Fused heteroaromatic ring compound, pharmaceutical composition thereof, and use thereof

Abstract

The present invention provides a fused heteroaromatic ring compound, a pharmaceutical composition thereof, and a use thereof. Specifically, the present invention provides a compound as represented by formula (I), a pharmaceutically acceptable salt and solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The fused heteroaromatic ring compound of the present invention has one or more of the following advantages: good selective inhibitory activity against JAK1 and / or TYK2; and good pharmacokinetic properties.

Description

Fused heteroaromatic ring compounds, pharmaceutical compositions thereof and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 2024108358653, filed on June 26, 2024. This application incorporates the entirety of the aforementioned Chinese Patent Application. TECHNICAL FIELD

[0002] The present application relates to fused heteroaromatic ring compounds, pharmaceutical compositions thereof and uses thereof. BACKGROUND

[0003] JAK1 and TYK2 are members of the Janus kinase family (JAKs), which also includes JAK2 and JAK3. JAKs are a class of non-receptor tyrosine kinases that play a crucial role in cell signaling, particularly in mediating the signaling of various cytokines, which are often associated with inflammation and immune responses.

[0004] Autoimmune diseases are a group of diseases that involve abnormal reactions of the immune system, leading to attacks on self-tissues and inflammation. These diseases include rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE), among others. Millions of people worldwide are affected by these chronic diseases, which not only reduce the quality of life of patients but also impose a significant economic burden. Traditional methods for treating autoimmune diseases include non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs). However, these treatments often have limited efficacy, multiple side effects, and poor patient compliance. In recent years, the emergence of biologics and JAK inhibitors has revolutionized the treatment of autoimmune diseases.

[0005] JAK inhibitors block the transmission of various cytokine signals by inhibiting the activity of the JAK kinase family, thereby reducing inflammation and immune responses. Although the first generation of JAK inhibitors, such as tofacitinib and baricitinib, have achieved some success in clinical practice, their broad inhibition spectrum can lead to adverse side effects, such as increased risk of infection, blood abnormalities, and tumor occurrence.

[0006] To overcome these limitations, researchers have begun to explore more selective JAK inhibitors, particularly dual inhibitors targeting TYK2 and JAK1. TYK2 / JAK1 inhibitors have attracted attention due to their high selectivity, as they can more precisely regulate immune responses while reducing inhibition of other JAK subtypes, potentially reducing the risk of side effects.

[0007] Currently, there are some TYK2 inhibitors on the market that have entered clinical trials and shown potential efficacy for a variety of autoimmune diseases. For example, deucravacitinib from BMS showed good efficacy and safety in the treatment of moderate-to-severe plaque psoriasis in clinical trials. In addition, brepocitinib, a TYK2 / JAK1 inhibitor from Pfizer, is also undergoing multiple phase II clinical trials, although it shows insufficient dose response in some indications, but it may have potential in other indications.

[0008] Despite the progress in the research and development of TYK2 / JAK1 inhibitors, there is still a need for new compounds and therapeutic methods to further optimize efficacy and safety to meet the unmet needs of patients. Therefore, the development of new TYK2 / JAK1 inhibitors, especially compounds with innovative structure design, pharmacokinetic properties and clinical applications, is of great significance to improve the treatment outcomes of patients with autoimmune diseases. SUMMARY

[0009] The technical problem to be solved by the present application is to provide a novel fused heteroaromatic ring compound, a pharmaceutical composition thereof and an application thereof to solve the problem of insufficient JAK1 and / or TYK2 selective inhibitors in the prior art. The fused heteroaromatic ring compound of the present application has one or more of the following advantages: good selective inhibitory activity on JAK1 and / or TYK2; good pharmacokinetic properties.

[0010] The present application solves the above technical problems by the following scheme.

