KR20240177341A - Novel pyrazolopyrimidine based compounds and use thereof - Google Patents

Abstract

The present invention provides a novel pyrazolopyrimidine compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The present invention is a novel compound having excellent activity for TYK2 inhibition, and is therefore useful as a therapeutic agent for TYK2-mediated diseases such as autoimmune diseases.

Description

{NOVEL PYRAZOLOPYRIMIDINE BASED COMPOUNDS AND USE THEREOF}

The present invention relates to a novel pyrazolopyrimidine compound, a pharmaceutical composition comprising the compound, and a use of the compound.

Immunity and inflammation are important areas of drug development, and Janus kinase (JAK) targets have been attracting attention in related research fields for the past 10 years. The JAK/STAT signaling pathway is a signaling pathway stimulated by cytokines and participates in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. JAK kinases include four family members, JAK1, JAK2, JAK3, and TYK2, respectively. Activation of these signaling pathways is closely related to the occurrence and development of various diseases, including various inflammatory diseases, lymphoma, leukemia, and solid tumors.

Currently, the FDA has already approved four JAK inhibitors: Ruxolitinib, developed jointly by Incyte and Novartis, was approved in November 2011 for the treatment of polycythemia vera (PCV); Tofacitinib, developed jointly by Pfizer, was approved in November 2012 for the treatment of rheumatoid arthritis (RA), and was later approved for the treatment of psoriatic arthritis and ulcerative colitis; Baricitinib, developed jointly by Incyte and Lilly, was approved for the treatment of rheumatoid arthritis in May 2018; and Oclacitinib, an oral formulation developed by Zoetis, was approved in May 2013 for the treatment of canine idiopathic dermatitis.

JAK inhibitors have also achieved excellent progress in other indications, such as atopic dermatitis, psoriasis, and alopecia areata. As a result of the study, the main factors related to the pathogenesis of psoriasis include changes in the functions of T cells, dendritic cells, keratinocytes, mast cells, and macrophages, and the interaction between these cells and their related cytokines and chemokines further mediates a series of inflammatory responses, epidermal proliferation, keratinocyte dysfunction, stratum spinosum hyperplasia, and vascular changes, and the main targets related to this are tumor necrosis factor-α (TNF-α), phosphodiesterase 4 (PDE4), JAK kinase, and interleukin and its receptor (IL&ILR).

TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 binds to the cytoplasmic domains of type I and type II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitins) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophin factor, cardiotrophin 1, cardiotrophin-like cytokines, and LIF). Activated TYK2 then begins to phosphorylate additional signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

In the IL family, the main targets of psoriasis drug therapy are IL-12, IL-17, and IL-23, and the downstream effector molecule TYK2 targeting IL-12/23 is a kind of excellent research direction. The expression of TYK2 in dendritic cells requires the production of IL-12, IL-23, and IFN-γ and the induction of differentiation of Th1 cells (Blood, 2007), and IL-23 secreted by dendritic cells can induce Th17 cells to secrete inflammatory mediators, such as IL-17A, IL-17F, and IL-22. These inflammatory mediators promote the activation and hyperproliferation of epidermal keratinocytes (KC). Through the interaction of Th17 and KC cells, activated KC cells can produce substances such as proinflammatory factors, chemokines, and antibacterial peptides, which can concentrate and activate immune cells to the inflamed skin site. This causes an expansion of the immune response, ultimately developing into clinical symptoms related to psoriasis. As can be seen from this, TYK2 plays a very important role in the occurrence and development of psoriasis, and targeting the inhibition of TYK2 is expected to control the disease in the early stage of inflammation.

Compounds that are selective for inhibiting the activity of TYK2 are advantageous. Such compounds have the advantage of delivering a pharmacological response that favorably treats while minimizing the known side effects of the JAK/STAT signaling pathway. Under these circumstances, the inventors of the present invention have developed novel compounds with high specificity for JH2 of TYK2, thereby completing the present invention.

The present invention provides a novel pyrazolopyrimidine compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

The present invention also provides the use of a novel pyrazolopyrimidine compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

The terminology used in this application is only used to describe specific embodiments and is not intended to limit the present invention. The singular expression includes the plural expression unless the context clearly indicates otherwise. In this application, it should be understood that the terms "comprise" or "have" are intended to specify that the described feature, step, structure or combination thereof is present, but do not exclude in advance the possibility of the presence or addition of one or more other features, steps, structures or combinations thereof.

The meanings of terms and symbols used in this document are as follows.

The term "halogen" in the present invention means a substituent selected from fluorine (F), chloro (Cl), bromo (Br), and iodo (I).

In the present invention, the term “unsubstituted” means a state in which no substituent is substituted and is absent or hydrogen.

In the present invention, the term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbon atoms of the main chain. "Substituted" or "substituted with ~" is defined to include the implicit condition that such substitution is dependent on the permissibility of the substituted atom and the substituent, and that the substitution leads to a stable compound, for example, a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, etc.

In the present invention, "single bond" means that two connected radicals are directly connected. For example, if L represents a single bond in A-L-Z, this structure is essentially A-Z.

In the present invention, “C _xy ” means having carbon number x or more and y or less.

The term "C _1-4 alkyl" as used herein means a straight or branched C _1-4 saturated hydrocarbon, such as, for example, methyl, ethyl, propyl, butyl, 2-methyl-propyl, isopropyl, and the like. Preferred alkyl groups contain about 1, 2, 3, or 4 carbon atoms in the chain. A side chain means that one or more lower alkyl groups, for example, methyl, ethyl, or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having from about 1 to about 4 carbon atoms in the chain, which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted by one or more substituents, which may be the same or different. Each substituent can be halogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, carboxy, etc. Each substituent can follow any of the definitions for each substituent mentioned herein.

The term "C _1-4 haloalkyl" as used herein means a C _1-4 straight-chain or branched-chain saturated hydrocarbon in which at least one hydrogen atom of the C _1-4 straight-chain or branched-chain saturated hydrocarbon is replaced with a halogen atom (i.e., F, Cl, Br, or I). For example, and not limited thereto, it may be CH ₂ F, CHF ₂ , CH ₂ CHF ₂ , CF ₃ , or the like.

The term "C _6-12 aryl" as used herein refers to an aromatic hydrocarbon containing 6 to 12 carbon atoms. For example, it can refer to a ring system such as monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, pentalenyl, azulenyl, tetrahydronaphthyl, tetrahydroindenyl). Preferably, aryl can be a phenyl group having a chemical formula of C ₆ H ₅ and having 6 carbon atoms arranged in a cyclic ring structure. Phenyl group is very stable and is a type of aromatic hydrocarbon found in many organic compounds. In addition, the above aryl may be substituted or unsubstituted, and when substituted, the hydrogen at the ortho, meta, or para position of the phenyl ring is replaced with halogen, C _1-4 alkyl, -O-(C _1-4 alkyl), -O-(C _1-4 alkylene)-(C _6-12 aryl), -C _1-4 alkanol, -CN, -OH, -NH ₂ , -NH-(C _1-4 alkyl), -N(C _1-4 alkyl)-(C _1-4 alkyl), -NO ₂ , C _1-4 haloalkyl, C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, -NH-(C _3-7 heterocycloalkyl), NHC(=O)-(C _3-8 cycloalkyl), -O-(C _3-7 heterocycloalkyl), C _2-12 heteroaryl, -(C _1-4 alkyl)-O-(C _1-4 alkyl), C _1-4 alkenyl, C _1-4 alkynyl, or -C _1-4 alkyl-CN may be substituted, and each substituent may follow any definition regulation for each substituent mentioned in the present specification.

The term "C _2-12 heteroaryl" as used herein refers to an optionally substituted aromatic ring containing 2 to 12 carbon atoms, wherein at least one of the ring carbon atoms is replaced by a heteroatom selected from oxygen (O), nitrogen (N) and sulfur (S), or an aromatic ring (e.g., a bicyclic or tricyclic ring system) fused to one or more rings such as a heteroaryl ring, an aryl ring, a heterocyclic ring, or a carbocyclic ring, each of which may have an optional substituent. For example, pyrans (e.g., 2H-pyran, 4H-pyran), pyrroles, pyrazoles, imidazoles, triazoles (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), furans, isoxazoles, oxazoles, oxadiazoles (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophenes, isothiazoles, thiazoles, thiadiazoles (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridines, pyridazines, pyrimidines, pyrazines, triazines (e.g., 1,2,4-triazine, 1,3,5-triazine), tetrazines, It may include monocyclic heteroaryl including pyridone (e.g., 2-pyridone, 4-pyridone), indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, isobenzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, benzodioxazole, carbazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), Polycyclic heteroaryls may include, but are not limited to, imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4 -d ]thiazole, 1H-pyrazolo[4,3- d ]thiazole, and imidazo[2,1-b]thiazole. In addition, the above heteroaryl may be substituted or unsubstituted, and when substituted, halogen, C _1-4 alkyl, -O-(C _1-4 alkyl), -O-(C _1-4 alkylene)-(C _6-12 aryl), -C _1-4 alkanol, -CN, -OH, -NH ₂ , -NH-(C _1-4 alkyl), -N(C _1-4 alkyl)-(C _1-4 alkyl), -NO ₂ , C _1-4 haloalkyl, C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, -NH-(C _3-7 heterocycloalkyl), NHC(=O)-(C _3-8 cycloalkyl), -O-(C _3-7 heterocycloalkyl), C _2-12 heteroaryl, -(C _1-4 alkyl)-O-(C _1-4 C _1-4 alkenyl, C _1-4 alkynyl, or -C _1-4 alkyl-CN, etc. may be substituted, and each substituent may follow any definition provision for each substituent mentioned in the present specification.

Additionally, the polycyclic heteroaryl group may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the heteroaryl ring, if the polycyclic heteroaryl group is bonded to the parent structure via an aromatic ring, and may be substituted or unsubstituted. Examples of polycyclic heteroaryl groups composed of a heteroaryl ring fused to a non-aromatic ring are described below.

The term “5-membered or 6-membered aromatic ring” in the present invention means an aromatic ring compound having 5 or 6 carbon atoms forming the ring.

Meanwhile, when referring to a 5- or 6-membered aromatic ring containing at least one N, it refers to one that necessarily contains at least one nitrogen atom (N) as a heteroatom forming the aromatic ring.

The term "C _3-8 cycloalkyl" as used herein means a saturated hydrocarbon ring containing 3 to 8 carbon atoms, and the saturated hydrocarbon ring includes both monocyclic and polycyclic rings, and ring structures in which two or more rings share one or more pairs of carbon atoms (e.g., fused ring, spiro ring, bridged ring, etc.). Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, etc. In addition, the cycloalkyl may be substituted or unsubstituted, and when substituted, may be substituted with -OH, -O-(C _1-4 alkyl), C _1-4 alkanol, C _1-4 alkyl, halogen, -CN, -NH _2, C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, -NH-(C _3-7 heterocycloalkyl), -O-(C _3-7 heterocycloalkyl), C _2-12 heteroaryl, -C _1-4 alkyl-CN, -NO ₂ , C _1-4 haloalkyl, -(C _1-4 alkyl)-O-(C _1-4 alkyl), C _1-4 alkenyl, C _1-4 alkynyl, or NHC(=O)-(C _3-8 cycloalkyl), and each substituent may follow any definition regulation for each substituent mentioned in the present specification. Specific examples thereof include cyclobutanone. In addition, one ring of the polycyclic cycloalkyl group may be aromatic if the polycyclic cycloalkyl group is attached to the parent structure via a non-aromatic carbon. Examples of polycyclic cycloalkyl groups consisting of a cycloalkyl group fused to an aromatic ring are described below.

The term "C _5-10 spirocycloalkyl" as used herein means a non-aromatic hydrocarbon residue containing at least two rings fused at a single carbon atom containing 5 to 10 carbon atoms. Spirocycloalkyl may be substituted or unsubstituted and includes, but is not limited to, spiropentyl, spirohexyl, spiroheptyl or cyclooctyl. That is, the "spirocycloalkyl" means a polycyclic hydrocarbon, which shares atoms (called spiro atoms) between monocyclic rings. They may contain one or more double bonds, but none of the atoms in the rings has a fully conjugated pi-electron system.

The term "C _3-7 heterocycloalkyl" in the present invention includes saturated monocyclic and polycyclic heterocyclic rings containing 1 to 4 heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S), or ring structures in which two or more rings share one or more pairs of carbon atoms (e.g., fused ring, spiro ring, bridged ring, etc.). Heterocycloalkyl is oxetanyl, morpholinyl, thiomorpholinyl, furyl, piperazinyl, pyranyl, 1,3-dioxanyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, thietanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one-yl, tetrahydro-1H-oxazolo[3,4-a]pyrazin-3( 5H )-one-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-yl, Including, but not limited to, 3-oxa-8-azabicyclo[3.2.1]octan-yl, hexahydro-2H-furo[3,2-b]pyrrole, azetidinyl, etc. In addition, the heterocycloalkyl may be substituted or unsubstituted, and when substituted, may be substituted with -OH, -O-(C _1-4 alkyl), C _1-4 alkanol, C _1-4 alkyl, halogen, -CN, -NH _2, C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, -NH-(C _3-7 heterocycloalkyl), -O-(C _3-7 heterocycloalkyl), C _2-12 heteroaryl, -C _1-4 alkyl-CN, -NO ₂ , C _1-4 haloalkyl, -(C _1-4 alkyl)-O-(C _1-4 alkyl), C _1-4 alkenyl, C _1-4 alkynyl, or NHC(=O)-(C _3-8 cycloalkyl), and each substituent may follow any definition regulation for each substituent mentioned in the present specification. When nitrogen is present in the heterocycloalkyl ring, it may exist in an oxidized state (i.e., N+-O-) as long as the properties of the adjacent atoms and groups permit. Examples include piperidinyl N-oxide and morpholinyl-N-oxide. In addition, when sulfur is present in the heterocycloalkyl ring, it may exist in an oxidized state (i.e., S+-O- or -SO ₂ -) as long as the properties of the adjacent atoms and groups permit. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. In addition, one ring of the polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl) if the polycyclic heterocycloalkyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. Examples of polycyclic heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are described below.

