carboxylic acid (25 mg, 55.60 µmol, 1 eq.) in DCM (3 ml) was added HATU (31.71 mg, 83.40 µmol, 1.5 eq.), TEA (11.25 mg, 111.20 µmol, 15.48 µl, 2 eq.) and morpholine (9.69 mg, 111.20 µmol, 9.79 µl, 2 eq.). The mixture was stirred at 25°C for 12 hours under N2. The mixture was concentrated under reduced pressure, then water (30 ml) was added, extracted with EtOAc (20 mlx3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 40%-70%, 10 min) followed by lyophilization to give [5 -(5-fluoro-3-pyridyl)-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]pyrazolo[1,5-a]pyrimidin-3-yl ]morpholino-methanone (8.45 mg, 13.61 µmol, 24.4% yield, 100% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.24 (s, 1H), 8.66 (d, J=2.6 Hz, 1H), 8.55-8.48 (m, 1H), 8, 34 (s, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.28 (d, J=7.9 Hz, 1H), 7.10-7.01 (m, 2H ), 6.99-6.93 (m, 1H), 4.54 (br s, 1H), 3.80 (s, 8H), 3.37-3.34 (m, 1H), 3, 20-3.05 (m, 1H), 3.04-2.87 (m, 2H), 2.36 (broad s, 1H), 2.28 (d, J=6.2 Hz, 1H) ; ER-LCMS m/z 512.3 [M+H]+.

Example 24.

Synthesis of I-25

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Synthesis scheme:

Step 1: 5-(5-fluoro-3-pyridyl)-N-methoxy-N-methyl-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]pyrazolo [1,5-a]pyrimidine-3-carboxamide (I-25)

Jo

To a solution of 5-(5-fluoro-3-pyridyl)-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1,5a]pyrimidine- 3-carboxylic acid (30 mg, 63.06 µmol, 1 eq.) in DCM (4 ml) was added HATU (35.97 mg, 94.59 µmol, 1.5 eq.), TEA (12.76 mg, 126.12 µmol, 17.55 µl, 2 eq) and N-methoxymethanamine (12.30 mg, 126.12 µmol, 2 eq, HCl). The mixture was stirred at 20° C. for 1 h under N ₂ atmosphere. The mixture was concentrated under reduced pressure, then water (30 ml) was added. The mixture was subjected to extraction with EtOAc (20 mlx3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The mixture was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 40% 70%, 10 min) followed by lyophilization to give 5-( 5-fluoro-3-pyridyl)-N-methoxy-N-methyl-7[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1,5- a] pyrimidine-3-carboxamide (15.98 mg, 26.86 µmol, 42.6% yield, 100% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.10 (s, 1H), 8.82 (d, J=2.8 Hz, 1H), 8.67 (s, 1H), 8.47 (d, J=9.3Hz, 1H), 7.39(d, J=7.5Hz, 1H), 7.35-7.25(m, 2H), 7.05(t, J=7.0 Hz, 1H), 7.00-6.91 (m, 1H), 4.69 (broad s, 1H), 3.87 (s, 3H), 3.43 (s, 3H), 3.18 -2.95 (m, 4H), 2.37 (dd, J=5.6, 10.2 Hz, 2H); ER-LCMS m/z 486.2 [M+H]+.

Example 25.

Synthesis I-26

1-26

Synthesis scheme:

1-26

Step 1: (3R)-N-(3-isopropyl-5-phenyl-pyrazolo[1,5-a]pyrimidin-7-yl)-2,3,4,9-tetrahydro-1Hcarbazole-3-amine (I -26)

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7-Chloro-3-isopropyl-5-phenyl-pyrazolo[1,5-a]pyrimidine mixture (60 mg, 218.15 µmol, 1 eq), (3R)2,3,4,9-tetrahydro-1H -carbazole-3-amine (44.69 mg, 239.96 µmol, 1.1 eq.), DIEA (84.58 mg, 654.44 µmol, 113.99 µl, 3 eq.) in i-PrOH ( 2 ml) was degassed and purged with N ₂ 3 times, then the mixture was stirred at 80° C. for 12 h under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini C18 250x50 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 35%-65% , 10 min) followed by lyophilization to give (3R)-N-(3-isopropyl-5-phenyl-pyrazolo[1,5-a]pyrimidin7-yl)-2,3,4,9-tetrahydro-1H-carbazole -3-amine (45.09 mg, 91.19 µmol, 41.8% yield, 100.0% purity, 2HCl) as a yellow solid.

1 H NMR (400 MHz, CD ₃ OD) δ ppm 8.12 (s, 1H), 7.97 (d, J=7.7 Hz, 2H), 7.68-7.50 (m, 3H), 7.39 (d, J=7.9 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 7.09-7.01 (m, 1H), 7.00-6 .92 (m, 1H), 6.78 (s, 1H), 4.56 (m, 1H), 3.39-3.33 (m, 2H), 3.16-2.90 (m, 3H ), 2.53-2.07 (m, 2H), 1.39 (d, J=6.8 Hz, 6H); ER-LCMS m/z 422.2 [M+H] ⁺ .

Example 26.

Synthesis of I-27a

Synthesis scheme:

Step 1: 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-[(5S)-4,5,6,7-tetrahydro-1H-benzimidazol-5yl]pyrazolo[1,5-a] pyrimidine-7-amine (I-27)

A mixture of 4,5,6,7-tetrahydro-III-benzimidazol-5-amine (62 mg, 451.95 µmol, 1 eq.), 7-chloro-5-(5fluoro-3-pyridyl)-3-isopropyl- pyrazolo[1,5-a]pyrimidine (145.99 mg, 451.95 µmol, 1 eq) and DIEA (175.24 mg, 1.36 mmol, 236.17 µl, 3 eq) in i-PrOH (3 ml) was stirred at 90°C for 12 h. The reaction mixture was concentrated under reduced pressure to dryness, obtaining a residue, which was purified using flash chromatography on silica gel (from PE/EtOAc = 20/0 to 0/1, TLC: PE/EtOAc = 1/1, Rf = 0.10). The desired fraction was dried under reduced pressure to dryness. The residue was separated by preparative SFC (column: AD (250 mm x 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O IPA]; V%: 35%-35%, min) to give peak 1 ( Rt = 5.226) and peak 2 (Rt = 5.531). The fraction corresponding to peak 1 was concentrated under reduced pressure to dryness to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B% : 20%-50%, 10 min). The desired fraction was lyophilized to give 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-[(5S)-4,5,6,7-tetrahydro-1H-benzimidazol5-yl]pyrazolo[1,5- a] pyrimidine-7-amine (25.12 mg, 50.16 µmol, 11.1% yield, 100.0% purity, 3HC1) (Rt = 5.226, [a] ^25.5 _D = -18.573 (0.105 g /100 ml in MeOH, ee% = 97.4%) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.08 (s, 1H), 8.83 (s, 1H), 8.77 (s, 1H), 8.47 (d, J=8.4 Hz, 1H), 8.25 (s, 1H), 7.07 (s, 1H), 4.72 (br s, 1H), 3.45-3.31 (m, 2H), 3.07-2 .87 (m, 3H), 2.44-2.35 (m, 1H), 2.33-2.22 (m, 1H), 1.39 (d, J=6.8 Hz, 6H); ER-LCMS m/z 392.2 [M+H]+.

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Example 27.

Synthesis of I-28a

Synthesis scheme:

Step 1: 2-(4-methoxyphenyl)propanenitrile

To a stirred solution of 1-(4-methoxyphenyl)ethanol (2 g, 13.14 mmol, 1 eq.) in DCM (10 ml) was added TMCCN solution (2.61 g, 26.28 mmol, 3.29 ml) dropwise , 2 eq.) and tribromindigan (465.90 mg, 1.31 mmol, 0.1 eq.) in DCM (10 ml) for 30 minutes. The resulting mixture was then stirred at 30° C. for 15 minutes. TLC (PE/EtOAc = 10/1, Rf = 0.55) indicated that the desired compound had been found. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 10/1, TLC: PE/EtOAc = 10/1, Rf = 0.55), affording 2-(4-methoxyphenyl)propanenitrile (1 g, 5.58 mmol, 42.5% yield, 90.0% purity) as a yellow oil.

'll NMR (400 MHz, CDCl ₃ ) δ ppm 7.27 (s, 2H), 6.97-6.86 (m, 2H), 3.91-3.79 (m, 4H), 1.63 (d, J=7.3 Hz, 3H).

Step 2: 2-(4-methoxyphenyl)propan-1-amine

To a solution of 2-(4-methoxyphenyl)propanenitrile (800 mg, 4.47 mmol, 1 eq.) in MeOH (40 ml) was added Raney-Ni (0.5 g). The mixture was degassed and purged with H ₂ three times and the mixture was stirred at 30° C. for 5 hours under H ₂ atmosphere. TLC (PE/EtOAc = 10/1, Rf = 0.10) indicated that reagent 1 was nearly used up and one new spot was detected. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (DCM/MeOH=10/1 to 5/1, TLC: DCM/MeOH=10/1, Rf=0.60), yielding 2-(4-methoxyphenyl)propan-1amine (710 mg, 3.87 mmol, 86.6% yield, 90.0% purity) as a yellow oil.

'll NMR (400 MHz, CDCl3) δ ppm 7.13 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 3.80 (s, 3H ), 2.88-2.69

- 127 041983 (m, 3H), 1.23 (d, J=6.8 Hz, 3H); ER-LCMS m/z 166.1 [M+H]+.

Step 3: 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-[2-(4-methoxyphenyl)propyl]pyrazolo[1,5a]pyrimidine-7-amine

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (250 mg, 773.93 µmol, 1.0 eq.) in i-PrOH (10 ml) was added DIEA (300.07 mg, 2.32 mmol, 404.41 μl, 3.0 eq.) and 2-(4methoxyphenyl)propan-1-amine (200 mg, 1.09 mmol, 1, 41 eq.). The mixture was stirred at 60° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.75) to give 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-[2-(4-methoxyphenyl)propyl]pyrazolo[1,5a]pyrimidine-7- amine (300 mg, 715.15 µmol, 92.4% yield, 100.0% purity) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm 9.02 (d, J=1.5 Hz, 1H), 8.53 (d, J=2.9 Hz, 1H), 8.19-8.12 ( m, 1H), 7.86 (s, 1H), 7.22 (d, J=8.6 Hz, 2H), 6.94-6.86 (m, 2H), 6.38 (t, J =5.7Hz, 1H), 6.19(s, 1H), 3.79(s, 3H), 3.68-3.53(m, 2H), 3.39-3.29(m, 1H), 3.22-3.13 (m, 1H), 1.47-1.39 (m, 9H); ER-LCMS m/z 420.2 [M+H] ⁺ .

Step 4: 4-[(1S)-2-[[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]-1methyl-ethyl ]phenol (I-28)

5-(5-fluoro-3-pyridyl)-3-isopropyl-N-[2-(4-methoxyphenyl)propyl]pyrazolo[1,5-a]pyrimidine-7amine (290.00 mg, 691.31 µmol , 1 eq.) was added to HBr (25 ml, 60% in water). The mixture was stirred at 120° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc= 3/1, Rf = 0.50). Compounds were separated by SFC (conditions: column: OJ (250 mm x 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; V%: 25%-25%, min). The separation solution was concentrated to give crude products which were purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)ACN]; B%: 45%-75 %, 10 min) followed by lyophilization to give 4-[(1S)-2-[[5-(5-fluoro-3-pyridyl)3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl] amino]-1-methyl-ethyl]phenol (26.29 mg, 54.96 µmol, 7.9% yield, 100.0% purity, 2HCl salt (Rt = 4.768 min, ee% = 100.0 and [a ] ²⁵ _D = +81.522 (MeOH, c = 0.104 g/100 ml)) as a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.81-8.79 (m, 2H), 8.24 (s, 1H), 8.11 (td, J=2.2, 9.0 Hz, 1H), 7.127.06 (m, 2H), 6.62-6.56 (m, 2H), 6.30 (s, 1H), 3.90-3.79 (m, 2H), 3 .30-3.25 (m, 1H), 3.19-3.11 (m, 1H), 1.41 (d, J=7.1 Hz, 3H), 1.36 (dd, J=2 .5, 6.9 Hz, 6H); ER-LCMS m/z 406.2 [M+H] ⁺ .

Example 28.

Synthesis I-29

- 128 041983

Synthesis scheme:

Stage 1: methyl 5-(5-fluoro-3-pyridyl)-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]pyrazolo [1,5-a] pyrimidine-3-carboxylate

To a solution of methyl 7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (300 mg, 929.31 µmol, 1 eq.) in i-PrOH ( 20 ml) was added DIEA (360.32 mg, 2.79 mmol, 485.61 μl, 3 eq.) and (3R)2,3,4,9-tetrahydro-1H-carbazole-3-amine (190.39 mg, 1.02 mmol, 1.1 eq.). The mixture was stirred at 60° C. for 3 h under N2. The mixture was concentrated under reduced pressure, then water (80 ml) was added. The mixture was subjected to extraction with EtOAc (50 mlx3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.6) to give the product methyl 5-(5-fluoro- 3-pyridyl)-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]pyrazolo[1,5-a]pyrimidine-3-carboxylate (270 mg, 561, 92 µmol, 60.4% yield, 95% purity) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.09 (s, 1H), 8.58 (d, J=2.6 Hz, 1H), 8.47 (s, 1H), 8.37-8 .25 (m, 1H), 7.95 (s, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7 .22-7.06 (m, 2H), 6.79 (d, J=8.6 Hz, 1H), 6.66 (s, 1H), 4.36 (br s, 1H), 3, 97 (s, 3H), 3.41 (dd, J=4.5, 15.3 Hz, 1H), 3.07-2.88 (m, 3H), 2.42-2.27 (m, 2H); ERLCMS m/z 457.2 [M+H]+.

Stage 2: methyl 5-(5-fluoro-3-pyridyl)-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]pyrazolo [1,5-a] pyrimidine-3-carboxylate

To a solution of methyl 5-(5-fluoro-3-pyridyl)-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]pyrazolo[1,5-a] pyrimidine-3-carboxylate (220 mg, 457.86 µmol, 1 eq.) in H2O (4 ml), MeOH (2 ml) and THF (2 ml) was added LiOH H ₂ O (275.60 mg, 6, 57 mmol, 14.34 eq.). The mixture was stirred at 50°C for 12 hours under N2. The residue was dissolved in water (30 ml), the pH was adjusted to 6 with 1 N. HCl, then extracted with EtOAc (40 mlx3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was concentrated under reduced pressure to give methyl 5-(5-fluoro-3-pyridyl)-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (150 mg, 315.29 µmol, 68.8% yield, 93.0% purity) as a yellow solid, which was used in the next step without further purification.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.25 (s, 1H), 8.59-8.50 (m, 2H), 8.49-8.40 (m, 1H), 7.38 ( d, J=7.8 Hz,

- 129 041983

1H), 7.26 (d, J=8.0 Hz, 1H), 7.09 (s, 1H), 7.06-6.87 (m, 2H), 4.50 (s, 1H), 3.28 (s, 1H), 3.15-3.02 (m, 1H), 3.002.83 (m, 2H), 2.43-2.31 (m, 1H), 2.30-2, 15 (m, 1H); ER-LCMS m/z 443.1 [M+H]+.

Step 3: [5-(5-fluoro-3-pyridyl)-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1,5a] pyrimidin-3-yl]-(4-methylpiperazin-1-yl) methanone (I-29)

To a solution of 5-(5-fluoro-3-pyridyl)-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1,5a]pyrimidine- 3-carboxylic acid (50 mg, 105.10 µmol, 1 eq.) in DCM (5 ml) were added HATU (59.94 mg, 157.65 µmol, 1.5 eq.) and TEA (21.27 mg, 210.20 µmol, 29.26 µl, 2 eq.) and 1-methylpiperazine (15.79 mg, 157.65 µmol, 17.49 µl, 1.5 eq.). The mixture was stirred at 20° C. for 1 h under N ₂ atmosphere. The mixture was concentrated under reduced pressure, then water (20 ml) was added. The mixture was subjected to extraction with EtOAc (20 mlx3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18 250x50 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 10%-40%, 10 min) followed by lyophilization to give [ 5-(5-fluoro-3-pyridyl)-7-[[(3K)-2,3,4,9tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1,5-а]pyrimidin-3- yl]-(4-methylpiperazin-1-yl)methanone (24.27 mg, 36.20 µmol, 34.4% yield, 100% purity, 4HCl) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.41 (s, 1H), 9.01-8.88 (m, 2H), 8.43 (s, 1H), 7.37 (d, J= 7.7 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 7.22 (s, 1H), 7.04 (t, J=7.5 Hz, 1H), 6 .99-6.93 (m, 1H), 4.79-4.51 (m, 3H), 3.60 (d, J=11.9 Hz, 4H), 3.29 (s, 3H), 3.20-3.07 (m, 1H), 3.03-2.90 (m, 5H), 2.43-2.21 (m, 2H); ER-LCMS m/z 525.3 [M+H] ⁺ .

Example 29.

Synthesis of I-30

Step 1: (3R)-N-(6-chloro-3-isopropyl-imidazo[1,2-a]pyrazin-8-yl)-2,3,4,9-tetrahydro-1Hcarbazole-3-amine

To a solution of 6,8-dichloro-3-isopropyl-imidazo[1,2-a]pyrazine (45 mg, 195.57 µmol, 1 eq.) and (3R)2,3,4,9-tetrahydro-1H- carbazole-3-amine (38.25 mg, 205.35 µmol, 1.05 eq.) in i-PrOH (5 ml) was added DIEA (75.83 mg, 586.72 µmol, 102.20 µl, 3 eq. .). The mixture was stirred at 60° C. for 3 hours. LC-MS indicated that 55% of the starting material remained and 5% of the desired compound was found. The mixture was stirred at 60° C. for 16 hours. LC-MS indicated that 34% of the starting material remained and 30% of the desired compound was found. The mixture was stirred at 60° C. for 16 hours. LC-MS indicated that 21% of the starting material remained and 53% of the desired compound was found. The mixture was stirred at 60° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC: PE/EtOAc = 3 /1, Rf = 0.45), obtaining the indicated product (3R)-N-(6-chloro-3-isopropylimidazo[1,2-a]pyrazin-8-yl)-2,3,4,9-tetrahydro -1H-carbazole-3-amine (60 mg, 157.94 µmol, 80.8% yield, 100.0% purity) as a light yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm 7.80 (s, 1H), 7.45 (d, J=7.5 Hz, 1H), 7.32 (s, 1H), 7.22 (s, 1H), 7.177.12 (m, 1H), 7.12-7.06 (m, 1H), 6.28 (d, J=9.3 Hz, 1H), 4.81 (br s, 1H ), 3.29 (dd, J=5.4, 16.0 Hz, 1H), 3.153.04 (m, 1H), 2.99-2.89 (m, 2H), 2.81 (dd, J=6.9, 15.1 Hz, 1H), 2.28-2.25(m, 1H), 2.23-2.15(m, 1H), 1.37(d, J=6, 8Hz, 6H); ER-LCMS m/z 380.2 [M+H]+.

Step 2: (3R)-N-[6-(5-fluoro-3-pyridyl)-3-isopropyl-imidazo[1,2-a]pyrazin-8-yl]-2,3,4,9tetrahydro-1 H-carbazole-3-amine (I-30)

To a solution of (3R)-N-(6-chloro-3-isopropyl-imidazo[1,2-a]pyrazin-8-yl)-2,3,4,9-tetrahydro-1Hcarbazole-3-amine (60 mg , 157.94 µmol, 1 eq.) and (5-fluoro-3-pyridyl)boronic acid (44.51 mg, 315.89 µmol, 2.0 eq.) in 1,4-dioxane (2 ml) and H ₂ O (0.5 ml) was added Pd(dppf)Cl ₂ (11.56 mg, 15.79 µmol, 0.1 eq.) and Cs ₂ CO ₃ (154.38 mg, 473.83 µmol, 3 0 equiv.). The sealed tube was purged with N ₂ for 3 min and heated at 110° C. for 0.5 h while being treated with microwave radiation. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified twice by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 40%- 70%, 10 min, column:

Gemini 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN]; B%: 50%-80%, 10 min) followed by lyophilization to give compound (3R)-N-[6-(5-fluoro-3-pyridyl)-3-isopropylimidazo[1,2-a]pyrazine-8 -yl]-2,3,4,9-tetrahydro-1H-carbazole-3-amine (26.85 mg, 60.59 µmol, 38.4% yield, 99.4% purity) as white solid .

1H NMR (400 MHz, CD3OD) δ ppm 9.07 (s, 1H), 8.38 (d, J=2.6 Hz, 1H), 8.25 (td, J=2.2, 10.2 Hz, 1H), 8.19 (s, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.28-7.23 (m, 2H), 7.04-6.97 (m, 1H), 6.96-6.89 (m, 1H), 4.82-4.74 (m, 1H), 4.59 (s, 1H), 3.39-3.31 (m , 1H), 3.27-3.21 (m, 1H), 2.93 (t, J=6.2 Hz, 2H), 2.83 (dd, J=7.2, 15.1 Hz, 1H), 2.35 (dt, J=2.5, 6.4 Hz, 1H), 2.25-2.13 (m, 1H), 1.38 (dd, J=2.3, 6, 7 Hz, 6H); ER-LCMS m/z 441.3 [M+H] ⁺ .

Example 30.

Synthesis I-31

- 131 041983

Stage 1: ethyl 7-hydroxy-3-isopropyl-pyrazolo[1,5-a]pyrimidine-6-carboxylate

A mixture of diethyl 2-(ethoxymethylene) propanedioate (621.89 mg, 2.88 mmol, 581.21 µl, 1 eq.), 4isopropyl-1H-pyrazole-5-amine (400 mg, 2.88 mmol, 1 eq. ) in AcOH (3 ml) was degassed and purged with N ₂ 3 times. The mixture was stirred at 120° C. for 2 h under N2. The reaction mixture was cooled to 0°C and filtered. The solid was washed with ethanol and petroleum ether and dried under reduced pressure to give ethyl 7-hydroxy-3-isopropyl-pyrazolo[1,5-a]pyrimidine-6-carboxylate (700 mg, 2.65 mmol, 92.3% yield, purity 94.5%) as a white solid which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 8.55 (s, 1H), 7.91 (s, 1H), 4.34 (q, J=7.2 Hz, 2H), 3.11 (m, 1H), 1.401.31 (m, 9H); ER-LCMS m/z 250.2 [M+H]+.

Stage 2: 3-isopropylpyrazolo[1,5-a]pyrimidin-7-ol

Hydrochloric acid (6.12 g, 61.27 mmol, 6 ml, 36.5%, 50.90 eq.). The mixture was stirred at 120°C for 12 hours. The reaction mixture was concentrated under reduced pressure to give 3-isopropylpyrazolo[1,5-a]pyrimidin-7-ol (200 mg, 902.92 µmol, 75.0% yield, purity 80.0%) as a black-brown solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 8.12 (s, 1H), 7.94 (d, J=7.5 Hz, 1H), 5.98 (d, J=7.3 Hz, 1H) , 2.91-2.78 (m, 1H), 1.25 (d, J=6.8 Hz, 6H); ER-LCMS m/z 178.1 [M+H] ⁺ .

Stage 3: 7-chloro-3-isopropyl-pyrazolo[1,5-a]pyrimidine

Solution of 3-isopropylpyrazolo[1,5-a]pyrimidin-7-ol (100 mg, 564.33 µmol, 1 eq.) in POCl ₃ (88.6 g, 577.83 mmol, 53.70 ml, 1023, 93 eq.) was stirred at 120°C for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with ice, then solid NaHCO ₃ was added to the above solution to pH 8. The reaction mixture was subjected to extraction with EtOAc (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 7-chloro-3-isopropyl-pyrazolo[1,5-a]pyrimidine (100 mg, 511.12 µmol, 90.6% yield) as a brown oil, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.34 (d, J=4.4 Hz, 1H), 8.11 (s, 1H), 6.93 (d, J=4.4 Hz, 1H ), 2.92-2.88 (m, 1H), 1.29 (d, J=6.8 Hz, 6H); ER-LCMS m/z 196.1 [M+H] ⁺

Step 4: N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-pyrazolo[1,5-a]n-pyrimidin-7-amine (I-31)

A mixture of 7-chloro-3-isopropyl-pyrazolo[1,5-a]pyrimidine (75.20 mg, 384.36 µmol, 1 eq.), 2-(1Hindol-3-yl)ethanamine (73.90 mg, 461.24 µmol, 1.2 eq.), DIEA (496.76 mg, 3.84 mmol, 669.49 µl, 10 eq.) in i-PrOH (2 ml) was degassed and flushed with N2 3 times. The mixture was stirred at 55°C for 3 h under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Syneri Max-RP C12 100x30 5u; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%-45 %, 12 min) followed by lyophilization to give N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-amine (22.81 mg, 54.77 µmol,

- 132 041983 yield 14.3%, purity 94.2%, 2HC1) as a yellow solid.

1H NMR (400 MHz, CD3CD) δ ppm 8.14 (s, 1H), 7.80 (d, J=7.1 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H) , 7.26 (d, J=8.2 Hz, 1H), 7.15-7.06 (m, 1H), 6.98 (t, J=7.5 Hz, 1H), 6.78 ( t, J=7.2 Hz, 1H), 5.95 (d, J=7.3 Hz, 1H), 3.93 (t, J=6.5 Hz, 2H), 3.21 (t, J=6.5 Hz, 2H), 3.10 (m, 1H), 1.32 (d, J=6.8 Hz, 6H); ER-LCMS m/z 320.0 [M+H]+.

Example 31.

Synthesis of I-32a

Synthesis scheme:

Step 1: 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-(4,5,6,7-tetrahydro-1H-indazol-6-yl)pyrazolo[1,5a]pyrimidin-7- amine

4,5,6,7-tetrahydro-1H-indazol-6-amine solution (40 mg, 291.58 µmol, 1 eq.), 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl- pyrazolo[1,5-a]pyrimidine (84.77 mg, 291.58 µmol, 1 eq.), DIEA (376.85 mg, 2.92 mmol, 507.89 µl, 10 eq.) in i-PrOH (4 ml) was stirred at 120° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc=100/1 to 1/1, TLC: PE /EtOAc=1/1, Rf=0.5) to give 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-(4,5,6,7-tetrahydro-1H-indazole-6- yl)pyrazolo[1,5-a]pyrimidine-7amine (90 mg, 218.42 µmol, 74.9% yield, 95.0% purity) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.16 (t, J=1.4 Hz, 1H), 8.52 (d, J=2.6 Hz, 1H), 8.37 (td, J= 2.2, 9.9 Hz, 1H), 7.93(s, 1H), 7.37(s, 1H), 6.77(s, 1H), 4.42(s, 1H), 3, 48-3.31 (m, 2H), 2.91-2.84 (m, 1H), 2.84-2.76 (m, 2H), 2.31-1.97 (m, 2H), 1.40 (d, J=6.8 Hz, 6H); ER-LCMS m/z 492.2 [M+H] ⁺ .

Step 2: 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-[(6S)-4,5,6,7-tetrahydro-1H-indazol-6yl]pyrazolo[1,5-a] pyrimidine-7-amine (I-32)

5-(5-fluoro-3-pyridyl)-3-isopropyl-N-(4,5,6,7-tetrahydro-1H-indαzol-6-yl)pyrazolo[1,5

a]pyrimidine-7-amine (130 mg, 327.45 µmol, 1 eq.) was separated by SFC (column: OD (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH ₃ H ₂ O MeOH ]; V%: 45%-45%, min) giving peak 1 (T _R = 1.465 min) and peak 2 (TR = 1.687 min). The reaction mixture (peak 1) was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 35% -65%, 10 min) followed by lyophilization to give 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-[(6S)-4,5,6,7-tetrahydro-1H-indazol-6yl ]pyrazolo[1,5-a]pyrimidine-7-amine (39.42 mg, 76.66 µmol, 23.4% yield, 97.4% purity, 3HCl) (EE = 99.3%, TR = 1.465 min), [a] ²⁶ _D = -27.146, C = 0.106 g/100 ml, MeOH) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.10 (s, 1H), 8.85 (d, J=2.2 Hz, 1H), 8.50 (d, J=8.8 Hz, 1H) , 8.27 (s, 1H), 8.09 (s, 1H), 7.09 (s, 1H), 4.76 (s, 1H), 3.50 (dd, J=5.3, 16 .5 Hz, 1H), 3.39 (m, J=6.8 Hz, 1H), 3.19-3.11 (m,

- 133 041983

1H), 2.93 (dd, J=4.4, 7.9 Hz, 2H), 2.41-2.30 (m, 1H), 2.28-2.14 (m, 1H), 1 .40 (d, J=6.8 Hz, 6H); ER-LCMS m/z

392.2 [M+H]+.

Example 32.

Synthesis I-33

Synthesis scheme:

Stage 1: tert-butyl-3-[2-[tert-butoxycarbonyl-[5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin7-yl]amino]ethyl]indole-1-carboxylate

To a solution of 5-(5-fluoro-3-pyridyl)-N-[2-(1 H-indol-3-yl)ethyl]pyrazolo[1,5-a]pyrimidin-7-amine (650 mg, 1, 75 mmol, 1 eq.) in 1,4-dioxane (30 ml) was added DMAP (639.72 mg, 5.24 mmol, 3 eq.) and (Boc) ₂ O (1.14 g, 5.24 mmol , 1.20 ml, 3 eq.). The mixture was stirred at 110° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc= 3/1, Rf = 0.75), giving the compound tert-butyl-3-[2-[tert-butoxycarbonyl-[5-(5-fluoro-3-pyridyl)pyrazolo[1,5a]pyrimidin-7-yl ]amino]ethyl]indole-1-carboxylate (575 mg, 985.06 µmol, 56.4% yield, 98.1% purity) as a yellow solid.

1H NMR (400 MHz, SES1h) δ ppm 8.74 (t, J=1.5 Hz, 1H), 8.55 (d, J=2.9 Hz, 1H), 8.19 (d, J= 2.2 Hz 1H), 8.01 (d, J=7.3 Hz, 1H), 7.87-7.81 (m, 1H), 7.47 (d, J=7.7 Hz, 1H ), 7.27-7.23 (m, 2H), 7.20-7.14 (m, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.57 (s, 1H), 4.25 (t, J=6.8 Hz, 2H), 3.13 (t, J=6.7 Hz, 2H), 1.62 (s, 9H), 1.42 (s, 9H); ER-LCMS m/z 573.3 [M+H] ⁺ .

Stage 2: tert-butyl-3-[2-[tert-butoxycarbonyl-[5-(5-fluoro-3-pyridyl)-3-iodo-pyrazolo[1.5

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a]pyrimidin-7-yl]amino]ethyl]indole-1-carboxylate

A mixture of tert-butyl-3-[2-[tert-butoxycarbonyl-[5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7yl]amino]ethyl]indole-1-carboxylate ( 250 mg, 428.29 µmol, 1 eq) and NIS (192.72 mg, 856.58 µmol, 2 eq) in DCM (10 ml) and MeCN (10 ml) were stirred at 25°C for 12 h TLC (PE/EtOAc = 4/1, Rf = 0.40) indicated that the starting material had been completely consumed. The reaction mixture was quenched with aqueous Na ₂ S ₂ O ₃ (10 ml) and extracted with DCM (10 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to dryness to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 20/1 to 5/1, TLC: PE/EtOAc = 4/1, Rf = 0.40). The desired fraction was concentrated under reduced pressure to dryness to give tert-butyl-3-[2-[tert-butoxycarbonyl-[5-(5-fluoro-3-pyridyl)-3-iodo-pyrazolo[1,5-a] pyrimidin7-yl]amino]ethyl]indole-1-carboxylate (280 mg, 400.84 µmol, 93.6% yield, 100.0% purity) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm 8.76 (s, 1H), 8.57 (d, J=2.4 Hz, 1H), 8.18 (s, 1H), 8.00 (br. s, 1H), 7.96-7.91 (m, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.26 (br s, 2H), 7.20-7 .15 (m, 1H), 6.58 (s, 1H), 4.23 (t, J=6.8 Hz, 2H), 3.12 (t, J=6.8 Hz, 2H), 1 .62 (s, 9H), 1.42 (s, 9H); ER-LCMS m/z 699.2 [M+H]+.

Stage 3: tert-butyl-3-[2-[[3-acetyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-tert-butoxycarbonyl-amino]ethyl] indole-1-carboxylate

A mixture of tert-butyl-3-[2-[tert-butoxycarbonyl-[5-(5-fluoro-3-pyridyl)-3-iodo-pyrazolo[1,5a]pyrimidin-7-yl]amino]ethyl]indol- 1-carboxylate (150 mg, 214.74 µmol, 1 eq.), tributyl(1ethoxyvinyl)stannane (310.21 mg, 858.95 µmol, 289.92 µl, 4 eq.) and Pd(dppf)Cl ₂ ( 31.43 mg, 42.95 µmol, 0.2 eq) in toluene (2 ml) was purged with N2 for 2 min and then tightly capped. The reaction mixture was irradiated under microwave radiation (1 bar) at 100° C. for 2 h. Aqueous KF (10 ml, 1 g/10 ml) was added to the mixture. The mixture was stirred at 25°C for 30 min and then extracted with EtOAc (10 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to dryness to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 2/1, TLC: PE/EtOAc = 4 /1, Rf = 0.20). The desired fraction was concentrated under reduced pressure to dryness to give tert-butyl-3-[2-[[3acetyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]- tert-butoxycarbonyl-amino]ethyl]indole 1-carboxylate (80 mg, 124.17 µmol, 57.80% yield, 95.4% purity) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.78 (s, 1H), 8.66 (d, J=2.0 Hz, 1H), 8.61 (s, 1H), 7.96 (broad s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.24-7.21 (m, 2H) , 7.14 (t, J=7.2 Hz, 1H), 6.65 (s, 1H), 4.33-4.27 (m, 2H), 3.14 (t, J=6.4 Hz, 2H), 2.84 (s, 3H), 1.59 (s, 9H), 1.43 (s, 9H); ER-LCMS m/z 615.3 [M+H] ⁺ .

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Step 4: 1-[5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3yl]ethanone

A mixture of tert-butyl-3-[2-[[3-acetyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-tert-butoxycarbonyl-amino]ethyl]indol- 1-carboxylate (80 mg, 124.17 µmol, 1 eq.) and TFA (4.62 g, 40.52 mmol, 3 ml, 326.32 eq.) in DCM (9 ml) was stirred at 25°C in within 30 min. TLC (PE/EtOAc = 1/1, Rf = 0.50) indicated that the starting material had been completely consumed. The reaction mixture was concentrated under reduced pressure at 30° C. to dryness. The residue was dissolved in water (10 ml), basified with saturated aqueous NaHCO ₃ to pH 8 and extracted with EtOAc (15 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to dryness, obtaining 1-[5-(5-fluoro-3-pyridyl)-7-[2-(1 H-indol-3 -yl) ethylamino]pyrazolo[1,5-a]pyrimidin-3 yl]ethanone (50 mg, 101.34 µmol, 81.6% yield, 84.0% purity) as a yellow solid, which was used in the next step without additional cleaning.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.81 (s, 1H), 9.16 (s, 1H), 8.71 (d, J=2.8 Hz, 1H), 8.62 (t, J=6.4 Hz, 1H), 8.53 (s, 1H), 8.26-8.20 (m, 1H), 7.65 (d, J=7.6 Hz, 1H) , 7.28 (d, J=8.0 Hz, 1H), 7.20 (s, 1H), 7.08-7.03 (m, 1H), 7.01-6.97 (m, 1H ), 6.86 (s, 1H), 3.94-3.85 (m, 2H), 3.13 (t, J=6.8 Hz, 2H), 2.71 (s, 3H); ER-LCMS m/z 415.1 [M+H]+.

Step 5: 1-[5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3yl]ethanol (I- 33)

To a solution of 1-[5-(5-fluoro-3-pyridyl)-7-[2-(1 H-indol-3-yl)ethylamino]pyrazolo[1,5-а]pyrimidin-3-yl]ethanone (50 mg, 101.34 µmol, 1 eq.) NaBH4 (38.34 mg, 1.01 mmol, 10 eq.) was added to MeOH (5 ml) and then the mixture was stirred at 25°C for 1 h. TLC (PE /EtOAc = 1/1, Rf = 0.40) showed that the starting material was completely consumed. The reaction mixture was quenched with water (10 ml) and concentrated under reduced pressure. The residue was subjected to extraction with EtOAc (15 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to dryness, obtaining a residue which was purified using preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% ammonium hydroxide vol. ./v)-ACN]; B%: 36%-66%, 10 min). The desired fraction was lyophilized to give 1-[5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3-yl]ethanol ( 3.29 mg, 7.90 µmol, 7.8% yield, 100.0% purity) as a white solid.

1H NMR (400 MHz, CDCI3) δ ppm 8.79 (s, 1H), 8.51 (d, J=2.8 Hz, 1H), 8.04 (broad s, 1H), 7.95 ( s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.22 (d, J=6.8 Hz, 2H), 7.07 (s, 1H), 6.56 (broad s, 1H), 6.09 (s, 1H), 5, 35 (s, 1H), 3.89-3.83 (m, 2H), 3.27 (t, J=6.4 Hz, 2H), 3.21 (d, J=3.6 Hz, 1H ), 1.70 (d, J=6.4 Hz, 3H); ER-LCMS m/z 417.2 [M+H]+.

Example 33.

Synthesis I-34

1-34

- 136 041983

Synthesis scheme:

Step 1: (3R)-N-[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-2,3,4,9-

7-Chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine mixture (50 mg, 171.13 µmol, 1 eq), (3R)-2, 3,4,9-tetrahydro-1H-carbazole-3-amine (31.87 mg, 171.13 µmol, 1 eq.) and DIEA (22.12 mg, 171.13 µmol, 29.81 µl, 1 eq. .) in i-PrOH (2 ml) was stirred at 80°C for 12 h. The reaction mixture was concentrated under reduced pressure to dryness, obtaining a residue which was purified using preparative HPLC (column: SynenMax-RP C12 100x30 5u; mobile phase: [water (0.05% HCl)-ACN]; B%: 50%-70%, 12 min). The desired fraction was lyophilized to give (3R)-N-[5-(5fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-2,3,4,9-tetrahydro -III-carbazole-3-amine (29.03 mg, 55.63 µmol, 32.5% yield, 100.0% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, DMSO-06) δ ppm 10.76 (s, 1H), 9.25 (s, 1H), 8.67 (d, J=2.8 Hz, 1H), 8.46 ( td, J=2.0, 10.4 Hz, 1H), 8.30 (broad s, 1H), 8.04 (s, 1H), 7.32 (d, J=7.6 Hz, 1H ), 7.24 (d, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.97 (t, J=6.8 Hz, 1H), 6.93-6.87 (m, 1H), 4.58-4.40 (m, 1H), 3.14-2.95 (m, 2H), 2.94-2.78 (m, 2H), 2.29 (s , 3H), 2.15 (br s, 2H); ER-LCMS m/z 413.2 [M+H]+.

Example 34.

Synthesis I-35

Synthesis scheme:

Step 1: (3R)-N-[5-(5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-yl]-2,3,4,9tetrahydro- 1 H-carbazole-3-amine (I-35)

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To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (35 mg, 102.58 µmol, 1 eq.) and (3R)- 2,3,4,9-tetrahydro-1H-carbazole-3-amine (21.02 mg, 112.83 µmol, 1.1 eq.) in i-PrOH (3 ml) was added DIEA (39.77 mg, 307.73 µmol, 53.60 µl, 3.0 eq.). The mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN ]; B%: 60%-90%, 10 min) followed by lyophilization to give (3R)-N-[5-(5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazolo[1,5-a ]pyrimidin-7-yl]-2,3,4,9-tetrahydro1H-carbazole-3-amine (28.79 mg, 49.45 µmol, 48.2% yield, 98.9% purity, 3HCl) as yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.36 (s, 1H), 8.87-8.79 (m, 2H), 8.34 (s, 1H), 7.37 (d, J=7 .7 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.17 (s, 1H), 7.06-6.99 (m, 1H), 6.98-6 .91 (m, 1H), 4.57-4.46 (m, 1H), 3.33-3.31 (m, 1H), 3.17-3.04 (m, 1H), 3.00 -2.88 (m, 2H), 2.42-2.33 (m, 1H), 2.31-2.19 (m, 1H); ER-LCMS m/z 467.2 [M+H]+.

Example 35.

Synthesis I-36

Synthesis scheme:

Step 1: (3R)-N-[6-chloro-2-(5-fluoro-3-pyridyl)pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazole-3amine

4,6-Dichloro-2-(5-fluoro-3-pyridyl)pyrimidine mixture (100 mg, 389.26 µmol, 1 eq), (3R)-2,3,4,9tetrahydro-1H-carbazole-3 -amine (79.75 mg, 428.19 µmol, 1.1 eq.), DIEA (150.93 mg, 1.17 mmol, 203.41 µl, 3 eq.) in i-PrOH (3 ml) was degassed and purged with N2 3 times. The mixture was stirred at 55°C for 12 hours under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R _f =0.4) , giving (3R)-N-[6-chloro-2-(5-fluoro-3-pyridyl)pyrimidin-4-yl]2,3,4,9-tetrahydro-1H-carbazole-3-amine (130 mg , 320.18 µmol, 82.3% yield, 97.0% purity) as a white solid.

1H NMR (400 MHz, CDCI3) δ ppm 9.38 (s, 1H), 8.55 (d, J=2.9 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H) , 7.91 (s, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.21-7.16 ( m, 1H), 7.14-7.10 (m, 1H), 6.34 (s, 1H), 3.25 (dd,

- 138 041983

J=5.0, 15.5 Hz, 1H), 3.04-2.74 (m, 4H), 2.23 (s, 2H); ER-LCMS m/z 394.1 [M+H]+.

Step 2: (3R)-N-[2-(5-fluoro-3-pyridyl)-6-pyrrolidin-1-yl-pyrimidin-4-yl]-2,3,4,9-tetrahydro1H-carbazole-3 -amine (I-36)

(3R)-N-[6-chloro-2-(5-fluoro-3-pyridyl)pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazole-3-amine (60 mg, 147.77 µmol, 1 eq.) and pyrrolidine (727.50 mg, 10.23 mmol, 853.87 µl, 69.22 eq.) were placed in a microwave tube in i-PrOH (2 ml). The sealed tube was heated at 135° C. for 3 hours while being treated with microwave radiation. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela Durashell C18 150x25 5u; mobile phase: [water (0.05% HCl)-ACN]; V%: 30%-60%, 12 min) followed by lyophilization to give (3R)-N-[2-(5-fluoro-3-pyridyl)-6-pyrrolidin-1-yl-pyrimidin-4-yl]-2,3,4,9tetrahydro- 1H-carbazole-3-amine (42.07 mg, 78.06 µmol, 52.8% yield, 99.8% purity, 3HCl) as a brown solid.

¹ H NMR (400 MHz, DMSO-H6) δ ppm 10.83 (s, 1H), 9.30 (s, 1H), 8.85 (s, 1H), 8.67-8.48 (m, 1H), 8.31 (s, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.26 (d, J=7.9 Hz, 1H), 7.03-6, 98 (m, 1H), 6.96-6.89 (m, 1H), 5.78 (s, 1H), 4.29 (m, 1H), 3.75-3.60 (m, 3H) , 3.51 (s, 1H), 3.10 (dd, J=4.6, 15.0 Hz, 1H), 3.02-2.89 (m, 2H), 2.76-2.63 (m, 1H), 2.222.02 (m, 2H), 1.98 (s, 4H); ER-LCMS m/z 429.3 [M+H] ⁺ .

Synthesis of I-37a

Synthesis scheme:

- 139 041983

Step 1: 5-(5-bromo-3-pyridyl)-3-isopropyl-N-(5-methoxyindan-2-yl)pyrazolo[1,5-a]pyrimidine-7amine

To a solution of 5-(5-bromo-3-pyridyl)-7-chloro-3-isopropyl-pyrazolo[1,5-a]pyrimidine (100.00 mg, 264.48 µmol, 1 eq.) in i-PrOH (5 ml) was added 5-methoxyindan-2-amine (52.81 mg, 264.48 µmol, 1 eq., HCl) and DIEA (341.82 mg, 2.64 mmol, 460.67 µl, 10 eq. ). The mixture was stirred at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.31) to give 5-(5-bromo-3-pyridyl)-3-isopropyl-N-(5-methoxyindan-2-yl)pyrazolo[1,5-a]pyrimidine-7 -amine (120 mg, 250.84 µmol, 94.8% yield, 100% purity) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.18 (d, J=1.8 Hz, 1H), 8.74 (d, J=2.2 Hz, 1H), 8.58 (t, J =2.1Hz, 1H), 7.87(s, 1H), 7.18(d, J=8.4Hz, 1H), 6.83(s, 1H), 6.79(dd, J =2.5, 8.3 Hz, 1H), 6.58 (d, J=7.7 Hz, 1H), 6.37 (s, 1H), 4.71-4.60 (m, 1H) , 3.81 (s, 3H), 3.50 (m, 2H), 3.37 (t, J=6.9 Hz, 1H), 3.08 (m, 2H), 1.42 (d, J=6.8 Hz, 6H); ER-LCMS m/z 478.1, 480.1 [M+H]+.

Step 2: 5-[3-isopropyl-7-[(5-methoxyindan-2-yl)amino]pyrazolo[1,5-a]pyrimidin-5yl]pyridine-3-carbonitrile

To a solution of 5-(5-bromo-3-pyridyl)-3-isopropyl-N-(5-methoxyindan-2-yl)pyrazolo[1,5-a]pyrimidine7-amine (120.0 mg, 250.84 µmol , 1 eq.) in DMF (6 ml) was added Zn(CN) ₂ (117.83 mg, 1.00 mmol, 4 eq.) and Pd(PPh ₃ ) ₄ (57.97 mg, 50.17 μmol, 0.2 equiv.) in an N2 atmosphere. The mixture was stirred at 85° C. for 32 hours. The reaction mixture was quenched by adding water (30 ml), then extracted with EtOAc (30 mlx3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 3/1 , TLC: PE/EtOAc=3/1, Rf=0.55) to give 5-[3-isopropyl-7-[(5-methoxyindan-2-yl)amino]pyrazolo[1,5-a]pyrimidin- 5-yl]pyridine-3 carbonitrile (80 mg, 188.46 µmol, 75.1% yield, 100% purity) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.47 (d, J=2.2 Hz, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.72 (t, J =2.1 Hz, 1H), 7.89 (s, 1H), 7.18 (d, J=8.2 Hz, 1H), 6.88-6.76 (m, 2H), 6.65 (d, J=7.5 Hz, 1H), 6.38 (s, 1H), 4.73-4.58 (m, 1H), 3.82 (s, 3H), 3.51 (m, 2H), 3.36 (t, J=7.0 Hz, 1H), 3.09 (m, 2H), 1.42 (d, J=6.8 Hz, 6H); ER-LCMS m/z 425.2 [M+H] ⁺ .

Step 3: 5-[7-[[(2S)-5-hydroxyindan-2-yl]amino]-3-isopropyl-pyrazolo[1,5-a]pyrimidin-5yl]pyridine-3-carbonitrile (I-37 )

5-[3-isopropyl-7-[(5-methoxyindan-2-yl)amino]pyrazolo[1,5-a]pyrimidin-5-yl]pyridine-3 carbonitrile mixture (35.00 mg, 74.21 µmol , 1 eq.) and pyridine hydrochloride (428.76 mg, 3.71 mmol, 50 eq.) were stirred at 190°C for 1 h under N ₂ atmosphere. The reaction mixture was quenched by slowly adding us. water. NaHCO ₃ (20 ml) then extracted with EtOAc (20 mlx3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative TLC.

- 140 041983 (PE/EtOAc = 1/1, TLC: PE/EtOAc = 1/1, R _f = 0.53) to give 5-[7-[(5-hydroxyindan-2-yl)amino]-3isopropyl -pyrazolo[1,5-a]pyrimidin-5-yl]pyridine-3-carbonitrile (15 mg, 34.20 µmol, 46.0% yield, 93.6% purity) as a yellow solid (note: 80 mg of Tatol from two lots was used for SFC separation). The racemate was separated by chiral SFC (AD (250 mm x 30 mm, 10 µm); mobile phase: [0.1% NH3H2O IPA]; B%: 55%-55%, min; peak 1 (Rt = 1.817) and peak 2 ( Rt = 2.477)). The separation solution was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 50%-80% ,10 min) followed by lyophilization to give 5-[7-[[(2S)-5hydroxyindan-2-yl]amino]-3-isopropyl-pyrazolo[1,5-a]pyrimidin-5-yl]pyridin-3 -carbonitrile (19.05 mg, 39.41 µmol, 22.7% yield, 100% purity, 2HCl) (EE=100%, Rt=1.817 min, [a] ²⁶ D=3.608 (c=1.03 mg /ml, MeOH)) in the form of a yellow solid.

Ή NMR (400 MHz, CD3OD) δ ppm 9.44 (d, J=2.2 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H), 8.84 (t, J= 2.1 Hz, 1H), 8.09 (s, 1H), 7.07 (d, J=8.2 Hz, 1H), 6.88 (s, 1H), 6.71 (s, 1H) , 6.64 (dd, J=2.2, 8.2 Hz, 1H), 4.96-4.90 (m, 1H), 3.50-3.41 (m, 2H), 3.38 -3.33 (m, 1H), 3.19-3.03 (m, 2H), 1.40 (d, J=7.1 Hz, 6H); ER-LCMS m/z 411.2 [M+H]+.

Example 37.

Synthesis I-38

1-38

Synthesis scheme:

1-38

Step 1: (3R)-N-[5-(5-bromo-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]-2,3,4,9tetrahydro-1 H-carbazole-3-amine

5-(5-Bromo-3-pyridyl)-7-chloro-3-isopropyl-pyrazolo[1,5-a]pyrimidine mixture (150 mg, 396.73 µmol, 1 eq), (3R)-2, 3,4,9-tetrahydro-1H-carbazole-3-amine (77.59 mg, 416.56 µmol, 1.05 eq) and DIEA (153.82 mg, 1.19 mmol, 207.31 µl, 3 eq.) in i-PrOH (10 ml) was degassed and purged with N2 3 times. The mixture was stirred at 80° C. for 2 hours under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc=1/0 to 10/3, TLC: PE/EtOAc=3/1, Rf=0.34) to give (3R)-N-[5-(5-6pom-3pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]-2,3,4,9-tetrahydro-III-carbazole- 3-amine (150 mg, 296.16 µmol, 74.6% yield, 99.0% purity) as a green solid.

- 141 041983

1H NMR (400 MHz, CDCl3) δ ppm 9.17 (d, J=1.8 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.60-8.55 ( m, 1H), 7.907.87 (m, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.19 ( br t, J=7.6 Hz, 1H), 7.15-7.10 (m, 1H), 6.58 (br d, J=8.8 Hz, 1H), 6.40 (s, 1H ), 4.32 (br s, 1H), 3.45-3.32 (m, 2H), 3.06-2.90 (m, 3H), 2.44-2.23 (m, 2H ),

1.43 (d, J=6.8 Hz, 6H); ER-LCMS m/z 501.1, 503.1 [M+H] ⁺ .

Step 2: 5-[3-isopropyl-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1,5a]pyrimidin-5-yl] pyridine-3-carbonitrile (I-38)

A mixture of (3R)-N-[5-(5-bromo-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]-2,3,4,9 tetrahydro-1H- carbazole-3-amine (80 mg, 157.95 µmol, 1 eq.), Pd(PPh ₃ ) ₄ (73.01 mg, 63.18 µmol, 0.4 eq.) and Zn(CN) ₂ (74 .19 mg, 631.81 µmol, 4 eq.) in DMF (5 ml) was degassed and purged with N2 3 times. The mixture was stirred at 85°C for 19 hours under N2. The mixture was concentrated and water (80 ml) was added, extracted with EtOAc (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated To a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% ammonium hydroxide o6./o6.)- ACN]; B%: 70%-100%, 10 min) to give the product 5-[3-isopropyl-7-[[(3R)-2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino ]pyrazolo[1,5-a]pyrimidin-5-yl]pyridine-3-carbonitrile (11.7 mg, 26.14 µmol, 16.6% yield, 100.0% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1H), 9.66 (d, J=2.0 Hz, 1H), 9.08-9.01 (m, 2H) , 8.03 (s, 1H), 7.96 (d, J=9.5 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.28 (d, J= 7.9 Hz, 1H), 7.06 (s, 1H), 7.01 (t, J=7.4 Hz, 1H), 6.96-6.90 (m, 1H), 4.53- 4.41 (m, 1H), 3.32-3.22 (m, 1H), 3.19-3.00 (m, 2H), 2.97-2.81 (m, 2H), 2. 23-2.13 (m, 2H), 1.38 (d, J=6.8 Hz, 6H); ER-LCMS m/z 448.2 [M+H]+.

Example 38.

Synthesis I-39

Step 1: 3-bromo-7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (50 mg, 168.39 µmol, 1 eq.) in DCM (2 ml) and ACN (4 ml ) was added NBS (32.97 mg, 185.23 µmol, 1.1 eq.). The mixture was stirred at 30°C for 1 hour under N2. The reaction mixture was concentrated under reduced pressure to give 3-bromo-7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (55.16 mg, 168.41 µmol, 100 yield, 0%, 100% pure) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl3) δ ppm 9.12 (s, 1H), 8.65 (d, J=2.6 Hz, 1H), 8.43-8.19 (m, 2H), 7, 51 (s, 1H);

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ER-LCMS m/z 327.0, 329.0 [M+H] ⁺ .

Stage 2: 3-bromo-5-(5-fluoro-3-pyridyl)-Sch2-(1 H-indol-3-yl)ethyl] pyrazolo [1,5-a] pyrimidin-7 amine (I-39)

To a solution of 3-bromo-7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (55.16 mg, 168.41 µmol, 1 eq.) in i-PrOH ( 4 ml) was added DIEA (65.30 mg, 505.22 µmol, 88.00 µl, 3 eq.) and 2-(1Hindol-3-yl)ethanamine (53.96 mg, 336.81 µmol, 2 eq. ). The mixture was stirred at 60° C. for 5 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela Durashell C18 150x25x5 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 40%-70%, 12 min) followed by lyophilization to give 3-bromo-5(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrazolo[1,5-a]pyrimidin-7 -amine (65 mg, 115.93 µmol, 68.8% yield, 100% purity, 3HCl) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.71 (s, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 7.70 (d, J=8.8 Hz , 1H), 7.62 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.05-6.91 (m, 3H), 5 .94 (s, 1H), 3.98 (t, J=5.9 Hz, 2H), 3.22 (t, J=6.0 Hz, 2H); ER-LCMS m/z 451.1, 453.1 [M+H] ⁺ .

Example 39.

Synthesis of I-40

Step 1: (3R)-N-[2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2, 3,4,9tetrahydro-1H-carbazole-3-αmin (I-40)

4-Chloro-2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine mixture (60.00 mg, 205.68 µmol, 1 eq .), (3R)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (42.14 mg, 226.25 µmol, 1.1 eq.), DIEA (79.75 mg, 617 .05 µmol, 107.48 µl, 3 eq.) in i-PrOH (4 ml) was degassed and flushed with N ₂ 3 times. The mixture was stirred at 55° C. for 3 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 70% 100%,10 min) followed by lyophilization to give (3R)-N-[2-(5-fluoro-3-pyridyl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl]- 2,3,4,9-tetrahydro-1H-carbazole-3-amine (42.07 mg, 75.45 µmol, 36.7% yield, 98.8% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.46 (s, 1H), 8.81 (d, J=9.3 Hz, 1H), 8.76 (s, 1H), 8.12-7, 92 (m, 1H), 7.37 (d, J=7.7 Hz, 1H), 7.27 (d, J=7.9 Hz, 1H), 7.08-7.00 (m, 1H ), 6.99-6.90(m, 1H), 3.34(s, 1H), 3.31-3.25

- 143 041983 (m, 2H), 3.18-2.79 (m, 3H), 2.44-2.21 (m, 2H), 1.42 (d, J=7.1 Hz, 6H) ; ER-LCMS m/z 442.2 [M+H]+.

Example 40.

Synthesis I-41

Synthesis scheme:

Step 1: (3R)-N-[5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-2,3,4,9-tetrahydro-1Hcarbazole-3- amine (I-41)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (50 mg, 166.91 µmol, 1.0 eq.) in i-PrOH (3 ml) was added DIEA (64.71 mg, 500.72 µmol, 87.21 µl, 3.0 eq.) and (3R)-2,3,4,9-tetrahydro1H-carbazole-3-amine (37.30 mg, 200 .29 µmol, 1.2 eq.). The mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 38%-68%, 10 min). The desired fraction was lyophilized to give (3R)-N-[5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-2,3,4,9-tetrahydro-1H- carbazole 3-amine (61.30 mg, 120.71 µmol, 72.3% yield, 100.0% purity, 3 HCl salt) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.01 (s, 1H), 8.77 (d, J=2.6 Hz, 1H), 8.34-8.27 (m, 2H), 7 .39 (d, J=7.7 Hz, 1H), 7.28 (d, J=7.9 Hz, 1H), 7.13 (s, 1H), 7.09-7.01 (m, 1H), 7.00-6.93(m, 1H), 6.66(d, J=2.2Hz, 1H), 4.68(s, 1H), 3.37-3.32(m , 2H), 3.14-3.01 (m, 2H), 2.44-2.28 (m, 2H); ER-LCMS m/z 339.2 [M+H]+.

Example 41.

Synthesis of I-42a

Synthesis scheme:

- 144 041983

Step 1: 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-[(5S)-4,5,6,7-tetrahydro-1H-indazol-5yl]pyrazolo[1,5-a] pyrimidine-7-amine (I-42)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (60 mg, 206.38 µmol, 1 eq.) in i-PrOH (5 ml) was added DIEA (266.73 mg, 2.06 mmol, 359.47 μl, 10 eq.) and 4,5,6,7tetrahydro-1H-indazol-5-amine (43.36 mg, 206.38 μmol , 1 equiv., 2HCl). The mixture was stirred at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 0/1, TLC: PE/EtOAc = 1/1, Rf=0.16) to give the product. The product was separated by chiral SFC (AD (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH3H2O IPA]; V%: 35%-35%, min; peak 1 (R _t = 5.512) and peak 2 ( _Rt = 6.038)). The separation solution was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 35%-65% , 10 min) followed by lyophilization to give 5-(5fluoro-3-pyridyl)-3-isopropyl-N-[(5S)-4,5,6,7-tetrahydro-1H-indazol-5-yl]pyrazolo[ 1,5-a]pyrimidine-7amine (29.07 mg, 58.0 µmol, 24.1% yield, 100% purity, 3HC1) (EE=94.6%, Rt=5.512 min, [a] ²⁶ D = 18.785 (c 1.05 mg/ml, MeOH)) as a yellow solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 9.07 (s, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.39 (td, J=2.2.9 .2 Hz, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 6.98 (s, 1H), 4.57 (s, 1H), 3.40-3.34 (m, 1H), 3.26 (dd, J=5.2, 15.3 Hz, 1H), 3.15-3.04 (m, 2H), 2.92 (dd, J=9.6 , 15.3 Hz, 1H), 2.45-2.36 (m, 1H), 2.31-2.19 (m, 1H), 1.41 (d, J=7.1 Hz, 6H) ; ER-LCMS m/z 392.2 [M+H]+.

Example 42 Synthesis of I-43 7 HN Al NC. As AT Yj “N 1-43 Synthesis scheme: 9 OO \ AXU ^Br \/ Xn o ^^ X k+ γ AA CDI, TEA, MgC1 ₂ , THF 7 OH Al 7 I y ROS1 ₃ vg \ Xs-XX -- ----► [^ A ^N but °C XV Ar lg Ga 1O ΗΝΓ [ Zn(CN) ₂ An- ^N v -------- [ I % Pd(PPh ₃ ) _{4 NC} vg\ A>A7'X TA N NH - Ο Ο ΗΝ\ ^HzN acetic acid I, 120 °C 'N 9 ¹ ^NH ---------------------*· DIEA Γ Χλ ja) HIT Ax Ti ⁿ A 1-43

- 145 041983

Stage 1: methyl 3-(5-bromo-3-pyridyl)-3-oxo-propanoate and methyl (Z)-3-(5-bromo-3-pyridyl)-3hydroxy-prop-2-enoate

To a mixture of 5-bromopyridine-3-carboxylic acid (5 g, 24.75 mmol, 1 eq.) and TEA (2.50 g, 24.75 mmol, 3.45 ml, 1 eq.) in THF (100 ml ) CDI (6.02 g, 37.13 mmol, 1.5 eq.) was added in one portion at 30° C. under N ₂ atmosphere. The mixture was stirred at 30° C. for 1 hour. Potassium was added; 3-methoxy-3-oxopropanoate (7.73 g, 49.50 mmol, 2 eq.) and MgCl ₂ (4.71 g, 49.50 mmol, 2 eq.) and the mixture was stirred at 30° C. for 16 including the pH of the mixture was adjusted to 5-6 with 3 n. HCl, extracted with EtOAc (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC: PE/EtOAc = 3/ 1, Rf = 0.47) to give methyl 3-(5-bromo-3-pyridyl)-3-oxopropanoate (1.85 g, 6.45 mmol, 26.1% yield, 90.0% purity) and methyl (Z)-3-(5-bromo-3-pyridyl)-3hydroxy-prop-2-enoate (1.85 g, 6.45 mmol, 26.1% yield, 90.0% purity) as white solid.

¹ H NMR (400 MHz, CDCl3) δ ppm 12.46 (s, 1H), 9.05 (d, J=2.0 Hz, 1H), 8.90-8.87 (m, 2H), 8 .75 (d, J=2.2 Hz, 1H), 8.39-8.36 (m, 1H), 8.21 (t, J=2.1 Hz, 1H), 5.72 (s, 1H), 4.02 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H); ERJHMS m/z 258.0, 260.0 [M+H] ⁺ .

Step 2: 5-(5-bromo-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-ol

A mixture of methyl 3-(5-bromo-3-pyridyl)-3-oxo-propanoate (1.11 g, 3.87 mmol, 1 eq.) and 1H-pyrazole-5-amine (386.37 mg, 4.65 mmol, 1.2 eq.) in AcOH (5 ml) was stirred at 120°C for 1 h. The reaction mixture was concentrated under reduced pressure to give 5-(5-bromo-3-pyridyl)pyrazolo[1,5a]pyrimidine -7-ol (1 g, 3.44 mmol, 88.7% yield, crude purity) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm 10.31 (s, 1H), 9.00 (d, J=2.0 Hz, 1H), 8.88 (d, J=2.0 Hz, 1H) , 8.52 (t, J=2.1 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.51 (s, 1H), 6.25-6.21 ( m, 2H); ER-LCMS m/z 293.0, 295.0 [M+H] ⁺ .

Step 3: 5-(5-bromo-3-pyridyl)-7-chloro-pyrazolo[1,5-a]pyrimidine

A solution of 5-(5-bromo-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-ol (1 g, 3.44 mmol, 1 eq.) in POCl ₃ (8 ml) was stirred at 100°C over 3 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative TLC (TLC: PE/EtOAc = 3/1, Rf = 0.65) to give 5-(5-bromo-3-pyridyl )-7-Chloro-pyrazolo[1,5-a]pyrimidine (0.8997 g, 2.91 mmol, 84.6% yield, 100.0% purity) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.18 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.62 (t, J =2.0 Hz, 1H), 8.30 (d, J=2.4 Hz, 1H), 7.44 (s, 1H), 6.91 (d, J=2.4 Hz, 1H); ER-LCMS m/z 309.0, 311.0 [M+H]+.

Step 4: 5-(5-bromo-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrazolo[1,5-a]pyrimidin-7-amine

To a mixture of 5-(5-bromo-3-pyridyl)-7-chloro-pyrazolo[1,5-a]pyrimidine (500 mg, 1.62 mmol, 1 eq.) and 2(1H-indol-3-yl )ethanamine (388.18 mg, 2.42 mmol, 1.5 eq.) in i-PrOH (20 ml) was added DIEA (626.28 mg,

- 146 041983

4.85 mmol, 844.04 µl, 3 eq) per serving. The mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC: PE/EtOAc = 3 /1, Rf = 0.35), giving 5-(5-bromo-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrazolo[1,5-a]pyrimidin-7 -amine (629 mg, 1.45 mmol, 89.9% yield, 100.0% purity) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm 8.87 (d, J=1.8 Hz, 1H), 8.71 (d, J=2.2 Hz, 1H), 8.41-8.37 ( m, 1H), 8.08 (br s, 1H), 8.01 (d, J=2.2 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7. 38 (d, J=8.2 Hz, 1H), 7.23-7.17 (m, 2H), 7.11 (s, 1H), 6.61 (broad s, 1H), 6.55 (d, J=2.2 Hz, 1H), 6.12 (s, 1H), 3.86 (q, J=6.2 Hz, 2H), 3.28 (t, J=6.6 Hz , 2H); ERLCMS m/z 435.0, 437.0 [M+H]+.

Step 5: 5-[7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-5-yl]pyridine-3carbonitrile (I-43)

5-(5-Bromo-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrazolo[1,5-a]pyrimidine-7-amine mixture (150 mg, 346.18 µmol , 1 eq.), Zn(CN) ₂ (162.60 mg, 1.38 mmol, 87.89 μl, 4 eq.) and Pd(PPh ₃ ) ₄ (80.01 mg, 69.24 μmol, 0 .2 eq.) in DMF (5 ml) was degassed and purged with N2 3 times. The mixture was stirred at 85°C for 19 hours under N2. The mixture was concentrated and saturated NaHCO ₃ solution (10 ml) was added. The mixture was subjected to extraction with EtOAc (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. MeOH (30 ml) was added to the crude product and stirred for 10 minutes. The suspension was filtered and the solid collected, washed

PE/EtOAc (2/1, 30 ml x 2), dried under vacuum to give

5-[7-[2-(1H-indol-3yl)ethylamino]pyrazolo[1,5-a]pyrimidin-5-yl]pyridine-3-carbonitrile (67.84 mg, 176.30 µmol, 50 yield, 9%, 98.6% pure) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (broad s, 1H), 9.46 (d, J=2.2 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H), 8.76 (t, J=2.1 Hz, 1H), 8.19 (broad s, 1H), 8.14 (d, J=2.4 Hz, 1H), 7, 65 (d, J=7.9 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.21 (s, 1H), 7.09-6.97 (m, 2H ), 6.70 (s, 1H), 6.52 (d, J=2.2 Hz, 1H), 3.85 (d, J=6.0 Hz, 2H), 3.14 (t, J = 7.3 Hz, 2H); ER-LCMS m/z 380.2 [M+H]+.

Example 43.

Synthesis I-44

Synthesis scheme:

- 147 041983

Step 1: 5-(5-fluoro-3-pyridyl)-N-indan-2-yl-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-amine (I44)

A mixture of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (50 mg, 168.55 µmol, 1 eq.), indan-2-amine ( 26.94 mg, 202.25 µmol, 1.2 eq.) and DIEA (65.35 mg, 505.64 µmol, 88.07 µl, 3 eq.) in i-PrOH (5 ml) were stirred at 80° C for 2 hours. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 60 %-90%, 10 min) to give 5(5-fluoro-3-pyridyl)-N-indan-2-yl-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-amine (27.63 mg, 59.44 µmol, 35.3% yield, 99.0% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.32 (t, J=1.6 Hz, 1H), 8.66 (d, J=2.8 Hz, 1H), 8.50-8 .46 (m, 1H), 8.16 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.28-7.25 (m, 2H), 7.20- 7.17 (m, 2H), 7.00 (s, 1H), 4.95-4.84 (m, 1H), 3.433.38 (m, 2H), 3.26-3.22 (m, 1H), 3.20-3.14 (m, 2H), 1.37 (d, J=7.2 Hz, 6H); ER-LCMS m/z 388.2 [M+H]+.

Example 44.

Synthesis I-45

A mixture of methyl 3-oxo-3-phenyl-propanoate (100 mg, 561.21 µmol, 1 eq.), 4-isopropyl-III-pyrazol5-amine (70.25 mg, 561.21 µmol, 1 eq.) in AcOH (33.70 mg, 561.21 µmol, 32.10 µl, 1 eq.) was degassed and flushed with N ₂ 3 times. The mixture was stirred at 120°C for 1 hour under N2. The reaction mixture was concentrated under reduced pressure to give 3-isopropyl-5-phenylpyrazolo[1,5-a]pyrimidin-7-ol (90 mg, 355.31 µmol, 63.3% yield) as a black-brown oil which was used in the next step without further purification. ER-LCMS m/z 254.1 [M+H]+.

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Stage 2: 7-chloro-3-isopropyl-5-phenyl-pyrazolo[1,5-a]pyrimidine

A solution of 3-isopropyl-5-phenyl-pyrazolo[1,5-a]pyrimidin-7-ol (90 mg, 355.31 µmol, 1 eq.) in POCl ₃ (2 ml) was stirred at 110°C for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with DCM (10 ml x 2), concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 10/1, TLC: PE /EtOAc = 10/1, Rf = 0.55) to give 7-chloro-3-isopropyl-5-phenyl-pyrazolo[1,5-a]pyrimidine (60 mg, 207.11 µmol, 58.3% yield , purity 93.8%) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.15-8.07 (m, 3H), 7.57-7.49 (m, 3H), 7.40 (s, 1H), 3.37-3 .48 (m, 1H), 1.45 (d, J=6.8 Hz, 6H); ER-LCMS m/z 272.1 [M+H]+.

Stage 3: N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-5-phenyl-pyrazolo[1,5-a]pyrimidin-7-amine (I-45)

A mixture of 7-chloro-3-isopropyl-5-phenyl-pyrazolo[1,5-a]pyrimidine (60 mg, 207.11 µmol, 1 eq.), 2(1H-indol-3-yl)ethanamine (49, 77 mg, 310.66 µmol, 1.5 eq) and DIEA (133.84 mg, 1.04 mmol, 180.37 µl, 5 eq) in i-PrOH (3 ml) were degassed and purged with N2 3 times. The mixture was stirred at 50° C. for 3 hours under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 250x50 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 35%-65% , 10 min) followed by lyophilization to give N-[2-(1 H-indol-3-yl)ethyl]-3-isopropyl-5-phenyl-pyrazolo[1,5-a]pyrimidin-7-amine (38 .50 mg, 81.29 µmol, 39.3% yield, 98.9% purity, 2HC1) as a gray solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 8.12 (s, 1H), 7.58-7.52 (m, 2H), 7.49-7.43 (m, 2H), 7.23 (d, J=8.2 Hz, 1H), 7.20-7.15 (m, 2H), 7.07-7.02 (m, 2H), 6.90-6.84 (m, 1H ), 5.71 (s, 1H), 3.96 (t, J=5.8 Hz, 2H), 3.29-3.23 (m, 1H), 3.23-3.19 (m, 2H), 1.33 (d, J=6.8 Hz, 6H); ER-LCMS m/z 396.2 [M+H] ⁺ .

Example 45.

Synthesis I-46

- 149 041983

Stage 1: 3-isopropyl-5-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-ol

A mixture of methyl 3-oxo-3-(3-pyridyl)propanoate (100 mg, 558.12 µmol, 1 eq) and 4-isopropyl-Spyrazole-5-amine (69.86 mg, 558.12 µmol, 1 eq.) in AcOH (2 ml) was stirred at 120°C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the crude product 7-ol (120 mg, 471.91 µmol, 84.6% yield, crude purity) as a brown oil, which was used in the next step without further purification.

1H NMR (400 MHz, DMSO-d6) δ ppm 9.47-8.95 (m, 1H), 8.80-8.70 (m, 1H), 8.30-8.20 (m, 1H) , 7.87, 7.38 (m, 1H), 7.60-7.50 (m, 1H), 7.08, 1.24 (d, J=6.8 Hz, 3H), 1.07 (dd, J=3.5, 6.8 Hz, 3H); ER-LCMS m/z 255.1 [M+H]+.

Step 2: 7-chloro-3-isopropyl-5-(3-pyridyl)pyrazolo[1,5-a]pyrimidine

Solution of 3-isopropyl-5-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-ol (120.00 mg, 471.91 µmol, 1 eq.) in POCl ₃ (4.95 g, 32 .28 mmol, 3 ml, 68.41 eq.) was stirred at 110°C for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with DCM (20 ml), which was purified by preparative-TLC (PE/EtOAc = 3 /1, TLC: PE/EtOAc=3/1, Rf=0.40) to give 7-chloro-3isopropyl-5-(3-pyridyl)pyrazolo[1,5-a]pyrimidine (58 mg, 212.66 µmol, 45.1% yield, 100.0% purity) as a green solid.

1H NMR (400 MHz, CDC13) δ ppm 9.32 (broad s, 1H), 8.75 (broad s, 1H), 8.45 (d, J=6.4 Hz, 1H), 8, 12 (br s, 1H), 7.52-7.44 (m, 1H), 7.43-7.39 (m, 1H), 3.45-3.40 (m, 1H), 1, 51-1.41 (m, 6H); ER-LCMS m/z 273.1 [M+H]+.

Step 3: N-[2-(1 H-indol-3-yl)ethyl]-3-isopropyl-5-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-amine (I-46)

To a solution of 7-chloro-3-isopropyl-5-(3-pyridyl)pyrazolo[1,5-a]pyrimidine (40 mg, 146.66 µmol, 1 eq.) and 2-(1H-indol-3-yl )ethanamine (35.25 mg, 220.00 µmol, 1.5 eq.) in i-PrOH (5 ml) was added DIEA (56.87 mg, 439.99 µmol, 76.64 µl, 3 eq.). The mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl) - ACN ]; B%: 25%-55%, 10 min) to give N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-5-(3pyridyl)pyrazolo[1,5-a] pyrimidine-7-amine (31.67 mg, 60.73 µmol, 41.4% yield, 97.0% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.84 (dd, J=1.2, 5.4 Hz, 1H), 8.74 (d, J=1.8 Hz, 1H), 8.11 ( s, 1H), 8.04-7.98 (m, 1H), 7.91 (dd, J=5.2, 7.8 Hz, 1H), 7.57 (d, J=7.9 Hz , 1H), 7.14 (d, J=7.9 Hz, 1H), 7.01-6.95 (m, 2H), 6.91-6.86 (m, 1H), 5.81 ( s, 1H), 4.00-3.94 (m, 2H), 3.24-3.16 (m, 3H), 1.32 (d, J=6.8 Hz, 6H); ER-LCMS m/z 397.2 [M+H] ⁺ .

- 150 041983

Example 46.

Synthesis I-47

1-47

Synthesis scheme:

He

1-47

Step 1: 5-(5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-ol one

To a solution of methyl-(Z)-3-(5-fluoro-3-pyridyl)-3-hydroxy-prop-2-enoate (100.00 mg, 486.91 µmol, 1 eq.) in AcOH (2 ml) 4-(trifluoromethyl)-1H-pyrazol-5-amine (91.32 mg, 486.91 µmol, 1 eq, HCl) was added. The mixture was stirred at 120° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product 5-(5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazolo[1,5a]pyrimidin-7-ol ( 100 mg, 335.35 µmol, 68.9% yield, crude) as a yellow solid, which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.00 (d, J=1.3 Hz, 1H), 8.87-8.79 (m, 2H), 8.35 (s, 1H), 8.23-8.11 (m, 2H); ER-LCMS m/z 299.0 [M+H]+.

Stage 2: 7-chloro-5-(5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine

Cl

A solution of 5-(5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-ol (100 mg, 335.35 µmol, 1 eq.) in POCl ₃ (18, 85 g, 122.94 mmol, 11.42 ml, 366.59 eq) was stirred at 110° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with DCM (20 ml x 2) and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.64) to give the title compound 7-chloro-5-(5-fluoro-3-pyridyl)-3(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (34 mg, 80.53 µmol, yield 24.0 %, purity 75.0%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.13 (s, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.30 (d, J=6.4 Hz , 1H), 7.65 (s, 1H); ER-LCMS m/z 317.1, 319.0 [M+H]+.

Step 3: 5-(5-fluoro-3-pyridyl)-N-[2-( 1 H-indol-3 -yl)ethyl]-3-(trifluoromethyl)pyrazolo [1.5

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a] pyrimidine-7-amine (I-47)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (30 mg, 71.06 µmol, 1 eq.) and 2-(1H -indol-3-yl)ethanamine (17.08 mg, 106.59 µmol, 1.5 eq.) in i-PrOH (5 ml) was added DIEA (27.55 mg, 213.18 µmol, 37.13 µl , 3.0 eq.). The mixture was stirred at 60°C for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% ammonium hydroxide o6. /o6.)-ACN]; B%: 52%-82%, 10 min) followed by lyophilization to give 5-(5-fluoro-3-pyridyl)-N-[2-(1H-indole-3- yl)ethyl]-3-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-7amine (24.84 mg, 45.09 µmol, 63.5% yield, 99.8% purity, 3HCl) as a solid yellow substances.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.77 (broad s, 1H), 8.67 (s, 1H), 8.28 (s, 1H), 7.91 (d, J=8, 2 Hz, 1H), 7.71-7.63 (m, 1H), 7.12-7.06 (m, 1H), 7.04-6.96 (m, 2H), 6.90 (s , 1H), 6.02 (s, 1H), 3.90 (t, J=6.1 Hz, 2H), 3.16 (t, J=6.1 Hz, 2H); ER-LCMS m/z 441.2 [M+H]+.