[0011] The present application provides a compound as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof,

[0012] wherein,

[0013]

[0014] R 1 C1-C6alkyl, C3-C6cycloalkyl, 4-6 membered heterocycloalkyl or C1-C6alkyl substituted with one or more R 1-1 substituted with one or more R

[0015] R 1-1 independently -OH, -CN or halogen;

[0016] R 2 C3-C6cycloalkyl, 4-12 membered heterocycloalkyl, C1-C6alkyl substituted with one or more R 12 substituted with one or more R 2-1 ​substituted C3-C6cycloalkyl; 12 substituted C3-C6cycloalkyl; 2-2 substituted 4-12 membered heterocycloalkyl;

[0017] R 2-1 independently halogen, -NR b R c or -OC(=O)R e ;

[0018] R 2-2 independently halogen, -NR b R c , -C(=O)R d or -OC(=O)R e ;

[0019] R a -CN, -NR a-1 R a-2 , -C(=O)R a-4 , C1-C6alkyl, C1-C6alkoxy, halogen or C1-C6alkyl substituted with one or more R a-3 ;

[0020] R a-1 and R a-2 are each independently -H, C1-C6alkyl, -S(=O)2R A-1 , -C(=O)R A-2 , C1-C6alkyl substituted with one or more R A-3 ;

[0021] R A-1 and R A-2 are each independently C1-C6alkyl, C3-C6cycloalkyl, 4-6 membered heterocycloalkyl, C1-C6alkoxy or -NR B-1 R B- 2 ;

[0022] R B-1 and R B-2 are each independently -H or C1-C6alkyl;

[0023] R A-3 independently halogen;

[0024] R a-4 -NR B-1 R B-2 ;

[0025] R a-3 independently halogen, -CN, -S(=O)2R A-1or -C(=O)R a-4 ;

[0026] R b and R c each independently -H, C1-C6alkyl, -S(=O)2R A-1 , -C(=O)R A-2 or C1-C6alkyl substituted with one or more R b-1 ;

[0027] R b-1 independently halogen;

[0028] R d C1-C6alkyl, C1-C6alkoxy, -NR d-2 R d-3 or C1-C6alkyl substituted with one or more R d-1 ;

[0029] R d-1 -CN;

[0030] R d-2 and R d-3 each independently -H or C1-C6alkyl;

[0031] R e -NR e-1 R e-2 ;

[0032] R e-1 and R e-2 each independently -H or C1-C6alkyl;

[0033] or, two R 2-1 on the same carbon atom together form C3-C6cycloalkyl, 4-6 membered heterocycloalkyl, C3-C6cycloalkyl substituted with one or more R C-1 or 4-6 membered heterocycloalkyl substituted with one or more R C-2 ;

[0034] or, two R 2-2 on the same carbon atom together form C3-C6cycloalkyl, 4-6 membered heterocycloalkyl, C3-C6cycloalkyl substituted with one or more R C-1 or 4-6 membered heterocycloalkyl substituted with one or more R C-2 ;

[0035] R C-1 and R C-2 each independently halogen, -NR b R c , -C(=O)R dor -OC(=O)R e ;

[0036] R 3 independently -H, halogen, -CN or Ci-C6alkyl;

[0037] n is 0, 1, 2 or 3;

[0038] each "4-6 membered heterocycloalkyl" is independently a 4-6 membered heterocycloalkyl having one or two heteroatoms selected from N, O and S;

[0039] each "4-12 membered heterocycloalkyl" is independently a 4-12 membered heterocycloalkyl having one, two or three heteroatoms selected from N, O and S.

[0040] In certain preferred embodiments of the application, certain groups in the compounds of formula (I), the pharmaceutically acceptable salts thereof, the solvates thereof or the solvates of the pharmaceutically acceptable salts thereof are defined as follows, the groups not mentioned being as defined in any of the schemes of the application (simply "in a scheme of the application").

[0041] In a scheme of the application, each "Ci-C6alkyl" is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl, for example methyl, ethyl or i-propyl.