The term "C _3-7 heterocycloalkenyl" as used herein refers to a monovalent radical of an unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S), which is not aromatic. The unsaturated heterocycle includes not only a monocyclic ring, a polycyclic ring, or a spirocyclic ring, but also a form fused with an aromatic hydrocarbon ring such as benzene, and may be bonded via a heteroatom or a carbon atom. Examples of such heterocycloalkenyl radicals may include monovalent radicals of non-aromatic unsaturated heterocycles such as tetrahydropyridinyl, dihydropyrrolyl, dihydrofuranyl, dihydropyranyl, 3H-indolyl, dihydroisoxazolyl, dihydropyrazolyl, 2H-pyrrolyl, and 2H-pyranyl. In addition, the heterocycloalkenyl may be substituted or unsubstituted, and when substituted, may be substituted with -C _1-4 alkyl, halogen, -O-(C _1-4 alkyl), C _1-4 alkanol, -OH, -CN, -NH ₂ , -NO ₂ , C _1-4 haloalkyl, -(C _1-4 alkyl)-O-(C _1-4 alkyl), C _1-4 alkenyl, C _1-4 alkynyl, -C _1-4 alkyl-CN, NHC(=O)-(C _3-8 cycloalkyl), or NH-(C _3-7 heterocycloalkyl), and each substituent may follow any definition regulation for each substituent mentioned in the present specification.

The term “C _1-4 alkanol” in the present invention means a C _1-4 straight-chain or branched-chain aliphatic alcohol, such as methanol, ethanol, isopropanol, etc.

The term “C _1-4 alkenyl” as used herein means an unsaturated branched, straight-chain or cyclic alkyl radical of C _1-4 having at least one carbon-carbon double bond obtained by removing one hydrogen atom from a single carbon atom of a parent alkene. The radical can be in the cis or trans form with respect to the double bond. Representative alkenyl groups include, but are not limited to, ethenyl (-CH=CH ₂ ), 1-propenyl (-CH ₂ CH=CH ₂ ), isopropenyl [-C(CH ₃ )=CH ₂ ], butenyl, and the like.

The term “C _1-4 alkynyl” as used herein means an unsaturated branched, straight-chain or cyclic alkyl radical of C _1-4 having at least one carbon-carbon double bond obtained by removing one hydrogen atom from a single carbon atom of a parent alkyne. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadienyl, and the like.

In the present invention, the term "enantiomer" refers to a case where two molecules having optical activity form a mirror-symmetric relationship. It is generally used as a synonym for mirror image isomer, and includes the forms of R-form, S-form, or racemic compounds, respectively.

Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms defined in commonly used dictionaries, such as those defined in common dictionaries, should be interpreted as having a meaning consistent with the meaning they have in the context of the relevant art, and will not be interpreted in an idealized or overly formal sense unless expressly defined in this application.

Novel pyrazolopyrimidine compounds, optical isomers thereof, or pharmaceutically acceptable salts thereof

To solve the above-mentioned technical problem, the present invention provides a compound represented by the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In the above chemical formula 1,

R ₁ is any one selected from the group consisting of C _3-8 cycloalkyl, C _5-10 spirocycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, C _1-4 alkyl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _1-4 alkyl-C _3-8 cycloalkyl, L ₁ -C _5-10 spirocycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl;

wherein the C _3-8 cycloalkyl, C _5-10 spirocycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _1-4 alkyl-C _3-8 cycloalkyl, L ₁ -C _5-10 spirocycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl are unsubstituted or substituted with at least one or more of -OH, -O-(C _1-4 alkyl), C _1-4 alkanol, C _1-4 alkyl, halogen, -CN, -NH _2, C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, -NH-(C _3-7 heterocycloalkyl), -O-(C _3-7 heterocycloalkyl), C _2-12 heteroaryl or -C _1-4 alkyl-CN is substituted;

wherein L ₁ is any one selected from the group consisting of -NR _a -, -NR _b C(=O)-, -C(=O)-, -O-, and -S-, wherein R _a and R _b are each independently -H or -C _1-4 alkyl;

is C _6-12 aryl or C _2-12 heteroaryl,

R ₂ is any one selected from the group consisting of halogen, C _1-4 alkyl, -O-(C _1-4 alkyl), -O-(C _1-4 alkylene)-(C _6-12 aryl), -C _1-4 alkanol, -CN, -OH, -NH ₂ , -NH-(C _1-4 alkyl), -N(C _1-4 alkyl)-(C _1-4 alkyl), -NO ₂ and C _1-4 haloalkyl;

n is an integer of 0, 1, or 2; and

Cy ₁ is unsubstituted or substituted C _3-8 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C _3-7 heterocycloalkyl comprising at least one N or O, C _3-7 heterocycloalkenyl or C _2-12 heteroaryl, wherein said substitution can be with at least one or more of -C _1-4 alkyl, halogen, -O-(C _1-4 alkyl), C _1-4 alkanol, -OH, -CN, -NH ₂ , -NO ₂ , C _1-4 haloalkyl, -(C _1-4 alkyl)-O-(C _1-4 alkyl), C _1-4 alkenyl, C _1-4 alkynyl, -C _1-4 alkyl-CN, NHC(=O)-(C _3-8 cycloalkyl), or NH-(C _3-7 heterocycloalkyl).

Specifically, in the C _3-8 cycloalkyl, C _5-10 spirocycloalkyl, C _3-7 heterocycloalkyl, C _3-7 heterocycloalkenyl, C _6-12 aryl, C _2-12 heteroaryl, C _1-4 alkyl, L ₁ -C _3-8 cycloalkyl, L _{1 -C 1-4} alkyl-C _3-8 cycloalkyl, L ₁ -C _5-10 spirocycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L _{1 -C 6-12} aryl and L ₁ -C _2-12 heteroaryl mentioned in the above R 1 , A or Cy 1 , C _3-8 cycloalkyl, C _5-10 spirocycloalkyl, C _3-7 heterocycloalkyl, C _3-7 heterocycloalkenyl, C _6-12 Aryl, C _2-12 heteroaryl, C _1-4 alkyl can be selected from the specific substituents mentioned below. The ones to which L ₁ is connected are omitted to minimize repetitive description:

The above C _3-8 cycloalkyl may be any one selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The above C _5-10 spirocycloalkyl may be any one selected from the group consisting of spiropentyl, spirohexyl, spiroheptyl and cyclooctyl.

The above C _3-7 heterocycloalkyl may be any one selected from the group consisting of oxetanyl, azetidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, thietanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one-yl, 3-oxa-8-azabicyclo[3.2.1]octan-yl, and hexahydro-2H-furo[3,2-b]pyrrole.

The above C _3-7 heterocycloalkenyl may be any one selected from the group consisting of tetrahydropyridinyl, dihydropyrrolyl, dihydrofuranyl, dihydropyranyl, 3H-indolyl, dihydroisoxazolyl, dihydropyrazolyl, 2H-pyrrolyl and 2H-pyranyl.

The above C _2-12 heteroaryl may be any one selected from the group consisting of thiophenyl, furanyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyranyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyridonyl, pyrimidinyl, benzofuranyl, benzothiophenyl, isobenzofuranyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoisooxazolyl, benzoxazolyl, isoindolyl, indolyl, indazolyl, benzothiadiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, carbazolyl, and benzodioxozolyl.

The above C _6-12 aryl may be any one selected from the group consisting of phenyl, naphthalenyl, indenyl, pentarenyl and azulenyl.

The above C _1-4 alkyl may be any one selected from the group consisting of methyl, ethyl, propyl, and butyl.

More specifically, said R ₁ is composed of C _1-4 alkyl, unsubstituted or substituted cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, spiroheptyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, oxopyridinyl, phenyl, quinolyl, isoquinolyl, L ₁ -cyclopropyl, L 1 -cyclobutyl, L ₁ -cyclohexyl, L ₁ -cycloheptyl, L ₁ -C _1-4 alkyl-cyclopropyl, L ₁ -spiroheptyl, L ₁ -tetrahydrofuranyl, L ₁ -tetrahydropyranyl, L ₁ -piperidinyl, L ₁ -piperazinyl, L ₁ -pyridonyl, L ₁ -pyridinyl, L ₁ -phenyl, L ₁ -quinolyl, and L ₁ -isoquinolyl _. Any one selected from the group consisting of: -OH, -C _1-4 alkyl, halogen, -CN, -NH _2, C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, -NH-(C _3-7 heterocycloalkyl), -O-(C _3-7 heterocycloalkyl), C _2-12 heteroaryl or -C _1-4 alkyl-CN.

More specifically, R ₁ is methyl, ethyl, unsubstituted or substituted , , , , , , , , , , , , , , and is any one selected from the group consisting of, wherein said substitution can be substitution with at least one or more of -OH, -C _1-4 alkyl, halogen, -CN, -NH _2, C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, -NH-(C _3-7 heterocycloalkyl), -O-(C _3-7 heterocycloalkyl), C _2-12 heteroaryl or -C _1-4 alkyl-CN.

More specifically, said R ₁ is any one selected from the group consisting of methyl, unsubstituted or substituted cyclopropyl, cyclohexyl, piperidinyl, tetrahydro-2H-pyranyl, quinolyl, isoquinolyl, -NHC(=O)-cyclopropyl, -NHC(=O)-methyl-cyclopropyl, -NH-cyclopropyl, -NH-cyclohexyl, -NH-cycloheptyl, -NH-spiroheptyl, -NHC(=O)-tetrahydro-2H-pyranyl, -NH-tetrahydro-2H-pyranyl, -NH-phenyl, -NH-piperidinyl, -NH-pyridinyl, -NH-pyridonyl, -NH-quinolyl, -NH-isoquinolyl, and -NC ₂ H ₅ -cyclopropyl, wherein said substitution is at least one or more of methyl, NH ₂ , It can be substituted with pyridinyl, piperazinyl, -NH-tetrahydro-2H-pyranyl, piperidinyl, piperidinyl-CH ₃ , -O-piperidinyl, triazolyl, triazolyl-CH ₃ , -CH ₂ -CN.

Specifically, the L ₁ is -NR _a -, or -NR _b C(=O)-, wherein R _a and R _b can each independently be -H or -C _1-4 alkyl.

Specifically, the R ₂ may be any one selected from the group consisting of fluorine (F), chlorine (Cl), methyl, ethyl, methoxy, ethoxy, -O-methylene-phenyl, -O-ethylene-phenyl =O, -CN, -OH, -NH ₂ , NH-CH ₃ , NH-C ₂ H ₅ , NH-C ₃ H ₇ , N-CH ₃ -CH ₃ , NC ₂ H ₅ -CH ₃ , NC ₂ H ₅ -C ₂ H ₅ , and trifluoromethyl (CF ₃ ).

Specifically, the Cy ₁ may be any one selected from the group consisting of unsubstituted or substituted cyclopropyl, dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, pyrrolidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzoimidazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl and benzoisothiazolyl, and benzothiadiazolyl.

More specifically, the Cy ₁ may be any one selected from the group consisting of unsubstituted or substituted cyclopropyl, tetrahydropyranyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indazolyl, benzoimidazolyl, benzotriazolyl, benzoxadiazolyl, and benzothiadiazolyl.

More specifically, the Cy ₁ is unsubstituted or substituted , , , , , , , , , , , , , , , , and It can be any one selected from the group consisting of .

Specifically, the A may be any one selected from the group consisting of phenyl, thiophenyl, furanyl, thiazolyl, oxazolyl, pyridinyl and 2-pyridonyl.

The compound represented by the above chemical formula 1 may be any one selected from the group consisting of compounds represented by the following chemical formulas 2 to 4:

[Chemical formula 2]

[Chemical Formula 3]

[Chemical Formula 4]

In the above chemical formulas 2 to 4,

R ₁ is any one selected from the group consisting of C _3-8 cycloalkyl, C _5-10 spirocycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, C _1-4 alkyl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _1-4 alkyl-C _3-8 cycloalkyl, L ₁ -C _5-10 spirocycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl,

wherein the C _3-8 cycloalkyl, C _5-10 spirocycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _1-4 alkyl-C _3-8 cycloalkyl, L ₁ -C _5-10 spirocycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl are unsubstituted or substituted with at least one or more of -OH, -O-(C _1-4 alkyl), C _1-4 alkanol, C _1-4 alkyl, halogen, -CN, -NH _2, C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, -NH-(C _3-7 heterocycloalkyl), -O-(C _3-7 heterocycloalkyl), C _2-12 heteroaryl or -C _1-4 alkyl-CN is substituted;

wherein L ₁ is any one selected from the group consisting of -NR _a -, -NR _b C(=O)-, -C(=O)-, -O-, and -S-, wherein R _a and R _b are each independently -H or -C _1-4 alkyl;

is an unsubstituted or substituted C _6-12 aryl or C _2-12 heteroaryl;

R ₂ is any one selected from the group consisting of halogen, C _1-4 alkyl, -O-(C _1-4 alkyl), -O-(C _1-4 alkylene)-(C _6-12 aryl), -C _1-4 alkanol, -CN, -OH, -NH ₂ , -NH-(C _1-4 alkyl), -N(C _1-4 alkyl)-(C _1-4 alkyl), -NO ₂ and C _1-4 haloalkyl;

n is an integer of 0, 1, or 2; and

Cy ₁ is unsubstituted or substituted C _3-8 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C _3-7 heterocycloalkyl comprising at least one N or O, C _3-7 heterocycloalkenyl or C _2-12 heteroaryl, wherein said substitution can be with at least one or more of C _1-4 alkyl, halogen, -O-(C _1-4 alkyl), C _1-4 alkanol, -OH, -CN, -NH ₂ , -NO ₂ , C _1-4 haloalkyl, -(C _1-4 alkyl)-O-(C _1-4 alkyl), C _1-4 alkenyl, C _1-4 alkynyl, -C _1-4 alkyl-CN, NHC(=O)-(C _3-8 cycloalkyl), or NH-(C _3-7 heterocycloalkyl).