Example 47.

Synthesis I-48

Synthesis scheme:

Step 1: 2-(5-fluoro-3-pyridyl)-9-isopropyl-N-(5-methoxyindan-2-yl)purine-6-amine

DIEA (170.13 mg, 1 eq.) in iPrOH (5 ml) 1.32 mmol, 229.29 µl, 8 eq) and 5-methoxyindan-2-amine (33.60

- 152041983 mg, 168.27 µmol, 1.02 eq., HCl) under N ₂ atmosphere. The mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give crude 2-(5-fluoro-3-pyridyl)9-isopropyl-N-(5-methoxyindan-2-yl)purin-6- amine (60 mg, 102.80 µmol, 62.4% yield, 71.7% purity) as a black-brown oil, which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 11.16 (s, 1H), 9.54 (s, 1H), 8.51 (d, J=2.9 Hz, 1H), 8.45 ( d, J=9.0Hz, 1H), 7.83(s, 1H), 7.17(d, J=7.9Hz, 1H), 6.83(s, 1H), 6.77( dd, J=2.5, 8.3 Hz, 1H), 4.92 (m, 1H), 4.04 (td, J=6.1, 12.3 Hz, 1H), 3.84-3 .79 (m, 3H), 3.48 (dt, J=7.3, 16.5 Hz, 2H), 3.05-2.92 (m, 2H), 1.22 (d, J=6 .2 Hz, 6H); ER-LCMS m/z 419.2 [M+H]+.

Step 2: 2-(5-fluoro-3-pyridyl)-9-isopropyl-N-(5-methoxyindan-2-yl)purine-6-amine (I-48)

Solution of 2-(5-fluoro-3-pyridyl)-9-isopropyl-N-(5-methoxyindan-2-yl)purine-6-amine (60 mg, 102.80 µmol, 1 eq.) in HBr (5 ml, 60% in water) was stirred at 120°C for 2 h.

The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini C18 250x50 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 40%-70% 10 min) followed by lyophilization to give 2-[[2-(5fluoro-3-pyridyl)-9-isopropyl-purin-6-yl]amino]indan-5-ol (21.36 mg, 44.75 µmol , yield 43.5%, purity 100%, 2HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.58 (s, 1H), 9.22 (s, 1H), 8.98 (d, J=8.4 Hz, 1H), 8.90 (s, 1H), 7.09 (d, J=8.2 Hz, 1H), 6.73 (s, 1H), 6.65 (dd, J=2.4, 8.2 Hz, 1H), 5, 24 (s, 1H), 5.16 (td, J=6.8, 13.6 Hz, 1H), 3.46 (ddd, J=7.2, 12.7, 15.8 Hz, 2H) , 3.02 (dt, J=4.5, 14.9 Hz, 2H), 1.75 (d, J=6.1 Hz, 6H); ER-LCMS m/z 405.1 [M+H]+

Example 48.

Synthesis I-49

Synthesis scheme:

Step 1: 4-[2-[[5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino]ethyl]phenol (I-49)

- 153 041983

DIEA ( 170.49 mg, 1.32 mmol, 229.77 μl, 8 eq.) and 4-(2-aminoethyl)phenol (33.93 mg, 247.34 μmol, 1.50 eq.) under N ₂ atmosphere. The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN ]; B%: 20%-50%, 10 min) followed by lyophilization to give 4-[2-[[5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino ]ethyl]phenol (46.38 mg, 109.83 µmol, 66.6% yield, 100% purity, 2HCl) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.85-8.75 (m, 2H), 8.27 (d, J=2.2 Hz, 1H), 8.09 (td, J=2, 3, 9.2 Hz, 1H), 7.07 (d, J=8.6 Hz, 2H), 6.65-6.56 (m, 3H), 6.46 (s, 1H), 3, 97 (t, J=6.6 Hz, 2H), 3.00 (t, J=6.5 Hz, 2H); ERJHMS m/z 350.2 [M+H]+.

Example 49.

Synthesis of I-50

Synthesis scheme:

Step 1: (6E)-6-Hydroxyimino-5H-cyclopenta[f][1,3]benzodioxol-7-one

ABOUT

KaAL / ⁿ AXI _o > but

A suspension of 5,6-dihydrocyclopenta[1][1,3]benzodioxol-7-one (0.5 g, 2.84 mmol, 1 eq.) in MeOH (45 ml) was heated to 45°C, then isopentyl nitrite ( 539.40 mg, 4.60 mmol, 0.62 ml, 1.62 eq) and con. HCl (12 M in water, 0.47 ml, 1.99 eq.). The mixture was stirred at 45° C. for 1.5 hours. The mixture was filtered, the filter cake was washed with cold MeOH (5 ml x 2), dried under vacuum to give the product (300 mg). The filtrate was concentrated under reduced pressure to give a residue, to which MeOH (5 ml) was added, then filtered, dried under vacuum to give the product (200 mg). Compound (6E)-6hydroxyimino-5H-cyclopenta[i ^: ][1,3]benzodioxol-7-one (500 mg, 2.44 mmol, 85.8% yield, 100% purity) was obtained as a yellow solid , which was used in the next step without further purification.

1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (s, 1H), 7.14 (d, J=10.4 Hz, 2H), 6.18 (s, 2H), 3.64 ( s, 2H); ER-LCMS m/z 206.1 [M+H] ⁺ .

Stage 2: 6,7-dihydro-5H-cyclopenta[f][1,3]benzodioxol-6-amine r-ACh^X ^h2n \ J. c /

To a solution of (6E)-6-hydroxyimino-5H-cyclopenta[f][1,3]benzodioxol-7-one (500 mg, 2.44 mmol, 1 eq.) in AcOH (25 ml) and con. H ₂ SO ₄ (0.3 ml) was added Pd/C (0.13 g, 10%). The mixture was stirred at 25° C. for 12 hours under H ₂ (30 psi). The mixture was filtered, the filtrate was concentrated under reduced pressure to give a residue, to which water (50 ml) was added, the pH was adjusted to 10-11 with 2N hydrochloric acid.

- 154 041983 water. NaOH, extracted with DCM (30 mlx3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 6,7-dihydro-5H-cyclonent[f][1,3]benzodioxol-6-amine (250 mg, 1.13 mmol, 46.3% yield, purity

80%) as a yellow solid, which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.68 (s, 2H), 5.90 (s, 2H), 3.91-3.76 (m, 1H), 3.09 (dd, J = 6.8.15.3 Hz, 2H), 2.58 (dd, J=4.9.15.4 Hz, 2H); ER-LCMS m/z The correct mass was not found.

Step 3: N-(6,7-dihydro-5H-cyclonent[f][1,3]benzodioxol-6-yl)-5-(5-fluoro-3pyridyl)pyrazolo[1,5-a]pyrimidin-7 -amine (I-50)

DIEA ( 127.87 mg, 989.37 µmol, 172.33 µl, 5 eq.) and 6,7-dihydro-5Hcyclopenta[f][1,3]benzodioxol-6-amine (65.74 mg, 296.81 µmol , 1.5 eq.). The mixture was stirred at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini C18 250x50 mmx10 µm; mobile phase: [water (0.05% HCl)- ACN]; B%: 40%-70%, 10 min) followed by lyophilization to give N-(6,7-dihydro-5H-cyclopenta[1][1,3]benzodioxol-6-yl)-5-( 5-Fluoro-3-pyridyl)pyrazolo[1,5a]pyrimidine-7-amine (21.53 mg, 46.43 µmol, 23.4% yield, 99.7% purity, 2HCl) as yellow solid colors.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.02 (t, J=1.3 Hz, 1H), 8.81 (d, J=2.6 Hz, 1H), 8.34-8 .29 (m, 1H), 8.28 (d, J=2.2 Hz, 1H), 7.05 (s, 1H), 6.76 (s, 2H), 6.66 (d, J= 2.2 Hz, 1H), 5.94-5.90 (m, 2H), 5.08 (t, J=6.8 Hz, 1H), 3.46 (dd, J=7.7, 15 .4 Hz, 2H), 3.18 (dd, J=6.3, 15.5 Hz, 2H); ER-LCMS m/z 390.1 [M+H]+.

Example 50.

Synthesis I-51

- 155 041983

Step 1: 5-(5-fluoro-3-pyridyl)-N-(5-methoxyindan-2-yl)-3-methyl-pyrazolo[1,5-a]pyrimidine-7amine

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (35 mg, 133.25 µmol, 1.0 eq.) in i-PrOH (4 ml) was added DIEA (86.10 mg, 666.24 µmol, 116.04 µl, 5.0 eq.) and 5-methoxyindan-2-amine (30 mg, 150.24 µmol, 1.13 eq., salt HCl). The mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give 5-(5-fluoro-3-pyridyl)-N-(5-methoxyindan-2-yl)-3-methyl-pyrazolo[1.5 -a]pyrimidine-7-amine (50 mg, 113.24 µmol, 85.0% yield, 88.2% purity) as a yellow oil, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.07 (s, 1H), 8.55 (d, J=2.6 Hz, 1H), 8.21 (d, J=9.9 Hz, 1H ), 7.86 (s, 1H), 7.18 (d, J=8.8 Hz, 1H), 6.87-6.75 (m, 2H), 6.60 (m, 1H), 6 .39 (s, 1H), 4.66 (s, 1H), 3.81 (s, 3H), 3.70-3.64 (m, 4H), 2.39 (s, 3H); ER-LCMS m/z 390.2 [M+H]+.

Step 2: 2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]indan-5-ol (I51)

5-(5-fluoro-3-pyridyl)-N-(5-methoxyindan-2-yl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-amine (50 mg, 113.24 µmol, 1 eq.) was added to HBr (5 ml, 60% in water) and the mixture was stirred at 120° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 µm, mobile phase: [water (0.05% HCl)-ACN]; V%: 35%-65%, 10 min). The desired fraction was lyophilized to give 2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]indan-5-ol (15.05 mg, 33.46 µmol, 29.5% yield, 99.6% purity, 2 salt HCl) as a yellow solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 9.03 (s, 1H), 8.75 (d, J=2.5 Hz, 1H), 8.31 (td, J=2.3.9 .3 Hz, 1H), 8.07 (s, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.89 (s, 1H), 6.72 (s, 1H), 6.68-6.62(m, 1H), 4.99-4.95(m, 1H), 3.50-3.41(m, 2H), 3.21-3.10(m, 2H ), 2.37 (s, 3H); ER-LCMS m/z 376.1 [M+H] ⁺ .

Example 51.

Synthesis I-52

- 156 041983

Synthesis scheme:

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (50 mg, 164.89 µmol, 1.0 eq.) in i-PrOH (6 ml) was added DIEA (106.56 mg, 824.47 µmol, 143.61 µl, 5.0 eq) and 5-methoxyindan-2amine (35 mg, 175.28 µmol, 1.06 eq, HCl salt). The mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was used in the next step without further purification. Compound 5-(5-fluoro-3-pyridyl)-N-(5-methoxyindan-2yl)pyrazolo[1,5-a]pyrimidin-7-amine (60 mg, 139.21 µmol, 84.4% yield, purity 87.1%) was obtained as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.97 (s, 1H), 8.49 (d, J=2.9 Hz, 1H), 8.09 (td, J=2.3, 9, 5 Hz, 1H), 7.94 (d, J=2.2 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.79-6.69 (m, 2H) , 6.51 (d, J=2.2 Hz, 1H), 6.37 (s, 1H), 4.63-4.55 (m, 1H), 3.77-3.68 (m, 3H ), 3.59 (dt, J=3.0, 6.6 Hz, 4H); ER-LCMS m/z 376.2 [M+H]+.

Step 2: 2-[[5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino]indan-5-o l

5-(5-fluoro-3-pyridyl)-N-(5-methoxyindan-2-yl)pyrazolo[1,5-a]pyrimidin-7-amine (60 mg, 139.21 µmol, 1 eq) was added in HBr (6 ml, 60% in water) and the mixture was stirred at 120° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 30%-60%, 10 min). The desired fraction was lyophilized to give 2-[[5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino]indan-5-ol (32.33 mg, 72.95 µmol, yield 52.4%, purity 98.0%, 2 salt HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.01 (s, 1H), 8.82 (s, 1H), 8.34-8.26 (m, 2H), 7.12-7.05 (m , 2H), 6.73 (s, 1H), 6.69-6.63 (m, 2H), 5.06 (s, 1H), 3.47 (td, J=8.3, 15.9 Hz, 2H), 3.27-3.15 (m, 2H); ER-LCMS m/z 362.1 [M+H] ⁺ .

- 157 041983

Example 52.

Synthesis I-53

1-53

Synthesis scheme:

Stage 1: 5-[4-chloro-6-(cyclopentoxy)pyrimidin-2-yl]pyridine-3-carbonitrile

CI

NaH (9.68 mg, 241.96 µmol, 60% in mineral oil, 60% in mineral oil, 1.5 eq.). The mixture was stirred at 0° C. for 30 minutes. 5-(4,6-Dichloropyrimidin-2-yl)pyridine-3-carbonitrile (50 mg, 161.31 µmol, 1 eq) was added to the above solution and the mixture was stirred at 28°C for 12 h. quenched by adding NH ₄ Cl (2 ml) and water (1 ml), then extracted with EtOAc (20 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative TLC (PE/EtOAc = 13/1, TLC: PE/EtOAc = 13/1, Rf = 0.54 ) to give 5-[4-chloro-6-(cyclopentoxy)pyrimidin-2-yl]pyridine-3-carbonitrile (35 mg, 108.23 µmol, 67.1% yield, 93.0% purity) as a solid white substances.

1H NMR (400 MHz, CD3OD) δ ppm 9.70 (d, J=2.2 Hz, 1H), 9.04 (d, J=2.0 Hz, 1H), 9.01 (t, J= 2.1 Hz, 1H), 6.91 (s, 1H), 5.72-5.67 (m, J=3.1, 6.0 Hz, 1H), 2.15-2.08 (m , 2H), 1.95-1.88 (m, 2H), 1.87-1.83 (m, 2H), 1.771.70 (m, 2H); ER-LCMS m/z 301.1 [M+H]+.

Stage 2: 5-[4-(Cyclopentoxy)-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-2-yl]pyridine-3carbonitrile (I-53)

5-[4-chloro-6-(cyclopentoxy)pyrimidin-2-yl]pyridine-3-carbonitrile (60 mg, 185.54 µmol, 1 eq.), 2-(1H-indol-3-yl)ethanamine ( 74.32 mg, 463.85 µmol, 2.5 eq) and DIEA (23.98 mg, 185.54 µmol, 32.32 µl, 1 eq) were placed in a microwave tube in i-PrOH (4 ml). The sealed tube was heated at 135° C. for 3 hours while being treated with microwave radiation. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 250x50 mmx10 µm; mobile phase: [water (0.05%

- 158 041983

HCl)-ACN]; B%: 60%-90%, 10 min) followed by lyophilization to give 5-[4-(cyclopentoxy)-6-[2(1H-indol-3-yl)ethylamino]pyrimidin-2-yl]pyridin-3 -carbonitrile (21.28 mg, 39.58 µmol, yield

21.3%, 99.3% pure, 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 10.81 (broad s, 1H), 9.61 (s, 1H), 9.10 (d, J=2.0 Hz, 1H), 8.87 ( s, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.46 (broad s, 1H), 7.31 (d, J=8.2 Hz, 1H), 7, 21-7.15 (m, 1H), 7.07-7.01 (m, 1H), 7.00-6.94 (m, 1H), 5.72 (s, 1H), 5.39 ( br s, 1H), 3.68 (br s, 2H), 2.96 (t, J=7.4 Hz, 2H), 1.96 (d, J=6.0 Hz, 2H), 1.74-1.64 (m, 4H), 1.62-1.52 (m, 2H); ER-LCMS m/z 425.2 [M+H]+.

Example 53.

Synthesis I-54

1-54

Synthesis scheme:

1-54

Stage 1: 5-(4,6-dichloropyrimidin-2-yl)pyridine-3-carbonitrile Cl

A mixture of 4,6-dichloro-2-iodo-pyrimidine (813.84 mg, 2.91 mmol, 1 eq.), (5-cyano-3-pyridyl)boronic acid (409.00 mg, 2.76 mmol, 0.95 eq.), Pd(dppf)Cl ₂ (212.96 mg, 291.04 µmol, 0.1 eq.), Na ₂ CO ₃ (925.42 mg, 8.73 mmol, 3.0 eq. .) and water (2.4 ml) in 1,4-dioxane (12 ml) were degassed and purged with N2 3 times, then the mixture was stirred at 80° C. for 1 h under N2 atmosphere. The reaction mixture was diluted with EtOAc (50 ml) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc=100/1 to 5/1, TLC: PE/EtOAc=5/1, _Rf =0.7), affording 5-(4,6-dichloropyrimidin-2-yl)pyridine3-carbonitrile (180 mg, 580.71 µmol, 20.0% yield, 81.0% purity) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.81 (d, J=2.4 Hz, 1H), 9.03 (d, J=2.0 Hz, 1H), 8.99 (d, J =2.0 Hz, 1H), 7.44 (s, 1H); ER-LCMS m/z 250.9, 252.9 [M+H]+.

Stage 2: 5-(4-chloro-6-isopropoxy-pyrimidin-2-yl) pyridine-3-carbonitrile

To a solution of i-PrOH (9.69 mg, 161.31 µmol, 12.35 µl, 1 eq.) in THF (3 ml) was added NaH (6.45 mg, 161.31 µmol, 60%, 1 eq. ). The mixture was stirred at 0° C. for 30 minutes. To the above solution was added 5-(4,6-dichloropyrimidin-2-yl)pyridine-3-carbonitrile (50 mg, 161.31 µmol, 1 eq.). Mixture

- 159 041983 was stirred at 28°C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with NH ₄ Cl (30 ml) and extracted with EtOAc (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative TLC (PE/EtOAc = 10/1, TLC: PE/EtOAc = 10/1, Rf = 0.55 ) to give 5-(4-chloro-6-isopropoxy-pyrimidin-2-yl)pyridine-3-carbonitrile (25 mg, 87.37 µmol, 54.2% yield, 96.0% purity) as a solid white.

1H NMR (400 MHz, CD3OD) δ ppm 9.70 (s, 1H), 9.05 (d, J=2.0 Hz, 1H), 9.01 (t, J=2.1 Hz, 1H) , 6.90 (s, 1H), 5.61 (td, J=6.3, 12.4 Hz, 1H), 1.44 (d, J=6.2 Hz, 6H); ER-LCMS m/z 275.1 [M+H]+.

Stage 3: 5-[4-[2-(1H-indol-3-yl)ethylamino]-6-isopropoxy-pyrimidin-2-yl]pyridine-3carbonitrile (I-54)

5-(4-chloro-6-isopropoxy-pyrimidin-2-yl)pyridine-3-carbonitrile (25 mg, 91.01 µmol, 1 eq.), 2(1H-indol-3-yl)ethanamine (21, 87 mg, 136.51 µmol, 1.5 eq) and DIEA (35.29 mg, 273.02 µmol, 47.56 µl, 3 eq) were placed in a microwave tube in i-PrOH (3 ml) . The sealed tube was heated at 135° C. for 5 hours while being treated with microwave radiation. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 250x50 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 55%-85% , 10 min) followed by lyophilization to give 5-[4-[2-(1H-indol-3-yl)ethylamino]-6isopropoxy-pyrimidin-2-yl]pyridine-3-carbonitrile (16.5 mg, 32 17 µmol, 35.3% yield, 99.0% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, DMSOCH) δ ppm 10.84 (s, 1H), 9.62 (s, 1H), 9.12 (d, J=2.0 Hz, 1H), 8.90 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.33 (d, J=7.9 Hz, 1H), 7.20 (s, 1H), 7.09-7, 02 (m, 1H), 7.01-6.95 (m, 1H), 5.74 (s, 1H), 5.41-5.30 (m, 1H), 3.71 (m, 2H) , 2.97 (t, J=7.3 Hz, 2H), 1.31 (d, J=6.2 Hz, 6H); ER-LCMS m/z 399.2 [M+H] ⁺ .

Example 54.

Synthesis of I-55

Step 1: [5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3-yl](1-piperidyl) ) methanone (I-55)

To a solution of 5-(5-fluoro-3-pyridyl)-7-[2-(1 H-indol-3 -yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 120, 07 µmol, 1 eq.) in pyridine (2 ml) was added piperidine (15.34 mg,

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180.11 µmol, 17.79 µl, 1.5 eq.) and T ₃ R (152.82 mg, 240.15 µmol, 142.82 µl, 50%, 2 eq.). The mixture was stirred at 25°C for 12 hours under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with EtOAc (10 ml) and extracted with EtOAc (30 mlx3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0 05% HCl)-ACN]; B%: 42%-72%, 10 min) followed by lyophilization to give [5-(5-fluoro-3-pyridyl)-7-[2(1H-indole-3- yl)ethylamino]pyrazolo[1,5-a]n-pyrimidin-3-yl]-(1-piperidyl)methanone (12.74 mg, 21.49 µmol, 17.9% yield, 100.0% purity, 3HCl) as a white solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.72-8.68 (m, 1H), 8.57 (s, 1H), 8.34 (s, 1H), 7.71 (td J=2, 4, 8.9 Hz, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.14 (d, J=7.9 Hz, 1H), 7.02-6.96 ( m, 2H), 6.94-6.89 (m, 1H), 6.03 (s, 1H), 4.00 (t, J=6.0 Hz, 2H), 3.71 (m, 4H ), 3.23 (t, J=6.1 Hz, 2H), 1.75 (m, 2H), 1.68 (m, 4H); ER-LCMS m/z 484.2 [M+H]+.

Example 55.

Synthesis I-56

5-(5-fluoro-3-pyridyl)-7-[2-(1 H-indol-3-yl)ethylamino]-N,N-dimethyl-pyrazolo [1.5] Step 1:

a] pyrimidine-3-carboxamide (I-56)

A mixture of 5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40 mg, 96.06 µmol, 1 eq.), N-methylmethanamine (23.50 mg, 288.18 µmol, 3 eq., HCl) and T ₃ R (611.29 mg, 960.60 µmol, 571.30 µl, 50% in EtOAc, 10 eq.) in pyridine (5 ml) was stirred at 30°C for 12 h. The mixture was concentrated under reduced pressure to give a residue which was diluted with EtOAc (20 ml) and water (20 ml), extracted with EtOAc (20 mlx3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 33% -63%, 10 min) to give 5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]-N,N-dimethyl-pyrazolo[1,5-a] pyrimidine-3-carboxamide (16.67 mg, 29.67 µmol, 30.9% yield, 98.4% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (broad s, 1H), 9.12 (s, 1H), 8.69 (d, J=3.2 Hz, 1H), 8, 43 (t, J=6.0 Hz, 1H), 8.31 (s, 1H), 8.21 (d, J=10.0 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.23 (d, J=1.6 Hz, 1H), 7.07-7.02 (m, 1H), 7.00-6.97 (m, 1H), 6.78 (s, 1H), 3.87 (q, J=6.8 Hz, 2H), 3.16-3.03 (m, 8H) ; ER-LCMS m/z 444.2 [M+H] ⁺ .

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Example 56.

Synthesis I-57

Step 1: yl]ethanone (I-57)

Synthesis scheme:

1-[5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-а]pyrimidin-3-

solution

-(5-fluoro-3-pyridyl)-7-[2-(1 H-indol-3 -yl)ethylamino]-N-methoxy-N-methyl pyrazolo[1,5-a]pyrimidine-3-carboxamide ( 50 mg, 96.85 µmol, 1 eq.) in THF (10 ml) MeMgBr (3 M in Et ₂ O, 4.68 ml, 145.10 eq.) was added dropwise at 25°C. The mixture was then stirred at 25° C. for 0.5 h. The mixture was quenched. NH4Cl (20 ml), extracted with EtOAc (20 mlx3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative TLC (SiO ₂ , PE/EA = 1/1, Rf = 0.56), then purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 40%-70%, 10 min) to give 1-[5-(5-Fluoro-3-pyridyl)-7-[2-(1 H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3-yl]ethanone (17.52 mg, 32.98 µmol, 34.1% yield, 98.6% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.81 (br s, 1H), 9.16 (s, 1H), 8.72 (d, J=2.8 Hz, 1H), 8 .62 (t, J=6.4 Hz, 1H), 8.53 (s, 1H), 8.23 (d, J=10.0 Hz, 1H), 7.65 (d, J=8, 0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.06-7.03 (m, 1H) , 7.02-6.99 (m, 1H), 6.87 (s, 1H), 3.89 (q, J=6.8 Hz, 2H), 3.14 (t, J=7.2 Hz, 2H), 2.72 (s, 3H); ER-LCMS m/z 415.2 [M+H]+.

Example 57.

Synthesis I-58

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Synthesis scheme:

1-58

Stage 1: tert-butyl 4-[5-(5-fluoro-3-pyridyl)-7-[2-(III-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3-carbonyl ] piper azine-1-carboxylate

5-(5-Fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3 carboxylic acid mixture (50 mg, 120.07 µmol, 1 eq.), tert-butyl piperazine-1-carboxylate (26.84 mg, 144.09 µmol, 1.2 eq.) and T ₃ P (382.06 mg, 600.37 µmol, 357.06 μl, 50%, 5 eq.) in pyridine (1 ml) was stirred at 25°C for 16 h. The reaction mixture was quenched with water (5 ml) and extracted with EtOAc (10 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to dryness, obtaining tert-butyl 4-[5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3yl) ethylamino]pyrazolo[1,5-a]pyrimidine-3-carbonyl]piperazine-1-carboxylate (100 mg, crude) as a brown solid, which was used directly in the next step without further purification.

Step 2: [5-(5-Fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3-yl]piperazin-1 -yl-methanone (I-58)

To a solution of tert-butyl-4-[5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5а]pyrimidine-3-carbonyl]piperazine -1-carboxylate (100 mg, 171.04 µmol, 1 eq.) in MeOH (3 ml) HCl/MeOH (4 M, 3 ml) was added and then the mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN]; B%: 20%- 50%, 10 min). The desired fraction was lyophilized to give [5(5-fluoro-3-pyridyl)-7-[2-(1 H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3-yl]-piperazine -1-ylmethanone (19.42 mg, 39.99 µmol, 23.4% yield, 99.8% purity) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.80 (s, 1H), 9.12 (s, 1H), 8.69 (d, J=2.8 Hz, 1H), 8, 41 (t, J=6.0 Hz, 1H), 8.32 (s, 1H), 8.23-8.16 (m, 1H), 7.63 (d, J=8.4 Hz, 1H ), 7.29 (d, J=8.0 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 7.00-6.95 (m, 1H), 6.77 (s, 1H), 3.87 (q, J=6.8 Hz, 2H), 3.54 (m, 4H), 3.13 (t, J=7.2 Hz, 2H), 2.77-2.73 (m, 4H); ER-LCMS m/z 485.2 [M+H]+.

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Example 58.

Synthesis I-59

To a suspension of 2-(1H-indol-3-yl)ethanamine (666.18 mg, 4.16 mmol, 1.05 equiv.) in dry THF (10 ml) , 60% in mineral oil, 1.41 eq.) in an ice bath, and N2. After stirring for 30 minutes, the suspension was cooled to -60° C. and a solution of 4,6-dichloro-2-methylsulfonyl-pyrimidine (900 mg, 3.96 mmol, 1.0 eq.) in dry THF (10 ml) was added dropwise and maintained the temperature below -55°C. The resulting mixture was stirred for 1 hour at -55°C. The reaction mixture was poured into water (100 ml) slowly and extracted with EtOAc (50 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 2/1, TLC: PE/EtOAc = 3/ 1, Rf=0.45) to give 4,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-2-amine (840 mg, 2.68 mmol, 67.6 yield %, purity 98.0%) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.04 (s, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H ), 7.23 (dt, J=1.1, 7.6 Hz, 1H), 7.19-7.14 (m, 1H), 6.98 (d, J=2.2 Hz, 1H) , 6.59 (s, 1H), 5.74 (s, 1H), 3.83-3.73 (m, 2H), 3.07 (t, J=6.8 Hz, 2H); ER-LCMS m/z 307.0, 309.0 [M+H]+.

Stage 2: 4-chloro-6-(cyclopentoxy)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-2-amine

To a solution of NaH (30.63 mg, 765.68 µmol, 60% in mineral oil, 1.2 eq.) in THF (3 ml) was added cyclopentanol (57.71 mg, 669.97 µmol, 60.81 µl, 1.05 equiv.). The mixture was stirred at 0° C. for 30 minutes. 4,6-Dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-2-164 041983 amine (200 mg, 638.07 µmol, 1 eq) was added to the above solution and the mixture was stirred at 15° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give 4-chloro-6-(cyclopentoxy)-N-[2-(1H-indol-3yl)ethyl]pyrimidin-2-amine (170 mg, 309.66 µmol, 48.5% yield, 65.0% purity) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.03 (s, 1H), 7.66 (t, J=7.5 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H ), 7.25-7.19 (m, 1H), 7.18-7.10 (m, 1H), 7.08-7.02 (m, 1H), 6.60 (s, 1H), 5.98 (s, 1H), 5.31 (m, 1H), 3.80-3.72 (m, 2H), 3.113.04 (m, 2H), 2.01-1.54 (m, 8H); ER-LCMS m/z 357.1, 358.1 [M+H]+.

Step 3: 4-(cyclopentoxy)-6-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-2-amine (I59)

4-chloro-6-(cyclopentoxy)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-2-amine (170 mg, 304.89 µmol, 1 eq.), (5-fluoro- 3-pyridyl)boronic acid (128.88 mg, 914.67 µmol, 3 eq.), Cs ₂ CO ₃ (298.02 mg, 914.67 µmol, 3.0 eq.) and Pd(dppf)Cl ₂ (22.31 mg, 30.49 µmol, 0.1 eq.) was placed in a microwave tube in 1,4-dioxane (6 ml) and water (1.2 ml). The sealed tube was heated at 80° C. for 30 minutes while being treated with microwave radiation. The reaction mixture was diluted with EtOAc (100 ml) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 2/1, TLC: PE/EtOAc = 3/1, R _f = 0.40), then repurified by preparative HPLC (HCl conditions, column: Phenomenex Gemini 150 x 25 mm x 10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 48% 78%, 10 min). The desired fraction was lyophilized to give 4-(cyclopentoxy)-6-(5-fluoro-3-pyridyl)N-[2-(1H-indol-3-yl)ethyl]pyrimidin-2-amine (25.91 mg, 48 .46 µmol, 15.9% yield, 98.5% purity, 3HCl salt) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.13 (s, 1H), 8.88 (s, 1H), 8.64 (s, 1H), 8.40 (d, J=7.3 Hz , 1H), 8.15 (s, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.25 (s , 1H), 7.20 (t, J=7.4 Hz, 1H), 7.15-7.09 (m, 1H), 6.32 (s, 1H), 5.27 (s, 1H) , 3.85 (q, J=6.5 Hz, 2H), 3.17 (t, J=6.8 Hz, 2H), 1.94 (d, J=5.8 Hz, 2H), 1 .84-1.74 (m, 4H), 1.70-1.62 (m, 2H); ER-LCMS m/z 418.2 [M+H] ⁺ .

Example 59.

Synthesis of I-60

Step 1: 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-piperazin-1-yl-pyrimidin-4-amine

- 165 041983

6-Chloro-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine mixture (60 mg, 161.50 µmol, 1 eq. ), piperazine (139.11 mg, 1.61 mmol, 10 eq.) and DIEA (104.36 mg, 807.49 μmol, 140.65 μl, 5 eq.) in i-PrOH (3 ml) were tightly capped and irradiated under microwave radiation (4 bar) at 150°C for 2 h. The reaction mixture was concentrated under reduced pressure to dryness, obtaining a residue which was purified using preparative HPLC (column: Phenomenex Gemini C18 250x50 mmx10 μm; mobile phase : [water (0.05% HCl)-ACN]; B%: 8%-38%, 10 min). The desired fraction was lyophilized to give 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6piperazin-1-yl-pyrimidin-4-amine (60.34 mg , 106.30 µmol, 65.8% yield, 99.2% purity, 4HCl) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.05 (s, 1H), 8.77 (d, J=2.8 Hz, 1H), 8.33 (d, J=9.2 Hz, 1H ), 7.64 (d, J=8.0 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.14 (s, 1H), 7.12-7.07 (m, 1H), 7.06-7.01 (m, 1H), 5.58 (br s, 1H), 3.86-3.72 (m, 6H), 3.27-3.24 (m, 4H), 3.14 (t, J=6.0 Hz, 2H); ER-LCMS m/z 418.1 [M+H] ⁺ .

Example 60.

Synthesis I-61

Stage 1: 5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]-N-methyl-pyrazolo[1,5a]pyrimidine-3-carboxamide (I- 61)

To a solution of 5-(5-fluoro-3-pyridyl)-7-[2-(1 H-indol-3 -yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3 carboxylic acid (60 mg, 144, 09 µmol, 1 eq.) in anhydrous DCM (5 ml) was added DIEA (55.87 mg, 432.27 µmol, 75.29 µl, 3 eq.), HATU (136.97 mg, 360.22 µmol, 2 .5 eq.) and methanamine hydrochloride (19.46 mg, 288.18 µmol, 2 eq.). The mixture was stirred at 25° C. for 12 hours. H ₂ O (10 ml) was added, the mixture was subjected to extraction with DCM (10 mlx3). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by preparative HPLC (MeCN/H ₂ O as eluents, acidic conditions, instrument: Phenomenex Gemini C18 250 x 50 mm x 10 µm / Mobile phase: water (0.05% HCl) -ACN / Gradient: B from 35% to 65% over 10 min / Flow rate: 25 ml / min) followed by lyophilization, obtaining 5-(5 -fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]-N-methyl-pyrazolo[1,5a]pyrimidine-3-carboxamide (19.25 mg, 35.73 µmol , yield 24.79%, purity 100%, 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.73 (d, J=12.5 Hz, 2H), 8.47 (s, 1H), 7.94 (d, J=9.0 Hz, 1H) , 7.70 (dd, J=3.0, 6.0 Hz, 1H), 7.15 (dd, J=2.9, 6.1 Hz, 1H), 7.07-7.02 (m , 2H), 6.97 (s, 1H), 6.07 (s, 1H), 3.97 (t, J=6.0 Hz, 2H), 3.23 (t, J=6.1 Hz , 2H), 3.04-2.99 (m, 3H); ER-LCMS m/z 452.1 [M+Na] ⁺ .

- 166 041983

62)

Example 61.

Synthesis I-62

Step 1: 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-(1-piperidyl)pyrimidin-4-amine (I-

6-Chloro-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine (60.61 mg, 163.13 µmol, 1, 0 eq.), piperidine (862.20 mg, 10.13 mmol, 1 ml, 62.07 eq.) and DIEA (63.25 mg, 489.39 µmol, 85.24 µl, 3.0 eq.) placed in a tube with microwave radiation in i-PrOH (3 ml). The sealed tube was heated at 150° C. for 3 hours while being treated with microwave radiation. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini C18 250x50 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 30 %-60%, 10 min) and the desired fraction was lyophilized to give 2(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-(1-piperidyl)pyrimidine -4-amine (33.57 mg, 63.84 µmol, 39.1% yield, 100.0% purity, 3HC1 salt) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 10.92 (s, 1H), 9.29 (s, 1H), 8.83 (s, 1H), 8.52 (d, J=6.8 Hz , 1H), 7.98 (s, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.40-7.25 (m, 2H), 7.16-6.91 ( m, 2H), 5.77 (s, 1H), 4.17 (s, 4H), 3.63 (d, J=6.6 Hz, 2H), 3.02 (t, J=6.7 Hz, 2H), 1.75-1.47 (m, 6H); ER-LCMS m/z 417.2 [M+H]+.

Example 62.

Synthesis I-63

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Step 1: 2-(5-fluoro-3-pyridyl)-N6-[2-(1H-indol-3-yl)ethyl]-N4,N4-dimethylpyrimidin-4,6diamine (I-63)

6-Chloro-2-(5-fluoro-3-pyridyl)-^[2-(III-indol-3-yl)ethyl]pyrimidin-4-amine (80.81 mg, 217.51 µmol, 1.0 eq.), N-methylmethanamine (177.36 mg, 2.18 mmol, 10 eq., HCl salt) and DIEA (168.66 mg, 1.31 mmol, 227.31 µl, 6.0 eq.) in i-PrOH (3 ml) was placed in a microwave tube. The sealed tube was heated at 150° C. for 3 hours while being treated with microwave radiation. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 20% -50%, 10 min) and the desired fraction was lyophilized to give 2-(5-fluoro-3-pyridyl)-N6-[2-(1H-indol-3-yl)ethyl]-N4,N4-dimethyl-pyrimidin- 4,6-diamine (28.13 mg, 56.54 µmol, 26.0% yield, 97.7% purity, 3HCl salt) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 9.31 (s, 1H), 8.85 (d, J=2.0 Hz, 1H), 8.55 (d, J=8.8 Hz, 1H), 8.09 (s, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.42-7.25 (m, 2H) , 7.10-7.04 (m, 1H), 7.02-6.96 (m, 1H), 5.59 (s, 1H), 4.04 (s, 6H), 3.62 (t , J=6.7 Hz, 2H), 3.03 (t, J=6.7 Hz, 2H); ER-LCMS m/z 377.2 [M+H]+.

Example 63.

Synthesis I-64

Step 1: 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-morpholino-pyrimidin-4-amine (I-64)

To a solution of 6-chloro-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amineα (60 mg, 161.50 µmol, 1 eq. .) in i-PrOH (1.5 ml) was added DIEA (208.72 mg, 1.61 mmol, 281.29 μl, 10 eq.), morpholine (281.39 mg, 3.23 mmol, 284.24 µl, 20 eq.). The mixture was stirred at 150°C for 1.5 h under the influence of microwave radiation. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 25%-55%, 10 min) followed by lyophilization to give 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-morpholinopyrimidin-4-amine (53.33 mg, 101.03 µmol, 62.5% yield, 100% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.87 (s, 1H), 9.30 (s, 1H), 8.86-8.32 (m, 2H), 7.59 (d, J=7.9Hz, 1H), 7.35(d, J=7.9Hz, 1H), 7.25(s, 1H), 7.11-7.04(m, 1H), 7, 03-6.94 (m, 1H), 5.70 (s, 1H), 3.78-3.60 (m, 11H), 3.01 (t, J=7.1 Hz, 2H); ER-LCMS m/z 419.2[M+H]+.

- 168 041983

Example 64.

Synthesis of I-65

Step 1: [5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3yl]morpholino-methanone (I- 65)

To a solution of 5 - (5-fluoro-3 -pyridyl) -7- [2- (1 H-indol-3 -yl) ethylamino] pyrazolo [1,5-a] pyrimidine-3 carboxylic acid (40 mg, 96, 06 µmol, 1 eq.) in pyridine (3 ml) were added T ₃ P (122.26 mg, 192.12 µmol, 114.26 µl, 50%, 2 eq.) and morpholine (16.74 mg, 192, 12 µmol, 16.91 µl, 2.0 eq.). The mixture was stirred at 25°C for 12 h.

The reaction mixture was quenched by adding water (50 ml), then extracted with EtOAc (30 mlx3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini C18 250x50 mmx10 μm; mobile phase: [water ( 0.05% HCl)-ACN]; B%: 30%-60%, 10 min) followed by lyophilization to give [5-(5-fluoro-3-pyridyl)-7-[2(III-indole-3 -yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3-yl]morpholino-methanone (19.50 mg, 32.66 µmol, 34.0% yield, 99.6% purity, 3HCl) as solid yellow substances.

1H NMR (400 MHz, CD3OD) δ ppm 8.71-8.59 (m, 2H), 8.34 (s, 1H), 7.73 (d, J=9.3 Hz, 1H), 7, 63 (d, J=7.7 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.05-6.90 (m, 3H), 6.06 (s, 1H ), 3.97 (t, J=6.1 Hz, 2H), 3.75 (s, 8H), 3.22 (t, J=5.8 Hz, 2H); ER-LCMS m/z 486.2 [M+H]+.

Example 65.

Synthesis I-66

- 169 041983

Synthesis scheme:

Stage 1: 7-fluoro-2-methyl-3-methylsulfanyl-1H-indole

equiv.) and

2-fluoroaniline (0.9 g, 8.10 mmol, 782.61 µl,

1-methylsulfanylpropan-2-one (371.24 mg,

3.56 mmol, 0.44 eq.) was initially introduced into n-butyl acetate (4 ml) and cooled to -30° C. under N 2 atmosphere. A solution of sulfuryl chloride (437.28 mg, 3.24 mmol, 323.91 μl, 0.4 eq.) in nbutyl acetate (4 ml) was added dropwise. The mixture was stirred for 2 hours at -30°C. The reaction mixture was quenched by adding water (50 ml) at 0°C, then was extracted with EtOAc (30 mlx3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 10/1 , TLC: PE/EtOAc = 20/1, Rf = 0.34) to give the product 7-fluoro-2-methyl-3-methylsulfanyl-1H-indole (1 g, 4.56 mmol, 56.3% yield, 89 purity .0%) as a red-brown oil.

1H NMR (400 MHz, CDC13) δ ppm 8.31 (s, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.07 (dt, J=4.7, 7.9 Hz, 1H), 6.89 (dd, J=7.8, 10.9 Hz, 1H), 2.56 (s, 3H), 2.27 (s, 3H); ER-LCMS m/z 195.9 [M+H]+.

Stage 2: 7-fluoro-2-methyl-1H-indole

2-sulfanylbenzoic acid (1.30 g, 8 .40 mmol, 2.5 equiv.). The mixture was stirred at 25° C. for 2 hours. TLC (PE/EtOAc = 20/1, Rf = 0.40) indicated that the starting material had been completely consumed and a new spot formed. The reaction mixture was quenched by the addition of water (100 ml), then the pH was adjusted to 10 with 1N HCl. water. NaOH, extracted with EtOAc (50 mlx3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 10/1, TLC : PE/EtOAc = 20/1, Rf = 0.40) to give 7fluoro-2-methyl-1H-indole (400 mg, 2.09 mmol, 62.3% yield, 78.0% purity) as an oil yellow color.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.33 (s, 1H), 7.20 (d, J=7.5 Hz, 1H), 6.92-6.74 (m, 2H) , 6.19 (s, 1H), 2.38 (s, 3H); ER-LCMS m/z The correct mass was not found.

Stage 3: 7-fluoro-2-methyl-1H-indole-3-carbaldehyde

To a solution of DMF (10 ml) was added dropwise POCl ₃ (481.07 mg, 3.14 mmol, 291.56 μl, 2.0 eq.) at -20° C. over a period of 10 min under N2 atmosphere. After 1 hour, 7-fluoro-2-methyl-1H-indole (300 mg, 1.57 mmol, 1 eq.) in DMF (2 ml) was added to the above solution, the temperature

- 170 041983 maintained below -20°C. The reaction mixture was stirred at 15° C. for 1 hour. The reaction mixture was quenched by adding water. NaHCO3 (50 ml) then extracted with EtOAc (30 mlx3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 3/1, TLC : PE/EtOAc = 3/1, R _f = 0.40) to give 7fluoro-2-methyl-1H-indole-3-carbaldehyde (200 mg, 936.93 µmol, 59.7% yield, 83.0 purity %) as a yellow solid.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm 12.44 (s, 1H), 10.08 (s, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.13 (dt, J=5.1, 7.8 Hz, 1H), 7.02 (dd, J=7.9, 11.2 Hz, 1H), 2.70 (s, 3H); ER-LCMS m/z 177.9 [M+H]+.

Stage 4: 7-fluoro-2-methyl-3-[(E)-2-nitrovinyl]-1H-indole

NO ₂

NH4OAC (216.66 mg, 2.81 mmol, 3 equiv.). The mixture was stirred at 110° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in EtOAc (50 ml), washed with water (10 ml), brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude which was purified by silica gel flash chromatography ( PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, R _f = 0.61) to give 7-fluoro-2-methyl-3-[(E)-2-nitrovinyl ]-1H-indole (150 mg, 619.89 µmol, 66.2% yield, 91.0% purity) as a yellow solid.

1H NMR (400 MHz, CDCI3) δ ppm 8.82 (broad s, 1H), 8.32 (d, J=13.5 Hz, 1H), 7.76 (d, J=13.5 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.25-7.16 (m, 1H), 7.01 (dd, J=8.2, 10.6 Hz, 1H ), 2.67 (s, 3H); ER-LCMS m/z 220.9 [M+H] ⁺ .

Step 5: 2-(7-fluoro-2-methyl-1H-indol-3-yl)ethanamine h ₂ n

LAH (1M in THF, 3.10 ml, 5 eq.) at 0°C. After the addition, the mixture was stirred at 80° C. for 2 h. The reaction mixture was diluted with THF (50 ml), quenched successively with water (0.05 ml), aq. NaOH (0.05 ml, 10% in water) and water (0.15 ml) at 0°C. After stirring for 30 minutes, the mixture was filtered through Celite, the filtrate was concentrated under reduced pressure to give crude 2-(7-fluoro-2-methyl-1H-indol-3-yl)ethanamine (100 mg, 436.97 µmol, yield 70.5%, 84.0% pure) as a yellow oil, which was used directly in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 7.23 (d, J=7.8 Hz, 1H), 6.93-6.82 (m, 1H), 6.72 (dd, J=7.9 , 11.4 Hz, 1H), 2.90-2.80 (m, 4H), 2.39 (s, 3H); ER-LCMS m/z 193.2 [M+H] ⁺ .

Stage 6: N-[2-(7-fluoro-2-methyl-1 H-indol-3 -yl)ethyl]-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo (I-66 )

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (40.82 mg, 137.59 µmol, 1 eq.) in i-PrOH (3 ml) was added DIEA (53.35 mg, 412.76 µmol, 71.89 µl, 3.0 eq.) and 2-(7-fluoro2-methyl-1H-indol-3-yl)ethanamine (37, 78 mg, 165.11 µmol, 1.2 eq.). The mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Gemini 150x25x5 µm; mobile phase: [water (0.05% ammonium hydroxide v/v .)-ACN]; B%: 70%-100%, 10 min) followed by lyophilization to give N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]-5 -(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5a]pyrimidine-7-amine (20.36 mg, 45.36 µmol, 33.0% yield, 99.5% purity) in in the form of a solid

- 171 041983 yellow.

Ή NMR (400 MHz, CD ₃ OD) δ ppm 8.58 (s, 1H), 8.45 (d, J=2.6 Hz, 1H), 7.89 (s, 1H), 7.64- 7.57 (m, 1H), 7.37 (d, J=7.9 Hz, 1H), 6.96 (dt, J=4.6, 7.8 Hz, 1H), 6.69 (dd , J=7.8, 11.6 Hz, 1H), 5.76 (s, 1H), 3.83 (t, J=6.2 Hz, 2H), 3.29-3.22 (m, 1H), 3.13 (t, J=6.1 Hz, 2H), 2.11 (s, 3H), 1.38 (d, J=7.1 Hz, 6H); ER-LCMS m/z 447.2 [M+H] ⁺ .

Example 66.

Synthesis I-67

Step 1: 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-(4-methylpiperazin-1-yl)pyrimidin4-amine (I-67 )

To a solution of 6-chloro-2-(5-fluoro-3-pyridyl)-X-[2-(III-indol-3-yl)ethyl]pyrimidin-4-amine (60 mg, 161.50 µmol, 1 eq. .) and 1-methylpiperazine (24.26 mg, 242.25 µmol, 26.87 µl, 1.5 eq.) in i-PrOH (5 ml) was added DIEA (62.62 mg, 484.49 µmol, 84 .39 µl, 3.0 eq.). The mixture was stirred at 110° C. for 16 hours. LC-MS indicated that 83% of the starting material remained and 17% of the desired compound was found. The mixture was placed in a tube with microwave radiation. 1-methylpiperazine (500 mg, 5 mmol) was added. The mixture was purged with N ₂ for 1 min. The sealed tube was heated at 150° C. for 3 hours while being treated with microwave radiation. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN]; B%: 42%-72%, 10 min) followed by lyophilization to give 2-(5-fluoro-3-pyridyl)-N[2-(1H-indol-3-yl)ethyl]-6-(4-methylpiperazin-1 -yl)pyrimidin-4-amine (49.11 mg, 113.81 µmol, 70.5% yield, 100.0% purity) as a white solid.

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.82 (broad s, 1H), 9.30 (s, 1H), 8.64 (d, J=2.9 Hz, 1H), 8 .32 (d, J=10.1 Hz, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.07 (t, J=7.2 Hz, 1H), 6.98 (t, J=7.4 Hz, 2H), 5.59 (broad . s, 1H), 3.60 (br. s, 2H), 3.51 (br. s, 4H), 2.97 (t, J=7.3 Hz, 2H), 2.37 (d, J=4.2 Hz, 4H), 2.20 (s, 3H); ER-LCMS m/z 432.2 [M+H]+.

Example 67.

Synthesis I-68

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Synthesis scheme:

1-68

Stage 1: [5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3-yl](4-methylpiperazine -1-yl) methanone (I-68)

To a solution of 5-(5-fluoro-3-pyridyl)-7-[2-(1 H-indol-3 -yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 120, 07 µmol, 1 eq.) and 1-methylpiperazine (18.04 mg, 180.11 µmol, 19.98 µl, 1.5 eq.) in DCM (5 ml) were added HATU (54.79 mg, 144.08 µmol, 1.2 eq.) and DIEA (46.55 mg, 360.21 µmol, 62.74 µl, 3.0 eq.). The mixture was stirred at 25° C. for 16 hours. LC-MS indicated that 42% of the starting material remained and 51% of the desired compound was found. 1-methylpiperazine (18.04 mg, 180.11 µmol, 19.98 µl, 1.5 eq.), HATU (54.79 mg, 144.08 µmol, 1.2 eq.), DIEA (46.55 mg , 360.21 µmol, 62.74 µl, 3.0 eq.) and DMF (2 ml). The mixture was stirred at 25°C for 5 hours. The reaction mixture was diluted with H2O (20 ml), extracted with DCM (20 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm;

mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN]; B%: 36%-66%, 10 min) followed by lyophilization to give [5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1, 5a]pyrimidin-3-yl]-(4-methylpiperazin-1-yl)methanone (15.94 mg, 31.97 µmol, 26.6% yield, 100.0% purity) as light yellow solid .

¹ H NMR (400 MHz, CD3OD) δ ppm 8.63 (s, 1H), 8.48 (d, J=2.9 Hz, 1H), 8.26 (s, 1H), 7.71-7 .62 (m, 2H), 7.19-7.13 (m, 1H), 7.07-6.95 (m, 3H), 6.05 (s, 1H), 3.90 (t, J =6.2 Hz, 2H), 3.75 (br s, 4H), 3.19 (t, J=6.1 Hz, 2H), 2.54 (br s, 4H), 2.33 (s, 3H); ER-LCMS m/z 499.2 [M+H]+.

Example 68.

Synthesis I-69

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Stage 1: N-[2-(5-fluoro-2-methyl-1H-indol-3-yl)ethyl]-2-(5-fluoro-3-pyridyl)-9-isopropyl-purine-6amine (I- 69)

DIEA (106.33 mg , 822.73 µmol, 143.31 µl, 5 eq.) and 2-(5-Fluoro-2-mstyl-1H-indol-3yl)ethanamine (37.96 mg, 197.46 µmol, 1.2 eq. ). The mixture was stirred at 60° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)- ACN]; B%: 45%-75%, 10 min) followed by lyophilization to give A2-(5-fluoro-2methyl-1H-indol-3-yl)ethyl]-2-(5-fluoro-3-pyridyl )-9-isonronyl-purine-6-amine (32.52 mg, 58.40 µmol, 35.5% yield, 100.0% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.35 (s, 1H), 8.93 (s, 1H), 8.77 (s, 1H), 8.62 (d, J=9.3 Hz, 1H), 7.156.94 (m, 2H), 6.63 (t, J=8.0 Hz, 1H), 5.10-4.99 (m, 1H), 4.04 (m, 2H), 3.09 (t, J=6.6 Hz, 2H), 2.30 (s, 3H), 1.71 (d, J=6.8 Hz, 6H); ER-LCMS m/z 448.0 [M+H]+.

Example 69.

Synthesis I-70

Step 1: 5-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-3-methyl-pyrazolo[1,5-a]n-pyrimidine-7amine (I- 70)

DIEA (59.04 mg, 456.85 µmol, 79.57 µl, 3 eq.) and 7-chloro-5-(5-fluoro-3-pyridyl)-3-methylpyrazolo[1,5-a]pyrimidine (40 mg, 152.28 µmol, 1 eq. .). The mixture was stirred at 50° C. for 16 h under N2. The reaction mixture was concentrated under reduced pressure to remove i-PrOH to give a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; in %: 35%-65%, 10 min) followed by lyophilization to give 5-(5-fluoro-3-pyridyl)-N-[2-(1 H-indol-3-yl)ethyl]-3-methyl-pyrazolo [ 1,5a]pyrimidine-7-amine (32.43 mg, 65.15 µmol, 42.8% yield, 99.6% purity, 3HCl) as a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.72 (d, J=2.6 Hz, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.56 -7.52 (m, 1H), 7.50-7.45 (m, 1H), 7.16-7.10 (m, 1H), 6.98 (s, 1H), 6.97-6 .92 (m, 1H), 6.85 (m, 1H), 5.76 (s, 1H), 4.06-3.99 (m,

- 174 041983

2H), 3.24-3.19 (m, 2H), 2.30 (s, 3H); ER-LCMS m/z 387.0 [M+H] ⁺ .

Example 70.

Synthesis I-71

1: N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]-2-(5-fluoro-3-pyridyl)-9-isopropyl-purine-6 Step amine (I- 71)

DIEA (53.16 mg, 411.37 µmol, 71.65 µl, 3.0 eq.), 2-(7-fluoro-2-methyl-1H-indol3-yl)ethanamine (37.66 mg, 164.55 µmol, 1, 2 eq.). The mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN ]; B%: 46%-76%, 10 min) followed by lyophilization to give N[2-(7-fluoro-2methyl-1H-indol-3-yl)ethyl]-2-(5-fluoro-3- pyridyl)-9-isopropyl-purine-6-amine (27.83 mg, 49.98 µmol, 36.4% yield, 100.0% purity, 3HCl) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.30 (s, 1H), 8.80 (s, 1H), 8.74 (dd, J=1.1, 2.9 Hz, 1H), 8 .61-8.56 (m, 1H), 7.28 (d, J=7.9 Hz, 1H), 6.84 (dt, J=4.7, 7.9 Hz, 1H), 6, 63 (dd, J=7.9, 11.7 Hz, 1H), 5.03 (td, J=6.9, 13.6 Hz, 1H), 4.04 (m, 2H), 3.12 (t, J=6.6 Hz, 2H), 2.30 (s, 3H), 1.70 (d, J=6.8 Hz, 6H); ER-LCMS m/z 447.9 [M+H]+.

Example 71.

Synthesis I-72

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Synthesis scheme:

1-72

Stage 1: 2,4-dichloro-6-isopropoxy-pyrimidine

CI

NaH (261.69 mg, 6.54 mmol, 60% in mineral oil, 1.2 eq.). The mixture was stirred at 0° C. for 30 minutes. To the above solution was added 2,4,6-trichloropyrimidine (1 g, 5.45 mmol, 625.00 µl, 1.0 eq.) and the mixture was stirred at 15° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with water (150 ml), extracted with EtOAc (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 50/1, TLC: PE/EtOAc = 100/1, Rf = 0.20) to give a mixture of 4,6-dichloro-2isopropoxy-pyrimidine (347 mg, crude) and 2,4-dichloro-6-isopropoxy-pyrimidine (173 mg, crude) as a colorless oil .

¹ H NMR (400 MHz, CDCl3) δ ppm 7.00 (s, 1H), 5.35-5.23 (m, 1H), 1.40 (d, J=6.2 Hz, 6H); ER-LCMS m/z 207.1, 209.1 [M+H] ⁺ .

Stage 2: 4-chloro-N-[2-(1H-indol-3-yl)ethyl]-6-isopropoxy-pyrimidin-2-αmin

To a solution of (2-(1H-indol-3-yl)ethanamine (680.92 mg, 4.25 mmol, 2.2 eq.) and 2,4-dichloro-6isopropoxypyrimidine (100 mg, 482.96 µmol , 0.25 eq.) in i-PrOH (5 ml) was added DIEA (749.01 mg, 5.80 mmol, 1.01 ml, 3.0 eq.) and 4,6-dichloro-2-isopropoxy- pyrimidine (200 mg, 965.92 µmol, 0.5 eq.) The mixture was stirred at 26°C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (from PE /EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, R _fl = 0.55, R _G = 0.45) to give 4-chloro-N-[2-(1H-indole -3yl)ethyl]-6-isopropoxy-pyrimidin-2-amine (90 mg, 220.37 µmol, 11.4% yield, 81.0% purity) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm 8.05 (s, 1H), 7.68-7.61 (m, 1H), 7.39 (d, J=8.2 Hz, 1H), 7, 25-7.19(m, 1H), 7.16-7.10(m, 1H), 7.05(s, 1H), 5.97(s, 1H), 3.78-3.69( m, 2H), 3.10-3.03 (m, 2H), 1.33 (d, J=5.3 Hz, 6H); ER-LCMS m/z 331.1, 332.1 [M+H] ⁺ .

Step 3: 4-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-isopropoxypyrimidine-2-αmin (I-72)

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4-chloro-N-[2-(1H-indol-3-yl)ethyl]-6-isopropoxy-pyrimidin-2-amine (90.00 mg, 220.37 µmol, 1 eq.), (5-fluoro -3-pyridyl)boronic acid (62.10 mg, 440.73 µmol, 2 eq.), Cs ₂ CO ₃ (215.40 mg, 661.10 µmol, 3.0 eq.) and Pd(dppf)Cl ₂ (16.12 mg, 22.04 µmol, 0.1 eq.) was placed in a microwave tube in 1,4-dioxane (3 ml) and water (0.6 ml). The sealed tube was heated at 120° C. for 30 minutes while being treated with microwave radiation. The reaction mixture was diluted with EtOAc (20 ml) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified with prep. HPLC (HCl conditions, column: column: Phenomenex Synergi C18 150x30 mmx4 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 37%-67%, 12 min) and the desired fraction was lyophilized, giving 4-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-isopropoxypyrimidin-2-amine (52.48 mg, 104.79 µmol, yield 47 .5%, 100.0% pure, 3HCl salt) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.75 (m, 2H), 8.06 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.0Hz, 1H), 7.14(s, 1H), 7.12-7.06(m, 1H), 7.04-6.99(m, 1H), 6.62(s , 1H), 5.18 (s, 1H), 3.92 (t, J=6.5 Hz, 2H), 3.15 (t, J=6.5 Hz, 2H), 1.36 (d , J=6.3 Hz, 6H); ER-LCMS m/z 392.2 [M+H]+.

Example 72.

Synthesis I-73

Synthesis scheme:

Stage 1: 2-methyl-3-oxo-propanenitrile

To a solution of DIPA (1.84 g, 18.16 mmol, 2.57 ml, 1 eq.) in THF (20 ml) was added n-BuLi (2.5 M in nhexane, 7.63 ml, 1.05 eq. .). The mixture was stirred at -65°C for 30 minutes. A solution of propanenitrile (1 g, 18.16 mmol, 1.30 ml, 1 eq.) in THF (10 ml) was added dropwise to the above mixture. The mixture was stirred at -65°C for 30 min under N2. A solution of ethyl formate (1.41 g, 19.06 mmol, 1.53 ml, 1.05 eq.) in THF (10 ml) was added dropwise and the mixture was stirred at -65° C. for 3 h. TLC (PE/ EtOAc = 1/1, R _f = 0.45) showed that one major new spot was found. The reaction mixture was quenched by adding 1 N. HCl solution (50 ml) at -65°C, extracted with EtOAc (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to give 2-methyl-3-oxo-propanenitrile (1.1 g, crude) as a yellow oil which was used in the next step without further cleaning.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.60 (s, 1H), 3.54 (d, J=7.5 Hz, 1H), 1.55 (s, 3H).

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Stage 2: 4-methyl-1H-pyrazole-5-amine

AcOH (1.39 g, 23.17 mmol, 1.32 ml, 1.75 eq.) and hydrazine (550.00 mg, 17.16 mmol, 620.77 µl, 1.3 eq.). The mixture was stirred at 90° C. for 12 hours. TLC (PE/EtOAc = 1/1, Rf = 0.10) indicated that one major new spot was found. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with NaHCO ₃ solution (100 ml), extracted with EtOAc (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (DCM/MeOH = 100/1 to 10/1, TLC: PE/EtOAc = 10/1, Rf = 0.75) to give 4-methyl-1Hpyrazol-5-amine (230 mg, 2.37 mmol, 17.9% yield, crude) as a yellow oil.

¹ H NMR (400 MHz, CDCl3) δ ppm 7.13 (s, 1H), 1.94-1.92 (m, 3H).

Step 3: 5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-ol

To a solution of methyl 3-(5-fluoro-3-pyridyl)-3-oxo-propanoate (400 mg, 1.99 mmol, 1 eq) in AcOH (6 ml) was added 4-methyl-1H-pyrazole-5 -amine (230 mg, 2.37 mmol, 1.19 eq.). The mixture was stirred at 120°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give 5-(5fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-ol (500 mg, crude) was obtained as a yellow oil, which was used in the next step without further purification. ER-LCMS m/z 245.2 [M+H]+.

Stage 4: 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine

To a solution of 5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-ol (500 mg, 655.14 µmol, 1 eq.) in POCl ₃ (5 ml ) was stirred at 120° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove POC. The residue was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 2/1, TLC: PE/EtOAc = 3/1, Rf = 0.40) to give 7-chloro-5-(5- fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (145 mg, 552.02 µmol, 84.3% yield, 100.0% purity) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm 9.10 (s, 1H), 8.60 (d, J=2.6 Hz, 1H), 8.24 (dd, J=1.8, 9.3 Hz, 1H), 8.14 (s, 1H), 7.39 (s, 1H), 2.47 (s, 3H); ER-LCMS m/z 262.9, 264.9 [M+H] ⁺ .

Step 5: 5-(5-fluoro-3-pyridyl)-3-methyl-N-[2-(2,5,7-trifluoro-1 H-indol-3-yl)ethyl]pyrazolo [1.5a] pyrimidine-7-amine (I-73)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (40 mg, 152.28 µmol, 1 eq.) in i-PrOH (3 ml) was added DIEA (157.45 mg, 1.22 mmol, 212.19 μl, 8.0 eq.) and 2-(5,7difluoro-2-methyl-1H-indol-3-yl)ethanamine (54, 87 mg, 182.74 µmol, 1.2 eq., oxalic acid salt). The mixture was stirred at 50° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 42%-62%, 10 min) and the desired fraction was lyophilized to give the compound 5-(5-fluoro-3-pyridyl)-3-methyl-N2(2,5,7-trifluoro -1H-indol-3-yl)ethyl]pyrazolo[1,5-a]pyrimidin-7-amine (15.56 mg, 27.91 µmol, 18.3% yield, 98.6% purity, 3HCl salt) as a yellow solid.

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1H NMR (400 MHz, CD3OD) δ ppm 8.75 (d, J=2.4 Hz, 1H), 8.45 (s, 1H), 8.11 (s, 1H), 7.66-7, 61 (m, 1H),

7.00 (dd, J=2.2, 9.3 Hz, 1H), 6.44 (ddd, J=2.2, 9.5, 11.2 Hz, 1H), 5.75 (s, 1H), 4.00 (t, J=5.7 Hz, 2H), 3.16-3.10 (m, 2H), 2.31 (s, 3H), 2.15 (s, 3H); ER-LCMS m/z 437.2 [M+H]+.

Example 73.

Synthesis I-74

Stage 1: N-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl]-2-(5-fluoro-3-pyrudyl)-6-isopropoxypyrimidine-4-amine ( I-74)

4-chloro-2-(5-fluoro-3-pyridyl)-6-isopropoxypyrimidine (90 mg, 322.77 µmol, 1.0 eq.), 2-(5,7difluoro-2-methyl-1H- indol-3-yl)ethanamine (145.37 mg, 484.15 µmol, 1.5 eq, oxalic acid) and DIEA (333.71 mg, 2.58 mmol, 449.75 µl, 8 eq) in i-PrOH (5 ml) was placed in a microwave tube. The sealed tube was heated at 150° C. for 6 hours while being treated with microwave radiation. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 2/1, TLC: PE/EtOAc = 3/1, R _f = 0.50) and then repurified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 60%90%, 10 min) and the desired the fraction was lyophilized to give N-[2-(5,7-difluoro-2-methyl-1H-undol-3yl)ethyl]-2-(5-fluoro-3-pyridyl)-6-isopropoxy-pyrimidin-4-amine (26.48 mg, 48.07 µmol, 14.9% yield, 100% purity, 3HCl salt) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.10 (s, 1H), 8.71 (d, J=2.6 Hz, 1H), 8.27 (s, 1H), 6.99 (d, J=9.3Hz, 1H), 6.54(t, J=9.9Hz, 1H), 5.69(s, 1H), 5.05(s, 1H), 3.74(m, 2H), 2.97 (t, J=6.6 Hz, 2H), 2.34 (s, 3H), 1.37 (d, J=6.2 Hz, 6H); ER-LCMS m/z 442.2 [M+H] ⁺ .

Example 74.

Synthesis of I-75a, I-75b and 1-75c

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Synthesis scheme:

Stage 1: tert-butyl N-(2,3,4,9-tetrahydro-1H-carbazol-3-yl)carbamate

MgSO ₄ (564.38 mg, 4.69 mmol , 1 eq.) and phenylhydrazine (507.05 mg, 4.69 mmol, 460.96 µl, 1 eq.). The mixture was stirred at 28°C for 2 hours Then MgSO ₄ was filtered off, the filtrate was evaporated under reduced pressure. The resulting brown oil was dissolved in toluene (20 ml), ZnCl ₂ (3.20 g, 23.44 mmol, 5 eq.) was added, the mixture was heated at 110°C for 4 h. The reaction mixture was concentrated under reduced pressure, obtaining the residue , which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 5/1, Rf = 0.30) to give tert-butyl N-(2.3 ,4,9-Tetrahydro-1H-carbazol-3-yl)carbamate (700 mg, 1.96 mmol, 41.7% yield, 80.0% purity) as a yellow solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 7.33 (d, J=7.5 Hz, 1H), 7.23 (td, J=0.9, 7.9 Hz, 1H), 7, 04-6.97 (m, 1H), 6.97-6.90 (m, 1H), 3.92-3.79 (m, 1H), 2.92-2.78 (m, 2H), 2.57-2.31 (m, 2H), 1.93-1.68 (m, 2H), 1.47 (s, 9H); ER-LCMS m/z 231.1 [M-t-Bu+H] ⁺ .

Stage 2: 2,3,4,9-Tetrahydro-1H-carbazole-3-amine

TFA (3 .08 g, 27.01 mmol, 2.0 ml, 13.81 eq.). The mixture was stirred at 28° C. for 2 hours. TLC (PE/EtOAc = 5/1, Rf = 0) showed that the starting material was completely consumed and one new spot formed. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with water (30 ml), the pH was adjusted to 10 with 1% NaOH solution. The mixture was subjected to extraction with EtOAc (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to give 2,3,4,9tetrahydro-1H-carbazole-3-amine (400 mg, 1.80 mmol, 92.3% yield, purity 84.0%) as a black-brown solid, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.80 (s, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.27-7.23 (m, 1H), 7 .13-7.04 (m, 2H), 3.34-3.24 (m, 1H), 3.07-2.97 (m, 1H), 2.81 (t, J=6.4 Hz , 2H), 2.50-2.43 (m, 1H), 2.13-2.05 (m, 1H), 1.841.76 (m, 1H); ER-LCMS m/z 187.0 [M+H]+.

Step 3: (3S)-N-[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]-2,3,4,9tetrahydro-III -carbazole-3-amine (I-75b) and (3R)-N-[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5a]pyrimidin-7-yl]-2, 3,4,9-tetrahydro-1H-carbazole-3-amine (I-75a)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (153.06 mg, 515.96 µmol, 1.0 eq.) in i -PrOH (10 ml) was added DIEA (200.05 mg, 1.55 mmol, 269.60 μl, 3.0 eq.) and

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2,3,4,9-tetrahydro-1H-carbazole-3-amine (145.09 mg, 654.35 µmol, 1.27 eq). The mixture was stirred at 50° C. for 15 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc= 3/1, Rf = 0.80). Compounds were separated by SFC (conditions: column: AD (250 mm x 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]; V%: 45%-45%, min). The separation solution was concentrated to give crude products which were purified by preparative HPLC (HCl conditions; column: Phenomenex Synergi C18 150x30 mmx4 µm; mobile phase: [water (0.05% HCl)ACN]; V%: 60%- 90%, 12 min) followed by lyophilization to give the enantiomer (36.18 mg, 65.79 µmol, 12.8% yield, 100.0% purity, 3HCl salt) (Rt = 4.768 min, ee% = 100.0 and [a] ²⁹ _D = -3.430 (i-PrOH, c = 0.107 g/100 ml)) as a yellow solid;

1H NMR (400 MHz, CD3OD) δ ppm 9.00 (s, 1H), 8.78 (s, 1H), 8.36-8.29 (m, 1H), 8.24 (d, J=1 .3 Hz, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.27 (d, J=7.9 Hz, 1H), 7.08-6.93 (m, 3H ), 4.63 (s, 1H), 3.43-3.32 (m, 2H), 3.18-2.93 (m, 3H), 2.43-2.26 (m, 2H), 1.40 (d, J=6.8 Hz, 6H); ER-LCMS m/z 441.2 [M+H]+; and the other enantiomer (36.49 mg, 66.36 µmol, 12.9% yield, 100.0% purity, 3HCl salt) (Rt = 5.778 min, ee% = 96.4 and [a] ²⁹ _D = +3.121 (i-PrOH, c=0.104 g/100 ml)) as a yellow solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 9.03 (s, 1H), 8.73 (d, J=2.6 Hz, 1H), 8.36-8.30 (m, 1H), 8.18 (s, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.29-7.25 (m, 1H), 7.04 (dt, J=1.2, 7.6 Hz, 1H), 7.00-6.93(m, 2H), 4.60(s, 1H), 3.403.32(m, 2H), 3.16-2.92(m, 3H ), 2.43-2.24 (m, 2H), 1.40 (d, J=6.8 Hz, 6H); ER-LCMS m/z 441.3 [M+H] ⁺ .

Example 75.

Synthesis I-77

POCl ₃ (4.11 g, 26.82 mmol, 2.49 ml, 2 eq.) was added dropwise to DMF (40 ml) at −20° C. over a period of 10 min under N ₂ atmosphere. After stirring for 1 hour, 5-fluoro-2-methyl-1H-indole (2 g, 13.41 mmol, 1 eq.) was added to the above solution while maintaining the temperature below -20°C. The reaction mixture was heated to 15° C. and stirred for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO ₃ (100 ml) and extracted with EtOAc (50 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc=1/0 to 1/1, TLC: PE/EtOAc= 1/1, Rf = 0.67) to give 5-fluoro-2-methyl-1H-indole-3-carbaldehyde (1.3 g, 5.73 mmol, 42.7% yield, 78.1% purity) as yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 10.17 (s, 1H), 8.39 (broad s, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.08 -6.89 (m, 1H), 2.75 (s, 3H); ER-LCMS m/z 178.0 [M+H] ⁺ .

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Stage 2: 5-fluoro-2-methyl-3-[(E)-2-nitrovinyl]-1H-indole

To a solution of 5-fluoro-2-methyl-1H-indole-3-carbaldehyde (1.1 g, 4.85 mmol, 1 eq.) in nitromethane (45 ml) was added NH ₄ OAc (1.12 g, 14 54 mmol, 3 eq.). The mixture was stirred at 110° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to remove nitromethane. The residue was subjected to extraction with EtOAc (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 5-fluoro-2-methyl-3-[(E)-2-nitrovinyl]-1Nindole (0.92 g, crude) as a solid brown substance, which was used in the next step without further purification; ER-LCMS m/z 221.0 [M+H]+.

Step 3: 2-(5-fluoro-2-methyl-1H-indol-3-yl)ethanamine

To a THF (30 ml) solution of 5-fluoro-2-methyl-3-[(E)-2-nitrovinyl]-1H-indole M, 31.79 ml, 5 eq.) at 0°C. After the addition, the mixture was stirred at 80° C. for 2 h. The reaction mixture was diluted with THF (10 ml) and then quenched by successively adding water (1.4 ml), 10% NaOH (1.4 ml) and water (4.2 ml) at 0°C. After stirring for 30 minutes, the mixture was filtered through celite.

The filtrate was concentrated under reduced pressure to give 2-(5-fluoro-2-methyl-1H-indol-3yl)ethanamine (1.0 g, crude) as a yellow oil which was used directly in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 7.14 (dd, J=8.8 Hz, 1H), 7.07 (dd, J=10.0 Hz, 1H), 6.72 (td, J= 5.0, 9.1 Hz, 1H), 2.85-2.74 (m, 4H), 2.33 (s, 3H); ER-LCMS m/z 192.1 [M+H] ⁺ .

Step 4: N-[2-(5-fluoro-2-methyl-1 H-indol-3-yl)ethyl]-5-(5-fluoro-3-pyridyl)-3-isopropylpyrazolo[1,5-a ]pyrimidine-7-amine (I-77)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (64.30 mg, 216.75 µmol, 1 eq.) in i-PrOH (5 ml) was added DIEA (140.07 mg, 1.08 mmol, 188.77 μl, 5 eq.) and 2-(5-fluoro-2methyl-1H-indol-3-yl)ethanamine (50 mg, 260 , 10 µmol, 1.2 eq.) the mixture was stirred at 60° C. for 16 h. The reaction mixture was concentrated under reduced pressure to remove i-PrOH to give a residue which was purified by preparative HPLC (Column: Phenomenex Gemini 150x25 mmx10 µm ; mobile phase: [water (0.05% HCl)-ACN]; B%: 50%-80%, 7 min) followed by lyophilization to give N-[2-(5-fluoro-2-methyl-1H -indol-3-yl)ethyl]-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5a]pyrimidin-7-amine (17.49 mg, 31.46 µmol, yield 14 .5%, 100.0% pure, 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.75 (d, J=2.4 Hz, 1H), 8.40 (s, 1H), 8.21 (s, 1H), 7.54 (d, J=8.6Hz, 1H), 7.07 (dd, J=2.3, 9.8Hz, 1H), 6.95 (dd, J=4.4, 8.6Hz, 1H), 6.59 (J=2.4, 9.0 Hz, 1H), 5.71 (s, 1H), 4.03-3.95 (m, 2H), 3.28-3.20 (m, 1H), 3.16-3.09 (m, 2H), 2.16 (s, 3H), 1.34 (d, J=6.8 Hz, 6H); ER-LCMS m/z 447.1 [M+H] ⁺ .

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Example 76.

Synthesis I-78

5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3 Step 1: Carboxamide (I-78)

5-(5-Fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid mixture (35 mg, 84.05 µmol, 1 eq.), HATU (63.92 mg, 168.10 µmol, 2 eq.), DIEA (32.59 mg, 252.16 µmol, 43.92 µl, 3 eq.) and NH ₄ Cl ( 13.49 mg, 252.16 µmol, 3 eq) in DMF (5 ml) was stirred at 25°C for 3 h. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 µm, mobile phase: [water (0.05% HCl)-ACN]; V%: 36%-56%, 10 min), lyophilized to give 5-(5-fluoro-3-pyridyl)-7-[ 2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3-carboxamide (16.47 mg, 31.08 µmol, 37.0% yield, 99.0% purity, 3HCl ) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.85 (s, 1H), 8.73 (s, 1H), 8.51 (s, 1H), 8.03 (d, J=9.2 Hz , 1H), 7.727.69 (m, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.04-7.01 (m, 2H), 6.95 (s, 1H) , 6.08 (s, 1H), 3.98 (t, J=5.6 Hz, 2H), 3.22 (t, J=5.6 Hz, 2H); ER-LCMS m/z 416.2 [M+H]+.

Example 77.