[0042] In a scheme of the application, each "C3-C6cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

[0043] In a scheme of the application, each "4-6 membered heterocycloalkyl" is independently a 4-6 membered heterocycloalkyl having one or two heteroatoms selected from N and / or O, for example oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl or piperazinyl.

[0044] In a scheme of the application, each "C3-C 12 cycloalkyl" is independently a C3-C6monocyclic cycloalkyl or a C6-C 12 bicyclic cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or C8spirocycloalkyl, further for example cyclohexyl or spiro[2.5]octanyl, preferably

[0045] In a preferred embodiment of the present application, each "4-12 membered heterocycloalkyl" is independently of the other 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N and / or O or 6-12 membered bicyclic heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N and / or O, for example oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl or piperazinyl, further for example tetrahydropyranyl or piperidinyl, preferably

[0046] In a preferred embodiment of the present application, each "halogen" is independently of the other F, CI, Br or I, for example F, CI or Br.

[0047] In a preferred embodiment of the present application, each "Ci-C6-alkoxy" is independently of the other methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy or t-butoxy, for example methoxy or ethoxy.

[0048] In a preferred embodiment of the present application,

[0049] In a preferred embodiment of the present application,

[0050] R 1 is Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R 1-1 ;

[0051] R 1-1 is independently of the other -OH;

[0052] R 2 is Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R 2-1 ; 12 cycloalkyl or 4-12 membered heterocycloalkyl substituted by one or more R 2-2 ;

[0053] R 2-1 and R 2-2 are each independently of the other

[0054] R a is -CN, -NR a-1 R a-2 or Ci-C6-alkyl substituted by one or more R a-3 ;

[0055] R a-1 and R a-2 are each independently of the other -H, Ci-C6-alkyl, -S(=0)2R A-1 or -C(=0)R A-2 ;

[0056] R A-1 and R A-2 each independently is C1-C6alkyl or C3-C6cycloalkyl;

[0057] R a-3 independently is halogen, -CN, -S(=O)2R A-1 or -C(=O)NR B-1 R B-2 ;

[0058] R B-1 and R B-2 each independently is -H or C1-C6alkyl;

[0059] R 3 independently is -H or halogen;

[0060] n is 0 or 1;

[0061] each "4-12 membered heterocycloalkyl" is independently of the other 4-12 membered heterocycloalkyl group a 4-12 membered heterocycloalkyl group having one, two or three heteroatoms selected from the group consisting of N, O and S.

[0062] In one embodiment of the present application, R 1-1 independently is -OH, -CN or -F.

[0063] In one embodiment of the present application, R 1 is C1-C3alkyl, C3-C4cycloalkyl or C1-C3alkyl substituted by one or more R 1-1 .

[0064] In one embodiment of the present application, R 1 is methyl, ethyl, isopropyl, cyclopropyl, wherein the carbon atom marked with an "*" is in R-configuration, S-configuration or a mixture thereof, preferably in R-configuration.

[0065] In one embodiment of the present application, R 1 is methyl, ethyl, isopropyl, cyclopropyl, preferably

[0066] In one embodiment of the present application, R a is -CN, -NR a-1 R a-2 , -C(=O)R a-4 , C1-C3alkoxy, halogen or C1-C3alkyl substituted by one or more R a- 3 , for example -CN, -NHS(=O)2RA-1 -NCH3S(=O)2R A-1 -NHC(=O)R A-2 -NCH3C(=O)R A-2 -C(=O)R a-4 C1-C3 alkoxy, halogen, or one or more R a-3 Substituted methyl groups, further for example -CN,

[0067] In inventing a certain solution, R 2-1 R 2-2 R C-1 and R C-2 Each independently is -F,

[0068] In one aspect of the present invention, R C-1 and R C-2 Each independently as -NR b R c ,For example

[0069] In one aspect of the present invention, R 2 Cyclohexyl, a 6-membered heterocyclic alkyl group, and formed by one or more R groups 2-1 Replacement C3-C 12 Cyclohexyl or cyclohexyl group with one or more R groups 2-2 Substituted 6-membered heterocyclic alkyl groups.