In the above chemical formulas 2 to 4, Cy ₁ is any one selected from the group consisting of unsubstituted or substituted cyclopropyl, dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydropyranyl, imidazolyl, triazolyl, pyrazolyl, oxazolyl, oxadiazolyl, phenyl, pyridinyl, pyrimidinyl, and piperidinyl, wherein the substitution may be substitution with at least one or more of C _1-4 alkyl, halogen, C _1-4 haloalkyl, -(C _1-4 alkyl)-O-(C _1-4 alkyl), C _1-4 alkanol, C _1-4 alkenyl, C _1-4 alkyl-CN, C _1-4 alkynyl, NHC(=O)-(C _3-8 cycloalkyl), NH-(C _3-7 heterocycloalkyl).

In the above chemical formulas 2 to 4, the R ₁ is any one selected from the group consisting of methyl, unsubstituted or substituted cyclopropyl, cyclohexyl, piperidinyl, tetrahydro-2H-pyranyl, quinolyl, isoquinolyl, -NHC(=O)-cyclopropyl, -NHC(=O)-methyl-cyclopropyl, -NH-cyclopropyl, -NH-cyclohexyl, -NH-cycloheptyl, -NH-spiroheptyl, -NHC(=O)-tetrahydro-2H-pyranyl, -NH-tetrahydro-2H-pyranyl, -NH-phenyl, -NH-piperidinyl, -NH-pyridonyl, -NH-quinolyl, -NH-isoquinolyl, and -NC ₂ H ₅ -cyclopropyl, wherein the substitution is at least one or more of methyl, NH ₂ , pyridinyl, It can be substituted with piperazinyl, -NH-tetrahydro-2H-pyranyl, piperidinyl, piperidinyl-CH ₃ , -O-piperidinyl, triazolyl, triazolyl-CH ₃ , -CH ₂ -CN.

The compound represented by the above chemical formula 2 may be any one selected from the group consisting of compounds represented by the following chemical formulas 2-1 to 2-7:

[Chemical Formula 2-1]

[Chemical Formula 2-2]

[Chemical Formula 2-3]

[Chemical Formula 2-4]

[Chemical Formula 2-5]

[Chemical Formula 2-6]

[Chemical Formula 2-7]

In chemical formulas 2-1 to 2-7,

R ₁ is any one selected from the group consisting of C _3-8 cycloalkyl, C _5-10 spirocycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, C _1-4 alkyl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _1-4 alkyl-C _3-8 cycloalkyl, L ₁ -C _5-10 spirocycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl;

wherein the C _3-8 cycloalkyl, C _5-10 spirocycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _1-4 alkyl-C _3-8 cycloalkyl, L ₁ -C _5-10 spirocycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl are unsubstituted or substituted with at least one or more of -OH, -O-(C _1-4 alkyl), C _1-4 alkanol, -C _1-4 alkyl, halogen, -CN, -NH _2, =O, C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, -NH-(C _3-7 substituted with -O-(C _3-7 heterocycloalkyl), C _2-12 heteroaryl or -C _1-4 alkyl-CN;

wherein L ₁ is any one selected from the group consisting of -NR _a -, -NR _b C(=O)-, -C(=O)-, -O-, and -S-, wherein R _a and R _b are each independently -H or -C _1-4 alkyl;

R ₂ is any one selected from the group consisting of halogen, C _1-4 alkyl, -O-(C _1-4 alkyl), -C _1-4 alkanol, -CN, -OH, -NH ₂ , -NH-(C _1-4 alkyl), -NO ₂ and C _1-4 haloalkyl;

R ₃ is any one selected from the group consisting of C _1-4 alkyl, halogen, -O-(C _1-4 alkyl), C _1-4 alkanol, -OH, -CN, -NH ₂ , -NO ₂ , C _1-4 haloalkyl, -(C _1-4 alkyl)-O-(C _1-4 alkyl), C _1-4 alkenyl, C _1-4 alkynyl, -C _1-4 alkyl-CN, NHC(=O)-(C _3-8 cycloalkyl), or NH-(C _3-7 heterocycloalkyl);

n and m are integers 0, 1, or 2;

X ₁ is carbon or nitrogen; and

Y ₁ and Y ₂ are NC _1-4 alkyl or NH.

Specifically, in the chemical formulae 2 to 4 and/or 2-1 to 2-4, the ring containing X ₁ may be oxazole or oxadiazole.

Specifically, in the chemical formula 3, R ₁ is L ₁ -C _3-8 cycloalkyl or L ₁ -C _1-4 alkyl-C _3-8 cycloalkyl, wherein L ₁ is -NR _a -, or -NR _b C(=O)-, wherein R _a and R _b can each independently be -H or -C _1-4 alkyl. In addition, Cy ₁ can be any one selected from unsubstituted or substituted imidazole or triazole.

Specifically, in the chemical formula 4, R ₁ is C _3-8 cycloalkyl, and Cy ₁ can be any one selected from unsubstituted or substituted imidazole or triazole.

In addition, the compound represented by the chemical formula 1 may be any one selected from compounds represented by the following chemical formulas 5 to 7:

[Chemical Formula 5]

[Chemical formula 6]

[Chemical formula 7]

In the above chemical formulas 5 to 7,

R ₁ is any one selected from the group consisting of C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl;

wherein said C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl are unsubstituted or substituted with at least one or more of -OH, -C _1-4 alkyl, halogen, or -CN;

wherein L ₁ is any one selected from the group consisting of -NR _a -, -NR _b C(=O)-, -C(=O)-, -O-, and -S-, wherein R _a and R _b are each independently -H or -C _1-4 alkyl;

R ₂ is any one selected from the group consisting of halogen, -C _1-4 alkyl, -O(C _1-4 alkyl), -CN, -OH, -NH ₂ , -NO ₂ and -C _1-4 haloalkyl;

n is an integer of 0, 1, or 2;

X ₂ is one selected from nitrogen, oxygen and sulfur,

X ₃ is any one selected from carbon, nitrogen, oxygen and sulfur; and

Cy ₁ is an unsubstituted or substituted 5- or 6-membered aromatic ring containing at least one N, wherein the substitution can be at least one of -C _1-4 alkyl, halogen, -O(C _1-4 alkyl), -OH, -CN, -NH ₂ , -NO ₂ , or -C _1-4 haloalkyl.

Specifically, in the chemical formula 5, R ₁ is C _3-8 cycloalkyl, and Cy ₁ may be any one selected from unsubstituted or substituted imidazole or triazole. In addition, the ring comprising X ₂ and X ₃ may be any one of thiophene, furan, thiazole, or oxazole.

Specifically, in the chemical formula 6, R ₁ is C _3-8 cycloalkyl, and Cy ₁ may be any one selected from the group consisting of unsubstituted or substituted pyridine, imidazole, and triazole.

Specifically, in the chemical formula 7, R ₁ is C _3-8 cycloalkyl, and Cy ₁ may be any one selected from the group consisting of unsubstituted or substituted pyridine, imidazole, and triazole.

According to a specific example of the present invention, the compound represented by the chemical formula 1 may be any one selected from the group consisting of compounds described below:

5-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1H-imidazol-2-yl)phenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide);

N-(3-(1H-imidazol-2-yl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-chloro-5-(4-methyl-1H-imidazol-1-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide);

5-cyclopropyl-N-(3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(5-fluoropyrimidin-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(5-fluoropyrimidin-2-yl)-4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(5-fluoropyridin-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-methoxy-5-(4-methyl-1H-imidazol-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(2-methoxy-3-(4-methyl-1H-imidazol-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1H-imidazol-2-yl)-2-methoxyphenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-amino-5-(1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(1-methyl-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(1-(2-methoxyethyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(1-(2,2-difluoroethyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1H-imidazol-5-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide);

5-cyclopropyl-N-(3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(oxazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(2-oxo-2H-[1,2'-bipyridin]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-fluoro-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-cyano-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)pyrazolo[1,5-a] pyrimidine-3-carboxamide;

N-(3-(1H-imidazol-2-yl)phenyl)-5-(cyclopropanecarboxamido)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-(cyclopropanecarboxamido)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1H-imidazol-2-yl)phenyl)-6-(cyclopropanecarboxamido)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

6-(cyclopropanecarboxamido)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

6-(2-cyclopropylacetamido)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1H-imidazol-2-yl)phenyl)-6-(2-cyclopropylacetamido)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-(cyclopropylamino)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

N-(3-(1H-imidazol-2-yl)phenyl)-5-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

N-(3-(1H-imidazol-2-yl)phenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(tetrahydro-2H-pyran-4-carboxamido)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(quinolin-8-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1H-imidazol-2-yl)phenyl)-5-(cyclopropyl(ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-(cyclopropyl(ethyl)amino)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-(cyclopropylamino)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(phenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(spiro[3.3]heptan-2-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

5-(cyclopropylamino)-N-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-(cyclopropylamino)-N-(3-(oxazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(oxazol-2-yl)phenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-(4-(cyanomethyl)piperidin-1-yl)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-(((1S,2R)-2-aminocyclohexyl)amino)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(pyrimidin-5-yl)phenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-(cycloheptylamino)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-(isoquinolin-8-yl)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

5-cyclopropyl-N-(3-(4,5-dichloro-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-fluoro-5-(1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(4-(1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide);

5-cyclopropyl-N-(2-methoxy-3-(1-methyl-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(pyrimidin-5-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-amino-5-(1-methyl-1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide);

N-(3-amino-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(1-(2-hydroxyethyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(6-methoxypyridin-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3'-cyano-[1,1'-biphenyl]-3-yl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(4'-(cyclopropylcarbamoyl)-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(4-((tetrahydro-2H-pyran-4-yl)amino)piperidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1-(cyanomethyl)-1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide);

5-cyclopropyl-N-(2'-vinyl-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1H-imidazol-2-yl)phenyl)-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

N-(3-(1H-imidazol-2-yl)phenyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

5-cyclohexyl-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(methylamino)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(4-((tetrahydro-2H-pyran-4-yl)amino)piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-((1-methylpiperidin-4-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

5-cyclopropyl-N-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-((1-(cyanomethyl)piperidin-4-yl)amino)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(5-(1H-imidazol-2-yl)pyridin-3-yl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-3-carboxamide;

N-(3-(1H-imidazol-2-yl)-5-(methylamino)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-cyclopropyl-N-(3-(dimethylamino)-5-(1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1H-imidazol-2-yl)-5-(isopropylamino)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-cyclopropyl-5-methoxyphenyl)-5-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-cyclopropyl-5-methoxyphenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-cyclopropyl-5-hydroxyphenyl)-5-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-cyclopropyl-5-hydroxyphenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-methoxy-5-(tetrahydro-2H-pyran-4-yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-(cyclopropylamino)-N-(3-methoxy-5-(tetrahydro-2H-pyran-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-(benzyloxy)-5-(3,6-dihydro-2H-pyran-4-yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(pyridin-2-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

N-(3-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(1-methylpiperidin-4-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(pyridin-2-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

N-(3-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

N-(3-hydroxy-5-(tetrahydro-2H-pyran-4-yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(1-methylpiperidin-4-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide);

5-(Cyclopropylamino)-N-(3-methoxy-5-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-(cyclopropylamino)-N-(3-hydroxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-hydroxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-hydroxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(1-methylpiperidin-4-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide); and

N-(3-hydroxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(pyridin-2-yl)phenyl)amino) pyrazolo[1,5-a]pyrimidine-3-carboxamide.

In the present invention, pharmaceutically acceptable salts mean salts commonly used in the pharmaceutical industry, and include, for example, inorganic ion salts manufactured with calcium, potassium, sodium, and magnesium; inorganic acid salts manufactured with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, and sulfuric acid; organic acid salts manufactured with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, and hydroiodonic acid; sulfonic acid salts manufactured with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid; Amino acid salts manufactured from glycine, arginine, lysine, etc.; and amine salts manufactured from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc.; however, the types of salts meant in the present invention are not limited by these listed salts.

Pharmaceutical composition

In another aspect of the present invention, a pharmaceutical composition is provided comprising a compound represented by formula 1 as defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

In another aspect of the present invention, a pharmaceutical composition is provided, comprising a compound represented by formula 1 as defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier, and may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods.

The pharmaceutically acceptable carriers include, but are not limited to, those commonly used in the art, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, the pharmaceutical composition of the present invention may include, but is not limited to, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants, and other pharmaceutically acceptable additives.

In another aspect of the present invention, a pharmaceutical composition for preventing or treating a TYK2-mediated disease is provided, comprising a compound represented by formula 1 as defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

The above TYK2-mediated disease means one or more diseases or disorders associated with the activity of TYK2 or a mutant thereof, and the diseases or disorders include, but are not limited to, autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, and diseases associated with transplantation.

The above autoimmune disease may be, but is not limited to, psoriasis, rheumatoid arthritis, vasculitis, Behcet's disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, dermatitis, osteoarthritis, asthma, inflammatory myopathy, allergic disease, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplant rejection, graft-versus-host disease (GVHD), systemic lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, or atopic dermatitis.