Synthesis I-79

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Synthesis scheme:

Step 1: 2-(5-fluoro-3-pyridyl)-9-isopropyl-N-[2-(2-methyl-1H-indol-3-yl)ethyl]purine-6-amine (179)

6-Chloro-2-(5-fluoro-3-pyridyl)-9-isopropyl-purine mixture (52.08 mg, 171.40 µmol, 1 eq.), 2-(2methyl-1H-indol-3-yl )ethanamine (29.87 mg, 171.40 µmol, 1 eq.) and DIEA (66.46 mg, 514.21 µmol, 89.57 µl, 3 eq.) in i-PrOH (3 ml) were stirred at 55 °C for 19 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 150x30 mmx4 µm; mobile phase: [water (0.05% HCl)-ACN]; B %: 42% 72%, 12 min) followed by lyophilization to give 2-(5-fluoro-3-pyridyl)-9-isopropyl-N-[2-(2-methyl1H-indol-3-yl)ethyl]purine -6-amine (18.99 mg, 34.91 µmol, 20.4% yield, 99.1% purity, 3 HCl salt) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.27-9.11 (m, 2H), 8.85 (s, 1H), 8.68 (d, J=8.78 Hz, 1H), 7, 51-7.43 (m, 1H), 7.07-7.00 (m, 1H), 6.92-6.83 (m, 2H), 5.13-5.00 (m, 1H), 4.07 (s, 2H), 3.11 (t, J=6.53 Hz, 2H), 2.27 (s, 3H), 1.73 (d, J=6.53 Hz, 6H); ER-LCMS m/z 430.2 [M+H]+.

Example 78. Synthesis of I-80 _r —-NH A ΊΠΑ ^Ν A 1-80 Synthesis scheme: Cl x ? Min > jfl - A- A / NaH, -60 °C CI ^ N ^ O ^Cl NI 0 * ⁰ -NH .. A ^ρ ν<ν ^Β ί ^ο Η) ₂ HN Ά TJ _ N * 1 (Ϊ Pd (dppf)CI ₂ , Cs ₂ CO ₃ ci'^ ^x 'N ^/ ^o Step 1: 4,6-dichloro-2-isopropoxypyrimidine Cl Ia SG N Λ r—NH DIEA NH Αά A Hell ^{N 0} MO

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To a suspension of NaH (248.00 mg, 6.20 mmol, 60% in mineral oil, 1.41 eq) in dry THF (10 ml) was added i-PrOH (277.91 mg, 4.62 mmol, 354 03 μl, 1.05 equiv.) in an ice bath and N ₂ . After stirring for 30 min, the suspension was cooled to -60°C and 4,6-dichloro-2-methylsulfonyl-pyrimidine (1 g, 4.40 mmol, 625.00 μl, 1.0 eq.) in dry THF was added dropwise (10 ml) and maintained the temperature below -55°C. The resulting mixture was stirred for 1 hour at -55°C. The reaction mixture was slowly poured into water (100 ml) and extracted with EtOAc (30 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give 4,6-dichloro-2isopropoxypyrimidine (565 mg, 2.56 mmol, 58.2% yield, 94% purity) as a yellow oil , which was used in the next step without further purification.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm 7.02-6.96 (m, 1H), 5.29 (m, 1H), 1.40 (d, J=6.0 Hz, 6H); ER-LCMS m/z 206.9, 208.9 [M+H]+.

Stage 2: 6-chloro-N-[2-(1H-indol-3-yl)ethyl]-2-isopropoxy-pyrimidin-4-amine

GA

Λα

Cr N O

DIEA (704.07 mg, 5.45 mmol, 948 .88 µl, 3.0 eq.) and 2-(1H-indol-3-yl)ethanamine (329.00 mg,

2.05 mmol, 1.13 eq.). The mixture was stirred at 26° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc= 3/1, Rf = 0.45) to give 6-chloro-Ni-[2-(Shindol-3-yl)ethyl]-2-isopropoxy-pyrimidin-4-amine (290 mg, 841.57 µmol, yield 46.3%, 96% pure as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm 8.10 (s, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.43-7.37 (m, 1H), 7, 24 (dt, J=1.0, 7.6 Hz, 1H), 7.18-7.12 (m, 1H), 7.05 (d, J=2.4 Hz, 1H), 5.95 (s, 1H), 5.26-5.17 (m, 1H), 3.68 (s, 2H), 3.08 (t, J=6.6 Hz, 2H), 1.35 (d, J=6.2 Hz, 6H); ER-LCMS m/z 330.9, 332.0 [M+H]+.

Stage 3: 6-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-2-isopropoxy-pyrimidin-4-amine (I-80)

6-Chloro-N-[2-(1H-indol-3-yl)ethyl]-2-isopropoxy-pyrimidin-4-amine (90 mg, 261.18 µmol, 1 eq), (5-fluoro-3 -pyridyl)boronic acid (92.00 mg, 652.94 µmol, 2.5 eq.), Cs ₂ CO ₃ (255.29 mg, 783.53 µmol, 3.0 eq.) and Pd(dppf)Cl ₂ (19.11 mg, 26.12 µmol, 0.1 eq.) was placed in a microwave tube in water (1.2 ml) and 1,4-dioxane (6 ml).

The sealed tube was heated at 120° C. for 30 minutes while being treated with microwave radiation. The reaction mixture was diluted with EtOAc (15 ml) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions, column: column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; V%: 25 %-55%, 10 min) and the desired fraction was lyophilized to give 6(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-2-isopropoxy-pyrimidin-4- amine (43.81 mg, 87.48 µmol, 33.5% yield, 100% purity, 3 HCl salt) as a yellow solid.

1H NMR (400 MHz, CD ₃ OD+Na ₂ CO ₃ ) δ ppm 8.92 (s, 1H), 8.53 (m, 1H), 8.12 (m, 1H), 7.61 (m, 1H), 7.33 (m, 1H), 7.09 (d, J=7.0 Hz, 2H), 7.02 (m, 1H), 6.57 (s, 1H), 5.38- 5.26 (m, 1H), 3.77 (m, 2H), 3.09 (t, J=7.0 Hz, 2H), 1.40 (d, J=5.8 Hz, 6H); ER-LCMS m/z 392.0 [M+H]+.

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Example 79.

Synthesis I-81

Synthesis scheme:

Br

Pd(PPh ₃ ) ₄

Step 1: methyl 3-(5-bromo-3-pyridyl)-3-oxo-propanoate

A mixture of 5-bromopyridine-3-carboxylic acid (1 g, 4.95 mmol, 1 eq.) and CDI (1.20 g, 7.43 mmol, 1.5 eq.) in THF (10 ml) was stirred at 20 °C for 1 h, TEA (500.93 mg, 4.95 mmol, 689.03 µl, 1 eq.) was added, the mixture was stirred at 20°C for 1 h, then (3-methoxy-3- oxopropanoyl)hydroxypotassium(1+) (1.55 g, 9.90 mmol, 2 eq.) and MgCl ₂ (942.66 mg, 9.90 mmol, 406.32 μl, 2 eq.). The mixture was stirred at 20° C. for 11 hours. The pH of the reaction mixture was adjusted to 2 with 2N HCl. HCl, extracted with EtOAc (20 mlx3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 10/1 to 5/1 , TLC: PE/EtOAc = 5/1, Rf = 0.58) to give methyl 3-(5-bromo-3-pyridyl)-3-oxo-propanoate (554 mg, 1.50 mmol, 30 yield, 4%, 70% pure) as a white solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 9.07-9.06 (m, 1H), 8.95 (d, J=1.6 Hz, 1H), 8.89 (d, J=2 .0 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.53-8.52 (m, 1H), 8.42 (t, J=2.0 Hz, 1H ), 5.97 (s, 1H), 3.82 (s, 3H), 3.74 (s, 3H); ERLCMS m/z 259.9, 261.9 [M+H]+.

Stage 2: 5-(5-bromo-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-ol

A mixture of methyl 3-(5-bromo-3-pyridyl)-3-oxo-propanoate (300 mg, 813.74 µmol, 1 eq.) and 4isopropyl-1H-pyrazol-5-amine (122.23 mg, 976 .49 µmol, 1.2 eq.) in AcOH (10 ml) was stirred at 120°C for 0.5 h. The mixture was concentrated under reduced pressure to give 5-(5-bromo-3-pyridyl)-3-isopropyl-pyrazolo [1,5-a]pyrimidin-7-ol (450 mg, crude) as a brown oil, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.99-8.88 (m, 1H), 8.74-8.73 (m, 1H), 8.39-8.37 (m, 2H), 7.79(s, 1H),

- 186 041983

3.21-3.20 (m, 1H), 1.39-1.33 (m, 6H); ER-LCMS m/z 333.0, 335.0 [M+H]+.

Step 3: 5-(5-bromo-3-pyridyl)-7-chloro-3-isopropyl-pyrazolo[1,5-a]pyrimidine

CI % / /

No. ⁷

A solution of 5-(5-bromo-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-ol (450 mg, 1.35 mmol, 1 eq.) in POCl ₃ (8.2 g, 53.48 mmol, 4.97 ml, 39.60 eq.) was stirred at 110° C. for 1 h. The mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (from PE/EtOAc = 10/1 to 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.58) to give 5-(5-bromo-3-pyridyl)-7-chloro-3-isopropyl-pyrazolo[1,5- a] pyrimidine (331 mg, 847.20 µmol, 62.7% yield, 90% purity) as a yellow solid.

1H NMR (400 MHz, CDC13) δ ppm 9.20 (s, 1H), 8.79 (d, J=2.4 Hz, 1H), 8.59 (t, J=2.4 Hz, 1H) , 8.14 (s, 1H), 7.37 (s, 1H), 3.42 (s, 1H), 1.45 (d, J=6.8 Hz, 6H); ER-LCMS m/z 350.9, 352.9 [M+H] ⁺ .

Stage 4: 5-(5-bromo-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-amine

5-(5-Bromo-3-pyridyl)-7-chloro-3-isopropyl-pyrazolo[1,5-a]pyrimidine mixture (60 mg, 153.57 µmol, 1 eq), 2-(1H-indole -3-yl)ethanamine (36.91 mg, 230.36 µmol, 1.5 eq.) and DIEA (59.54 mg, 460.71 µmol, 80.25 µl, 3 eq.) in i-PrOH ( 10 ml) was stirred at 80° C. for 2 h. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative TLC (SiO ₂ , PE/EtOAc=1/1, Rf=0.28) to give 5- (5-bromo-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (70 mg, 117.80 µmol , yield 76.7%, purity 80%) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 9.21 (d, J=1.6 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.62 (s, 1H), 7.997.95 (m, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.09-6.99 (m, 2H), 6.66 (s, 1H), 3.84 (q, J=6.0 Hz, 2H), 3, 27-3.22 (m, 1H), 3.13-3.10 (m, 2H), 1.35 (d, J=6.8 Hz, 6H); ER-LCMS m/z 474.9, 476.9 [M+H] ⁺ .

Step 5: 5-[7-[2-(1H-indol-3-yl)ethylamino]-3-isopropylpyrazolo[1,5-a]pyrimidin-5yl]pyridine-3-carbonitrile (I-81 )

A mixture of 5-(5-bromo-3-pyridyl)-N-[2-(1 H-indol-3-yl)ethyl]-3-isopropyl-pyrazolo[1,5-a]pyrimidine-7 amine (70 mg , 117.80 µmol, 1 eq.), Pd(PPh ₃ ) ₄ (13.61 mg, 11.78 µmol, 0.1 eq.) and Zn(CN) ₂ (27.67 mg, 235.60 µmol , 2 eq.) in DMF (5 ml) was degassed and purged with N2 3 times. The mixture was stirred at 85°C for 12 hours under N2. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Gemini 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 60%- 90%, 10 min) to give 5-[7-[2(1H-indol-3-yl)ethylamino]-3-isopropyl-pyrazolo[1,5-a]pyrimidin-5-yl]pyridin-3- carbonitrile (18.46 mg, 43.72 µmol, 37.1% yield, 99.819% purity) as a yellow solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 9.07 (d, J=2.0 Hz, 1H), 8.86 (d, J=1.6 Hz, 1H), 7.97 (t, J=2.0 Hz, 1H), 7.90 (s, 1H), 7.74-7.71 (m, 1H), 7.18-7.17 (m, 1H), 7.13-7 .10 (m, 2H), 6.95 (s, 1H), 5.86 (s, 1H), 3.87 (t, J=6.0 Hz, 2H), 3.28-3.19 ( m, 1H), 3.18 (t, J=6.0 Hz, 2H), 1.37 (d, J=6.8 Hz, 6H); ER-LCMS m/z 422.0 [M+H] ⁺ .

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Example 80.

Synthesis of I-82a, I-82b and 1-82c

EtOH/ΤΓΦ

HE

Synthesis scheme:

Stage 1: N-Benzyl-6-methoxy-tetralin-2-amine

To a solution of 6-methoxytetralin-2-one (300 mg, 1.70 mmol, 1 eq.) in anhydrous DCM (5 ml) was added phenylmethanamine (182.43 mg, 1.70 mmol, 185.58 μl, 1 eq. ), AcOH (102.23 mg, 1.70 mmol, 97.37 µl, 1 eq.) and NaBH(OAc) ₃ (541.24 mg, 2.55 mmol, 1.5 eq.). The mixture was stirred at 25° C. for 12 hours. Aq. NaOH (IM, 20 ml) and the mixture was subjected to extraction with DCM (20 mlx3). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/1, TLC : PE/EtOAc=2/1, Rf=0.67) to give N-benzyl-6-methoxytetralin-2-amine (255 mg, 883.18 µmol, 51.88% yield, 92.6% purity) in brown oil.

1H NMR (400 MHz, CD3OD) δ ppm 7.38-7.28 (m, 4H), 7.26-7.21 (m, 1H), 6.98 (d, J=8.4 Hz, 1H ), 6.67 (dd, J=2.5, 8.3 Hz, 1H), 6.61 (d, J=2.4 Hz, 1H), 3.89 (s, 2H), 3.75 (s, 3H), 3.04-2.93 (m, 2H), 2.91-2.72 (m, 2H), 2.64-2.50 (m, 1H), 2.12-1 .99 (m, 1H), 1.62-1.56 (m, 2H); ER-LCMS m/z 268.2 [M+H]+.

Stage 2: 6-methoxytetralin-2-amine

Pd/C (10%, 255 mg) under N2 atmosphere. The suspension was degassed and purged with H ₂ 3 times. The mixture was stirred in H ₂ (50 psi) at 50° C. for 8 h. The mixture was filtered and concentrated to give the crude product 6-methoxytetralin-2-amine (210 mg, 874.40 µmol, 99.0% yield, 73 purity .8%) as a black oil, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 6.94 (d, J=8.4 Hz, 1H), 6.68-6.64 (m, 1H), 6.62 (d, J=2.4 Hz, 1H), 3.74-3.71 (m, 3H), 3.10 (ddt, J=3.3, 5.1, 10.2 Hz, 1H), 2.93 (dd, J= 4.1, 15.5 Hz, 1H), 2.88-2.81 (m, 2H), 2.49 (dd, J=9.8, 15.5 Hz, 1H), 2.06-1 .97 (m, 1H), 1.64-1.51 (m, 1H); ER-LCMS m/z 178.3 [M+H] ⁺ .

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Solution of 6-methoxytetralin-2-amine (210 mg, 874.39 µmol, 1 eq.) in HBr solution (5 ml) Step 3: 2-aminotetralin-6-ol

sieved at 100° C. for 8 h. The mixture was concentrated to give the crude product 2-aminotetralin-6-ol (195 mg, 350.66 µmol, 40.10% yield, 43.9% purity, HBr) as a brown solid , which was used in the next step without further purification.

¹ H NMR (400 MHz, CD3OD) δ ppm 6.91 (d, J=8.4 Hz, 1H), 6.58 (dd, J=2.4, 8.4 Hz, 1H), 6.53 (s, 1H), 3.54-3.44 (m, 1H), 3.06 (dd, J=5.1, 15.4 Hz, 1H), 2.86 (dd, J=5.1 , 8.2 Hz, 2H), 2.71 (dd, J=10.1, 15.4 Hz, 1H), 2.21-2.12 (m, 1H), 1.85-1.75 ( m, 1H); ER-LCMS m/z 164.2 [M+H]+.

Step 4: 2-[[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]tetralin-6-

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (100 mg, 337.09 µmol, 1 eq.) in i-prOH (5 ml) DIEA (130.70 mg, 1.01 mmol, 176.14 μl, 3 eq.) and 2-aminotetralin-6-ol (150.39 mg, 404.51 μmol, 1.2 eq.) were added. The mixture was stirred at 120° C. for 3 hours while being treated with microwave radiation under N2 atmosphere. The mixture was concentrated to remove the solvent. H2O (10 ml) was added, extracted with EtOAc (10 mlx3). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 5/1, TLC : PE/EtOAc = 1/1, Rf = 0.60) to give 2-[[5-(5-fluoro-3-pyridyl)-3isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino ]tetralin-6-ol (78 mg, 184.97 µmol, 54.9% yield, 99.0% purity) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.15 (s, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.36 (d, J=9.3 Hz, 1H ), 7.92 (s, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.74 (s, 1H), 6.61-6.53 (m, 2H), 4 .58 (s, 2H), 4.35-4.23 (m, 1H), 2.94-2.81 (m, 2H), 2.35-2.18 (m, 1H), 2.09 -1.86 (m, 2H), 1.40 (d, J=7.1 Hz, 6H); ER-LCMS m/z 418.0 [M+H] ⁺ .

Step 5: (2R)-2-[[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7yl]amino]tetralin-6-ol (I-82b ) and (2S)-2-[[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin7-yl]amino]tetralin-6-ol (I-82a)

2-[[5-(5-Fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]tetralin-6-ol (78mg, 184.97µmol , 1 eq.) was separated by SFC (column: AD (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH3H2O IPA]; B%: 40%-40%, min). The separation solution was concentrated to give crude products which were purified by preparative HPLC (MeCN/H ₂ O as eluents, acidic conditions, instrument: Phenomenex Synergi C18 150x30 mmx4 µm/mobile phase: water (0.05% HCl)ACN/ gradient: B from 55% to 85% over 12 min/Flow rate: 25 ml/min) followed by lyophilization to give the enantiomer (24.75 mg, 50.47 µmol, 27.3% yield, 100% purity, 2HCl , SFC: T _R = 5.168 min, ee = 100%, or [a] ^26.6 _D = 167.660) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.97 (s, 1H), 8.79 (d, J=2.6 Hz, 1H), 8.34-8.28 (m, 1H), 8, 25 (s, 1H), 6.98-6.91 (m, 2H), 6.61-6.55 (m, 2H), 4.47 (s, 1H), 3.40-3.33 ( m, 1H), 3.18 (dd, J=4.6, 15.4 Hz, 1H), 3.09-2.99 (m, 2H), 2.96-2.87 (m, 1H) , 2.25 (s, 1H), 2.07 (dq, J=5.5, 11.8 Hz, 1H), 1.38 (d, J=7.1 Hz, 6H); ER-LCMS m/z 418.0 [M+H] ⁺ ; and the other enantiomer (26.47 mg, 53.98 µmol, 29.2% yield, 100% purity, 2HCl, SFC: TR = 5.742 min, ee = 100%, or [a] ^26.8 D = -167.394) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.97 (s, 1H), 8.78 (d, J=2.9 Hz, 1H), 8.30 (td, J=2.2, 9.0 Hz, 1H), 8.24 (s, 1H), 6.98-6.91 (m, 2H), 6.62-6.54 (m, 2H), 4.48 (s, 1H), 3 .37-3.31 (m, 1H), 3.22-3.13 (m, 1H), 3.09-2.98 (m, 2H), 2.96-2.87 (m, 1H) , 2.26 (d, J=10.4 Hz, 1H), 2.07 (tdd, J=5.6, 11.6, 17.7 Hz, 1H), 1.38 (d, J=6 .8 Hz, 6H); ER-LCMS m/z 418.0 [M+H] ⁺ .

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Example 81.

Synthesis I-83

Step 1: 5-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-2-methyl-pyrazolo[1,5a]pyrimidin-7- amine (I-83)

7-Chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine mixture (50 mg, 160.79 µmol, 1 eq), 2- (1H-indol-3-yl)ethanamine (25.76 mg, 160.79 µmol, 1 eq.) and DIEA (62.34 mg, 482.37 µmol, 84.02 µl, 3 eq.) in i- PrOH (5 ml) was stirred at 80° C. for 2 h. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 150x30 mmx4 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 50%80%, 12 min) to give 5-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-3- isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-7-amine (41.24 mg, 76.67 µmol, 47.7% yield, 100% purity, 3HCl) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.68 (d, J=2.8 Hz, 1H), 8.33 (s, 1H), 7.51 (d, J=7.8 Hz, 1H ), 7.47-7.45 (m, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.02 (s, 1H), 6.97 (t, J=7, 6 Hz, 1H), 6.84-6.82 (m, 1H), 5.71 (s, 1H), 4.01-3.97 (m, 2H), 3.27 (t, J=7 .2 Hz, 1H), 3.23-3.19 (m, 2H), 2.57 (s, 3H), 1.36 (d, J=7.2 Hz, 6H); ER-LCMS m/z 429.3 [M+H] ⁺ .

Example 82.

Synthesis I-84

- 190 041983

Synthesis scheme:

Stage 1: 2-Acetyl-3-methyl-butanenitrile

To a mixture of DIPA (1.22 g, 12.03 mmol, 1.70 ml, 1 eq.) in THF (10 ml) was added n-BuLi (2.5 M in THF, 5.05 ml, 1.05 eq. .) drop by drop at -78°C under N2. The mixture was stirred at -78°C for 15 min, then warmed to 0°C and stirred for 1 h. The mixture was cooled to -78°C, 3-methylbutanenitrile (1 g, 12.03 mmol, 1. 27 ml, 1 eq.) in THF (10 ml) and stirred at -78°C for 15 min. A solution of ethyl acetate (1.11 g, 12.63 mmol, 1.24 ml, 1.05 eq.) in THF (10 ml) was added dropwise. The mixture was stirred at 20° C. for 16 hours. TLC (PE/EtOAc = 1/1, Rf = 0.74) showed that one new spot had formed. The mixture was quenched with 2N. HCl (10 ml), extracted with EtOAc (50 mlx3), washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (from PE /EtOAc = 10/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.74) to give 2-acetyl-3-methyl-butanenitrile (661 mg, 4.22 mmol, 35 yield, 1%, purity 80.0%) as a yellow oil.

1H NMR (400 MHz, CDC13) δ ppm 3.32 (d, J=5.2 Hz, 1H), 2.44-2.38 (m, 1H), 2.37 (s, 3H), 1, 11 (d, J=6.8 Hz, 3H), 1.09-1.05 (m, 3H); ER-LCMS: The correct mass was not found.

Stage 2: 4-isopropyl-3-methyl-1H-pyrazole-5-amine

A mixture of 2-acetyl-3-methyl-butanenitrile (750.00 mg, 4.79 mmol, 1 eq.), hydrazine hydrate (311.96 mg, 6.23 mmol, 302.87 µl, 1.3 eq.) and AcOH (503.76 mg, 8.39 mmol, 479.77 μl, 1.75 eq.) in EtOH (20 ml) was stirred at 90° C. for 16 h under N 2 atmosphere. The mixture was concentrated under reduced pressure to give a residue which was diluted with us. NaHCO ₃ (20 ml) and extracted with DCM (20 mlx3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 4-isopropyl-3-methyl-1H-pyrazole-5-amine (560 mg, 3.62 mmol, 75.5% yield, 90.0 purity %) as a yellow solid.

1 H NMR (400 MHz, CDCI3) δ ppm 2.82-2.69 (m, 1H), 2.18 (s, 3H), 1.23 (d, J=6.8 Hz, 6H); ER-LCMS m/z 140.2 [M+H]+.

Step 3: 5-(5-fluoro-3-pyridyl)-3-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidin-7-ol

A mixture of 4-isopropyl-3-methyl-1H-pyrazol-5-amine (502.05 mg, 3.25 mmol, 0.8 eq.) and methyl-3- (5-191 041983 fluoro-3-pyridyl) - 3-oxo-propanoate (816.33 mg, 4.06 mmol, 1 eq.) in AcOH (10 ml) was stirred at

120°C for 3 hours. The mixture was concentrated under reduced pressure to give 5-(5-fluoro-3-pyridyl)3-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidin-7-ol (1, 2 g, crude) as a purple solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 8.82 (s, 1H), 8.68-8.66 (m, 1H), 8.14-8.08 (m, 2H), 3.30-3 .24 (m, 1H), 2.46-2.41 (m, 3H), 1.37 (d, J=7.2 Hz, 6H); ER-LCMS m/z 287.2 [M+H]+.

Stage 4: 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine

Solution of 5-(5-fluoro-3-pyridyl)-3-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidin-7-ol (1.2 g, 4.19 mmol, 1 eq) in POCl ₃ (16.3 g, 106.31 mmol, 9.88 ml, 25.36 eq) was stirred at 110° C. for 2 h. The mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (PE/EtOAc = 10/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.75) to give 7-chloro-5-(5-fluoro-3-pyridyl)- 3-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine (381 mg, 1.23 mmol, 29.2% yield, 98.0% purity) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.08 (s, 1H), 8.57 (d, J=2.4 Hz, 1H), 8.20-8.15 (m, 1H), 7, 28 (s, 1H), 3.36-3.24 (m, 1H), 2.57 (s, 3H), 1.48 (d, J=6.8 Hz, 6H); ER-LCMS m/z 305.0 [M+H] ⁺ .

Stage 5: N-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl]-5-(5-fluoro-3-pyridyl)-3-isopropyl-2methyl-pyrazolo[ 1,5-a]pyrimidine-7-amine (I-84)

7-Chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine mixture (50 mg, 160.79 µmol, 1 eq), 2- (5,7-difluoro-2-methyl-1H-indol-3-yl)ethanamine (33.80 mg, 160.79 µmol, 1 eq) and DIEA (62.34 mg, 482.36 µmol, 84, 02 µl, 3 eq.) in i-PrOH (10 ml) was stirred at 80° C. for 2 h. phase: [water (0.05% HCl)-ACN]; V%: 58%-78%, 10 min) to give N-[2-(5,7-difluoro-2-methyl-1H-indole-3 -yl)ethyl]-5-(5-fluoro-3pyridyl)-3-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidin-7-amine (32.01 mg, 54.45 µmol, yield 33 .9%, 100% pure, 3HCl) as a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.75 (d, J=2.8 Hz, 1H), 8.43 (s, 1H), 7.66-7.63 (m, 1H) , 6.93-6.89 (m, 1H), 6.46-6.39 (m, 1H), 5.73 (s, 1H), 3.97-3.94 (m, 2H), 3 .31-3.23(m, 1H), 3.13-3.09(m, 2H), 2.57(s, 3H), 2.23(s, 3H), 1.36(d, J = 7.2 Hz, 6H); ER-LCMS m/z 479.3 [M+H] ⁺ .

Example 83.

Synthesis of I-85

- 192 041983

Synthesis scheme:

Step 1: N-(2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl)-5-(5-fluoropyridin-3-yl)pyrazolo[1,5a]pyrimidin-7 -amine (I-85)

7-Chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine mixture (40 mg, 147.68 µmol, 1 eq.), 2(5,7-difluoro-2-methyl -1H-indol-3-yl)ethanamine (60 mg, 153.73 µmol, 1.04 eq., 2 oxalic acid) and DIEA (60.00 mg, 464.24 µmol, 80.86 µl, 3.14 eq.) in i-PrOH (3 ml) was stirred at 50°C for 19 h. The mixture was concentrated under reduced pressure to dryness, obtaining a residue which was purified using preparative HPLC (column: Phenomenex Synergi C18 150x30 mmx4 μm; mobile phase: [water (0.05% HCl)-ACN]; V%: 30%-52%, 12 min). The desired fraction was lyophilized to give N-(2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl)-5-(5-fluoropyridin-3-yl)pyrazolo[1,5a]pyrimidine -7-amine (22.94 mg, 43.14 µmol, 29.2% yield, 100.0% purity, 3HCl) as an off-white solid.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.71 (d, J=2.4 Hz, 1H), 8.47 (s, 1H), 8.22 (d, J=2.4 Hz , 1H), 7.59 (td, J=2.4, 9.2 Hz, 1H), 7.01 (dd, J=2.4, 9.2 Hz, 1H), 6.51 (d, J=2.4Hz, 1H), 6.44(ddd, J=2.4, 9.6, 11.2Hz, 1H), 5.85(s, 1H), 4.04-3.92 (m, 2H), 3.17-3.08 (m, 2H), 2.13 (s, 3H); ER-LCMS m/z 423.2 [M+H]+.

Example 84.

Synthesis I-86

1-86

Synthesis scheme:

- 193 041983

Stage 1: 2-cyclopropyl-3-oxo-propanenitrile

To a solution of DIPA (3.74 g, 36.98 mmol, 5.23 ml, 1 eq.) in THF (15 ml) was added n-BuLi (2.5 M in nhexane, 15.53 ml, 1.05 eq. .). The mixture was stirred at -78°C for 10 minutes. To the above mixture was added dropwise a solution of 2-cyclopropylacetonitrile (3 g, 36.98 mmol, 3.42 ml, 1 eq.) in THF (15 ml). The mixture was then stirred at -78°C for 10 min under N2. A solution of ethyl formate (2.88 g, 38.88 mmol, 3.13 ml, 1.05 eq.) in THF (15 ml) was added dropwise and stirred at -78°C for 40 min. The reaction mixture was then heated to 25° C. for 12 hours. TLC (PE/EtOAc = 1/1, Rf = 0.50) indicated that one major new spot was found. The reaction mixture was quenched by adding 1 N. HCl solution (50 ml) at 0°C, extracted with EtOAc (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 1/1, TLC: PE/EtOAc = 1 /1, Rf=0.50) to give 2-cyclopropyl-3-oxo-propanenitrile (3.4 g, crude) as a yellow oil.

1H NMR (400 MHz, CDC13) δ ppm 9.61 (d, J=1.1 Hz, 1H), 4.61-4.55 (m, 1H), 4.01-3.84 (m, 1H ), 1.92-1.79 (m, 2H), 1.66-1.52 (m, 2H).

Stage 2: 4-cyclopropyl-1H-pyrazole-5-amine

AcOH (3.27 g, 54.52 mmol, 3.12 ml, 1.75 eq.) and hydrazine (1.30 g, 40.50 mmol, 1.46 ml, 1.3 eq.). The mixture was stirred at 90° C. for 12 hours. TLC (PE/EtOAc = 1/1, Rf = 0.10) indicated that one major new spot was found. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with NaHCO ₃ solution (200 ml) and extracted with EtOAc (100 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (DCM/MeOH = 100/1 to 10/1, TLC: PE/EtOAc = 10 /1, Rf = 0.70) to give 4-cyclopropyl-1H-pyrazol-5amine (1.7 g, crude) as a brown solid.

1H NMR (400 MHz, CDC13) δ ppm 7.04 (d, J=0.7 Hz, 1H), 1.49-1.39 (m, 1H), 0.83-0.75 (m, 2H ), 0.49-0.41 (m, 2H); ER-LCMS m/z did not detect the desired MS.

Stage 3: 3-cyclopropyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-ol

To a solution of methyl 3-(5-fluoro-3-pyridyl)-3-oxo-propanoate (500 mg, 2.49 mmol, 1 eq.) in AcOH (6 ml) -amine (370.54 mg, 3.01 mmol, 1.21 eq.). The mixture was stirred at 120°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give 3-cyclopropyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-ol (830 mg, crude ) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.90 (s, 1H), 8.80 (d, J=2.6 Hz, 1H), 8.25 (td, J=2.2, 9.7 Hz, 1H), 7.68 (s, 1H), 6.09 (s, 1H), 2.05 (m, 2H), 0.94-0.87 (m, 2H), 0, 73-0.64 (m, 2H); ER-LCMS m/z 271.2 [M+H]+.

Step 4: 7-chloro-3-cyclopropyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine

A solution of 3-cyclopropyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-ol (830 mg, 3.07 mmol, 1 eq.) in POCl ₃ (5 ml) was stirred at 110° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 2/1, TLC: PE/EtOAc = 3/ 1, Rf = 0.40) to give 7-chloro-3-cyclopropyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (290 mg, 924.12 µmol, yield 30.1%, purity 92.0%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.09 (s, 1H), 8.60 (d, J=2.6 Hz, 1H), 8.20 (td, J=2.1, 9, 4 Hz, 1H), 8.01 (s, 1H), 7.37 (s, 1H), 2.17 (tt, J=5.2, 8.4 Hz, 1H), 1.11-1, 03 (m, 2H), 1.02-0.95 (m, 2H); ER-LCMS m/z 289.0,

291.0 [M+H]+.

Stage

5:

3-Cyclopropyl-5-(5-fluoro-3-pyridyl)-N-[2-(1H-ivdol-3-yl)ethyl]n-pyrazolo[1.5

a] pyrimidine-7-amine (I-86)

To a solution of 7-chloro-3-cyclopropyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (45 mg, 143.40 µmol, 1.0 eq.) in i-PrOH ( 3 ml) was added DIEA (55.60 mg, 430.19 µmol, 74.93 µl, 3.0 eq) and 2-(1Hindol-3-yl)ethanamine (29.87 mg, 186.42 µmol, 1, 3 eq.). The mixture was stirred at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions, column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 43%-73%, 10 min) and the desired fraction was lyophilized to give 3-cyclopropyl-5-(5-fluoro-3-pyridyl)-N-[2-(1 H-indole -3-yl)ethyl]pyrazolo[1,5-a]pyrimidin-7amine (40.50 mg, 77.61 µmol, 54.1% yield, 100% purity, 3HCl salt) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.73 (d, J=2.5 Hz, 1H), 8.36 (s, 1H), 8.00 (s, 1H), 7.54-7 .46 (m, 2H), 7.15 (d, J=8.0 Hz, 1H), 7.00 (s, 1H), 6.97 (t, J=7.5 Hz, 1H), 6 .85-6.80(m, 1H), 5.78(s, 1H), 4.07-3.99(m, 2H), 3.26-3.19(m, 2H), 1.96 -1.87 (m, 1H), 1.05-0.97 (m, 2H), 0.78-0.70 (m, 2H); ER-LCMS m/z 412.9 [M+H]+.

Example 85.

Synthesis I-87

3-cyclopropyl-N-(2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl)-5-(5-fluoropyridine-3Step 1:

yl)pyrazolo[1,5-a]pyrimidin-7-amine (I-87)

A mixture of 7-chloro-3-cyclopropyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (40 mg, 127.46 µmol, 1 eq.), 2-(5,7- difluoro-2-methyl-1H-indol-3-yl)ethanamine (54.72 mg, 140.21 µmol, 1.1 eq., 2 oxalic acid) and DIEA (0.055 g, 425.56 µmol, 74.12 µl, 3.34 eq.) in i-PrOH (3 ml) was stirred at 50° C. for 19 h. The mixture was concentrated under reduced pressure to dryness to give a residue which was purified by preparative HPLC : Phenomenex Synergi C18

150x30 mmx4 microns; mobile phase: [water (0.05% HCl)-ACN; B%: 45%-75%, 12 min). The desired fraction was lyophilized to give 3-cyclopropyl-N-(2-(5,7-difluoro-2-methyl-1 H-indol-3-yl)ethyl)-5-(5-fluoropyridin-3-yl)pyrazolo[1 ,5-a]pyrimidine-7-amine (22.33 mg, 37.39 µmol, 29.3% yield, purity

95.7%, 3HCl) as an off-white solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.73 (d, J=1.6 Hz, 1H), 8.43 (s, 1H), 7.97 (s, 1H), 7.62 (d, J=8.8Hz, 1H), 6.93(dd, J=2.0, 9.2Hz, 1H), 6.49-6.35(m, 1H), 5.73(s, 1H ), 3.96 (t, J=5.2 Hz, 2H), 3.10 (t, J=5.6 Hz, 2H), 2.14 (s, 3H), 1.98-1.86 (m, 1H), 1.07-0.94 (m, 2H), 0.79-0.67 (m, 2H); ER-LCMS m/z 463.2 [M+H]+.

Example 86.

Synthesis I-88

Step 1: N-[2-(5,7-difluoro-1H-indol-3-yl)ethyl]-2-(5-fluoro-3-pyridyl)-6-isopropoxypyrimidine4-amine (I-88)

4-chloro-2-(5-fluoro-3-pyridyl)-6-isopropoxy-pyrimidine (55 mg, 172.59 µmol, 1 eq.), 2-(5,7difluoro-1H-indol-3-yl) ethanamine (50.31 mg, 225.64 µmol, 1.31 eq) and DIEA (66.92 mg, 517.77 µmol, 90.19 µl, 3.0 eq) in i-PrOH (3 ml) placed in a tube with microwave radiation. The sealed tube was heated at 125° C. for 6 hours while being treated with microwave radiation. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenomenex Synergi C18 150x30 mmx4 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 65 % - 95%, 12 min). The desired fraction was lyophilized to give N-[2(5,7-difluoro-1H-indol-3-yl)ethyl]-2-(5-fluoro-3-pyridyl)-6-isopropoxy-pyrimidin-4-amine (15 .59 mg, 28.70 µmol, 16.6% yield, 98.81% purity, 3HCl salt) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.12 (s, 1H), 8.76 (d, J=2.5 Hz, 1H), 8.36 (d, J=8.8 Hz, 1H ), 7.21 (s, 1H), 7.11 (dd, J=1.6, 9.2 Hz, 1H), 6.66 (t, J=9.9 Hz, 1H), 5.80 (s, 1H), 5.07 (s, 1H), 3.81 (s, 2H), 3.06 (t, J=6.7 Hz, 2H), 1.39 (d, J=6, 0 Hz, 6H); ER-LCMS m/z 428.2 [M+H]+.

Example 87.

Synthesis I-89

- 196 041983

Synthesis scheme:

Step 1: 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-[2-(2-methyl-1H-indol-3-yl)ethyl]pyrazolo[1,5a]pyrimidin-7-amine (I-89)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (40 mg, 132.08 µmol, 1 eq.) and 2-(2- methyl-1H-indol-3-yl)ethanamine (34.52 mg, 198.13 µmol, 1.5 eq.) in i-PrOH (10 ml) was added DIEA (51.21 mg, 396.25 µmol, 69 .02 µl, 3.0 eq.). The mixture was stirred at 70° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 150x30 mmx4 µm; mobile phase: [water (0.05% HCl)- ACN]; B%: 47%-72%, 12 min) followed by lyophilization to give 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-[2-(2-methyl-1H-indole- 3-yl)ethyl]pyrazolo[1,5-a]pyrimidin-7-amine (47.07 mg, 86.87 µmol, 65.8% yield, 99.3% purity, 3HCl) as a red solid .

1H NMR (400 MHz, CD3OD) δ ppm 8.68 (d, J=2.0 Hz, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.32-7.27(m, 1H), 6.86-6.82(m, 1H), 6.69(dquin, J=1.3, 7, 0 Hz, 2H), 5.43 (s, 1H), 3.89-3.83 (m, 2H), 3.15-3.07 (m, 1H), 3.03-2.98 (m , 2H), 1.95 (s, 3H), 1.19 (d, J=6.8 Hz, 6H); ER-LCMS m/z 429.3 [M+H]+.

Example 88.

Synthesis I-90

Step 1: 3-tert-butyl-5-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrazolo[1,5-a]pyrimidine7-amine ( I-90)

To a solution of 3-tert-butyl-7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (40 mg, 128.63 µmol, 1 eq.) and 2-(1H -indol-3-yl)ethanamine (30.91 mg, 192.95 µmol, 1.5 eq.) in i-PrOH (10 ml) was added DIEA (49.87 mg, 385.89 µmol, 67.21 µl , 3.0 eq.). The mixture was stirred at 70°C for 16 hours.

- 197 041983

The reaction mixture was concentrated under reduced pressure to remove the solvent to give a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 150x30 mmx4 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 70% -90%, 12 min) followed by lyophilization to give 3-tert-butyl-5-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrazolo[1, 5-a]pyrimidine 7-amine (42.66 mg, 78.86 µmol, 61.3% yield, 99.4% purity, 3HCl) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.82 (broad s, 1H), 9.13 (s, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.22 (d, J=8.6 Hz, 1H), 8.04 (broad s, 1H), 7.94 (s, 1H), 7.64 (d, J=7.9 Hz, 1H ), 7.31 (d, J=7.9 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.10-6.95 (m, 2H), 6.64 (s, 1H), 3.83 (q, J=6.9 Hz, 2H), 3.11 (t, J=7.1 Hz, 2H), 1.46 (s, 9H); ERLCMS m/z 429.3 [M+H]+.

Example 89.

Synthesis I-91

Synthesis scheme:

1-91

Stage 1: 2-formyl-3,3-dimethyl-butanenitrile

To a mixture of DIPA (833.20 mg, 8.23 mmol, 1.16 ml, 1 eq.) in THF (20 ml) was added dropwise n-BuLi (2.5 M, 3.46 ml, 1.05 eq. .) at -78°C in an N ₂ atmosphere. The mixture was stirred at -78°C for 10 min, then warmed to 0°C and stirred for 1 h. The mixture was cooled to -78°C, 3,3-dimethylbutanenitrile dissolved in THF (15 ml, anhydrous) was added dropwise (800 mg, 8.23 mmol, 12.66 ml, 1 eq) and stirred at -78°C for 10 min. A solution of ethyl formate (640.46 mg, 8.65 mmol, 695.40 μl, 1.05 eq.) in THF (15 ml, anhydrous) was added dropwise and stirred at -78°C for 40 min, then the mixture was heated to 5-14°C for 16 hours. TLC (PE/EtOAc = 3/1, Rf = 0.34) showed that one major new spot was detected. The reaction mixture was quenched by adding 1 N. HCl solution (50) ml at -78°C was extracted with DCM (50 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified

- 198 041983 using silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC: PE/EtOAc = 3/1,

Rf = 0.34) to give the title product 2-formyl-3,3-dimethyl-butanenitrile (750 mg, 5.39 mmol, yield

65.5%, 90.0% pure as a yellow oil.

¹ H NMR (400 MHz, CDC13) δ ppm 9.66 (d, J=2.2 Hz, 1H), 3.27 (d, J=2.4 Hz, 1H), 1.23 (s, 9H ).

Stage 2: 4-tert-butyl-1H-pyrazole-5-amine

A mixture of 2-formyl-3,3-dimethyl-butanenitrile (750 mg, 5.39 mmol, 1 eq.), hydrazine (224.65 mg, 7.01 mmol, 253.56 µl, 1.3 eq.) and AcOH (566.71 mg, 9.44 mmol, 539.73 μl, 1.75 eq.) in EtOH (20 ml) was degassed and flushed with N2 3 times. The mixture was then stirred at 80-90°C (reflux) for 16 hours under N2. TLC (PE/EtOAc = 1/1, Rf = 0.55) indicated that most of the starting material had been consumed and one major new spot of greater polarity was found. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (20 ml), the pH was adjusted to 9-10 with solid NaHCO ₃ and extracted with DCM (20 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product 4-tert-butyl-1H-pyrazol-5-amine (750 mg, 5.39 mmol, 99.9% yield, purity crude) as a yellow solid, which was used in the next step without further purification.

1 H NMR (400 MHz, CDCI3) δ ppm 7.12 (s, 1H), 1.30 (s, 9H).

Step 3: 5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-o l

4-tert-Butyl-1H -pyrazole-5-amine (747.23 mg, 5.37 mmol, 1 eq.). The mixture was stirred at 120°C for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, obtaining the crude product 5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5a]pyrimidine- 7-ol (1.46 g, 5.36 mmol, 100.0% yield, crude) as a yellow oil, which was used in the next step without further purification.

Step 4: 3-tert-butyl-7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine

A mixture of 3-tert-butyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-ol (1.67 g, 5.83 mmol, 1 eq.) in POC13 (37 .81 g, 246.59 mmol, 22.92 ml, 42.28 eq.) was degassed and purged with N2 3 times. The mixture was then stirred at 110° C. for 3 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with DCM (50 mlx2) and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC: PE/EtOAc = 3/1, Rf = 0.48) to give the title product 3-tert-butyl-7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (950 mg, 3.05 mmol, 52 yield, 4%, 98.0% pure) as a yellow solid.

1H NMR (400 MHz, CDC13) δ ppm 9.13 (t, J=1.5 Hz, 1H), 8.61 (d, J=2.8 Hz, 1H), 8.22-8.16 ( m, 1H), 8.12 (s, 1H), 7.41 (s, 1H), 1.56 (s, 9H); ER-LCMS m/z 305.1, 307.1 [M+H]+.

- 199 041983

Step 5: 3-tert-Butyl-N-[2-(5,7-difluoro-2-methyl-1 H-indol-3-yl)ethyl]-5-(5-fluoro-3-pyridyl)pyrazolo[1 ,5-а]pyrimidine-7-amine (I-91)

To a solution of 3-tert-butyl-7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (40 mg, 128.63 µmol, 1 eq.) and 2-(5 ,7-difluoro-2-methyl-1H-indol-3-yl)ethanamine (57.93 mg, 192.95 µmol, 1.5 eq., oxalic acid) in i-PrOH (10 ml) was added with DIEA (49 .87 mg, 385.89 µmol, 67.21 µl, 3.0 eq.). The mixture was stirred at 70° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 150x30 mmx4 µm; mobile phase: [water (0.05% HCl)- ACN]; B%: 70%-90%, 12 min) 3-tert-butyl-N[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl]-5-( 5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine-7-amine (34.14 mg, 57.39 µmol, 44.6% yield, 98.8% purity, 3HCl) as a solid orange.

1H NMR (400 MHz, DMSOCH) δ ppm 11.21 (s, 1H), 9.06-8.98 (m, 1H), 8.66 (d, J=2.6 Hz, 1H), 8, 13-8.01 (m, 2H), 7.95 (s, 1H), 7.22 (dd, J=2.1, 9.6 Hz, 1H), 6.76 (ddd, J=2, 2, 9.6, 11.4 Hz, 1H), 6.42 (s, 1H), 3.71 (q, J=6.8 Hz, 2H), 3.01 (t, J=6.6 Hz, 2H), 2.20 (s, 3H), 1.47 (s, 9H); ER-LCMS m/z 479.3 [M+H]+.

Example 90 Synthesis of I-92 Synthesis scheme: .v HN A soci ₂ h ₂ n V _o MeOH h ₂ but ⁷ POCI ₃ no °c TJ LiOH s o N _r __NH HN^ g As. All ^N a- / --N Ν O \ O-- 1-92 0 0 ° ^H _X NX^N'A hn LJ _l 1 7 \ / Sr ^{1 F} \z?\A Ay z=< - ⁵ ► FlT N \= o AcOH, 110 °CL 0 X ₀ °C ^N ° Cl ^NH Al hn^AA 'A _o ^diea / XA ° TA ^N x nq ' ^NH fL iO \\ _HN >A*··' / ri I M A'\\ HATU P^A _n X/ z^o L II to / NO / zZ Ν NO ^Z \ I-92

- 200 041983

Stage 1: methyl 5-amino-1H-pyrazole-4-carboxylate

A solution of 5-amino-1H-pyrazole-4-carboxylic acid (1 g, 7.87 mmol, 1 eq) in HCl/MeOH (4 M, 40 ml, 20.34 eq) was stirred at 60° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give methyl 5-amino-1H-pyrazole-4-carboxylate (1.4 g, 7.49 mmol, 95.2% yield, 95.0% purity, HCl) in as a white solid, which was used in the next step without further purification.

1 H NMR (400 MHz, CD3OD) δ ppm 8.31 (s, 1H), 3.84 (s, 3H); ER-LCMS m/z 142.2 [M+H]+.

Stage 2: methyl 5-(5-fluoro-3-pyridyl)-7-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate

Methyl 5-amino-1H-pyrazole -4-carboxylate (148.67 mg, 795.28 µmol, 1 eq, HCl). The mixture was stirred at 120° C. for 4 hours. The reaction mixture was concentrated to give methyl 5(5-fluoro-3-pyridyl)-7-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate (230 mg, crude) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD ₃ OD) δ ppm 8.83 (s, 1H), 8.72 (d, J=2.6 Hz, 1H), 8.29 (s, 1H), 8.22 ( s, 1H), 6.34 (s, 1H), 3.92 (s, 3H); ER-LCMS m/z 289.2 [M+H] ⁺ .

Stage 3: methyl 7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

A solution of methyl 5-(5-fluoro-3-pyridyl)-7-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate (230 mg, 797.96 µmol, 1 eq.) in POCl ₃ (5 ml) was stirred at 110° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: gradient 0 ~50% ethyl acetate/petroleum ether at a flow rate of 30 ml/min) giving methyl 7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (180 mg , 516.50 µmol, 64.7% yield, 88.0% purity) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.08 (s, 1H), 8.65 (s, 1H), 8.59 (d, J=2.6 Hz, 1H), 7.69 ( s, 1H), 7.56 (s, 1H), 3.93 (s, 3H); ER-LCMS m/z 307.1, 309.1 [M+H]+.

Step 4: Methyl 5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidine3-carboxylate

To a solution of methyl 7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (180 mg, 516.50 µmol, 1 eq.), 2-(1H -indol-3-yl)ethanamine (82.75 mg, 516.50 µmol, 1 eq.) in i-PrOH (10 ml) was added DIEA (200.26 mg, 1.55 mmol, 269.90 µl, 3 equiv.). The mixture was then stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give methyl 5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[ 1,5-a]pyrimidine-3-carboxylate (120 mg, 242.55

- 201041983 µmol, yield 47.0%, purity 87.0%) as an off-white solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 8.59 (s, 1H), 8.46 (d, J=2.9 Hz, 1H), 8.41 (s, 1H), 7.84 (br. s, 1H),

7.15-7.15(m, 1H), 7.13-7.08(m, 3H), 6.94(s, 1H), 6.07(s, 1H), 3.86(s, 3H), 3.11-3.05 (m, 4H); ER-LCMS m/z 431.1 [M+H]+.

Stage 5: 5-(5-fluoro-3-pyridyl)-7-[2-( 1 H-indol-3 -yl(ethylamino]pyrazolo [1,5-a]pyrimidine-3 carboxylic acid

To a solution of methyl 5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidine3-carboxylate (60 mg, 121.27 µmol, 1 eq.) in MeOH (2 ml), THF (2 ml) and water (4 ml) was added LiOH-H ₂ O (72.00 mg, 1.72 mmol, 14.15 eq.) and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with EtOAc (20 ml) and extracted with EtOAc (20 mlx2). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 5-(5-fluoro3-pyridyl)-7-[2-(1H-indol-3-yl) ethylamino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 84.05 µmol, 69.3% yield, 70.0% purity) as a brown solid, which was used in the next step without additional cleaning.

1H NMR (400 MHz, CD3OD) δ ppm 8.58 (s, 1H), 8.46 (d, J=2.4 Hz, 1H), 8.40 (s, 1H), 7.62 (s, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H) , 6.95 (m, 2H), 6.07 (s, 1H), 3.90 (t, J=6.2 Hz, 2H), 3.13-3.08 (m, 2H); ER-LCMS m/z 417.2 [M+H]+.

Step 6: 5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]-N-methoxy-N-methyl-pyrazolo[1,5a]pyrimidin-3- carboxamide (I-92)

To a solution of 5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 84, 05 µmol, 1 eq.) and N-methoxymethanamine (12.30 mg, 126.08 µmol, 1.5 eq., HCl) in DCM (5 ml) were added HATU (47.94 mg, 126.08 µmol, 1 .5 eq.) and TEA (17.01 mg, 168.10 µmol, 23.40 µl, 2 eq.). The mixture was then stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with EtOAc (20 ml) and extracted with EtOAc (20 mlx2). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0 05% HCl)-ACN]; B%: 30%-60%, 10 min). The desired fraction was evaporated to give 5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]-N-methoxy-N-methyl-pyrazolo[1,5-a] pyrimidine-3-carboxamide (20.19 mg, 35.14 µmol, 41.8% yield, 99.0% purity, 3HCl) as a light yellow solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 8.74 (d, J=2.6 Hz, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 7.57- 7.51 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 7.01 (s, 1H), 6.94 (t, J=7.3 Hz, 1H), 6.87-6.81 (m, 1H), 6.04 (s, 1H), 4.07 (t, J=5.8 Hz, 2H), 3.85 (s, 3H), 3.37 (s, 3H), 3.24 (t, J=5.7 Hz, 2H); ER-LCMS m/z 460.4 [M+H]+.

- 202 041983

Example 91.

Synthesis I-93

Stage 1: 2-(5-fluoro-3-pyridyl)-N6-[2-(1H-indol-3-yl)ethyl]-N4-isopropyl-N4-methyl-pyrimidine4,6-diamine (I-93)

6-Chloro-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine (60 mg, 163.13 µmol, 1.0 eq .), N-methylpropan-2-amine (702.00 mg, 9.60 mmol, 1 ml, 58.84 eq.) and DIEA (63.25 mg, 489.39 µmol, 85.24 µl, 3, 0 eq.) in i-PrOH (2 ml) was placed in a tube with microwave radiation. The sealed tube was heated at 125° C. for 10 hours while being treated with microwave radiation. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: column: Phenomenex Synergi C18 150x30 mmx4 µm; mobile phase: [water (0.05% HCl)-ACN]; V% : 22%-52%, 12 min) and the desired fraction was lyophilized to give 2-(5-fluoro-3-pyridyl)-N6-[2-(1H-indol-3-yl)ethyl]-N4-isopropyl-N4 -methylpyrimidine-4,6-diamine (19.96 mg, 49.25 µmol, 30.2% yield, 99.80% purity, 3 HCl salt) as a yellow solid.

1H NMR (400 MHz, SW3OP+HSO3) δ ppm 9.26 (s, 1H), 8.47 (d, J=2.6 Hz, 1H), 8.39-8.33 (m, 1H), 7.65-7.59 (m, 1H), 7.35-7.31 (m, 1H), 7.12-7.06 (m, 2H), 7.04-6.98 (m, 1H ), 5.34 (s, 1H), 4.95 (s, 1H), 3.66 (t, J=6.9 Hz, 2H), 3.07 (t, J=6.9 Hz, 2H ), 2.79 (s, 3H), 1.18 (d, J=6.8 Hz, 6H); ER-LCMS m/z 405.3 [M+H]+.

Example 92.

Synthesis of I-94a

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Synthesis scheme:

Stage 1: 3-aminotetralin-6-ol

To a solution of 7-hydroxytetralin-2-one (500 mg, 3.08 mmol, 1 eq.) in anhydrous MeOH (5 ml) was added NH ₄ OAc (7.13 g, 92.49 mmol, 30 eq.). After stirring for 5 h, NaBH ₄ (349.88 mg, 9.25 mmol, 3 eq.) was added. The mixture was stirred at 25° C. for 3 hours. The mixture was concentrated to remove the solvent. H2O (10 ml) was added, the mixture was subjected to extraction with EtOAc (20 mlx2). The water was adjusted by 3 n. HCl at pH 6-7, extracted with EtOAc (10 mlx2). The pH of the aqueous solution was adjusted to 6-7 with 1N. NaOH. The mixture was then lyophilized to give a solid. The solid was dissolved in i-PrOH (10 ml). The resulting mixture was filtered and concentrated to give 3-aminotetralin-6-ol (550 mg, 2.66 mmol, 86.4% yield, 79.0% purity) as a yellow oil, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 6.91 (d, J=8.2 Hz, 1H), 6.58 (dd, J=2.4, 8.4 Hz, 1H), 6.51 ( s, 1H), 3.53-3.42 (m, 1H), 3.06 (dd, J=5.4, 15.5 Hz, 1H), 2.89-2.73 (m, 3H) , 2.17 (d, J=10.1 Hz, 1H), 1.84-1.74 (m, 1H); ER-LCMS m/z 164.3 [M+H] ⁺ .

Step 2: 3-[[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]tetralin6-ol

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (100 mg, 330.21 µmol, 1 eq.) in i-PrOH (10 ml) DIEA (128.03 mg, 990.63 µmol, 172.55 µl, 3 eq) and 3-aminotetralin-6-ol (204.67 mg, 990.63 µmol, 3 eq) were added. The mixture was stirred at 120° C. for 3 hours while being treated with microwave radiation under N2 atmosphere. The mixture was concentrated to remove the solvent. H2O (10 ml) was added, the mixture was subjected to extraction with EtOAc (10 mlx3). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 3/1, TLC : PE/EtOAc=2/1, Rf=0.50) to give 3-[[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino ]tetralin-6-ol (63 mg, 138.83 µmol, 42.0% yield, 92.0% purity) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.19 (s, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.45-8.37 (m, 1H), 7 .96 (s, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.78 (s, 1H), 6.66-6.56 (m, 2H), 4.62 ( s, 2H), 4.32 (s, 1H), 3.01-2.89 (m, 3H), 2.28 (s, 1H), 2.03 (d, J=5.5 Hz, 1H ), 1.44 (d, J=7.0 Hz, 6H); ER-LCMS m/z 418.2 [M+H]+.

- 204 041983

Step 3: (3R)-3-[[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]tetralin-6-ol (I -94)

3-[[5-(5-Fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]tetralin-6-ol (100 mg, 220.37 µmol, 1 eq.) was separated by SFC (column: Chiralcel OD 250x30 5u; mobile phase: [0.1% NH ₃ .H ₂ O EtOH]; V%: 45%-45%, min) to give the title product (Rt = 3.922 min) which was purified by preparative HPLC (MeCN/H ₂ O as eluents, acidic conditions, instrument: Phenomenex Gemini 150x25 mmx10 µm/Mobile phase: water (0.05% HCl)-ACN/Gradient: V from 50 % to 80% in 10 min/Flow rate: 25 ml/min) followed by lyophilization to give (3R)-3-[[5(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[ 1.5 -a]pyrimidin-7-yl]amino]tetralin-6-ol (19.02 mg, 45.10 µmol, 20.47% yield, 99.0% purity) ([a] ²⁵ _D = -23.996) in form of a yellow solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 8.99 (s, 1H), 8.81 (d, J=2.4 Hz, 1H), 8.38-8.31 (m, 1H), 8.25 (s, 1H), 7.00-6.91 (m, 2H), 6.60 (dd, J=2.5, 8.3 Hz, 1H), 6.55 (d, J= 2.4 Hz, 1H), 4.50 (s, 1H), 3.41-3.32 (m, 1H), 3.233.15 (m, 1H), 3.11-3.02 (m, 1H ), 3.01-2.94 (m, 1H), 2.94-2.86 (m, 1H), 2.32-2.21 (m, 1H), 2.14-2.02 (m , 1H), 1.38 (d, J=6.8 Hz, 6H); ER-LCMS m/z 418.2[M+H]+.

Example 93.

Synthesis I-95

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (270 mg, 659.39 µmol, 1 eq., 71.0%) in DMF (10 ml) and MeOH (8 ml) were added Et ₃ N (333.62 mg, 3.30 mmol, 458.90 μl, 5.0 eq.), Pd(OAc) ₂ (22.21 mg, 98 .91 µmol, 0.15 eq.) and DPPF (54.83 mg, 98.91 µmol, 0.15 eq.). The mixture was purged with CO (50 psi) three times and stirred at 70° C. for 24 h under CO (50 psi). The reaction mixture was concentrated under high vacuum to give a residue which was purified by silica gel column chromatography (PE/EtOAc=1/0 to 10/3, TLC: PE/EtOAc=3/1, Rf=0.47) to give the indicated product methyl 5-(5-fluoro-3-pyridyl)-3-isopropyl- 205 041983 pyrazolo[1,5-a]pyrimidine-7-carboxylate (180 mg, 538.32 µmol, 81.6% yield, 94.0% pure as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.17 (d, J=6.8 Hz, 1H), 8.62 (d, J=5.3 Hz, 1H), 8.22 (dd, J = 7.9, 17.9 Hz, 2H), 7.81 (d, J=8.2 Hz, 1H), 4.22-4.00 (t, 3H), 3.47-3.45 ( m, 1H), 1.47 (t, J=7.4 Hz, 6H); ER-LCMS m/z 315.3 [M+H]+.

Stage 2: 5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine-7-carboxylic acid

To a solution of methyl 5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine-7-carboxylate (180 mg, 538.32 µmol, 1 eq.) in MeOH (10 ml) and THF (10 ml), H2O (5 ml) was added LiOH (128.92 mg, 5.38 mmol, 10 eq.). The mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (20 ml), the pH was adjusted to 3-4 with 1 N sodium hydroxide. HCl solution was extracted with DCM (20 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product 5(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine-7-carboxylic acid (100 mg, 293.05 µmol, 54.4% yield, 88.0% purity) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl3) δ ppm 9.23 (s, 1H), 8.65 (d, J=2.6 Hz, 1H), 8.26 (td, J=2.3, 9.3 Hz, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 3.59-3.35 (m, 1H), 1.49 (d, J=6.8 Hz, 6H ); ER-LCMS m/z 301.1 [M+H]+.

Stage 3: 5-(5-fluoro-3-pyridyl)-N-[(3-hydroxyphenyl)methyl]-3-isopropyl-pyrazolo[1,5-

To a solution of 5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine-7-carboxylic acid (70 mg, 205.14 µmol, 1 eq.) and 3-(aminomethyl )phenol (50.53 mg, 410.27 µmol, 2.0 eq.) in DCM (20 ml) were added HATU (117.00 mg, 307.71 µmol, 1.5 eq.) and DIEA (79.54 mg, 615.41 µmol, 107.19 µl, 3.0 eq.). The mixture was stirred at 25°C for 16 hours. The combined reaction mixture was diluted with H2O (20 ml), extracted with EtOAc (20 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 150x30 mmx4 µm; mobile phase: [water (0.05% HCl)- ACN]; B%: 47%-77%, 12 min) followed by lyophilization to give 5-(5-fluoro-3-pyridyl)-N-[(3-hydroxyphenyl)methyl]-3-isopropyl-pyrazolo[1.5 -a]pyrimidine-7-carboxamide (16.16 mg, 33.78 µmol, 16.5% yield, 100.0% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 10.41 (t, J=5.8 Hz, 1H), 9.34-9.27 (m, 1H), 8.76 (d, J=2 .9 Hz, 1H), 8.62-8.49 (m, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 7.15 (t, J=7.7 Hz , 1H), 6.88-6.80 (m, 2H), 6.72-6.61 (m, 1H), 4.62 (d, J=6.0 Hz, 2H), 3.42- 3.35 (m, 1H), 1.41 (d, J=7.1 Hz, 6H); ER-LCMS m/z 406.2 [M+H]+.

Example 94.

Synthesis I-96

1-96

- 206 041983

Synthesis scheme:

Stage 1: N-[2-(5,7-difluoro-1H-indol-3-yl)ethyl]-2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5a][1 ,3,5]triazine-4-amine (I-96)

4-Chloro-2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine mixture (40 mg, 137.12 µmol, 1 eq.) , 2-(5,7-difluoro-III-indol-3-yl)ethanamine (45.86 mg, 205.68 µmol, 1.5 eq) and DIEA (17.72 mg, 137.12 µmol, 23 .88 µl, 1 eq.) in i-PrOH (10 ml) was stirred at 80°C for 2 h. The mixture was concentrated under reduced pressure to give a residue which was washed with MeOH (10 ml), filtered and dried under reduced pressure, obtaining N-[2-(5,7-difluoro-1H-indol-3-yl)ethyl]-2-(5-fluoro-3pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3 ,5]triazine-4-amine (18.95 mg, 41.98 µmol, 30.6% yield, 100% purity) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 11.37 (s, 1H), 9.29 (t, J=1.6 Hz, 1H), 9.03-9.01 (m, 1H), 8.70 (d, J=2.8 Hz, 1H), 8.26-8.22 (m, 1H), 8.10 (s, 1H), 7.34 (d, J=2.0 Hz , 1H), 7.27 (dd, J=2.0, 7.2 Hz, 1H), 6.91-6.87 (m, 1H), 3.92 (q, J=6.8 Hz, 2H), 3.22-3.15 (m, 1H), 3.09 (t, J=7.2 Hz, 2H), 1.35 (d, J=6.8 Hz, 6H); ER-LCMS m/z 452.2 [M+H]+.

Example 95.

Synthesis of I-97a

Synthesis scheme:

Stage 1: 1-methoxy-4-[(E)-2-nitroprop-1-enyl]benzene

- 207 041983

A mixture of 4-methoxybenzaldehyde (5 g, 36.72 mmol, 4.46 ml, 1 eq.), NH4OAC (566.17 mg, 7.34 mmol, 0.2 eq.) in EtNO ₂ (50 ml) was stirred at 110°С for 5 h under N2 atmosphere. The mixture was then stirred at 110° C. for another 40 h. TLC (PE/EtOAc = 5/1, R _f = 0.73) showed that the starting material had been completely consumed and one new spot had formed. The mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 10/1 to 5/1, TLC: PE/EtOAc = 5/1, R _f = 0.73), affording 1-methoxy-4-[(E)-2-nitroprop-1enyl]benzene (3.7 g, 18.19 mmol, 49.5% yield, 95% purity) as a yellow solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 8.06 (s, 1H), 7.52-7.49 (m, 2H), 7.05-7.02 (m, 2H), 3.85 (s, 3H), 2.45 (s, 3H); ER-LCMS m/z 194.0 [M+H] ⁺ .

Step 2: 1-(4-methoxyphenyl)propan-2-amine

A mixture of 1-methoxy-4-[(E)-2-nitroprop-1-enyl]benzene (1 g, 4.92 mmol, 1 eq.) and LAH (1M in THF, 14.75 ml, 3 eq.) in THF (10 ml) was stirred at 60°C for 14 h. The mixture was quenched with water (0.5 ml), 15% NaOH (0.5 ml) and water (1.5 ml), the mixture was stirred for 3 h at 20°C. The mixture was filtered and concentrated under reduced pressure to give 1-(4-methoxyphenyl)propan-2-amine (800 mg, crude) as a yellow oil.

¹ H NMR (400 MHz, CD3OD) δ ppm 7.08 (d, J=8.4 Hz, 2H), 6.86-6.81 (m, 2H), 3.72 (s, 3H), 2 .96-2.91 (m, 1H), 2.51-2.42 (m, 2H), 0.92 (d, J=6.4 Hz, 3H); ER-LCMS m/z 166.2 [M+H]+.

Stage 3: 4-(2-aminopropyl)phenol

A mixture of 1-(4-methoxyphenyl)propan-2-amine (1.2 g, 7.26 mmol, 1 eq.) in a solution of HBr (8 ml) in H ₂ O (3 ml) was stirred at 100°C in for 3 h. The mixture was subjected to extraction with EtOAc (20 ml), the pH was adjusted to 9 with 15% NaOH, the aqueous solution was subjected to extraction with EtOAc (20 mlx3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure, obtaining 4- (2aminopropyl)phenol (445 mg, crude) as a brown solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 7.00 (d, J=8.4 Hz, 2H), 6.73-6.70 (m, 2H), 3.07-3.01 (m, 1H ), 2.562.51 (m, 2H), 1.07 (d, J=6.4 Hz, 3H); ER-LCMS m/z 152.2 [M+H] ⁺ .

Stage

4:

4-[(2R)-2-[[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo [1,5-a] pyrimidin-7 yl]amino]propyl]phenol (I-97)

7-Chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine mixture (100 mg, 330.21 µmol, 1 eq), 4-(2-aminopropyl )phenol (99.86 mg, 660.42 µmol, 2 eq.) and DIEA (128.03 mg, 990.63 µmol, 172.55 µl, 3 eq.) in i-PrOH (10 ml) were degassed and purged with N2 3 times, the mixture was stirred at 80° C. for 12 hours under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue which was purified with SFC (column: CHIRALPAK AS-H 250x30 5u; mobile phase: [0.1% NH ₃ H ₂ O EtOH]; V%: 20%-20%, min ) to give 4-[(2R)-2-[[5-(5-fluoro-3-pyridyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl]amino]propyl]phenol (Rt = 4.781 min, 50 mg) and preparative HPLC (column: Phenomenex Synergi C18 150x30 mm x 4 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 52%-62%, 12 min) yielding 4 -[(2R)-2-[[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7yl]amino]propyl]phenol (27.45 mg, 57 .15 µmol, 17.3% yield, 99.6% purity, 2HCl) ([a] ²⁵ D = -90.432) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.81-8.76 (m, 2H), 8.25 (s, 1H), 8.12-8.07 (m, 1H), 7.04 (d , J=8.4 Hz, 2H), 6.54 (d, J=8.4 Hz, 2H), 6.34 (s, 1H), 4.42 (broad s, 1H), 3.31 -3.29 (m, 1H), 3.04 (dd, J=4.4, 13.6 Hz, 1H), 2.87-2.83 (m, 1H), 1.54 (d, J =6.4 Hz, 3H), 1.36 (t, J=6.8 Hz, 6H); ER-LCMS m/z 406.2 [M+H] ⁺ .

- 208 041983

Example 96.

Synthesis of I-98a

Synthesis scheme:

Step 1: 3-[(E)-2-nitroprop-1-enyl]-1H-indole

A mixture of 1H-indole-3-carbaldehyde (5 g, 34.45 mmol, 1 eq.), NH ₄ OAC (531.02 mg, 6.89 mmol, 0.2 eq.) in nitroethane (50 ml) was stirred at 110° C. for 24 hours. TLC (DCM/MeOH = 10/1, Rf = 0.8) showed that the starting material was completely consumed and one new spot formed. The mixture was cooled to 0°C. The mixture was filtered and the filter cake was dried under reduced pressure to give 3-[(E)-2-nitroprop-1-enyl]-1H-indole (5.1 g, 25.22 mmol, 73.2% yield, 100 purity %) as a brown solid.

^] H NMR (400 MHz, CD3OD) δ ppm 8.53 (s, 1H), 7.79-7.75 (m, 2H), 7.46 (d, J=8.0 Hz, 1H), 7 .26-7.20 (m, 2H), 2.52 (s, 3H); ER-LCMS m/z 203.0 [M+H] ⁺ .

Step 2: 1-(1H-indol-3-yl)propan-2-amine

LAH (1M in THF, 14.84 ml, 3 equiv.) at 0°C. The mixture was then stirred at 60°C for 2 hours. The mixture was diluted with EtOAc (200 ml), quenched with water (0.5 ml), 15% NaOH (0.5 ml), water (1.5 ml), stirred for 3 h, filtered and concentrated under reduced pressure to give 1-(III-indol-3-yl)propan2-amine (1.3 g, 3.73 mmol, 75.4% yield, 50% purity) as a yellow oil. the color that was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 7.56-7.53 (m, 1H), 7.35-7.30 (m, 1H), 7.10-7.06 (m, 2H), 7 .01-6.97(m, 1H), 3.21-3.17(m, 1H), 2.85-2.79(m, 1H), 2.73-2.69(m, 1H) , 1.15-1.10 (m, 3H); ER-LCMS m/z 175.2 [M+H]+.

- 209 041983

Stage 3: 5-(5-fluoro-3-pyridyl)-N-[(1S)-2-(1H-indol-3-yl)-1-methyl-ethyl]-3-isopropylpyrazolo [1,5-a ]pyrimidine-7-amine (I-98)

1-(1H-indol-3-yl)propan-2-amine mixture (172.61 mg, 495.32 µmol, 1.5 eq.), 7-chloro-5-(5-fluoro-3-pyridyl)-3 -isopropyl-pyrazolo[1,5-a]pyrimidine (100 mg, 330.21 µmol, 1 eq.) and DIEA (42.68 mg, 330.21 µmol, 57.52 µl, 1 eq.) in i- PrOH (10 ml) was degassed and purged with N ₂ 3 times, the mixture was stirred at 50° C. for 3 hours under N ₂ atmosphere. The mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (SiO ₂ , PE/EtOAc = 10/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.55) and further separated by SFC (column: OD (250 mm x 30 mm, 5 μm); mobile phase: [0.1% NH ₃ /H ₂ O EtOH]; B%: 30%-30%, min) to give 5- (5-fluoro-3-pyridyl) -N-[(1S)-2-(1 H-indol-3 -yl)-1-methyl-ethyl] -3-isopropyl-pyrazolo [1,5а]pyrimidine-7 -amine (Rt = 3.870 min, 30 mg) which was purified by preparative HPLC (column: Phenomenex Synergi C18 150x30 mmx4 µm; mobile phase: [water (0.05% HCl) - ACN]; V%: 50% 80 %, 12 min) to give 5-(5-fluoro-3-pyridyl)-N-[(1S)-2-(1H-indol-3-yl)-1-methyl-ethyl]-3-isopropylpyrazolo[1 ,5-a]pyrimidine-7-amine (16.33 mg, 29.93 µmol, 9.1% yield, 98.6% purity, 3HCl) ([a] ²⁵ _D = 261.788) as yellow solid .

1H NMR (400 MHz, CD3OD) δ ppm 8.67 (d, J=2.4 Hz, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 7.54 (d, J=7.6Hz, 1H), 7.45(d, J=2.0, 8.8Hz, 1H), 7.14(d, J=8.4Hz, 1H), 6.99( s, 1H), 6.95 (t, J=7.5 Hz, 1H), 6.83-6.81 (m, 1H), 5.80 (s, 1H), 4.48-4.43 (m, 1H), 3.28 (d, J=2.8 Hz, 1H), 3.23-3.17 (m, 1H), 3.05-3.01 (m, 1H), 1, 64 (d, J=6.4 Hz, 3H), 1.34 (t, J=7.2 Hz, 6H); ER-LCMS m/z 429.3 [M+H]+.

Example 97.

Synthesis I-99

1-99

Synthesis scheme:

F

Cl

1-99

- 210 041983

Stage 1: tert-butyl N-(2-bromo-4,6-difluoro-phenyl) carbamate

A mixture of 2-bromo-4,6-difluoroaniline (10 g, 48.08 mmol, 1 eq.), Boc ₂ O (31.48 g, 144.23 mmol, 33.13 ml, 3 eq.), DMAP (587.34 mg, 4.81 mmol, 0.1 eq.) in THF (100 ml) was degassed and flushed with N ₂ 3 times. The mixture was stirred at 70° C. for 16 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was dissolved in MeOH (100 ml), K ₂ CO ₃ (19.93 g, 144.23 mmol, 3 eq) was added and stirred at 70°C for 4 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Water (100 ml) was added to the crude mixture, extracted with EtOAc (100 mlx3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 10/1 , TLC: PE/EtOAc = 10/1, Rf = 0.36) to give tert-butyl N-(2-bromo-4,6-difluorophenyl)carbamate (12.5 g, 40.57 mmol, yield 84.3%, 100% pure) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.10 (td, J=2.3, 7.7 Hz, 1H), 6.86-6.77 (m, 1H), 5.84 (s, 1H), 1.43(s, 9H); ER-LCMS m/z 251.9, 253.9 [Mt-Bu+H] ⁺ .

Stage 2: tert-butyl N-[2,4-difluoro-6-(2-trimethylsilylethynyl)phenyl]carbamate

A mixture of tert-butyl N-(2-bromo-4,6-difluorophenyl)carbamate (4 g, 12.98 mmol, 1 eq.), ethynyl(trimethyl)silane (1.91 g, 19.47 mmol, 2.70 ml, 1.5 eq.), TEA (3.94 g, 38.95 mmol, 5.42 ml, 3.0 eq.), CuI (247.24 mg, 1.30 mmol, 0, 1 eq.) and Pd(PPh ₃ ) ₂ Cl ₂ (455.60 mg, 649.10 μmol, 0.05 eq.) in DMF (80 ml) were degassed and purged with N2 3 times, then stirred at 100°C for 16 hours in an N2 atmosphere. The reaction mixture was quenched by adding water (300 ml), then extracted with EtOAc (200 mlx3). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 10/ 1, TLC: PE/EtOAc = 20/1, Rf = 0.31) to give tert-butyl N-[2,4-difluoro-6-(2-trimethylsilylethynyl)phenyl]carbamate (3.0 g, 8. 20 mmol, 63.2% yield, 89.0% purity) as a black-brown solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.00-6.93 (m, 1H), 6.90-6.81 (m, 1H), 6.09 (s, 1H), 1.49 (s, 9H), 0.26 (s, 9H); ER-LCMS m/z 270.1 [Mt-Bu+H]+.

Stage 3: 5,7-difluoro-III-indole

Na (1.51 g, 65.64 mmol, 8 eq.) was added slowly to a solution of EtOH (150 ml). After stirring for 1 hour at 15° C. when Na was completely dissolved, tert-butyl N-[2,4difluoro-6-(2-trimethylsilylethynyl)phenyl]carbamate (3.0 g, 8.20 mmol, 1 eq.) and the mixture was stirred at 85°C for 16 hours, the Reaction mixture was concentrated under reduced pressure to remove EtOH. water (100 ml) was added to the residue, extracted with EtOAc (60 mlx3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 10/1 , TLC: PE/EtOAc = 10/1, Rf = 0.17) to give 5,7-difluoro-III-indole (600 mg, 3.68 mmol, 44.8% yield, 94.0% purity) in yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.36 (s, 1H), 7.27-7.25 (m, 1H), 7.09 (dd, J=2.0, 9.0 Hz, 1H), 6.74 (dt, J=2.1, 10.2 Hz, 1H), 6.60-6.47 (m, 1H); ER-LCMS m/z was not found.