[0070] In one aspect of the present invention, R 2 for For example Further examples

[0071] In one aspect of the present invention, R 3 It can be -H, -F, -Cl, -Br, -CN, or -CH3 independently.

[0072] In one embodiment of the present invention, n is 1, 2 or 3.

[0073] In one aspect of the present invention, for R 3-1 R 3-2 and R 3-3 The definition of R is the same as in any embodiment of this invention. 3 .

[0074] In one aspect of the present invention, For R 3-1 , R 3-2 and R 3-3 are defined as R 3 in any one of the schemes of the present application.

[0075] In one scheme of the present application, R 3-1 , R 3-2 and R 3-3 are each independently -H, -F, -Cl, -Br, -CN or -CH3.

[0076] In one scheme of the present application, R 3-2 is independently H or F.

[0077] In one scheme of the present application, R 3-3 is independently H.

[0078] In one scheme of the present application, the compound of formula (I) is any one of the following compounds:

[0079] The present application also provides a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to any one of the above schemes, and a pharmaceutically acceptable excipient.

[0080] The present application also provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or the above pharmaceutical composition according to any one of the above schemes in the manufacture of a JAK1 and / or TYK2 selective inhibitor.

[0081] The present application also provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or the above pharmaceutical composition according to any one of the above schemes in the manufacture of a medicament for preventing and / or treating a disease associated with JAK1 and / or TYK2, preferably an autoimmune disease.

[0082] The present application also provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or the above pharmaceutical composition according to any one of the above schemes in the manufacture of a medicament for preventing and / or treating an autoimmune disease.

[0083] In addition to the foregoing, the following terms, as used in the specification and claims, have the following meanings unless otherwise specifically indicated:

[0084] The term "pharmaceutically acceptable salt" means a salt of a compound of the present application prepared from a relatively nontoxic, pharmaceutically acceptable acid or base. Alkali addition salts can be prepared from the neutral form of the compounds of the present application by contacting these compounds in pure solution or in a suitable inert solvent with a sufficient amount of the pharmaceutically acceptable base to produce the desired salt. Acid addition salts can be prepared by contacting the neutral form of the compounds of the present application in pure solution or in a suitable inert solvent with a sufficient amount of the pharmaceutically acceptable acid to produce the desired salt.

[0085] The term "solvate" means a compound in combination with a solvent. Solvates are classified into stoichiometric solvates and non-stoichiometric solvates.

[0086] The term "solvate of a pharmaceutically acceptable salt" means a compound in combination with a pharmaceutically acceptable acid or base, a solvent. The amount of solvent can be stoichiometric or non-stoichiometric.

[0087] The term "halogen" means F, Cl, Br, I.

[0088] The term "alkyl" means a straight or branched, saturated, monovalent hydrocarbon group having the indicated number of carbon atoms (e.g., C 1-6 , C 1-3 ). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0089] The term "alkoxy" means the group -O-R X , wherein R X is alkyl as defined above.

[0090] The term "cycloalkyl" means a saturated monocyclic or polycyclic ring group having the indicated number of ring carbon atoms (e.g., C 3-12 or C 3-6 ). The ring atoms consist only of carbon atoms. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or spiro[2.5]octyl, and the like.

[0091] The term "heterocycloalkyl" means a saturated monocyclic or polycyclic ring group having the indicated number of ring atoms (e.g., 3-12 membered, 3-6 membered), the indicated number of heteroatoms (e.g., 1, 2, or 3), and the indicated number of kinds of heteroatoms (e.g., 1, 2, or 3 of N, O, and S). Heterocycloalkyl groups include, but are not limited to, oxiranyl, aziridinyl, oxetanyl, azetidinyl, pyrrolinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, or piperazinyl.

[0092] The term "halogen" refers to F, Cl, Br, I.