The above inflammatory diseases include, but are not limited to, sepsis, acute sepsis, alopecia, hair loss syndrome, gout, arthritis, rheumatoid arthritis, sclerosis, inflammatory bowel disease, ankylosing spondylitis (AS), antiphospholipid antibody syndrome (APS), myositis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, vasculitis, familial Mediterranean fever, neonatal-onset multisystem inflammatory disease, Behcet's disease, dermatitis, type 1 diabetes, autoimmune diseases, psoriasis, psoriatic arthritis, dermatitis herpetiformis, pemphigus vulgaris, vitiligo, multiple sclerosis, systemic sclerosis, Addison's disease, Graves' disease, Hashimoto's disease, myasthenia gravis, Guillain-Barre syndrome, autoimmune uveitis, autoimmune hemolytic anemia It can be any of the following: hemolytic anemia, Wegener's granulomatosis, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, celiac disease, chronic inflammation, rheumatism, encephalomyelitis, postinfectious cerebellitis, neuromyelitis optica, Devic's disease, encephalitis, metabolic encephalopathy, asthma, periodontitis, ulcerative colitis, interstitial fibromas in the lung, myelofibrosis, liver fibrosis, myocarditis, primary biliary cirrhosis, Crohn's disease, sinusitis, orchitis, polymyositis, dermatomyositis, autoimmune oophoritis, autoimmune adrenalitis, systemic lupus erythematosus, scleroderma, or peptic ulcer.

The proliferative disease may be, but is not limited to, any one of blood cancers, leukemia (e.g., T-cell leukemia, T-cell acute lymphoblastic leukemia (T-ALL)), polycythemia vera, myelofibrosis, or essential thrombocythemia.

The above endocrine diseases may include, but are not limited to, polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

The neurological diseases include, but are not limited to, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth (CMT; including type 4J (CMT4J)), Yunis-Varon syndrome, autophagy, congenital brain lesions, polymicrogyria, temporo-occipital polymicrogyria, Pick's disease, Parkinson's disease, Parkinson's disease with Lewy bodies, dementia with Lewy bodies, Lewy body disease, fronto-temporal dementia, diseases of neuronal nuclear inclusions of polyglutamine and intranuclear inclusions. polyglutamine and intranuclear inclusion bodies), disease of Marinesco and Hiranobodies, tauopathy, Alzheimer's disease, neurodegeneration, spongiform neurodegeneration, peripheral neuropathy, leukoencephalopathy, motorneuropathy, sensoryneuropathy, inclusion body disease, progressive supranuclearpalsy, corticobasal syndrome, chronic traumatic encephalopathy, traumatic braininjury (TBI), cerebralischemia, Guillain-Barre Syndrome, chronic inflammatory demyelinating polyneuropathy demyelinating polyneuropathy, multiple sclerosis, Niemann-Pick C disease, Tay-Sachs disease, Mucolipidosis type IV, Mucolipidosis type V, neuropathy, Huntington's disease, apsychiatric disorder, ADHD, schizophrenia, mood disorder, major depressive disorder, depression, bipolar disorder I, bipolar disorder II. FTD, orchronictraumatic encephalopathy, Fabry's disorder, Gaucher's disorder, or progressive muscle atrophy.

Diseases associated with the above transplantation may include, but are not limited to, graft rejection or graft-versus-host disease.

The term “prevention” in the present invention means any act of inhibiting or delaying the onset of a TYK2-mediated disease by administration of the composition.

The term “treatment” in the present invention means any action by which the symptoms of the disease are improved or beneficially changed by administration of the composition.

The pharmaceutical composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method, and the dosage varies depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and type and severity of the disease.

The route of administration of the pharmaceutical composition of the present invention may be administered to mammals such as rats, mice, livestock, and humans through any general route as long as it can reach the target tissue, but is not limited thereto, and may be administered by subcutaneous injection using an osmotic pump, intradermal injection, intravein injection, intraperitoneal injection, intravitreal injection, intrathecal, inner ear, abdominal cavity, or intravenous, muscular, subcutaneous, intrauterine epidural, sublingual, or intracerebrovascular injection.

The pharmaceutical composition of the present invention may contain 0.001 to 95 wt%, preferably 0.01 to 80 wt%, of the compound represented by chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.

When the pharmaceutical composition of the present invention is formulated as an oral solid preparation, it includes tablets, pills, powders, granules, capsules, etc., and such solid preparations may include at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., and include, but are not limited to, lubricants, such as magnesium stearate and talc.

When the pharmaceutical composition of the present invention is formulated as an oral liquid, it includes a suspension, an oral solution, an emulsion, a syrup, etc., and includes, but is not limited to, a diluent such as water or liquid paraffin, a wetting agent, a sweetener, an air freshener, a preservative, etc.

When the pharmaceutical composition of the present invention is formulated for parenteral use, it includes a sterile aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilized preparation, and a suppository. Non-aqueous solvents and suspensions include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Bases for suppositories include, but are not limited to, witepsol, macrogol, Tween 61, cacao butter, laurin butter, and glycerogelatin.

In another aspect of the present invention, a TYK2 inhibitor is provided, comprising a compound represented by formula 1 as defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

In one aspect of the present invention, a method of treating a TYK2-mediated disease is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula 1 as defined in any embodiment described herein, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

In the present invention, the term “compound represented by chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof” or “TYK2-mediated disease” is as described above.

The term "subject" of the present invention means any animal that has developed or may develop a TYK2-mediated disease, and typically may be an animal that can exhibit a beneficial effect by treatment with a compound represented by Chemical Formula 1 of the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, but includes, without limitation, a subject that has symptoms of a TYK2-mediated disease or may have such symptoms. As described above, by administering the pharmaceutical composition of the present invention to a subject, the above-described disease can be effectively prevented or treated. The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent, or can be administered in combination with existing therapeutic agents for TYK2-mediated diseases, and can be administered sequentially or simultaneously with the existing therapeutic agents.

The term "therapeutically effective amount" as used herein means an amount sufficient to prevent or treat a disease at a reasonable benefit/risk ratio applicable to medical prevention or treatment, and refers to an amount of a compound represented by Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof that is effective for the prevention or treatment of said disease. The effective dosage level can be determined depending on factors including the severity of the disease, the activity of the drug, the age, weight, health, sex of the patient, the sensitivity of the patient to the drug, the time of administration of the composition of the present invention used, the route of administration and the excretion rate, the treatment period, drugs combined with or used simultaneously with the composition of the present invention used, and other factors well known in the medical field. For example, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof can be administered at 0.0001 to 100 mg/kg per day, and the administration can be administered once a day or in several divided doses.

The term "administration" of the present invention means introducing a predetermined substance into a patient by an appropriate method, and the route of administration of the composition may be administered through any general route as long as it can reach the target tissue. In addition, the pharmaceutical composition of the present invention may be administered by any device through which the active substance can move to the target tissue. For example, it may be administered by oral administration, intrathecal administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, inner ear administration, intrauterine epidural administration, sublingual administration, and intracerebrovascular injection, but is not limited thereto. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories.

The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. Taking all of the above factors into consideration, it may be administered in an amount that can obtain the maximum effect with the minimum amount without causing side effects, which can be easily determined by those skilled in the art.

The method of treatment of the present invention includes not only treating the disease itself before the onset of symptoms, but also inhibiting or avoiding the symptoms thereof by administering a compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. In the management of a disease, the prophylactic or therapeutic dosage of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. The dosage and frequency of administration will vary depending on the age, weight and response of the individual patient. Appropriate dosage regimens can be readily selected by one skilled in the art, taking these factors into consideration. In addition, the treatment method of the present invention may further include administration of a therapeutically effective amount of an additional active agent helpful in treating a disease together with the compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the additional active agent may exhibit a synergistic or auxiliary effect together with the compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a use of a compound represented by the chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating a TYK2-mediated disease.

In addition, the present invention provides a compound represented by the chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the prevention or treatment of a TYK2-mediated disease.

In addition, the present invention provides a pharmaceutical composition comprising a compound represented by the chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the prevention or treatment of a TYK2-mediated disease.

In addition, the present invention provides the use of a compound represented by the chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the prevention or treatment of a TYK2-mediated disease.

The present invention is a novel compound having excellent inhibitory activity against TYK2, and thus can be usefully utilized as a therapeutic agent for TYK2-mediated diseases such as autoimmune diseases.

Hereinafter, in order to help understand the present invention, examples and the like will be described in detail. However, the examples according to the present invention may be modified in various different forms, and the scope of the present invention should not be construed as being limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to a person having average knowledge in the art.

The reagents and solvents mentioned below were purchased from Merck KGaA, TCI, BLDpharm, Enamine, Combi-Blocks, etc., unless otherwise specified, and structural analysis and purification were performed under the following conditions.

1. HPLC analysis conditions (A)

Device name: Shimadzu

Column: YMC-pack pro C18, 150x4.6mm I.D., 5 νm, 40℃

Mobile phase: 5% -> 100% acetonitrile/ _H2O + 0.1% trifluoroacetic acid,

Analysis time: 9 minutes, flow rate: 1 ml/min

UV detector: 254nm

2. HPLC analysis conditions (B)

Device Name: Thermo Scientific Ultimate 3000RSLC

Column: Kinetex® 2.6 νM Biphenyl 100Å, 100x2.1mm

Mobile phase: 5% -> 100% acetonitrile/ _H2O + 0.1% trifluoroacetic acid,

Analysis time: 8 minutes, flow rate: 0.7 ml/min

UV detector: 254nm

3. LC-MS analysis conditions

Device name: Shimadzu LCMS-2020

Column: ACE Excel2 C18, 75x2.1 mm

Mobile phase: Acetonitrile/ _H2O + 0.1% trifluoroacetic acid

Flow rate: 1mL/min

UV detector: 254nm

4. MPLC purification conditions

Device Name: CombiFlash®Rf ⁺

UV detector: 254nm

5. Prep-HPLC purification conditions

Device name: Gilson GX-281, 321 pump, UV/VIS-155

Column: Luna® 10 νM C18 (2) 100 Å, 50x21.2 m

Mobile phase: Acetonitrile/0.1% trifluoroacetic acid _H2O

Flow rate: 15mL/min

UV detector: 254nm

6. ¹ H NMR analysis conditions

Device name: Bruker Avance (400 MHz)

¹ H nuclear magnetic resonance (NMR) spectra were all consistent with the chemical structures of the exemplary compounds in the present invention.

Characteristic chemical shifts (δ) are given in parts-per-million (ppm) relative to residual proton signals in deuterated solvents (CDCl ₃ : 7.26 ppm; CD ₃ OD: 3.31 ppm; DMSO- d ₆ : 2.50 ppm) and are reported with the conventional abbreviations for designating major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.

<Example>

Example 1. Preparation of 5-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

5-Methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 0.282 mmol), 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (68 mg, 0.282 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyrimidinium 3-oxidehexafluorophosphate (107 mg, 0.282 mmol), N,N-diisopropylethylamine (0.148 ml, 0.846 mmol) were dissolved in N,N-dimethylformamide (1 ml), and the mixture was stirred at room temperature for 24 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by Prep HPLC to produce the target compound (18 mg, 20%, pink solid). LC/MS(ESI) m/z: 401 [M+H] ⁺

Examples 2 to 28.

The target compounds of Examples 2 to 28 were prepared by performing similar methods and procedures as those used in Example 1. The relevant compound names, NMR, MS, and HPLC data are summarized in Table 1.

Example 29. Preparation of N-(3-(1H-imidazol-2-yl)phenyl)-5-(cyclopropanecarboxamido)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of N-(3-(1H-imidazol-2-yl)phenyl)-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide

5-Chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (50 mg, 0.231 mmol), 3-(1H-imidazol-2-yl)aniline (37 mg, 0.231 mmol), and triethylamine (0.065 ml, 0.463 mmol) were dissolved in dichloromethane and stirred at room temperature for 16 h. After the reaction was completed, the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to produce the target compound (21 mg, 26%, yellow solid). LC/MS(ESI) m/z: 339 [M+H] ⁺

Step 2: Preparation of N-(3-(1H-imidazol-2-yl)phenyl)-5-(cyclopropanecarboxamido)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-(3-(1H-imidazol-2-yl)phenyl)-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide (21 mg, 0.061 mmol), cyclopropanecarboxyamide (5.2 mg, 0.061 mmol), and potassium carbonate (25 mg, 0.184 mmol) were dissolved in 1,4-dioxene (0.2 mL). Tris(dibenzylideneacetone)dipalladium(0) (5.6 mg, 0.006 mmol) and Xphos (3 mg, 0.006 mmol) were added, and the mixture was stirred at 80 °C for 1 h. After the reaction was completed, the reaction mixture was filtered through a Celite filter and washed with ethyl acetate. After concentration under reduced pressure, the residue was purified by Prep HPLC to produce the target compound (1.3 mg, 9%, white solid). LC/MS(ESI) m/z: 388 [M+H] ⁺

Examples 30 to 37.

The target compounds of Examples 30 to 37 were prepared by performing similar methods and procedures as those used in Example 29 above. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Example 38. Preparation of 5-(cyclopropylamino)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 5-chloro-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to that used in step 1 of the above Example 29. LC/MS (ESI) m/z: 384 [M+H] ⁺

Step 2: Preparation of 5-(cyclopropylamino)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

5-Chloro-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 0.130 mmol), cyclopropanamine (9.5 uL, 0.137 mmol), and diisopropylethylamine (68 uL, 0.391 mmol) were dissolved in acetonitrile and stirred at 70 ℃ for 16 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to produce the target compound (15 mg, 29%, white solid). LC/MS(ESI) m/z: 405 [M+H] ⁺

Examples 39 to 56.