Stage 4: 5,7-difluoro-1H-indole-3-carbaldehyde

- 211 041983

To a solution of DMF (18 ml) was added dropwise POCl ₃ (1.13 g, 7.37 mmol, 684.54 μl, 2.0 eq.) at -20° C. over a period of 10 min under N 2 atmosphere. After 1 h, 5,7-difluoro-III-indole (600 mg, 3.68 mmol, 1 eq.) in DMF (2 ml) was added to the above solution while the temperature was maintained below -20°C. The reaction mixture was heated to 15°C and stirred at 15°C for 1 h. TLC (PE/EtOAc = 1/1, Rf = 0.40) showed that the starting material was completely consumed and one new spot formed. The reaction mixture was quenched by adding NaHCO ₃ (100 ml) at 0°C, extracted with EtOAc (100 mlx3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 1/2 , TLC: PE/EtOAc = 1/1, Rf = 0.40) to give 5,7-difluoro-1H-indole-3-carbaldehyde (500 mg, 2.35 mmol, 63.7% yield, 85 purity, 0%) as a yellow solid.

1H NMR (400 MHz, Acetone) δ ppm 11.72 (s, 1H), 10.05 (s, 1H), 8.36 (s, 1H), 7.73 (dd, J=2.4.9 .0 Hz, 1H), 7.02 (ddd, J=2.2, 9.4, 11.3 Hz, 1H); ER-LCMS m/z 182.1 [M+H]+.

Step 5: 5,7-difluoro-3-[(E)-2-nitrovinyl]-1H-indole

NH ₄ OAC (542.57 mg, 7.04 mmol, 3 0 equiv.). The mixture was stirred at 110° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to remove nitromethane. The residue was diluted in EtOAc (50 ml), washed with water (10 ml), brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography ( PE/EtOAc=1/0 to 3/1, TLC: PE/EtOAc=1/1, Rf=0.70) to give 5,7-difluoro-3-[(E)-2-nitrovinyl]-1H -indole (420 mg, 1.82 mmol, 77.4% yield, 97.0% purity) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.23 (d, J=13.5 Hz, 1H), 7.76-7.57 (m, 2H), 7.25-7.16 (m, 1H), 6.916.78 (m, 1H); ER-LCMS m/z 225.1 [M+H] ⁺ .

Step 6: 2-(5,7-difluoro-1H-indol-3-yl)ethanamine

LAH (1M in THF , 6.36 ml, 3.5 eq.) at 0°C. After the addition, the mixture was stirred at 80° C. for 2 hours. TLC (PE/EtOAc = 3/1, Rf = 0.04) indicated that the starting material had been completely consumed and a new spot formed. The reaction mixture was diluted with THF (75 ml), quenched by adding water (0.25 ml), aq. NaOH (0.25 ml, 10% in water), water (0.75 ml) at 0°C in sequence. After stirring for 20 minutes, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give crude 2-(5,7-difluoro-1H-indol-3-yl)ethanamine (320 mg, 1.44 mmol, 78.9% yield, 88.0% purity) as a solid brown substance, which was used directly in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 7.18 (s, 1H), 7.08 (dd, J=2.1, 9.4 Hz, 1H), 6.70 (ddd, J=2.3 , 9.5, 11.3 Hz, 1H), 2.94-2.82 (m, 4H); ER-LCMS m/z 197.1 [M+H] ⁺ .

Step 7: N-[2-(5,7-difluoro-1H-indol-3-yl)ethyl]-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5a]pyrimidine- 7-amine (I-99)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (40 mg, 132.08 µmol, 1 eq.), 2-(5, 7-difluoro-1H-indol-3-yl)ethanamine (44.17 mg, 198.13 µmol, 1.5 eq) in i-PrOH (3 ml) was added DIEA (85.35 mg, 660.42 µmol , 115.03 µl, 5 eq.). The mixture was stirred at 60° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which

- 212 041983 was purified by preparative TLC (DCM/MeOH = 20/1, TLC: DCM/MeOH = 20/1, Rf = 0.48) to give N-[2-(5,7-difluoro-1H-indole -3-yl)ethyl]-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5a]pyrimidin-7-amine (30.31 mg, 66.35 µmol, 50.2 yield %, purity 98.6%) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.82 (t, J=1.4 Hz, 1H), 8.49 (d, J=2.6 Hz, 1H), 7.97-7.85 ( m, 2H), 7.21-7.11 (m, 2H), 6.72-6.58 (m, 1H), 6.11 (s, 1H), 3.85 (t, J=6, 5 Hz, 2H), 3.30-3.24 (m, 1H), 3.15 (t, J=6.3 Hz, 2H), 1.38 (d, J=7.1 Hz, 6H) ; ER-LCMS m/z 451.3 [M+H]+.

Example 98.

Synthesis I-100

Step 1: 5-(5-fluoro-3-pyridyl)-N-[(4-hydroxyphenyl)methyl]-3-isopropyl-pyrazolo[1,5a]pyrimidine-7-carboxamide (I-100)

To a solution of 5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine-7-carboxylic acid (40 mg, 130.54 µmol, 1 eq.) and 4-(aminomethyl )phenol (19.29 mg, 156.65 µmol, 1.2 eq.) in DCM (20 ml) were added HATU (74.45 mg, 195.81 µmol, 1.5 eq.) and DIEA (50.61 mg, 391.63 µmol, 68.21 µl, 3.0 eq.). The mixture was stirred at 25°C for 16 hours. The combined reaction mixture was diluted with H2O (20 ml), extracted with EtOAc (20 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 150x30 mmx4 µm; mobile phase: [water (0.05% HCl)- ACN]; B%: 47%-77%, 12 min) followed by lyophilization to give 5-(5-fluoro-3-pyridyl)-N-[(4-hydroxyphenyl)methyl]-3-isopropyl-pyrazolo[1.5 -a]pyrimidine-7-carboxamide (14.42 mg, 29.79 µmol, 22.8% yield, 98.8% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 9.35 (s, 1H), 8.77 (d, J=2.9 Hz, 1H), 8.69 (d, J=9.3 Hz, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 7.26 (d, J=8.6 Hz, 2H), 6.82-6.72 (m, 2H), 4.66 (s, 2H), 3.48-3.42 (m, 1H), 1.46 (d, J=6.8 Hz, 6H); ER-LCMS m/z 406.1 [M+H] ⁺ .

Example 99.

Synthesis I-101

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Synthesis scheme:

1-101

Step 1: 2-(5-fluoro-3-pyridyl)-8-isopropyl-N-[2-(1H-pyrrolo[3,2-b]pyridin-3yl)ethyl]pyrazolo[1,5-a][ 1,3,5]triazine-4-amine (I-101)

To a solution of 4-chloro-2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine (40 mg, 137.12 µmol, 1 eq. ) and 2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethanamine (33.58 mg, 164.55 µmol, 1.2 eq.) in iPrOH (10 ml) was added DIEA (53, 17 mg, 411.37 µmol, 71.65 µl, 3 eq.). The mixture was stirred at 90° C. for 3 hours. The mixture was concentrated under reduced pressure to give a residue which was purified with prep. HPLC (column: Phenomenex Synergi C18 150x30 mmx4 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 20%-50%, 12 min) yielding 2-(5-fluoro-3- pyridyl)-8-isopropyl-N-[2-(1Hpyrrolo[3,2-b]pyridin-3-yl)ethyl]pyrazolo[1,5-a][1,3,5]triazin-4-amine ( 26.15 mg, 49.73 µmol, 36.27% yield, 100% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.43-9.38 (m, 1H), 9.00-8.93 (m, 2H), 8.49 (d, J=5.6 Hz, 1H ), 8.41 (d, J=8.2 Hz, 1H), 8.01 (s, 2H), 7.59-7.54 (m, 1H), 4.19 (t, J=6, 4 Hz, 2H), 3.41-3.37 (m, 2H), 3.29-3.22 (m, 1H), 1.39 (d, J=6.8 Hz, 6H); ER-LCMS m/z 417.3 [M+H]+.

Example 100.

Synthesis I-102

1-102

Synthesis scheme:

1-102

Stage 1: 2-methyl-4-[(E)-2-nitrovinyl]phenol

A mixture of 4-hydroxy-3-methyl-benzaldehyde (1 g, 7.34 mmol, 1 eq) and NaOAc (602.53 mg, 7.34 mmol, 1

- 214 041983 eq.) in CH3NO2 (10 ml) was stirred at 110°C for 48 h. TLC (PE/EtOAc = 5/1, Rf = 0.23) showed that the starting material was completely consumed and one new spot. The mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.23) to give 2methyl- 4-[(E)-2-nitrovinyl]phenol (400 mg, 1.12 mmol, 15.2% yield, 50% purity) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J=13.6 Hz, 1H), 7.75 (d, J=13.6 Hz, 1H), 7.65-7.59 ( m, 1H), 7.46-7.37 (m, 1H), 6.88 (d, J=8.4 Hz, 1H), 2.24 (s, 3H); ER-LCMS m/z 180.1 [M+H]+

Stage 2: 4-(2-aminoethyl)-2-methyl-phenol

To a solution of 2-methyl-4-[(E)-2-nitrovinyl]phenol (400 mg, 1.12 mmol, 1 eq.) in THF (10 ml) was added LAH (1 M, 3.35 ml, 3 eq. .) at 0°C. The mixture was then stirred at 70° C. for 2 hours. The mixture was quenched with water (0.25 ml), 15% NaOH (0.25 ml) and water (0.75 ml). The mixture was then stirred at 20° C. for 3 hours. The mixture was filtered and concentrated under reduced pressure to give 4-(2-aminoethyl)-2-methylphenol (350 mg, crude) as a brown oil which was used in the next step without additional cleaning.

1H NMR (400 MHz, CD3OD) δ ppm 7.05 (s, 1H), 6.92 (s, 1H), 6.85-6.84 (m, 1H), 3.58-3.55 (m , 2H), 2.17 (s, 3H), 1.60-1.57 (m, 2H); ER-LCMS m/z 152.1 [M+H]+.

Step 3: 4-[2-[[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]ethyl]-2methyl-phenol (I -102)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (50 mg, 165.11 µmol, 1.0 eq.) and 4-( 2-aminoethyl)-2-methyl-phenol (29.96 mg, 198.13 µmol, 1.2 eq.) in i-PrOH (10 ml) was added DIEA (64.02 mg, 495.33 µmol, 86, 28 µl, 3 eq.). The mixture was stirred at 80° C. for 12 hours. The mixture was concentrated under reduced pressure to give a residue which was washed with MeOH (20 ml), filtered. The filter cake was lyophilized to give 4-[2-[[5-(5-fluoro-3-pyridyl)-3isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]ethyl]-2-methyl- phenol (26.08 mg, 63.29 µmol, 38.3% yield, 98.4% purity) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.24 (s, 1H), 9.03 (s, 1H), 8.67 (s, 1H), 8.40-8.36 (m, 1H), 7.99 (s, 1H), 7.92 (t, J=6.0 Hz, 1H), 7.02 (s, 1H), 6.90 (dd, J=2.0, 8 .2 Hz, 1H), 6.73 (s, 1H), 6.64 (d, J=8.2 Hz, 1H), 3.743.67 (m, 2H), 3.27-3.19 (m , 1H), 2.85 (t, J=7.6 Hz, 2H), 2.07 (s, 3H), 1.36 (d, J=6.8 Hz, 6H); ER-LCMS m/z 406.2 [M+H]+.

Example 101.

Synthesis I-103

- 215 041983

Synthesis scheme:

Step 1: 5-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrazolo[1,5-a]pyrimidin-7-amine (I103)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (30 mg, 110.76 µmol, 1.0 eq.) in i-PrOH (3 ml) was added DIEA (42.94 mg, 332.28 µmol, 57.88 µl, 3.0 eq.) and 2-(III-indol-3yl)ethanamine (24.00 mg, 149.80 µmol, 1.35 eq. ). The mixture was stirred at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 29%-49%, 10 min). The desired fraction was lyophilized to give 5-(5fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrazolo[1,5-a]pyrimidin-7-amine (25.41 mg, 52.74 µmol, 47.62% yield, 100% purity, 3HCl salt) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.73 (d, J=2.5 Hz, 1H), 8.38 (s, 1H), 8.26 (d, J=2.3 Hz, 1H ), 7.56 (d, J=7.8 Hz, 1H), 7.46 (td, J=2.3, 9.0 Hz, 1H), 7.12 (d, J=8.0 Hz , 1H), 7.00 (s, 1H), 6.96 (t, J=7.2 Hz, 1H), 6.896.84 (m, 1H), 6.52 (d, J=2.3 Hz , 1H), 5.88 (s, 1H), 4.07 (t, J=5.9 Hz, 2H), 3.27-3.23 (m, 2H); ER-LCMS m/z 373.3 [M+H]+.

Example 102.

Synthesis I-104

Synthesis scheme:

Stage 1: 4-chloro-2-(5-fluoro-3-pyridyl)-6-isopropoxy-pyrimidine

NaH (34.42 mg, 860.47 µmol, 60% purity, 1, 2 eq.). The mixture was stirred at 0° C. for 30 minutes. To the above solution was added 4,6-dichloro-2-(5-fluoro-3-pyridyl)pyrimidine (175 mg, 717.06 µmol, 1.0 eq) and the mixture was stirred at 15°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with water (50 ml) and extracted with EtOAc (30 mlx3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-chloro-2-(5-fluoro-3-pyridyl)-6-isopropoxy-pyrimidine (220 mg, 690.36 µmol, yield 96.2%, 84.0% pure) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.41 (s, 1H), 8.58 (d, J=2.8 Hz, 1H), 8.40-8.31 (m, 1H), 6 .67 (s, 1H), 5.53 (m, 1H), 1.43 (d, J=6.3 Hz, 6H); ER-LCMS m/z 268.1, 270.1 [M+H]+.

Step 2: 2-(5-fluoro-3-pyridyl)-6-isopropoxy-N-[2-(1H-pyrrolo[3,2-b]pyridin-3yl)ethyl]pyrimidin-4-amine (I-104 )

4-chloro-2-(5-fluoro-3-pyridyl)-6-isopropoxypyrimidine (60 mg, 188.28 µmol, 1.0 eq.), 2-(1Hpyrrolo[3,2-b]pyridine- 3-yl)ethanamine (45 mg, 220.53 µmol, 1.17 eq.) and DIEA (73.00 mg, 564.84 µmol, 98.38 µl, 3.0 eq.) in i-PrOH (3 ml) was placed in a tube with microwave radiation. The sealed tube was heated at 125° C. for 6 hours while being treated with microwave radiation. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 25%-55%, 10 min). The desired fraction was lyophilized to give 2-(5-fluoro-3-niridyl)-6-isopropoxy-N-[2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]pyrimidin-4-amine (20.08 mg, 38.97 µmol, 20.7% yield, 97.4% purity, 3HCl salt) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.20 (s, 1H), 8.93 (dd, J=1.0, 2.5 Hz, 1H), 8.62 (s, 1H), 8, 53-8.46 (m, 2H), 8.06 (s, 1H), 7.65-7.58 (m, 1H), 6.03 (s, 1H), 5.22 (s, 1H) , 5.29-5.16 (m, 1H), 3.96 (m, 2H), 3.30-3.27 (m, 2H), 1.42 (d, J=6.0 Hz, 6H ); ER-LCMS m/z 393.2 [M+H] ⁺ .

Example 103.

Synthesis of I-105

Step 1: 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-pyrrolidin-1-yl-pyrimidin-4-amine (I-105)

6-Chloro-2-(5-fluoro-3-niridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine (80 mg, 215.33 µmol, 1.0 eq .), pyrrolidine (1.28 g, 17.97 mmol, 1.5 ml, 83.45 eq.) and DIEA (139.15 mg, 1.08 mmol, 187.53 µl,

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5.0 eq.) was placed in a microwave tube in i-PrOH (1.5 ml). The sealed tube was heated at 130° C. for 3 hours while being treated with microwave radiation. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 25%-55%, 10 min). The desired fraction was lyophilized to give 2-(5fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-pyrrolidin-1-yl-pyrimidin-4-amine (47.28 mg , 91.26 µmol, 42.3% yield, 98.8% purity, 3HCl salt) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.00 (s, 1H), 8.77 (s, 1H), 8.22 (s, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.33 (d, J=7.9 Hz, 1H), 7.16-6.98 (m, 4H), 3.72 (d, J=6.0 Hz, 4H), 3, 15 (t, J=5.8 Hz, 4H), 2.00 (s, 4H); ER-LCMS m/z 403.3 [M+H]+.

Example 104.

Synthesis I-106

Synthesis scheme:

Stage 1: 1-amino-3-methyl-butan-2-ol

Pd(dppf)CI _2l CS2CO3 dioxane, HgO

A mixture of 2-isopropyloxirane (600 mg, 6.97 mmol, 1 eq.) in NH3H2O (5 ml) was degassed and purged with N2 3 times. Then the mixture was stirred at 10–15°C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude product 1-amino-3methyl-butan-2-ol (700 mg, 6.79 mmol, 97.4% yield, crude) as a colorless oil which was used in the next step without further cleaning.

1H NMR (400 MHz, CDCl3) δ ppm 3.39-3.22 (m, 1H), 2.91-2.72 (m, 1H), 2.60-2.49 (m, 1H), 1 .71-1.62 (m, 1H), 0.98-0.91 (m, 6H); ER-LCMS m/z The correct mass was not found.

Stage 2: 1-[(3-chloropyrazin-2-yl)amino]-3-methyl-butan-2-ol

A mixture of 2,3-dichloropyrazine (670 mg, 4.50 mmol, 1 eq) and 1-amino-3-methyl-butan-2-ol (695.93 mg,

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6.75 mmol, 1.5 eq.) in 1,4-dioxane (3 ml) was degassed and flushed with N2 3 times. The mixture was stirred at 110° C. for 16 h under N ₂ atmosphere. TLC (PE/EtOAc = 5/1, Rf = 0.54) indicated that the starting material had not been completely consumed and new spots were found. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.54) to give the indicated product 1-[(3-chloropyrazin-2-yl)amino]-3-methyl-butan-2-ol (500 mg, 2.27 mmol, 50.5% yield, 98.0% purity) as colorless oils.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.92 (d, J=2.9 Hz, 1H), 7.60 (d, J=2.6 Hz, 1H), 5.61 (broad s , 1H), 3.74 (ddd, J=2.4, 6.5, 13.8 Hz, 1H), 3.59-3.58 (m, 1H), 3.44-3.37 (m , 1H), 2.83 (d, J=4.4 Hz, 1H), 1.89-1.72 (m, 1H), 1.03 (dd, J=6.8, 10.6 Hz, 6H); ER-LCMS m/z 216.0, 218.1 [M+H] ⁺ .

Stage 3: 1-[(3,5-dichloropyrazin-2-yl)amino]-3-methyl-butan-2-ol

A mixture of 1-[(3-chloropyrazin-2-yl)amino]-3-methyl-butan-2-ol (380 mg, 1.73 mmol, 1 eq.) and NCS (276.68 mg, 2.07 mmol , 1.2 eq.) in CHCl ₃ (10 ml) was degassed and purged with N2 3 times and stirred at 70° C. for 2 h under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc=1/0 to 10/3, TLC: PE/EtOAc=3/1, Rf=0.46) to give the indicated product 1-[(3,5dichloropyrazin-2-yl)amino]-3-methyl-butan-2-ol (345 mg, 1.23 mmol, 71.1% yield, 89.0% purity) as an oil yellow color.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.95 (s, 1H), 5.59 (broad s, 1H), 3.74 (ddd, J=2.8, 6.7, 13.7 Hz, 1H), 3.58-3.56 (m, 1H), 3.38-3.33 (m, 1H), 1.83-1.73 (m, 1H), 1.03 (dd, J=6.8, 10.1 Hz, 6H); ER-LCMS m/z 250.0, 252.0 [M+H]+.

Stage 4: 1-[(3,5-dichloropyrazin-2-yl)amino]-3-methyl-butan-2-one

Dess's reagent -Martin (733.47 mg, 1.73 mmol, 1.2 eq.). The mixture was stirred at 20° C. for 2 hours. TLC (PE/EtOAc = 3/1, Rf = 0.51) indicated that approximately 50% of the starting material remained. Dess-Martin reagent (300 mg, 0.71 mmol) was added and the reaction mixture was stirred at 20° C. for 16 h. TLC (PE/EtOAc = 3/1, Rf = 0.51) indicated that approximately 20% original substance. The reaction mixture was quenched by adding us. Na2S2O3 solution (50 ml) was extracted with EtOAc (50 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3 /1, Rf = 0.51) to give the title product 1-[(3,5-dichloropyrazin-2-yl)amino]-3-methyl-butan-2-one (200 mg, 669.06 µmol, yield 46 .4%, purity 83.0%) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.96 (s, 1H), 6.03 (broad s, 1H), 4.35 (d, J=4.4 Hz, 2H), 2.76 (m, 1H), 1.22 (d, J=6.8 Hz, 6H); ER-LCMS m/z 247.9, 249.9 [M+H]+.

Stage 5: 6,8-dichloro-3-isopropyl-imidazo[1,2-a]pyrazine

TFAA ( 379.41 mg, 1.81 mmol, 251.27 µl, 3 eq.). The mixture was stirred at 20° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC: PE/EtOAc = 3 /1, Rf = 0.48) to give the title product 6,8-dichloro-3-isopropyl-imidazo[1,2a]pyrazine (120 mg, 521.53 µmol, 86.6% yield, 100.0% purity ) as a light yellow solid.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm 7.94 (s, 1H), 7.69 (s, 1H), 3.22-3.16 (m, 1H), 1.44 (d, J= 6.8 Hz, 6H); ER-LCMS m/z 230.0, 232.0 [M+H] ⁺ .

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Stage 6: 6-χΛορ-Ν-[2-( 1 H-indol-3 -yl)ethyl] -3-isopropyl-imidazo [1,2-a] pyrazin-8-amine

To a solution of 6,8-dichloro-3-isopropyl-imidazo[1,2-a]pyrazine (50 mg, 217.30 µmol, 1 eq.) and 2-(1Hindol-3-yl)ethanamine (41.78 mg , 260.76 µmol, 1.2 eq.) in i-PrOH (3 ml) was added DIEA (84.25 mg, 651.91 µmol, 113.55 µl, 3.0 eq.). The mixture was stirred at 45° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC: PE/EtOAc = 1 /1, R _f = 0.44), obtaining the indicated product 6-chloro-N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-umidazo[1,2-a]pyrazine-8 -amine (60 mg, 162.78 µmol, 74.9% yield, 96.0% purity) as a brown oil.

1H NMR (400 MHz, CDCI3) δ ppm 8.07 (broad s, 1H), 7.71 (d, J=7.9 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.30 (s, 1H), 7.24-7.19 (m, 2H), 7.17-7.12 (m, 1H), 7.11 (d, J=2.2 Hz , 1H), 6.21 (br s, 1H), 4.02-3.89 (m, 2H), 3.17 (t, J=6.8 Hz, 2H), 3.12-3, 02 (m, 1H), 1.37 (d, J=7.1 Hz, 6H); ER-LCMS m/z 354.0, 356.1 [M+H]+.

Stage 7: 6-(5-fluoro-3-pyridyl)-N-[2-(1 H-indol-3-yl)ethyl]-3-isopropyl-imidazo[1,2-a]pyrazine-8amine (I -106)

6-Chloro-N-[2-(1H-indol-3-yl)ethyl]-3-uzopropyl-imidazo[1,2-a]pyrazine-8-amine (60 mg, 162.78 µmol, 1 eq. ), (5-fluoro-3-pyridyl)boronic acid (45.87 mg, 325.56 µmol, 2.0 eq.), Pd(dppf)Cl ₂ (11.91 mg, 16.28 µmol, 0, 1 eq.) and Cs ₂ CO ₃ (159.11 mg, 488.35 µmol, 3.0 eq.) were placed in a microwave tube in 1,4-dioxane (2 ml) and H2O (0.5 ml) . The mixture was purged with N2 for 3 minutes. The sealed tube was heated at 110° C. for 30 minutes while being treated with microwave radiation. The reaction mixture was diluted (20 ml) and extracted with ethyl acetate (20 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 150x30 mmx4 µm; mobile phase: [water (0.05% HCl)- ACN]; B%: 30%-60%, 12 min) followed by lyophilization to give 6-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-3isopropyl -imidazo[1,2-a]pyrazine-8-amine (50.13 mg, 94.00 µmol, 57.8% yield, 98.2% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.21 (broad s, 1H), 8.86 (broad s, 1H), 8.74 (d, J=9.0 Hz, 1H), 8, 57 (s, 1H), 7.89 (s, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 7. 09 (s, 1H), 6.94 (t, J=7.5 Hz, 1H), 6.896.81 (m, 1H), 4.06 (t, J=6.1 Hz, 2H), 3, 46 (d, J=6.0 Hz, 1H), 3.18 (t, J=6.3 Hz, 2H), 1.42 (d, J=6.3 Hz, 6H); ERJHMS m/z 415.3 [M+H] ⁺ .

Example 105.

Synthesis I-107

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Synthesis scheme:

Stage 1: N-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl]-5-(5-fluoro-3-pyridyl)-3-isopropylpyrazolo [1,5- a] pyrimidine-7-amine (I-107)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (120 mg, 404.51 µmol, 1 eq.) and 2-(5, 7-difluoro-2-methyl-1H-indol-3-yl)ethanamine (182.19 mg, 606.76 µmol, 1.5 eq., oxalic acid) in i-PrOH (20 ml) was added with DIEA (261, 40 mg, 2.02 mmol, 352.29 µl, 5.0 eq.). The mixture was stirred at 70° C. for 18 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm;

mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN]; B%: 63%-93%, 10 min) followed by lyophilization to give N-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl]-5-(5- fluoro-3-pyridyl)3-isopropyl-pyrazolo[1,5-a]pyrimidine-7-amine (94.41 mg, 196.14 µmol, 48.5% yield, 96.5% purity, 92.85 mg remained) in the form of a light yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.16 (s, 1H), 8.96 (s, 1H), 8.61 (d, J=2.8 Hz, 1H), 8, 06-7.95 (m, 3H), 7.20 (dd, J=2.0, 9.5 Hz, 1H), 6.80-6.68 (m, 1H), 6.34 (s, 1H), 3.69 (q, J=6.5 Hz, 2H), 3.19 (spt, J=6.8 Hz, 1H), 2.99 (t, J=6.7 Hz, 2H) , 2.16 (s, 3H), 1.33 (d, J=7.0 Hz, 6H); ER-LCMS m/z 465.3 [M+H]+.

Example 106.

Synthesis I-108

Synthesis scheme:

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Step 1: 4-[2-[[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]ethyl]phenol (I-108)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (52.08 mg, 171.99 µmol, 1 eq.) in i-PrOH (3 ml) was added 4-(2-aminoethyl)phenol (28.31 mg, 206.38 µmol, 1.2 eq.) and DIEA (66.68 mg, 515.96 µmol, 89.87 µl, 3 eq. .). The mixture was stirred at 60° C. for 16 hours. The mixture was concentrated to give the crude product, which was purified by preparative HPLC (MeCN/H ₂ O as eluents, acidic conditions, instrument: Phenomenex Gemini 150x25 mmx10 μm/Mobile phase: water ( 0.05% HCl)-CAM / Gradient: B 42% to 72% over 10 min / Flow rate: 25 ml/min) followed by lyophilization to give 4-[2-[[5-(5-fluoro- 3-pyridyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl]amino]ethyl]phenol (49.37 mg, 105.68 µmol, 61.5% yield, 99.4% purity, 2HCl ) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.83 (d, J=2.5 Hz, 2H), 8.27 (s, 1H), 8.16 (dd, J=1.8, 8.8 Hz, 1H), 7.08 (d, J=8.3 Hz, 2H), 6.63 (d, J=8.3 Hz, 2H), 6.38 (s, 1H), 3.97 ( t, J=6.5 Hz, 2H), 3.38 - 3.34 (m, 1H), 3.01 (t, J=6.5 Hz, 2H), 1.39 (d, J=7 .0 Hz, 6H); ER-LCMS m/z 392.1 [M+H]+.

Example 107.

Synthesis I-109

Synthesis scheme:

Step 1: 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-(5-methoxyindan-2-yl)pyrazolo[1,5-a]pyrimidine-7amine

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (80 mg, 264.17 µmol, 1.0 eq.) in i-PrOH (3 ml) DIEA (102.42 mg, 792.51 µmol, 138.04 µl, 3.0 eq) and 5-methoxyindan-2-amine (60 mg, 367.61 µmol, 1.39 eq) were added. The mixture was stirred at 50° C. for 15 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc= 3/1, R _f =

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0.70) to give 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-(5-methoxyindan-2-yl)pyrazolo[1,5-a]pyrimidin-7-amine (120 mg, 155 .51 µmol, yield 58.9%, purity 54.1%) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.08 (s, 1H), 8.55 (d, J=2.8 Hz, 1H), 8.21 (td, J=2.3, 9, 5 Hz, 1H), 7.87 (s, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.83 (s, 1H), 6.57 (d, J=7, 5 Hz, 1H), 6.41 (s, 1H), 4.70-4.60 (m, 1H), 3.81 (s, 3H), 3.50 (ddd, J=6.8, 12 .6, 15.7 Hz, 2H), 3.42 - 3.30 (m, 1H), 3.08 (dt, J=4.5, 16.1 Hz, 2H), 1.42 (d, J=6.8 Hz, 6H); ER-LCMS m/z 418.1 [M+H]+.

Step 2: 2-[[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]indan-5-ol (I-109)

To a solution of 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-(5-methoxyindan-2-yl)pyrazolo[1,5-а]pyrimidine

7-amine (95 mg, 123.11 µmol, 1 eq.) in HBr (9 ml) was stirred at 120° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (conditions with HCl, column: Phenomenex Gemini 150x25 mmx10 µm, mobile phase: [water (0.05% HCl)-ACN]; B%: 49%-79%, 10 min). The desired fraction was lyophilized to give 2-[[5(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]indan-5-ol (30.69 mg , 61.40 µmol, 49.8% yield, 95.3% purity, 2HCl salt) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.00 (s, 1H), 8.83 (d, J=2.5 Hz, 1H), 8.35 (td, J=2.3, 9.0 Hz, 1H), 8.24 (s, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.96 (s, 1H), 6.71 (s, 1H), 6, 65 (dd, J=2.3, 8.0 Hz, 1H), 5.02 (t, J=6.9 Hz, 1H), 3.51-3.40 (m, 2H), 3.40 -3.32 (m, 1H), 3.25-3.12 (m, 2H), 1.39 (d, J=7.0 Hz, 6H); ER-LCMS m/z 404.2 [M+H] ⁺ .

Example 108.

Synthesis of I-110

Step 1: 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-[2-(1H-pyrrolo[3,2-b]pyridin-3yl)ethyl]pyrazolo[1,5-a]pyrimidine -7-amine (I-110)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (45 mg, 123.83 µmol, 1.0 eq.) in i-PrOH (2 ml) DIEA (48.01 mg, 371.49 µmol, 64.70 µl, 3.0 eq.) and 2-(1H-223 041983 pyrrolo[3,2-b]pyridin-3-yl) were added ethanamine (25 mg, 155.08 µmol, 1.25 eq.). The mixture was stirred at 50° C. for 15 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; V%: 20%-50%, 10 min). The desired fraction was lyophilized to give 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-[2-(1 H-pyrrolo[3,2-b]pyridin-3 yl)ethyl]pyrazolo[1.5 -a]pyrimidine-7-amine (16.32 mg, 30.38 µmol, 24.5% yield, 97.7% purity, 3HCl salt) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.97 (s, 1H), 8.84 (d, J=2.4 Hz, 1H), 8.57-8.52 (m, 2H), 8, 35 (td, J=2.1, 9.0 Hz, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.70-7.65 (m, 1H), 6 .90 (s, 1H), 4.15 (t, J=6.9 Hz, 2H), 3.45 (t, J=6.9 Hz, 2H), 3.38-3.33 (m, 1H), 1.38 (d, J=6.8 Hz, 6H); ER-LCMS m/z 416.2 [M+H]+.

Example 109.

Synthesis I-120

NaH (1.06 g, 26.42 mmol, 1.5 eq.). The mixture was stirred for 30 min at 0° C. under N2. A solution of 4,6-dichloro-2-methylsulfonyl-pyrimidine (4 g, 17.62 mmol, 1 eq.) in THF (50 ml) was added dropwise to the mixture. The mixture was stirred at -55°C for 12 hours. To the reaction mixture was added 1N. NH4C1 solution (5 ml) and concentrated. The residue was purified by silica gel flash chromatography (PE/EtOAc = 3/1, R _f = 0.5) to give 4,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidine -2-amine (2.1 g, 5.81 mmol, 33.0% yield, 85% purity) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.68 (s, 1H), 8.00 (d, J=10.8 Hz, 1H), 7.64 (t, J=6.1 Hz, 1H ), 7.39-7.33 (m, 1H), 7.26-7.20 (m, 1H), 7.16-7.09 (m, 1H), 7.08-6.99 (m , 1H), 6.61-6.53 (m, 1H), 3.84-3.70 (m, 2H), 3.05 (d, J=6.1 Hz, 2H); ER-LCMS m/z 307.0, 309.1 [M+H]+.

Stage 2: 4-chloro-6-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-2-amine

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To a mixture of 4,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-2-amine (300 mg, 830.14 mol, 1 eq.) and (5fluoro-3-pyridyl) boronic acid (93.58 mg, 664.11 mol, 0.8 eq.) in 1,4-dioxane (3 ml) and H ₂ O (2 ml) was added Cs ₂ CO ₃ (540.95 mg, 1, 66 mmol, 2 eq.) and Pd(dppf)Cl ₂ (60.74 mg, 83.01 mol, 0.1 eq.) under N2 atmosphere. The mixture was stirred at 110° C. for 20 minutes while being treated with microwave radiation. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (pure PE to PE/EtOAc = 3/1, TLC: PE/EtOAc = 3/1, R _f = 0.33) to give 4-chloro-6-(5-fluoro -3pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrimidine-2-amine (70 mg, 171.29 mol, 20.6% yield, 90% purity) as a light solid yellow color.

1H NMR (400 MHz, CDCI3) δ ppm 8.91 (br s, 1H), 8.50 (br s, 1H), 7.97 (br s, 2H), 7.60 (d, J =7.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.15 (t, J=7.6 Hz, 1H), 7.10-7.04 (m , 1H), 7.02 (br s, 1H), 6.92 (s, 1H), 5.39 (br s, 1H), 3.79 (br s, 2H), 3.05 ( t, J=6.7 Hz, 2H); ER-LCMS m/z 368.1, 370.1 [M+H]+.

Step 3: 4-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-2-amine (I-120) n

Ν^Ν

XT N

To a solution of 4-chloro-6-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-2-amine (70 mg, 171.29 mol, 1 eq. .) in MeOH (5 ml) and NH ₃ H ₂ O (0.2 ml) was added Pd/C (30 mg, 10% purity). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred in H ₂ (15 psi) atmosphere at 10° C. for 0.5 h. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 μm; mobile phase: [water (0.05% HCl)-ACN]; V%: 33%-63%, 8 min) followed by lyophilization to give 4- (5-fluoro-3pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-2-amine (20.8 mg, 50.20 µmol, 29.3% yield, 98.1 purity %, 2 HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.06 (br s, 1H), 8.74 (br s, 1H), 8.32-8.06 (m, 2H), 7.59-7 .55 (m, 1H), 7.43 (d, J=6.6 Hz, 1H), 7.24-7.04 (m, 2H), 7.01-6.93 (m, 2H), 4.05-3.96 (m, 2H), 3.15 (t, J=6.4 Hz, 2H); ER-LCMS m/z 334.1 [M+H] ⁺ .

Example 110.

Synthesis I-121

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Synthesis scheme:

1-121

Step 1: (3R)-N-(2-Methylsulfanylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-2,3,4,9-tetrahydro-1Hcarbazole-3-amine

DIEA ( 1.31 g, 10.12 mmol, 1.76 ml, 6 eq) and (3R)-2,3,4,9-tetrahydro-1Hcarbazole-3-amine (314.20 mg, 1.69 mmol, 1 equivalent). The mixture was stirred at 50° C. for 2 hours. The mixture was concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc=2/1, TLC: PE/EtOAc=3/1, Rf=0.4) to give (3R)-N-(2methylsulfanylpyrazolo[1 ,5-a][1,3,5]triazin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (300 mg, 770.46 µmol, 45.7% yield , 90% pure) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.90-7.77 (m, 2H), 7.44 (d, J=7.8 Hz, 1H), 7.30 (d, J=8 .1 Hz, 1H), 7.187.12 (m, 1H), 7.11-7.06 (m, 1H), 6.61 (d, J=8.3 Hz, 1H), 6.21 (s , 1H), 3.28 (dd, J=5.0, 15.5 Hz, 1H), 3.00-2.78 (m, 4H), 2.55 (s, 3H), 2.31- 2.15 (m, 2H); ER-LCMS m/z 351.2 [M+H]+.

Step 2: tert-butyl (3R)-3-[tert-butoxycarbonyl-(2-methylsulfanylpyrazolo[1,5a][1,3,5]triazin-4-yl)amino]-1,2,3,4- tetrahydrocarbazole-9-carboxylate

To a solution of (3R)-N-(2-methylsulfanylpyrazolo[1,5-а][1,3,5]triazin-4-yl)-2,3,4,9-tetrahydro-1Hcarbazole-3-amine (200 mg, 513.64 µmol, 1 eq.) in 1,4-dioxane (30 ml) was added DMAP (188.25 mg, 1.54 mmol, 3 eq.) and Boc ₂ O (672.60 mg, 3. 08 mmol, 708.00 µl, 6 eq.). The mixture was stirred at 110° C. for 24 hours. The mixture was concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc = 3/1, TLC: PE/EtOAc = 5/1, Rf = 0.5) to give tert-butyl (3R)-3-[tert- butoxycarbonyl-(2-methylsulfanylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino]1,2,3,4-tetrahydrocarbazole-9-carboxylate (300 mg, 492.49 µmol, yield 95.9%, purity 90.4%) as off-white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.11-8.02 (m, 2H), 7.33 (d, J=7.6 Hz, 1H), 7.23-7.14 (m, 2H), 6.41 (s, 1H), 4.79-4.72 (m, 1H), 3.31-3.01 (m, 4H), 2.56 (s, 3H), 2.41 -2.17 (m, 2H), 1.64 (s, 9H), 1.32 (s, 9H); ERJHMS m/z 551.3 [M+H] ⁺ .

- 226 041983

Stage 3: tert-butyl (3R)-3-[(8-bromo-2-methylsulfanyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)-tert-butoxycarbonyl-amino]-1 ,2,3,4-tetrahydrocarbazole-9-carboxylate

To a solution of tert-butyl (3R)-3-[tert-butoxycarbonyl-(2-methylsulfanylpyrazolo[1,5а][1,3,5]triazin-4-yl)amino]-1,2,3,4-tetrahydrocarbazole -9-carboxylate (260 mg, 426.82 µmol, 1 eq.) in MeCN (20 ml) and DCM (20 ml) was added NBS (79.76 mg, 448.17 µmol, 1.05 eq.). The mixture was stirred at 10° C. for 30 minutes. The mixture was concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc = 5/1 to 2/1, TLC: PE/EtOAc = 5/1, Rf = 0.58) to give tert-butyl (3R)-3-[ (8-bromo-2-methylsulfanyl-pyrazolo[1,5-a] [1,3,5]triazin-4-yl)-tert-butoxycarbonyl-amino]1,2,3,4-tetrahydrocarbazole-9-carboxylate (200 mg, 299.89 µmol, 70.3% yield, 94.4% purity) as a yellow solid.

1H NMR (400 MHz, CDC13) δ ppm 8.09 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 7.34 (d, J=8.0 Hz, 1H) , 7.25-7.17(m, 2H), 4.83-4.73(m, 1H), 3.34-3.25(m, 1H), 3.23-3.02(m, 3H), 2.62 (s, 3H), 2.36 (td, J=6.2, 12.0 Hz, 1H), 2.23-2.21 (m, 1H), 1.66 (s , 9H), 1.36 (s, 9H); ER-LCMS m/z 629.2, 631.2 [M+H]+.

Stage 4: tert-butyl (3C)-3-[tert-butoxycarbonyl-(8-isopropenyl-2-methylsulfanylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino]-1, 2,3,4-tetrahydrocarbazole-9-carboxylate

Vos

N

To a solution of tert-butyl (3C)-3-[(8-bromo-2-methylsulfanyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)-tert-butoxycarbonyl-amino]-1, 2,3,4-tetrahydrocarbazole-9-carboxylate (200 mg, 299.89 µmol, 1 eq.), 2isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (75.59 mg, 449.83 µmol, 1.5 eq.) in 1,4-dioxane (4 ml) and H2O (2 ml) were added Cs ₂ CO ₃ (293.13 mg, 899.67 µmol, 3 eq.) and Pd( dppf)Cl ₂ (21.94 mg, 29.99 µmol, 0.1 eq) under N2. The mixture was stirred at 110° C. for 1 hour while being treated with microwave radiation. After filtration, the filtrate was concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc = 5/1, TLC: PE/EtOAc = 5/1, R _f = 0.65) to give tert-butyl (3R)-3- [tert-butoxycarbonyl-(8-isopropenyl-2methylsulfanyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino]-1,2,3,4-tetrahydrocarbazole-9-carboxylate ( 180 mg, 274.23 µmol, 91.5% yield, 90% purity) as a yellow solid.

1H NMR (400 MHz, CDC13) δ ppm 8.13-8.05 (m, 2H), 7.32 (d, J=7.6 Hz, 1H), 7.23-7.15 (m, 2H ), 5.86 (s, 1H), 5.12 (s, 1H), 4.79-4.74 (m, 1H), 3.29-3.01 (m, 4H), 2.57 ( s, 3H), 2.33-2.18 (m, 5H), 1.34 (s, 9H), 1.26 (s, 9H); ER-LCMS m/z 591.3 [M+H] ⁺ .

Step 5: tert-butyl (3R)-3-[tert-butoxycarbonyl-[2-(3-fluorophenyl)-8-isopropenyl-pyrazolo[1,5a][1,3,5]triazin-4-yl]amino ]-1,2,3,4-tetrahydrocarbazole-9-carboxylate

A mixture of tert-butyl (3R)-3-[tert-butoxycarbonyl-(8-isopropenyl-2-methylsulfanyl-pyrazolo[1,5a][1,3,5]triazin-4-yl)amino]-1,2, 3,4-tetrahydrocarbazole-9-carboxylate (140 mg, 213.29 µmol, 1 eq.), (3-fluorophenyl)boronic acid (89.53 mg, 639.88 µmol, 3 eq.), Pd(PPh ₃ ) ₄ (24.65 mg, 21.33 µmol, 0.1 eq.) and CuTC (122.02 mg, 639.88 µmol, 3 eq.) in THF (2 ml) were placed in a tube with microwave radiation in the atmosphere _N2 . The mixture was stirred at 100° C. for 3 hours while being treated with microwave radiation. After filtration, the filtrate was concentrated. The residue was purified by preparative TLC (PE/EtOAc = 5/1, R _f = 0.68) to give t-butyl (3R)-3-[t-butoxycarbonyl-[2-(3-fluorophenyl)-8isopropenylpyrazolo [1,5-а][1,3,5]triazin-4-yl]amino]-1,2,3,4-tetrahydrocarbazole-9-carboxylate (70

- 227041983 mg, 64.11 µmol, 30.1% yield, 58.5% purity) as a yellow solid.

1H NMR (400 MHz, CDCls) δ ppm 8.21-8.13 (m, 2H), 8.02 (d, J=8.1 Hz, 2H), 7.31-7.23 (m, 2H ), 7.13-7.06 (m, 3H), 5.97 (s, 1H), 5.17 (s, 1H), 4.85-4.83 (m, 1H), 3.10- 2.97 (m, 4H), 2.22-2.14 (m, 5H), 1.29 (d, J=4.4 Hz, 18H); ER-LCMS m/z 639.4 [M+H] ⁺ .

Step 6: (3R)-N-[2-(3-fluorophenyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4, 9tetrahydro-1 H-carbazole-3-amine (I-121)

To a solution of tert-butyl (3R)-3-[tert-butoxycarbonyl-[2-(3-fluorophenyl)-8-isopropenylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino] -1,2,3,4-tetrahydrocarbazole-9-carboxylate (60 mg, 54.95 µmol, 1 eq.) and NH3H2O (546.00 mg, 4.36 mmol, 600.00 µl, 28% purity, 79 .38 eq.) in MeOH (15 mL) was added Pd/C (30 mg, 9.16 µmol, 10% purity). The mixture was stirred in H ₂ atmosphere (15 psi) at 25°C for 6 h. After filtration, the filtrate was concentrated, DCM (3 ml) and TFA (1.54 g, 13.51 mmol, 1 ml, 245 78 equivalents). The mixture was stirred at 15° C. for 1 hour. The mixture was concentrated to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 μm; mobile phase: [water (0.05% HCl)-ACN]; B% : 80%-100%, 8 min) followed by lyophilization to give (3R)-N-[2-(3-fluorophenyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine -4-yl]2,3,4,9-tetrahydro-1H-carbazole-3-αmin (12.51 mg, 26.23 µmol, 9.8% yield, 100% purity, HCl, or [a] ^{22 ,4} D = +9.972, (MeOH, c = 0.071 g/100 ml)) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.24 (d, J=8.1 Hz, 1H), 8.09 (d, J=10.3 Hz, 1H), 7.95 (s, 1H ), 7.45 (dt, J=5.9, 7.9 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.26 (d, J=7.8 Hz , 1H), 7.20 (dt, J=2.1, 8.3 Hz, 1H), 7.02 (t, J=7.2 Hz, 1H), 6.97-6.91 (m, 1H), 4.89-4.85 (m, 1H), 3.28-3.23 (m, 1H), 3.08-2.87 (m, 3H), 2.43-2.33 ( m, 1H), 2.30-2.19 (m, 1H), 1.39 (d, J=6.8 Hz, 6H); ER-LCMS m/z 441.3 [M+H] ⁺ .

Example 111.

Synthesis of I-122

- 228 041983

Synthesis scheme:

Stage 1: ethyl N-(1H-pyrazol-5-ylcarbamothioyl)carbamate

To a suspension of 3H-pyrazole-3-amine (15.84 g, 190.62 mmol, 1 eq.) in DCM (160 ml) was added ethoxycarbonyl isothiocyanate (25 g, 190.62 mmol, 22.52 ml, 1 eq.) at 0°C. The mixture was stirred at 25°C for 12 hours under N2. The mixture was filtered. The filter residue was washed with DCM (20 mL x 2), dried to give ethyl N-(1H-pyrazol-5-ylcarbamothioyl)carbamate (26 g, 109.22 mmol, 57.3% yield, 90% purity) as a white solid colors.

¹ H NMR (400 MHz, CD3OD) δ ppm 7.59 (d, J=2.2 Hz, 1H), 7.12 (s, 1H), 4.27 (q, J=7.2 Hz, 2H ), 1.34 (t, J=7.1 Hz, 3H); ER-LCMS m/z 215.1 [M+H]+.

Step 2: 2-thioxo-1H-pyrazolo[1,5-a][1,3,5]triazin-4-one

K ₂ CO ₃ (44.42 g, 321, 36 mmol, 3 eq.). The mixture was stirred at 85° C. for 4 hours. The mixture was diluted with water (100 ml) and the pH was adjusted to 5-6 with 2N HCl HCl. The solvents were evaporated and the residue was suspended in water (600 ml). The solid was filtered off, washed with water (60 mL×2), dried to give 2-thioxo-1H-pyrazolo[1,5-a][1,3,5]triazin-4-one (16 g, 90.38 mmol, yield 84.4%, 95% pure) as a white solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 7.83 (s, 1H), 5.93 (d, J=1.7 Hz, 1H); ER-LCMS m/z 169.1 [M+H] ⁺ .

Step 3: 2-Methylsulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

NaOH ( 7.23 g, 180.76 mmol, 2 eq.) in H2O (9.6 ml), MeI (15.96 g, 112.44 mmol, 7.0 ml, 1.24 eq.) was added dropwise. The mixture was stirred at 15° C. for 1 hour. The mixture was acidified with 1 N hydrochloric acid. water. HCl (80 ml) and evaporated with EtOH. The mixture was filtered, washed with H ₂ O (50 mlx2). The filter cake was dried to give 2-methylsulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (16 g, 83.42 mmol, 92.3% yield, 95% purity ) as a white solid.

- 229 041983

1H NMR (400 MHz, CD3OD) δ ppm 7.74 (d, J=2.0 Hz, 1H), 5.99 (d, J=2.2 Hz, 1H), 2.48 (s, 3H) ; ERJHMS m/z 183.2 [M+H] ⁺ .

Stage 4: 8-bromo-2-methylsulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

To a solution of 2-methylsulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (3.0 g, 15.64 mmol, 1 eq.) in DMF (30 ml) was added NBS (2.51 g, 14.08 mmol, 0.9 eq.). The mixture was stirred at 15° C. for 0.5 h. The mixture was concentrated to give 8-bromo-2-methylsulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (4 g , 12.26 mmol, 78.4% yield, 80% purity) as a green oil.

1 H NMR (400 MHz, CD3OD) δ ppm 7.72 (s, 1H), 2.49 (s, 3H); ER-LCMS m/z 261.0, 263.0 [M+H] ⁺ .

Step 5: 8-bromo-4-chloro-2-methylsulfanyl-pyrazolo[1,5-a][1,3,5]triazine

Suspension of 8-bromo-2-methylsulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (2.0 g, 6.13 mmol, 1 eq) and N,N -dimethylaniline (742.58 mg, 6.13 mmol, 776.76 μl, 1 eq.) in POCl ₃ (16.50 g, 107.61 mmol, 10 ml, 17.56 eq.) was stirred at 130°C for 4 h. The mixture was added to water (100 ml) at 0°C, extracted with EtOAc (200 mlx3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc = 3/1, TLC: PE/EtOAc = 3/1, R _f = 0.8) to give 8-bromo-4-chloro-2 -methylsulfanyl-pyrazolo[1,5-a][1,3,5]triazine (600 mg, 2.08 mmol, 33.9% yield, 97% purity) as a white solid.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm 8.12 (s, 1H), 2.66 (s, 3H); ER-LCMS m/z 278.9, 280.9 [M+H]+.

Step 6: (3R)-N-(8-bromo-2-methylsulfanyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)-2,3,4,9 tetrahydro-1 N-carbazole-3-amine

To a solution of 8-bromo-4-chloro-2-methylsulfanyl-pyrazolo[1,5-a][1,3,5]triazine (600 mg, 2.08 mmol, 1 eq.) in i-PrOH (12 ml ) DIEA (807.22 mg, 6.25 mmol, 1.09 ml, 3 eq.) and (3R)-2,3,4,9-tetrahydro1H-carbazole-3-amine (426.55 mg, 2 .29 mmol, 1.10 eq.). The mixture was stirred at 50°C for 2 hours. The mixture was concentrated, extracted with EtOAc (60 mlx3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give (3R)-N-(8bromo-2-methylsulfanyl-pyrazolo[1,5-a][1,3,5 ]triazin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (800 mg, 1.68 mmol, 80.6% yield, 90% purity) as a yellow solid .

1 H NMR (400 MHz, CDCl ₃ ) δ ppm 7.86-7.80 (m, 2H), 7.45 (d, J=7.6 Hz, 1H), 7.32 (d, J=8, 1 Hz, 1H), 7.17 (t, J=6.8 Hz, 1H), 7.13-7.07 (m, 1H), 6.59 (d, J=8.3 Hz, 1H) , 4.82-4.78 (m, 1H), 3.31-3.26 (m, 1H), 2.99-2.84 (m, 3H), 2.61 (s, 3H), 2 .30-2.20 (m, 2H); ER-LCMS m/z 429.1, 431.1 [M+H] ⁺ .

Step 7: (3R)-N-(8-isopropenyl-2-methylsulfanyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)-2,3,4,9 tetrahydro-1 N-carbazole-3-amine

To a mixture of (3R)-N-(8-bromo-2-methylsulfanyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)-2,3,4,9-tetrahydroIII-carbazole -3-amine (400 mg, 838.50 µmol, 1 eq.), Pd(dppf)Cl ₂ (61.35 mg, 83.85 µmol, 0.1 eq.), Cs ₂ CO ₃ (683.00 mg, 2.10 mmol, 2.5 eq.) in 1,4-dioxane (10 ml) and H ₂ O (2.5 ml) was added 2-isopropenyl4,4,5,5-tetramethyl-1,3, 2-dioxaborolane (704.51 mg, 4.19 mmol, 5 eq) under N2. The mixture was stirred at 110° C. for 1.5 h under N2 while being treated with microwave radiation. The combined reaction mixture was concentrated, extracted with EtOAc (50 mlx3). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc = 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.46) to give (3R)-N-(8-isopropenyl -2-methylsulfanylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (250 mg, 550.57 µmol , yield 65.6%, purity 86%) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm 7.87 (s, 1H), 7.81 (s, 1H), 7.45 (d, J=7.8 Hz 1H), 7.32 (d, J =7.8Hz, 1H), 7.17(t, J=7.5Hz, 1H), 7.13-7.08(m, 1H), 6.57(d, J=8.6Hz , 1H), 5.86 (s, 1H), 5.06 (s, 1H), 4.82-4.77 (m, 1H), 3.29 (dd, J=4.8, 15.5 Hz, 1H), 2.99-2.82 (m, 3H), 2.58 (s, 3H), 2.32-2.23 (m, 2H), 2.21 (s, 3H); ER-LCMS m/z 391.2 [M+H]+.

Step 8: (3R)-N-(8-isopropyl-2-methylsulfanyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)-2,3,4,9tetrahydro-1 H -carbazole-3-amine (I-122)

To a mixture of (3R)-N-(8-isopropenyl-2-methylsulfanyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)-2,3,4,9tetrahydro-1H-carbazole -3-amine (100 mg, 220.23 µmol, 1 eq.) in EtOAc (12 ml) was added PtO ₂ (250 mg, 1.10 mmol, 5.00 eq.) under N 2 atmosphere. The mixture was stirred at 15°C for 20 min under H ₂ (15 psi). The mixture was filtered. The filtrate was concentrated. The residue was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 70% 100%, 8 min) followed by lyophilization to give (3R) -N-(8-isopropyl-2-methylsulfanylpyrazolo[1,5-а][1,3,5]triazin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-amine ( 50 mg, 116.56 µmol, 52.9% yield, 100% purity, HCl) as a white solid.

1H NMR (400 MHz, CD3OD) δ ppm 7.90 (s, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.26 (d, J=7.6 Hz, 1H) , 7.08-7.00 (m, 1H), 6.96 (t, J=7.3 Hz, 1H), 4.73-4.68 (m, 1H), 3.23 (dd, J =4.9, 14.7 Hz, 1H), 3.14-3.11 (m, 1H), 2.95 (s, 2H), 2.91-2.82 (m, 1H), 2, 58 (s, 3H), 2.30 (s, 1H), 2.21 (d, J=6.4 Hz, 1H), 1.33 (d, J=6.8 Hz, 6H); ER-LCMS m/z 393.2 [M+H] ⁺ .

Example 112.

Synthesis of I-123

1-123

Synthesis scheme:

1-123

- 231 041983

Step 1: (3R)-N-[8-(cyclohexen-1-yl)-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazine-4- yl]2,3,4,9-tetrahydro-1 H-carbazole-3-amine

(3R)-N-[8-bromo-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4 mixture ,9-tetrahydro1H-carbazole-3-amine (200 mg, 408.10 µmol, 1 eq.), 2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane ( 84.94 mg, 408.10 µmol, 87.75 µl, 1 eq.), Pd(dppf)Cl ₂ (29.87 mg, 40.81 µmol, 0.1 eq.), Cs ₂ CO ₃ (332 .47 mg, 1.02 mmol, 2.5 eq.) in H ₂ O (2 ml) and 1,4-dioxane (6 ml) was degassed and purged with N ₂ 3 times, the mixture was stirred at 90°C for 2 h in N ₂ atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EA = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, R _f =0, 7) to give (3R)-N-[8-(cyclohexen-1-yl)-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazine-4 -yl]-2,3,4,9tetrahydro-1H-carbazole-3-amine (110 mg, 193.83 µmol, 47.5% yield, 84.5% purity) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (s, 1H), 9.38 (s, 1H), 9.08 (d, J=8.6 Hz, 1H), 8.79- 8.66 (m, 1H), 8.48-8.37 (m, 1H), 8.28 (s, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.05-6.97 (m, 1H), 6.966.88 (m, 1H), 6.73 (br s, 1H), 4.84- 4.82 (m, 1H), 3.64 (s, 2H), 3.12 (dd, J=5.1, 14.9 Hz, 1H), 3.07-2.83 (m, 3H) , 2.24-2.15 (m, 4H), 1.77-1.75 (m, 2H), 1.67-1.65 (m, 2H); ER-LCMS m/z 480.3 [M+H]+.

Step 2: (3R)-N-[8-cyclohexyl-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2.3 ,4,9tetrahydro- 1 H-carbazole-3-amine (I-123) hn ^v _n <S _n ^n

Yj ^N AN \ )

To a solution of (3R)-N-[8-(cyclohexen-1-yl)-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-а][1,3,5]triazin-4-yl ]2,3,4,9-tetrahydro-1H-carbazole-3-amine (90 mg, 158.59 µmol, 1 eq.) in EtOAc (5 mL) Pd/C (50 mg, 10% purity) was added to N ₂ atmosphere. The suspension was degassed several times and purged with H2. The mixture was stirred in H ₂ (15 psi) at 10° C. for 12 hours. The reaction mixture was filtered and the filtrate was concentrated to give a residue which was purified by preparative HPLC (HCl conditions; column: Agela ASB 150x25 mmx5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 85%-100%, 8 min) followed by lyophilization to give (3R)-N-[8-cyclohexyl-2-(5-fluoro-3- pyridyl)pyrazolo[1,5a][1,3,5]triazin-4-yl]-2,3,4,9-tetrahydro-1H-carbazole-3-amine (16.46 mg, 28.78 µmol, 18.2% yield, 96.9% purity, 2HC1, or [a] ^24.6 D = 9.235 (7.5 mg/10 ml in MeOH)) as yellow solid (Optical rotation: [a] ²⁵ D = 9.235 (7.5 mg/10 ml in MeOH)).

1H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (s, 1H), 9.37 (s, 1H), 9.02 (d, J=8.6 Hz, 1H), 8.70 ( d, J=2.7 Hz, 1H), 8.44 (dd, J=1.6, 9.9 Hz, 1H), 8.13 (s, 1H), 7.34 (d, J=7 .6 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.07-6.97 (m, 1H), 6.96-6.88 (m, 1H), 4 .90-4.75 (m, 1H), 3.15-3.07 (m, 1H), 3.05-2.80 (m, 4H), 2.20-2.19 (m, 2H) , 1.82-1.79 (m, 2H), 1.87-1.69 (m, 3H), 1.62-1.59 (m, 2H), 1.44-1.41 (m, 2H), 1.31-1.22 (m, 1H); ER-LCMS m/z 482.3 [M+H] ⁺ .

Example 113.

Synthesis of I-124

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Synthesis scheme:

Step 1: 3-Methylpyrazolo[1,5-a]pyrimidine-5,7-diol

To a solution of 4-methyl-1H-pyrazol-5-amine (2 g, 20.59 mmol, 1 eq.) and dimethyl propanedioate (2.86 g, 21.62 mmol, 2.48 ml, 1.05 eq.) in MeOH (20 ml) was added a solution of Na (946.88 mg, 41.19 mmol, 976.16 μl, 2.0 eq.) in MeOH (20 ml) under N2 at 20°C. The mixture was stirred at 80° C. for 12 hours. The reaction mixture was cooled to 20° C., filtered and a white solid was collected. The solid was diluted with 1N. HCl (20 mL) and stirred for 10 min, filtered and the solid dried under reduced pressure to give the product 3-methylpyrazolo[1,5-a]pyrimidine-5,7-diol (2 g, 12.11 mmol, yield 58.8%, crude purity) as a white solid, which was used in the next step without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.54 (br s, 1H), 7.31 (s, 1H), 4.21 (br s, 1H), 1.96 (s , 3H).

Stage 2: 5,7-dichloro-3-methyl-pyrazolo[1,5-a]pyrimidine

A solution of 3-methylpyrazolo[1,5-a]pyrimidine-5,7-diol (500 mg, 3.03 mmol, 1 eq.) in POCl ₃ (5 ml) was stirred at 110°C for 3 hours. The reaction mixture concentrated under reduced pressure. The residue was diluted with DCM (20 mlx2) and concentrated under reduced pressure. The residue was diluted with DCM (20 ml), the pH was adjusted to 9-10 with DIEA and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 10/1, Rf = 0.68) to give the product 5,7-dichloro-3-methyl-pyrazolo[1,5a]pyrimidine (400 mg, 1.98 mmol, 65.3% yield, purity 99.8%) as a white solid.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm 8.09 (s, 1H), 6.93 (s, 1H), 2.37 (s, 3H); ER-LCMS m/z 202.0, 204.0 [M+H]+.

Stage 3: 5-chloro-7-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine

Cl

5,7-dichloro-3-methyl-pyrazolo[1,5-a]pyrimidine (190 mg, 938.52 µmol, 1 eq.), (5-fluoro-3-pyridyl)boronic acid (138.86 mg, 985, 45 µmol, 1.05 eq.), Pd(dppf)Cl ₂ (68.67 mg, 93.85 µmol, 0.1 eq.) and Cs ₂ CO ₃ (611.58 mg, 1.88 mmol, 2 equiv.) were placed in a tube with microwave radiation in 1,4dioxane (3 ml) and H ₂ O (1 ml). The sealed tube was heated at 110° C. for 1 hour while being treated with microwave radiation. The mixture was concentrated and water (10 ml) was added. The mixture was subjected to extraction with EtOAc (20 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC: PE/EtOAc = 3/1, Rf = 0.50) to give 5-chloro-7-(5-fluoro-3-pyridyl)-3methyl-pyrazolo[1,5-a]pyrimidine (130 mg, 494.92 µmol, 52.7% yield, purity 100.0%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.97 (s, 1H), 8.69 (d, J=2.7 Hz, 1H), 8.38-8.31 (m, 1H), 8 .04 (s, 1H),

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6.92 (s, 1H), 2.40 (s, 3H); ER-LCMS m/z 263.0, 265.0 [M+H] ⁺ .

Step 4: 7-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-3-methyl-pyrazolo[1,5-a]pyrimidin-5-amine ( I-124)

5-chloro-7-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (70 mg, 266.49 µmol, 1 eq), 2(1H-indole-3 -yl)ethanamine (64.04 mg, 399.74 µmol, 1.5 eq.) and DIEA (103.33 mg, 799.48 µmol, 139.26 µl, 3 eq.) were placed in a microwave tube in i-PrOH (2 ml). The sealed tube was heated at 150° C. for 3 hours while being treated with microwave radiation. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela Durashell C18 150x25 5u; mobile phase: [water (0.05% HCl)-ACN]; B%: 32%-55%, 9 min) followed by lyophilization to give 7-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3yl)ethyl]-3-methyl-pyrazolo[1,5-a]pyrimidine-5 -amine (28.21 mg, 59.77 µmol, 22.4% yield, 97.3% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD+Na2CO3) δ ppm 8.80 (br s, 1H), 8.62 (d, J=2.7 Hz, 1H), 8.18 (br s, 1H), 7.74-7.65 (m, 2H), 7.31 (d, J=8.1 Hz, 1H), 7.12-7.04 (m, 2H), 7.03-6.97 ( m, 1H), 6.27 (br s, 1H), 3.78 (t, J=7.2 Hz, 2H), 3.11 (t, J=7.3 Hz, 2H), 2, 24 (s, 3H); ER-LCMS m/z 387.1 [M+H] ⁺ .

Example 114.

Synthesis of I-125

Synthesis scheme:

Stage 1: 5-fluoro-N-(1H-imidazol-2-yl)pyridine-3-carboxamidine

To a mixture of ethyl 5-fluoropyridine-3-carboximidate (1 g, 5.65 mmol, 1 eq.) and 1H-imidazole-2-amine (563.27 mg, 6.78 mmol, 1.2 eq.) in ACN (15 ml) was added AcONa (926.84 mg, 11.30 mmol, 2 eq.). The mixture was stirred at 80° C. for 25 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 2/1, TLC: PE/EtOAc = 2/1, Rf = 0.35) to give 5-fluoro-N-(1H-imidazol-2yl)pyridine-3-carboxamidine (400 mg, 1.75 mmol, 31.1% yield, 90.0% purity) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.67 (br s, 1H), 9.97 (br s, 1H), 9.05 (s, 1H), 8.70 (d, J=2.4Hz, 1H), 8.29-8.12(m, 2H), 6.92(s, 1H), 6.85(s, 1H); ER-LCMS m/z 206.1 [M+H]+.

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Step 2: 2-(5-fluoro-3-pyridyl)imidazo[1,2-a][1,3,5]triazin-4-ol

To a solution of 5-fluoro-N-(1H-imidazol-2-yl)pyridine-3-carboxamidine (400 mg, 1.75 mmol, 1 eq.) in THF (5 ml) and 1,4-dioxane (5 ml ) diphosgene (694.18 mg, 3.51 mmol, 423.28 µl, 2 eq.) was added. The mixture was stirred at 80° C. for 2 hours under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was washed with DMF (5 ml), filtered and concentrated to give 2-(5-fluoro-3-pyridyl)imidazo[1,2-a][1,3,5]triazine -4-ol (250 mg, 973.24 µmol, 55.5% yield, 90.0% purity) as a white solid, which was used in the next step without further purification.

1H NMR (400 MHz, DMSO-d6) δ ppm 13.64 (broad s, 1H), 9.29 (s, 1H), 8.78 (d, J=2.7 Hz, 1H), 8, 35 (J=10.0 Hz, 1H), 7.73-7.65 (m, 2H); ER-LCMS m/z 232.0 [M+H]+.

Stage 3: 4-chloro-2-(5-fluoro-3-pyridyl)imidazo[1,2-a][1,3,5]triazine

To a solution of 2-(5-fluoro-3-pyridyl)imidazo[1,2-a][1,3,5]triazin-4-ol (100 mg, 389.30 µmol, 1 eq.) in POCl ₃ ( 12 ml) was added DIEA (1.48 g, 11.48 mmol, 2 ml, 29.49 eq.). The mixture was stirred at 120° C. for 3 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give 4chloro-2-(5-fluoro-3-pyridyl)imidazo[1,2-a][1,3,5]triazine (90 mg, 360.53 µmol, 92.6 yield %, crude) as a black solid, which was used in the next step without further purification. ER-LCMS m/z 350.1 [M+H]+.

Step 4: (3R)-N-[2-(5-fluoro-3-pyridyl)imidazo[1,2-a][1,3,5]triazin-4-yl]-2,3,4,9 -tetrahydro-1Hcarbazole-3-amine (I-125)

To a mixture of 4-chloro-2-(5-fluoro-3-pyridyl)imidazo[1,2-a][1,3,5]triazine (90 mg, 360.53 µmol, 1 eq.) and (3R) -2,3,4,9-tetrahydro-1H-carbazole-3-amine (80.58 mg, 432.64 µmol, 1.2 eq.) in ACN (10 ml) was added DIEA (5.34 g, 41 .34 mmol, 7.20 ml, 114.65 eq.). The mixture was stirred at 80° C. for 2 hours under N ₂ atmosphere. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC (column: Agela DuraShell 150 mm x 25 mm x 5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 23%-53%, 8, 5 min) followed by lyophilization to give a product which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN]; B%: 40%-70%, 8 min) followed by lyophilization to give (3R)-N-[2(5-fluoro-3-pyridyl)imidazo[1,2-a][1,3,5]triazine-4- yl]-2,3,4,9-tetrahydro-1H-carbazole-3-amine (15.11 mg, 37.83 µmol, 10.5% yield, 100.0% purity, [a] ²⁴ D = 98 .97 (MeOH, c = 0.050 g/100 ml)) as a yellow solid.

Ή NMR (400 MHz, CD3OD) δ ppm 9.39 (s, 1H), 8.55-8.47 (m, 2H), 7.93 (d, J=1.7 Hz, 1H), 7, 56 (s, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.05-6.98 (m, 1H ), 6.97-6.90 (m, 1H), 4.85-4.79 (m, 1H), 3.36 (J=5.1 Hz, 1H), 3.08-2.83 ( m, 3H), 2.44 (J=9.8 Hz, 1H), 2.26-2.14 (m, 1H); ER-LCMS m/z 400.2 [M+H] ⁺ .

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Example 115.

Synthesis I-126

DIEA (193.84 mg, 1.50 mmol, 261.24 µl, 3 eq.) and (3R)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (93.11 mg, 499.94 µmol, 1 eq.). The mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc=100/1 to 1/1, TLC: PE/EtOAc=1/ 1, Rf = 0.5) to give (3R)N-(2-chloropyrido[3,2-d]pyrimidin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (150 mg, 428.80 µmol, 85.8% yield, 100.0% purity) as a yellow solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 8.72 (dd, J=1.5, 4.4 Hz, 1H), 7.95 (dd, J=1.5, 8.3 Hz, 1H ), 7.75 (dd, J=4.2, 8.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 7.26 (d, J=8.1Hz , 1H), 7.07-7.00 (m, 1H), 6.98-6.92 (m, 1H), 4.804.68 (m, 1H), 3.21 (dd, J=5.1 , 15.2 Hz, 1H), 3.06-2.80 (m, 3H), 2.37-2.12 (m, 2H); ER-LCMS m/z 350.1 [M+H]+.

Step 2: (3R)-N-[2-(5-fluoro-3-pyridyl)pyrido[3,2-d]pyrimidin-4-yl]-2,3,4,9-tetrahydro-1Hcarbazole-3- amine (I-126)

(3R)-N-(2-chloropyrido[3,2-d]pyrimidin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (60 mg, 171.52 µmol, 1 eq.), (5-fluoro-3-pyridyl)boronic acid (29.00 mg, 205.82 µmol, 1.2 eq.), Pd(dppf)Cl ₂ (12.55 mg, 17.15 µmol , 0.1 eq.) and Cs ₂ CO ₃ (167.65 mg, 514.56 µmol, 3 eq.) were placed in a microwave tube in 1,4-dioxane (2 ml) and H ₂ O (0. 5 ml). The sealed tube was heated at 110° C. for 0.5 h while being treated with microwave radiation. The reaction mixture was diluted with water (5 ml) and extracted with EtOAc (10 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN] ; V%: 55%-85%, 8 min) followed by lyophilization to give (3R)-N-[2-(5-fluoro-3-pyridyl)pyrido[3,2d]pyrimidin-4-yl]-2 ,3,4,9-tetrahydro-1H-carbazole-3-amine (39.09 mg, 95.24 µmol, 55.5% yield, 100.0% purity, or [a] ^23.6 _D = 0.471 ( MeOH, c = 0.110 g / 100 ml).) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.32 (s, 1H), 9.01 (dd, J=1.2, 4.4 Hz, 1H), 8.83 (d, J=2.4 Hz, 1H), 8.61-8.49 (m, 1H), 8.32 (dd, J=1.2, 8.6 Hz, 1H), 8.04 (dd, J=4.4, 8.6 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 6.98 (t, J=7, 5 Hz, 1H), 6.91-6.81 (m, 1H), 5.22-5.04 (m, 1H), 3.28 (s, 1H), 3.12-2.86 (m , 3Н),

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2.43-2.27 (m, 2H); ER-LCMS m/z 411.2 [M+H]+.

Example 116.

Synthesis of I-128a

Synthesis scheme:

(6S)-N6-[2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-а][1,3,5]triazin-4-yl]-4,5,6 ,7 Stage 1:

tetrahydro-1,3-benzothiazole-2,6-diamine (I- 128а)

4-Chloro-2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine mixture (70 mg, 236.12 µmol, 1 eq.) , (6S)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine (43.96 mg, 259.74 µmol, 1.1 eq) and DIEA (91.55 mg , 708.37 µmol, 123.39 µl, 3 eq) in i-PrOH (10 ml) was stirred at 80°C for 2 h. The mixture was concentrated under reduced pressure to give a residue which was washed with MeOH (20 mlx2), obtaining (6S)-N6-[2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-4.5, 6,7tetrahydro-1,3-benzothiazole-2,6-diamine (22.62 mg, 53.29 µmol, 22.6% yield, 100.0% purity, SFC: Rt = 5.691 min, ee = 99.8 %, or [a] ^21.9 _D = -34.176 (CHCl ₃ , c = 0.104 g / 100 ml)) as a white solid.

Ή NMR (400 MHz, DMSO) δ ppm 9.37 (s, 1H), 8.97 (broad s, 1H), 8.71 (d, J=2.8 Hz, 1H), 8.44 ( d, J=10.0 Hz, 1H), 8.13 (s, 1H), 6.72 (s, 2H), 4.75-4.72 (m, 1H), 3.49-3.19 (m, 1H), 2.90-2.83 (m, 2H), 2.65-2.58 (m, 1H), 2.54-2.50 (m, 1H), 2.09-2 .05 (m, 2H), 1.36 (d, J=6.8 Hz, 6H); ER-LCMS m/z 425.2 [M+H]+

Example 117.

Synthesis of I-128b

Synthesis scheme:

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Step 1: (6R)-N6-[2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-4, 5,6,7tetrahydro-1,3-benzothiazole-2,6-diamine (I-128b)

4-Chloro-2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine mixture (70 mg, 236.12 µmol, 1 eq.) , (6R)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine (43.96 mg, 259.74 µmol, 1.1 eq) and DIEA (91.55 mg , 708.37 µmol, 123.38 µl, 3 eq.) in i-PrOH (10 ml) was stirred at 80°C for 2 h. The mixture was concentrated under reduced pressure to give a residue which was washed with MeOH (20 mlx2), obtaining (6R)-N6-[2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-4.5, 6,7tetrahydro-1,3-benzothiazole-2,6-diamine (20.56 mg, 48.43 µmol, 20.5% yield, 100.0% purity, SFC: Rt = 7.228 min, ee = 98.44 %, or [a] ^22.1 D = 29.753 (CHCl ₃ , c = 0.100 g/100 ml)) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.37 (s, 1H), 8.97 (d, J=8.4 Hz, 1H), 8.71 (d, J=2.8 Hz , 1H), 8.468.42 (m, 1H), 8.13 (s, 1H), 6.72 (s, 2H), 4.77-4.72 (m, 1H), 3.23-3, 17 (m, 1H), 2.90-2.83 (m, 2H), 2.67-2.64 (m, 1H), 2.58-2.53 (m, 1H), 2.07- 2.05 (m, 2H), 1.36 (d, J=6.8 Hz, 6H); ER-LCMS m/z 425.2 [M+H] ⁺ .

Example 118.

Synthesis I-129

Step 1: N-[4-(dimethylamino)-1H-pyrazol-5-yl]-5-fluoro-pyridine-3-carboxamidine

Ethyl 5-fluoropyridine-3-carboximidate (1.11 g, 6.27 mmol, 1 eq.). The mixture was stirred at 60°C for 12 hours under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (DCM/MeOH=1/0 to 5/1, TLC: DCM/MeOH=10/1, Rf=0.3) to give N-[4-(dimethylamino)-1H-pyrazol5-yl]-5-fluoro-pyridine-3-carboxamidine (700 mg, 2.52 mmol, 40.2% yield, 89.5% purity) as a solid yellow color.

1H NMR (400 MHz, DMSO^) δ ppm 11.96 (br s, 1H), 9.07 (s, 1H), 8.66 (d, J=2.0 Hz, 1H), 8.17 (d, J=10.0 Hz, 1H), 7.18 (s, 1H), 2.72 (bd s, 6H); ER-LCMS m/z 248.9 [M+H]+.

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Step 2: 2-8-(dimethylamino)-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-ol

To a solution of N-[4-(dimethylamino)-1H-n-pyrazol-5-yl]-5-fluoro-pyridine-3-carboxamidine (160 mg, 576.82 µmol, 1 eq.) in THF (1 ml) and toluene (8 ml) diphosgene (342.34 mg, 1.73 mmol, 208.74 μl, 3 eq.) was added under N2 at 15°C, the mixture was stirred at 15°C for 0.5 h. The mixture was then stirred at 130°C for 2 h in an atmosphere of N ₂ . The reaction mixture was concentrated under reduced pressure to give 8-(dimethylamino)-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-ol (150 mg, crude ) as a yellow solid, which was used in the next step without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.15 (s, 1H), 9.07 (s, 1H), 8.92 (d, J=2.3 Hz, 1H), 8, 79 (d, J=2.8 Hz, 1H), 8.03 (s, 1H), 3.03 (s, 6H); ER-LCMS m/z 275.1 [M+H]+.