The target compounds of Examples 39 to 56 were prepared by performing similar methods and procedures as those used in Example 38 above. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Example 57. Preparation of 5-(isoquinolin-8-yl)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 5-chloro-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to that used in step 1 of the above Example 29. LC/MS (ESI) m/z: 384 [M+H] ⁺

Step 2: Preparation of 5-(isoquinolin-8-yl)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

5-Chloro-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20 mg, 0.052 mmol), isoquinolin-8-ylboronic acid (11 mg, 0.063 mmol), tetrakis(triphenylphosphine)palladium(0) (3 mg, 2.6 μmol), and sodium hydroxide (6.3 mg, 0.156 mmol) were dissolved in tetrahydrofuran (0.5 ml) and reacted at 80 ℃ for 16 h. After the reaction was complete, the mixture was concentrated and purified by Prep HPLC to obtain the target compound (22 mg, 89%, yellow solid). LC/MS(ESI) m/z: 477 [M+H] ⁺

Example 58. Preparation of 5-cyclopropyl-N-(3-(4,5-dichloro-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 4,5-dichloro-2-(3-nitrophenyl)-1H-imidazole

(3-Nitrophenyl)boronic acid (0.2 g, 1.2 mmol), 2-bromo-4,5-dichloro-1H-imidazole (0.26 g, 1.2 mmol), tripotassium phosphate (0.63 g, 3.59 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (98 mg, 0.12 mmol) were dissolved in 1,4-dioxane (3 mL), water (0.7 ml) was added, and the mixture was stirred at 100 ℃ for 16 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The organic residue was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by MPLC to give the target compound (0.14 g, 45%, yellow solid). LC/MS(ESI) m/z: 259 [M+H] ⁺

Step 2: Preparation of 3-(4,5-dichloro-1H-imidazol-2-yl)aniline

4,5-Dichloro-2-(3-nitrophenyl)-1H-imidazole (0.14 g, 0.541 mmol), iron (91 mg, 1.62 mmol), and 37% hydrochloric acid (0.23 ml, 7.57 mmol) were dissolved in ethanol and reacted at 80 °C for 3 hours. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to produce the target compound (117 mg, 94%, yellow oil). LC/MS(ESI) m/z: 229 [M+H] ⁺

Step 3: Preparation of 5-cyclopropyl-N-(3-(4,5-dichloro-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 414 [M+H] ⁺

Examples 59 and 60.

The target compounds of Examples 59 and 60 were prepared by following similar methods and procedures as those used in Example 58 above. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Example 61. Preparation of 5-cyclopropyl-N-(2-methoxy-3-(1-methyl-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 2-methoxy-3-(1-methyl-1H-imidazol-2-yl)aniline

2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (619 mg, 2.49 mmol), 2-bromo-1-methyl-1H-imidazole (400 mg, 2.49 mmol), cesium carbonate (2.43 g, 7.45 mmol), tetrakis(triphenylphosphine)palladium (0) (287 mg, 0.25 mmol) were dissolved in 1,4-dioxane (2 mL) and reacted at 100 ℃ for 16 h. After the reaction was completed, the mixture was concentrated and purified by MPLC to produce the target compound (199 mg, 39%, pale yellow solid). LC/MS(ESI) m/z: 204 [M+H] ⁺

Step 2: Preparation of 5-cyclopropyl-N-(2-methoxy-3-(1-methyl-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 389 [M+H] ⁺

Example 62.

The target compound of Example 62 was prepared by performing a method and procedure similar to that used in Example 61 above. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Example 63. Preparation of N-(3-amino-5-(1-methyl-1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazole[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 3-(1-methyl-1H-imidazol-2-yl)-5-nitroaniline

(3-Amino-5-nitrophenyl)boronic acid (0.2 g, 1.01 mmol), 2-bromo-1-methyl-1H-imidazole (265 mg, 1.65 mmol), cesium carbonate (716 mg, 2.2 mmol), and tetrakis(triphenylphosphine)palladium(0) (127 mg, 0.11 mmol) were dissolved in 1,4-dioxane (2 mL), water (0.5 ml) was added, and the mixture was reacted in a microwave at 110 ℃ for 50 h. After the reaction was completed, the mixture was concentrated and purified by MPLC to give the target compound (114 mg, 66%, yellow solid). LC/MS(ESI) m/z: 219 [M+H] ⁺

Step 2: Preparation of 5-(1-methyl-1H-imidazol-2-yl)benzene-1,3-diamine

3-(1-Methyl-1H-imidazol-2-yl)-5-nitroaniline (114 mg, 0.788 mmol) and 10% Pd/C (55 mg, 0.05 mmol) were dissolved in ethanol (3 ml) and stirred under hydrogen gas for 6 h. After completion of the reaction, the reaction product was filtered through a celite filter and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to produce the target compound (97 mg, 99%, white solid). LC/MS(ESI) m/z: 189 [M+H] ⁺

Step 3: Preparation of N-(3-amino-5-(1-methyl-1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazole[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 374 [M+H] ⁺

Example 64.

The target compound of Example 64 was prepared by performing a method and procedure similar to that used in Example 63 above. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Example 65. Preparation of 5-cyclopropyl-N-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 3-(1-methyl-1H-pyrazol-4-yl)aniline

The target compound was prepared similarly by performing similar methods and procedures as those used in step 1 of the above Example 61. LC/MS (ESI) m/z: 174 [M+H] ⁺

Step 2: Preparation of 5-cyclopropyl-N-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 359 [M+H] ⁺

Example 66. Preparation of 5-cyclopropyl-N-(3-(1-(2-hydroxyethyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-(3-(1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide (0.05 g, 0.145 mmol) obtained in the above Example 3 was dissolved in dimethylformamide (1 mL), and sodium hydride (3.83 mg, 0.160 mmol) was added at 0 °C. Then, 2-bromoethane-1-ol (0.018 g, 0.145 mmol) was slowly added, and the mixture was stirred at 80 °C for 16 hours. After completion of the reaction, the mixture was diluted with dichloromethane and washed with water and brine. The organic residue was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by Prep HPLC to produce the target compound (6.4 mg, 11%, yellow solid). LC/MS(ESI) m/z: 389 [M+H] ⁺

Example 67. Preparation of 5-cyclopropyl-N-(3-(6-methoxypyridin-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 3-(6-methoxypyridin-3-yl)aniline

The target compound was prepared by performing a method and procedure similar to that used in step 1 of the above Example 61. LC/MS (ESI) m/z: 201 [M+H] ⁺

Step 2: Preparation of 5-cyclopropyl-N-(3-(6-methoxypyridin-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 386 [M+H] ⁺

Example 68.

The target compound of Example 68 was prepared by performing a method and procedure similar to that used in Example 67 above. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Example 69. Preparation of 5-cyclopropyl-N-(4'-(cyclopropylcarbamoyl)-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 3'-amino-N-cyclopropyl-[1,1'-biphenyl]-4-carboxamide

The target compound was prepared similarly by performing similar methods and procedures as those used in step 2 of the above Example 63. LC/MS (ESI) m/z: 253 [M+H] ⁺

Step 2: Preparation of 5-cyclopropyl-N-(4'-(cyclopropylcarbamoyl)-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 438 [M+H] ⁺

Example 70. Preparation of 5-cyclopropyl-N-(3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 2-(3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)ethan-1-ol

3-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole (100 mg, 0.45 mmol), 2-bromoethane-1-ol (60 mg, 0.48 mmol), and potassium carbonate (188 mg, 1.37 mmol) were dissolved in acetonitrile (2 mL) and reacted at 60 ℃ for 6 h. After the reaction was completed, the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by MPLC to produce the target compound (80 mg, 67%, white solid). LC/MS(ESI) m/z: 265 [M+H] ⁺

Step 2: Preparation of 2-(3-(3-amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)ethan-1-ol

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 63. LC/MS (ESI) m/z: 235 [M+H] ⁺

Step 3: Preparation of 5-cyclopropyl-N-(3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 420 [M+H] ⁺

Example 71.

The target compound of Example 71 was prepared by performing a method and procedure similar to that used in Example 70 above. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Example 72. Preparation of 5-cyclopropyl-N-(3-(4-((tetrahydro-2H-pyran-4-yl)amino)piperidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 1-(3-nitrophenyl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine

1-Bromo-3-nitrobenzene (0.3 g, 1.5 mmol), N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (0.52 g, 1.8 mmol), cesium carbonate (2.5 g, 7.4 mmol), 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphene (98 mg, 0.12 mmol), diacetoxypalladium (0.033 g, 0.15 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 80 ℃ for 16 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer residue was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to give the target compound (0.29 g, 64%, white solid). Manufactured. LC/MS(ESI) m/z: 306 [M+H] ⁺

Step 2: Preparation of 1-(3-aminophenyl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 63. LC/MS (ESI) m/z: 276 [M+H] ⁺

Step 3: Preparation of 5-cyclopropyl-N-(3-(4-((tetrahydro-2H-pyran-4-yl)amino)piperidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 461 [M+H] ⁺

Example 73. Preparation of N-(3-(1-(cyanomethyl)-1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 2-(2-(3-nitrophenyl)-1H-imidazol-1-yl)acetonitrile

2-(3-Nitrophenyl)-1H-imidazole (1.0 g, 5.3 mmol), 2-bromoacetonitrile (1.27 g, 10.5 mmol), and potassium carbonate (3.65 g, 26.4 mmol) were dissolved in N,N-dimethylformamide (10 ml) and stirred at room temperature for 16 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to produce the target compound (0.45 g, 37%, yellow solid). LC/MS(ESI) m/z: 229 [M+H] ⁺

Step 2: Preparation of 2-(2-(3-aminophenyl)-1H-imidazol-1-yl)acetonitrile

2-(2-(3-nitrophenyl)-1H-imidazol-1-yl)acetonitrile (0.45 g, 1.97 mmol) and tin(II) chloride dihydrate (2.2 g, 9.86 mmol) were dissolved in ethyl acetate (5 ml) and stirred at 60 ℃ for 16 h. After completion of the reaction, the reaction product was filtered through a celite filter and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to produce the target compound (200 mg, 51.2%, yellow solid). LC/MS(ESI) m/z: 199 [M+H] ⁺

Step 3: Preparation of N-(3-(1-(cyanomethyl)-1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazole[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 384 [M+H] ⁺

Example 74. Preparation of 5-cyclopropyl-N-(2'-vinyl-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 2'-vinyl-[1,1'-biphenyl]-3-amine

The target compound was prepared by performing a method and procedure similar to that used in step 1 of the above Example 58. LC/MS (ESI) m/z: 196 [M+H] ⁺

Step 2: Preparation of 5-cyclopropyl-N-(2'-vinyl-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 381 [M+H] ⁺

Example 75. Preparation of 5-cyclopropyl-N-(2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 2-fluoro-3'-nitro-4-(trifluoromethyl)-1,1'-biphenyl

The target compound was prepared by performing a method and procedure similar to that used in step 1 of the above Example 58. LC/MS (ESI) m/z: 286 [M+H] ⁺

Step 2: Preparation of 2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-amine

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 63. LC/MS (ESI) m/z: 256 [M+H] ⁺

Step 3: Preparation of 5-cyclopropyl-N-(2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 441 [M+H] ⁺

Example 76. Preparation of N-(3-(1H-imidazol-2-yl)phenyl)-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of ethyl 5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazole[1,5-a]pyrimidine-3-carboxylate

Ethyl 5-chloropyrazole[1,5-a]pyrimidine-3-carboxylate (0.5 g, 2.22 mmol), 3-amino-1-methylpyridine-2(1H)-one (303 mg, 2.44 mmol), sodium carbonate (5.54 mL, 11.08 mmol), xantphos (128 mg, 0.22 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.2 g, 0.22 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 80 ℃ for 16 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by MPLC to produce the target compound (0.69 g, 89%, yellow solid). LC/MS(ESI) m/z: 314 [M+H] ⁺

Step 2: Preparation of 5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazole[1,5-a]pyrimidine-3-carboxylic acid

Ethyl 5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazole[1,5-a]pyrimidine-3-carboxylate (370 mg, 0.584 mmol) and 2 M sodium hydroxide (3 mL) were dissolved in tetrahydrofuran and stirred at 80 ℃ for 16 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and 1 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the desired compound (110 mg, 33%, white solid). LC/MS(ESI) m/z: 286 [M+H] ⁺

Step 3: Preparation of N-(3-(1H-imidazol-2-yl)phenyl)-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

5-Methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (30 mg, 0.11 mmol), 3-(1H-imidazol-2-yl)aniline (19 mg, 0.12 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyrimidinium 3-oxidehexafluorophosphate (48 mg, 0.13 mmol), N,N-diisopropylethylamine (41 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (1 ml) and stirred at room temperature for 24 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by Prep HPLC to produce the target compound (2.5 mg, 5%, yellow solid). LC/MS(ESI) m/z: 427 [M+H] ⁺

Example 77. Preparation of N-(3-(1H-imidazol-2-yl)phenyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of ethyl 5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazole[1,5-a]pyrimidine-3-carboxylate

The target compound was prepared by performing a method and procedure similar to that used in step 1 of the above Example 76. LC/MS (ESI) m/z: 377 [M+H] ⁺

Step 2: Preparation of 5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazole[1,5-a]pyrimidine-3-carboxylic acid

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 76. LC/MS (ESI) m/z: 349 [M+H] ⁺

Step 3: Preparation of N-(3-(1H-imidazol-2-yl)phenyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to that used in step 3 of the above Example 76. LC/MS (ESI) m/z: 490 [M+H] ⁺

Example 78. Preparation of 5-cyclohexyl-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of ethyl 5-(cyclohex-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (0.2 g, 0.88 mmol), cyclohex-1-en-ylboronic acid (167 mg, 1.33 mmol), PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (72 mg, 0.08 mmol), and tripotasium phosphate (564 mg, 2.66 mmol) were dissolved in 1,4-dioxane (2 mL), and water (0.2 ml) was added. The mixture was reacted at 80 ℃ for 15 h. After the reaction was completed, the mixture was filtered through a celite filter and washed with ethyl acetate. After concentration under reduced pressure, the mixture was purified by MPLC to obtain the target compound (222 mg, 92%, yellow solid). LC/MS(ESI) m/z: 272 [M+H] ⁺

Step 2: Preparation of 5-(cyclohex-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

Ethyl 5-(cyclohex-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (222 mg, 0.74 mmol) prepared in the above step 1 was dissolved in ethanol, 1 M sodium hydroxide (4 mL, 4.09 mmol) was added, and the reaction was performed at 80 ℃ for 1 h. After the reaction was completed, the mixture was neutralized with 1 M HCl, diluted with dichloromethane, and washed with water and brine. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by MPLC to prepare the target compound (180 mg, 90%, white solid). LC/MS(ESI) m/z: 244 [M+H] ⁺

Step 3: Preparation of 5-(cyclohex-1-en-1-yl)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 400 [M+H] ⁺

Step 4: Preparation of 5-cyclohexyl-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

5-(Cyclohex-1-en-1-yl)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 0.07 mmol) prepared in the above step 3 was dissolved in ethanol, 10% Pd/C (3 mg, 3 μmol) was added, and the mixture was stirred under hydrogen gas for 20 hours. After the reaction was completed, the reaction product was filtered through a celite filter and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by MPLC to prepare the target compound (9.2 mg, 30%, white solid). LC/MS(ESI) m/z: 174 [M+H] ⁺

Example 79. Preparation of 5-cyclopropyl-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(methylamino)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 3-(3-fluoro-5-nitrophenyl)-1-methyl-1H-1,2,4-triazole

The target compound was prepared by performing a method and procedure similar to that used in step 1 of the above Example 58. LC/MS (ESI) m/z: 223 [M+H] ⁺

Step 2: Preparation of N-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitroaniline

3-(3-Fluoro-5-nitrophenyl)-1-methyl-1H-1,2,4-triazole (106 mg, 0.478 mmol), 40% methylamine (0.478 ml, 0.955 mmol), potassium carbonate (231 mg, 1.671 mmol) were dissolved in dimethyl sulfoxide (1 mL) and reacted at 100 °C for 5 h. After the reaction was completed, the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by MPLC to produce the target compound (104 mg, 93%, orange solid). LC/MS(ESI) m/z: 234 [M+H] ⁺

Step 3: Preparation of N1-methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)benzene-1,3-diamine

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 63. LC/MS (ESI) m/z: 204 [M+H] ⁺

Step 4: Preparation of 5-cyclopropyl-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(methylamino)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 389 [M+H] ⁺

Example 80. Preparation of N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(4-((tetrahydro-2H-pyran-4-yl)amino)piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine

Tert-butyl 4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylate (0.1 g, 0.352 mmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (0.81 ml, 10.55 mmol), and stirred at room temperature for about 1 hour. After completion of the reaction, the solvent was concentrated to prepare the target compound (0.105 g, 100%, white solid). LC/MS(ESI) m/z: 185 [M+H] ⁺

Step 2: Preparation of N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(4-((tetrahydro-2H-pyran-4-yl)amino)piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 38. LC/MS (ESI) m/z: 502 [M+H] ⁺

Example 81. Preparation of N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-((1-methylpiperidin-4-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 1-methyl-4-(3-nitrophenoxy)piperidine

3-Nitrophenol (0.5 g, 3.59 mmol) and triphenylphosphine (1.885 g, 7.19 mmol) were dissolved in tetrahydrofuran (30 ml), and 1-methylpiperidin-4-ol (0.845 ml, 7.19 mmol) and diisopropyl azodicarboxylate (1.398 ml, 7.19 mmol) were added at 0 °C under a nitrogen atmosphere. The mixture was stirred for 10 minutes at 0 °C and then stirred overnight at room temperature. After the reaction was completed, it was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to give the target compound (0.77 g, 91%, yellow liquid). LC/MS(ESI) m/z: 237 [M+H] ⁺

Step 2: Preparation of 3-((1-methylpiperidin-4-yl)oxy)aniline

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 63. LC/MS (ESI) m/z: 207 [M+H] ⁺

Step 3: Preparation of N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(4-((tetrahydro-2H-pyran-4-yl)amino)piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 29. LC/MS (ESI) m/z: 524 [M+H] ⁺

Example 82. Preparation of 5-cyclopropyl-N-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of tert-butyl (4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)carbamate

The target compound was prepared by performing a method and procedure similar to that used in step 1 of the above Example 58. LC/MS (ESI) m/z: 275 [M+H] ⁺

Step 2: Preparation of 4-(1-methyl-1H-1,2,4-triazol-3-yl)aniline

Tert-butyl (4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)carbamate (0.167 g, 0.609 mmol) was dissolved in dichloromethane (4 ml) and trifluoroacetic acid (1.407 ml, 18.26 mmol), and stirred at room temperature for about 1.5 h. After completion of the reaction, the mixture was concentrated and neutralized to pH 8-9 with 2 N aqueous sodium hydroxide solution. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to give the target compound (0.067 g, 63%, pink solid). LC/MS(ESI) m/z: 175 [M+H] ⁺

Step 3: Preparation of 5-cyclopropyl-N-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 360 [M+H] ⁺

Example 83. Preparation of 5-((1-(cyanomethyl)piperidin-4-yl)amino)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of tert-butyl (1-(cyanomethyl)piperidin-4-yl)carbamate

Tert-Butyl piperidin-4-ylcarbamate (0.15 g, 0.749 mmol) and potassium carbonate (0.207 g, 1.498 mmol) were dissolved in acetonitrile (5 ml), 2-bromoacetonitrile (0.078 ml, 1.123 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to give the target compound (0.237 g, 99%, white solid). LC/MS(ESI) m/z: 240 [M+H] ⁺

Step 2: Preparation of 2-(4-aminopiperidin-1-yl)acetonitrile

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 82. LC/MS (ESI) m/z: 140 [M+H] ⁺

Step 3: Preparation of 5-((1-(cyanomethyl)piperidin-4-yl)amino)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 29. LC/MS (ESI) m/z: 457 [M+H] ⁺

Example 84. Preparation of N-(5-(1H-imidazol-2-yl)pyridin-3-yl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound of Example 84 was prepared by performing a method and procedure similar to that used in Example 58 above. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Example 85. Preparation of 5-cyclopropyl-N-(4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-amine

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.2 g, 0.909 mmol) was added 3-bromo-1-methyl-1H-1,2,4-triazole (0.162 g, 1.0 mmol), 1,4-dioxane (4 ml), water (1 ml), sodium bicarbonate (0.229 g, 2.73 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.066 g, 0.091 mmol), and the mixture was stirred for 1 h at 150 ℃ in a microwave oven. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane:methanol (99:1) and filtered through a Celite filter. After concentration under reduced pressure, the product was purified by MPLC to produce the target compound (0.097 g, 61%, purple solid). LC/MS(ESI) m/z: 176 [M+H] ⁺

Step 2: Preparation of 5-cyclopropyl-N-(4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to those used in Example 1 above. LC/MS (ESI) m/z: 361 [M+H] ⁺

Examples 86 to 88.

The target compounds of Examples 86 to 88 were prepared by following similar methods and procedures as those used in Example 79 above. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Example 89. Preparation of N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound of Example 89 was prepared using a similar method and procedure as that used in Example 29 using 5-chloro-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Example 90. Preparation of N-(3-cyclopropyl-5-methoxyphenyl)-5-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride

Dissolve oxalyl dichloride (0.66 ml, 7.59 mmol) in dichloromethane (10 mL), and then add DMF (1 drop). Stir at room temperature for about 30 minutes and slowly add 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1 g, 5.06 mmol). Stir at room temperature for about 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the target compound (1.09 g, 100%, ivory solid).

Step 2: Preparation of 3-cyclopropyl-5-methoxyaniline

3-Bromo-5-methoxyaniline (0.5 g, 2.47 mmol), cyclopropylboronic acid (0.31 g, 3.71 mmol), tripotasium phosphate (1.0 g, 4.95 mmol), triphenylphosphine (65 mg, 0.24 mmol), Pd(OAc) ₂ (56 mg, 0.24 mmol) were dissolved in toluene (4 mL) and stirred at 100 ℃ for 15 h. After the reaction was completed, dilute with dichloromethane and wash with water and brine. The organic layer residue was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to produce the target compound (0.2 g, 49%). LC/MS(ESI) m/z: 164 [M+H] ⁺

Step 3: Preparation of 5-chloro-N-(3-cyclopropyl-5-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

5-Chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (0.16 g, 0.741 mmol) prepared in step 1 was dissolved in dichloromethane (1 mL), and 3-cyclopropyl-5-methoxyaniline (0.14 g, 0.889 mmol) and triethylamine (0.2 mL, 1.481 mmol) prepared in step 2 were sequentially added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by MPLC to prepare the target compound. LC/MS(ESI) m/z: 343 [M+H] ⁺

Step 4: Preparation of N-(3-cyclopropyl-5-methoxyphenyl)-5-(cyclopyrrolylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 29. LC/MS (ESI) m/z: 364 [M+H] ⁺

Example 91. Preparation of N-(3-cyclopropyl-5-methoxyphenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound of Example 91 was prepared by performing a method and procedure similar to that of Example 90. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Example 92. Preparation of N-(3-cyclopropyl-5-hydroxyphenyl)-5-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-(3-cyclopropyl-5-methoxyphenyl)-5-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20 mg, 0.05 mmol) prepared in the above Example 90 was dissolved in dichloromethane (0.5 mL), and 1M BBr ₃ dichloromethane solution (0.05 mL, 0.05 mmol) was slowly added dropwise. Stirred at room temperature for 3 hours. After completion of the reaction, diluted with dichloromethane and washed with water and brine. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by prep HPLC to prepare the target compound (3.6 mg, 18%, white solid). LC/MS(ESI) m/z: 350 [M+H] ⁺

Example 93. Preparation of N-(3-cyclopropyl-5-hydroxyphenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound of Example 93 was prepared by following a similar method and procedure as in Example 92 using N-(3-cyclopropyl-5-methoxyphenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide prepared in Example 91 above. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Example 94. Preparation of N-(3-methoxy-5-(tetrahydro-2H-pyran-4yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 3-(3,6-dihydro-2H-pyran-4-yl)-5-methoxyaniline

3-Bromo-5-methoxyaniline (500 mg, 2.48 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (780 mg, 3.71 mmol), 2 M sodium carbonate (2.5 ml, 4.95 mmol), PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (202 mg, 0.247 mmol) were added to 1,4-dioxane (8 ml). The reaction mixture was stirred at 100 ℃ for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the solid was dissolved in dichloromethane and filtered through a celite filter. After concentration under reduced pressure, the product was purified by MPLC to obtain the target compound (307 mg, 60%, orange solid). LC/MS(ESI) m/z : 206 [M+H] ⁺

Step 2: Preparation of 3-methoxy-5-(tetrahydro-2H-pyran-4-yl)aniline

The target compound was prepared by performing a method and procedure similar to that used in step 4 of the above Example 78. LC/MS (ESI) m/z: 208 [M+H] ⁺

Step 3: Preparation of 5-chloro-N-(3-methoxy-5-(tetrahydro-2H-pyran-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to that used in step 3 of the above Example 90. LC/MS (ESI) m/z: 387 [M+H] ⁺

Step 4: Preparation of N-(3-methoxy-5-(tetrahydro-2H-pyran-4yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 29. LC/MS (ESI) m/z: 525 [M+H] ⁺

Example 95. Preparation of 5-(cyclopropylamino)-N-(3-methoxy-5-(tetrahydro-2H-pyran-4yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 5-(cyclopropylamino)-N-(3-methoxy-5-(tetrahydro-2H-pyran-4yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 38. LC/MS (ESI) m/z: 408 [M+H] ⁺

Example 96. Preparation of N-(3-(benzyloxy)-5-(3,6-dihydro-2H-pyran-4yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 1-(benzyloxy)-3-bromo-5-nitrobenzene

3-Bromo-5-nitrophenol (500 mg, 2.29 mmol) and sodium hydride (138 mg, 3.44 mmol, 60%) were added to N,N-dichloroformaldehyde (5 ml) and stirred for 10 minutes. Benzyl chloride (320 ul, 2.75 mmol) was added and stirred at 70 ℃ for 2 hours. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer residue was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by MPLC to give the target compound (380 mg, 54%, yellow oil).

Step 2: Preparation of 4-(3-(benzyloxy)-5-nitrophenyl)-3,6-dihydro-2H-pyran

1-(Benzyloxy)-3-bromo-5-nitrobenzene (380 mg, 1.23 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (389 mg, 1.85 mmol), sodium carbonate (392 mg, 3.70 mmol) and Pd(PPh ₃ ) ₄ (143 mg, 0.123 mmol) were added to 1,4-dioxane (8 ml) and water (2.67 ml). The reaction mixture was stirred at 100 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the solid was dissolved in dichloromethane and filtered through a Celite filter. After concentration under reduced pressure, the residue was purified by MPLC to give the target compound (209 mg, 54%, yellow oil).