Stage 3 4-chloro-2-(5-fluoro-3-pyridyl)-N,N-dimethyl-pyrazolo[1,5-a][1,3,5]triazine-8-amine

A mixture of 8-(dimethylamino)-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-ol (150 mg, 546.94 µmol, 1 eq. ) in POCl ₃ (9 g, 58.70 mmol, 5.45 ml, 107.32 eq.) was degassed and purged with N ₂ 3 times, stirred at 120° C. for 1 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was quenched by the addition of water (50 ml), the pH was adjusted to 8 with aq. NaHCO ₃ was extracted with EtOAc (30 mlx3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 3/1 , TLC: PE/EtOAc=3/1, Rf=0.31) to give 4-chloro-2-(5-fluoro-3-pyridyl)-N,N-dimethyl-pyrazolo[1,5-a][1, 3,5]triazine-8-amine (25 mg, 76.87 µmol, 14.0% yield, 90% purity) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.35 (s, 1H), 8.51 (broad s, 1H), 8.27 (d, J=8.8 Hz, 1H), 7.85 (s, 1H), 3.05 (s, 6H); ER-LCMS m/z 293.1, 295.0 [M+H] ⁺ .

Step 4: 2-(5-fluoro-3-piridyl)-N8,N8-dimethyl-N4-[(3R)-2,3,4,9-metrahydro-1H-carbazol-3yl]pyrazolo[1,5- a][1,3,5]triazine-4,8-diamine (I-129)

To a solution of 4-chloro-2-(5-fluoro-3-pyridyl)-N,N-dimethyl-pyrazolo[1,5-a][1,3,5]triazine-8-amine (25 mg, 76, 87 µmol, 1 eq.) in i-PrOH (3 ml) was added (3R)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (17.18 mg, 92.24 µmol, 1, 2 eq.). The mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 μm; mobile phase: [water (0.05% HCl)-ACN]; B %: 38%-68%, 8 min) twice followed by lyophilization to give 2-(5-fluoro-3-pyridyl)-N8,N8-dimethyl-N4-[(3R)-2,3,4,9- tetrahydro-1Hcarbazol-3-yl]pyrazolo[1,5-a][1,3,5]triazine-4,8-diamine (34.45 mg, 62.30 µmol, 81.0% yield, 99 purity, 8%, 3HCl, [a] ^20.6 _D = +36.080 (MeOH, c = 0.1 g/100 ml)) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.51 (br s, 1H), 8.74 (m, 2H), 8.42 (br s, 1H), 7.37 (d, J=7 .8 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H), 6.99-6.92 (m, 1H ), 5.00-4.92 (m, 1H), 3.53 (br s, 6H), 3.28-2.89 (m, 4H), 2.44-2.23 (m, 2H ); ER-LCMS m/z 443.2 [M+H] ⁺ .

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Example 119.

Synthesis of I-130

Stage 1: tert-butyl (3R)-3-[[8-bromo-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl] tert-butoxycarbonyl-amino]-1,2,3,4-tetrahydrocarbazole-9-carboxylate

(3R)-N-[8-bromo-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4 mixture ,9-tetrahydro1H-carbazole-3-amine (560 mg, 1.09 mmol, 1 eq.), Boc ₂ O (1.43 g, 6.57 mmol, 1.51 ml, 6 eq.) and DMAP ( 534.93 mg, 4.38 mmol, 4 eq.) in 1,4-dioxane (50 ml) was stirred at 110°C for 12 h. TLC (PE/EtOAc = 5/1, Rf = 0.65) showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 10/1, TLC: PE/EtOAc = 5/1, Rf = 0.65), obtaining tert-butyl (3R)-3-[[8-bromo-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-tert-butoxycarbonyl -amino]-1,2,3,4-tetrahydrocarbazole-9-carboxylate (660 mg, 972.66 µmol, 88.9% yield, 100.0% purity) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.49 (s, 1H), 8.60 (d, J=2.8 Hz, 1H), 8.44 (d, J=8.4 Hz, 1H ), 8.23 (s, 1H), 8.10 (d, J=8.4Hz, 1H), 7.33 (d, J=7.8Hz, 1H), 7.22-7.16 (m, 2H), 4.92 (br s, 1H), 3.34 (d, J=16.8 Hz, 1H), 3.25-3.11 (m, 3H), 2.50 ( m, 1H), 2.33 (m, 1H), 1.67 (s, 9H), 1.39 (s, 9H); ER-LCMS m/z 678.2, 680.2 [M+H]+.

Step 2: 2-(5-fluoro-3-pyridyl)-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1,5a] [ 1,3,5]triazine-8-carbonitrile (I-130)

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A mixture of tert-butyl (3R)-3-[[8-bromo-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-tert-butoxycarbonyl -amino]-1,2,3,4-tetrahydrocarbazole-9-carboxylate (50 mg, 72.36 µmol, 1 eq.), Zn(CN) ₂ (33.99 mg, 289.44 µmol, 18.37 μl, 4 eq.) and Pd(PPh ₃ ) ₄ (16.72 mg, 14.47 μmol, 0.2 eq.) in DMF (3 ml) were placed in a microwave tube and then purged with N2 for 1 min. The sealed tube was stirred at 170° C. for 20 minutes while being treated with microwave radiation (1 bar). The reaction mixture was subjected to extraction with EtOAc (20 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 μm; mobile phase: [water (0.05% HCl)-ACN]; B% : 55%-85%, 8 min) followed by lyophilization to give 2-(5-fluoro3-pyridyl)-4-[[(3R)-2,3,4,9-tetrahydro-III-carbazol-3-yl ]amino]pyrazolo[1,5-a][1,3,5]triazine-8carbonitrile (15.36 mg, 29.98 µmol, 41.4% yield, 97.1% purity, 2HCl, [a] ¹⁸¹ D = 45.287, (MeOH, c = 0.078 g/100 ml)) as a yellow solid.

Ή NMR (400 MHz, CD3OD) δ ppm 9.48 (s, 1H), 8.80-8.71 (m, 2H), 8.43 (s, 1H), 7.32 (d, J=7 .6 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 7.00 (t, J=7.5 Hz, 1H), 6.94-6.88 (m, 1H ), 4.83 (m, 1H), 3.26 (m, 1H), 3.08-2.88 (m, 3H), 2.37-2.35 (m, 1H), 2.31- 2.18 (m, 1H); ER-LCMS m/z 425.2 [M+H]+.

Example 120.

Synthesis I-131

Step 1: N-(2-(1H-indol-3-yl)ethyl)-8-(tert-butyl)-2-(5-fluoropyridin-3-yl)pyrazolo[1.5a][1.3, 5]triazine-4-amine (I-131)

To a solution of 8-tert-butyl-4-chloro-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazine (60 mg, 176.62 µmol, 1 eq. .) in i-PrOH (3 ml) was added 2-(1H-indol-3-yl)ethanamine (29.43 mg, 183.68 µmol, 1.04 eq.) and DIPEA (114.13 mg, 883, 10 µmol, 153.82 µl, 5 eq.). The reaction mixture was stirred at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela Durashell C18 150x25 5u; mobile phase: [water (0.05% HCl)- ACN]; B%: 75%-95%, 8 min) followed by lyophilization to give 8-tert-butyl-2(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl )ethyl]pyrazolo[ 1,5-a] [ 1,3,5]triazine-4-amine (27.49 mg, 54.18 µmol, 30.7% yield, 99.0% purity, 2HCl) as yellow solid.

Ή NMR (400 MHz, CD3OD) δ ppm 9.13 (s, 1H), 8.80 (s, 1H), 8.55 (d, J=8.6 Hz, 1H), 7.95 (s, 1H), 7.697.62 (m, 1H), 7.19-7.12 (m, 1H), 7.01-6.93 (m, 3H), 4.02 (J=6.7 Hz, 2H ), 3.16 (t, J=6.7 Hz, 2H), 1.48 (s, 9H); ER-LCMS m/z 430.3 [M+H]+.

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Synthesis of I-132

Synthesis scheme:

Step 1: (Z)-N'-(4-(tert-butyl)-1H-pyrazol-5-yl)-5-fluoronicotinimide

To a solution of ethyl 5-fluoropyridine-3-carboximidate (400 mg, 2.26 mmol, 1 eq.) in toluene (15 ml) was added 4-tert-butyl-1H-pyrazole-5-amine (314.54 mg, 2 .26 mmol, 1 eq.). The mixture was stirred at 130° C. for 24 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 1/1, R _f = 0.23), giving N'-(4-tert-butyl-1H-pyrazol-5-yl)-5-fluoro-pyridine-3-carboxamidine (400 mg, 1.45 mmol, 64.4% yield, 95.0% purity) as white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.59 (s, 1H), 8.94 (s, 1H), 8.57-8.48 (m, 1H), 8.02 (d, J =9.5 Hz, 1H), 7.23 (s, 1H), 1.41 (s, 9H); ER-LCMS m/z 262.1 [M+H]+.

Step 2: 8-(tert-butyl)-2-(5-fluoropyridin-3-yl)pyrazolo[1,5-a][1,3,5]triazin-4-ol

To a solution of N'-(4-tert-butyl-1H-pyrazol-5-yl)-5-fluoro-pyridine-3-carboxamidine (400 mg, 1.45 mmol, 1 eq.) in 1,4-dioxane ( 5 ml) and THF (5 ml) were added diphosgene (575.40 mg, 2.91 mmol, 350.85 μl, 2 eq.). The mixture was stirred at 80° C. for 7 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give 8-tert-butyl-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin4-ol (400 mg, 1.32 mmol, yield 91.0%, purity 95.0%) as a yellow solid, which was used in the next step without further purification.

'H NMR (400 MHz, CD3OD) δ ppm 9.22 (s, 1H), 8.89 (s, 1H), 8.55 (d, J=9.0 Hz, 1H), 8.03 (s , 1H), 1.49 (s,

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9H); ER-LCMS m/z 287.8 [M+H]+.

Step 3: 8-(tert-butyl)-4-chloro-2-(5-fluoropyridin-3-yl)pyrazolo[1,5-a][1,3,5]triazine

8-tert-Butyl-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-ol solution (400 mg, 1.32 mmol, 1 eq. ) in POCl ₃ (2 g, 13.04 mmol, 1.21 ml, 9.86 eq.) was stirred at 110° C. for 2 h under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ice water (10 ml) and extracted with DCM (10 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 3/1, Rf = 0.7) to give 8-tert-butyl-4-chloro-2-(5-fluoro3-pyridyl)pyrazolo[1,5-a][1.3.5]triazine (130 mg, 382.68 µmol, yield 28.9%, purity 90.0%) as a yellow solid.

' and NMR (400 MHz, CDCl ₃ ) δ ppm 9.44 (s, 1H), 8.56 (s, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.11 ( s, 1H), 1.47 (s, 9H); ER-LCMS m/z 305.7 [M+H] ⁺ .

Step 4: (R)-N-(8-(tert-butyl)-2-(5-fluoropyridin-3-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl) -2,3,4,9tetrahydro- 1H-carbazole-3-amine (I-132)

To a solution of 8-tert-butyl-4-chloro-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazine (60 mg, 176.62 µmol, 1 eq. .) in i-PrOH (3 ml) was added (3R)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (34.21 mg, 183.69 µmol, 1.04 eq.) and DIPEA (114.14 mg, 883.11 µmol, 153.82 µl, 5 eq.). The reaction mixture was stirred at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela Durashell C18 150x25 5u; mobile phase: [water (0.05% HCl)- ACN]; B%: 75%-95%, 8 min) followed by lyophilization to give (3R)-N-[8-t-butyl-2-(5-fluoro-3-pyridyl)pyrazolo[1,5- a][1,3,5]triazin-4-yl]-2,3,4,9-tetrahydro1H-carbazole-3-amine (28.87 mg, 53.29 µmol, 30.2% yield, 97 purity .6%, 2HCl, [a] ²¹ _D = 18.883 (MeOH, c = 0.100 g / 100 ml)) as a yellow solid.

'H NMR (400 MHz, CD3OD) δ ppm 9.41 (s, 1H), 8.69-8.61 (m, 2H), 7.94 (s, 1H), 7.35 (d, J= 7.8 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.01 (t, J=7.5 Hz, 1H), 6.97-6.87 (m, 1H), 4.81 (m, 1H), 3.25 (d, J=4.9 Hz, 1H), 3.102.84 (m, 3H), 2.35 (m, 1H), 2.29- 2.18 (m, 1H), 1.50 (s, 9H); ER-LCMS m/z 456.3 [M+H] ⁺ .

Example 122.

Synthesis of I-133

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Synthesis scheme:

To a solution of 2-(7-benzyloxy-1H-indol-3-yl)ethanamine (150 mg, 563.19 µmol, 1 eq.) in MeOH (10 mL) was added Pd/C (50 mg, 10%). The mixture was degassed and purged with H ₂ 3 times and stirred at 50°C for 1 hour. The mixture was filtered and concentrated to give 3-(2-aminoethyl)-1H-indol-7ol (90 mg, 510.74 µmol, 90 yield .7%) as a yellow solid, which was used in the next step without further purification.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.06-7.00 (m, 2H), 6.85-6.77 (m, 1H), 6.50 (d, J=7.6 Hz, 1H), 2.962.83 (m, 4H).

Step 2: 3-[2-[[5-(5-fluoro-3-pyridyl)-3-(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-7yl]amino]ethyl]-1 H-indol- 7-ol (I-133)

[7-Chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanol mixture (55 mg, 171.12 µmol, 1 eq), 3-(2 -aminoethyl)-1H-indol-7-ol (39.20 mg, 222.45 µmol, 1.3 eq.) and DIEA (66.35 mg, 513.35 µmol, 89.42 µl, 3 eq.) in i-PrOH (10 ml) was degassed and purged with N2 3 times. The mixture was stirred at 80° C. for 5 hours under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [Water-ACN]; V%: 17%-47%, 8.5 min) followed by lyophilization to give 3-[2-[[5-(5-fluoro-3-pyridyl)-3-(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-7yl]amino]ethyl]-III-indole-7- ol (16.9 mg, 38.27 µmol, 22.4% yield, 94.8% purity) as a gray solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.67 (s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.06 (s, 1H), 7.73-7, 67 (m, 1H), 7.21 (d, J=8.1 Hz, 1H), 6.94-6.87 (m, 2H), 6.51 (d, J=7.3 Hz, 1H ), 5.96 (s, 1H), 4.80 (s, 2H), 3.88 (t, J=6.1 Hz, 2H), 3.21-3.11 (m, 2H); ER-LCMS m/z 419.1 [M+H]+.

Example 123.

Synthesis of I-135

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Synthesis scheme:

DIPEA (119.93 mg, 927 92 µmol, 161.63 µl, 1.43 eq.) and (3R)-2,3,4,9-tetrahydro-1Hcarbazole-3-amine (125.69 mg, 674.85 µmol, 1.04 eq. ) in THF (5 ml) at 0°C. The mixture was stirred at 0° C. for 1 h and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 1/1 , Rf = 0.47) to give (3R)-N-(4-chloro-6-isopropoxy-1,3,5-triazin-2-yl)-2,3,4,9-tetrahydro-1H-carbazole -3-amine (220 mg, 553.33 µmol, 85.3% yield, 90.0% purity) as a yellow solid.

1H NMR (400 MHz, CDCI3) δ ppm 7.80 (d, J=6.4 Hz, 1H), 7.45-7.38 (m, 1H), 7.29 (dd, J=3.1 , 7.7 Hz, 1H), 7.18-7.05 (m, 2H), 6.06-5.59 (m, 1H), 5.41-4.98 (m, 1H), 4, 65-4.51 (m, 1H), 3.16 (d, J=15.4 Hz, 1H), 2.96-2.66 (m, 3H), 2.18-2.06 (m, 2H), 1.31 (d, J=5.1 Hz, 6H); ER-LCMS m/z 358.1 [M+H]+.

Step 2: (3R)-N-[4-(5-fluoro-3-pyridyl)-6-isopropoxy-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1Hcarbazole -3-amine (I-135)

To a solution of (3R)-N-(4-chloro-6-isopropoxy-1,3,5-triazin-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-3amine (200 mg, 503 .02 µmol, 1 eq.) in 1,4-dioxane (3 ml) and H2O (1 ml) was added (5-fluoro-3-pyridyl)boronic acid (70.88 mg, 503.02 µmol, 1 eq.), Pd(dppf)Cl ₂ (36.81 mg, 50.30 µmol, 0.1 eq.) and Cs ₂ CO ₃ (491.68 mg, 1.51 mmol, 3 eq.) under N2 atmosphere. The mixture was stirred at 100° C. for 3 h under N2. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC (HCl conditions; column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 60%-90% , 8 min) to give (3R)-N-[4-(5-fluoro-3-pyridyl)-6-isopropoxy-1,3,5triazin-2-yl]-2,3,4,9-tetrahydro- 1H-carbazole-3-amine (55.56 mg, 113.07 µmol, 22.5% yield, 100.0% purity, 2HCl, [a] ^21.2 _D = 56.652 (MeOH, c = 0.100 g/100 ml) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.26 (s, 1H), 8.75 (s, 1H), 8.50 (d, J=7.6 Hz, 1H), 7.30 (d, J=7.6Hz, 1H), 7.20(d, J=7.8Hz, 1H), 7.03-6.86(m, 2H), 5.44(s, 1H), 4, 65-4.37 (m, 1H), 3.16 (d, J=14.7 Hz, 1H), 2.89 (s, 2H), 2.70 (dd, J=8.8, 14, 2 Hz, 1H), 2.24 (s, 1H), 2.03 (s, 1H), 1.41 (d, J=5.1 Hz, 6H); ER-LCMS m/z 419.0 [M+H] ⁺ .

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Example 124.

Synthesis of I-136

Stage 1: 2,4-dichloro-6-isopropoxy-1,3,5-triazine

NaH (253.76 mg, 6.34 mmol, 60% purity, 1.3 eq.) at 0° C. under N ₂ atmosphere. The mixture was stirred at 0°C for 0.5 h. Then 2,4,6-trichloro-1,3,5-triazine (1 g, 4.88 mmol, 1 eq.) in THF ( 8 ml) at 0°C. The mixture was stirred at 10° C. for 11.5 hours under N ₂ atmosphere. TLC (PE/EtOAc = 6:1, R _f = 0.6) indicated that the reaction was complete. The reaction mixture was slowly dissolved in water (50 ml) at 0°C. The mixture was subjected to extraction with EtOAc (50 mlx3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 20/1, TLC: PE /EtOAc = 6/1, Rf = 0.6) to give 2,4-dichloro-6-isopropoxy-1,3,5-triazine (430 mg, 1.86 mmol, 38.1% yield, 90 purity, 0%) as a white solid.

1 H NMR (400 MHz, CDCI3) δ ppm 5.40-5.25 (m, 1H), 1.37 (d, J=6.1 Hz, 6H).

Stage 2: 4-chloro-N-[2-(1H-indol-3-yl)ethyl]-6-isopropoxy-1,3,5-triazin-2-amine

DIPEA (79.95 mg, 618 62 µmol, 107.75 µl, 1.43 eq) and 2-(1H-indol-3yl)ethanamine (72.08 mg, 449.90 µmol, 1.04 eq) in THF (5 ml) at 0 °C. The mixture was stirred at 0° C. for 1 h and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 1/1 , Rf = 0.47) to give 4-chloro-N-[2-(1H-indol-3-yl)ethyl]-6-isopropoxy-1,3,5-triazin-2-amine (90 mg, 244 .12 µmol, yield 56.4%, purity 90.0%) as a yellow solid.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm 8.13-7.96 (m, 1H), 7.59-7.47 (m, 1H), 7.33-7.24 (m, 1H), 7.16-7.10 (m,

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1H), 7.09-7.04 (m, 1H), 6.96 (t, J=10.9 Hz, 1H), 5.39-4.97 (m, 1H), 3.84-3 .59 (m, 2H), 3.48 (d, J=4.9 Hz, 1H),

3.09-2.86 (m, 2H), 1.25-1.19 (m, 6H); ER-LCMS m/z 332.1, 334.1 [M+H] ⁺ .

Step 3: 4-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-isopropoxy-1,3,5-triazin-2-amine (I136)

To a solution of 4-chloro-N-[2-(1H-indol-3-yl)ethyl]-6-isopropoxy-1,3,5-triazine-2-amine (90 mg, 244.12 µmol, 1 eq. ) in 1,4-dioxane (3 ml) and H ₂ O (1 ml) was added (5-fluoro-3-pyridyl)boronic acid (34.40 mg, 244.12 μmol, 1 eq.), Cs ₂ CO ₃ (238.62 mg, 732.37 µmol, 3 eq) and Pd(dppf)Cl ₂ (17.86 mg, 24.41 µmol, 0.1 eq) under N2. The mixture was stirred at 100° C. for 3 h under N2. The reaction mixture was filtered and concentrated to give a residue which was purified by preparative HPLC (HCl conditions; column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 55%- 85%, 8 min) to give 4-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6isopropoxy-1,3,5-triazin-2-amine (25.60 mg, 55.01 µmol, 22.5% yield, 100.0% purity, 2HCl) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.80 (s, 1H), 9.24 (d, J=16.1 Hz, 1H), 8.75 (s, 1H), 8, 38-8.18 (m, 2H), 7.56 (dd, J=8.2, 13.8 Hz, 1H), 7.29 (t, J=8.4 Hz, 1H), 7.16 (s, 1H), 7.06-6.99 (m, 1H), 6.98-6.90 (m, 1H), 5.36-5.16 (m, 1H), 3.75-3 .51 (m, 2H), 2.95 (s, 2H), 1.34-1.26 (m, 6H); ER-LCMS m/z 393.1 [M+H]+.

Example 125.

Synthesis of I-137a, I-137b and I-137c

nh ₂ oh-hci

M37s I37b

Stage 1: 1,4,6,7-tetrahydroindol-5-one oxime

Synthesis scheme:

Mixture of 1,4,6,7-tetrahydroindol-5-one (150 mg, 1.11 mmol, 1 eq.), NH ₂ OH-HCl (92.54 mg, 1.33 mmol, 1.2 eq.) and NaOAc (136.56 mg, 1.66 mmol, 1.5 eq.) in THF (10 ml) was stirred at 60°C for 3 h. TLC (PE/EtOAc = 1/1, R _f = 0, 20) showed that the starting material was completely consumed. The reaction mixture was diluted with H2O (20 ml) and extracted with EtOAc (20 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1,4,6,7tetrahydroindol-5-one oxime (160 mg, crude) as a brown gum, which was used

- 247 041983 whether at the next stage without further purification.

1H NMR (400 MHz, CDC13) δ 7.81 (broad s, 1H), 6.69-6.64 (m, 1H), 6.06-5.98 (m, 1H), 3.63- 3.35 (m, 2H), 2.81-2.74 (m, 2H), 2.68-2.53 (m, 2H); ER-LCMS m/z 151.1 [M+H]+.

Stage 2: 4,5,6,7-tetrahydro-III-indole-5-amine

A mixture of 1,4,6,7-tetrahydroindol-5-one oxime (160 mg, 1.07 mmol, 1 eq.) and Raney-Ni (200 mg) in MeOH (10 ml) was stirred in H ₂ (15 Psi) at 10° C. for 12 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 4,5,6,7-tetrahydro-1H-indole-5-amine (140 mg, crude) as a brown solid which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 6.55 (d, J=2.4 Hz, 1H), 5.80 (d, J=2.4 Hz, 1H), 3.17-3.05 ( m, 1H), 2.79 (dd, J=4.8, 14.8 Hz, 1H), 2.71-2.63 (m, 2H), 2.33 (dd, J=8.8, 14.8 Hz, 1H), 2.06-1.96 (m, 1H), 1.77-1.64 (m, 1H); ER-LCMS m/z 137.2 [M+H] ⁺ .

Stage 3: 2-(5-fluoro-3-pyridyl)-8-isopropyl-N-[(5,5)-4,5,6,7-tetrahydro-1H-indol-5yl]pyrazolo[1,5- a][1,3,5]triazine-4-amine (I-137a) and 2-(5-fluoro-3-πiridyl)-8-isopropyl-N-[(5R)-4,5,6,7tetrahydro -1 H-indol-5-yl]πirazolo[1,5-a][1,3,5]triazine-4-amine (I- 137b)

To a solution of 4-chloro-2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine (120.48 mg, 330.41 µmol, 1 equiv.) and 4,5,6,7-tetrahydro-1H-indole-5-amine (45 mg, 330.41 µmol, 1 equiv.) in i-PrOH (10 ml) was added DIEA (341.63 mg, 2.64 mmol, 460.41 µl, 8 eq.). The mixture was stirred at 50° C. for 2 hours. TLC (PE/EtOAc = 3/1, Rf = 0.5) indicated that the starting material had been completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.50), obtaining a product which was separated by chiral SFC (column: DAICEL CHIRALCEL OJ-H (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH ₃ H ₂ O MeOH]; B%: 35%-35%) , giving peak 1 (SFC: Rt = 3.442) and peak 2 (SFC: Rt = 3.780). The fraction corresponding to peak 1 was concentrated to give a residue which was purified by preparative HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 75%-100% , 8 min) followed by lyophilization to give the enantiomer (17.61 mg, 35.16 µmol, 10.6% yield, 100.0% purity, 3HCl, SFC: Rt = 3.442, ee = 100%, or [a] ^20.2 D=-0.069 (MeOH c=0.086 g/100 ml)) as a gray solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (broad s, 1H), 9.36 (s, 1H), 8.87 (d, J=8.8 Hz, 1H), 8, 71 (d, J=2.7 Hz, 1H), 8.46-8.39 (m, 1H), 8.13 (s, 1H), 6.56 (t, J=2.4 Hz, 1H ), 5.77 (t, J=2.4 Hz, 1H), 4.66 (broad s, 1H), 3.27-3.17 (m, 1H), 2.86-2.74 ( m, 3H), 2.68 (d, J=7.8 Hz, 1H), 2.12-1.97 (m, 2H), 1.36 (d, J=6.8 Hz, 6H); ER-LCMS m/z 392.2 [M+H] ⁺ .

Peak 2 (SFC: Rt = 3.780) was concentrated to give a residue which was purified by preparative HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 75% -100%, 8 min) followed by lyophilization to give the other enantiomer (16.18 mg, 32.31 µmol, 9.8% yield, 100.0% purity, 3HCl, SFC: Rt = 3.780, ee = 99.12 %, or [α] ²⁽ % = 0.066 (MeOH c = 0.084 g / 100 ml)) in the form of a gray solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 10.38 (broad s, 1H), 9.36 (s, 1H), 8.88 (d, J=8.6 Hz, 1H), 8, 71 (d, J=2.4 Hz, 1H), 8.46-8.38 (m, 1H), 8.13 (s, 1H), 6.56 (broad s, 1H), 5.77 (br s, 1H), 4.66 (br s, 1H), 3.21 (td, J=6.8, 13.7 Hz, 1H), 2.84-2.72 (m, 3H ), 2.71-2.66 (m, 1H), 2.12-1.99 (m, 2H), 1.36 (d, J=6.8 Hz, 6H); ERJHMS m/z 392.2 [M+H] ⁺ .

- 248 041983

Example 126.

Synthesis of I-139a, I-139b and 1-139c

Synthesis scheme:

Stage 1: (3S)-6,8-difluoro-N-[2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4yl ]-2,3,4,9-tetrahydro-1H-carbazole-3-amine (I-139a) and (3R)-6,8-difluoro-N-[2-(5-fluoro-3-pyridyl)- 8isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4,9-tetrahydro-1H-carbazole-3-amine (I-139b)

To a solution of 6,8-difluoro-2,3,4,9-tetrahydro-1H-carbazole-3-amine (180 mg, 509.83 µmol, 1 eq., TFA) and 4-chloro-2-(5- fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine (221.40 mg, 607.18 µmol, 1.19 eq.) in i-PrOH (10 ml) DIEA (527.13 mg, 4.08 mmol, 710.42 μl, 8 eq.) was added. The mixture was stirred at 50° C. for 2 hours. TLC (PE/EtOAc = 3/1, Rf = 0.5) indicated that the starting material had been completely consumed. The reaction mixture was concentrated under reduced pressure to dryness to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0, 50). The desired fraction was concentrated under reduced pressure to give a product which was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 µm); mobile phase: [0.1% NH ₃ H ₂ O IPA]; B%: 45 %-45%, min) giving Peak 1 (SFC: Rt = 1.851) and Peak 2 (SFC: Rt = 2.254). The fraction corresponding to peak 1 was concentrated to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 75%-100% , 8 min). The desired fraction was lyophilized to give the enantiomer (64.24 mg, 114.88 µmol, 22.5% yield, 98.4% purity, 2HCl, SFC: Rt = 1.851, ee = 100%, or [a] ^20.2 _D = 0.206 (MeOH c = 0.110 g/100 ml)) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.38 (s, 1H), 9.38 (s, 1H), 9.06 (d, J=8.6 Hz, 1H), 8.69 (d, J=2.2 Hz, 1H), 8.44 (d, J=10.0 Hz, 1H), 8.15 (s, 1H), 7.02 (d, J=9.0 Hz , 1H), 6.86 (m, J=10.6 Hz, 1H), 4.84 (broad s, 1H), 3.22 (d, J=7.1, 14.0 Hz, 1H) , 3.12-2.98 (m, 2H), 2.88 (d, J=15.4 Hz, 2H), 2.20 (br s, 2H), 1.37 (d, J=6 .8 Hz, 6H); ER-LCMS m/z 478.3 [M+H]+. The fraction corresponding to peak 2 was concentrated to give

- 249 041983 residue, which was purified using preparative HPLC (column: Agela ASB 150x25 mmx5 μm;

mobile phase: [water (0.05% HCl)-ACN]; B%: 75%-100%, 8 min). The desired fraction was lyophilized to give the other enantiomer (70.3 mg, 125.02 µmol, 24.5% yield, 97.9% purity, 2HCl, SFC: Rt =

2.254, ee = 99.79%, or [a] ^20.2 D = -0.239 (MeOH c = 0.117 g/100 ml)) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (s, 1H), 9.38 (s, 1H), 9.05 (d, J=8.6 Hz, 1H), 8.69 ( d, J=2.9Hz, 1H), 8.49-8.38(m, 1H), 8.15(s, 1H), 7.02(dd, J=1.8, 9.4Hz , 1H), 6.91-6.80 (m, 1H), 4.94-4.75 (m, 1H), 3.22 (d, J=6.9, 13.8 Hz, 1H), 3.13-2.98 (m, 2H), 2.96-2.83 (m, 2H), 2.28-2.13 (m, 2H), 1.37 (d, J=6.8 Hz, 6H); ER-LCMS m/z 478.2 [M+H]+.

Example 127.

Synthesis I-141

1: 8-bromo-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrazolo[1,5-a][1,3,5]triazine -4Amin stage (I-141)

To a solution of 8-bromo-4-chloro-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazine (50 mg, 152.19 µmol, 1 eq.) in i-PrOH (3 ml) was added DIEA (59.01 mg, 456.58 µmol, 79.53 µl, 3 eq.) and 2-(1Hindol-3-yl)ethanamine (29.26 mg, 182.63 µmol, 1.2 eq.). The mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN ]; B%: 55%-85%, 8 min) followed by lyophilization to give 8-bromo-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrazolo [1,5-a][1,3,5]triazine-4-amine (19.80 mg, 37.70 µmol, 24.8% yield, 100.0% purity, 2HCl) as yellow solid .

1H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1H), 9.34 (s, 2H), 8.76 (s, 1H), 8.38 (s, 1H), 8, 29 (d, J=9.8 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.20 ( s, 1H), 7.04 (t, J=7.6 Hz, 1H), 7.00-6.91 (m, 1H), 3.95 (t, J=7.2 Hz, 2H), 3.13 (t, J=7.2 Hz, 2H); ER-LCMS m/z 452.1, 454.1 [M+H] ⁺ .

Example 128.

Synthesis I-143

- 250 041983

Synthesis scheme:

Step 1: 3-[2-[[5-(5-fluoro-3-pyridyl)-3-(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-7yl]amino]ethyl]-1 H-indole-5 -ol (I-143)

To a solution of [7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanol (80 mg, 287.08 µmol, 1 eq.) in i-PrOH (4 ml) was added 3-(2-aminoethyl)-1H-indol-5-ol (50.59 mg, 287.08 µmol, 1 eq.) and DIEA (111.31 mg, 861.24 µmol, 150, 01 µl, 3 equiv.). The mixture was stirred at 90° C. for 3 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN]; B%: 20%-50%, 8 min) followed by lyophilization to give 3-[2-[[5-(5-fluoro-3-pyridyl)-3-(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-7yl] amino]ethyl]-1H-indol-5-ol (3.76 mg, 8.99 µmol, 3.1% yield, 100% purity) as a white solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.73 (s, 1H), 8.48 (s, 1H), 8.06 (s, 1H), 7.78 (d, J=9.5 Hz, 1H), 7.097.02 (m, 2H), 6.93 (s, 1H), 6.67 (d, J=8.8 Hz, 1H), 6.05 (s, 1H), 4.80 ( s, 2H), 3.86 (t, J=6.1 Hz, 2H), 3.13 (t, J=5.9 Hz, 2H); ER-LCMS m/z 440.8 [M+Na]+.

Example 129.

Synthesis of I-144a

- 251 041983

Stage 1: 7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde

Cl

ΧιΑ

A /A/

L Η clear Ν

POCl ₃ (5 g) was added dropwise to a DMF solution (10 ml) at −20° C. over a period of 12 min under N2 atmosphere. After 1 hour, 7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (1 g, 3.76 mmol, 1 eq.) in DMF (5 ml) was added to the above solution, while the temperature was maintained below -20°C. The mixture was heated to 20° C. and stirred for 12 hours under N2. To the above solution was added POCl ₃ (12.85 g) in DMF (10 ml). The mixture was stirred at 20°C for 12 hours under N2. The mixture was concentrated and water (200 ml) was added. The mixture was subjected to extraction with DCM (50 mlx3). The combined organic layers were washed with 5% LiCl (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give 7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5a]pyrimidine-3-carbaldehyde (800 mg, 2.77 mmol, 73.5% yield, 95.7% purity) as a yellow solid, which was used in the next step without further purification.

¹ H NMR (400 MHz, CD3OD) δ ppm 10.29 (s, 1H), 9.42 (s, 1H), 8.9-8.79 (m, 2H), 8.63 (d, J= 10.0 Hz, 1H), 8.52(s, 1H); ER-LCMS m/z 277.0 [M+H]+.

Step 2: [7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanol

CI

Hell

A mixture of 7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (400 mg, 1.38 mmol, 1 eq.) in THF (10 ml) was added with NaBH ₄ (78.52 mg, 2.08 mmol, 1.5 eq.) at 0°C, the mixture was stirred at 20°C for 12 h under N2. To the reaction mixture was added 0.5 N. aq. HCl (0.05 ml). The mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.27) to give [ 7chloro-5-(5-Fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanol (130 mg, 421.25 µmol, 30.4% yield, 90.3% purity) in form of a yellow solid.

1H NMR (400 MHz, DMSO-dg) δ ppm 10.28 (s, 1H), 9.70 (d, J=2.2 Hz, 1H), 9.48 (d, J=10.3 Hz, 1H), 9.33 (s, 1H), 9.15 (s, 1H), 6.10 (br s, 1H), 5.71 (br s, 2H); ER-LCMS m/z 279.0 [M+H] ⁺ .

Step 3: (1S)-2-[[5-(5-fluoro-3-pyridyl)-3-(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino]1-(1H-indole -3-yl)ethanol (1-144a)

To a solution of [7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanol (55 mg, 178.22 µmol, 1 eq.) in i-PrOH (3 ml) was added (18)-2-amino-1-(1H-indol-3-yl)ethanol (36.95 mg, 178.22 µmol, 1 eq.) and DIEA (69.10 mg, 534, 66 µmol, 93.13 µl, 3 eq.). The mixture was stirred at 90°C for 3 hours under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 25%-55%, 8 min) followed by lyophilization to give (18)-2-[[5-(5-fluoro-3-pyridyl)-3-(hydroxymethyl)pyrazolo[1,5a]pyrimidin-7-yl ]amino]-1-(1H-indol-3-yl)ethanol (40 mg, 94.55 µmol, 53.0% yield, 98.9% purity, SFC: Rt=4.476, ee=99.1%, [a] ^19.6 _D = -11.254 (MeOH, c = 0.106 g/100 ml)) as a white solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 8.73 (s, 1H), 8.48 (d, J=2.2 Hz, 1H), 8.07 (s, 1H), 7.88- 7.81 (m, 2H), 7.29-7.21 (m, 1H), 7.18 (s, 1H), 7.13-7.05 (m, 2H), 6.16 (s, 1H), 5.30 (t, J=5.6 Hz, 1H), 4.81 (s, 2H), 4.07-3.95 (m, 2H); ER-LCMS m/z 419.1 [M+H] ⁺ .

- 252 041983

Example 130.

Synthesis of I-144b

Step 1: (1R)-2-[[5-(5-fluoro-3-pyridyl)-3-(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino]1-(1H-indole -3-yl)ethanol (I-144b)

HN

To a solution of [7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanol (66.45 mg, 215.31 µmol, 1 eq.) in i -PrOH (3 ml) was added DIEA (83.48 mg, 645.93 µmol, 112.51 µl, 3 eq.) and (1R)-2amino-1-(1H-indol-3-yl)ethanol (53, 32 mg, 279.90 µmol, 1.3 eq.). The reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified twice by preparative HPLC (basic conditions; column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05 % ammonium hydroxide o6./o6.)-ACN]; B%: 25%-55%, 8 min). The desired fraction was lyophilized to give (1R)-2-[[5-(5-fluoro-3-pyridyl)-3(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino]-1-(1H -indol-3-yl)ethanol (18.50 mg, 44.21 µmol, 20.5% yield, 100.0% purity, SFC: Rt= 3.628 min, ee=99.4%, [a] ^{19, 5} D = +12.650 (MeOH, c = 0.106 g/100 ml)) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.74 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.08 (s, 1H), 7.90-7, 80 (m, 2H), 7.25 (d, J=8.3 Hz, 1H), 7.18 (s, 1H), 7.13-7.05 (m, 2H), 6.17 (s , 1H), 5.31 (t, J=5.7 Hz, 1H), 4.81 (s, 2H), 4.09-

3.95 (m, 2H); ER-LCMS m/z 419.1 [M+H]+. Example 131. Synthesis of X-150a %h ^NH but/,, J(R) \^/ HIT Hell j A g I-150a

- 253 041983

Synthesis scheme:

Stage 1:

(1R)-2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]-1-(1Hindol-3-yl) ethanol (1-150a)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (50 mg, 185.97 µmol, 1 eq.) in i-PrOH (3 ml) was added DIEA (120.18 mg, 929.87 µmol, 161.96 µl, 5 eq.) and (1R)-2amino-1-(1H-indol-3-yl)ethanol (46.06 mg, 241 .77 µmol, 1.3 eq.). The mixture was stirred at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 1/2, TLC: PE/EtOAc = 1/1, R _f = 0.12) to give (1R)-2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl ]amino]-1(1H-indol-3-yl)ethanol (15.35 mg, 38.14 µmol, 20.5% yield, 100% purity, SFC: Rt = 1.560, ee = 99.008%, [a] ^22.1 _D = +6.048 (MeOH, c = 0.133 g/100 ml)) as a yellow solid.

'and NMR (400 MHz, CD3OD) δ ppm 8.73 (s, 1H), 8.48 (d, J=2.8 Hz, 1H), 7.89 (s, 1H), 7.85-7 .79 (m, 2H), 7.25 (d, J=7.0 Hz, 1H), 7.19 (s, 1H), 7.12-7.05 (m, 2H), 6.11 ( s, 1H), 5.30 (t, J=5.6 Hz, 1H), 4.06-3.96 (m, 2H), 2.31 (s, 3H); ER-LCMS m/z 403.1 [M+H] ⁺ .

Example 132.

Synthesis of I-150b

- 254 041983

Synthesis scheme:

Stage 1: 2-(1H-indol-3-yl)-2-oxo-acetyl chloride

To a solution of indole (10 g, 85.36 mmol, 1 eq.) in THF (100 ml) was added dropwise (COCl) ₂ (11.05 g, 87.07 mmol, 7.62 ml, 1.02 eq. ) at 0-5°C in an atmosphere of N ₂ . The mixture was stirred at 0-5°C for 3 hours. The yellow suspension was filtered, the filter cake was washed with PE (10 mlx2), dried under reduced pressure, obtaining crude 2-(1H-indol-3-yl)-2-oxo -acetyl chloride (15 g, 72.25 mmol, 84.6% yield, 100% purity) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 13.31 (br s, 1H), 8.64-8.57 (m, 1H), 8.34-8.25 (m, 1H), 7, 45-7.38(m, 1H), 7.26-7.15(m, 2H).

Stage 2: 2-(1H-indol-3-yl)-2-oxo-acetamide

To a solution of NH3-H2O (42.20 g, 337.17 mmol, 46.37 ml, 28%, 10 eq.) in EtOH (100 ml) acetyl chloride (7 g, 33.72 mmol, 1 eq.). The mixture was stirred at 0°C for 1.5 hours. The suspension was filtered, the filter cake was washed with water (20 mlx2), dried under reduced pressure, obtaining 2-(1H-indol-3-yl)-2-oxo-acetamide ( 5.5 g, 28.00 mmol, 83.0% yield, 95.8% purity as a white solid, which was used in the next step without further purification.

1H NMR (400 MHz, DMSO-d6) δ ppm 12.18 (br s, 1H), 8.69 (s, 1H), 8.27-8.17 (m, 1H), 8.08 (br s, 1H), 7.71 (br s, 1H), 7.58-7.48 (m, 1H), 7.30-7.19 (m, 2H); ER-LCMS m/z 189.1 [M+H]+.

Stage 3: 1H-indole-3-carbonyl cyanide

To a solution of 2-(1H-indol-3-yl)-2-oxo-acetamide (5.5 g, 28.00 mmol, 1 eq.) and pyridine (6.64 g, 84.00 mmol, 6.78 ml, 3 eq.) in EtOAc (100 ml) was added TFAA (8.82 g, 42.00 mmol, 5.84 ml, 1.5 eq.) at 10° C. under N ₂ atmosphere. The mixture was stirred at 10° C. for 4 hours. The reaction mixture was quenched by adding NaHCO ₃ (100 ml), extracted with EtOAc (80 mlx3). The combined organic layers were washed with 0.5N aq. HCl (20 ml), brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give crude 1H-indole-3-carbonyl cyanide (3.2 g, 12.73 mmol, 45 yield, 5%, 67.7% pure) as a white solid, which was used in the next

- 255 041983 stage without further purification.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.88 (br s, 1H), 8.63 (s, 1H), 8.07-8.01 (m, 1H), 7.58 ( dd,

J=1.3, 7.0 Hz, 1H), 7.34 (dq, J=1.3, 7.2 Hz, 2H); ER-LCMS m/z 171.1 [M+H]+.

Step 4: (1S)-2-amino-1-(1H-indol-3-yl)ethanol ^NH

Η ₂ ΙΨ

To a solution of 1H-indole-3-carbonyl cyanide (1 g, 3.98 mmol, 1 eq.) in THF (40 ml) was added LAH (302.00 mg, 7.96 mmol, 2 eq.) at 0°C in N2 atmosphere. The mixture was stirred at 15° C. for 2 hours. TLC (PE/EtOAc = 3/1, Rf = 0.18) indicated that the starting material had been completely consumed. The mixture was diluted with THF (50 ml), cooled to 0° C., quenched successively with water (0.3 ml), 10% aq. NaOH (0.3 ml), water (0.9 ml). After stirring for 30 minutes, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (EtOAc/MeOH=1/0 to 1/1, TLC: EtOAc/MeOH=10/1, Rf=0.18) to give the product, which was purified by SFC separation twice (first: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 µm); mobile phase: [0.1% NH ₃ H ₂ O IPA]; B%: 35%-35%. second: column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 5 µm) mobile phase: [0.1% NH3H2O IPA] %: 45%45% to give (1R)-2-amino-1-(1H-indole -3-yl)ethanol (120 mg, 629.91 µmol, 15.8% yield, 92.5% purity, ee = 92.5%) as a yellow oil.

1H NMR (400 MHz, CD3OD) δ ppm 7.66 (d, J=7.8 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.22 (s, 1H) , 7.10 (t, J=7.2 Hz, 1H), 7.05-6.95 (m, 1H), 4.96 (t, J=6.3 Hz, 1H), 3.02 ( d, J=6.3 Hz, 2H); ER-LCMS m/z 159.2 [MH ₂ O+H] ⁺ . and (1S)-2-amino-1-(1H-indol-3-yl)ethanol (125 mg, 602.96 µmol, 15.2% yield, 85.0% purity, ee = 98.698%) as an oil yellow color.

1H NMR (400 MHz, CD3OD) δ ppm 7.67 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.23 (s, 1H) , 7.11 (t, J=7.2 Hz, 1H), 7.05-6.99 (m, 1H), 4.99 (t, J=6.3 Hz, 1H), 3.08- 3.02 (m, 2H); ER-LCMS m/z 159.2 [MH2O+H] ⁺ .

Step 5 (1S)-2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]-1-(1Hindole-3- yl)ethanol (I-150b)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (50 mg, 185.97 µmol, 1 eq.) in i-PrOH (3 ml) was added DIEA (72.11 mg, 557.92 µmol, 97.18 µl, 3 eq.) and (1S)-2amino-1-(1H-indol-3-yl)ethanol (57.47 mg, 277 .22 µmol, 1.49 eq.). The mixture was stirred at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 1/2, TLC: PE/EtOAc = 1/1, Rf=0.18) to give (1S)-2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl] amino]-1(1H-indol-3-yl)ethanol (29.26 mg, 71.26 µmol, 38.3% yield, 98.0% purity, SFC: Rt = 2.204, ee = 98.378, [a] ^21.4 D = -8.227 (MeOH, c = 0.10 g/100 ml)) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.72 (s, 1H), 8.48 (d, J=2.2 Hz, 1H), 7.89 (s, 1H), 7.82 (d, J=5.9Hz, 2H), 7.25(d, J=8.3Hz, 1H), 7.19(s, 1H), 7.14-7.02(m, 2H), 6, 10 (s, 1H), 5.30 (t, J=5.7 Hz, 1H), 4.08-3.95 (m, 2H), 2.31 (s, 3H); ER-LCMS m/z 403.2 [M+H] ⁺ .

Example 133.

Synthesis of I-152a, I-152b, I-152c

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Synthesis scheme:

Step 1: (3R)-6,8-difluoro-N-[2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4yl ]-2,3,4,9-tetrahydro-1Н-carbazole-3-amine (1-152b) and (3S)-6,8-difluoro-N-[2-(5-fluoro-3-pyridyl)- 8isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4,9-tetrahydro-1P-carbazole-3-amine (1-152a)

To a solution of 6,8-difluoro-2,3,4,9-tetrahydro-1H-carbazole-3-amine (180 mg, 509.83 µmol, 1 eq., TFA) and 4-chloro-2-(5- fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine (221.40 mg, 607.18 µmol, 1.19 eq.) in i-PrOH (10 ml) DIEA (527.13 mg, 4.08 mmol, 710.42 μl, 8 eq.) was added. The mixture was stirred at 50° C. for 2 hours. TLC (PE/EtOAc = 3/1, R _f = 0.5) indicated that the starting material had been completely consumed. The reaction mixture was concentrated under reduced pressure to dryness to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, R _f = 0 ,50). The desired fraction was concentrated under reduced pressure to give a product which was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 µm); mobile phase: [0.1% NH ₃ H ₂ O IPA]; B%: 45 %-45%, min) giving Peak 1 (SFC: Rt = 1.851) and Peak 2 (SFC: Rt = 2.254). The fraction corresponding to peak 1 was concentrated to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 75%-100% , 8 min). The desired fraction was lyophilized to give the enantiomer (64.24 mg, 114.88 µmol, 22.5% yield, 98.4% purity, 2HCl, SFC: Rt = 1.851, ee = 100%, or [a] ^20.2 D = 0.206 (MeOH c = 0.110 g/100 ml)) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d^ δ ppm 11.38 (s, 1H), 9.38 (s, 1H), 9.06 (d, J=8.6 Hz, 1H), 8.69 (d, J=2.2Hz, 1H), 8.44 (d, J=10.0Hz, 1H), 8.15 (s, 1H), 7.02 (d, J=9.0Hz , 1H), 6.86 (m, J=10.6 Hz, 1H), 4.84 (broad s, 1H), 3.22 (d, J=7.1, 14.0 Hz, 1H) , 3.12-2.98 (m, 2H), 2.88 (d, J=15.4 Hz, 2H), 2.20 (br s, 2H), 1.37 (d, J=6 8 Hz, 6H); phase: [water (0.05% HCl)-ACN]; V%: 75%-100%, 8 min) The desired fraction was lyophilized to give the other enantiomer (70.3 mg, 125.02 µmol, yield 24.5 %, purity 97.9%, 2HCl, SFC: Rt = 2.254, ee = 99.79%, or [a] ^20.2 D = -0.239 (MeOH c = 0.117 g / 100 ml)) as a yellow solid colors.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.38 (s, 1H), 9.38 (s, 1H), 9.05 (d, J=8.6 Hz, 1H), 8.69 (d, J=2.9 Hz, 1H), 8.49-8.38 (m, 1H), 8.15 (s, 1H), 7.02 (dd, J=1.8, 9.4 Hz, 1H), 6.91-6.80 (m, 1H), 4.94-4.75 (m, 1H), 3.22 (d, J=6.9, 13.8 Hz, 1H) , 3.13-2.98 (m, 2H), 2.96-2.83 (m, 2H), 2.28-2.13 (m, 2H), 1.37 (d, J=6, 8 Hz, 6H); ER-LCMS m/z 478.2 [M+H] ⁺ .

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Example 134.

Synthesis I-154

Synthesis scheme:

Step 1: 8-bromo-4-chloro-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazine

To a solution of 4-chloro-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazine (110 mg, 423.02 µmol, 1 eq.) in MeCN (2 ml) and DCM (1 ml) were added NBS (82.82 mg, 465.33 µmol, 1.1 eq.). The mixture was stirred at 30° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give 8-bromo-4-chloro-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3 ,5]triazine (120 mg, 365.27 µmol, 86.4% yield) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl3) δ ppm 9.56 (s, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.51 (d, J=9.3 Hz, 1H) , 8.32 (s, 1H); ER-LCMS m/z 327.9, 329.9 [M+H] ⁺ .

Stage 2: (3R)-N-[8-bromo-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-ul]-2,3 ,4,9tetrahydro-1H-carbazole-3-amine (I-154)

A mixture of 8-bromo-4-chloro-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazine (70 mg, 204.55 µmol, 1 eq.), (3R)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (41.91 mg, 225.00 µmol, 1.1 eq) and DIEA (79.31 mg, 613.65 µmol , 106.89 µl, 3 eq.) in i-PrOH (3 ml) was degassed and purged with N2 3 times, the mixture was stirred at 60° C. for 3 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 63%-93%, 8 min) followed by lyophilization to give (3R)-N-[8-bromo-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4yl]- 2,3,4,9-tetrahydro-1H-carbazole-3-amine (32.48 mg, 58.92 µmol, 28.8% yield, 100.0% purity, 2HCl, or [a] ^22.1 D = 0.234 (MeOH, c = 0.105 g/100 ml) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.45 (s, 1H), 8.85-8.72 (m, 2H), 8.12 (s, 1H), 7.34 (d, J= 7.8 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.02 (t, J=7.6 Hz, 1H), 6.97-6.89 (m, 1H), 4.89-4.83(m, 1H), 3.27(m, 1H), 3.08-2.86(m, 3H), 2.43-2.17(m, 2H) ; ER-LCMS m/z 480.1, 482.1 [M+H]+.

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Example 135.

Synthesis of I-155

NaH (237.58 mg, 5.94 mmol , 1.5 equiv.) in an ice bath under N2 atmosphere. After stirring for 30 min, the mixture was cooled to -60°C and 4,6-dichloro-2-methylsulfonyl-pyrimidine (900 mg, 3.96 mmol, 1 eq.) in dry THF (10 ml) was added dropwise and maintained the temperature below -55°C. The resulting mixture was stirred for 1 hour at -55°C. The reaction mixture was quenched by adding H2O (15 ml), diluted with H2O (15 ml) and extracted with EtOAc (20 mlx3). The combined organic layers were washed with H2O (15 mlx2), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 1/3, Rf = 0.43) to give 4,6-dichloro-N-[ 2-(1H-indol-3-yl)ethyl]pyrimidin-2-amine (570 mg, 1.48 mmol, 37.5% yield, 80% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.96 (broad s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.15 (t, J=7.6 Hz, 1H), 7.11-7.05 (m, 1H), 6.99 (d, J=2.0 Hz, 1H), 6.52 (s, 1H), 5.37 (br s, 1H), 3.73-3.68 (m, 2H), 3.00 (t, J=6.7 Hz, 2H); ER-LCMS m/z 307.0, 309.0 [M+H]+.

Stage 2: 4-chloro-N-[2-(1H-indol-3-yl)ethyl]-6-isopropoxy-pyrimidin-2-amine

To a solution of i-PrOH (75.12 mg, 1.25 mmol, 95.70 μl, 1.2 eq.) in THF (3 ml) was added NaH (62.50 mg, 1.56 mmol, 1.5 eq. .), the mixture was stirred at 0°C for 30 min. To the mixture was added a solution of 4,6dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-2-amine (400 mg, 1.04 mmol, 1 eq.) in THF (3 ml), the mixture stirred at 60°C for 12 h. H2O (3 mL) was added to the mixture and concentrated to give a residue which was purified by preparative TLC (PE/EtOAc = 3/1, R _f = 0.5) , giving 4-χλορ-Ν-[2(1H-indol-3-yl)ethyl]-6-isopropoxy-pyrimidin-2-amine (470 mg, 710.37 µmol, 68.2% yield, purity

50%) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm 8.03 (broad s, 1H), 7.66-7.60 (m, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.15-7.09 (m, 1H), 7.03 (s, 1H), 6.57 (s, 1H), 5.26 (d, J=19.3 Hz, 1H), 3.78-3.69 (m, 2H), 3.05 (t, J=6.4 Hz, 2H), 1.62-1.18 ( m, 6H); ER-LCMS m/z 331.1 [M+H]+.

Stage 3: N-(2-(1H-indol-3-yl)ethyl)-4-isopropoxy-6-phenylpyrimidin-2-amine (1-155)

To a mixture of 4-chloro-N-[2-(1H-indol-3-yl)ethyl]-6-isopropoxy-pyrimidin-2-amine (450 mg, 680.15 µmol, 1 eq.) and phenylboronic acid (124 .39 mg, 1.02 mmol, 1.5 eq.) in 1,4-dioxane (10 ml) and H ₂ O (2 ml) was added Pd(dppf)Cl ₂ (49.77 mg, 68.01 μmol , 0.1 eq.) and Cs ₂ CO ₃ (664.81 mg, 2.04 mmol, 3 eq.) in an N ₂ atmosphere. The mixture was placed in a microwave tube and heated at 110° C. for 30 minutes. The mixture was concentrated to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 40%-70%, 8 min) with followed by lyophilization to give N-[2-(1H-indol-3-yl)ethyl]-4-isopropoxy-6-phenyl-pyrimidine2-amine (19.18 mg, 44.68 µmol, 6.6% yield, purity 95.3%, HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 7.76 (d, J=7.3 Hz, 2H), 7.69-7.62 (m, 1H), 7.58 (t, J=6.6 Hz, 3H), 7.31 (d, J=8.1 Hz, 1H), 7.12 (s, 1H), 7.07 (t, J=7.3 Hz, 1H), 7.01- 6.96 (m, 1H), 6.50 (s, 1H), 5.13 (td, J=6.1, 12.2 Hz, 1H), 3.89 (t, J=6.6 Hz , 2H), 3.13 (t, J=6.6 Hz, 2H), 1.32 (d, J=6.1 Hz, 6H); ER-LCMS m/z 373.3 [M+H] ⁺ .

Example 136.

Synthesis of I-160a, I-160b and I-160c

I-160a I-160b I-160c

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Synthesis scheme:

Step 1: 2-[1-(benzenesulfonyl)indol-3-yl]acetonitrile

A solution of 1-(benzenesulfonyl)-3-(bromomethyl)indole (7 g, 19.99 mmol, 1 eq.) in THF (50 ml) was added dropwise to a well stirred suspension of KCN (2.07 g, 31.79 mmol , 1.59 eq.) in DMSO (50 ml) and THF (20 ml) at 0° C. under N ₂ atmosphere. The mixture was heated to 25° C. and stirred for 15.5 h under N ₂ atmosphere. TLC (PE/EtOAc = 3/1, Rf = 0.30) indicated that one major new spot was found and the original material remained. KCN (1.76 g, 27.03 mmol, 1.35 eq.) was added to the mixture. The mixture was stirred for 16 h under N ₂ atmosphere. Ice water (200 ml) was added to the mixture. The mixture was subjected to extraction with EtOAc (200 mlx3). The combined organic layers were washed with brine (150 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC: PE /EtOAc=3/1, Rf=0.30) to give 2-[1-(benzenesulfonyl)indol-3-yl]acetonitrile (2.0 g, 5.47 mmol, 27.6% yield, 81 purity, 0%) as a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.02 (d, J=8.3 Hz, 1H), 7.97-7.93 (m, 2H), 7.71 (s, 1H) , 7.64-7.59 (m, 2H), 7.55-7.49 (m, 2H), 7.42-7.37 (m, 1H), 7.33-7.28 (m, 1H), 3.97 (d, J=1.0 Hz, 2H); ER-LCMS m/z 297.1 [M+H]+.

Step 2: 2-[1-(Benzenesulfonyl)indol-3-yl]propanenitrile

n-BuLi (2.5 M, 1.09 ml , 1 equiv.) dropwise at -78°C under N2 atmosphere. The mixture was stirred at 78° C. under N ₂ atmosphere for 1 hour. A solution of MeI (387.96 mg, 2.73 mmol, 170.16 μl, 1 eq.) in THF (5 ml) was added dropwise to the mixture. The mixture was stirred at 20° C. under N2 for 3 hours. TLC (PE/EtOAc = 3/1, Rf = 0.38) indicated that one major new spot was found. Ice water (30 ml) was added to the mixture and the mixture was subjected to extraction with EtOAc (50 mlx3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 5/1 , TLC: PE/EtOAc = 3/1, Rf = 0.38) to give 2-[1-(benzenesulfonyl)indol-3-yl]propanenitrile (420 mg, 1.14 mmol, 41.6% yield, purity 84.0%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.03 (d, J=8.3 Hz, 1H), 7.94-7.89 (m, 2H), 7.62-7.55 (m , 3H), 7.52-7.46 (m, 2H), 7.42-7.37 (m, 1H), 7.34-7.29 (m, 1H), 4.13 (q, J =7.1 Hz, 1H), 1.75 (d, J=7.1 Hz, Zn); ER-LCMS m/z 311.1 [M+H]+.

Step 3: 2-[1-(benzenesulfonyl)indol-3-yl]propan-1-amine

Raney-Ni (453.70 mg, 5.30 mmol , 4.66 eq.) and NH3 H ₂ O (910.00 mg, 6.49 mmol, 1 ml, 5.71 eq.). The mixture was degassed and purged with H ₂ 3 times, stirred at 25° C. for 16 hours. TLC (PE/EtOAc = 3/1, Rf = 0.16) indicated that one major new spot was detected. The reaction mixture was filtered and concentrated to give 2-[1-(benzenesulfonyl)indol-3-yl]propan-1amine (330 mg, 818.70 µmol, 72.0% yield, 78.0% purity) as a white solid the color that was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.01 (d, J=8.3 Hz, 1H), 7.87 (d, J=7.5 Hz, 2H), 7.58-7, 51 (m, 2H), 7.487.40 (m, 2H), 7.38-7.30 (m, 2H), 7.26-7.21 (m, 1H), 4.93 (br s, 2H), 3.08-2.93 (m, 2H), 2.92-2.86 (m, 1H), 1.34 (d, J=6.8 Hz, 3H); ER-LCMS m/z 315.1 [M+H] ⁺ .

Step 4: 2-(1H-indol-3-yl)-propane-1-amine

NaOH (327.46 mg, 8 19 mmol, 10 eq.). The mixture was stirred at 50° C. for 4 hours under N ₂ atmosphere. TCX (DCM/MeOH = 10/1, Rf = 0.20) showed that one major new spot was found. The mixture was concentrated and water (10 ml) was added. The mixture was subjected to extraction with EtOAc (10 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give 2-(1H-indol-3-yl)propan-1-amine (130 mg, 746.09 µmol, 91.1% yield, crude) as a white solid which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.05 (br s, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.42-7.36 (m, 1H ), 7.21 (t, J=7.5 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 3.18-3.10 (m, 1H), 3.05-2.92 (m, 2H), 1.40-1.36 (m, 3H).

Stage 5: 5-(5-fluoro-3-pyridyl)-N-[(2S)-2-( 1 H-indol-3 -yl)propyl] -3-methyl-pyrazolo[1,5a]pyrimidin-7 -amine and 5-(5-fluoro-3-pyridyl)-N-[(2R)-2-(1 H-indol-3-yl)propyl]-3-methyl-pyrazolo[1,5a]pyrimidin-7 -amine (I-160a, I-160b)

To a mixture of 2-(1H-indol-3-yl)propan-1-amine (130 mg, 746.09 µmol, 1 eq.) and 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl- pyrazolo[1,5-a]pyrimidine (200.59 mg, 746.09 µmol, 1 eq.) in i-PrOH (10 ml) was added DIEA (289.28 mg, 2.24 mmol, 389.87 µl, 3 eq.). The mixture was stirred at 80° C. for 15 h under N ₂ and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc 1/0 to 10/3, TLC: PE/EtOAc = 3/1, Rf = 0.34), obtaining 5-(5-fluoro-3-pyridyl)-N-[2-( 1 H-indol-3 -yl)propyl] -3-methyl-pyrazolo [ 1, 5-a]pyrimidine-7 amine (300 mg, 689.22 µmol, 92.4% yield, 92.0% purity) as a yellow solid which was isolated by SFC (column: DAICEL CHIRALCEL OJ (250 mm x 30 mm , 10 µm); mobile phase: [0.1% NH3H2O EtOH]; B%: 40%-40%, min). The solution was concentrated to give crude products which were purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 48%-68%, 8 min) followed by lyophilization to give the enantiomer (27.27 mg, 57.61 µmol, 8.4% yield, 100.0% purity, 2HCl, SFC: Rt = 3.079 min, ee =

98.49%, or [a] ^23.9 _D = +48.385 (MeOH, c = 0.110 g/100 ml)) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.73 (d, J=2.7 Hz, 1H), 8.39 (s, 1H), 8.09 (s, 1H), 7.54 (d , J=8.1 Hz,

2H), 7.11 (d, J=8.1 Hz, 1H), 7.05 (s, 1H), 6.91 (t, J=7.6 Hz, 1H), 6.76 (t, J=7.1Hz, 1H), 5.74(s, 1H), 4.00-3.94(m, 2H), 3.58-3.51(m, 1H), 2.27(s , 3H), 1.59 (d, J=7.1 Hz, 3H); ER-LCMS m/z 401.1 [M+H] ⁺ ; and the other enantiomer (64.75 mg, 136.78 µmol, 19.85% yield, 100% purity, 2HCl, SFC: Rt = 3.374 min, ee = 98.93%, or [a] ^23.8 _D = - 32.08 (MeOH, c = 0.120 g/100 ml)) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.73 (d, J=2.7 Hz, 1H), 8.39 (s, 1H), 8.09 (s, 1H), 7.57-7, 51 (m, 2H), 7.12 (d, J=8.3 Hz, 1H), 7.06 (s, 1H), 6.92 (t, J=7.6 Hz, 1H), 6, 76 (t, J=7.5 Hz, 1H), 5.75 (s, 1H), 4.02-3.92 (m, 2H), 3.59-3.51 (m, 1H), 2 .28 (s, 3H), 1.60 (d, J=7.1 Hz, 3H); ER-LCMS m/z 401.1 [M+H] ⁺ .

Example 137.

Synthesis I-162

Step 1: (3R)-N-[2-(5-fluoro-3-pyridyl)-9-isopropyl-purin-6-yl]-2,3,4,9-tetrahydro-1H-carbazole3-amine (I -162)

6-chloro-2-(5-fluoro-3-pyridyl)-9-isopropyl-purine mixture (60 mg, 187.17 µmol, 1 eq.), (3R)-2,3,4,9tetrahydro-III- carbazole-3-amine (38.35 mg, 205.89 µmol, 1.1 eq.) and DIEA (72.57 mg, 561.51 µmol, 97.81 µl, 3 eq.) in i-PrOH (6 ml) was degassed and purged with N ₂ 3 times. The mixture was stirred at 80°C for 15 hours under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 60%-90%, 8 min) followed by lyophilization to give (3R)-N-[2-(5-fluoro-3-pyridyl)-9-isopropyl-purin-6-yl]-2,3,4,9-tetrahydro-1H- carbazole-3amine (30.19 mg, 58.51 µmol, 31.3% yield, 99.7% purity, 2HCl, [a] ²² ' ³ D = -22.78 (MeOH, c = 0.149 g/100 ml ) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.57 (br.s, 1H), 9.40 (s, 1H), 9.14 (J=8.0 Hz, 1H), 8.99 (br.s. s, 1H), 7.31 (J=7.5Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 7.00 (t, J=7.5Hz, 1H) , 6.94-6.87 (m, 1H), 5.23-5.12 (m, 1H), 5.01 (m, 1H), 3.28 (J=5.0 Hz, 1H), 3.01-2.94 (m, 2H), 2.90 (J=6.8, 15.3 Hz, 1H), 2.42-2.32 (m, 1H), 2.27 (td, J=7.0, 13.7 Hz, 1H), 1.78-1.74 (m, 6H); ER-LCMS m/z 442.1 [M+H]+.

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Example 138.

Synthesis I-163

Step 1: 2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]-1-(1H-indol-3yl )ethanol

A mixture of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (70 mg, 260.36 µmol, 1 eq.), 2-amino-1- (1H-indol-3-yl)ethanol (53.72 mg, 260.36 µmol, 1 eq.), DIEA (100.95 mg, 781.09 µmol, 136.05 µl, 3 eq.) in i- PrOH (15 ml) was stirred at 80° C. for 12 h. The reaction mixture was concentrated to give a residue which was purified by silica gel column chromatography (pure DCM to DCM/MeOH = 10/1, TLC: DCM/MeOH = 10 /1, Rf = 0.60) to give 2-[[5-(5-fluoro3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]-1-(1H -indol-3-yl)ethanol (80 mg, 152.08 µmol, 58.4% yield, 76.5% purity) as a brown solid.

¹ H NMR (400 MHz, CDCl3) δ ppm 8.77 (s, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 7.91 (d, J=8.3 Hz , 1H), 7.82 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.20 (d , J=2.2 Hz, 1H), 6.83-6.76 (m, 1H), 6.07 (s, 1H), 5.38 (t, J=5.4 Hz, 1H), 3 .92 (t, J=5.9 Hz, 2H), 2.35 (s, 3H); ER-LCMS m/z 403.2 [M+H] ⁺ .

Step 2: 2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]-1-(1H-indol-3yl) )ethanone (I-163)

To a solution of 2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-а]pyrimidin-7-yl]amino]-1-(1 H-indole

- 264 041983

3-yl)ethanol (80 mg, 152.08 µmol, 1 eq.) in DCM (10 ml) was added MnO ₂ (396.64 mg, 4.56 mmol, 30 eq.). The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC (column: Agela DuraShell 150 mm x 25 mm x 5 µm; mobile phase: water (0.05% HCl)-ACN; B %: 40%-70%, 8 min) twice followed by lyophilization to give 2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl ]amino]-1(1H-indol-3-yl)ethanone (13.82 mg, 27.88 µmol, 18.3% yield, 95.5% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.95 (s, 1H), 8.76 (d, J=2.7 Hz, 1H), 8.38 (d, J=3.2 Hz, 1H) , 8.28-8.24 (m, 1H), 8.23-8.18 (m, 2H), 7.48 (d, J=7.1 Hz, 1H), 7.29-7.20 (m, 2H), 6.87 (s, 1H), 5.24 (s, 2H), 2.40 (s, 3H); ER-LCMS m/z 401.2 [M+H]+.

Example 139.

Synthesis I-164

Synthesis scheme:

Step 1: 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-8-methyl-pyrazolo[1,5-a][1,3,5 ]triazine4-amine (I-164)

To a solution of 4-chloro-2-(5-fluoro-3-pyridyl)-8-methyl-pyrazolo[1,5-a][1,3,5]triazine (50 mg, 182.24 µmol, 1 eq. ) and 2-(1H-indol-3-yl)ethanamine (32.12 mg, 200.47 µmol, 1.1 eq.) in i-PrOH (10 ml) was added DIEA (188.43 mg, 1.46 mmol, 253.95 µl, 8 eq.). The mixture was stirred at 50° C. for 3 hours. TLC (PE/EtOAc = 3/1, Rf = 0.2) indicated that the starting material had been completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Agela DuraShell 150 mm x 25 mm x 5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 45 %-75%, 9 min). The desired fraction was lyophilized to give 2-(5fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-8-methyl-pyrazolo[1,5-a][1.3.5 ]triazine-4-amine (22.72 mg, 48.65 µmol, 26.7% yield, 98.6% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.15 (s, 1H), 8.83 (broad s, 1H), 8.59 (d, J=9.0 Hz, 1H), 7.95 ( s, 1H), 7.68 (dd, J=2.4, 6.1 Hz, 1H), 7.20-7.12 (m, 1H), 7.05-6.91 (m, 3H) , 4.05 (t, J=6.7 Hz, 2H), 3.19 (t, J=6.7 Hz, 2H), 2.29 (s, 3H); ER-LCMS m/z 388.2 [M+H]+.

- 265 041983

Example 140.

Synthesis I-165

Step 1: (3R)-N-[2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4,9 -tetrahydro-1Hcarbazole-3-amine (I-165)

4-Chloro-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazine mixture (44.89 mg, 172.65 µmol, 1 eq), (3R )-2,3,4,9-tetrahydro-1H-carbazole-3-amine (39.30 mg, 189.92 µmol, 1.1 eq) and DIEA (66.94 mg, 517.95 µmol, 90 .22 μl, 3 eq.) in i-PrOH (3 ml) was degassed and flushed with N2 3 times. The mixture was stirred at 80°C for 12 hours under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 55%-85%, 8 min) followed by lyophilization to give (3R)-N-[2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2, 3,4,9tetrahydro-1H-carbazole-3-amine (20.39 mg, 42.52 µmol, 24.6% yield, 98.5% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.46 (s, 1H), 8.90 (d, J=9.0 Hz, 1H), 8.82 (s, 1H), 8.13 (d, J=2.2Hz, 1H), 7.35(d, J=7.8Hz, 1H), 7.25(d, J=8.1Hz, 1H), 7.06-6.98( m, 1H), 6.97-6.91 (m, 1H), 6.57 (d, J=2.0 Hz, 1H), 4.89 (m, 1H), 3.31-3.26 (m, 1H), 3.11-2.88 (m, 3H), 2.42-2.34 (m, 1H), 2.33-2.21 (m, 1H); ER-LCMS m/z 400.2 [M+H]+; Optical rotation ([a] ²¹⁴ _D = 0.396 (MeOH, c = 0.102 g / 100 ml).

Example 141.

Synthesis I-166

HN

1-166

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Synthesis scheme:

Step 1: 2-(5-fluoro-3-pyridyl)-8-isopropyl-N-[2-(1H-pyrrol-3-yl)ethyl]pyrazolo[1.5a][1.3.5]triazine- 4-amine (I-166)

To a solution of 4-chloro-2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine (50 mg, 168.66 µmol, 1 eq. ) in i-PrOH (3 ml) was added DIEA (21.80 mg, 168.66 µmol, 29.38 µl, 1 eq.) and 2-(1Hpyrrol-3-yl)ethanamine (27.87 mg, 252, 99 µmol, 1.5 eq.). The mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN ];

B%: 60%-90%, 8 min) followed by lyophilization to give 2-(5-fluoro-3-pyridyl)-8-isopropylN-[2-(1H-pyrrol-3-yl)ethyl]pyrazolo[1 ,5-a][1,3,5]triazine-4-amine (15.28 mg, 32.18 µmol, 19.1% yield, 100.0% purity, 3HCl) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (s, 1H), 9.39 (s, 1H), 8.93 (t, J=5.6 Hz, 1H), 8.73 (d, J=2.9Hz, 1H), 8.41 (d, J=8.8Hz, 1H), 8.11 (s, 1H), 6.65 (d, J=2.4Hz , 2H), 5.98 (s, 1H), 3.84-3.75 (m, 2H), 3.23-3.16 (m, 1H), 2.84 (t, J=7.3 Hz, 2H), 1.35 (d, J=6.8 Hz, 6H); ER-LCMS m/z 366.2 [M+H]+.

Example 142.

Synthesis I-169

Step 1: methyl 3-(5-fluoro-3-pyridyl)-2-methyl-3-oxo-propanoate

To a solution of methyl-(2)-3-(5-fluoro-3-pyridyl)-3-hydroxy-prop-2-enoate (600.00 mg, 2.83 µmol, 1 eq.) and MeI (401.71 mg, 2.83 µmol, 176.19 µl, 1 eq.) in DMF (20 ml) was added K ₂ CO ₃ (391.14 mg, 2.83

- 267 041983 µmol, 1 eq.). The mixture was stirred at 20°C for 3 hours. The reaction mixture was quenched by adding H2O (50 ml), extracted with EtOAc (50 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/1, TLC: PE/EtOAc = 10 /1, Rf = 0.37) to give the title product methyl 3-(5-fluoro-3-pyridyl)-2-methyl-3-oxopropanoate (605 mg, 2.69 µmol, 95.0% yield, purity 93.9%) as a yellow oil.

1 H NMR (400 MHz CDCl ₃ ) δ ppm 9.00 (d, J=1.5 Hz, 1H), 8.78-8.61 (m, 1H), 8.03-7.90 (m, 1H ), 4.36 (q, J=7.1 Hz, 1H), 3.71 (s, 3H), 1.57-1.52 (m, 3H); ER-LCMS m/z 212.1 [M+H]+.

Step 2: 5-(5-fluoro-3-pyridyl)-3,6-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ol

Methyl 3-(5-fluoro-3-pyridyl)-2-methyl-3-oxo-propanoate (300 mg, 1.33 µmol, 1 eq.), 4-methyl-1Hpyrazol-5-amine (647.37 mg, 6.67 µmol, 5 eq.) were placed in a microwave tube in AcOH (5 ml). The sealed tube was heated at 150° C. for 1 hour while being treated with microwave radiation. The mixture was concentrated under reduced pressure to give 5-(5-fluoro-3-pyridyl)-3,6dimethyl-pyrazolo[1,5-a]pyrimidin-7-ol (300 mg, 1.16 µmol, 87.14% yield ) as a white solid, which was used in the next step without further purification.

Step 3: 7-chloro-5-(5-fluoro-3-pyridyl)-3,6-dimethyl-pyrazolo[1,5-a]pyrimidine

Solution of 5-(5-fluoro-3-pyridyl)-3,6-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ol (270 mg, 1.05 µmol, 1 eq.) in POCl ₃ (8 .25 g, 53.80 µmol, 5.00 ml, 51.46 eq.) was stirred at 110°C for 3 hours. The reaction mixture was poured into ice water (50 g), extracted with DCM (50 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3 /1, Rf = 0.51) to give 7-chloro-5-(5-fluoro-3-pyridyl)-3,6-dimethyl-pyrazolo[1,5a]pyrimidine (200 mg, 337.55 µmol, yield 32.3%, 46.7% pure) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.01 (d, J=1.2 Hz, 1H), 8.68 (s, 1H), 8.61 (s, 1H), 8.08 (s , 1H), 2.65 (s, 3H), 2.63 (s, 3H); ER-LCMS m/z 277.1 [M+H]+.