Step 3: Preparation of 3-(benzyloxy)-5-(3,6-dihydro-2H-pyran-4-yl)aniline

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 58. LC/MS (ESI) m/z: 282 [M+H] ⁺

Step 4: Preparation of N-(3-(benzyloxy)-5-(3,6-dihydro-2H-pyran-4-yl)phenyl)-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to that used in step 3 of the above Example 90. LC/MS (ESI) m/z: 461 [M+H] ⁺

Step 5: Preparation of N-(3-(benzyloxy)-5-(3,6-dihydro-2H-pyran-4yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 29. LC/MS (ESI) m/z: 599 [M+H] ⁺

Example 97. Preparation of N-(3-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(pyridin-2-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound of Example 97 was prepared by performing a similar method and procedure as in Example 94. The related compound names, NMR, MS and HPLC data are summarized in Table 1. LC/MS(ESI) m/z: 518 [M+H] ⁺

Example 98. Preparation of N-(3-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(1-methylpiperidin-4-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of 1-methyl-4-(3-nitrophenyl)1,2,3,6-tetrahydropyridine

The target compound was prepared by performing similar methods and procedures as in step 1 of the above Example 61. LC/MS (ESI) m/z: 219 [M+H] ⁺

Step 2: Preparation of 3-(1-methylpiperidin-4-yl)aniline

The target compound was prepared by performing a method and procedure similar to that used in step 2 of the above Example 63. LC/MS (ESI) m/z: 191 [M+H] ⁺

Step 3: Preparation of N-(3-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(1-methylpiperidin-4-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

5-Chloro-N-(3-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazole[1,5-a]pyrimidine-3-carbamate (0.025 g, 0.065 mmol) was added n-BuOH (0.5 ml) and 12N HCl (0.1 mL) and stirred at 100 ℃ for 17 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by prep-HPLC to give the target compound (2 mg, 5.49%, yellow solid). LC/MS(ESI) m/z: 538[M+H]+

Example 99. Preparation of N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(pyridin-2-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by following similar methods and procedures as those used in Example 29 above. The relevant compound names, NMR, MS, and HPLC data are summarized in Table 1.

Example 100. Preparation of N-(3-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound of Example 100 was prepared by following the similar method and procedure as in Step 2 of Example 29 using 5-chloro-N-(3-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazole[1,5-a]pyrimidine-3-carbamate. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Example 101. Preparation of N-(3-hydroxy-5-(tetrahydro-2H-pyran-4-yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Preparation of N-(3-hydroxy-5-(tetrahydro-2H-pyran-4-yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-(3-(benzyloxy)-5-(3,6-dihydro-2H-pyran-4yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (10 mg, 0.017 mmol) prepared in Example 96 and 10% Pd/C (8.89 mg, 0.008 mmol) were added to methanol (1 ml) and tetrahydrofuran (1 ml). The reaction mixture was stirred under hydrogen gas for 2 days. Methanol (1 ml) and 10% Pd/C (8.89 mg, 0.008 mmol) were further added, and the mixture was stirred under hydrogen gas for 2 days. After completion of the reaction, the mixture was diluted with dichloromethane and filtered through a Celite filter. After concentration under reduced pressure, the residue was purified by prep-HPLC to obtain the target compound (2.7 mg, 31%, white solid).

Example 102. Preparation of N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(1-methylpiperidin-4-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound was prepared by following similar methods and procedures as those used in Example 29 above. The relevant compound names, NMR, MS, and HPLC data are summarized in Table 1.

Example 103. Preparation of 5-(cyclopropylamino)-N-(3-methoxy-5-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound of Example 103 was prepared by following similar methods and procedures as those used in Example 95 above. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Examples 104 to 106.

The target compounds of Examples 104 to 106 were prepared by following similar methods and procedures as those used in Example 92 above. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

Example 107. Preparation of N-(3-hydroxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(pyridin-2-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The target compound of Example 107 was prepared by performing a method and procedure similar to that of Example 29. The relevant compound names, NMR, MS and HPLC data are summarized in Table 1.

The compound structures and compound names of Examples 1 to 107 are as shown in Table 1 below.

<Experimental example>

Experimental Example 1. Evaluation of TYK2 (JH2) domain binding inhibition ability

In order to evaluate the TYK2 (JH2) domain binding inhibitory ability of the compound according to the present invention, the following TYK2 JH2 Binding assay experiment was performed.

Specifically, TYK2 (JH2) domain protein was added to a black 384-well plate at a concentration of 3.5 ng/μl, and compounds diluted using D.W were added at concentrations of 5 μM, 0.1 μM, or 0.5 μM. To this, a fluorescently labeled JH2 probe was added at a concentration of 3 nM, and incubated for 1 hour at room temperature. Thereafter, the TYK2 (JH2) domain binding inhibitory ability of the compounds was measured by measuring the fluorescent polarization value using a microplate reader. The measured values were used to calculate the degree of inhibition using GraphPad Prism 7.0 (GraphPad Software Inc.), and were classified as A when the measured degree of inhibition was 80% or more but less than 100%, B when 60% or more but less than 80%, C when 40% or more but less than 60%, and D when less than 40%, and these are listed in Table 2 below.

Example TYK2 JH2 binding affinity
%@5uM TYK2 JH2 binding affinity
%@0.5uM Example TYK2 JH2 binding affinity
%@5uM TYK2 JH2 binding affinity
%@0.5uM TYK2 JH2 binding affinity
%@0.1uM 1 D 55 B 2 A 56 A 3 B 57 D 4 A 58 D 5 A 59 B 6 D 60 D 7 A 61 C 8 B 62 A 9 B 63 B 10 B 64 B 11 A 65 A 12 A 66 C 13 D 67 A 14 A 68 A 15 A 69 B 16 A 70 A 17 B 71 A 18 C 72 B 19 C 73 D 20 A 74 D 21 B 75 D 22 A 76 D 23 C 77 D 24 B 78 D 25 D 79 B 26 D 80 A 27 C 81 B 28 C 82 D 29 B 83 A D 30 D 84 C 31 D 85 D 32 D 86 D 33 D 87 D 34 D 88 D 35 D 89 D 36 D 90 D 37 A 91 D 38 A 92 D 39 C 93 D 40 A 94 D 41 A 95 D 42 A 96 D 43 B 97 D 44 A 98 D 45 A 99 D 46 A 100 D 47 A 101 D 48 A 102 B 49 A 103 D 50 A 104 D 51 A 105 D 52 A 106 C 53 A 107 D 54 A

According to Table 2 above, it was confirmed that the compounds of the present invention effectively bind to TYK2 and inhibit its function.

The specification has omitted detailed descriptions of matters that can be sufficiently recognized and inferred by those with ordinary skill in the technical field of the present invention, and various modifications are possible within the scope that does not change the technical idea or essential configuration of the present invention other than the specific examples described in this specification. Accordingly, the present invention can be implemented in a manner other than that specifically described and exemplified in this specification, and this is a matter that can be understood by those with ordinary skill in the technical field of the present invention.

Claims (19)

A compound represented by the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In the above chemical formula 1,
R ₁ is any one selected from the group consisting of C _3-8 cycloalkyl, C _5-10 spirocycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, C _1-4 alkyl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _1-4 alkyl-C _3-8 cycloalkyl, L ₁ -C _5-10 spirocycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl,
wherein the C _3-8 cycloalkyl, C _5-10 spirocycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _1-4 alkyl-C _3-8 cycloalkyl, L ₁ -C _5-10 spirocycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl are unsubstituted or substituted with at least one or more of -OH, -O-(C _1-4 alkyl), C _1-4 alkanol, C _1-4 alkyl, halogen, -CN, -NH ₂ , C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, -NH-(C _3-7 heterocycloalkyl), -O-(C _3-7 heterocycloalkyl), C _2-12 heteroaryl or -C _1-4 alkyl-CN is substituted;
wherein L ₁ is any one selected from the group consisting of -NR _a -, -NR _b C(=O)-, -C(=O)-, -O-, and -S-, wherein R _a and R _b are each independently -H or -C _1-4 alkyl;
is C _6-12 aryl or C _2-12 heteroaryl,
R ₂ is any one selected from the group consisting of halogen, C _1-4 alkyl, -O-(C _1-4 alkyl), -O-(C _1-4 alkylene)-(C _6-12 aryl), -C _1-4 alkanol, -CN, -OH, -NH ₂ , -NH-(C _1-4 alkyl), -N(C _1-4 alkyl)-(C _1-4 alkyl), -NO ₂ and C _1-4 haloalkyl;
n is an integer of 0, 1, or 2; and
Cy ₁ is unsubstituted or substituted C _3-8 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C _3-7 heterocycloalkyl comprising at least one N or O, C _3-7 heterocycloalkenyl or C _2-12 heteroaryl, wherein said substitution is with at least one or more of -C _1-4 alkyl, halogen, -O-(C _1-4 alkyl), C _1-4 alkanol, -OH, -CN, -NH ₂ , -NO ₂ , C _1-4 haloalkyl, -(C _1-4 alkyl)-O-(C _1-4 alkyl), C _1-4 alkenyl, C _1-4 alkynyl, -C _1-4 alkyl-CN, NHC(=O)-(C _3-8 cycloalkyl), or NH-(C _3-7 heterocycloalkyl).
In the first paragraph,
wherein the above C _3-8 cycloalkyl is any one selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl,
The above C _5-10 spirocycloalkyl is any one selected from the group consisting of spiropentyl, spirohexyl, spiroheptyl and cyclooctyl,
The above C _3-7 heterocycloalkyl is any one selected from the group consisting of oxetanyl, azetidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, thietanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one-yl, 3-oxa-8-azabicyclo[3.2.1]octan-yl, and hexahydro-2H-furo[3,2-b]pyrrole,
The above C _3-7 heterocycloalkenyl is any one selected from the group consisting of tetrahydropyridinyl, dihydropyrrolyl, dihydrofuranyl, dihydropyranyl, 3H-indolyl, dihydroisoxazolyl, dihydropyrazolyl, 2H-pyrrolyl and 2H-pyranyl,
The above C _2-12 heteroaryl is any one selected from the group consisting of thiophenyl, furanyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyranyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyridonyl, pyrimidinyl, benzofuranyl, benzothiophenyl, isobenzofuranyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoisooxazolyl, benzoxazolyl, isoindolyl, indolyl, indazolyl, benzothiadiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, carbazolyl, and benzodioxozolyl,
wherein the above C _6-12 aryl is any one selected from the group consisting of phenyl, naphthalenyl, indenyl, pentarenyl and azulenyl,
A compound represented by the formula 1, wherein the C _1-4 alkyl is any one selected from the group consisting of methyl, ethyl, propyl, and butyl, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
In the first paragraph,
wherein R ₁ is selected from the group consisting of C _1-4 alkyl, unsubstituted or substituted cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, spiroheptyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, oxopyridinyl, phenyl, quinolyl, isoquinolyl, L ₁ -cyclopropyl, L ₁ -cyclobutyl, L ₁ -cyclohexyl, L _{1 -cycloheptyl, L 1 -C 1-4} alkyl-cyclopropyl, L ₁ -spiroheptyl, L 1 -tetrahydrofuranyl, L ₁ -tetrahydropyranyl, L ₁ -piperidinyl, L ₁ -piperazinyl, L ₁ -pyridonyl, L ₁ -pyridinyl, L ₁ -phenyl, L ₁ -quinolyl, and L ₁ -isoquinolyl _. Either one,
A compound represented by formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein said substitution is at least one or more of -OH, -C _1-4 alkyl, halogen, -CN, -NH ₂ , C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, -NH-(C _3-7 heterocycloalkyl), -O-(C _3-7 heterocycloalkyl), C _2-12 heteroaryl or -C _1-4 alkyl-CN.
In the first paragraph,
The above R ₁ is methyl, ethyl, unsubstituted or substituted , , , , , , , , , , , , , , , and is one selected from the group consisting of,
A compound represented by formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein said substitution is at least one or more of -OH, -C _1-4 alkyl, halogen, -CN, -NH ₂ , C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, -NH-(C _3-7 heterocycloalkyl), -O-(C _3-7 heterocycloalkyl), C _2-12 heteroaryl or -C _1-4 alkyl-CN.
In the first paragraph,
A compound represented by chemical formula 1, wherein L ₁ is -NR _a -, or -NR _b C(=O)-, wherein R _a and R _b are each independently -H or -C _1-4 alkyl, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
In the first paragraph,
wherein R ₁ is any one selected from the group consisting of methyl, unsubstituted or substituted cyclopropyl, cyclohexyl, piperidinyl, tetrahydro-2H-pyranyl, quinolyl, isoquinolyl, -NHC(=O)-cyclopropyl, -NHC(=O)-methyl-cyclopropyl, -NH-cyclopropyl, -NH-cyclohexyl, -NH-cycloheptyl, -NH-spiroheptyl, -NHC(=O)-tetrahydro-2H-pyranyl, -NH-tetrahydro-2H-pyranyl, -NH-phenyl, -NH-piperidinyl, -NH-pyridinyl, -NH-pyridonyl, -NH-quinolyl, -NH-isoquinolyl, and -NC ₂ H ₅ -cyclopropyl,
A compound represented by formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein said substitution is at least one or more of methyl, NH ₂ , pyridinyl, piperazinyl, -NH-tetrahydro-2H-pyranyl, piperidinyl, piperidinyl-CH ₃ , -O-piperidinyl, triazolyl, triazolyl-CH ₃ , -CH ₂ -CN.
In the first paragraph,
A compound represented by formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein R ₂ is any one _selected from the group consisting of fluorine (F), chlorine (Cl), methyl, ethyl, methoxy, ethoxy, -O-methylene-phenyl, -O-ethylene-phenyl =O, -CN, -OH, -NH ₂ , NH-CH _{3 , NH-C 2 H 5 , NH-C 3 H 7 , N-CH 3 -CH 3 , NC 2 H 5 -CH 3 ,} NC ₂ H 5 -C ₂ H ₅ , and trifluoromethyl (CF ₃ ).
In the first paragraph,
Cy ₁ is any one selected from the group consisting of unsubstituted or substituted cyclopropyl, dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, pyrrolidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzoimidazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl and benzoisothiazolyl, and benzothiadiazolyl, represented by chemical formula 1. A compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
In the first paragraph,
A compound represented by chemical formula 1, wherein Cy ₁ is any one selected from the group consisting of unsubstituted or substituted cyclopropyl, tetrahydropyranyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indazolyl, benzoimidazolyl, benzotriazolyl, benzoxadiazolyl and benzothiadiazolyl, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
In the first paragraph,
Cy ₁ is unsubstituted or substituted , , , , , , , , , , , , , , , , and A compound represented by the chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
In the first paragraph,
A compound represented by chemical formula 1, wherein A is any one selected from the group consisting of phenyl, thiophenyl, furanyl, thiazolyl, oxazolyl, pyridinyl and 2-pyridonyl, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
In the first paragraph,
The compound represented by the above chemical formula 1 is any one compound selected from the group consisting of compounds represented by the following chemical formulas 2 to 4, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Chemical formula 2]