Step 4: 5-(5-Fluoro-3-pyridyl)-N-[2-(1 H-indol-3-yl)ethyl]-3,6-dimethylpyrazolo[1,5-a]pyrimidine7-amine (I-169)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3,6-dimethyl-pyrazolo[1,5-a]pyrimidine (100 mg, 168.78 µmol, 1 eq.) and 2-( 1H-indol-3-yl)ethanamine (40.56 mg, 253.17 µmol, 1.5 eq.) in i-PrOH (4 mL) was added DIEA (87.25 mg, 675.11 µmol, 117.59 µl, 4 eq.). The mixture was stirred at 70° C. for 3 h and concentrated to give a residue which was purified by preparative HPLC (Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN] ; B%: 50%80%, 8 min) followed by lyophilization to give 5-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]3,6-dimethyl -pyrazolo[1,5-a]pyrimidine-7-amine (33.61 mg, 83.93 µmol, 49.7% yield, 100.0% purity) as a yellow solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 8.49 (d, J=2.7 Hz, 1H), 8.13 (s, 1H), 7.89 (s, 1H), 7.52 ( d, J=7.8 Hz, 1H), 7.30-7.26 (m, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.07 (t, J=7 .5 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.71 (s, 1H), 4.16-4.12 (m, 2H), 3.12-3 .09 (m, 2H), 2.26 (s, 3H), 1.88 (s, 3H); ER-LCMS m/z 401.2 [M+H]+.

- 268 041983

Example 143.

Synthesis I-171

Stage 1: 5-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)propyl]-3-methyl-pyrazolo[1,5-a]pyrimidine7-amine (I- 171)

A mixture of 2-(1H-indol-3-yl)propan-1-amine (30 mg, 172.17 µmol, 1 eq.) and 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo [1,5-a]pyrimidine (46.29 mg, 172.17 µmol, 1 eq.) in i-PrOH (6 ml) was added DIEA (66.76 mg, 516.52 µmol, 89.97 µl, 3 equiv.). The mixture was stirred at 80°C for 15 hours under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 48%-68%, 8 min) followed by lyophilization to give 5-(5-fluoro-3pyridyl)-N-[2-(1H-indol-3-yl)propyl]-3-methyl-pyrazolo[1,5-a]pyrimidin-7 -amine (18.71 mg, 39.52 µmol, 23.0% yield, 100.0% purity, 2HCl) as an orange solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.80 (br s, 1H), 8.44 (br s, 1H), 8.09 (s, 1H), 7.64 (br s, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 7.05 (s, 1H), 6.92 (t, J=7.3 Hz, 1H), 6.80-6.74 (m, 1H), 5.75 (s, 1H), 4.04-3.92 (m, 2H), 3.59-3 .50 (m, 1H), 2.28 (s, 3H), 1.59 (d, J=7.3 Hz, 3H); ER-LCMS m/z 401.1 [M+H]+.

Example 144.

Synthesis I-172

- 269 041983

Synthesis scheme:

Stage 1: 7-methoxy-1H-indole-3-carbaldehyde

To a solution of POC13 (1.13 g, 7.37 mmol, 684.85 µl, 1.08 eq.) in DMF (12 ml) was added 7-methoxy1H-indole (1 g, 6.79 mmol, 884.96 µl , 1 equiv.) at 0°С. The mixture was stirred at 0~20°C for 3 hours under N ₂ atmosphere. TCX (PE/EtOAc = 3/1, Rf = 0.25) showed that one major new spot was found. The pH of the mixture was adjusted to 10-12 with 2N. NaOH. The mixture was subjected to extraction with DCM (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 5/2, TLC: PE/EtOAc = 3/1, Rf = 0.25) to give 7-methoxy-1H-indole-3-carbaldehyde (900 mg, 5.03 mmol, 74.1% yield, 98.0% purity) as a pink solid.

1H NMR (400 MHz, CDC13) δ ppm 10.07 (s, 1H), 9.18 (broad s, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.81 ( d, J=3.1 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 6.78 (d, J=7.7 Hz, 1H), 3.98 (s, 3H); ER-LCMS m/z 176.1 [M+H]+.

Stage 2: 7-methoxy-3-[(E)-2-nitrovinyl]-1H-indole

A mixture of 7-methoxy-1H-indole-3-carbaldehyde (900 mg, 5.03 mmol, 1 eq.) and NH ₄ OAc (504.52 mg, 6.55 mmol, 1.3 eq.) in THF (10 ml) was added CH ₃ NO ₂ (11.30 g, 185.12 mmol, 10 ml, 36.77 eq.). The mixture was degassed and purged with N2 3 times and stirred at 80° C. for 19 hours under N2. TCX (PE/EtOAc = 1/1, Rf = 0.60) showed that one major new spot was found. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 5/2, TLC: PE/EtOAc = 1/1, Rf = 0.60) to give 7-Methoxy-3-[(E)-2-nitrovinyl]-1H-indole (660 mg, 2.87 mmol, 57.1% yield, 95.0% purity) as an orange solid.

1H NMR (400 MHz, CDCI3) δ ppm 8.92 (broad s, 1H), 8.29 (d, J=13.5 Hz, 1H), 7.79 (d, J=13.5 Hz, 1H), 7.63 (d, J=3.1 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.26-7.24 (m, 1H), 6, 80 (d, J=7.7 Hz, 1H), 4.00 (s, 3H).

Stage 3: 2-(7-methoxy-1H-indol-3-yl)ethanamine

- 270 041983

LiAlH ₄ (247.86 mg, 6 .53 mmol, 5 eq.). The mixture was stirred at 80° C. for 2 hours under N ₂ atmosphere. TCX (PE/EtOAc = 3/1, Rf = 0.10) showed that one major new spot was found. 2 ml of H2O and 1 ml of 2N hydrochloric acid were added to the mixture. NaOH. The mixture was filtered and concentrated to give 2-(7methoxy-1H-indol-3-yl)ethanamine (240 mg, 1.20 mmol, 91.8% yield, 95.0% purity) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.22 (br s, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.07-7.01 (m, 2H) , 6.66 (d, J=7.6 Hz, 1H), 3.97 (s, 3H), 3.06-3.01 (m, 2H), 2.93-2.87 (m, 2H ).

Step 4: 5-(5-fluoro-3-pyridyl)-N-[2-(7-methoxy-1H-indol-3-yl)ethyl]-3-methyl-pyrazolo[1,5a]pyrimidin-7- amine

A mixture of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (230 mg, 855.48 µmol, 1 eq.), 2-(7-methoxy -1H-indol-3-yl)ethanamine (217.00 mg, 1.03 mmol, 1.2 eq.) and DIEA (331.70 mg, 2.57 mmol, 447.03 µl, 3 eq.) i-PrOH (10 ml) was degassed and purged with N2 3 times. The mixture was stirred at 80° C. for 16 h under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela DuraShell 150 mm x 25 mm x 5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 35%-65% , 9 min) followed by lyophilization to give 5-(5-fluoro-3-pyridyl)-N-[2-(7-methoxy-1H-indol-3-yl)ethyl]-3methyl-pyrazolo[1,5- a] pyrimidine-7-amine (240 mg, 490.42 µmol, 57.3% yield, 100.0% purity, 2HCl) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.72 (d, J=2.7 Hz, 1H), 8.30 (s, 1H), 8.10 (s, 1H), 7.43 (td , J=2.3, 9.0 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 6.87 (s, 1H), 6.80 (t, J=7, 8 Hz, 1H), 6.48 (d, J=7.6 Hz, 1H), 5.62 (s, 1H), 4.043.98 (m, 2H), 3.81 (s, 3H), 3 .21-3.16 (m, 2H), 2.29 (s, 3H); ER-LCMS m/z 417.1 [M+H]+.

Step 5: 3-[2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]ethyl]-1Hindol-7-ol (I-172)

To a solution of 5-(5-fluoro-3-pyridyl)-N-[2-(7-methoxy-1H-indol-3-yl)ethyl]-3-methyl-pyrazolo[1,5а]pyrimidin-7-amine (200 mg, 480.25 µmol, 1 eq.) in DCM (10 ml) was added BBr ₃ (240.63 mg, 960.50 µmol, 92.55 µl, 2 eq.) at 0°C. The mixture was stirred at 0~20°C for 0.5 h under N2 atmosphere. 1 ml of MeOH was added to the mixture. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 35%-65%, 8 min) followed by lyophilization to give 3-[2-[[5-(5fluoro-3-niridyl)-3-methyl-n-pyrazolo[1,5-a]pyrimidin-7-yl]amino]ethyl]-1H-indole -7-ol (22.74 mg, 45.54 µmol, 9.5% yield, 95.2% purity, 2HCl) as an orange solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.71 (d, J=2.7 Hz, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.43 (J =9.0 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 6.87 (s, 1H), 6.69 (td, J=3.8, 7.9 Hz , 1H), 6.36 (d, J=7.6 Hz, 1H), 5.65 (s, 1H), 4.04-3.98 (m, 2H), 3.21-3.15 ( m, 2H), 2.29 (s, 3H); ER-LCMS m/z 403.1 [M+H] ⁺ .

Example 145.

Synthesis I-175

- 271 041983

5-(5-fluoro-3-pyridyl)-N3,N3-dimethyl-N7-[(3R)-2,3,4,9-tetrahydro-1H-carbazole-3 [Step 1:

yl]pyrazolo[1,5-a]pyrimidine-3,7-diamine (I-175)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-N,N-dimethyl-pyrazolo[1,5-a]pyrimidine-3-amine (50 mg, 171.40 µmol, 1 eq.) in i-PrOH (5 ml) was added DIEA (66.46 mg, 514.21 µmol, 89.56 µl, 3 eq.) and (3R)2,3,4,9-tetrahydro-1H-carbazole-3- amine (35.12 mg, 188.54 µmol, 1.1 eq.). The mixture was stirred at 90°C for 12 hours under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela DuraShell 150 mm x 25 mm x 5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 30%-60% , 8 min) followed by lyophilization to give 5-(5-fluoro-3-pyridyl)-N3,N3-dimethyl-N7-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3yl] pyrazolo[1,5-a]pyrimidine-3,7-diamine (22.71 mg, 43.35 µmol, 25.3% yield, 98.2% purity, 2HCl) as a yellow solid.

¹ H NMR (400 MHz, DMSOL) δ ppm 10.82 (s, 1H), 9.41 (s, 1H), 8.72 (s, 1H), 8.66-8.55 (m, 2H) , 8.49 (br s, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.31-7.25 (m, 2H), 7.04-6.98 (m , 1H), 6.96-6.91 (m, 1H), 4.56 (br s, 1H), 3.37 (s, 6H), 3.18-3.01 (m, 2H), 2.99-2.82 (m, 2H), 2.28-2.09 (m, 2H); ER-LCMS m/z 442.3 [M+H]+.

Example 146.

Synthesis I-177

Step 1: 2-[5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3yl]propan-2- ol (I-177)

- 272 041983

To MeLi (1.3 M, 5 ml, 57.13 eq.) was added a solution of 1-[5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3yl)ethylamino]pyrazolo[ 1,5-a]pyrimidin-3-yl]ethanone (50 mg, 113.77 µmol, 1 eq.) in THF (2 ml) dropwise under N ₂ atmosphere at -20°C. The mixture was stirred under N2 atmosphere at -20°C for 0.5 h. The reaction was quenched with water (10 ml) and the reaction mixture was extracted with EtOAc (50 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela Durashell C18 150x30 5u;

mobile phase: [water (10 mm NH ₄ HCO ₃ )-ACN]; B%: 40%-60%, 9 min). The desired fraction was lyophilized to give 2-[5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5a]pyrimidin-3-yl]propan- 2-ol (13.48 mg, 31.31 µmol, 27.5% yield, 100.0% purity) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.69 (s, 1H), 8.43 (d, J=2.8 Hz, 1H), 7.98 (s, 1H), 7.74 (td , J=2.0, 9.6 Hz, 1H), 7.68 (dd, J=2.8, 6.0 Hz, 1H), 7.24-7.16 (m, 1H), 7, 09-7.02 (m, 2H), 6.98 (s, 1H), 6.00 (s, 1H), 3.86 (t, J=6.0 Hz, 2H), 3.18 (t , J=6.0 Hz, 2H), 1.72 (s, 6H); ER-LCMS m/z 431.1 [M+H]+.

Example 147.

Synthesis I-179

To a solution of POCl ₃ (1.13 g, 7.37 mmol, 684.85 μl, 1.08 eq.) in DMF (12 ml) was added 7-methoxy1H-indole (1 g, 6.79 mmol, 884.96 µl, 1 eq.) at 0°C. The mixture was stirred at 0~20°C for 3 hours under N2 atmosphere. TLC (PE/EtOAc = 3/1, Rf = 0.25) showed that one major new spot was found. The pH of the mixture was adjusted to 10~12 with 2N. NaOH. The mixture was subjected to extraction with DCM (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 5/2, TLC: PE/EtOAc = 3/1, Rf = 0.25) to give 7-methoxy-1H-indole-3-carbaldehyde (900 mg, 5.03 mmol, 74.1% yield, 98.0% purity) as a pink solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 10.07 (s, 1H), 9.18 (broad s, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.81 (d,

- 273 041983

J=3.1Hz, 1H), 7.24(t, J=7.9Hz, 1H), 6.78(d, J=7.7Hz, 1H), 3.98(s, 3H) ; ER-LCMS m/z 176.1 [M+H]+.

Stage 2: 7-methoxy-3-[(E)-2-nitrovinyl]-1H-indole

A mixture of 7-methoxy-1H-indole-3-carbaldehyde (900 mg, 5.03 mmol, 1 eq.) and NH ₄ OAC (504.52 mg, 6.55 mmol, 1.3 eq.) in THF (10 ml) was added CH ₃ NO ₂ (11.30 g, 185.12 mmol, 10 ml, 36.77 eq.). The mixture was degassed and purged with N2 3 times and stirred at 80° C. for 19 hours under N2. TLC (PE/EtOAc = 1/1, Rf = 0.60) showed that one major new spot was found. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 5/2, TLC: PE/EtOAc = 1/1, Rf = 0.60) to give 7-Methoxy-3-[(E)-2-nitrovinyl]-1H-indole (660 mg, 2.87 mmol, 57.1% yield, 95.0% purity) as an orange solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.92 (broad s, 1H), 8.29 (d, J=13.5 Hz, 1H), 7.79 (d, J=13.5 Hz , 1H), 7.63 (d, J=3.1 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.26-7.24 (m, 1H), 6 .80 (d, J=7.7 Hz, 1H), 4.00 (s, 3H).

Stage 3: 2-(7-methoxy-1H-indol-3-yl)ethanamine

LiAlH ₄ (247.86 mg, 6 .53 mmol, 5 eq.). The mixture was stirred at 80° C. for 2 hours under N ₂ atmosphere. TCX (PE/EtOAc = 3/1, Rf = 0.10) showed that one major new spot was found. H ₂ O (2 ml) was added to the mixture, followed by 2N. NaOH (1 ml). The mixture was filtered and concentrated to give 2(7-methoxy-1H-indol-3-yl)ethanamine (240 mg, 1.20 mmol, 91.8% yield, 95.0% purity) as a yellow solid which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.22 (br s, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.07-7.01 (m, 2H) , 6.66 (d, J=7.6 Hz, 1H), 3.97 (s, 3H), 3.06-3.01 (m, 2H), 2.93-2.87 (m, 2H ).

Step 4: 5-(5-fluoro-3-pyridyl)-N-[2-(7-methoxy-1 H-indol-3-yl)ethyl]-3-methyl-pyrazolo[1,5a]pyrimidine-7 -amine (I-179)

A mixture of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (230 mg, 855.48 µmol, 1 eq.), 2-(7-methoxy -1H-indol-3-yl)ethanamine (217.00 mg, 1.03 mmol, 1.2 eq.) and DIEA (331.70 mg, 2.57 mmol, 447.03 µl, 3 eq.) i-PrOH (10 ml) was degassed and purged with N2 3 times. The mixture was stirred at 80° C. for 16 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela DuraShell 150 mm x 25 mm x 5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 35%-65% , 9 min) followed by lyophilization to give 5-(5-fluoro-3-pyridyl)-N-[2-(7-methoxy-1H-indol-3-yl)ethyl]-3methyl-pyrazolo[1,5- a] pyrimidine-7-amine (240 mg, 490.42 µmol, 57.3% yield, 100.0% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.72 (d, J=2.7 Hz, 1H), 8.30 (s, 1H), 8.10 (s, 1H), 7.43 (td, J=2.3, 9.0 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 6.87 (s, 1H), 6.80 (t, J=7.8 Hz, 1H), 6.48 (d, J=7.6 Hz, 1H), 5.62 (s, 1H), 4.043.98 (m, 2H), 3.81 (s, 3H), 3, 21-3.16 (m, 2H), 2.29 (s, 3H); ER-LCMS m/z 417.1 [M+H] ⁺ .

Example 148.

Synthesis I-180

- 274 041983

Synthesis scheme:

Step 1: 2-(1H-pyrazol-3-yl)acetonitrile

_KCN (300 mg, 4.61 mmol, 197.37 μl, 2.01 eq.) and H ₂ O (1 ml). The mixture was stirred at 50° C. for 12 hours. TLC (DCM/MeOH = 10/1, R _f = 0.4) showed that the starting material had been completely consumed and one new spot had formed. The reaction mixture was diluted with H ₂ O (10 ml) and extracted with EtOAc (20 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 2-(1H-pyrazol-3-yl)acetonitrile (150 mg, 1.33 mmol, 58.2% yield, 95.0% purity ) as a yellow oil, which was used in the next step without further purification.

1H NMR (400 MHz, DMSO-b ₆ ) δ ppm 12.84 (s, 1H), 7.73 (s, 1H), 6.23 (s, 1H), 3.95 (s, 2H); ER-LCMS: The correct mass was not found.

Step 2: 2-(1H-pyrazol-3-yl)ethanamine

To a solution of 2-(1H-pyrazol-3-yl)acetonitrile (150 mg, 1.33 mmol, 1 eq) in MeOH (10 ml) was added Raney-Ni (600 mg, 7.00 mmol, 5.26 eq. .) in an Ar atmosphere. The suspension was degassed and purged with H ₂ 3 times. The mixture was stirred in H ₂ (15 psi) at 20° C. for 12 hours. TLC (DCM/MeOH = 10/1, Rf = 0.4) indicated that the starting material had been completely consumed. The reaction mixture was filtered and concentrated under reduced pressure to give 2-(1H-pyrazol-3-yl)ethanamine (100 mg, 899.73 µmol, 67.6% yield, crude) as a brown solid which was used in the next step without further purification.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.64 (s, 1H), 7.42-7.35 (m, 1H), 5.98 (s, 1H), 3.10-2, 94 (m, 2H), 2.82 (d, J=17.6 Hz, 2H); ER-LCMS: The correct mass was not found.

Step 3: 5-(5-fluoro-3-pyridyl)-3-methyl-N-[2-(1H-pyrazol-3-yl)ethyl]pyrazolo[1,5-a]pyrimidin-7 amine (I -180)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (75 mg, 279.53

- 275 041983 µmol, 1 eq.) in i-PrOH (3 ml) was added DIEA (180.64 mg, 1.40 mmol, 243.45 µl, 5 eq.) and 2-(1Hpyrazol-3-yl)ethanamine (62.14 mg, 559.07 µmol, 2 eq). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN ]; B%: 15%-45%, 9 min) followed by lyophilization to give 5-(5-fluoro-3pyridyl)-3-methyl-N-[2-(1H-pyrazol-3-yl)ethyl]pyrazolo [1,5-a]pyrimidine-7-amine (21.84 mg, 48.89 µmol, 17.5% yield, 100.0% purity, 3HCl) as a yellow solid.

Ή NMR (400 MHz, CD3OD) δ ppm 9.07 (s, 1H), 8.88 (d, J=2.4 Hz, 1H), 8.45 (td, J=2.3, 8.9 Hz, 1H), 8.21 (d, J=2.7 Hz, 1H), 8.16 (s, 1H), 7.01 (s, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.16 (t, J=7.0 Hz, 2H), 3.37 (t, J=7.0 Hz, 2H), 2.40 (s, 3H); ER-LCMS m/z 338.1 [M+H] ⁺ .

Example 149.

Synthesis I-186

Synthesis scheme:

Step 1: 2-(5-fluoro-3-pyridyl)-8-methyl-N-[2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]pyrazolo[1,5a][ 1,3,5]triazine-4-amine (I-186)

To a solution of 4-chloro-2-(5-fluoro-3-pyridyl)-8-methyl-pyrazolo[1,5-a][1,3,5]triazine (50 mg, 189.64 µmol, 1 eq. ) in i-PrOH (5 ml) was added DIEA (73.53 mg, 568.92 µmol, 99.09 µl, 3 eq.) and 2-(1Hpyrrolo[3,2-b]pyridin-3-yl)ethanamine (40 mg, 248.13 µmol, 1.31 eq.). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; V%: 10%-40%, 9 min). The desired fraction was lyophilized to give 2-(5-fluoro-3-pyridyl)-8-methyl-N-[2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]pyrazolo[1.5a ][1,3,5]triazine-4-amine (30.06 mg, 60.39 µmol, 31.8% yield, 100.0% purity, 3HCl) as a yellow solid.

Ή NMR (400 MHz, CD3OD) δ ppm 9.37 (d, J=1.3 Hz, 1H), 8.92 (d, J=2.3 Hz, 1H), 8.82 (d, J= 8.8 Hz, 1H), 8.48 (d, J=5.8 Hz, 1H), 8.40 (d, J=8.3 Hz, 1H), 7.98 (d, J=10, 5 Hz, 2H), 7.55 (dd, J=5.9, 8.2 Hz, 1H), 4.19 (t, J=6.3 Hz, 2H), 3.38 (t, J= 6.4 Hz, 2H), 2.29 (s, 3H); ER-LCMS m/z 389.1 [M+H]+.

Example 150.

Synthesis of I-187b

- 276 041983

Synthesis scheme:

Step 1: (2S)-2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]-3-(1Hindole-3 -yl) propanoic acid

7-Chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine mixture (100 mg, 380.71 µmol, 1 eq), (2S)-2- amino-3-(1H-indol-3-yl)propanoic acid (77.75 mg, 380.71 µmol, 1 eq.), DIEA (147.61 mg, 1.14 mmol, 198.93 µl, 3 eq. .) in i-PrOH (10 ml) was stirred at 80°C for 12 hours. The reaction mixture was concentrated to give (2S)-2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo [1,5-a]pyrimidin-7yl]amino]-3-(1H-indol-3-yl)propanoic acid (160 mg, 371.72 µmol, 97.6% yield, 100.0% purity) as brown oil, which was used in the next step without further purification.

1H NMR (400 MHz, DMSO-d6) δ ppm 10.69 (s, 1H), 8.91 (s, 1H), 8.57 (d, J=2.7 Hz, 1H), 7.96 ( d, J=10.0 Hz, 1H), 7.88 (s, 1H), 7.59-7.50 (m, 2H), 7.19 (d, J=8.1 Hz, 1H), 7.02-6.94 (m, 2H), 6.91-6.85 (m, 1H), 6.29 (s, 1H), 4.62 (s, 1H), 3.58-3, 54 (m, 1H), 2.94 (s, 2H), 2.21 (s, 3H); ER-LCMS m/z 431.2[M+H]+.

Step 2: (2S)-2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]-3-(1Hindole-3 -yl)-N,N-dimethyl-propanamide (I-187b)

To a solution of (2S)-2-[[5-(5-fluoro-3-iiridyl)-3-methyl-iirazolo[1,5-а]iirimidin-7-yl]amino]-3-(1Hindole-3- yl) propanoic acid (80 mg, 183.26 µmol, 1 eq) and N-methylmethanamine; hydrochloride (29.89 mg, 366.52 µmol, 2.0 eq.) in DMF (20 ml) was added HATU (139.36 mg, 366.52 µmol, 2.0 eq.) and Et ₃ N (92, 72 mg, 916.30 µmol, 127.54 µl, 5.0 eq.). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 30%-60%, 9 min) followed by lyophilization to give (2S)-2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1.5 -a] pyrimidin-7-yl] amino]-3 -(1 H-indol-3 -yl)-N,N-dimethyl-propanamide (17.77 mg, 32.74 µmol, 17.9% yield, purity 97.7%, 2HCl) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.73 (d, J=2.3 Hz, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.57 (d , J=8.3Hz, 1H), 7.45(d, J=8.0Hz, 1H), 7.07(d, J=8.0Hz, 1H), 7.01(s, 1H ), 6.91 (t, J=7.4 Hz, 1H), 6.84-6.77 (m, 1H), 5.83 (s, 1H), 5.40 (d, J=8, 5 Hz, 1H), 3.52 (dd, J=3.0, 14.6 Hz, 1H), 3.31 (s, 3H), 3.13-3.07 (m, 1H), 3, 04 (s, 3H), 2.27 (s, 3H); ER-LCMS m/z 458.3 [M+H]+.

Example 151.

Synthesis I-192

Synthesis scheme:

Step 1: 3-bromo-5-(5-fluoro-3-pyridyl)-N-[2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]pyrazolo[1,5a]pyrimidine -7-amine (I-192)

To a solution of 3-bromo-7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (100 mg, 305.31 µmol, 1 eq.) in i-PrOH (5 ml ) 2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethanamine (50 mg, 310.17 µmol, 1.02 eq.) and DIEA (118.38 mg, 915.92 µmol, 159.54 µl, 3 eq.). The mixture was stirred at 60°C for 12 hours under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; V%: 25%-55%, 9 min) followed by lyophilization to give 3-bromo-5-(5-fluoro-3-pyridyl)-N-[2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]pyrazolo[ 1,5-a]pyrimidine 7-amine (37.41 mg, 65.74 µmol, 21.5% yield, 98.7% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.11 (s, 1H), 8.72 (d, J=2.5 Hz, 1H), 8.50-8.47 (m, 2H), 8, 46 (s, 1H), 8.12 (s, 1H), 8.05 (s, 1H), 7.62 (dd, J=5.9, 8.2 Hz, 1H), 6.69 (s , 1H), 4.03 (t, J=6.7 Hz, 2H), 3.39 (t, J=6.8 Hz, 2H); ER-LCMS m/z 452.0, 454.0 [M+H] ⁺ .

Example 152.

Synthesis I-195

Synthesis scheme:

- 278 041983

Stage 1: tert-butyl N-[2-[4-(methanesulfonamido)phenyl]ethyl]carbamate

MsCl (327.20 mg, 2.86 mmol, 221.08 µl, 4.5 eq.) and TEA (321.16 mg, 3.17 mmol, 441.76 µl, 5 eq.). The mixture was stirred at 20° C. for 20 hours. The reaction mixture was quenched by adding saturated NaHCO ₃ (50 ml), extracted with EtOAc (30 mlx3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 1/1 , TLC: PE/EtOAc = 1/1, Rf = 0.37) to give tert-butyl N-[2-[4(methanesulfonamido)phenyl]ethyl]carbamate (190 mg, 186.13 µmol, yield 29.3 %, purity 30.8%) as a colorless oil.

1H NMR (400 MHz, CDCI3) δ ppm 7.25-7.11 (m, 4H), 6.45 (br s, 1H), 4.58-4.49 (m, 1H), 3.37 (d, J=6.8 Hz, 2H), 3.01 (s, 3H), 2.79 (t, J=7.0 Hz, 2H), 1.44 (s, 9H); ER-LCMS m/z 337.1 [M+Na]+.

Stage 2: N-[4-(2-aminoethyl)phenyl]methanesulfonamide h ₂ n

TFA (212.23 mg, 1 86 mmol, 137.81 µl, 10 eq.). The mixture was stirred at 20° C. for 20 minutes. TLC (PE/EtOAc = 1/1, Rf = 0.06) indicated that the starting material had been consumed. The reaction mixture was concentrated under reduced pressure to give crude N[4-(2-aminoethyl)phenyl]methanesulfonamide (61 mg, crude, TFA) as a yellow oil, which was used in the next step without further purification.

Step 3: N-[4-[2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7yl]amino]ethyl]phenyl]methanesulfonamide (I -195)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (48.80 mg, 185.80 µmol, 1 eq.) in i-PrOH (10 ml) was added DIEA (120.07 mg, 929.01 µmol, 161.81 µl, 5 eq.) and N-[4-(2aminoethyl)phenyl]methanesulfonamide (61 mg, 185.80 µmol, 1 eq. , TFU). The mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini C18 250x50 mmx10 μm; mobile phase: [water (0.05% HCl)- ACN]; B%: 25%-55%, 9 min) followed by lyophilization to give N-[4-[2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1, 5-a]pyrimidin-7yl]amino]ethyl]phenyl]methanesulfonamide (50.35 mg, 95.81 µmol, 51.5% yield, 97.7% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.89 (s, 1H), 8.85 (d, J=2.3 Hz, 1H), 8.27-8.22 (m, 1H), 8, 14 (s, 1H), 7.26 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.5 Hz, 2H), 6.53 (s, 1H), 4, 01 (t, J=6.7 Hz, 2H), 3.08 (t, J=6.7 Hz, 2H), 2.87 (s, 3H), 2.36 (s, 3H); ER-LCMS m/z 441.0 [M+H] ⁺ .

Example 153.

- 279 041983

Synthesis I-196

Synthesis scheme:

Step 1: 3-[(E)-2-nitrovinyl]-1H-pyrrole

NH4OAC (891.60 mg, 11.57 mmol, 1.1 equiv.). The mixture was stirred at 80° C. for 12 hours. TLC (TLC: PE/EtOAc = 3/1, Rf = 0.45) showed that no starting material remained and one large new spot with less polarity was found. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC: PE/EtOAc = 3/1, Rf = 0.45) to give the indicated product 3-[(E)-2-nitrovinyl]-III-pyrrole (1.2 g, 7.82 mmol, 74.4% yield, 90.0% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.64 (broad s, 1H), 8.03 (d, J=13.4 Hz, 1H), 7.44 (d, J=13.3 Hz, 1H), 7.22 (td, J=1.6, 2.8 Hz, 1H), 6.88 (q, J=2.4 Hz, 1H), 6.49-6.43 (m , 1H).

Step 2: 2-(1H-pyrrol-3-yl)ethanamine

LiAlH ₄ (370.96 mg, 9.77 mmol, 5.0 equiv.) under ice baths. The mixture was stirred at 80° C. for 2 hours. TLC (TLC: PE/EtOAc = 3/1, Rf = 0.56) indicated that no starting material remained and one major new spot with greater polarity was found. The reaction mixture was quenched by adding H ₂ O (1.5 ml), 1N. NaOH (1.5 ml) and H ₂ O (1.5 ml) under ice baths, filtered and concentrated under reduced pressure to give the crude product 2-(1P-pyrrol-3-yl)ethanamine (180 mg, 1.63 mmol, 83.6% yield, crude purity) as a brown oil, which was used in the next step without further purification.

1H NMR (400 MHz, CDC13) δ ppm 8.12 (broad s, 1P), 6.80-6.72 (m, 1H), 6.63 (d, J=1.3 Hz, 1P), 6.146.08 (m, 1P), 2.93-2.85 (m, 2H), 2.63 (t, J=6.7 Hz, 2H).

Step 3: 5-(5-fluoro-3-pyridyl)-3-methyl-N-[2-(1 P-pyrrol-3-yl)ethyl]pyrazolo[1,5-a]pyrimidin-7 amine (I -196)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (50 mg, 190.35 µmol, 1 eq.) and 2-(1P- pyrrol-3-yl)ethanamine (41.94 mg, 380.71 µmol, 2.0 eq.) in i-PrOH (10 ml) was added with DIEA (73.81 mg, 571.06 µmol, 99 .47 µl, 3.0 eq.). The mixture was stirred at 70° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HC1)-ACN ]; B%: 30%-60%, 9 min) to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% ammonium hydroxide o6./o6. )-ACN]; B%: 35%-65%, 10 min) followed by lyophilization to give 5-(5-fluoro-3-pyridyl)-3methyl-L1-[2-(1H-pyrrol-3-yl) ethyl]pyrazolo[1,5-a]pyrimidine-7-amine (15.72 mg, 46.73 µmol, 24.6% yield, 100.0% purity) as a yellow solid.

*H NMR (400 MHz, CD ₃ OD) δ ppm 9.03 (s, 1H), 8.53 (d, J=2.7 Hz, 1H), 8.19 (d, J=9.5 Hz , 2H), 7.87 (s, 1H), 6.80 (d, J=2.4 Hz, 1H), 6.72 (s, 1H), 6.48 (broad s, 1H), 6 .27 (s, 1H), 6.19 (broad s, 1H), 3.69 (q, J=6.4 Hz, 2H), 2.99 (t, J=6.8 Hz, 2H) , 2.39 (s, 3N); ER-LCMS m/z 337.2 [M+H] ⁺ .

Example 154.

Synthesis 1-197

Step 1: [5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3yl]methanol (1-197)

To a solution of 5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3carboxylic acid (50 mg, 110.71 µmol , 1 eq.) in THF (8 ml) was added LAH (50 mg, 1.32 mmol, 11.90 eq.) at 0°C. The mixture was stirred at 80° C. for 12 hours under N ₂ . The reaction mixture was diluted with THF (40 ml), quenched by adding water (0.5 ml), 10% NaOH (0.5 ml) and water (1.5 ml) successively at 0°C. After stirring for 30 minutes, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Xbridge 150x30 mmx10 μm; mobile phase: [water (0.05% ammonium hydroxide v/v) ACN]; V%: 25%- 55%, 8 min) followed by lyophilization to give [5-(5-fluoro-3-pyridyl)-7-[2-(1Hin to l-3-yl)ethylamino]pyrazolo[1,5-a]pyrimide in -3-yl]methanol (6 mg, 14.91 µmol, 13.5% yield, 100% purity) as a yellow solid.

*H NMR (400 MHz, CD3OD) δ ppm 8.65 (s, 1H), 8.47 (d, J=2.7 Hz, 1H), 8.06 (s, 1H), 7.74 (d , J=9.8 Hz, 1H), 7.71-7.66 (m, 1H), 7.24-7.18 (m, 1H), 7.12-7.02 (m, 2H), 6.98 (s, 1H), 6.00 (s, 1H), 4.80 (s, 2H), 3.88 (t, J=6.2 Hz, 2H), 3.20 (t, J =6.1 Hz, 2H); ER-LCMS m/z 403.2 [M+H] ⁺ .

Example 155.

Synthesis of I-198a, I-198b and I-198c

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Step 1: (3R)-N-[3-bromo-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-2,3,4,9-tetrahydro1 H -carbazole-3 -amine

Synthesis scheme:

3-Bromo-7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine mixture (440 mg, 1.34 mmol, 1 eq), (3R)-2.3 ,4,9-tetrahydro-1H-carbazole-3-amine (274.54 mg, 1.47 mmol, 1.1 eq.) and DIEA (519.56 mg, 4.02 mmol, 700.21 µl, 3 eq.) in i-PrOH (10 mL) was stirred at 80°C for 12 h. The reaction mixture was concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 2/1, TLC: PE/EtOAc=2/1, Rf=0.25) to give (3R)-N-[3-bromo-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine-7- yl]-2,3,4,9-tetrahydro-1H-carbazole-3-amine (520 mg, 1.06 mmol, 79.2% yield, 97.4% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-66) δ ppm 10.76 (s, 1H), 9.30 (s, 1H), 8.65 (d, J=2.9 Hz, 1H), 8.46 (td, J=2.2, 10.4 Hz, 1H), 8.32-8.24 (m, 2H), 7.33 (d, J=7.5 Hz, 1H), 7.24 ( d, J=7.9Hz, 1H), 7.15(s, 1H), 7.02-6.86(m, 2H), 4.49(td, J=4.8, 9.4Hz , 1H), 3.14-2.98 (m, 2H), 2.94-2.79 (m, 2H), 2.23-2.10 (m, 2H); ER-LCMS m/z 477.1, 479.1 [M+H]+.

Stage 2: tert-butyl (3R)-3-[[3-bromo-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-tert-butoxycarbonyl-amino]-1 ,2,3,4-tetrahydrocarbazole-9-carboxylate

Mixture of (3R)-N-[3-bromo-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-а]pyrimidin-7-yl]-2,3,4,9-tetrahydro-1H

- 282 041983 carbazole-3-amine (500 mg, 1.02 mmol, 1 eq.), Boc ₂ O (556.67 mg, 2.55 mmol, 585.97 μl, 2.5 eq.) and

DMAP (373.93 mg, 3.06 mmol, 3 eq.) in 1,4-dioxane (10 mL) was stirred at 110° C. for 5 h. The reaction mixture was concentrated to give a residue which was purified by silica gel flash chromatography (pure PE to PE/EtOAc = 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.7) to give tert-butyl (3R)-3-[[3-6pom-5-(5 -fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-tert-butoxycarbonyl-amino]-1,2,3,4-tetrahydrocarbazole-9-carboxylate (600 mg, 664.15 µmol, yield 65.1%, 75.0% pure) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.06 (s, 1H), 8.60 (d, J=3.0 Hz, 1H), 8.26-8.18 (m, 2H), 8.06 (d, J=8.0 Hz, 1H), 7.29 (s, 1H), 7.25-7.13 (m, 3H), 4.86-4.76 (m, 1H) , 3.26-3.16 (m, 2H), 2.66 (d, J=10.5 Hz, 1H), 2.36 (m, 1H), 2.10-1.92 (m, 2H ), 1.64 (s, 9H), 1.34 (s, 9H); ER-LCMS m/z 677.2, 679.2 [M+H]+.

Stage 3: tert-butyl (3R)-3-[[3-acetyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-tert-butoxycarbonyl-amino]-1 ,2,3,4-tetrahydrocarbazole-9-carboxylate

Vos /

tert-Butyl (3R)-3-[[3-bromo-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-tert-butoxycarbonyl-amino]-1,2, 3,4-tetrahydrocarbazole-9-carboxylate (550 mg, 608.80 µmol, 1 eq.), tributyl(1-ethoxyvinyl)stannan (1.02 g, 2.82 mmol, 953.27 µl, 4.64 eq. .) and Pd(dppf)Cl ₂ (89.09 mg, 121.76 µmol, 0.2 eq.) in toluene (8 ml) were placed in a microwave tube and then purged with N 2 for 1 min. The sealed tube was heated at 120° C. for 5 hours while being treated with microwave radiation (1 bar). Aqueous KF (10 ml, 1 g/10 ml) was added to the mixture. The mixture was stirred at 25°C for 30 minutes and was extracted with EtOAc (30 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by silica gel flash chromatography (pure PE to PE/EtOAc = 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.45) to give tert-butyl (3R)-3-[[3-acetyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-tert-butoxycarbonyl-amino ]-1,2,3,4-tetrahydrocarbazole-9-carboxylate (340 mg, 524.83 µmol, 91.0% yield, 98.9% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.12 (s, 1H), 8.73 (s, 1H), 8.64 (d, J=2.5 Hz, 1H), 8.15 ( d, J=9.5 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.25-7.19 (m, 1H), 7.18-7.13(m, 1H), 4.83(s, 1H), 3.27-3.11(m, 3H), 2.90(s, 3H), 2.72-2, 62 (m, 1H), 2.37 (s, 1H), 2.13-2.06 (m, 1H), 2.05 (s, 1H), 1.64 (s, 9H), 1.34 (s, 9H); ERJHMS m/z 641.4 [M+H] ⁺ .

Step 4: 1-[5-(5-fluoro-3-pyridyl)-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]pyrazolo [1,5- a]pyrimidin-3-yl]ethanone

To a solution of tert-butyl (3K)-3-[[3-acetyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-а]pyrimidin-7-yl]tert-butoxycarbonyl-amino]-1 ,2,3,4-tetrahydrocarbazole-9-carboxylate (340 mg, 524.83 µmol, 1 eq.) in DCM (8 ml) TFA (3.08 g, 27.01 mmol, 2 ml, 51.47 equiv.). The reaction mixture was stirred at 20° C. for 30 min. The reaction mixture was concentrated. The residue was dissolved in water (10 ml), basified with saturated aqueous NaHCO ₃ to pH 8 and extracted with DCM (30 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give 1-[5-(5-fluoro-3-pyridyl)-7-[[(3R)2,3,4,9-tetrahydro-1H-carbazole- 3-yl]amino]pyrazolo[1,5-a]pyrimidin-3-yl]ethanone (250 mg, 515.36 µmol, 98.2% yield, 90.8% purity) as a yellow solid which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.11 (s, 1H), 8.58 (d, J=2.9 Hz, 1H), 8.49 (s, 1H), 8.20 ( td, J=2.4, 9.4 Hz, 1H), 7.90 (s, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.33 (d, J=8 .2 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.13-7.07 (m, 1H), 6.76 (d, J=8.4 Hz, 1H ), 6.63 (s, 1H), 4.34 (s, 1H), 3.38 (dd, J=4.9, 15.0 Hz, 1H), 3.02-2.91 (m, 3H), 2.84 (s, 3H), 2.35 (m, 1H), 2.31-2.23 (m, 1H); ER-LCMS m/z 441.3 [M+H] ⁺ .

Step 5: (1R)-1-[5-(5-fluoro-3-pyridyl)-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]pyrazolo[ 1,5-a]pyrimidin-3-yl]ethanol (I-198a) and (1S)-1-[5-(5-fluoro-3-pyridyl)-7-[[(3R) - 283 041983

2,3,4,9-tetrahydro-III-carbazol-3-yl]amino]pyrazolo[1,5-a]pyrimidin-3-yl]ethanol (I-198b) n n

F

To a solution of 1-[5-(5-fluoro-3-pyridyl)-7-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]pyrazolo[1,5-a ]pyrimidin-3-yl]ethanone (100 mg, 206.14 µmol, 1 eq.) in MeOH (2.5 ml) and EtOH (2.5 ml) NaBH ₄ (31.19 mg, 824.57 µmol, 4 equiv.) at 20°C. The reaction mixture was stirred at 20° C. for 0.5 h. H ₂ O (10 ml) was added to quench the reaction and extracted with DCM (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by preparative HPLC (column: Gemini 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN ]; B%: 55%-70%, 8 min) followed by lyophilization to give the enantiomer (12.50 mg, 28.25 µmol, 13.7% yield, 100.0% purity) (SFC: Rt = 6.742, ee = 100%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-de) δ ppm 10.79 (s, 1H), 9.34 (s, 1H), 8.66 (d, J=2.8 Hz, 1H), 8.50 (td, J=2.2, 10.4 Hz, 1H), 8.12 (s, 1H), 7.99 (d, J=9.3 Hz, 1H), 7.37 (d, J= 7.8 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.07 (s, 1H), 7.04-6.98 (m, 1H), 6.97- 6.91 (m, 1H), 5.20-5.12 (m, 1H), 5.05 (d, J=4.5 Hz, 1H), 4.50 (d, J=8.8 Hz , 1H), 3.183.00 (m, 2H), 2.98-2.82 (m, 2H), 2.24-2.13 (m, 2H), 1.57 (d, J=6.3 Hz, 3H); ER-LCMS m/z 443.2 [M+H]+; and the other enantiomer (18.17 mg, 40.22 µmol, 19.5% yield, 97.9% purity) (SFC: Rt=5.398, ee=82.9%) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.75 (s, 1H), 9.30 (s, 1H), 8.62 (d, J=2.7 Hz, 1H), 8.50 -8.43(m, 1H), 8.08(s, 1H), 7.95(d, J=9.3Hz, 1H), 7.32(d, J=7.8Hz, 1H) , 7.24 (d, J=7.8 Hz, 1H), 7.03 (s, 1H), 7.00-6.94 (m, 1H), 6.93-6.87 (m, 1H ), 5.16-5.08 (m, 1H), 4.99 (d, J=4.4 Hz, 1H), 4.46 (d, J=8.8 Hz, 1H), 3.13 -2.98 (m, 2H), 2.92-2.79 (m, 2H), 2.14 (m, 2H), 1.53 (d, J=6.4 Hz, 3H); ER-LCMS m/z 443.2 [M+H] ⁺ .

Example 156.

Synthesis of I-200

Stage 1: 5-fluoro-N'-(1H-pyrazol-5-yl)pyridine-3-carboxamidine

A mixture of 5-fluoropyridine-3-carbonitrile (1 g, 7.78 mmol, 1 eq.) and 1H-pyrazol-5-amine (775.80 mg, 9.34 mmol, 1.2 eq.) in xylene (15 ml) was stirred at 70°C for 30 min, then AlMe ₃ (2 M, 7.78 ml, 2 eq.) (2 M in toluene, 19.45 ml, 1 eq.) was added in one portion at 70°C . The mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (DCM/MeOH=100/1 to 10/1,

- 284 041983

TLC: DCM/MeOH=10/1, Rf=0.3) to give 5-fluoro-N-(1H-pyrazol-5-yl)pyridine-3-carboxamidine (700 mg, 2.73 mmol, 35 yield, 1%, 80.0% pure) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.89 (s, 1H), 8.59 (d, J=2.7 Hz, 1H), 8.06 (d, J=9.3 Hz, 1H) , 7.56 (d, J=2.2 Hz, 1H), 6.16 (d, J=2.2 Hz, 1H); ER-LCMS m/z 206.3 [M+H]+.

Step 2: 2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-ol one

Mixture of 5-fluoro-N-(1H-pyrazol-5-yl)pyridine-3-carboxamidine (600 mg, 2.34 mmol, 1 eq.), CDI (758.62 mg, 4.68 mmol, 2 eq. ) and DMAP (142.89 mg, 1.17 mmol, 0.5 eq.) in DMSO (10 ml) was stirred at 130°C for 12 h. ; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%-43%, 9 min) followed by lyophilization to give 2-(5-fluoro-3-pyridyl)pyrazolo[1.5 -a][1,3,5]triazin-4-ol (150 mg, 627.42 µmol, 26.8% yield, 96.7% purity) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.17 (s, 1H), 8.82 (d, J=2.4 Hz, 1H), 8.55-8.36 (m, 1H), 8 .10 (d, J=2.0 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H); ER-LCMS m/z 232.1 [M+H]+.

Step 3: 4-chloro-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazine

CI

XY ^N N

A mixture of 2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-ol (150 mg, 627.42 µmol, 1 eq) and N,N- dimethylaniline (304.12 mg, 2.51 mmol, 318.12 μl, 4 eq.) in POCl ₃ (59.33 g, 386.94 mmol, 35.96 ml, 616.72 eq.) was degassed and purged with N ₂ 3 times. The mixture was stirred at 110° C. for 3 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with ice water, then saturated NaHCO ₃ was added to the above solution to adjust pH to 8, extracted with EtOAc (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc=100/1 to 3/1. TLC: PE/EtOAc=3 /1, Rf = 0.5) to give 4-chloro-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazine (50 mg, 172.65 µmol , yield 27.5%, purity 86.2%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.51 (s, 1H), 8.65 (d, J=2.7 Hz, 1H), 8.50-8.42 (m, 1H), 8 .34 (d, J=2.2 Hz, 1H), 6.86 (d, J=2.2 Hz, 1H); ER-LCMS m/z 250.0, 252.1 [M+H]+.

Step 4: N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]-2-(5-fluoro-3-pyridyl)pyrazolo[1.5a][1.3, 5]triazine-4-amine (I-200)

4-Chloro-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazine mixture (50 mg, 172.65 µmol, 1 eq.), 2(7- fluoro-2-methyl-1H-indol-3-yl)ethanamine (57.03 mg, 224.45 µmol, 1.3 eq, HCl) and DIEA (111.57 mg, 863.27 µmol, 150.37 μl, 5 eq.) in i-PrOH (2 ml) was degassed and purged with N ₂ 3 times. The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN ]; B%: 55%-85%, 9 min) followed by lyophilization to give N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]-2-(5-fluoro -3pyridyl)pyrazolo[1,5-a][1,3,5]triazine-4-amine (19.54 mg, 40.85 µmol, 23.7% yield, 100.0% purity, 2HCl) as white solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.15 (s, 1H), 8.53 (d, J=2.9 Hz, 1H), 8.12 (d, J=9.5 Hz, 1H) , 8.05 (d, J=2.0 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 6.86 (dt, J=4.6, 7.8 Hz, 1H), 6.61 (dd, J=7.8, 11.2 Hz, 1H), 6.43 (d, J=2.0 Hz, 1H), 3.98 (t, J=6.8 Hz, 2H), 3.13 (t, J=6.8 Hz, 2H), 2.26 (s, 3H); ER-LCMS m/z 406.1 [M+H]+.

Example 157.

Synthesis of I-201

- 285 041983

Synthesis scheme:

(3R)-N-[2-(5-fluoro-3-pyridyl)-8-methyl-pyrazolo[1,5-а][1,3,5]triazin-4-yl]-2,3,4 ,9 Stage 1:

tetrahydro-1 H-carbazole-3-amine (I-201)

4-Chloro-2-(5-fluoro-3-pyridyl)-8-methyl-pyrazolo[1,5-a][1,3,5]triazine mixture (11 mg, 24.27 µmol, 1 eq.) , (3R)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (5.43 mg, 29.13 µmol, 1.2 eq) and DIEA (15.69 mg, 121.37 µmol, 21.14 µl, 5 eq.) in i-PrOH (2 ml) was stirred at 80° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm, mobile phase: [water (0.05% HCl)-ACN]; B%: 60%-90%, 9 min) followed by lyophilization to give (3R)-N-[2-(5-fluoro -3-pyridyl)-8-methylpyrazolo[1,5-а][1,3,5]triazin-4-yl]-2,3,4,9-tetrahydro-1H-carbazole-3-amine (4, 32 mg, 8.72 µmol, 35.9% yield, 98.2% purity, 2HCl) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.48 (s, 1H), 8.94 (d, J=9.2 Hz, 1H), 8.82 (broad s, 1H), 7.96 (s, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.04-6.98 (m, 1H) , 6.96-6.90 (m, 1H), 4.86 (m, 1H), 3.25 (d, J=5.6 Hz, 1H), 3.12-2.84 (m, 3H ), 2.40-2.33 (m, 1H), 2.32 (s, 3H), 2.29-2.17 (m, 1H); ER-LCMS m/z 414.2 [M+H]+.

Example 158.

Synthesis of I-202

Synthesis scheme:

- 286 041983

Step 1: 5-fluoro-N-(4-methyl-1H-pyrazol-5-yl)pyridine-3-carboxamidine

Mixture of 5-fluoropyridine-3-carbonitrile (1 g, 6.55 mmol, 1 eq.) and 4-methyl-1H-pyrazol-5-amine (707.02 mg, 6.55 mmol, 1 eq.) in xylene (10 ml) was stirred at 70°C for 0.5 h. Then AlMe ₃ (2 M, 3.93 ml, 1.2 eq.) was added to the mixture in one portion at 100°C. The mixture was stirred at 100° C. for 16 hours. The mixture was quenched with MeOH (30 ml) and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (DCM/MeOH = 1/0 to 5/1, TLC: DCM/MeOH = 5/1, Rf = 0.40) to give the product 5-fluoro-N-(4 -methyl-1H-pyrazol-5-yl)pyridine-3-carboxamidine (1.09 g, 3.86 mmol, 58.9% yield, 77.7% purity) as a yellow oil.

1H NMR (400 MHz, CD3OD) δ ppm 8.98 (s, 1H), 8.60 (d, J=2.4 Hz, 1H), 7.38 (s, 1H), 7.17 (s, 1H), 2.14 (s, 3H); ER-LCMS m/z 220.2 [M+H] ⁺ .

Step 2: 2-(5-fluoro-3-pyridyl)-8-methyl-pyrazolo[1,5-a][1,3,5]triazin-4-ol

5-Fluoro-N-(4-methyl-1H-pyrazol-5-yl)pyridine-3-carboxamidine mixture (600 mg, 2.46 mmol, 1 eq), CDI (799.20 mg, 4.93 mmol , 2 eq.) and DMAP (301.07 mg, 2.46 mmol, 1 eq.) in DMSO (15 mL) were stirred under N2 atmosphere at 130°C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; V%: 14%-44%, 9 min) followed by lyophilization to give 2- (5-fluoro-3-pyridyl)-8-methyl-pyrazolo[1,5-a][1,3,5]triazin-4-ol (120 mg, 412.82 µmol, 16.8% yield, purity 96.9%, HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.12 (s, 1H), 8.72 (s, 1H), 8.34 (s, 1H), 7.95 (s, 1H), 2.28 ( s, 3H); ERJHMS m/z 246.1 [M+H] ⁺ .

Step 3: 4-chloro-2-(5-fluoro-3-pyridyl)-8-methyl-pyrazolo[1,5-a][1,3,5]triazine

2-(5-Fluoro-3-pyridyl)-8-methyl-pyrazolo[1,5-a][1,3,5]triazin-4-ol mixture (150 mg, 422.79 µmol, 1 eq., 2HCl), N,N-dimethylaniline (69.12 mg, 570.36 µmol, 72.30 µl, 1.35 eq.) and POCl ₃ (11.40 g, 74.38 mmol, 6.91 ml, 175 ,91 eq.) was stirred at 110° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, ice water (50 ml) was added to the residue. The mixture was basified with NaHCO ₃ to pH 8 and extracted with EtOAc (50 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 2/1, TLC: PE/EtOAc = 2/1, Rf = 0.40) to give 4chloro-2-(5-fluoro-3-pyridyl)-8-methyl-pyrazolo[1,5-a][1,3,5]triazine (100 mg, 379.28 µmol , yield 89.7%, purity 100.0%) as a white solid.

1H NMR (400 MHz, CDC13) δ ppm 9.52 (s, 1H), 8.63 (d, J=2.8 Hz, 1H), 8.46 (d, J=9.2 Hz, 1H) , 8.19 (s, 1H), 2.44 (s, 3H); ER-LCMS m/z 264.0, 266.0 [M+H]+.

Step 4: N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]-2-(5-fluoro-3-pyridyl)-8-methyl-pyrazolo[1.5

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a][1,3,5]triazine-4-amine (I-202)

4-Chloro-2-(5-fluoro-3-pyridyl)-8-methyl-pyrazolo[1,5-a][1,3,5]triazine mixture (20 mg, 75.86 µmol, 1 eq.) , 2-(7-fluoro-2-methyl-1H-indol-3-yl)ethanamine (21.20 mg, 83.44 µmol, 1.1 eq., HCl) and DIEA (49.02 mg, 379, 28 µmol, 66.06 µl, 5 eq) in i-PrOH (2 ml) was stirred at 90° C. for 10 h. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm, mobile phase: [water (0.05% HCl)-ACN]; B%: 55%-85%, 9 min) to give N-[2-(7-fluoro-2-methyl-1H- indol-3-yl)ethyl]-2-(5-fluoro-3-pyridyl)-8-methylpyrazolo[1,5-a][1,3,5]triazin-4-amine (4.66 mg, 9 .21 µmol, 12.1% yield, 97.3% purity, 2HCl) as a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.17 (s, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.18 (d, J=8.8 Hz , 1H), 7.88 (s, 1H), 7.33 (d, J=7.6 Hz, 1H), 6.92-6.76 (m, 1H), 6.60 (dd, J= 7.6, 11.2 Hz, 1H), 3.95 (t, J=6.8 Hz, 2H), 3.10 (t, J=6.8 Hz, 2H), 2.27 (s, 3H), 2.23 (s, 3H); ER-LCMS m/z 420.2 [M+H]+.

Example 159.

Synthesis of I-203

Synthesis scheme:

Stage 1: tert-butyl N-(4-nitro-1H-pyrazol-5-yl)carbamate

TEA (22.55 g, 222.81 mmol, 31.01 ml , 2.5 eq.) and DPPA (26.98 g, 98.04 mmol, 21.24 ml, 1.1 eq.) at 25°C. The mixture was stirred at 25°C for 1.5 h. To the above solution was added tBuOH (66.06 g, 891.24 mmol, 85.24 ml, 10 eq.), the mixture was stirred at 130°C for 12 h in N ₂ atmosphere. TLC (PE/EtOAc = 1/1, Rf = 0.49) showed that the starting material was completely consumed and a main spot was formed. The reaction mixture was quenched by adding saturated NaHCO ₃ (100 ml), extracted with EtOAc (80 mlx3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 1/1 , TLC: PE/EtOAc=1/1, Rf=0.49) to give tert-butyl N-(4-nitro-1H-pyrazol-5-yl)carbamate (6.0 g,

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21.03 mmol, 23.6% yield, 80% purity) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.80-13.47 (m, 1H), 9.35 (br s, 1H), 8.58-7.94 (m, 1H), 1.44 (br s, 9H).

Stage 2: tert-butyl N-(4-amino-1H-pyrazol-5-yl)carbamate

A mixture of tert-butyl N-(4-nitro-1H-pyrazol-5-yl)carbamate (5 g, 17.53 mmol, 1 eq.), Raney-Ni (5 g, in water) and NH3H2O (2.19 g, 17.53 mmol, 2.41 ml, 28%, 1 eq.) in MeOH (100 ml) was degassed and purged with H ₂ 3 times, the mixture was stirred at 20° C. for 2 h under H ₂ atmosphere (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product tert-butyl N-(4-amino-1H-pyrazol-5-yl)carbamate (3.47 g, 16.44 mmol, 93.7% yield, purity 93.9%) as a purple solid, which was used in the next step without further purification.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.65 (br s, 1H), 8.76 (br s, 1H), 7.00 (s, 1H), 3.50 (br s, 1H) s, 2H), 1.50-1.36 (m, 9H); ER-LCMS m/z 143.1 [Mt-Bu+H]+.

Stage 3: tert-butyl N-[4-(dimethylamino)-1H-pyrazol-5-yl]carbamate

To a solution of tert-butyl N-(4-amino-1H-pyrazol-5-yl)carbamate (1.5 g, 7.11 mmol, 1 eq.) in MeOH (30 ml) 31.26 mmol, 4.4 eq.) and NaBH ₃ CN (4.47 g, 71.06 mmol, 10 eq.). The mixture was stirred at 50° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was quenched with water (100 ml), extracted with EtOAc (80 mlx3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 0/1 , TLC: PE/EtOAc=1/1, Rf=0.20) to give tert-butyl N-[4-(dimethylamino)-1H-pyrazol-5-yl]carbamate (1.2 g, 3.87 mmol , yield 54.4%, purity 73.0%) as a red-brown oil.

1H NMR (400 MHz, CD3OD) δ ppm 7.29 (s, 1H), 2.64 (s, 6H), 1.49 (s, 9H).

Stage 4: N4,N4-dimethyl-1H-pyrazole-4,5-diamine

A mixture of tert-butyl N-[4-(dimethylamino)-1H-pyrazol-5-yl]carbamate (1.2 g, 3.87 mmol, 1 eq.) in HCl/MeOH (4 M, 15 mL) was degassed and purged with N2 3 times, the mixture was stirred at 15° C. for 12 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude product N4,N4-dimethyl-1H-pyrazol-4,5-diamine (629 mg, crude, HCl) as a white solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD ₃ OD) δ ppm 8.47 (s, 1H), 3.32 (s, 6H).

Step 5: 3-(dimethylamino)-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-ol

N4,N4-dimethyl-1H-pyrazole-4,5-diamine (300 mg, 1.57 mmol, 1 eq., HCl) was dissolved in MeOH (10 ml), then the pH was adjusted to 9-10 with 2N hydrochloric acid. water. NaOH. The mixture was concentrated under reduced pressure to give a residue. The residue and methyl (Z)-3-(5-fluoro-3-pyridyl)-3-hydroxy-prop-2-enoate (332.44 mg, 1.57 mmol, 1 eq.) in AcOH (15 ml) were stirred at 120° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product 3-(dimethylamino)-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-ol (616 mg , crude, 2HOAC) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.71 (s, 1H), 9.05 (s, 1H), 8.89 (d, J=1.5 Hz, 1H), 8.30 (s, 1H), 7.97 (s, 1H), 6.37 (s, 1H), 2.72-2.52 (m, 6H); ER-LCMS m/z 274.2 [M+H]+.

Step 6: 7-chloro-5-(5-fluoro-3-pyridyl)-N,N-dimethyl-pyrazolo[1,5-a]pyrimidine-3-amine

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Solution of 3-(dimethylamino)-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-ol (616 mg, 1.57 mmol, 1 eq., 2HOAC) in POCl ₃ ( 16.50 g, 10 ml) was degassed and purged with N ₂ 3 times, the mixture was stirred at 110° C. for 4 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was quenched by adding ice water (100 ml) at 0°C, adjusted to pH 9-10 with saturated NaHCO ₃ , extracted with EtOAc (80 mlx3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 1/1, TLC : PE/EtOAc = 3/1, R _f = 0.21) to give 7chloro-5-(5-fluoro-3-pyridyl)-N,N-dimethyl-pyrazolo[1,5-a]pyrimidine-3- amine (190 mg, 651.33 µmol, 41.5% yield, 100% purity) as a red solid.

1H NMR (400 MHz, CDCI3) δ ppm 9.08 (s, 1H), 8.57 (d, J=2.8 Hz, 1H), 8.18-8.10 (m, 1H), 7, 87 (s, 1H), 7.30 (s, 1H), 3.10 (s, 6H); ER-LCMS m/z 292.2, 294.2 [M+H]+.

Step 7: 5-(5-fluoro-3-pyridyl)-N 7-[2-(1 H-indol-3-yl)ethyl]-N3,N3-dimethylpyrazolo[1,5a]pyrimidin-3, 7-diamine (I-203)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-N,N-dimethyl-pyrazolo[1,5-a]pyrimidine-3-amine (40 mg, 137.12 µmol, 1 eq.) in i-PrOH (5 ml) was added DIEA (53.17 mg, 411.37 µmol, 71.65 µl, 3 eq.) and 2(1H-indol-3-yl)ethanamine (28.56 mg, 178, 26 µmol, 1.3 eq.). The mixture was stirred at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini C18 250x50 mmx10 µm; mobile phase: [water (0.05% HCl)- ACN]; B%: 25%-55%, 9 min) followed by lyophilization to give 5-(5-fluoro-3pyridyl)-N7-[2-(1H-indol-3-yl)ethyl]-N3,N3 -dimethyl-pyrazolo[1,5-a]pyrimidine-3,7-diamine (27.03 mg, 55.35 µmol, 40.3% yield, 100% purity, 2HC1) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.87 (d, J=1.0 Hz, 1H), 8.82 (d, J=1.2 Hz, 1H), 8.36 (s, 1H) , 8.17-8.12(m, 1H), 7.71-7.67(m, 1H), 7.17-7.11(m, 1H), 7.07-7.00(m, 2H), 6.98 (s, 1H), 6.18 (s, 1H), 3.96 (t, J=6.1 Hz, 2H), 3.48 (s, 6H), 3.21 ( t, J=6.0 Hz, 2H); ER-LCMS m/z 416.1 [M+H] ⁺ .

Example 160.

Synthesis 1-204a

Synthesis scheme:

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Pd/C, H ₂ con. H ₂ SO ₄ , Ακοή.

ABOUT'

Stage 1: (2E)-2-hydroxyimino-5-methoxy-indan-1-one

A solution of 5-methoxyindan-1-one (5 g, 30.83 mmol, 1 eq.) in MeOH (500 ml) was heated to 45°C, isopentyl nitrite (5.42 g, 46.24 mmol, 6.23 ml) was added , 1.5 equiv.) and con. HCl (12 M, 5.14 ml, 2 eq.). The mixture was stirred at 45° C. for 2 hours. The mixture was concentrated under reduced pressure to give a residue and MeOH (30 ml) was added. The suspension was filtered, dried under vacuum to give (2E)-2hydroxyimino-5-methoxy-indan-1-one (5.0 g, 22.75 mmol, 73.8% yield, 87.0% purity) as a solid brown, which was used in the next step without further purification.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.14 (d, J=2.0 Hz , 1H), 7.01 (dd, J=2.3, 8.5 Hz, 1H), 3.92-3.84 (m, 3H), 3.71 (s, 2H); ER-LCMS m/z 192.1 [M+H]+.

Stage 2: (2R)-5-methoxyindan-2-amine

To a solution of (2E)-2-hydroxyimino-5-methoxy-indan-1-one (5 g, 22.75 mmol, 1 eq.) in AcOH (250 ml) and con. H2SO4 (3.5 ml) Pd/C (1 g, 10%) was added. The mixture was stirred at 25°C for 12 h in an atmosphere of H ₂ (15 psi). The mixture was filtered, the filtrate was concentrated under reduced pressure to give a residue which was poured into ice water (200 ml), the pH was adjusted to 10-11 with 2N hydrochloric acid. NaOH, extracted with EtOAc (150 mlx3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product 5-methoxyindan-2-amine (2.0 g, 11.48 mmol, 50.4 yield %, purity 93.7%) as a brown solid. 5-methoxyindan-2-amine (1 g, 5.74 mmol) was separated by chiral SFC (column: AD-3_EtOH (DEA), AD (250 mm x 30 mm, 10 µm); mobile phase: [0.1% NH ₃ H ₂ O IPA]; V%: 55%-55%, min) three times to give (2R)-5-methoxyindan-2-amine (220 mg, 1.35 mmol, 23.4% yield, 100% purity ) (Rt = 3.581 min, ee = 100%, [a] ²² _D = 24.733 (13.5 mg/10 ml, CHCl ₃ )) as a brown oil.

¹ H NMR (400 MHz, CDCl3) δ ppm 7.11 (d, J=8.2 Hz, 1H), 6.78 (s, 1H), 6.72 (dd, J=2.5, 8, 3 Hz, 1H), 3.883.81 (m, 1H), 3.79 (s, 3H), 3.15 (dt, J=6.7, 14.6 Hz, 2H), 2.71-2, 59 (m, 2H); ER-LCMS m/z 164.2 [M+H] ⁺ . and (2S)-5-methoxyindan-2-amine (350 mg, 2.14 mmol, 37.3% yield, 100% purity) (Rt = 3.762 min, ee = 100%, [a] ²² D = -16.666 (10.3 mg/10 ml, CHCl ₃ )) as a brown oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.11 (d, J=7.9 Hz, 1H), 6.78 (s, 1H), 6.72 (dd, J=2.5, 8, 3 Hz, 1H), 3.873.81 (m, 1H), 3.79 (s, 3H), 3.15 (dt, J=6.8, 14.7 Hz, 2H), 2.71-2, 57 (m, 2H); ER-LCMS m/z 164.2 [M+H] ⁺ .

Step 3: 5-(5-fluoro-3-pyridyl)-N 7-[(2R)-5-methoxyindan-2-yl]-N3,N3-dimethyl-pyrazolo[1,5a]pyrimidine-3,7- diamine

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To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-N,N-dimethyl-pyrazolo[1,5-a]pyrimidine-3-amine (50 mg, 171.40 µmol, 1 eq.) in i-PrOH (5 ml) was added DIEA (66.46 mg, 514.21 µmol, 89.56 µl, 3 eq.) and (2R)5-methoxyindan-2-amine (36.37 mg, 222.82 µmol, 1.3 eq.). The mixture was stirred at 70° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give crude 5-(5-fluoro-3-pyridyl)-N7-[(2R)-5-methoxyindan-2-yl]-N3,N3- dimethyl-pyrazolo[1,5-a]pyrimidine-3,7-diamine (71 mg, 123.18 µmol, 71.9% yield, 72.6% purity) as a red-brown oil, which was used in the next step without further purification.

'H NMR (400 MHz, CDCI3) δ ppm 9.01 (s, 1H), 8.44 (d, J=2.7 Hz, 1H), 8.17-8.10 (m, 1H), 7 .58 (s, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.75 (s, 1H), 6.71 (dd, J=2.3, 8.2 Hz, 1H), 6.43 (d, J=7.6 Hz, 1H), 6.29 (s, 1H), 4.63-4.55 (m, 1H), 3.73 (s, 3H), 3.58-3.54 (m, 2H), 3.46-3.37 (m, 2H), 2.93 (s, 6H); ER-LCMS m/z 419.2 [M+H]+.

Stage

4:

yl]amino]indan-5-ol (1-204a) (2R)-2-[[3-(dimethylamino)-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine-7Solution

5-(5-fluoro-3-pyridyl)-N7-[(2R)-5-methoxyindan-2-yl]-N3,N3-dimethyl-pyrazolo[1,5a]pyrimidine-3,7-diamine (71 mg , 123.18 µmol, 1 eq.) in aq. HBr (5 ml, 60%) was stirred at 120° C. for 2 h under N2. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 23%-53%, 8 min) followed by lyophilization to give (2R)-2-[[3-(dimethylamino)-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino]indan -5-ol (33.84 mg, 67.84 µmol, 55.1% yield, 95.7% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.68 (s, 1H), 9.31 (d, J=9.0 Hz, 1H), 9.12 (s, 1H), 8.43 (s, 1H), 7.24 (s, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.72 (s, 1H), 6.65 (d, J=8.1 Hz, 1H), 4.97-4.94 (m, 1H), 3.54 (s, 6H), 3.52-3.43 (m, 2H), 3.19-3.02 (m, 2H) ; ER-LCMS m/z 405.2 [M+H]+.

Example 161.

Synthesis of I-204b

Synthesis scheme:

- 292 041983

Step 1: 5-(5-fluoro-3-pyridyl)-N7-[(2S)-5-methoxyindan-2-yl]-N3,N3-dimethyl-pyrazolo[1,5a]pyrimidin-3,7-diamine

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-^^-dimethyl-pyrazolo[1,5-a]pyrimidine-3-amine (50 mg, 171.40 µmol, 1 eq.) in i -PrOH (5 ml) was added DIEA (66.46 mg, 514.20 µmol, 89.56 µl, 3 eq.) and (2S)5-methoxyindan-2-amine (27.98 mg, 171.40 µmol, 1 equivalent). The mixture was stirred at 70° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give crude 5-(5-fluoro-3-pyridyl)-N7-[(2S)-5-methoxyindan-2-yl]-N3,N3- dimethyl-pyrazolo[1,5-a]pyrimidine-3,7-diamine (71 mg, 128.27 µmol, 74.8% yield, 75.6% purity) as a red-brown oil, which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.12-9.05 (m, 1H), 8.52 (d, J=2.7 Hz, 1H), 8.21 (td, J=2 .2, 9.8 Hz, 1H), 7.66 (s, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.86-6.76 (m, 2H), 6 .51 (d, J=7.6 Hz, 1H), 6.37 (s, 1H), 4.72-4.57 (m, 1H), 3.81 (s, 3H), 3.66 ( d, J=4.9 Hz, 2H), 3.50 (ddd, J=7.0, 12.6, 15.9 Hz, 2H), 3.01 (s, 6H); ER-LCMS m/z 419.2 [M+H]+.

Stage

2:

(2S)-2-[[3-(dimethylamino)-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7yl]amino]indan-5-ol (I-204b)

Solution

5-(5-fluoro-3-pyridyl)-N7-[(2S)-5-methoxyindan-2-yl]-N3,N3-dimethyl-pyrazolo[1,5

a] pyrimidine-3,7-diamine (71 mg, 128.27 µmol, 1 eq.) in aq. HBr (5 ml, 60%) was stirred at 120° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0 05% HCl)-ACN]; B%: 20%-50%, 8 min) followed by lyophilization to give (2S)-2-[[3(dimethylamino)-5-(5-fluoro-3-pyridyl) pyrazolo[1,5-a]pyrimidin-7-yl]amino]indan-5-ol (32.5 mg, 77.95 µmol, 60.7% yield, 97.0% purity) as yellow solid .

1H NMR (400 MHz, CD3OD) δ ppm 9.64 (s, 1H), 9.25 (d, J=9.3 Hz, 1H), 9.08 (s, 1H), 8.43 (s, 1H), 7.22 (s, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.72 (s, 1H), 6.65 (d, J=8.1 Hz, 1H), 4.97-4.92(m, 1H), 3.54(s, 6H), 3.44-3.41(m, 2H), 3.18-3.03(m, 2H) ; ER-LCMS m/z 405.2 [M+H]+.

Example 162.

Synthesis of I-208

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Synthesis scheme:

-(5-fluoro-3-pyridyl)-N -[2-(1 H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]pyrazolo [1.5 Step 1:

a] pyrimidine-7-amine (I-208)

7-Chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine mixture (60 mg, 225.62 µmol, 1 eq), 2(1H-pyrrolo[3,2-b ]pyridin-3-yl)ethanamine (43.65 mg, 270.75 µmol, 1.2 eq.), DIEA (87.48 mg, 676.87 µmol, 117.90 µl, 3 eq.) in i- PrOH (10 ml) was stirred at 80° C. for 12 hours. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 μm; mobile phase: [water (0.05% HCl)- ACN]; B%: 5%-35%, 9 min) followed by lyophilization to give 5-(5-fluoro-3-pyridyl)-N-[2-(1H-pyrrolo[3,2-b]pyridine -3-yl)ethyl]pyrazolo[1,5a]pyrimidin-7-amine (37.11 mg, 75.38 µmol, 33.4% yield, 98.7% purity, 3 HCl) as a yellow solid colors.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.99 (s, 1H), 8.82 (s, 1H), 8.56-8.50 (m, 2H), 8.35 (d, J= 8.8 Hz, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 7.69-7.63 (m, 1H), 7.04 (s, 1H), 6, 65 (d, J=2.0 Hz, 1H), 4.22-4.13 (m, 2H), 3.46 (t, J=6.6 Hz, 2H); ER-LCMS m/z 374.2 [M+H]+.

Example 163.

Synthesis of I-209

Synthesis scheme:

Step 1: 5-(5-fluoro-3-pyridyl)-3-methyl-N-[2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]pyrazolo[1,5a]pyrimidine -7-amine (I-209)

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To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (60 mg, 228.42 µmol, 1 eq.) in i-PrOH (5 ml) was added DIEA (88.56 mg, 685.27 µmol, 119.36 µl, 3 eq.) and 2-(1Hpyrrolo[3,2-b]pyridin-3-yl)ethanamine (45 mg, 279.15 µmol, 1.22 eq.). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%-45%, 9 min). The desired fraction was lyophilized to give 5-(5-fluoro-3-pyridyl)-3-methyl-N-[2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]pyrazolo[1.5a ]pyrimidine-7-amine (28.89 mg, 56.64 µmol, 24.8% yield, 97.4% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.94 (s, 1H), 8.79 (d, J=2.7 Hz, 1H), 8.57-8.50 (m, 2H), 8, 31-8.24 (m, 1H), 8.09 (d, J=7.6 Hz, 2H), 7.71-7.63 (m, 1H), 6.80 (s, 1H), 4 .12 (t, J=7.0 Hz, 2H), 3.43 (t, J=6.8 Hz, 2H), 2.37 (s, 3H); ER-LCMS m/z 388.2 [M+H]+.

Example 164.

Synthesis of I-210

Synthesis scheme:

Step 1: 5-(5-fluoro-3-pyridyl)-N-[2-(3-methoxyphenyl)ethyl]-3-methyl-pyrazolo[1,5-a]pyrimidine-7amine

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (50 mg, 190.35 µmol, 1 eq.) in i-PrOH (3 ml) 2-(3-methoxyphenyl)ethanamine (43.17 mg, 285.53 µmol, 41.92

- 295 041983 µl, 1.5 eq.) and DIEA (73.81 mg, 571.06 µmol, 99.47 µl, 3 eq.). The mixture was stirred at 60° C. for 3 h under N2. The reaction mixture was concentrated under reduced pressure to give 5-(5fluoro-3-pyridyl)-N-[2-(3-methoxyphenyl)ethyl]-3-methyl-pyrazolo[1,5-a]pyrimidine-7-amine (70 mg, 185.47 µmol, 97.4% yield) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 9.01 (s, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.25-8.18 (m, 1H), 7, 89 (s, 1H), 7.18-7.10 (m, 1H), 6.89-6.83 (m, 2H), 6.73-6.65 (m, 1H), 6.36 ( s, 1H), 3.83 (t, J=6.8 Hz, 2H), 3.67 (s, 3H), 3.03 (t, J=6.8 Hz, 2H), 2.33 ( s, 3H); ER-LCMS m/z 378.2 [M+H]+.

Stage 2: 3-[2-[[5-(5-Fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]ethyl]phenol (I-210)

A mixture of 5-(5-fluoro-3-pyridyl)-N-[2-(3-methoxyphenyl)ethyl]-3-methyl-pyrazolo[1,5-a]pyrimidine-7amine (70 mg, 185.47 µmol , 1 eq.) and aq. HBr (4.47 g, 33.15 mmol, 3 ml, 60% purity, 178.72 eq.) was degassed and purged with N2 3 times. The mixture was stirred at 120°C for 1 h under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini C18 250x50 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 35%-65% , 10 min) followed by lyophilization to give 3-[2-[[5-(5fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]ethyl]phenol ( 40.74 mg, 93.37 µmol, 50.3% yield, 100% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, CO3OD) δ ppm 8.87-8.85 (m, 2H), 8.22 (d, J=8.8 Hz, 1H), 8.14 (s, 1H), 7, 06-6.95 (m, 1H), 6.77-6.68 (m, 2H), 6.60-6.51 (m, 1H), 6.44 (s, 1H), 4.01 ( t, J=6.5 Hz, 2H), 3.02 (t, J=6.4 Hz, 2H), 2.36 (s, 3H); ER-LCMS m/z 364.1 [M+H] ⁺ .

Example 165.

Synthesis of I-211

Synthesis scheme:

1: N-[2-(4-aminophenyl)ethyl]-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine-7 Stage amine (I-211)

To a solution of 4-(2-aminoethyl)aniline (25.92 mg, 190.35 µmol, 1 eq.) in i-PrOH (3 ml) was added 7chloro-5-(5-fluoro-3-pyridyl)-3- methyl pyrazolo[1,5-a]pyrimidine (50 mg, 190.35 µmol, 1 eq.) and DIEA (73.81 mg, 571.06 µmol, 99.47 µl, 3 eq.). The mixture was stirred at 50°C for 12 hours.

- 296 041983 the mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]);

B%: 20%-50%, 8 min) followed by lyophilization to give N-[2-(4-aminophenyl)ethyl]-5-(5-fluoro-3pyridyl)-3-methyl-pyrazolo[1,5- a] pyrimidine-7-amine (73.99 mg, 155.10 µmol, 81.5% yield, purity

98.9%, 3HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.94 (s, 1H), 8.80 (d, J=2.7 Hz, 1H), 8.28 (td, J=2.4, 8.9 Hz, 1H), 8.11 (s, 1H), 7.54 (d, J=8.6 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H), 6.80 ( s, 1H), 4.02 (t, J=7.2 Hz, 2H), 3.19 (t, J=7.2 Hz, 2H), 2.37 (s, 3H); ER-LCMS m/z 363.3 [M+H]+.

Example 166.

Synthesis of I-213

Synthesis scheme:

4-[2-[[5-(5-Fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]ethyl]phenol

Stage 1: (I-213)

To a mixture of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (60 mg, 228.42 µmol, 1 eq) and 4-(2- aminoethyl)phenol (37.60 mg, 274.11 µmol, 1.2 eq.) in i-PrOH (12 ml) was added DIEA (88.57 mg, 685.27 µmol, 119.36 µl, 3 eq.) . The mixture was stirred at 75° C. for 19 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 30%-60%, 9 min) followed by lyophilization to give 4-[2-[[5-(5-fluoro-3-pyridyl)3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]ethyl]phenol ( 55.37 mg, 126.91 µmol, 55.6% yield, 100.0% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.84 (broad s, 2H), 8.23-8.12 (m, 2H), 7.06 (d, J=8.6 Hz, 2H), 6.636.57 (m, 2H), 6.36 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.99 (t, J=6.5 Hz, 2H), 2.36 (s, 3H); ER-LCMS m/z 364.0 [M+H]+.

Example 167.

Synthesis of I-214

- 297 041983

Synthesis scheme:

Step 1: N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]-5-(5-fluoro-3-pyridyl)pyrazolo[1,5a]pyrimidin-7-amine (I-214) n

To a mixture of 7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (100 mg, 376.04 µmol, 1 eq.) in DIEA (5 ml) and i-PrOH ( 3 ml) was added 2-(7-fluoro-2-methyl-1H-indol-3-yl)ethanamine (95.55 mg, 376.04 µmol, 1 eq, HCl). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Gemini 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide o6./o6 .)-ACN]; B%: 45% 75%, 8 min) followed by lyophilization to give N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]-5-( 5fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine-7-amine (58.73 mg, 141.11 µmol, 37.5% yield, 97.2% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCl3) δ ppm 8.70 (s, 1H), 8.44 (d, J=2.8 Hz, 1H), 7.93 (d, J=2.4 Hz, 1H ), 7.81-7.76 (m, 1H), 7.25 (d, J=7.6Hz, 1H), 6.99 (dt, J=4.8, 8.0Hz, 1H) , 6.83-6.79 (m, 1H), 6.47 (d, J=2.4 Hz, 1H), 5.99 (s, 1H), 3.72 (q, J=6.4 Hz, 2H), 3.11 (t, J=6.4 Hz, 2H), 2.24 (s, 3H); ER-LCMS m/z 405.2 [M+H]+.

Example 168.

Synthesis of I-215

Step 1: 3-[2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]ethyl]-1Hindol-5-ol (I-215)

% Y N

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (60 mg, 228.42 µmol, 1 eq.), 3-(2- aminoethyl)-1H-indol-5-ol (60.37 mg, 283.87 µmol, 1.24 eq., HCl) in i-PrOH (5 ml)

- 298 041983 DIEA (147.61 mg, 1.14 µmol, 198.94 µl, 5 eq.) was added. The mixture was stirred at 60° C. for 4 hours. The reaction mixture was concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf=0.25) to give the title product 3-[2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]ethyl ]-1Hindol-5-ol (73.19 mg, 179.69 µmol, 78.7% yield, 98.8% purity) as a yellow solid.

1H NMR (400 MHz, DMSO-66) δ ppm 10.52 (br s, 1H), 9.16 (s, 1H), 8.77-8.55 (m, 2H), 8.27 (d , J=9.7 Hz, 1H), 8.07-7.93 (m, 2H), 7.20-7.02 (m, 2H), 6.91 (d, J=1.8 Hz, 1H), 6.65 (s, 1H), 6.62-6.58 (m, 1H), 3.913.74 (m, 2H), 3.03 (t, J=7.1 Hz, 2H), 2.28 (s, 3H); ER-LCMS m/z 403.2 [M+H]+.

Example 169.

Synthesis of I-216a

Synthesis scheme:

Step 1: (3R)-8-fluoro-N-[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-2,3,4 ,9tetrahydro-1 H-carbazole-3-amine (I-216а)

7-Chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine mixture (50 mg, 190.35 µmol, 1 eq), (3R)-8- fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-amine (47.36 mg, 209.39 µmol, 1.1 eq) and DIEA (123.01 mg, 951.76 µmol, 165 .78 µl, 5 eq.) in i-PrOH (2 ml) was stirred at 90°C for 12 h. µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 50%-80%, 10 min). The desired fraction was lyophilized to give (3R)-8fluoro-N-[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-2,3,4 ,9-Tetrahydro-1H-carbazole3-amine (21.98 mg, 51.06 µmol, 26.8% yield, 100.0 purity) as yellow solid (SFC: Rt = 2.106, ee% = 97 .3%).

1H NMR (400 MHz, CD3OD) δ ppm 8.97 (s, 1H), 8.75 (d, J=2.4 Hz, 1H), 8.29 (td, J=2.0, 9.2 Hz, 1H), 8.13 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.00 (s, 1H), 6.89 (dt, J=4.8 , 8.0 Hz, 1H), 6.76 (dd, J=8.0, 11.6 Hz, 1H), 4.62 (m, 1H), 3.32 (s, 1H), 3.16 -3.06 (m, 1H), 3.03-2.95 (m, 2H), 2.37 (s, 3H), 2.36-2.23 (m, 2H); ER-LCMS m/z 431.2 [M+H]+.

Example 170.

Synthesis of I-218

1-218

- 299 041983

Synthesis scheme:

Step 1: 5-(5-fluoro-3-pyridyl)-3-methyl-N-(2-phenylethyl)pyrazolo[1,5-a]pyrimidin-7-amine (I-218)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (50 mg, 190.35 µmol, 1 eq.) in i-PrOH (3 ml) DIEA (73.80 mg, 571.06 µmol, 99.47 µl, 3 eq) and 2-phenylethanamine (34.60 mg, 285.53 µmol, 35.86 µl, 1.5 eq) were added. The mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN ]; B%: 45%-75%, 9 min) followed by lyophilization to give 5-(5-fluoro-3-pyridyl)3-methyl-N-(2-phenylethyl)pyrazolo[1,5-a]pyrimidine -7-amine (37.43 mg, 89.05 µmol, 46.78% yield, 100% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.83-8.78 (m, 2H), 8.17-8.13 (m, 2H), 7.32-7.27 (m, 2H), 7 .23 (t, J=7.3 Hz, 2H), 7.18-7.13 (m, 1H), 6.51 (s, 1H), 4.01 (t, J=6.7 Hz, 2H), 3.09 (t, J=6.7 Hz, 2H), 2.34 (s, 3H); ERLCMS m/z 348.2 [M+H]+.

Example 171.

Synthesis of I-219

1-219

Synthesis scheme:

- 300 041983

Stage 1: 5-(5-Fluoro-3-niridyl)-N-[(2S)-5-methoxyindan-2-yl]-3-methyl-pyrazolo[1,5-a]pyrimidine 7-amine

7-Chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine mixture (50 mg, 190.35 µmol, 1 eq), (2S)-5- methoxyindan-2-amine (33.05 mg, 190.35 µmol, 1 eq.), DIEA (73.80 mg, 571.06 µmol, 99.47 µl, 3 eq.) in i-PrOH (10 ml) stirred at 80° C. for 12 hours. The reaction mixture was concentrated to give 5-(5-fluoro-3-pyridyl)-N-[(2S)-5-methoxyindan-2-yl]-3-methyl-pyrazolo [1 ,5a]pyrimidine-7-amine (60 mg, 122.03 µmol, 64.1% yield, 79.2% purity) as a brown oil, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl3) δ ppm 9.06-8.95 (m, 1H), 8.58-8.43 (m, 1H), 8.22-8.09 (m, 1H), 7 .79 (s, 1H), 7.15-7.00 (m, 1H), 6.80-6.61 (m, 2H), 6.53 (d, J=7.1 Hz, 1H), 6.32 (s, 1H), 4.59 (s, 1H), 3.74 (s, 3H), 3.60 (d, J=6.4 Hz, 2H), 3.06-3.02 (m, 2H), 2.31 (s, 3H); ER-LCMS m/z 390.2 [M+H] ⁺ .

Step 2: (2S)-2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]indan-5-ol (I -219)

5-(5-fluoro-3-pyridyl)^-[(2S)-5-methoxyindan-2-yl]-3-methyl-pyrazolo[1,5-a]pyrimidin-7-amine (60 mg, 122, 03 µmol, 1 eq.) in HBr (5 ml, 60% in water) was stirred at 120°C for 2 h. ; mobile phase: [water (0.05% HCl)-ACN]; B%: 30%-60%, 10 min) followed by lyophilization to give (2S)-2-[[5-(5-fluoro-3 -pyridyl)-3-methyl-pyrazolo[1,5a]pyrimidin-7-yl]amino]indan-5-ol (23.51 mg, 52.44 µmol, 43.0% yield, 100.0% purity, 2 HCl) ((SFC: Rt = 2.090, ee = 100%) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.08 (s, 1H), 8.90 (s, 1H), 8.45 (d, J=9.0 Hz, 1H), 8.16 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.01 (s, 1H), 6.73 (s, 1H), 6.66 (dd, J=2.0, 8 .0 Hz, 1H), 5.11-5.02 (m, 1H), 3.54-3.42 (m, 2H), 3.28-3.14 (m, 2H), 2.41 ( s, 3H); ER-LCMS m/z 376.2 [M+H]+.

Synthesis of I-220

- 301 041983

Synthesis scheme:

-(5-fluoro-3-pyridyl)-3-isopropyl-N-[(2S)-5-methoxyindan-2-yl]pyrazolo [1.5 Step 1:

a] pyrimidine-7-amine

7-Chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine mixture (50 mg, 154.79 µmol, 1 eq), (2S)-5- methoxyindan-2-amine (26.88 mg, 154.79 µmol, 1 eq) and DIEA (60.02 mg, 464.36 µmol, 80.88 µl, 3 eq) in i-PrOH (10 ml) stirred at 80° C. for 12 hours. The reaction mixture was concentrated to give 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-[(2S)-5-methoxyindan-2-yl]pyrazolo[1, 5a]pyrimidine-7-amine (60 mg, 115.69 µmol, 74.7% yield, 80.5% purity) as a brown oil, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.06-8.93 (m, 1H), 8.54-8.42 (m, 1H), 8.13 (d, J=7.3 Hz, 1H), 7.79 (s, 1H), 7.10 (d, J=7.9 Hz, 1H), 6.79-6.58 (m, 2H), 6.51 (d, J=7 .3 Hz, 1H), 6.33 (s, 1H), 4.57 (s, 1H), 3.75-3.62 (m, 3H), 3.59 (d, J=6.8 Hz , 2H), 3.02 (d, J=8.6 Hz, 3H), 1.15 (d, J=2.2 Hz, 6H); ER-LCMS m/z 418.2[M+H]+.

Step 2: (2S)-2-[[5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrαzolo[1,5-a]pyrimidin-7-yl]αmino]indan5-ol (I-220 )

-(5-fluoro-3-pyridyl)-3-isopropyl-N-[(2 S)-5-methoxyindan-2-yl] pyrazolo[1,5-a]pyrimidin-7-amine (60 mg, 115, 69 µmol, 1 eq.) in HBr (5 ml, 60% in water) was stirred at 120°C for 2 h. ; mobile phase: [water (0.05% HCl)-ACN]; B%: 40% 70%, 10 min) followed by lyophilization to give (2S)-2-[[5-(5-fluoro-3- pyridyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl]amino]indan-5-ol (17.20 mg, 36.11 µmol, 31.2% yield, 100.0% purity, 2 HCl) (SFC: Rt = 2.050, ee = 99.374%) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.04 (s, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.40 (d, J=9.0 Hz, 1H) , 8.26 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.99 (s, 1H), 6.73 (s, 1H), 6.66 (dd, J=2.5, 8.0 Hz, 1H), 5.09-5.01 (m, 1H), 3.543.43 (m, 2H), 3.39 (td, J=6.8, 13, 9 Hz, 1H), 3.26-3.15 (m, 2H), 1.41 (d, J=7.0 Hz, 6H); ER-LCMS m/z 404.2 [M+H]+.

Example 173.

Synthesis of I-222a, I-222b and I-222c

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Stage 1: 7-chloro-5-(5-fluoro-3-pyridyl)-3-iodo-pyrazolo[1,5-a]pyrimidine

Synthesis scheme:

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine (600 mg, 2.24 mmol, 1 eq.) in DCM (25 ml) and MeCN (25 ml ) was added in portions of NIS (1.01 g, 4.48 mmol, 2 eq.) and the mixture was stirred at 20°C for 24 h. TLC (PE/EtOAc = 3/1, Rf = 0.41) showed that the starting material was completely consumed. The reaction mixture was quenched with saturated Na ₂ S ₂ O ₃ (100 ml) and concentrated under reduced pressure to remove DCM and MeCN. The residue was subjected to extraction with EtOAc (100 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 4/1, TLC: PE/EtOAc = 3/ 1, R _f = 0.41) to give 7-chloro-5-(5-fluoro-3-pyridyl)-3-iodo-pyrazolo[1,5a]pyrimidine (1.03 g, 2.75 mmol, yield 61.4%, 100.0% pure) as a yellow solid.

1H NMR (400 MHz, CDCI3) δ ppm 9.12 (s, 1H), 8.64 (d, J=2.8 Hz, 1H), 8.34-8.26 (m, 2H), 7.53 -7.45 (m, 1H); ER-LCMS m/z 374.9 [M+H]+.

Step 2: 5-(5-fluoro-3-pyridyl)-N-[2-(1 H-indol-3-yl)ethyl]-3-iodo-pyrazolo[1,5-a]pyrimidine-7 amine

7-Chloro-5-(5-fluoro-3-pyridyl)-3-iodo-pyrazolo[1,5-a]pyrimidine mixture (650 mg, 1.74 mmol, 1 eq), 2-(1H-indole -3-yl)ethanamine (333.66 mg, 2.08 mmol, 1.2 eq.) and DIEA (672.89 mg, 5.21 mmol, 906.86 µl, 3

- 303 041983 eq.) in i-PrOH (50 ml) was stirred at 60°C for 12 h. TLC (PE/EtOAc = 2/1, Rf = 0.30) showed that the starting material was completely consumed. The reaction mixture was cooled to 20°C and filtered. The solid was washed with i-PrOH (5 ml), dried under reduced pressure to give 5-(5fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-3-iodo-pyrazolo[ 1,5-a]pyrimidine-7-amine (620 mg, 1.24 mmol, 71.3% yield, 99.3% purity) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.78 (s, 1H), 8.52 (d, J=2.4 Hz, 1H), 8.10-7.90 (m, 3H), 7 .68 (d, J=7.6 Hz, 1H), 7.39-7.32 (m, 1H), 7.24-7.18 (m, 2H), 7.06 (s, 1H), 6.57 (broad s, 1H), 6.12 (s, 1H), 3.86 (q, J=6.4 Hz, 2H), 3.27 (t, J=6.4 Hz, 2H ); ER-LCMS m/z 499.1 [M+H]+.

Stage 3: tert-butyl-3-[2-[tert-butoxycarbonyl-[5-(5-fluoro-3-pyridyl)-3-iodo-pyrazolo[1,5a] pyrimidin-7-yl] amino] ethyl] indole-1-carboxylate

Vos /

N

A mixture of 5-(5-fluoro-3-pyridyl)-N-[2-(1 H-indol-3-yl)ethyl]-3-iodo-pyrazolo[1,5-а]pyrimidin-7-amine (900 mg, 1.81 mmol, 1 eq), Boc ₂ O (1.58 g, 7.22 mmol, 1.66 ml, 4 eq.) and DMAP (1.10 g, 9.03 mmol, 5 eq. ) in 1,4-dioxane (60 ml) was stirred at 120° C. for 12 h. TLC (PE/EtOAc = 3/1, Rf = 0.60) showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 3/1, Rf = 0.60), obtaining tert-butyl-3-[2-[tert-butoxycarbonyl-[5-(5-fluoro-3-pyridyl)-3-iodo-pyrazolo[1,5-a]pyrimidin-7-yl]amino]ethyl]indol- 1 carboxylate (1 g, 1.41 mmol, 78.2% yield, 98.7% purity) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.73 (s, 1H), 8.55 (d, J=2.4 Hz, 1H), 8.15 (s, 1H), 7.98 (broad s, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.25-7.23 (m, 2H) , 7.19-7.12(m, 1H), 6.55(s, 1H), 4.24-4.18(m, 2H), 3.15-3.06(m, 2H), 1 .59 (s, 9H), 1.39 (s, 9H); ER-LCMS m/z 699.2 [M+H]+.

Stage 4: tert-butyl-3-[2-[[3-acetyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-tert-butoxycarbonyl-amino]ethyl] indole-1-carboxylate

A mixture of tert-butyl-3-[2-[tert-butoxycarbonyl-[5-(5-fluoro-3-pyridyl)-3-iodo-pyrazolo[1,5a]pyrimidin-7-yl]amino]ethyl]indol- 1-carboxylate (200 mg, 282.60 µmol, 1 eq.), tributyl(1ethoxyvinyl)stannane (880 mg, 2.44 mmol, 822.43 µl, 8.62 eq.) and Pd(dppf)Cl ₂ ( 206.78 mg, 282.60 µmol, 1 eq) in toluene (6 ml) was purged with N 2 for 2 min and tightly capped. The reaction mixture was irradiated under microwave radiation (1 bar) at 100° C. for 2 hours. The reactions were carried out in parallel 5 times. KF (100 ml, 2M) was added to the combined mixture. The mixture was stirred at 25°C for 1 h and extracted with EtOAc (100 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 4/1, TLC: PE/EtOAc = 3/1, Rf = 0.40) to give tert-butyl-3-[2-[[3-acetyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-tert-butoxycarbonylamino ]ethyl]indole-1-carboxylate (450 mg, 732.11 µmol, 51.8% yield, 100.0% purity) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.79 (s, 1H), 8.66 (s, 1H), 8.61 (d, J=2.4 Hz, 1H), 7.97 (d , J=6.4Hz, 1H), 7.80 (td, J=2.4, 9.2Hz, 1H), 7.42 (d, J=7.6Hz, 1H), 7.26 -7.20 (m, 2H), 7.17-7.11 (m, 1H), 6.65 (s, 1H), 4.30 (t, J=6.4 Hz, 2H), 3, 18-3.12 (m, 2H), 2.84 (s, 3H), 1.59 (s, 9H), 1.43 (s, 9H); ER-LCMS m/z 615.3 [M+H] ⁺ .

- 304 041983

Step 5: 1-[5-(5-Fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3yl]ethanone

To a mixture of tert-butyl-3-[2-[[3-acetyl-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-tert-butoxycarbonyl-amino]ethyl]indole -1-carboxylate (450 mg, 732.11 µmol, 1 eq.) in MeOH (50 ml) was added HCl/H ₂ O (6 M, 150 ml, 1229.33 eq.) at 20°C. The mixture was stirred at 35° C. for 3 hours. The mixture was basified with aqueous NaOH (15%) to pH 8 and concentrated under reduced pressure to remove MeOH. The residue was subjected to extraction with EtOAc (50 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-[5-(5-fluoro-3-pyridyl)-7[2-(1H-indol-3-yl)ethylamino]pyrazolo[1 ,5-a]pyrimidin-3-yl]ethanone (300 mg, 723.88 µmol, 98.9% yield, 100.0% purity) as a yellow solid, which was used in the next step without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.77 (br s, 1H), 9.11 (s, 1H), 8.67 (d, J=2.4 Hz, 1H), 8.60 (t, J=6.0 Hz, 1H), 8.49 (s, 1H), 8.18 (d, J=10.4 Hz, 1H), 7.61 (d, J=7 .6 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 7.05-6.99 (m, 1H ), 6.98-6.93 (m, 1H), 6.82 (s, 1H), 3.84 (q, J=6.4 Hz, 2H), 3.09 (t, J=6, 8 Hz, 2H), 2.67 (s, 3H); ER-LCMS m/z 415.1 [M+H]+.

Step 6: (1S)-1-[5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidin3-yl] ethanol (I-222b) and (1R)-1-[5-(5-fluoro-3-pyridyl)-7-[2-(1H-indol-3-yl)ethylamino]pyrazolo[1,5а]pyrimidin- 3-yl]ethanol (I-222a)

To a solution of 1-[5-(5-fluoro-3-pyridyl)-7-[2-(1 H-indol-3-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3-yl]ethanone (250 mg, 603.23 µmol, 1 eq.) in THF (50 ml) and EtOH (20 ml), NaBH ₄ (114.11 mg, 3.02 mmol, 5 eq.) was added portionwise at 20°C. The mixture was stirred at 20° C. for 3 hours. The reaction mixture was quenched with water (50 ml) and concentrated under reduced pressure at 30° C. to remove EtOH and THF. The residue was subjected to extraction with EtOAc (80 mlx3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure, obtaining a residue, which was separated by chiral SFC (column: DAICEL CHIRALPAK AD-H (250 mmx30 mm, 5 μm); mobile phase : [0.1% NH ₃ -H2O/EtOH] B%: 40%-40%). The fraction corresponding to peak 1 was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN] ; B%: 40%-70%, 10 min). The desired fraction was lyophilized to give the enantiomer (32.78 mg, 76.81 µmol, 12.7% yield, 97.6% purity) as a white solid (SFC: Rt = 6.825, ee = 98.8%; Optical rotation: [a] ^22.3 _D = -9.540 (10.04 mg/10 ml in MeOH)).

1H NMR (400 MHz, CDC13) δ ppm 8.78 (s, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.07 (broad s, 1H), 7.95 (s , 1H), 7.87-7.80 (m, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.40-7.32 (m, 1H), 7.26- 7.18 (m, 2H), 7.06 (s, 1H), 6.56 (broad s, 1H), 6.08 (s, 1H), 5.34 (d, J=6.0 Hz , 1H), 3.89-3.83 (m, 2H), 3.29-3.24 (m, 3H), 1.70 (d, J=6.4 Hz, 3H); ERJHMS m/z 417.2 [M+H] ⁺ . The fraction corresponding to peak 2 was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN] ; B%: 40%70%, 10 min). The desired fraction was lyophilized to give a residue which was again separated by chiral SFC (column: DAICEL CHIRALPAK AD-H (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH ₃ -H2O/EtOH]; V%: 40 %-40%). The desired fraction was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN]; B%: 42%-72%, 10 min). The desired fraction was lyophilized to give the other enantiomer (30.13 mg, 72.35 µmol, yield

- 305 041983

12.0%, 100.0% pure as a white solid (SFC: Rt = 7.042, ee = 99.0%; Optical rotation: [a] ^22.2 D = 1.916 (6.44 mg/10 ml to MeOH)).

1H NMR (400 MHz, CDCI3) δ ppm 8.77 (s, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.11 (broad s, 1H), 7.95 ( s, 1H), 7.83 (td, J=2.0, 9.6 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.36 (d, J=8 .0 Hz, 1H), 7.27-7.18 (m, 2H), 7.06 (d, J=2.0 Hz, 1H), 6.58 (t, J=5.6 Hz, 1H ), 6.07 (s, 1H), 5.42-5.26 (m, 1H), 3.85 (q, J=6.4 Hz, 2H), 3.34-3.22 (m, 3H), 1.70 (d, J=6.4 Hz, 3H); ER-LCMS m/z 417.2 [M+H]+.

Example 174.

Synthesis of I-224

Step 1: N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]-5-(5-fluoro-3-pyridyl)-3-methylpyrazolo (I224)

A mixture of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (60 mg, 228.42 µmol, 1 eq) and 2-(7-fluoro DIEA (88.57 mg, 685 .27 µmol, 119.36 µl, 3 eq) and purged with N ₂ 3 times. The mixture was stirred at 80° C. for 16 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela Durashell C18 150x25 5u; mobile phase: [water (0.05% HCl)-ACN]; B%: 30%-60%, 12 min) to give a product which was purified by preparative HPLC (column: Gemini 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN]; B%: 55%-85% , 8 min) followed by lyophilization to give N-[2-(7-fluoro-2-methyl-1 H-indol-3-yl)ethyl]-5-(5-fluoro-3-pyridyl)-3-methylpyrazolo [1,5-a]pyrimidine-7-amine (16.79 mg, 40.13 µmol, 17.6% yield, 100.0% purity) as a yellow solid.

1H NMR (400 MHz, CDCI3) δ ppm 8.80 (s, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.00 (br s, 1H), 7.95- 7.82 (m, 2H), 7.32 (d, J=7.9 Hz, 1H), 7.10-7.03 (m, 1H), 6.89 (dd, J=8.2, 11.0 Hz, 1H), 6.49 (br s, 1H), 6.01 (s, 1H), 3.78 (q, J=6.5 Hz, 2H), 3.21-3, 13 (m, 2H), 2.38 (s, 3H), 2.29 (s, 3H); ER-LCMS m/z 419.2 [M+H]+.

Example 175.

Synthesis of I-225

- 306 041983

Synthesis scheme:

Stage 1: methyl 7-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethylamino]-5-(5-fluoro-3pyridyl)pyrazolo[1,5-a]pyrimidine-3 - carboxylate

Methyl-7-chloro- 5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (63.52 mg, 196.77 µmol, 1 eq) and DIEA (76.29 mg, 590.31 µmol, 102.82 µl, 3 eq.). The mixture was stirred at 60° C. for 3 h under N2. The mixture was concentrated under reduced pressure and water (50 ml) was added. The mixture was subjected to extraction with EtOAc (30 mlx3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give methyl-7-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethylamino]- 5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine 3-carboxylate (90 mg, 173.79 µmol, 88.3% yield, 89.3% purity) as a yellow solid, which was used in the next step without further purification.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.51-8.46 (m, 2H), 8.41 (s, 1H), 7.72-7.65 (m, 1H), 7, 38 (d, J=8.0 Hz, 1H), 6.98-6.92 (m, 1H), 6.69-6.60 (m, 1H), 5.85 (s, 1H), 3 .88 (s, 3H), 3.83 (br s, 2H), 3.16-3.07 (m, 2H), 2.08 (s, 3H); ER-LCMS m/z 463.2 [M+H]+.

Stage 2: 7-[2-(7-Fluoro-2-methyl-1 H-indol-3 -yl)ethylamino]-5-(5-fluoro-3-pyridyl)pyrazolo[1,5a]pyrimidine-3- carboxylic acid

To a solution of methyl-7-[2-(7-fluoro-2-methyl-1 H-indol-3 -yl)ethylamino]-5-(5-fluoro-3 pyridyl)pyrazolo[1,5-a]pyrimidine- 3-carboxylate (90 mg, 173.79 µmol, 1 eq.) in MeOH (5 ml) NaOH (2 M, 4.96 ml, 57.09 eq.) was added. The mixture was stirred at 50° C. for 4 hours under N2. The mixture was concentrated under reduced pressure. The residue was dissolved in water (50 ml), the pH was adjusted to 3 with 1 N sodium hydroxide. HCl solution was extracted with EtOAc (20 mlx3). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered and concentrated to give 7-[2-(7fluoro-2-methyl-1H-indol-3-yl)ethylamino]-5-(5-fluoro- 3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (80 mg, 160.56 µmol, 92.4% yield, 90.0% purity) as a yellow solid, which was used in the next step without further purification.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.48 (s, 2H), 8.41 (s, 1H), 7.68 (d, J=9.8 Hz, 1H), 7.38 (d , J=7.8Hz, 1H), 6.95(dt, J=4.5, 7.9Hz, 1H), 6.68-6.60(m, 1H), 5.85(s, 1H), 3.89-3.83 (m, 2H), 3.15-3.08 (m, 2H), 2.08 (s, 3H); ER-LCMS m/z 449.2 [M+H] ⁺ .

- 307 041983

Step 3: [7-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethylamino]-5-(5-fluoro-3-pyridyl)pyrazolo[1,5a]pyrimidine-3 - silt] morpholino-methanone (I-225)

To a solution of 7 - [2- (7-fluoro-2-methyl-1 H-indol-3 -yl) ethylamino] -5 - (5-fluoro-3 -pyridyl) pyrazolo [1,5a] pyrimidine-3-carboxylic acid (80 mg, 160.56 µmol, 1 eq.) in DCM (10 ml) was added morpholine (20.98 mg, 240.84 µmol, 21.19 µl, 1.5 eq.), HATU (91.58 mg, 240.84 µmol, 1.5 eq.) and TEA (32.49 mg, 321.12 µmol, 44.70 µl, 2 eq.). The mixture was stirred at 20° C. for 1 h under N ₂ atmosphere. The mixture was concentrated under reduced pressure, water (30 ml) was added. The mixture was subjected to extraction with EtOAc (20 mlx3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini C18 250x50 mmx10 μm; mobile phase: [water (0.05 % HCl)-ACN]; B%: 33%-63%, 10 min) followed by lyophilization to give [7-[2-(7-fluoro-2-methyl-1H-indol-3yl)ethylamino]-5- (5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-3-yl]morpholino-methanone (29.09 mg, 56.21 µmol, 35.0% yield, 100% purity) as a solid yellow substances.

1H NMR (400 MHz, CD3OD) δ ppm 8.78 (d, J=2.5 Hz, 1H), 8.60 (s, 1H), 8.38 (s, 1H), 7.79-7, 70 (m, 1H), 7.34 (d, J=8.0 Hz, 1H), 6.87 (dt, J=4.7, 7.8 Hz, 1H), 6.60 (dd, J = 7.7, 11.4 Hz, 1H), 5.88 (s, 1H), 4.01-3.93 (m, 2H), 3.76 (s, 8H), 3.20-3, 14 (m, 2H), 2.12 (s, 3H); ER-LCMS m/z 518.3 [M+H]+.

Example 176.

Synthesis of I-226

Synthesis scheme:

Dtbbpy, K ₂ HPO ₄ [lr{dFCF ₃ ppy} ₂ (bpy)]PF ₆

NiCI(1,2-dimethoxyethane)

THF, fluorescent light

DMAP, DXM

Stage 1: tert-butyl-3-[2-[[3-bromo-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-tert-butoxycarbonyl-amino]ethyl] indole-1-carboxylate

Vos

To a solution of 3-bromo-5-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrazolo[1,5-a]pyrimidin-7

- 308 041983 amine (750 mg, 1.63 mmol, 1 eq.) in 1,4-dioxane (30 ml) was added DMAP (596.31 mg, 4.88 mmol, 3 eq.) and (Boc)2O ( 887.73 mg, 4.07 mmol, 934.45 µl, 2.5 eq.). The mixture was stirred at 110° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc= 3/1, Rf = 0.75) to give tert-butyl-3-[2-[[3-bromo-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidine-7- yl]-tert-butoxycarbonyl-amino]ethyl]indole-1-carboxylate (950 mg, 1.46 mmol, 89.6% yield, 100.0% purity) as a yellow solid.

¹ H NMR (400 MHz, CDC13) δ ppm 8.73 (s, 1H), 8.57 (d, J=2.8 Hz, 1H), 8.16 (s, 1H), 8.00 (d , J=7.0 Hz, 1H), 7.91 (td, J=2.1, 9.3 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.27 -7.21 (m, 2H), 7.21-7.14 (m, 1H), 6.57 (s, 1H), 4.24 (t, J=6.8 Hz, 2H), 3, 12 (t, J=6.7 Hz, 2H), 1.62 (s, 9H), 1.42 (s, 9H); ER-LCMS m/z 651.2, 652.2 [M+H]+.

Stage 2: tert-butyl-3-[2-[tert-butoxycarbonyl-[5-(5-fluoro-3-pyridyl)-3-tetrahydrofuran-2-ylpyrazolo[1,5-a]pyrimidin-7-yl] amino]ethyl]indole-1-carboxylate

4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (24.72 mg, 92.09 µmol, 0.1 eq.) and dichloronickel; 1,2-dimethoxyethane (20.23 mg, 92.09 µmol, 0.1 eq.) was added in THF (4 mL). The mixture was stirred at 50° C. under N2 until a green solution was obtained. [Ir{dFCF ₃ ppy} ₂ (bpy)]PF ₆ (51.66 mg, 46.05 µmol, 0.05 eq.), K2HPO4 (320.81 mg, 1.84 mmol, 2 eq.) and in the above mixture was added a solution of tert-butyl-3-[2-[[3-bromo-5-(5-fluoro-3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]-tert-butoxycarbonylamino] ethyl]indole-1-carboxylate (600 mg, 920.92 µmol, 1 eq.) in THF (20 ml) under N ₂ atmosphere. The resulting mixture was stirred and irradiated with a standard 72 W LED lamp at 25° C. for 12 h. , TLC: PE/EtOAc = 3/1, Rf = 0.45) to give tert-butyl-3-[2-[tert-butoxycarbonyl-[5-(5-fluoro-3-pyridyl)-3-tetrahydrofuran- 2-yl-pyrazolo[1,5a]pyrimidin-7-yl]amino]ethyl]indole-1-carboxylate (190 mg, 274.04 µmol, 29.8% yield, 92.7% purity) as yellow oil colors.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.83-8.76 (m, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H ), 7.90-7.79 (m, 1H), 7.47 (t, J=6.9 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.19 (t, J=7.6 Hz, 2H), 6.59 (s, 1H), 5.38-5.29 (m, 1H), 4.21-4.15 (m, 2H), 4, 10 (m, 1H), 4.01-3.92 (m, 1H), 3.11 (t, J=6.9 Hz, 2H), 2.45-2.35 (m, 1H), 2 .33-2.24 (m, 1H), 2.23-2.16 (m, 1H), 2.15-2.07 (m, 1H), 1.60 (s, 9H), 1.46 -1.39 (m, 9H); ER-LCMS m/z 643.3 [M+H] ⁺ .

Step 3: 5-(5-Fluoro-3-niridyl)-N-[2-(1H-indol-3-yl)ethyl]-3-tetrahydrofurαn-2-yl-pyrazolo[1,5a]pyrimidine-7- amine (I-226)

To a stirred solution of tert-butyl-3-[2-[tert-butoxycarbonyl-[5-(5-fluoro-3-pyridyl)-3tetrahydrofuran-2-yl-pyrazolo[1,5-a]pyrimidin-7-yl] amino]ethyl]indole-1-carboxylate (70 mg, 100.96 μmol, 1 eq.) in DCM (8 ml) was added ZnBr ₂ (2.27 g, 10.10 mmol, 100 eq.). The reaction mixture was stirred at 25° C. for 15 hours. TLC (PE/EtOAc = 1/1, Rf = 0.35) indicated that one major new spot was found. MeOH (30 ml) was added to the reaction mixture and diluted with water (50 ml), pH adjusted to 8-9 with saturated NaHCO ₃ solution, extracted with EtOAc (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 2/1, TLC: PE/EtOAc = 1 /1, Rf = 0.35) to give a residue which was repurified by preparative HPLC (basic conditions; column: Gemini 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN ]; B%: 55%-75%, 8 min). The desired fraction was lyophilized to give 5-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-3-tetrahydrofuran-2-yl-pyrazolo[1,5a]pyrimidine -7-amine (5.91 mg, 12.85 µmol, 12.7% yield, 96.2% purity) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.80 (s, 1H), 8.50 (s, 1H), 8.03 (s, 2H), 7.85 (d, J=9.5 Hz , 1H), 7.69 (d, J=7.5 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.26-7.18 (m, 2H), 7 .05 (d, J=2.0 Hz, 1H), 6.54 (s, 1H), 6.07 (s, 1H), 5.29

- 309 041983 (t, J=7.3 Hz, 1H), 4.12 (q, J=7.3 Hz, 1H), 3.99-3.90 (m, 1H), 3.85 (q , J=6.3Hz, 2H), 3.25(t, J=6.5Hz, 2H), 2.392.28(m, 2H), 2.24-2.15(m, 1H), 2 .14-2.04 (m, 1H); ER-LCMS m/z 443.2 [M+H]+.

Example 177.

Synthesis of I-227

Η

1-227

Synthesis scheme:

Vos /

Ι-227

Stage 1: 1,3-benzodioxol-4-yl(trimethyl)stannan

Trimethyl(trimethylstannyl)stannan (132.10 mg, 403.20 µmol , 83.61 µl, 1 eq.) and 4diphenylphosphanylbutyl(diphenyl)phosphane (17.20 mg, 40.32 µmol, 0.1 eq.) were purged with N2 for 15 min. Pd(OAc) ₂ (9.05 mg, 40.32 µmol, 0.1 eq) was added and the mixture was stirred at 110° C. for 3 h. TLC (PE/EtOAc = 10/1, Rf = 0.44 ) showed that a single large new spot with less polarity was detected. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc=1/0 to 10/3, TLC: PE/EtOAc=3/1, Rf=0.44) to give the indicated product 1,3-benzodioxol-4-yl(trimethyl)stannan (80 mg, 252.70 µmol, 62.7% yield, 90.0% purity) as a colorless oil.

1 H NMR (400 MHz, CDC13) δ ppm 6.88-6.76 (m, 3H), 5.91 (s, 2H), 0.42-0.26 (s, 9H).

Step 2: tert-butyl-3-[2-[[5-(1,3-benzodioxol-4-yl)-3-isopropyl-pyrazolo[1,5-a] pyrimidin-7 yl]-tert-butoxycarbonyl- amino]ethyl]indole-1-carboxylate

Vos /

A solution of 1,3-benzodioxol-4-yl(trimethyl)stannan (50 mg, 157.94 µmol, 1 eq.) and tert-butyl-3-[2[tert-butoxycarbonyl-(5-chloro-3-isopropyl- pyrazolo[1,5-a]pyrimidin-7-yl)amino]ethyl]indole-1-carboxylate (75.06 mg, 134.25 µmol, 0.85 eq.) in DMF (5 mL) was purged with N2 for 25 min. Pd(dppf)Cl ₂ (10.98 mg, 15.00 µmol, 0.095 eq) and CuI (2.86 mg, 15.00 µmol, 0.095 eq) were added and the mixture was stirred at 110° C. for 2 h when treated with microwave radiation. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified with

- 310 041983 using preparative TLC (TLC: PE/EtOAc = 10/1, Rf = 0.46) to give the indicated product tert-butyl-3-[2-[[5-(1,3-benzodioxol-4-yl)- 3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]-tert-butoxycarbonyl-amino]ethyl]indole-1-carboxylate (80 mg, 106.42 µmol, 67.4% yield, 85.1% purity ) as a yellow oil.

1H NMR (400 MHz, CDC13) δ ppm 8.03 (s, 2H), 7.99 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.50 (d, J=7.1 Hz, 1H), 7.39 (br s, 2H), 7.23-7.14 (m, 1H), 7.03-6.96 (m, 1H), 6.95 -6.90 (m, 1H), 6.09-6.04 (m, 2H), 4.19 (t, J=7.5 Hz, 2H), 3.46-3.37 (m, 1H ), 3.06 (t, J=6.9 Hz, 2H), 1.63 (s, 9H), 1.45 (d, J=6.4 Hz, 6H), 1.36 (s, 9H ); ERJHMS m/z 640.4 [M+H]+.

Step 3: 5-(1,3-benzodioxol-4-yl)-N-[2-(1 H-indol-3-yl)ethyl]-3-isopropylpyrazolo[1,5a]pyrimidin-7-amine (I-227)

Solution of tert-butyl-3-[2-[[5-(1,3-benzodioxol-4-yl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]tert-butoxycarbonyl-amino] ethyl]indole-1-carboxylate (80 mg, 106.42 µmol, 1 eq.) in HCl/MeOH (4 M, 5 ml, 187.94 eq.) was stirred at 25°C for 12 h. LC-MS showed that the original substance was not completely consumed. The mixture was stirred at 25°C for another 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HC1)ACN ]; B%: 35%-65%, 9 min) followed by lyophilization to give 5-(1,3-benzodioxol-4-yl)-N-[2(1H-indol-3-yl)ethyl]-3 -isopropyl-pyrazolo[1,5-a]pyrimidine-7-amine (47.73 mg, 100.08 µmol, 94.0% yield, 99.8% purity, HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.16 (s, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H) , 7.05-7.00 (m, 2H), 6.97-6.92 (m, 2H), 6.86-6.80 (m, 1H), 6.53 (d, J=8, 0 Hz, 1H), 6.07 (s, 2H), 5.76 (s, 1H), 3.96 (t, J=5.8 Hz, 2H), 3.23-3.18 (m, 3H), 1.33 (d, J=6.8 Hz, 6H); ER-LCMS m/z 440.3 [M+H]+.

Example 178.

Synthesis of I-229

Stage 1: tert-butyl (3R)-3-[tert-butoxycarbonyl-(3-isopropyl-5-pyrimidin-5-yl-pyrazolo[1,5a]pyrimidin-7-yl)amino]-1,2,3 ,4-tetrahydrocarbazole-9-carboxylate

tert-butyl (3R)-3-[tert-butoxycarbonyl-(5-chloro-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl)amino]-1,2,3,4-tetrahydrocarbazole- 9-carboxylate (200 mg, 316.66 µmol, 1 eq.), pyrimidin-5ylboronic acid (47.08 mg, 379.99 µmol, 1.2 eq.), Cs ₂ CO ₃ (309.52 mg, 949 .98 µmol, 3 eq.) and

- 311 041983

Pd(dppf)Cl ₂ (23.17 mg, 31.67 µmol, 0.1 eq.) was placed in a microwave tube in 1,4dioxane (6 ml) and H ₂ O (2 ml). The sealed tube was heated at 110° C. for 1 hour while being treated with microwave radiation (2 bar). The mixture was concentrated and then saturated NaHCO ₃ (10 ml) was added, extracted with EtOAc (10 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC: PE/EtOAc = 3/1, R _f = 0.30) to give tert-butyl (3R)-3-[tert-butoxycarbonyl-(3-isopropyl-5-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-7-yl)amino ]1,2,3,4-tetrahydrocarbazole-9-carboxylate (180 mg, 288.58 µmol, 91.1% yield, 100.0% purity) as a yellow resin.

1H NMR (400 MHz, CD3OD) δ ppm 9.39 (s, 2H), 9.22 (s, 1H), 8.14 (s, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.46 (s, 1H), 7.19 (br s, 1H), 7.14-7.02 (m, 2H), 4.79 (m, 1H), 3.48 (m , 1H), 3.43-3.36(m, 2H), 3.18-3.08(m, 2H), 2.36-2.28(m, 2H), 1.63(s, 9H ), 1.45 (d, J=7.1 Hz, 6H), 1.30 (s, 9H); ER-LCMS m/z 624.4 [M+H] ⁺ .

Stage 2: (3R)-N-(3-isopropyl-5-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-7-yl)-2,3,4,9 tetrahydro-1 H-carbazole -3-amine (I-229) n

Αν-Λ

^Πγν

To a solution of tert-butyl (3R)-3-[tert-butoxycarbonyl-(3-isopropyl-5-pyrimidin-5-ylpyrazolo[1,5-a]pyrimidin-7-yl)amino]-1,2,3, 4-tetrahydrocarbazole-9-carboxylate (180 mg, 288.58 µmol, 1 eq.) in DCM (5 ml) was added with TFA (1 ml). The mixture was degassed and purged with N2 3 times, the mixture was stirred under N2 atmosphere at 20° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase : [water (0.05% HCl)-ACN]; B%: 50%-80%, 9 min) to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN]; B%: 56% 86%, 10 min) followed by lyophilization to give (3R)-N-(3-isopropyl-5-pyrimidine-5- ylpyrazolo[1,5-a]pyrimidin-7-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (12 mg, 28.33 µmol, 9.8% yield, 100 purity, 0%) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.51 (s, 2H), 9.21 (s, 1H), 7.95 (s, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 7.07-7.01 (m, 1H), 6.99-6.93 (m, 1H), 6.84 (s , 1H), 4.47 (m, J=8.6 Hz, 1H), 3.37-3.34 (m, 2H), 3.14-3.03 (m, 1H), 3.00- 2.88 (m, 2H), 2.41-2.33 (m, 1H), 2.28-2.19 (m, 1H), 1.42 (d, J=6.8 Hz, 6H) ; ERJHMS m/z 424.2 [M+H] ⁺ .

Example 179.

Synthesis of I-230

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Step 1: 5-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-3-vinyl-pyrazolo[1,5-a]pyrimidine-7amine (I- 230)

A mixture of 5-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-3-iodo-pyrazolo[1,5-a]pyrimidin-7-amine (55 mg, 109.71 µmol, 1 eq.), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (50.69 mg, 329.14 µmol, 55.83 µl, 3 eq.), Cs ₂ CO ₃ (178.74 mg, 548.57 µmol, 5 eq.) and Pd(dppf)Cl ₂ (40.14 mg, 54.86 µmol, 0.5 eq.) in 1, 4-dioxane (3 ml) and H ₂ O (1.5 ml) was purged with N 2 for 2 minutes and tightly closed. The reaction mixture was irradiated under microwave radiation (2 bar) at 120° C. for 2 h. The reaction mixture was diluted with H2O (10 ml) and extracted with EtOAc (10 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative TLC (PE/EtOAc = 2/1, R _f = 0.23) and then by preparative HPLC (column: Gemini 150x25 5u, mobile phase: [water (0.05% ammonium hydroxide o6./o6.)-ACN]; B%: 60%-90%, 8 min). The desired fraction was lyophilized to give 5-(5-fluoro-3-pyridyl)-N-[2-(1Hindol-3-yl)ethyl]-3-vinyl-pyrazolo[1,5-a]pyrimidin-7-amine ( 15.4 mg, 38.65 µmol, 35.2% yield, 100.0% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.82 (s, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.06 (s, 2H), 7.95- 7.88 (m, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.39-7.33 (m, 1H), 7.27-7.18 (m, 2H) , 7.06 (d, J=2.0 Hz, 1H), 6.90 (dd, J=11.2, 17.6 Hz, 1H), 6.55 (t, J=6.4 Hz, 1H), 6.11 (s, 1H), 6.07 (dd, J=1.6, 17.6 Hz, 1H), 5.27 (dd, J=2.0, 11.2 Hz, 1H ), 3.85 (q, J=6.4 Hz, 2H), 3.27 (t, J=6.4 Hz, 2H); ER-LCMS m/z 399.2 [M+H]+.

Example 180.

Synthesis of I-232

1-232

Synthesis scheme:

Step 1: 5-(5-fluoro-3-pyridyl)-N-[(2R)-5-methoxyindan-2-yl]-3-methyl-pyrazolo[1,5-a]pyrimidine7-amine

To a mixture of 7-chloro-5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidine (50 mg, 190.35 µmol, 1 eq.), (2R)-5 -methoxyindan-2-amine (38.01 mg, 190.35 µmol, 1 eq, HCl) in i-PrOH (5 ml) was added DIEA (73.80 mg, 571.06 µmol, 99.47 µl, 3 equiv.). The mixture was stirred at 80° C. for 12 hours. The mixture was concentrated to give the crude compound 5-(5-fluoro-3-pyridyl)-N-[(2R)-5-methoxyindan-2yl]-3-methyl-pyrazolo[1 ,5-a]pyrimidine-7-amine (70 mg, 130.90 µmol, 68.8% yield, 72.8% purity) as a yellow oil, which was used in the next step without further purification; ERZhHMS m/z 390.2 [M+H] ⁺ .

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Step 2: (2R)-2-[[5-(5-fluoro-3-pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]indan-5-ol (I -232)

5-(5-Fluoro-3-niridyl)-N-[(2R)-5-methoxyindan-2-yl]-3-methyl-pyrazolo[1,5-a]pyrimidine-7amine mixture (70 mg, 130, 90 µmol, 1 eq.) in HBr solution (7.45 g, 55.25 mmol, 5 ml, 60%, 422.06 eq.) was stirred at 80° C. for 1 h. The mixture was concentrated to give a residue which purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 30%-60%, 6 min). The desired fraction was lyophilized to give (2R)-2-[[5-(5-fluoro-3pyridyl)-3-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]indan-5-ol (17 .22 mg, 38.27 µmol, 29.2% yield, 99.6% purity, 2HCl, ee = 98.2%) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.98 (s, 1H), 8.80 (d, J=2.4 Hz, 1H), 8.29 (td, J=2.4, 9, 2 Hz, 1H), 8.11 (s, 1H), 7.06 (d, J=8.0 Hz, 1H), 6.94 (s, 1H), 6.69 (s, 1H), 6 .63 (dd, J=2.4, 8.0 Hz, 1H), 5.07-4.96 (m, 1H), 3.473.39 (m, 2H), 3.23-3.15 (m , 2H), 2.36 (s, 3H); ER-LCMS m/z 376.1 [M+H]+.

Example 181.

Synthesis of I-234

Synthesis scheme:

5-(5-fluoro-3-pyrudyl)-3-isopropyl-N-[(2R)-5-methoxyindan-2-yl]pyrazolo[1.5Step 1:

a] pyrimidine-7-amine

To a mixture of 7-chloro-5-(5-fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine (50 mg, 154.79 µmol, 1 eq.), (2R)-5 -methoxyindan-2-amine (27.79 mg, 170.27 µmol, 1.1 eq.) in i-PrOH (5 ml) was added DIEA (60.01 mg, 464.36 µmol, 80.88 µl, 3 equiv.). The mixture was stirred at 80° C. for 12 hours. The mixture was concentrated to give the title product 5-(5-fluoro-3-pyridyl)-3-isopropyl-N-[(2R)-5methoxyindan-2-yl]pyrazolo[1, 5-a]pyrimidine-7-amine (60 mg, 102.65 µmol, 66.3% yield, 71.4% purity) as a yellow oil, which was used in the next step without further purification. ER-LCMS m/z 418.2 [M+H] ⁺ .

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Step 2: (2R)-2-[[5-(5-fluoro-3-pyridyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7yl]amino]indan-5-ol (I- 234)

5-(5-Fluoro-3-pyridyl)-3-isopropyl-N-[(2R)-5-methoxyindan-2-yl]pyrazolo[1,5-a]pyrimidine7-amine mixture (60 mg, 102.04 µmol, 1 eq.) in HBr solution (5.29 g, 39.22 mmol, 3.55 ml, 60%, 384.39 eq.) was stirred at 120°C for 2 h. The mixture was concentrated to give a residue, which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 45%-75%, 9 min). The desired fraction was lyophilized to give (2R)-2-[[5-(5fluoro-3-pyridyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-yl]amino]indan-5-ol (13 .92 mg, 31.34 µmol, 30.7% yield, 99.0% purity, HCl) (97.1% ee) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.98 (s, 1H), 8.80 (d, J=2.0 Hz, 1H), 8.32-8.29 (m, 1H), 8, 21 (s, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.92 (s, 1H), 6.62 (dd, J=2.4, 8.4 Hz, 1H ), 6.61 (m, 1H), 5.02-4.93 (m, 1H), 3.49-3.40 (m, 2H), 3.37-3.31 (m, 1H), 3.21-3.09 (m, 2H), 1.36 (d, J=6.8 Hz, 6H); ER-LCMS m/z 404.3 [M+H]+.

Example 182.

Synthesis of I-235

Step 1: N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]-5-(5-fluoro-3-pyridyl)-3(trifluoromethyl)pyrazolo[1,5- a] pyrimidine-7-amine (I-235)

To a solution of 7-chloro-5-(5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (30 mg, 87.92 µmol, 1 eq.) and 2-(7 -fluoro-2-methyl-1H-indol-3-yl)ethanamine (24.15 mg, 105.51 µmol, 1.2 eq) in iPrOH (5 mL) was added DIEA (34.09 mg, 263.77 µmol, 45.94 µl, 3.0 eq.). The mixture was stirred at 80° C. for 9 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN ]; B%: 50%-80%, 10 min) followed by lyophilization to give N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]-5-(5- fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazolo [1,5a]pyrimidine-7-amine (10.90 mg, 19.97 µmol, 22.7% yield, 99.9% purity, 2HCl) as yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.86 (dd, J=1.3, 2.5 Hz, 1H), 8.74 (d, J=1.5 Hz, 1H), 8.34 (s, 1H), 7.94 (td, J=2.3, 8.7 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 6.98 (dt, J= 4.8, 7.9 Hz, 1H), 6.67 (dd, J=7.9, 11.4 Hz, 1H), 5.92

- 315 041983 (s, 1H), 3.98-3.91 (m, 2H), 3.21-3.14 (m, 2H), 2.13-2.05 (m, 3H); ER-LCMS m/z 473.2 [M+H]+.

Example 183.

Synthesis of I-237

Step 1: 3-Ethyl-5-(5-fluoro-3-nirugyl)-N-[2-(1H-indol-3-yl)ethyl]nipαzolo[1,5-a]nirimidin-7amine (I-237 )

A mixture of 5-(5-fluoro-3-pyridyl)-N-[2-(1 H-indol-3-yl)ethyl]-3-vinyl-pyrazolo[1,5-a]pyrimidine-7 amine (140 mg , 196.77 µmol, 1 eq.) and Pd/C (50 mg, 10% purity) in EtOAc (20 ml) was stirred in H ₂ (15 Psi) at 25°C for 12 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini C18 250x50 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 35%-65%, 10 min). The desired fraction was lyophilized to give 3-ethyl-5-(5-fluoro-3-niridyl)-N-[2-(1H-indol-3yl)ethyl]pyrazolo[1,5-a]pyrimidin-7-amine (7 .13 mg, 15.06 µmol, 7.7% yield, 100.0% purity, 2HCl) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.65 (d J=2.4 Hz, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 7.53 (d, J=8.0Hz, 1H), 7.50-7.46(m, 1H), 7.14(d, J=8.0Hz, 1H), 6.99(s, 1H), 6, 96 (t, J=7.6 Hz, 1H), 6.87-6.82 (m, 1H), 5.78 (s, 1H), 3.98 (t, J=5.6 Hz, 2H ), 3.20 (t, J=5.6 Hz, 2H), 2.72 (q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H); ER-LCMS m/z 401.2 [M+H] ⁺ .

Example 184.

Synthesis of I-240

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Stage 1: tert-butyl-3-[2-[tert-butoxycarbonyl-[3-isopropyl-5-(2-methoxyphenyl)pyrazolo[1,5a]pyrimidin-7-yl]amino]ethyl]indole-1-carboxylate

To a solution of tert-butyl-3-[2-[tert-butoxycarbonyl-(5-chloro-3-isopropyl-pyrazolo[1,5-а]pyrimidin-7-yl)amino]ethyl]indole-1-carboxylate (100 mg, 178.86 µmol, 1 eq.) in 1,4-dioxane (6 ml) and water (2 ml) was added (2-methoxyphenyl)boronic acid (81.53 mg, 536.57 µmol, 3 eq.) , K ₃ PO ₄ (113.89 mg, 536.57 µmol, 3 eq.) and sphos palladacycle (13.61 mg, 17.89 µmol, 0.1 eq.). The mixture was stirred at 110°C for 1 h under N ₂ atmosphere. The mixture was concentrated under reduced pressure, then water (30 ml) was added. The mixture was subjected to extraction with EtOAc (50 mlx3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give t-butyl-3-[2-[t-butoxycarbonyl-[3-isopropyl-5-(2-methoxyphenyl)pyrazolo [1,5-a]pyrimidin-7-yl]amino]ethyl]indole-1-carboxylate (200 mg, 164.28 µmol, 91.8% yield, 51.4% purity) as a yellow oil which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 7.96 (s, 1H), 7.92-7.87 (m, 1H), 7.73 (dd, J=1.7, 7.6 Hz, 1H ), 7.657.60 (m, 1H), 7.47 (dd, J=1.4, 8.7 Hz, 1H), 7.19-7.13 (m, 2H), 7.07 (s, 1H), 6.97-6.94 (m, 1H), 6.94-6.91 (m, 2H), 4.1 (m, 2H), 3.81 (s, 3H), 3.36 (s, 1H), 3.06 (t, J=6.4 Hz, 2H), 1.61-1.55 (m, 9H), 1.48-1.45 (m, 6H), 1.371, 35 (m, 9H); ER-LCMS m/z 626.4 [M+H] ⁺ .

Stage 2: N-[2-(1H-Indol-3-yl)ethyl]-3-isopropyl-5-(2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine7-amine (I-240)

To a solution of tert-butyl-3-[2-[tert-butoxycarbonyl-[3-isopropyl-5-(2-methoxyphenyl) pyrazolo[1,5а]pyrimidin-7-yl]amino]ethyl]indole-1-carboxylate ( 185 mg, 151.96 µmol, 1 eq.) in DCM (10 ml) was added TFA (3.08 g, 27.01 mmol, 2 ml, 177.76 eq.). The mixture was stirred at 25° C. for 2 h under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 23%-53%, 10 min) followed by lyophilization to give N-[2-(1Hindol-3-yl)ethyl]-3-isopropyl-5-(2-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-amine (27, 57 mg, 63.69 µmol, 41.9% yield, 98.3% purity) as a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.11 (s, 1H), 7.57-7.47 (m, 2H), 7.25 (d, J=8.0 Hz, 1H) , 7.13 (d, J=8.3 Hz, 1H), 7.06-6.95 (m, 3H), 6.84 (t, J=7.5 Hz, 2H), 5.79 ( s, 1H), 3.93 (t, J=6.1 Hz, 2H), 3.83 (s, 3H), 3.21 (t, J=6.1 Hz, 2H), 3.19- 3.12 (m, 1H), 1.33 (d, J=6.8 Hz, 6H); ER-LCMS m/z 426.2 [M+H]+.

Example 185.

Synthesis of I-241

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Synthesis scheme:

Step 1: tert-butyl-3-[2-[tert-butoxycarbonyl-(3-isopropyl-5-pyrimidin-5-yl-pyrazolo[1,5a]pyrimidin-7-yl)amino]ethyl]indol-1- carboxylate

tert-Butyl 3-[2-[tert-butoxycarbonyl-(5-chloro-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7yl)amino]ethyl]indole-1-carboxylate (100 mg, 178, 86 µmol, 1 eq.), pyrimidin-5-ylboronic acid (22.16 mg, 178.86 µmol, 1 eq.), Pd(dppf)Cl ₂ (13.09 mg, 17.89 µmol, 0.1 eq.) and Cs ₂ CO ₃ (174.82 mg, 536.57 µmol, 3 eq.) were placed in a microwave tube in H2O (2 ml) and 1,4-dioxane (6 ml). The sealed tube was heated at 110° C. for 1 hour while being treated with microwave radiation. The mixture was concentrated and saturated NaHCO ₃ (10 ml) was added, extracted with EtOAc (10 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give tert-butyl-3-[2-[tert-butoxycarbonyl-(3-isopropyl-5-pyrimidin-5-yl-pyrazolo[1,5-a] pyrimidin-7 yl)amino]ethyl]indole-1-carboxylate (100 mg, 167.31 µmol, 93.5% yield, crude) as a brown solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD ₃ OD) δ ppm 9.23-9.22 (m, 1H), 9.21-9.20 (m, 1H), 8.97 (s, 1H), 7.81 (d, J=7.6Hz, 1H), 7.45 (d, J=7.6Hz, 2H), 7.41 (d, J=8.4Hz, 1H), 7.09-7 .02 (m, 2H), 6.93 (t, J=8.0 Hz, 1H), 4.33 (d, J=6.4 Hz, 2H), 4.30 (s, 1H), 3 .11 (t, J=6.4 Hz, 2H), 1.59 (s, 9H), 1.39 (s, 6H), 1.37 (s, 9H); ER-LCMS m/z 598.4 [M+H]+.

Step 2: N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-5-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-7 amine (I-241)

To a solution of tert-butyl-3-[2-[tert-butoxycarbonyl-(3-isopropyl-5-pyrimidin-5-yl-pyrazolo[1,5а]pyrimidin-7-yl)amino]ethyl]indole-1-carboxylate (100 mg, 167.31 µmol, 1 eq.) in DCM (7.5 ml) was added TFA (1.5 ml). The mixture was degassed and purged with N ₂ 3 times and stirred under N 2 atmosphere at 20° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini C18 250x50 mmx10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 35%-65%, 10 min). The desired fraction was lyophilized to give N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-5-pyrimidin-5-ylpyrazolo[1,5-a]pyrimidin-7-amine (17.94 mg , 34.12 µmol, 20.4% yield, 96.4% purity, 3HCl) as a yellow solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 9.31 (s, 1H), 8.68 (s, 2H), 8.18 (s, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.99-6.92 (m, 1H), 6.83-6.77 (m, 1H), 5.83 (s, 1H), 4.04-3.97 (m, 2H), 3.25-3.16 (m, 3H), 1.35 (d, J=6 .8 Hz, 6H); ER-LCMS m/z 398.1 [M+H] ⁺ .

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Example 186.

Synthesis of I-242

tert-butyl-3 - [2-[tert-butoxycarbonyl-(5-chloro-3-isopropyl-pyrazolo [1,5-a] pyrimidin-7 yl) amino] ethyl] indole-1-carboxylate (100 mg, 178 .86 µmol, 1 eq.), (3-fluorophenyl)boronic acid (75.08 mg, 536.57 µmol, 3 eq.), Pd(dppf)Cl2 (13.09 mg, 17.89 µmol, 0, 1 eq.), CS2CO3 (174.82 mg, 536.57 µmol, 3 eq.) and H ₂ O (2 ml) were placed in a microwave tube in 1,4-dioxane (6 ml). The sealed tube was heated at 110° C. for 1 hour while being treated with microwave radiation. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with aq. NaHCO ₃ (20 ml) and extracted with EtOAc (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give tert-butyl 3-[2-[tert-butoxycarbonyl-[5-(3-fluorophenyl)-3-isopropyl-pyrazolo[1,5-a]pyrimidine -7-yl]amino]ethyl]indole-1-carboxylate (100 mg, 97.77 µmol, 54.7% yield, 60.0% purity) as a brown solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD ₃ OD) δ ppm 7.98 (s, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.59 (d, J=1.2 Hz, 1H), 7.56 (d, J=2.4 Hz, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.48 (d, J=3.6 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.26 (s, 1H), 7.19-7.15 (m, 1H), 6.65-6.57 (m , 1H), 4.24-4.21 (m, 2H), 3.58-3.44 (m, 1H), 3.11 (t, J=6.4 Hz, 2H), 1.56 ( s, 9H), 1.50-1.45 (m, 6H), 1.37 (s, 9H); ER-LCMS m/z 614.3 [M+H]+.

Step 2: 5-(3-fluorophenyl)-N-[2-(1 H-indol-3-yl)ethyl]-3-isopropylpyrazolo[1,5-a]pyrimidine-7 amine (I-242)

H

A solution of tert-butyl-3-[2-[tert-butoxycarbonyl-[5-(3-fluorophenyl)-3-isopropyl-pyrazolo[1,5a]pyrimidin-7-yl]amino]ethyl]indole-1-carboxylate ( 80 mg, 78.21 µmol, 1 eq.) in HCl/MeOH (4 M, 3 ml, 153.43 eq.) was stirred at 25°C for 2 h under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini C18 250x50 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 35%-65% , 10 min) followed by lyophilization to give 5-(3-fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-amine (38.32 mg, 76.97 µmol, 98.4% yield, 97.7% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 8.16 (s, 1H), 7.55-7.46 (m, 2H), 7.31-7.36 (m, 1H), 7.20 (d , J=8.0 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.06-6.92 (m, 3H), 6.85 (t, J=7, 6 Hz, 1H), 5.74 (s, 1H), 4.08-3.92 (m, 2H), 3.29

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3.24 (m, 1H), 3.24-3.19 (m, 2H), 1.34 (d, J=6.8 Hz, 6H); ER-LCMS m/z 414.2 [M+H] ⁺ .

Example 187.

Synthesis of I-245

Synthesis scheme:

Stage 1: 3-isopropyl-5-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-ol

A mixture of methyl 3-oxo-3-(3-pyridyl)propanoate (440 mg, 2.46 mmol, equiv.) and 4-isopropyl-1Hpyrazol-5-amine (307.39 mg, 2.46 mmol, 1 equiv. .) in AcOH (20 ml) was stirred at 120°C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 3-isopropyl-5-(3pyridyl)pyrazolo[1,5-a]pyrimidin-7-ol (600 mg, 1.60 mmol, 65.3% yield, crude, 2 HOAC) as a brown oil which was used in the next step without further purification.

1H NMR (400 MHz, CDC13) δ ppm 9.19-9.17 (m, 1H), 8.83-8.78 (m, 1H), 8.27 (td, J=1.9, 8, 0 Hz, 1H), 7.50-7.42 (m, 2H), 7.14 (s, 1H), 2.84-2.75 (m, 1H), 1.22 (d, J=2 .0 Hz, 6H); ER-LCMS m/z 255.1 [M+H] ⁺ .

Stage 2: 7-chloro-3-isopropyl-5-(3-pyridyl)pyrazolo[1,5-a]pyrimidine

A solution of 3-isopropyl-5-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-ol (600 mg, 1.60 mmol, 1 eq., 2HOAC) in POCl ₃ (15 mL) was degassed and purged by N ₂ 3 times. The mixture was stirred at 110° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was adjusted to pH 7-8 with TEA. The residue was purified by silica gel column chromatography (PE/EtOAc=1/0 to 10/3, TLC: PE/EtOAc=3/1, Rf=0.35) to give 7-chloro-3isopropyl-5-(3 -pyridyl)pyrazolo[1,5-a]pyrimidine (100 mg, 322.66 µmol, 20.1% yield, 88.0% purity) as a green solid.

1H NMR (400 MHz, CDC13) δ ppm 9.33 (d, J=1.8 Hz, 1H), 8.74 (dd, J=1.5, 4.9 Hz, 1H), 8.46 ( td, J=2.0, 7.9 Hz, 1H), 8.13 (s, 1H), 7.50 (dd, J=4.7, 8.0 Hz, 1H), 7.40 (s , 1H), 3.42 (td, J=6.9, 13.8 Hz, 1H), 1.46 (d, J=7.1 Hz, 6H); ER-LCMS m/z 273.0 [M+H]+.

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Step 3: (3R)-N-[3-isopropyl-5-(3-pyridyl)pyrazolo[1,5-a]nirimidin-7-ul]-2,3,4,9-tetrahydro1H-carbazole-3- amine (I-245)

7-Chloro-3-isopropyl-5-(3-pyridyl)pyrazolo[1,5-a]pyrimidine mixture (60 mg, 193.60 µmol, 1 eq), (3R)-2,3,4,9 -tetrahydro-1H-carbazole-3-amine (36.06 mg, 193.60 µmol, 1 eq.) and DIEA (75.06 mg, 580.79 µmol, 101.16 µl, 3 eq.) in i- PrOH (10 ml) was degassed and purged with N ₂ 3 times. The mixture was stirred at 80° C. for 3 hours under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini 150x25 mmx10 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 42%-70%, 7 min) followed by lyophilization to give (3R)-N-[3-isopropyl-5-(3-pyridyl)pyrazolo[1,5-a]pyrimidin-7-yl]2,3,4,9-tetrahydro- 1H-carbazole-3-amine (40.65 mg, 76.42 µmol, 39.5% yield, 100.0% purity, 3HCl) as a red solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.52 (s, 1H), 9.17 (J=8.2 Hz, 1H), 8.97 (J=5.3 Hz, 1H), 8.21 -8.15 (m, 2H), 7.34 (d, J=7.7 Hz, 1H), 7.23 (d, J=7.9 Hz, 1H), 7.10 (s, 1H) , 7.00 (t, J=7.2 Hz, 1H), 6.95-6.88 (m, 1H), 4.62 (bd s, 1H), 3.41 (td, J=7 .0, 13.8 Hz, 1H), 3.27 (J=4.9 Hz, 1H), 3.13 (J=9.7 Hz, 1H), 3.01-2.91 (m, 2H ), 2.422.22 (m, 2H), 1.42 (dd, J=3.1, 6.8 Hz, 6H); ER-LCMS m/z 423.2 [M+H]+.

Example 188.

Synthesis of I-246

Η

Synthesis scheme:

1-246

Step 1: 3-isopropyl-4H-n-pyrazolo[1,5-a]pyrimidine-5,7-dione

Na (367.33 mg, 15.98 mmol, 2 eq.) was added in EtOH (25 ml) and the mixture was stirred at 24°C for 2 hours. 4-isopropyl-1H-pyrazole-5 was added to the above reaction mixture -amine (1 g, 7.99

- 321 041983 mmol, 1 eq.) and diethylpropanedioate (1.41 g, 8.79 mmol, 1.33 ml, 1.1 eq.) and stirred at 80°C for 5 hours. The solution was cooled to room temperature and filtered. The resulting solid was washed with EtOH and dissolved in water (20 ml). The solution was then acidified to pH 1-2 with concentrated hydrochloric acid in an ice bath. The precipitate was filtered, washed with water and dried under reduced pressure to give 3-isopropyl-4H-pyrazolo[1,5-a]pyrimidine-5,7-dione (300 mg, 1.55 mmol, 19.4% yield, 100 purity). .0%) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CD3OD) δ ppm 7.80-7.73 (m, 2H), 3.02 (td, J=6.7, 13.7 Hz, 1H), 1.28 (d, J =7.1 Hz, 6H); ER-LCMS m/z 194.2 [M+H]+.

Stage 2: 5,7-dichloro-3-isopropyl-pyrazolo[1,5-a]pyrimidine

3-isopropyl-4H-pyrazolo[1,5-a]pyrimidine-5,7-dione (285 mg, 1.48 mmol, 1 eq.) was added to POCl ₃ (20 ml). The reaction mixture was stirred at 110° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 5/1, TLC: PE/EtOAc = 10/1, Rf = 0.30) to give 5,7-dichloro-3isopropyl-pyrazolo[1,5-a]pyrimidine (300 mg, 1.30 mmol, 88.4% yield, 100.0% purity ) as a yellow solid.

1H NMR (400 MHz, CDCI3) δ ppm 8.10 (s, 1H), 6.94-6.90 (m, 1H), 3.37-3.26 (m, 1H), 1.37 (d , J=6.8 Hz, 6H); ER-LCMS m/z 230.1, 232.1 [M+H]+.

Step 3: 5-Chloro-N-[2-(1H-indol-3-yl)ethyl]-3-isopropylpyrazolo[1,5-a]pyrimidine-7-amine

DIEA (337.02 mg, 2 61 mmol, 454.20 µl, 3 eq.) and 2-(1H-indol-3-yl)ethanamine (167.11 mg, 1.04 mmol, 1.2 eq.). The mixture was stirred at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/ 1, Rf = 0.60) to give 5chloro-N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-amine (240 mg, 672.83 µmol, 77.4% yield, 99.2% purity) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.11 (s, 1H), 7.81 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.41 (d , J=8.3 Hz, 1H), 7.27-7.22 (m, 1H), 7.20-7.13 (m, 1H), 7.11 (d, J=2.3 Hz, 1H), 6.45 (s, 1H), 5.88 (s, 1H), 3.71 (q, J=6.6 Hz, 2H), 3.33-3.18 (m, 3H), 1.33 (d, J=7.0 Hz, 6H); ER-LCMS m/z 354.1, 355.1 [M+H] ⁺ .

Stage 4: tert-butyl-3-[2-[tert-butoxycarbonyl-(5-chloro-3-isopropyl-pyrazolo[1,5-a]pyrimidin7-yl)amino]ethyl]indole-1-carboxylate

To a solution of 5-chloro-N-[2-(N-indol-3-yl)ethyl]-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7-amine (120 mg, 336.42 µmol, 1 eq. .) in 1,4-dioxane (6 ml) was added DMAP (123.30 mg, 1.01 mmol, 3 eq.) and (Boc) ₂ O (183.56 mg, 841.04 µmol, 193.22 µl , 2.5 eq.). The mixture was stirred at 110° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc= 3/1, Rf = 0.75) to give tert-butyl-3-[2-[tert-butoxycarbonyl-(5-chloro-3-isopropyl-pyrazolo[1,5-a]pyrimidin-7yl)amino]ethyl ]indole-1-carboxylate (150 mg, 262.33 µmol, 77.9% yield, 96.9% purity) as a yellow solid.

1H NMR (400 MHz, CDCI3) δ ppm 8.09 (d, J=6.4 Hz, 1H), 7.97 (s, 1H), 7.43 (d, J=7.9 Hz, 1H) , 7.35(s,

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1H), 7.32-7.27(m, 1H), 7.20-7.13(m, 1H), 6.39(s, 1H), 4.21-4.15(m, 2H) , 3.28 (td, J=7.0, 13.9 Hz, 1H), 3.06 (t, J=7.4 Hz, 2H), 1.67 (s, 9H), 1.41 ( s, 9H), 1.36 (d, J=7.1 Hz, 6H); ER-LCMS m/z 554.3, 556.3 [M+H]+.

Step 5: 5-(1,3-Benzodioxol-5-ηλ)-Ν-[2-(1 H-indol-3-yl)ethyl]-3-isopropylpyrazolo[1,5a]pyrimidine-7-amine (I-246)

To a solution of tert-butyl-3 - [2-[tert-butoxycarbonyl- (5-chloro-3-isopropyl-pyrazolo [1,5a] pyrimidin-7-yl) amino] ethyl] indole-1-carboxylate (100 mg, 174.88 µmol, 1 eq.) in 1,4-dioxane (6 ml) and water (2 ml) was added K ₃ PO ₄ (111.37 mg, 524.65 µmol, 3 eq.), sphos cycle with palladium (sphos palladacycle) (13.30 mg, 17.49 µmol, 0.1 eq.) and 1,3-benzodioxol-5-ylboronic acid (87.06 mg, 524.65 µmol, 3 eq.). The mixture was degassed and purged with N2 three times and stirred at 110° C. for 1 hour while being treated with microwave radiation. The reaction mixture was diluted with EtOAc (50 ml) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue which was dissolved in DCM (1 ml) and HCl/EtOAc (1 ml, 4M) added. The reaction mixture was stirred at 25° C. for 14 hours. The reaction mixture was diluted with water (50 ml) and the pH was adjusted to 2 with 10% aq. NaOH solution. The mixture was subjected to extraction with EtOAc (50 mlx3), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated to give a residue which was purified using preparative HPLC (HCl conditions; column: Phenomenex Gemini 150x25 mmx10 μm; mobile phase: [water ( 0.05% HCl)-ACN]; B%: 30%-60%, 10 min). The desired fraction was lyophilized to give 5-(1,3-benzodioxol-5-yl)-N-[2-(1H-indol-3-yl)ethyl]-3-isopropyl-pyrazolo[1,5-a]pyrimigine-7- amine (22.10 mg, 43.13 µmol, 25.1% yield, 100.0% purity, 2 HCl) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.09 (s, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.22 (d, J=8.2 Hz, 1H ), 7.08-7.02 (m, 2H), 6.92-6.86 (m, 2H), 6.80 (d, J=1.8 Hz, 1H), 6.73 (dd, J=1.9, 8.3Hz, 1H), 6.08(s, 2H), 5.70(s, 1H), 3.993.93(m, 2H), 3.28-3.18(m , 3H), 1.33 (d, J=6.8 Hz, 6H); ER-LCMS m/z 440.2 [M+H] ⁺ .

Example 189. Synthesis of I-249a, I-249b and I-249c J^) II A -\ γ ΛΆ X I- _249a < Raney-Ni/H ₂ ί Tj X—\ MeOH 7 H /= _SFC_^ _n ^ _n -n /A/ Yj ^N l N ^z l-249b xT\ \ _Ν Λ _Ν > nn I-249b I-249c ν' 1 / X— (NH ₄ ) ₂ co _{3 r} toluene p—V ' )1 E ₃ O ll ^H Η m , \^N /=\ nh _oh.hci < || \ /\ NaOAc ^r HO^ _N <XXL#Vy TAX « „nAAAO ^DEA FLX/ l-249a Yj ⁿ % N ^z =\ /=x J Aa/vJ ⁺ Yj ^N % ^N l-249a

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Step 1: 1-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)pyrrolidine

QQ~ ⁿ O

To a mixture of 1,4-dioxaspiro[4,5]decan-8-one (18 g, 115.25 mmol, 1 eq.), TsOH (198.47 mg, 1.15 mmol, 0.01 eq.) in toluene (200 ml) was added pyrrolidine (12.30 g, 172.88 mmol, 14.43 ml, 1.5 eq.) under N 2 atmosphere. The mixture was stirred at 110°C for 12 hours under N2.