[Chemical Formula 3]

[Chemical Formula 4]

In the above chemical formulas 2 to 4,
R ₁ is any one selected from the group consisting of C _3-8 cycloalkyl, C _5-10 spirocycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, C _1-4 alkyl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _1-4 alkyl-C _3-8 cycloalkyl, L ₁ -C _5-10 spirocycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl,
wherein the C _3-8 cycloalkyl, C _5-10 spirocycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _1-4 alkyl-C _3-8 cycloalkyl, L ₁ -C _5-10 spirocycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl are unsubstituted or substituted with at least one or more of -OH, -O-(C _1-4 alkyl), C _1-4 alkanol, C _1-4 alkyl, halogen, -CN, -NH _2, C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, -NH-(C _3-7 heterocycloalkyl), -O-(C _3-7 heterocycloalkyl), C _2-12 heteroaryl or -C _1-4 alkyl-CN is substituted;
wherein L ₁ is any one selected from the group consisting of -NR _a -, -NR _b C(=O)-, -C(=O)-, -O-, and -S-, wherein R _a and R _b are each independently -H or -C _1-4 alkyl;
is an unsubstituted or substituted C _6-12 aryl or C _2-12 heteroaryl.
R ₂ is any one selected from the group consisting of halogen, C _1-4 alkyl, -O-(C _1-4 alkyl), -O-(C _1-4 alkylene)-(C _6-12 aryl), -C _1-4 alkanol, -CN, -OH, -NH ₂ , -NH-(C _1-4 alkyl), -N(C _1-4 alkyl)-(C _1-4 alkyl), -NO ₂ and C _1-4 haloalkyl;
n is an integer of 0, 1, or 2; and
Cy ₁ is unsubstituted or substituted C _3-8 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C _3-7 heterocycloalkyl comprising at least one N or O, C _3-7 heterocycloalkenyl or C _2-12 heteroaryl, wherein said substitution is with at least one or more of C _1-4 alkyl, halogen, -O-(C _1-4 alkyl), C _1-4 alkanol, -OH, -CN, -NH ₂ , -NO ₂ , C _1-4 haloalkyl, -(C _1-4 alkyl)-O-(C _1-4 alkyl), C _1-4 alkenyl, C _1-4 alkynyl, -C _1-4 alkyl-CN, NHC(=O)-(C _3-8 cycloalkyl), or NH-(C _3-7 heterocycloalkyl).
In Article 10,
In the above chemical formula 2,
Cy ₁ is any one selected from the group consisting of unsubstituted or substituted cyclopropyl, dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydropyranyl, imidazolyl, triazolyl, pyrazolyl, oxazolyl, oxadiazolyl, phenyl, pyridinyl, pyrimidinyl, piperidinyl, wherein the substitution is at least one or more of C _1-4 alkyl, halogen, C _1-4 haloalkyl, -(C _1-4 alkyl)-O-(C _1-4 alkyl), C _1-4 alkanol, C _1-4 alkenyl, C _1-4 alkyl-CN, C _1-4 alkynyl, NHC(=O)-(C _3-8 cycloalkyl), NH-(C _3-7 heterocycloalkyl), a compound represented by formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Acceptable salt.
In Article 10,
In the above chemical formula 2,
R ₁ is any one selected from the group consisting of methyl, unsubstituted or substituted cyclopropyl, cyclohexyl, piperidinyl, tetrahydro-2H-pyranyl, quinolyl, isoquinolyl, -NHC(=O)-cyclopropyl, -NHC(=O)-methyl-cyclopropyl, -NH-cyclopropyl, -NH-cyclohexyl, -NH-cycloheptyl, -NH-spiroheptyl, -NHC(=O)-tetrahydro-2H-pyranyl, -NH-tetrahydro-2H-pyranyl, -NH-phenyl, -NH-piperidinyl, -NH-pyridonyl, -NH-quinolyl, -NH-isoquinolyl, and -NC ₂ H ₅ -cyclopropyl,
A compound represented by formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein said substitution is at least one or more of methyl, NH ₂ , pyridinyl, piperazinyl, -NH-tetrahydro-2H-pyranyl, piperidinyl, piperidinyl-CH ₃ , -O-piperidinyl, triazolyl, triazolyl-CH ₃ , -CH ₂ -CN.
In Article 12,
The compound represented by the above chemical formula 2 is any one compound selected from the group consisting of compounds represented by the following chemical formulas 2-1 to 2-7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 2-1]

[Chemical Formula 2-2]

[Chemical Formula 2-3]

[Chemical Formula 2-4]

[Chemical Formula 2-5]

[Chemical Formula 2-6]

[Chemical Formula 2-7]

In chemical formulas 2-1 to 2-7,
R ₁ is any one selected from the group consisting of C _3-8 cycloalkyl, C _5-10 spirocycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, C _1-4 alkyl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _1-4 alkyl-C _3-8 cycloalkyl, L ₁ -C _5-10 spirocycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl,
wherein the C _3-8 cycloalkyl, C _5-10 spirocycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _1-4 alkyl-C _3-8 cycloalkyl, L ₁ -C _5-10 spirocycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl are unsubstituted or substituted with at least one or more of -OH, -O-(C _1-4 alkyl), C _1-4 alkanol, -C _1-4 alkyl, halogen, -CN, -NH _2, =O, C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, -NH-(C _3-7 substituted with -O-(C _3-7 heterocycloalkyl), C _2-12 heteroaryl or -C _1-4 alkyl-CN;
wherein L ₁ is any one selected from the group consisting of -NR _a -, -NR _b C(=O)-, -C(=O)-, -O-, and -S-, wherein R _a and R _b are each independently -H or -C _1-4 alkyl;
R ₂ is any one selected from the group consisting of halogen, C _1-4 alkyl, -O-(C _1-4 alkyl), -C _1-4 alkanol, -CN, -OH, -NH ₂ , -NH-(C _1-4 alkyl), -NO ₂ and C _1-4 haloalkyl;
R ₃ is any one selected from the group consisting of C _1-4 alkyl, halogen, -O-(C _1-4 alkyl), C _1-4 alkanol, -OH, -CN, -NH ₂ , -NO ₂ , C _1-4 haloalkyl, -(C _1-4 alkyl)-O-(C _1-4 alkyl), C _1-4 alkenyl, C _1-4 alkynyl, -C _1-4 alkyl-CN, NHC(=O)-(C _3-8 cycloalkyl), or NH-(C _3-7 heterocycloalkyl);
n and m are integers 0, 1, or 2;
X ₁ is carbon or nitrogen; and
Y ₁ and Y ₂ are NC _1-4 alkyl or NH.
In the first paragraph,
The compound represented by the above chemical formula 1 is any one compound selected from the group consisting of compounds represented by the following chemical formulas 5 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 5]

[Chemical formula 6]

[Chemical formula 7]

In the above chemical formulas 5 to 7,
R ₁ is any one selected from the group consisting of C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl,
wherein said C _3-8 cycloalkyl, C _3-7 heterocycloalkyl, C _6-12 aryl, C _2-12 heteroaryl, L ₁ -C _3-8 cycloalkyl, L ₁ -C _3-7 heterocycloalkyl, L ₁ -C _6-12 aryl and L ₁ -C _2-12 heteroaryl are unsubstituted or substituted with at least one or more of -OH, -C _1-4 alkyl, halogen, or -CN;
wherein L ₁ is any one selected from the group consisting of -NR _a -, -NR _b C(=O)-, -C(=O)-, -O-, and -S-, wherein R _a and R _b are each independently -H or -C _1-4 alkyl;
R ₂ is any one selected from the group consisting of halogen, -C _1-4 alkyl, -O(C _1-4 alkyl), -CN, -OH, -NH ₂ , -NO ₂ and -C _1-4 haloalkyl;
n is an integer of 0, 1, or 2;
X ₂ is one selected from nitrogen, oxygen and sulfur,
X ₃ is any one selected from carbon, nitrogen, oxygen and sulfur; and
Cy ₁ is an unsubstituted or substituted 5- or 6-membered aromatic ring comprising at least one N, wherein said substitution is with at least one of -C _1-4 alkyl, halogen, -O(C _1-4 alkyl), -OH, -CN, -NH ₂ , -NO ₂ , or -C _1-4 haloalkyl.
In the first paragraph,
The compound represented by the above chemical formula 1 is any one selected from the group consisting of the compounds described below, a compound represented by the chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
5-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-2-yl)phenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-2-yl)phenyl)-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-chloro-5-(4-methyl-1H-imidazol-1-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(5-fluoropyrimidin-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(5-fluoropyrimidin-2-yl)-4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(5-fluoropyridin-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-methoxy-5-(4-methyl-1H-imidazol-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(2-methoxy-3-(4-methyl-1H-imidazol-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-2-yl)-2-methoxyphenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-amino-5-(1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(1-methyl-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(1-(2-methoxyethyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(1-(2,2-difluoroethyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-5-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(oxazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(2-oxo-2H-[1,2'-bipyridin]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-fluoro-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-cyano-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-2-yl)phenyl)-5-(cyclopropanecarboxamido)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(Cyclopropanecarboxamido)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-2-yl)phenyl)-6-(cyclopropanecarboxamido)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
6-(Cyclopropanecarboxamido)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
6-(2-Cyclopropylacetamido)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-2-yl)phenyl)-6-(2-cyclopropylacetamido)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(Cyclopropylamino)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-2-yl)phenyl)-5-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-2-yl)phenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(tetrahydro-2H-pyran-4-carboxamido)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(quinolin-8-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-2-yl)phenyl)-5-(cyclopropyl(ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(Cyclopropyl(ethyl)amino)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(Cyclopropylamino)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(phenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(spiro[3.3]heptan-2-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(Cyclopropylamino)-N-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(Cyclopropylamino)-N-(3-(oxazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(oxazol-2-yl)phenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(4-(Cyanomethyl)piperidin-1-yl)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(((1S,2R)-2-Aminocyclohexyl)amino)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(pyrimidin-5-yl)phenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(Cycloheptylamino)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(Isoquinolin-8-yl)-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(4,5-dichloro-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-fluoro-5-(1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(4-(1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(2-methoxy-3-(1-methyl-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(pyrimidin-5-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-amino-5-(1-methyl-1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-amino-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(1-(2-hydroxyethyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(6-methoxypyridin-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3'-cyano-[1,1'-biphenyl]-3-yl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(4'-(cyclopropylcarbamoyl)-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(4-((tetrahydro-2H-pyran-4-yl)amino)piperidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1-(cyanomethyl)-1H-imidazol-2-yl)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(2'-vinyl-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-2-yl)phenyl)-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-2-yl)phenyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclohexyl-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(methylamino)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(4-((tetrahydro-2H-pyran-4-yl)amino)piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-((1-methylpiperidin-4-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-((1-(cyanomethyl)piperidin-4-yl)amino)-N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(5-(1H-imidazol-2-yl)pyridin-3-yl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-2-yl)-5-(methylamino)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-Cyclopropyl-N-(3-(dimethylamino)-5-(1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1H-imidazol-2-yl)-5-(isopropylamino)phenyl)-5-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-cyclopropyl-5-methoxyphenyl)-5-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-cyclopropyl-5-methoxyphenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-cyclopropyl-5-hydroxyphenyl)-5-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-cyclopropyl-5-hydroxyphenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-methoxy-5-(tetrahydro-2H-pyran-4-yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(Cyclopropylamino)-N-(3-methoxy-5-(tetrahydro-2H-pyran-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(benzyloxy)-5-(3,6-dihydro-2H-pyran-4-yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(pyridin-2-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(1-methylpiperidin-4-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(pyridin-2-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-hydroxy-5-(tetrahydro-2H-pyran-4-yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(1-methylpiperidin-4-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(Cyclopropylamino)-N-(3-methoxy-5-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(Cyclopropylamino)-N-(3-hydroxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-hydroxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-(3-hydroxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(1-methylpiperidin-4-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide; and
N-(3-hydroxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-((3-(pyridin-2-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
A pharmaceutical composition for preventing or treating a TYK2-mediated disease, comprising a compound according to any one of claims 1 to 17, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
In Article 18,
A pharmaceutical composition for preventing or treating a TYK2-mediated disease, wherein the TYK2-mediated disease is any one selected from the group consisting of autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, and diseases associated with transplantation.