The reaction mixture was concentrated to give 1-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)pyrrolidine (24 g, 103.21 mmol, 89.6% yield, 90% purity) as brown oils.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.17 (t, J=3.7 Hz, 1H), 4.11 (s, 2H), 4.07-4.05 (m, 2H), 3.12 (t, J=6.5 Hz, 2H), 2.97 (t, J=6.2 Hz, 2H), 2.59 (t, J=7.1 Hz, 2H), 2, 54-2.49 (m, 1H), 2.45-2.43 (m, 1H), 2.09 (t, J=7.1 Hz, 2H), 1.94-1.90 (m, 2H), 1.87-1.73 (m, 2H).

Step 2: 7-phenacyl-1,4-dioxaspiro[4,5]decan-8-one o/o o

A solution of 1-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)pyrrolidine (24 g, 103.21 mmol, 1 eq.) in toluene (200 ml) was refluxed under atmospheric N2 and 2-bromo-1-phenylethanone (20.54 g, 103.21 mmol, 1 eq.) in toluene (60 mL) was added slowly. The mixture was stirred at 110° C. for 2 h under N2. Then H2O (60 ml) was added and the mixture was stirred at 110° C. for an additional 2 h under N2 atmosphere. The mixture was concentrated and water (50 ml) was added, extracted with EtOAc (100 mlx3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc=2/1, TLC: PE/EtOAc=3/1, Rf=0.4) to give 7-phenacyl-1,4dioxaspiro[4, 5]decan-8-one (13 g, 42.65 mmol, 41.3% yield, 90% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.01-7.93 (m, 2H), 7.59-7.53 (m, 1H), 7.49-7.43 (m, 2H) , 4.17-4.06 (m, 2H), 4.05-3.96 (m, 2H), 3.64-3.45 (m, 2H), 2.85-2.68 (m, 2H), 2.48-2.39 (m, 1H), 2.25-2.14 (m, 1H), 2.13-2.02 (m, 2H), 1.89-1.77 ( m, 1H); ER-LCMS m/z 275.1 [M+H]+.

Stage 3: 2'-phenylspiro [1,3-dioxolane-2,5'-1,4,6,7-tetrahydroindole] n\-o

A mixture of 7-phenacyl-1,4-dioxaspiro[4,5]decan-8-one (5 g, 16.40 mmol, 1 eq) and (NH ₄ ) ₂ CO ₃ (5.00 g, 52.04 mmol, 5.56 ml, 3.17 equiv.) in a tightly closed tube was stirred at 110°C for 2 h under N2 atmosphere. Water (50 ml) was added to the mixture, extracted with EtOAc (100 mlx2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated to give 2'-phenylspiro[1,3-dioxolane-2,5'-1,4,6,7-tetrahydroindole] (4 g, 14.10 mmol, 86.0% yield, 90% purity) as a brown solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.07-7.86 (m, 1H), 7.40 (d, J=7.8 Hz, 2H), 7.36-7.29 (m , 2H), 7.20-7.10 (m, 1H), 6.25 (d, J=2.4 Hz, 1H), 4.08-3.99 (m, 4H), 2.84 ( t, J=6.6 Hz, 2H), 2.80 (s, 2H), 2.02 (t, J=6.5 Hz, 2H); ER-LCMS m/z 256.1 [M+H] ⁺ .

Stage 4: 2-phenyl-1,4,6,7-tetrahydroindol-5-one

To a solution of 2'-phenylspiro[1,3-dioxolane-2,5'-1,4,6,7-tetrahydroindole] (3.9 g, 13.75 mmol, 1 eq.) in acetone (30 ml) was added HCl (1 M, 13.75 ml, 1 eq.), the mixture was stirred at 50°C for 3 h. The mixture was concentrated and brought to pH 7 with saturated NaHCO ₃ solution, extracted with EtOAc (80 mlx2). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc=2/1, TLC: PE/EtOAc=3/1, Rf=0.3) to give 2-phenyl1,4,6,7- tetrahydroindol-5-one (0.7 g, 2.32 mmol, 16.9% yield, 70.0% purity) as a yellow solid.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm 8.15 (s, 1H), 7.44 (d, J=7.6 Hz, 2H), 7.36 (t, J=7.7 Hz, 2H ), 7.23-7.17 (m, 1H), 6.29 (d, J=2.4 Hz, 1H), 3.45 (s, 2H), 3.09-3.03 (m, 2H), 2.74 (t, J=6.8 Hz, 2H); ER-LCMS m/z 212.1 [M+H] ⁺ .

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Stage 5: 2-phenyl-1,4,6,7-tetrahydroindol-5-one oxime

NaOAc (244.64 mg, 2.98 mmol , 1.5 eq.) and NH ₂ OH-HCl (165.78 mg, 2.39 mmol, 1.2 eq.). The mixture was stirred at 60° C. for 3 hours. The mixture was filtered. The filtrate was concentrated to give a residue which was purified by silica gel column chromatography (pure PE to PE/EtOAc=1/1, TLC: PE/EtOAc=1/1, Rf=0.4) to give 2-phenyl-1 ,4,6,7-Tetrahydroindol-5-one oxime (350 mg, 1.24 mmol, 62.2% yield, 80% purity) as a red solid.

Ή NMR (400 MHz, CDCl ₃ ) δ ppm 8.02 (s, 1H), 7.47-7.41 (m, 2H), 7.38-7.33 (m, 2H), 7.21- 7.16 (m, 1H), 6.32 (d, J=2.4 Hz, 1H), 3.66 (s, 2H), 2.89-2.81 (m, 2H), 2.71 -2.63 (m, 1H); ER-LCMS m/z 227.1 [M+H] ⁺ .

Stage 6: 2-phenyl-4,5,6,7-tetrahydro-1H-indole-5-amine h ₂ n '

Raney-Ni (200 mg, 2.33 mmol, 1.89 equiv.) in an N2 atmosphere. The mixture was stirred at 20° C. for 1 hour under H2 (15 psi). The mixture was filtered. The filtrate was concentrated to give 2-phenyl4,5,6,7-tetrahydro-1H-indole-5-amine (250 mg, 942.11 µmol, 76.1% yield, 80% purity) as a black-brown solid colors.

Ή NMR (500 MHz, CD3OD) δ ppm 7.50-7.46 (m, 2H), 7.26 (t, J=7.9 Hz, 2H), 7.09-7.03 (m, 1H ), 6.18 (s, 1H), 3.12-3.04 (m, 1H), 2.86-2.63 (m, 3H), 2.30 (dd, J=8.9, 14 .8 Hz, 1H), 2.05-1.97 (m, 1H), 1.73-1.64 (m, 1H); ER-LCMS m/z 213.2 [M+H] ⁺ .

Step 7: 2-(5-fluoro-3-pyridyl)-8-isopropyl-N-[(5R)-2-phenyl-4,5,6,7-tetrahydro-1H-indol-5yl]pyrazolo[1, 5-а][1,3,5]triazine-4-amine (1-249b) and 2-(5-fluoro-3-pyridyl)-8-isopropyl-N-[(5S)-2-phenyl4,5 ,6,7-Tetrahydro-1H-indol-5-yl]pyrazolo[1,5-a][1,3,5]triazin-4-amine (I-249a)

To a solution of 2-phenyl-4,5,6,7-tetrahydro-1H-indole-5-amine (207.84 mg, 783.24 µmol, 1.2 eq.) and DIEA (253.07 mg, 1, 96 mmol, 341.07 μl, 3 eq.) in i-PrOH (15 ml) was added 4-chloro-2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1, 3,5]triazine (200 mg, 652.70 µmol, 1 eq.). The mixture was stirred at 50° C. for 2 hours. The mixture was concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc = 2/1, TLC: PE/EtOAc = 2/1, Rf = 0.5) to give a residue which was separated by SFC (column: DAICEL CHIRALCEL OJ-H (250 mm x 30 mm, 5 µm), mobile phase: [0.1% NH3H2O EtOH]; B%: 40%-40%, min) to give peak 1 and peak 2. The fraction corresponding to peak 1, concentrated and purified by preparative HPLC (column: Agela ASB 150x25 mmx5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 75%-100%, 8 min) followed by lyophilization to give the enantiomer (18.68 mg, 31.16 µmol, 4.8% yield, 96.249% purity, 3 HCl. SFC: Rt = 5.229 min, ee = 95.522%, [a] ^26.5 D = +24.339, (CHCl ₃ , c = 0.1015 g/100 ml)) as a yellow solid.

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.89 (s, 1H), 9.38 (s, 1H), 8.89 (d, J=8.6 Hz, 1H), 8.70 (d, J=2.9 Hz, 1H), 8.43 (td, J=2.2, 9.8 Hz, 1H), 8.18-8.07 (m, 1H), 7.55 ( d, J=7.6 Hz, 2H), 7.30 (t, J=7.7 Hz, 2H), 7.147.03 (m, 1H), 6.27 (d, J=2.2 Hz, 1H), 4.77-4.60 (m, 1H), 3.26-3.15 (m, 1H), 2.93-2.71 (m, 4H), 2.17-2.00 ( m, 2H), 1.36 (d, J=7.1 Hz, 6H); ER-LCMS m/z 468.3 [M+H] ⁺ .

The fraction corresponding to peak 2 was concentrated to give a residue which was dissolved in MeCN (20 ml), 1 M HCl (1.2 ml) and H ₂ O (40 ml) followed by lyophilization to give the other enantiomer (23.41 mg ^; _{_} 1002 g/100 ml)) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.90 (broad s, 1H), 9.38 (s, 1H), 8.89 (d, J=8.6 Hz, 1H), 8.70 (d, J=2.7 Hz, 1H), 8.43 (d, J=9.8 Hz, 1H), 8.23-8.04 (m, 1H), 7.55 (d , J=7.6 Hz, 2H), 7.30 (t, J=7.8 Hz, 2H), 7.177.03 (m, 1H), 6.27 (d, J=2.2 Hz, 1H ), 4.68 (d, J=5.1 Hz, 1H), 3.27-3.13 (m, 1H), 2.92-2.66 (m, 4H), 2.19-2, 00 (m, 2H), 1.36 (d, J=6.8 Hz, 6H); ER-LCMS m/z 468.3 [M+H] ⁺ .

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Synthesis scheme:

Example 190.

Synthesis of I-252a, I-252b and I-252c

Stage 1: 2-chloro-N-(4,5,6,7-tetrahydro-1H-indol-5-yl)pyrido[3,2-d]pyrimidin-4-amine

A mixture of 2,4-dichloropyrido[3,2-d]pyrimidine (150 mg, 749.91 µmol, 1 eq.), 4,5,6,7-tetrahydro-1Hindole-5-amine (113.48 mg, 749 .91 µmol, 1 eq.) and DIEA (387.68 mg, 3.00 mmol, 522.48 µl, 4 eq.) in iPrOH (10 ml) were stirred at 55°C for 2 h.

The reaction mixture was concentrated to give a residue which was purified by silica gel column chromatography (PE/EtOAc=3/1 to 1/1, TLC: PE/EtOAc=1/1, Rf=0.50) to give 2chloro-N -(4,5,6,7-tetrahydro-1H-indol-5-yl)pyrido[3,2-d]pyrimidin-4-amine (120 mg, 397.52 µmol, 53.0% yield, 99 purity .3%) as a yellow solid.

1H NMR (400 MHz, CDC13) δ ppm 8.64 (dd, J=1.5, 4.3 Hz, 1H), 8.01 (dd, J=1.5, 8.5 Hz, 1H), 7.85 (s, 1H), 7.64 (dd, J=4.3, 8.3 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 6.70 (t , J=2.6 Hz, 1H), 6.04 (t, J=2.6 Hz, 1H), 4.80-4.70 (m, 1H), 3.10 (dd, J=5, 3, 15.3 Hz, 1H), 2.99-2.45 (m, 3H), 2.24-2.08 (m, 2H); ER-LCMS m/z 300.1 [M+H]+.

Stage

2:

d] pyrimidine-4-amine

2-(5-fluoro-3-pyridyl)-N-[(5R)-4,5,6,7-tetrahydro-1H-indol-5-yl]pyrido[3,2(I-252b) and 2- (5-fluoro-3-pyridyl)-N-[(5S)-4,5,6,7-tetrahydro-1H-indol-5 yl] pyrido [3,2-d] pyrimidin-4-amine (I- 252a)

2-chloro-N-(4,5,6,7-tetrahydro-1H-indol-5-yl)pyrido[3,2-d]pyrimidin-4-amine (120 mg, 397.52 µmol, 1 eq. ), (5-fluoro-3-pyridyl)boronic acid (168.04 mg, 1.19 mmol, 3 eq.), Pd(dppf)C1 ₂ (29.09 mg, 39.75 µmol, 0.1 eq. .) and Cs ₂ CO ₃ (518.08 mg, 1.59 mmol, 4 eq.) in 1,4-dioxane (3 ml) and H 2 O (1 ml) were placed in a microwave tube and purged with N ₂ into within 1 min. The sealed tube was heated at 110° C. for 1 hour while being treated with microwave radiation. The reaction mixture was concentrated. The residue was purified by silica gel flash chromatography (pure PE to PE/EtOAc = 1/1, TLC: PE/EtOAc = 2/1, Rf = 0.40) to give a residue which was separated by chiral SFC (column: DAICEL CHTRALCEL OJ-H (250 mm x 30 mm, 5 µm), mobile phase: [0.1% NH ₃ H ₂ O EtOH]; V%: 40%-40%) to give the enantiomer (19.36 mg, 52.04 µmol, 13.1% yield, 96.9% purity, SFC: Rt = 4.040, ee = 100%, Optical rotation: [a] ^23.9 D = -8.542 (CHCl ₃ , c = 0.075 g /100 ml)) as a red solid;

¹ H NMR (400 MHz, CD3OD) δ ppm 9.43 (s, 1H), 8.71 (dd, J=1.5, 4.2 Hz, 1H), 8.56-8.48 (m, 2H), 8.15 (dd, J=1.5, 8.6 Hz, 1H), 7.76-7.73 (m, 1H), 6.62 (d, J=2.4 Hz, 1H ), 5.90 (d, J=2.4 Hz, 1H), 4.84-4.78 (m, 1H), 3.09 (dd, J=4.9, 15.2 Hz, 1H) , 2.85-2.69 (m, 3H), 2.27 (d, J=12.5 Hz, 1H), 2.14 (d, J=6.6 Hz, 1H); ER-LCMS m/z 361.2 [M+H]+ and other enantiomer (17.54 mg, 47.86 µmol, 12.0% yield, 98.3% purity) as red solid (SFC: Rt = 4.941, ee = 100%, Optical rotation: [a] ²⁵⁰ _D = +10.973 (CHCl ₃ , c = 0.054 g/100 ml)).

1H NMR (400 MHz, CD3OD) δ ppm 9.44 (s, 1H), 8.71 (dd, J=1.2, 4.2 Hz, 1H), 8.57-8.49 (m, 2H ), 8.16 (dd, J=1.2, 8.6Hz, 1H), 7.75 (dd, J=4.2, 8.6Hz, 1H), 6.64 (s, 1H) , 5.92 (d, J=2.4 Hz, 1H), 4.86-4.81 (m, 1H), 3.11 (dd, J=5.0, 15.0 Hz, 1H), 2.88-2.70 (m, 3H), 2.28 (d, J=9.8 Hz, 1H), 2.19-2.11 (m, 1H); ER-LCMS m/z 361.2 [M+H] ⁺ .

Example 191.

Synthesis of I-253

Synthesis scheme:

Step 1: (3R)-N-[2-(5-fluoro-3-pyridyl)-8-(2-tetrahydropyran-2-ylpyrazol-3-yl)pyrazolo[1,5a] [ 1,3,5] triazin-4-yl]-2,3,4,9-tetrahydro-1 H-carbazole-3-amine

(3R)-N-[8-bromo-2-(5-fluoro-3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4, 9-tetrahydro-1Hcarbazole-3-amine (100 mg, 202.79 µmol, 1 eq.), Cs ₂ CO ₃ (66.07 mg, 202.79 µmol, 1 eq.), Pd(dppf)Cl ₂ ( 148.39 mg, 202.79 µmol, 1 eq) and 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrazole (56, 41 mg, 202.79 µmol, 1 eq) were placed in a microwave tube in 1,4dioxane (6 ml) and H2O (2 ml). The sealed tube was heated at 110° C. for 30 minutes while being treated with microwave radiation. TLC (PE/EtOAc = 1/1, R _f = 0.4) indicated that the starting material had been completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EA = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, R _f = 0.4) , giving (3R)-N-[2-(5-fluoro-3-pyridyl)-8-(2-tetrahydropyran-2ylpyrazol-3-yl)pyrazolo[1,5-a][1,3,5]triazine -4-yl]-2,3,4,9-tetrahydro-1H-carbazole-3-amine (70 mg, 122.27 µmol, 60.3% yield, 96.0% purity) as yellow solid .

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1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.82 (s, 1H), 9.41-9.38 (m, 2H), 8.73 (d, J=2.7 Hz, 1H) , 8.49-8.47 (d, J=9.0 Hz, 1H), 8.38 (s, 1H), 7.64 (s, 1H), 7.37-7.35 (d, J =7.8 Hz, 1H), 7.29-7.27 (d, J=7.8 Hz, 1H), 7.02-6.99 (m, 1H), 6.95-6.92 ( m, 1H), 6.74 (s, 1H), 5.66-5.64 (d, J=9.0 Hz, 1H), 4.89 (d, 1H), 3.95-3.91 (m, 2H), 3.59-3.57 (m, 1H), 3.15-2.88 (m, 4H), 2.23 (br s, 2H), 1.64-1.52 (m, 3H), 1.23 (m, 1H), 0.85-0.83 (d, J=7.8 Hz, 1H);

ER-LCMS m/z 550.3 [M+H]+.

Step 2: (3R)-N-[2-(5-fluoro-3-pyridyl)-8-(1H-pyrazol-5-yl)pyrazolo[1,5-a][1,3,5]triazin- 4-yl]2,3,4,9-tetrahydro-1H-carbazole-3-amine (I-253)

A solution of (3R)-N-[2-(5-fluoro-3-pyridyl)-8-(2-tetrahydropyran-2-ylpyrazol-3-yl)pyrazolo[1,5а][1,3,5]triazin- 4-yl]-2,3,4,9-tetrahydro-III-carbazole-3-amine (70 mg, 122.27 µmol, 1 eq.) in HCl/MeOH (10 ml) was stirred at 15°C for 20 minutes. The reaction mixture was basified with aqueous NaHCO ₃ to pH 7-8, extracted with EtOAc (50 mlx3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl conditions; column: Agela ASB 150x25 mmx5 µm, mobile phase: [water (0.05% HCl)-ACN], B%: 53%-83%, 8 min) to give (3R)-N-[2-(5-fluoro- 3-pyridyl)-8-(1H-nirazol-5yl)pyrazolo[1,5-а][1,3,5]triazin-4-yl]-2,3,4,9-tetrahydro-1H-carbazole- 3-amine (19.45 mg, 33.83 µmol, 27.7% yield, 100.0% purity, 3HCl, [a] ^26.4 D = +13.329 (MeOH, c = 0.098 g/100 ml)) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.82 (s, 1H), 9.51 (s, 1H), 9.29-9.27 (d, J=8.6 Hz, 1H) , 8.75 (d, J=2.7 Hz, 1H), 8.68 (d, J=10.0 Hz, 1H), 8.64 (s, 1H), 7.84-7.83 ( d, J=2.0 Hz, 1H), 7.37-7.35 (d, J=7.6 Hz, 1H), 7.29-7.27 (d, J=8.1 Hz, 1H ), 7.04-7.00 (m, 2H), 6.95-6.93 (m, 1H), 4.89-4.87 (d, J=7.6 Hz, 1H), 3, 17-3.12 (m, J=5.5, 14.8 Hz, 1H), 3.04-2.88 (m, 3H), 2.24-2.23 (d, J=3.7 Hz, 2H); ER-LCMS m/z 466.2 [M+H] ⁺ .

Example 192.

Synthesis of I-254

Stage 1: tert-butyl (3R)-3-[tert-butoxycarbonyl-(8-isopropyl-2-morpholino-pyrazolo[1,5a][1,3,5]triazin-4-yl)amino]-1, 2,3,4-tetrahydrocarbazole-9-carboxylate

Vos /

tert-butyl-(3R)-3-[tert-butoxycarbonyl-(8-isopropyl-2-methylsulfinyl-pyrazolo[1.5a][1.3.5]triazin-4-yl)amino]-1,2, 3,4-tetrahydrocarbazole-9-carboxylate (100 mg, 156.06 µmol, 1 eq.) and morpholine (40.79 mg, 468.17 µmol, 41.20 µl, 3 eq.) in t-BuOH (4 ml) was placed in a microwave tube and purged with N ₂ for 1 min. The sealed tube was heated at

- 328 041983

120°C for 2 hours when treated with microwave radiation. The reaction mixture was concentrated to give t-butyl-(3R)-3-[t-butoxycarbonyl-(8-isopropyl-2-morpholino-pyrazolo[1,5a][1,3,5]triazin-4-yl)amino] -1,2,3,4-tetrahydrocarbazole-9-carboxylate (100 mg, 142.46 µmol, yield

91.3%, 90% pure) as a yellow oil, which was used in the next step without purification.

Ή NMR (400 MHz, CDCl ₃ ) δ ppm 8.10 (d, J=8.0 Hz, 1H), 7.82 (s, 1H), 7.35 (d, J=7.5 Hz, 1H ), 7.22 (dd, J=6.7, 13.9 Hz, 2H), 4.74 (s, 1H), 3.79-3.74 (m, 8H), 3.23 (d, J=10.8Hz, 2H), 3.15-3.07(m, 3H), 2.26(d, J=4.3Hz, 2H), 1.65(s, 9H), 1, 36 (s, 9H), 1.33 (d, J=7.0 Hz, 6H); ER-LCMS m/z 632.3 [M+H]+.

Step 2: (3R)-N-(8-isopropyl-2-morpholino-nirazolo[1,5-a][1,3,5]triazin-4-yl)-2,3,4,9tetrahydro-1 H -carbazole-3-amine (I-254)

/-To a solution of tert-butyl-(3R)-3-[tert-butoxycarbonyl-(8-isopropyl-2-morpholino-pyrazolo[1,5а][1,3,5]triazin-4-yl)amino]- 1,2,3,4-Tetrahydrocarbazole-9-carboxylate (100 mg, 142.46 µmol, 1 eq.) in DCM (4 mL) TFA (1.54 g, 13.51 mmol, 1 mL, 94, 81 eq.). The reaction mixture was stirred at 20° C. for 0.5 h. The reaction mixture was concentrated. The residue was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 50%-80%, 8 min) followed by lyophilization to give (3R )-N-(8-isopropyl-2-morpholinopyrazolo[1,5-а][1,3,5]triazin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (28.19 mg, 59.32 µmol, 41.6% yield, 98.5% purity, HCl, [a] ^24.7 _D =+84.327, MeOH, c=0.074 g/100 mL) as solid white.

¹ H NMR (400 MHz, CD3OD) δ ppm 7.95 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H ), 7.08-7.02(m, 1H), 7.00-6.94(m, 1H), 4.72-4.63(m, 1H), 3.93-3.87(m , 4H), 3.83-3.78 (m, 4H), 3.27-3.19 (m, 2H), 3.032.86 (m, 3H), 2.35-2.18 (m, 2H ), 1.32 (d, J=6.8 Hz, 6H); ER-LCMS m/z 432.3 [M+H] ⁺ .

Example 193.

Synthesis of I-255

Step 1: (3R)-N-[8-isopropyl-2-(3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4,9tetrahydro -1 H-carbazole-3-amine (I-255)

(3R)-N-(8-isopropyl-2-methylsulfanyl-pyrazolo[1,5-а][1,3,5]triazin-4-yl)-2,3,4,9-tetrahydro-1Hcarbazole-3 -amine (100 mg, 242.03 µmol, 1 eq.), 3-pyridylboronic acid (89.25 mg, 726.08 µmol, 3 eq.), Pd(PPh ₃ ) ₄ (27.97 mg, 24, 20 µmol, 0.1 eq.) and thiophene-2-carbonyloxycopper (138.46 mg, 726.08 µmol, 3 eq.) in 1,4-dioxane (3 ml) were placed in a microwave tube and blown through

- 329 041983 with N2 for 1 min. The sealed tube was heated at 120° C. for 2 hours while being treated with microwave radiation. The reaction mixture was filtered and concentrated to give a residue which was purified by preparative HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 35%-65%, 8 min) twice followed by lyophilization to give (3R)-N-[8-isopropyl-2-(3-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2, 3,4,9-tetrahydro-1Hcarbazole-3-amine (28.39 mg, 56.08 µmol, 23.2% yield, 98.1% purity, 2 HCl, [a] ^25.1 D = +34.261 ( MeOH, c = 0.071 g / 100 ml)) in the form of a yellow solid.

¹ H NMR (400 MHz, CD3OD) δ ppm 9.69 (s, 1H), 9.49 (d, J=8.3 Hz, 1H), 8.89 (d, J=4.5 Hz, 1H ), 8.16-8.10 (m, 1H), 8.06 (s, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.29 (d, J=8, 0 Hz, 1H), 7.08-7.03 (m, 1H), 7.00-6.94 (m, 1H), 4.90-4.88 (m, 1H), 3.37-3 .34 (m, 1H), 3.30 (d, J=7.0 Hz, 1H), 3.13-2.90 (m, 3H), 2.44-2.24 (m, 2H), 1.45 (d, J=7.0 Hz, 6H); ER-LCMS m/z 424.3 [M+H] ⁺ .

Example 194.

Synthesis of I-256

Synthesis scheme:

O.

/-RgON,

Pd(dppf)CI ₂ , Cs ₂ CO ₃ , 1,4-dioxane, HgO

POCI3, E13N HCl tightly closed tube

Stage 1: ethyl 1-aminoimidazole-2-carboxylate

Ha nh ₂ ^0Et

A solution of ethyl 1H-imidazole-2-carboxylate (1 g, 7.14 mmol, 1 eq.) in DMF (80 ml) was cooled to 10° C. LiHMDS (1M, 7.85 ml, 1.1 eq.) was added. . The mixture was stirred at -10° C. for 0.5 h. N-diphenylphosphorylhydroxylamine (1.83 g, 7.85 mmol, 1.1 eq.) was added to the mixture. The mixture was stirred at 15°C for 11.5 h. The mixture was quenched with saturated aqueous NH ₄ Cl (50 ml) at -10°C. The mixture was concentrated and EtOAc (100 ml) was added to the residue. After filtration, it was washed with EtOAc (50 mlx3), the filtrate was concentrated to give ethyl 1-aminoimidazole-2-carboxylate (3 g, crude) as a yellow solid, which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.10 (s, 1H), 6.98 (s, 1H), 5.74 (s, 2H), 4.33 (q, J=7.2 Hz , 2H), 1.361.33 (m, 3H); ER-LCMS m/z 156.0 [M+H]+.

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Step 2: Ethyl 1-[bis(ethoxycarbonyl)amino]imidazole-2-carboxylate

Na 2 CO _{3 ( 12.67} g , 119.56 mmol, 7 eq.) and ethyl chloroformate (8.47 g, 78.05 mmol, 7.43 ml, 4.57 eq.). The mixture was stirred at 15°C for 2 h. H2O (100 ml) was added to the mixture, extracted with EtOAc (100 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (pure PE to PE/EtOAc=3/1, TLC: PE/EtOAc=3/1, Rf=0.6) to give ethyl 1-[bis(ethoxycarbonyl)amino] imidazole 2-carboxylate (2.69 g, 6.29 mmol, 36.8% yield, 70% purity) as a yellow solid.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm 7.30 (d, J=1.0 Hz, 1H), 7.10 (s, 1H), 4.44-4.33 (m, 4H), 4 .19-4.08 (m, 2H), 1.39 (td, J=7.3, 16.3 Hz, 6H), 1.08 (t, J=7.2 Hz, 3H); ER-LCMS m/z 300.1 [M+H]+.

Step 3: 1H-imidazo[2,1-1[[1,2,4]triazine-2,4-dione

A solution of ethyl 1-[bis(ethoxycarbonyl)amino]imidazole-2-carboxylate (2.1 g, 4.91 mmol, 1 eq.) and NH3H2O (97.50 g, 778.99 mmol, 107.14 ml, 158.59 eq.) in i-PrOH (20 ml) was stirred in a tightly closed tube at 120°C for 16 h. The mixture was concentrated, PE/MeOH (10/1, 50 ml) was added to the residue and stirred at room temperature within 10 min. After filtration, it was washed with PE/MeOH (10/1, 15 ml), the filter residue was dried under vacuum. The crude product (1 g) was purified by silica gel column chromatography (DCM/MeOH=10/1 to 1/2, TLC: DCM/MeOH=10/1, Rf=0.3) to give 1H-imidazo[2 ,1-1][1,2,4]triazine-2,4-dione (0.9 g, 96.4% yield, 80.0% purity).

1H NMR (400 MHz, DMSO-d6) δ ppm 10.02 (br s, 1H), 7.24 (s, 1H), 7.13 (br s, 1H), 7.07 (s, 1H ).

Step 4: 2,4-dichloroimidazo[2,1-1][1,2,4]triazine

A mixture of 1H-imidazo[2,1-1][1,2,4]triazine-2,4-dione (500 mg, 2.63 mmol, 1 eq.), N,N-diethylethanamine hydrochloride (723.95 mg , 5.26 mmol, 2 eq.) and POCl ₃ (87.18 g, 568.57 mmol, 52.84 ml, 216.21 eq.) were stirred in a tightly closed tube at 120°C for 24 hours. concentrated and DCM (30 ml) was added to the residue. The mixture was poured into ice water (50 ml), extracted with DCM (30 mlx2). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated to give 2,4-dichloroimidazo[2,1-1][1,2,4]triazine (400 mg, 1.27 mmol, yield 48.3%, 60% pure) as a yellow solid.

1H NMR (400 MHz, CDCI3) δ ppm 8.09 (s, 1H), 8.02 (s, 1H); ER-LCMS m/z 189.2, 191.1 [M+H] ⁺ .

Step 5: (3R)-N-(2-chloroimidazo[2,1-f][1,2,4]triazin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-3- amine

2,4-dichloroimidazo[2,1-1][1,2,4]triazine mixture (400 mg, 1.27 mmol, 1 eq), DIEA (492.34 mg, 3.81 mmol, 663.53 μl, 3 eq.) and (3R)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (236.51 mg, 1.27 mmol, 1 eq.) in CH ₃ CN (15 ml ) was stirred at 70° C. for 6 hours. The mixture was concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc = 5/1 to 1/2, TLC: PE/EtOAc = 1/1, Rf = 0.4) to give (3R)-N-(2-chloroimidazo [2,1-f][1,2,4]triazin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (220 mg, 636.38 µmol, yield 50, 1%, 98.0% pure) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.83 (br s, 1H), 7.67 (s, 1H), 7.48-7.36 (m, 2H), 7.30 (d, J=7.8Hz, 1H), 7.18-7.12(m, 1H), 7.11-7.04(m, 1H), 6.84(d, J=7.3Hz, 1H ), 4.86-4.84 (m, 1H), 3.27 (dd, J=4.9, 15.7 Hz, 1H), 2.98-2.80 (m, 3H), 2, 29-2.17 (m, 2H); ER-LCMS m/z 339.1 [M+H] ⁺ .

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Step 6: (3R)-N-[2-(5-fluoro-3-pyridyl)imidazo[2,1-f][1,2,4]triazin-4-yl]-2,3,4,9 -tetrahydro-1Hcarbazole-3-amine (I-256)

A mixture of (3R)-N-(2-chloroimidazo[2,1-f][1,2,4]triazin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-amine ( 100 mg, 289.26 µmol, 1 eq.), (5-fluoro-3-pyridyl)boronic acid (81.52 mg, 578.52 µmol, 2 eq.), Cs ₂ CO ₃ (282.74 mg, 867.78 µmol, 3 eq.) and pd(dppf)C1 ₂ (21.17 mg, 28.93 µmol, 0.1 eq.) in 1,4-dioxane (2 ml) and H2O (0.5 ml ) was stirred at 110°С for 2 h under N2 atmosphere. After filtration, the filtrate was concentrated. The residue was purified by preparative TLC (PE/EtOAc = 1/1, R _f = 0.3) to give (3R)-N-[2-(5-fluoro-3-pyridyl)imidazo[2,1-f] [1,2,4]triazin-4-yl]-2,3,4,9-tetrahydro-1H-carbazole-3-amine (60.97 mg, 152.65 µmol, 52.8% yield, purity 100%, [α] ²⁶ % = + 9.272 (MeOH, c = 0.101 g/100 ml)) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.30 (s, 1H), 8.54 (d, J=2.7 Hz, 1H), 8.42 (td, J=2.1, 9.8 Hz, 1H), 7.96 (d, J=1.0 Hz, 1H), 7.55 (s, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.25 ( d, J=8.1 Hz, 1H), 7.05-6.97 (m, 1H), 6.96-6.89 (m, 1H), 4.98-4.90 (m, 1H) , 3.26 (br s, 1H), 2.97 (t, J=5.7 Hz, 2H), 2.90 (dd, J=7.2, 15.3 Hz, 1H), 2. 40-2.32 (m, 1H); 2.31-2.21 (m, 1H); ER-LCMS m/z 399.9 [M+H] ⁺ .

Example 195.

Synthesis of I-257

DIEA (193.84 mg, 1.50 mmol, 261.24 µl, 3 eq.) and 2-(1H-indol-3-yl)ethanamine (88.11 mg, 549.93 µmol, 1.1 eq.). The mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, R _f = 0.2) to give 2-chloro-N-[2-(1H-indol-3yl)ethyl]pyrido[3,2-d]pyrimidin-4-amine (90 mg, 271, 57 µmol, 54.3% yield, 97.7% purity) as a yellow solid.

1H NMR (400 MHz, CDC13) δ ppm 8.61 (dd, J=1.3, 4.3 Hz, 1H), 8.07 (s, 1H), 8.01 (dd, J=1.3 , 8.4 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.63 (dd, J=4.3, 8.4 Hz, 1H), 7.47 (s , 1H), 7.41 (d, J=8.1 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 7.18-7.12 (m, 2H), 4 .03 (q, J=6.7 Hz, 2H), 3.22 (t, J=6.8 Hz, 2H); ER-LCMS m/z 324.1 [M+H]+.

Step 2: 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]pyrido[3,2-d]pyrimidin-4-amine (I-257)

- 332 041983

2-chloro-N-[2-(1H-indol-3-yl)ethyl]pyrido[3,2-d]pyrimidine-4-amine (50 mg, 150.87 µmol, 1 eq), (5- fluoro-3-pyridyl)boronic acid (25.51 mg, 181.05 µmol, 1.2 eq.), Pd(dppf)Cl ₂ (11.04 mg, 15.09 µmol, 0.1 eq.) and Cs ₂ CO ₃ (147.47 mg, 452.62 µmol, 3 eq.) was placed in a microwave tube in 1,4-dioxane (2 ml) and H 2 O (1 ml). The sealed tube was heated at 110° C. for 0.5 h while being treated with microwave radiation. The reaction mixture was diluted with water (5 ml) and extracted with EtOAc (10 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN] ; B%: 45%-75%, 8 min) followed by lyophilization to give 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3yl)ethyl]pyrido[3,2- d] pyrimidine-4-amine (24.02 mg, 51.42 µmol, 34.1% yield, 97.9% purity, 2HCl) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.03 (s, 1H), 9.01 (dd, J=1.3, 4.3 Hz, 1H), 8.82 (d, J=2.7 Hz, 1H), 8.20 (dd, J=1.5, 8.6 Hz, 1H), 8.10-8.05 (m, 1H), 8.01 (dd, J=4.3, 8.7 Hz, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.05 (s, 1H), 6 .92 (t, J=7.2 Hz, 1H), 6.85-6.71 (m, 1H), 4.26 (t, J=6.6 Hz, 2H), 3.26 (t, J=6.6 Hz, 2H); ER-LCMS m/z 385.2 [M+H]+.

Example 196.

Synthesis of I-258

Synthesis scheme:

Pd ₂ (dba) ₃ , CuTC

1,4-dioxane, 130°C

Stage 1: (3R)-N-[2-(3,6-Dihydro-2H-pyran-4-yl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4 -yl]2,3,4,9-tetrahydro-1H-carbazole-3-amine

To a stirred solution of (3R)-N-(8-isopropyl-2-methylsulfanyl-pyrazolo[1,5a][1,3,5]triazin-4-yl)-2,3,4,9-tetrahydro-1H- carbazole-3-amine (300 mg, 703.15 µmol, 1 eq) and 2-(3,6dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2 -dioxaborolane (443.15 mg, 2.11 mmol, 3 eq.) in 1,4dioxane (15 ml) was degassed and purged with N ₂ then thiophene-2carbonyloxycopper (268.17 mg, 1.41 mmol, 2 eq.) was added. ) and Pd ₂ (dba) ₃ (64.39 mg, 70.31 µmol, 0.1 eq.). The reaction mixture was stirred at 130° C. for 12 hours under N ₂ atmosphere. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to give a residue which was purified by silica gel flash chromatography (PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, R _f = 0.55) to give (3R)- N-[2-(3,6-dihydro-2H-pyran-4-yl)-8-isopropyl-pyrazolo[1,5-а][1,3,5]triazin-4-yl]-2,3 ,4,9tetrahydro-1H-carbazole-3-amine (60 mg, 127.97 µmol, 18.2% yield, 91.4% purity) as a white solid.

1H NMR (400 MHz, CD3OD) δ ppm 7.87 (s, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.29-7.20 (m, 2H), 7, 03 (t, J=7.1 Hz, 1H), 6.98-6.92 (m, 1H), 4.73 (s, 1H), 4.34 (d, J=2.7 Hz, 2H ), 3.89 (t, J=5.5 Hz, 2H), 3.29-3.15 (m, 2H), 3.00-333 041983

2.91 (m, 2H), 2.86 (dd, J=8.9, 15.0 Hz, 1H), 2.69 (d, J=1.7 Hz, 2H), 2.32 (s , 1H), 2.26-2.17 (m, 1H), 1.35 (d,

J=7.1 Hz, 6H); ER-LCMS m/z 429.3 [M+H]+.

Step 2: (3R)-N-(8-isopropyl-2-tetrahydropyran-4-yl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)-2,3,4, 9tetrahydro-1 H-carbazole-3-amine (I-25 8)

To a stirred solution of (3R)-N-[2-(3,6-dihydro-2H-pyran-4-yl)-8-isopropyl-pyrazolo[1,5a][1,3,5]triazin-4-yl ]-2,3,4,9-tetrahydro-III-carbazole-3-amine (55 mg, 117.31 µmol, 1 eq.) in MeOH (20 ml) was added Pd/C (0.1 g, 10% masses). The reaction mixture was stirred at 20° C. for 5 h under an H ₂ atmosphere (15 psi). The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to give a residue which was purified by preparative HPLC (HCl conditions; column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 55%-85%, 8 min). The desired fraction was lyophilized to give (3R)-N-(8-isopropyl-2-tetrahydropyran-4-yl-pyrazolo[1,5a][1,3,5]triazin-4-yl)-2,3,4, 9-tetrahydro-1H-carbazole-3-amine (16.60 mg, 36.74 µmol, 31.3% yield, 95.3% purity, [a] ^25.0 D = +9.739 (MeOH, c = 0.098 g /100 ml)) in the form of a white solid.

Ή NMR (400 MHz, CD3OD) δ ppm 8.08 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H) , 7.07-7.01 (m, 1H), 6.99-6.93 (m, 1H), 4.86-4.77 (m, 1H), 4.05 (dd, J=2, 0, 11.5 Hz, 2H), 3.61-3.50 (m, 2H), 3.28-3.17 (m, 2H), 3.10-2.88 (m, 4H), 2 .39-2.20 (m, 2H), 2.11-1.98 (m, 2H), 1.96-1.87 (m, 2H), 1.35 (d, J=6.8 Hz , 6H); ERJHMS m/z 431.3 [M+H] ⁺ .

Example 197.

Synthesis of I-259a, I-259b and I-259c

Synthesis scheme:

Step 1: 2-(5-fluoro-3-pyridyl)-8-methyl-N-[(5R)-4,5,6,7-tetrahydro-1H-indol-5-yl]pyrazolo[1,5a] [1,3,5]triazine-4-amine (I-259b) and 2-(5-fluoro-3-pyridyl)-8-methyl-N-[(5S)-4,5,6,7-tetrahydro -1H-indol-5yl]pyrazolo[1,5-a][1,3,5]triazine-4-amine (I-259a)

- 334 041983

4-Chloro-2-(5-fluoro-3-pyridyl)-8-methyl-pyrazolo[1,5-a][1,3,5]triazine mixture (100 mg, 379.28 µmol, 1 eq.) , 4,5,6,7-tetrahydro-1H-indole-5-amine (56.82 mg, 417.21 µmol, 1.1 eq) and DIEA (147.06 mg, 1.14 mmol, 198, 19 μl, 3 eq.) in i-PrOH (3 ml) was stirred at 60°C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (from PE 0 to 2/1, TLC: PE/EtOAc = 1/1, Rf = 0.60) to give a crude product which was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm x 50 mm, 10 µm); mobile phase: [0.1% NH ₃ H ₂ O/IPA] B%: 40%-40%) to give peak 1 and peak 2. The fraction corresponding to peak 1 was concentrated under reduced pressure to give a residue which was dissolved in MeCN ( 20 ml) and H2O (40 ml) and lyophilized to give the enantiomer (20.50 mg, 56.41 µmol, 14.9% yield, 100.0% purity, SFC: Rt = 1.488, ee = 100%, [a ] ^26.1 _D \u003d - 32.731 (CHCl ₃ , c \u003d 0.108 g / 100 ml)) in the form of TV porous substance off-white.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.51 (s, 1H), 8.56 (d, J=2.8 Hz, 1H), 8.50-8.41 (m, 1H), 7 .94-7.87 (m, 1H), 7.85 (s, 1H), 6.72 (t, J=2.4 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 6.05 (t, J=2.4 Hz, 1H), 4.88-4.77 (m, 1H), 3.17 (dd, J=4.8, 15.2 Hz, 1H ), 2.88-2.71 (m, 3H), 2.35 (s, 3H), 2.28 (dq, J=2.4, 6.0 Hz, 1H), 2.23-2, 12 (m, 1H); ERLCMS m/z 364.2 [M+H]+. The fraction corresponding to peak 2 was concentrated under reduced pressure to give a residue which was dissolved in MeCN (20 ml) and H2O (40 ml) and lyophilized to give the other enantiomer (19.32 mg, 53.17 µmol, 14.0% yield , purity 100.0%, SFC: Rt = 1.691, ee = 100%, [a] ^26.0 D = + 10.595 (CHCl ₃ , c = 0.102 g/100 ml)) as an off-white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.51 (br s, 1H), 8.56 (br s, 1H), 8.46 (d, J=9.2 Hz, 1H), 7.90 (s, 1H), 7.85 (s, 1H), 6.72 (s, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.05 (s, 1H ), 4.90-4.80 (m, 1H), 3.16 (d, J=10.8 Hz, 1H), 2.87-2.73 (m, 3H), 2.35 (s, 3H), 2.30-2.22 (m, 1H), 2.20-2.10 (m, 1H); ER-LCMS m/z 364.2 [M+H] ⁺ .

Example 198.

Synthesis of I-262

1-262

Synthesis scheme:

Step 1: 2-(5-fluoro-3-niridyl)-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1,5a][ 1,3,5]triazine-8-carboxylate

2-(5-Fluoro-3-pyridyl)-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1.5] solution

- 335 041983

a][1,3,5]triazine-8-carbonitrile (200 mg, 335.51 µmol, 1 eq.) in HCl/MeOH (4 M, 10 ml) was stirred at 70°C for 12 h in a tightly closed tube. The reaction mixture was concentrated under reduced pressure to give a residue which was quenched by adding water (50 ml), adjusted to pH 9 with aqueous NaHCO ₃ , extracted with EtOAc (50 mlx3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative TLC (PE/EtOAc = 1/2, TLC: PE/EtOAc = 1 /2, Rf = 0.53) to give methyl 2-(5-fluoro-3-pyridyl)-4-[[(3R)-2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino ]pyrazolo[1,5-a][1,3,5]triazine-8-carboxylate (50 mg, 96.84 µmol, 28.8% yield, 88.6% purity) as a yellow solid.

1H NMR (400 MHz, CDC13) δ ppm 9.57 (br s, 1H), 8.67-8.48 (m, 2H), 8.41 (s, 1H), 7.98 (s, 1H ), 7.557.42 (m, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.19 (t, J=7.7 Hz, 1H), 7.15-7.10 (m, 1H), 6.96 (d, J=8.1 Hz, 1H), 4.99 (s, 1H), 3.98 (s, 3H), 3.39 (dd, J=4, 8, 15.3 Hz, 1H), 3.09-2.97 (m, 3H), 2.43-2.32 (m, 2H); ER-LCMS m/z 458.2 [M+H]+.

Step 2: 2-(5-fluoro-3-pyridyl)-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1,5a] [ 1,3,5]triazine-8-carboxylic acid

To a solution of methyl 2-(5-fluoro-3-pyridyl)-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]pyrazolo[1,5-a] [1,3,5]triazine-8-carboxylate (140 mg, 306.04 μmol, 1 eq.) in THF (2 ml), MeOH (2 ml) and H ₂ O (1 ml) 29 mg, 3.06 mmol, 10 eq.) was stirred at 50° C. for 12 h. aqueous HCl solution was concentrated to give 2-(5-fluoro-3-pyridyl)-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1 ,5-a][1,3,5]triazine8-carboxylic acid (120 mg, 187.00 µmol, 61.1% yield, 69.1% purity) as a yellow solid, which was used in the next step without additional cleaning.

1H NMR (400 MHz, CD3OD) δ ppm 9.69 (s, 1H), 9.21 (d, J=6.6 Hz, 1H), 8.93 (s, 1H), 8.49 (s, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.29-7.17 (m, 1H), 7.08-6.89 (m, 2H), 4.93 (d , J=4.2 Hz, 1H), 3.30-3.20 (m, 1H), 3.19-2.88 (m, 3H), 2.53-2.08 (m, 2H); ER-LCMS m/z 444.1 [M+H] ⁺ .

Step 3: [2-(5-fluoro-3-pyridyl)-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1,5a] [1,3,5]triazin-8-yl]morpholino-methanone (I-262)

To a solution of 2-(5-fluoro-3-pyridyl)-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1,5а][1 ,3,5]triazine-8-carboxylic acid (50 mg, 77.91 µmol, 1 eq.), morpholine (20.36 mg, 233.74 µmol, 20.57 µl, 3 eq.) in DMF (2 ml) HATU (35.55 mg, 93.50 µmol, 1.2 eq.) and TEA (23.65 mg, 233.74 µmol, 32.53 µl, 3 eq.) were added. The mixture was stirred at 15° C. for 12 hours. The reaction mixture was quenched by adding water (50 ml), extracted with EtOAc (30 mlx3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: DuraShell 150x25 mmx5 μm; mobile phase: [water (0, 05% HC1)-ACN]; B%: 32%-62%, 7 min) followed by lyophilization to give [2-(5-fluoro-3-pyridyl)-4-[[(3R)-2.3, 4,9-tetrahydro-1H-carbazol-3yl]amino]pyrazolo[1,5-a][1,3,5]triazin-8-yl]morpholino-methanone (15.18 mg, 25.93 µmol, yield 33.2%, 100% pure, 2HC1, [a] ^24.3 D = +20.863 (MeOH, c = 0.059 g/100 ml)) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.52 (s, 1H), 8.90 (dd, J=1.5, 9.0 Hz, 1H), 8.85 (s, 1H), 8, 35 (s, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.04 (t, J=7.0 Hz, 1H), 6.99-6.93 (m, 1H), 4.99-4.92 (m, 1H), 3.81 (s, 8H), 3.29 (d, J=5, 6 Hz, 1H), 3.17-2.91 (m, 3H), 2.46-2.23 (m, 2H); ER-LCMS m/z 513.3 [M+H] ⁺ .

- 336 041983

Synthesis scheme:

Example 199.

Synthesis of I-263a, I-263b and I-263c

Step 1: (2S)-N-[2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-1, 2,3,4tetrahydrocyclopenta[b]indole-2-amine (I-263a) and (2R)-N-[2-(5-fluoro-3-pyridyl)-8-isopropylpyrazolo[1,5-a][1 ,3,5]triazin-4-yl]-1,2,3,4-tetrahydrocyclopenta[b]indole-2-amine (I-263b)

To a solution of 4-chloro-2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine (120 mg, 391.62 µmol, 1 eq. ) and 1,2,3,4-tetrahydrocyclopenta[b]indole-2-amine (67.45 mg, 391.62 µmol, 1 eq.) in i-PrOH (10 ml) was added DIEA (404.91 mg, 3.13 mmol, 545.71 µl, 8 eq.). The mixture was stirred at 50° C. for 2 hours and concentrated to give N-[2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1.5a][1.3.5]triazine-4- yl]-1,2,3,4-tetrahydrocyclopenta[b]indole-2-amine (120 mg, 274.65 µmol, 70.1% yield, 97.8% purity), which was separated by chiral SFC (column: DAICEL CHIRALCEL OJ-H (250 mm x 30 mm, 5 µm) mobile phase: [0.1% NH ₃ H ₂ O EtOH] B%: 40%-40%) to give peak 1 and peak 2. Fraction corresponding to peak 1 was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 68%-98% , 8 min). The desired fraction was lyophilized to give the enantiomer (31.51 mg, 62.97 µmol, 16.1% yield, 100.0% purity, 2HCl, SFC: Rt = 5.092, ee = 99.41%, [a] ^24.5 _D = + 37.706 (MeOH, c = 0.093 g/100 ml)) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.94 (s, 1H), 9.43-9.40 (m, 2H), 8.71 (d, J=2.9 Hz, 1H ), 8.45-8.41 (m, 1H), 8.15 (s, 1H), 7.35-7.31 (m, 2H), 7.00-6.95 (m, 2H), 5.65-5.60 (m, 1H), 3.43-3.34 (m, 2H), 3.24-3.19 (m, 2H), 3.03 (dd, J=6.6 , 13.9 Hz, 1H), 1.37 (d, J=6.8 Hz, 6H); ER-LCMS m/z 428.2 [M+H] ⁺ .

The fraction corresponding to peak 2 was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 68% -98%, 8 min). The desired fraction was lyophilized to give the other enantiomer (24.54 mg, 49.04 µmol, 12.5% yield, 100.0% purity, 2HCl, SFC: Rt = 6.749, ee = 99.76%, [a] ²⁴⁶ _D = - 41.018 (MeOH, c = 0.087 g/100 ml)) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.93 (s, 1H), 9.43-9.40 (m, 2H), 8.71 (d, J=2.7 Hz, 1H ), 8.45-8.41

- 337 041983 (m, 1H), 8.15 (s, 1H), 7.35-7.31 (m, 2H), 7.02-6.95 (m, J=7.0, 15.1 Hz, 2H), 5.67-5.60 (m, 1H), 3.41-3.34 (m,

2H), 3.24-3.21 (m, J=7.2, 14.1 Hz, 2H), 3.04-2.99 (dd, J=6.4, 13.9 Hz, 1H) , 1.37 (d, J=6.8 Hz, 6H); ER-LCMS m/z 428.2 [M+H] ⁺ .

Example 200.

Synthesis of I-264

Synthesis scheme:

_Boc2O , DMAP

1,4-dioxane 110 °C, 26 h

Stage 1: tert-butyl (3R)-3-[tert-butoxycarbonyl-(8-isopropyl-2-methylsulfanyl-pyrazolo[1,5a][1,3,5]triazin-4-yl)amino]-1, 2,3,4-tetrahydrocarbazole-9-carboxylate

To a solution of (3R)-N-(8-isopropyl-2-methylsulfanyl-pyrazolo[1,5-а][1,3,5]triazin-4-yl)-2,3,4,9tetrahydro-1H-carbazole -3-amine (300 mg, 726.08 µmol, 1 eq.) in 1,4-dioxane (30 ml) was added DMAP (266.12 mg, 2.18 mmol, 3 eq.) and Boc ₂ O (950 .78 mg, 4.36 mmol, 1.00 ml, 6 eq.). The mixture was stirred at 110° C. for 10 hours. Boc ₂ O (950.78 mg, 4.36 mmol, 1.00 ml, 6 eq.) was added to the mixture. The mixture was stirred at 110° C. for another 16 hours. The mixture was concentrated. The crude material was purified by silica gel column chromatography (pure PE to PE/EtOAc = 3/1, TLC: PE/EtOAc = 5/1, Rf = 0.7) to give tert-butyl (3R)-3-[ tert-butoxycarbonyl-(8-isopropyl-2-methylsulfanylpyrazolo[1,5-а][1,3,5]triazin-4-yl)amino]-1,2,3,4-tetrahydrocarbazole-9-carboxylate (420 mg, 637.71 µmol, 87.8% yield, 90.0% purity) as a yellow solid.

1H NMR (400 MHz, CDCI3) δ ppm 8.10-8.04 (m, 1H), 7.93 (s, 1H), 7.33 (d, J=7.3 Hz, 1H), 7, 23-7.13 (m, 2H), 4.76-4.74 (m, 1H), 3.33-2.97 (m, 5H), 2.59-2.51 (m, 3H), 2.37-2.27(m, 1H), 2.24-2.26(m, 1H), 1.63(s, 9H), 1.54(s, 9H), 1.36(d, J=6.8 Hz, 6H); ER-LCMS m/z 593.3 [M+H]+.

Stage 2: tert-butyl (3R)-3-[tert-butoxycarbonyl-(8-isopropyl-2-methylsulfinyl-pyrazolo[1,5a][1,3,5]triazin-4-yl)amino]-1, 2,3,4-tetrahydrocarbazole-9-carboxylate

To a solution of tert-butyl (3R)-3-[tert-butoxycarbonyl-(8-isopropyl-2-methylsulfanyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino]-1 ,2,3,4-tetrahydrocarbazole-9-carboxylate (400 mg, 607.34 µmol, 1 eq.)

- 338 041983 in MeOH (20 ml) was added oxon (373.37 mg, 607.34 μmol, 1 eq.). The mixture was stirred at 15° C. for 3 hours. After that, the mixture was filtered, EtOAc (80 ml) was added to the filtered mixture and quenched by adding a saturated solution of Na ₂ SO ₃ (50 ml). The aqueous layer was subjected to extraction with EtOAc (30 mlx3) and the combined organic layers were washed with saline (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by silica gel column chromatography (PE/EtOAc = 10/1 to 2/1, TLC: PE/EtOAc = 5/1, Rf = 0.2) to give tert-butyl (3R)3-[ tert-butoxycarbonyl-(8-isopropyl-2-methylsulfinyl-pyrazolo[1,5-а][1,3,5]triazin-4-yl)amino]1,2,3,4-tetrahydrocarbazole-9-carboxylate ( 250 mg, 403.70 µmol, 66.5% yield, 98.3% purity) as a yellow solid.

1H NMR (400 MHz, CDC13) δ ppm 8.16 (s, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H) , 7.24-7.14 (m, 2H), 4.85-4.83 (m, 1H), 3.40 (td, J=6.8, 13.8 Hz, 1H), 3.34 -3.01 (m, 4H), 2.94 (d, J=2.7 Hz, 3H), 2.43 (d, J=12.0 Hz, 1H), 2.27 (d, J= 8.1 Hz, 1H), 1.64 (s, 9H), 1.45-1.29 (m, 15H); ER-LCMS m/z 631.3 [M+Na]+.

Stage 3: tert-butyl (3R)-3-[[8-isopropyl-2-(1-piperidyl)pyrazolo[1,5-a][1,3,5]triazin-4yl]amino]-1,2 ,3,4-tetrahydrocarbazole-9-carboxylate

Vos /

A solution of tert-butyl (3R)-3-[tert-butoxycarbonyl-(8-isopropyl-2-methylsulfinyl-pyrazolo[1.5a][1.3.5]triazin-4-yl)amino]-1.2, 3,4-tetrahydrocarbazole-9-carboxylate (100 mg, 161.48 µmol, 1 eq.) and piperidine (172.44 mg, 2.03 mmol, 0.2 ml, 12.54 eq.) in t-BuOH (1 ml) was irradiated and stirred at 120°C for 2 h under microwave treatment. The mixture was concentrated to give tert-butyl (3R)-3-[[8-isopropyl-2-(1-piperidyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]-1, 2,3,4-Tetrahydrocarbazole-9-carboxylate (80 mg, 137.44 µmol, 85.1% yield, 91.0% purity) as a yellow solid.

1H NMR (400 MHz, CDC13) δ ppm 8.11 (d, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.35 (d, J=7.1 Hz, 1H) , 7.27 (br s, 1H), 7.23-7.17 (m, 1H), 6.26 (d, J=7.8 Hz, 1H), 4.60-4.59 (m , 1H), 3.79 (d, J=4.6 Hz, 4H), 3.35 (d, J=5.1 Hz, 3H), 3.27-3.14 (m, 3H), 3 .02 (td, J=6.8, 13.8 Hz, 1H), 2.72 (dd, J=7.7, 14.6 Hz, 1H), 2.25 (br. s, 1H), 2.12 (d, J=8.3 Hz, 1H), 1.54-1.39 (m, 12H), 1.28 (d, J=6.8 Hz, 6H); ER-LCMS m/z 530.4 [M+H] ⁺ .

Step 4: (3R)-N-[8-isopropyl-2-(1-piperidyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4,9tetrahydro - 1 N-carbazole-3-amine (I-264)

Solution of tert-butyl (3R)-3-[[8-isopropyl-2-(1-piperidyl)pyrazolo[1,5-a][1,3,5]triazin-4yl]amino]-1,2,3 ,4-tetrahydrocarbazole-9-carboxylate (80 mg, 137.44 µmol, 1 eq.) and TFA (1.12 g, 9.83 mmol, 728.00 µl, 71.54 eq.) in DCM (5 ml ) was stirred at 20° C. for 2 hours. The mixture was concentrated. The residue was purified by preparative HPLC (column: Agela ASB 150x25 mmx5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 50%-80%, 8 min) followed by lyophilization to give (3R )-N-[8-isopropyl-2-(1-piperidyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4,9-tetrahydro-1Hcarbazole- 3-amine (34.59 mg, 71.55 µmol, 52.1% yield, 96.4% purity, HCl; Optical rotation: [a] ^22.2 D = +82.409, (MeOH, c = 0.096 g/ 100 ml)) as a yellow solid.

1H NMR (400 MHz, CD ₃ OD) δ ppm 7.89 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H), 7.00-6.93 (m, 1H), 4.69-4.57 (m, 1H), 3.87 (broad s, 4H), 3.28-3.16 (m, 2H), 2.97 (br s, 2H), 2.93-2.82 (m, 1H), 2.37-2.15 (m, 2H), 1.74 (br s, 6H), 1.31 (d, J=6.8 Hz, 6H); ER-LCMS m/z 430.3 [M+H] ⁺ .

- 339 041983

Example 201.

Synthesis of I-265

Step 1: 2-(5-fluoro-3-pyridyl)-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrazolo[1,5a][ 1,3,5]triazine-8-carboxamide (I-265)

A solution of 2-(5-fluoro-3-pyridyl)-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]pyrazolo[1.5a][1.3, 5]triazine-8-carbonitrile (170 mg, 396.53 µmol, 1 eq.) in HCl/MeOH (4 M in MeOH, 30 mL) was stirred at 80° C. for 12 h. The reaction mixture was concentrated under reduced pressure, obtaining a residue, which was extinguished by adding saturated aqueous NaHCO ₃ (50 ml), was extracted with EtOAc (30 mlx3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue.

The residue was purified by silica gel flash chromatography (PE/EtOAc = 1/0 to 0/1, TLC: PE/EtOAc = 1/1, Rf = 0.11) to give 2-(5-fluoro-3- pyridyl)-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]pyrazolo[1,5-а][1,3,5]triazine-8-carboxamide ( 60 mg, 135.61 µmol, 34.2% yield, 100% purity, [a] ^23.7 D = +21.368 (MeOH, c = 0.088 g/100 ml)) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.79 (s, 1H), 9.56-9.41 (m, 2H), 8.78-8.67 (m, 2H), 8, 50 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.28 (d, J=7 .8 Hz, 1H), 7.05-6.98(m, 1H), 6.97-6.89(m, 1H), 4.86(s, 1H), 3.23-2.77( m, 4H), 2.22 (s, 2H); ER-LCMS m/z 443.1 [M+H] ⁺ .

Example 202.

Synthesis of I-267

- 340 041983

Synthesis scheme:

Stage 1: ethyl N-[[4-(trifluoromethyl)-1H-pyrazol-5-yl]carbamothioyl]carbamate

A solution of 4-(trifluoromethyl)-1H-nirazol-5-amine; hydrochloride (1 g, 4.46 mmol, 1 eq., HCl) and ethyl-N(thioxomethylene) carbamate (585.47 mg, 4.46 mmol, 1 eq.) in DCM (10 ml) and DMF (10 ml ) was stirred at 20°C for 2.5 hours. The reaction mixture was concentrated under reduced pressure to give the residue of ethyl N-[[4-(trifluoromethyl)-1H-pyrazol-5-yl]carbamothioyl]carbamate (1.1 g , 3.90 mmol, 87.3% yield, crude purity) as a yellow solid, which was used in the next step without further purification.

¹ H NMR (400 MHz, DMSO-b ₆ ) δ ppm 11.52 (s, 1H), 11.06 (s, 1H), 8.34 (s, 1H), 4.21 (q, J=7 .0 Hz, 2H), 1.25 (t, J=7.0 Hz, 3H); ER-LCMS m/z 283.0 [M+H] ⁺ .

Step 2: 2-thioxo-8-(trifluoromethyl)-1H-pyrazolo[1,5-a][1,3,5]triazin-4-one

_K2CO3 ( 1.62 g, 11.69 mmol, 3.0 eq.). The mixture was stirred at 60° C. for 3 hours. The reaction mixture was quenched with AcOH solution (6 ml), diluted with H2O (50 ml) and extracted with EtOAc (50 mlx3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was diluted with EtOAc/PE (2 ml/10 ml), filtered and the solid was collected to give 2-thioxo-8-(trifluoromethyl)-1Hpyrazolo[1,5-a][1,3,5]triazin-4-one (900 mg, 3.33 mmol, 85.4% yield, 87.3% purity) as a yellow solid, which was used in the next step without further purification.

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.65 (br s, 1H), 8.16 (s, 1H); ER-LCMS m/z 237.0 [M+H]+.

Step 3: 2-Methylsulfanyl-8-(trifluoromethyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

To a solution of 2-thioxo-8-(trifluoromethyl)-1H-pyrazolo[1,5-a][1,3,5]triazin-4-one (900 mg, 3.33 mmol, 1 eq.) in EtOH ( 15 ml) was added a solution of NaOH (266.12 mg, 6.65 mmol, 2 eq.) in H2O (6 ml) and then MeI (472.20 mg, 3.33 mmol, 207.11 µl, 1 equiv.). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was acidified with 1 N hydrochloric acid. HCl solution (10 mL) and concentrated under reduced pressure to remove EtOH, solid formed, filtered and collected solid to give 2-methylsulfanyl-8-(trifluoromethyl)-3H-pyrazolo[1,5-a][1,3 ,5]triazin-4-one (800 mg, 3.00 mmol, 90.2% yield, 93.8% purity) as a yellow solid, which was used in the next step without further purification.

¹ H NMR (400 MHz, CD3OD) δ ppm 8.16 (s, 1H), 2.64 (s, 3H); ER-LCMS m/z 251.1 [M+H] ⁺ .

- 341 041983

Step 4: 4-chloro-2-methylsulfanyl-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazine

A solution of 2-methylsulfanyl-8-(trifluoromethyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (200 mg, 749.80 µmol, 1 eq) and DIEA (290 .72 mg, 2.25 mmol, 391.80 µl, 3.0 eq.) in POC13 (34.43 g, 224.55 mmol, 20.87 ml, 299.47 eq.) was stirred at 130°C in for 12 h in an atmosphere of N ₂ . The reaction mixture was concentrated under reduced pressure to give 4-chloro-2-methylsulfanyl-8(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazine (200 mg, 744.47 µmol, 99.3% yield , crude purity) as a black-brown oil, which was used in the next step without further purification.

1 H NMR (400 MHz, CDC13) δ ppm 8.29 (s, 1H), 2.66-2.64 (m, 3H).

Step 5: (3R)-N-[2-Methylsulfanyl-8-(trifluoromethyl)pyrazolo[1,5-][1,3,5]triazin-4-yl]-2,3,4,9tetrahydro-1 H -carbazole-3 -amine

To a solution of 4-chloro-2-methylsulfanyl-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazine (200 mg, 744.47 µmol, 1 eq.) and (3R)-2 ,3,4,9-tetrahydro-1H-carbazole-3-amine (166.39 mg, 893.37 µmol, 1.2 eq.) in ACN (10 mL) was added DIEA (962.18 mg, 7.44 mmol, 1.30 ml, 10 eq.). The mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC:

PE/EtOAc

3/1, RF

0.32) to give the indicated product (3R)-N-[2-methylsulfanyl-8(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4 ,9-tetrahydro-1H-carbazole-3-amine (150 mg, 353.10 µmol, 47.4% yield, 98.5% purity) as a brown oil.

¹ H NMR (400 MHz, CDC13) δ ppm 7.99 (s, 1H), 7.84 (broad s, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.24-7.08 (m, 2H), 6.65 (d, J=9.3 Hz, 1H), 4.82 (m, 1H) , 3.31 (dd, J=5.4, 15.4 Hz, 1H), 3.03-2.84 (m, 3H), 2.60 (s, 3H), 2.31-2.21 (m, 2H); ER-LCMS m/z 419.1 [M+H]+.

Step 6: (3R)-N-(5-fluoro-3-pyridyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3, 4,9tetrahydro-1 H-carbazole-3-amine (I-267)

To a solution of (3R)-N-[2-methylsulfanyl-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4,9tetrahydro-1H- carbazole-3-amine (100 mg, 235.40 µmol, 1 eq) and (5-fluoro-3-pyridyl)boronic acid (99.51 mg, 706.20 µmol, 3.0 eq) in 1, 4-dioxane (6 ml) was added Pd(PPh ₃ ) ₄ (27.20 mg, 23.54 µmol, 0.1 eq.) and thiophene-2-carbonyloxycopper (89.78 mg, 470.80 µmol, 2, 0 equiv.). The mixture was purged with N2 for 1 min and stirred at 120° C. for 5 h under microwave treatment. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 10/3, TLC: PE/EtOAc = 3/1, Rf = 0.38) and preparative HPLC (column: DuraShell 150x25 mmx5 µm; mobile phase: [water (0.05% HC1)-ACN]; B%: 45%-75%, 8 min) followed by lyophilization to give the title product (3R)- N-[2-(5-fluoro-3-pyridyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4,9tetrahydro- 1H-carbazole-3-amine (36.04 mg, 66.30 µmol, 28.2% yield, 99.4% purity, 2HC1, Optical rotation: ([a] ^24.3 _D = +51.474, (MeOH, c=0.048 g/100 ml)) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ ppm 9.48 (broad s, 1H), 8.71 (d, J=8.8 Hz, 2H), 8.35 (s, 1H), 7.36 ( d, J=7.8Hz, 1H), 7.26(d, J=8.3Hz, 1H), 7.06-6.99(m, 1H), 6.97-6.88(m , 1H), 4.91 (d, J=3.8 Hz, 1H), 3.29 (d, J=5.5 Hz, 1H), 3.10-2.90 (m, 3H), 2 .45-2.35 (m, 1H), 2.33-2.21 (m, 1H); ER-LCMS m/z 468.2 [M+H]+.

- 342 041983

Example 203.

Synthesis of I-270

Stage 1: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

Synthesis scheme:

5-bromopyrimidine mixture (1 g, 6.29 mmol, 1 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl )-1,3,2-dioxaborolane (1.76 g, 6.93 mmol, 1.10 eq.), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (513.66 mg, 628.99 µmol, 0 1 eq.), KOAc (1.85 g, 18.87 mmol, 3 eq.) in 1,4-dioxane (40 ml) and DMF (10 ml) were stirred at 100°C for 2 h under N ₂ . The mixture was concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, R _f = 0.23) to give 5-(4.4.5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (1.5 g, 5.82 mmol, 92.6% yield, 80% purity) as a red oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.25 (s, 1H), 9.00 (broad s, 2H), 1.33 (s, 12H).

Step 2: (3R)-N-(8-isopropyl-2-pyrimidin-5-yl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)-2,3,4, 9 tetrahydro-1 H-carbazole-3-amine (I-270)

A mixture of (3R)-N(8-isopropyl-2-methylsulfanyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)-2,3,4,9 tetrahydro-1H-carbazole- 3-amine (150 mg, 351.57 µmol, 1 eq.), 5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrimidine (271.66 mg, 1.05 mmol, 3 equiv.), Pd ₂ (dba) ₃ (32.19 mg, 35.16 µmol, 0.1 equiv.) and copper (I) thiophene-2-carbonyloxy (134.08 mg, 703.15 µmol , 2 eq.) in 1,4-dioxane (4 ml) was stirred at 110° C. for 12 h under N ₂ atmosphere. The mixture was concentrated to give crude material which was purified by silica gel column chromatography (PE/EtOAc = 1/0 to 2/1, TLC: PE/EtOAc = 3/1, R _f = 0.25) to give a solid gray, which was suspended with MeCN/H ₂ O/DMF (3/1/0.5, 10 ml). After filtration, the filter cake was washed with MeCN (10 ml x 3) and dried under vacuum to give (3R)-N-(8-isopropyl-2-pyrimidin-5-yl-pyrazolo[1,5a][1,3,5]triazine -4-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (42.34 mg, 99.74 µmol, 28.4% yield, 100% purity, [a] ^24.5 D = +83.175 (DMSO, c = 0.102 g/100 ml)) as a gray solid.

1H NMR (400 MHz, DMSO) δ ppm 10.75 (s, 1H), 9.57 (s, 2H), 9.26 (s, 1H), 9.01 (broad s, 1H), 8, 12 (s, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 7.01-6.94 (m, 1H ), 6.93-6.86 (m, 1H), 4.80-4.77 (m, 1H), 3.11-3.00 (m, 2H), 2.99-2.81 (m , 3H), 2.18 (m, 2H), 1.34 (d, J=6.8 Hz, 6H); ER-LCMS m/z 425.2 [M+H] ⁺ .

Although the authors of the present invention have described a number of embodiments of the present invention, it is obvious that these basic examples can be modified to obtain other implementations that use the compounds and methods according to the present invention. Therefore, it is obvious that the scope of the present invention is determined by the appended claims, and not by specific implementation options, which are given as an example.

Claims (25)

CLAIM 1. A compound selected from one of formulas IX-a and IX-b: IX-a IX-b or a pharmaceutically acceptable salt thereof, wherein X is N or CH; each of R ^x , R ^y and R ^z is independently selected from R, halo, cyano, nitro, -OR, -SR, -N(R)2, -N(R)C(O)R, -C(O) N(R)2, -C(O)N(R)OR, -N(R)C(O)N(R)2, -N(R)C(O)OR, -OC(O)N( R)2, -N(R)SO2R, -SO2RN(R)2, -C(O)R, -C(O)OR, -OC(O)R, -S(O)R or -SO2R, or two R ^x at the same carbon atom are combined to form ═O or ═S; or two R ^y at the same carbon atom combined to form ═O or ═S; each R is independently hydrogen, deuterium, or a substituted or unsubstituted group selected from C _1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring; 4-8-membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10-membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or two R's on the same nitrogen atom are combined with intermediate atoms between them to form a 4-7 membered saturated, partially unsaturated, or aromatic ring containing 1-2 heteroatoms in addition to said nitrogen atom, independently selected from oxygen, nitrogen or sulfur; each p is independently 0, 1, or 2, depending on valence; and each m and n is independently 1, 2, 3, 4, or 5. 2. A compound selected from one of the formulas X-a, X-b, X-c, X-d, X-e, X-f, X-g, X-h and X-i: or a pharmaceutically acceptable salt thereof, wherein X is N or CH; each of R ^x , R ^y and R ^z is independently selected from R, halo, cyano, nitro, -OR, -SR, -N(R) ₂ , -N(R)C(O)R, -C(O) N(R)2, -C(O)N(R)OR, -N(R)C(O)N(R)2, -N(R)C(O)OR, -OC(O)N( R)2, -N(R)SO2R, -SO2RN(R)2, -C(O)R, -C(O)OR, -OC(O)R, -S(O)R or -SO2R, or two R ^x at the same carbon atom are combined to form ═O or ═S; or - 344 041983 two R ^y at the same carbon atom are combined to form ═O or ═S; each R is independently hydrogen, deuterium, or a substituted or unsubstituted group selected from C _1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring; 4-8-membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10-membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or two R's on the same nitrogen atom are combined with intermediate atoms between them to form a 4-7 membered saturated, partially unsaturated, or aromatic ring containing 1-2 heteroatoms in addition to said nitrogen atom, independently selected from oxygen, nitrogen, or sulfur; each p is independently 0, 1, or 2, depending on valence; and each m and n is independently 1, 2, 3, 4, or 5. 3. A compound according to claim 2, wherein said compound is selected from one of the formulas XI-a, XI-b, XI-c, XI-d, XI-e, XI-f, XI-g, XI-h and XI- i: or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 2, where the specified compound is selected from one of the formulas XII-a, XII-b and XII-c: £ j£ \ _ χ+Α χ+Α HP-a HP-b and or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 2, where the specified compound is selected from: r- NH Gu “ xf ^ J 7 tg / Ν HN \=/ xY-N guy Ν HP-s; Hu νΓ-ν ^ГГ ⁷ - 345 041983 - 346 041983 - 347 041983 - 348 041983 - 349 041983 - 350 041983 - 351 041983 - 352 041983 - 353 041983 - 354 041983 - 355 041983 - 356 041983 or a pharmaceutically acceptable salt thereof. 6. A composition for the treatment of an aryl-hydrocarboxylic receptor (AHR)-mediated disorder, comprising a compound according to claim 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 7. A composition for the treatment of an AHR-mediated disorder, comprising a compound according to claim 5 or - 357 041983 its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, adjuvant or carrier medium. 8. The compound of claim 2, wherein said compound is selected from or a pharmaceutically acceptable salt thereof. 9. A composition for the treatment of an AHR-mediated disorder, comprising a compound according to claim 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 10. A compound according to claim 8, wherein said compound is or a pharmaceutically acceptable salt thereof. 11. A composition for the treatment of an AHR-mediated disorder, comprising a compound according to claim 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 12. A compound according to claim 8, wherein said compound is - 358 041983 or a pharmaceutically acceptable salt thereof. 13. A composition for the treatment of an AHR-mediated disorder, comprising a compound according to claim 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or transfer medium. 14. A compound according to claim 8, wherein said compound is or a pharmaceutically acceptable salt thereof. 15. A composition for the treatment of an AHR-mediated disorder, comprising a compound according to claim 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 16. A compound according to claim 8, wherein said compound is or a pharmaceutically acceptable salt thereof. 17. A composition for the treatment of an AHR-mediated disorder, comprising a compound according to claim 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 18. A method of treating an AHR-mediated disorder in a patient in need thereof, comprising administering to said patient a compound according to any one of claims 1-5, 8, 10, 12, 14 and 16, or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 6 , 7, 9, 11, 13, 15 and 17. 19. The method of claim 18, wherein said AHR-mediated disorder is cancer. 20. The method of claim 18, wherein said AHR mediated disorder is an inflammatory disorder. 21. The method of claim 19, wherein the cancer is selected from bladder cancer, melanoma, ovarian cancer, head and neck squamous cell carcinoma (HNKS), lung cancer, kidney cancer, gastric cancer, esophageal cancer, and acute myeloid leukemia (AML). 22. The method of claim 19 or 21 wherein said compound, or a pharmaceutically acceptable salt or composition thereof, is administered in combination with an anticancer cytotoxin or chemotherapeutic agent. 23. The method of claim 19 or 21, wherein said compound, or a pharmaceutically acceptable salt or composition thereof, is administered in combination with an immuno-oncological agent. 24. The method of claim 23 wherein said immuno-oncological agent is a PD-1 antagonist. 25. The method of claim 23, wherein said compound, or a pharmaceutically acceptable salt or composition thereof, is administered prior to, simultaneously with, or after administration of said immuno-oncological agent.