[0093] The term "one or more" refers to 1, 2, 3, 4 or more, for example 1, 2 or 3.

[0094] As understood by those skilled in the art, the use of means that the corresponding group R is connected to other fragments, groups in the compound via this site.

[0095] Herein, a substituent group used in this text can be preceded by a single dash "-" to indicate that the named substituent is attached to the parent moiety by a single bond.

[0096] The term "pharmaceutically acceptable excipient" refers to excipients and additives used in the production of pharmaceutical products and the dispensing of prescriptions, and all substances included in pharmaceutical preparations other than the active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) Volume IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0097] The term "treatment" refers to therapeutic treatment. When referring to a particular condition, treatment means: (1) alleviating one or more biological manifestations of the disease or condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) improving one or more symptoms, effects or side effects associated with the condition or one or more symptoms, effects or side effects associated with the condition or its treatment, or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0098] The term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0099] In the application, the inhibitors can be used in vivo in mammalian organisms; they can also be used in vitro, mainly as experimental purposes, such as providing a standard or control sample for comparison, or according to conventional methods in the art to prepare a kit for rapid detection of JAK1 and / or TYK2 inhibition effect.

[0100] On the basis of common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain each preferred example of the present application.

[0101] The reagents and raw materials used in the present application are commercially available.

[0102] The positive progress effect of the present application is that the fused heteroaromatic ring compound has good selective inhibitory activity on JAK1 and / or TYK2. DETAILED DESCRIPTION

[0103] The present application is further illustrated by the following examples without thereby limiting the present application to the examples described. The experimental methods in the following examples, if not otherwise specified, are carried out according to the conventional methods and conditions, or according to the instructions of the commercial products.

[0104] General procedure

[0105] When the preparation route is not included, the raw materials and reagents used in the present application are known products, which can be synthesized according to the known methods in the art, or can be obtained by purchasing commercial products. The commercial reagents used do not need to be further purified.

[0106] Room temperature refers to 20-30℃.

[0107] The reactions in the reaction examples are carried out under nitrogen atmosphere, if not otherwise specified. The nitrogen atmosphere refers to that the reaction bottle is connected to a nitrogen balloon of about 1L.

[0108] The hydrogenation reaction is usually vacuumed and filled with hydrogen, and the operation is repeated for 3 times. The hydrogen atmosphere refers to that the reaction bottle is connected to a hydrogen balloon of about 1L.

[0109] Microwave reaction uses Initiator + microwave reactor.

[0110] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR is measured by a (BRUKER AVANCE III type, 400M) nuclear magnetic instrument, and the measuring solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, brs = broad singlet, d = doublet, t = triplet, m = multiplet. The coupling constant is listed as J value, measured in Hz.

[0111] The flash column chromatography uses the automatic column machine of Ajil (FS-9200T), and the pre-packed column of silica gel uses the pre-packed column of SanTai. The thin layer chromatography silica gel plate uses the silica gel plate of Yantai Huanghai HSGF254 or Qingdao GF254, and the specification used for the thin layer chromatography separation and purification product is 0.4mm-0.5mm.

[0112] The reverse phase preparative chromatography uses the Waters-3767 reverse phase preparative chromatograph.

[0113] Preparation column: Waters SunFire, 250*19mm, 5mm

[0114] or Xbridge Prep C18 or Gemini C18 21.2*250 5um

[0115] Mobile phase: A: 0.05% Ammonia in water; B: Acetonitrile

[0116] Detection wavelength: 254nm & 214nm

[0117] Flow rate: 20 mL / min

[0118] LC / MS used Waters ARC HPLC-QDA type instrument.

[0119] Column: ACQUITY UPLC BEH C18 3.5m 3.0*50mm

[0120] Ion source: ESI

[0121] Mobile phase: A: 0.05% Ammonia in water; B: 0.05% Ammonia in Acetonitrile

[0122] Detection wavelength: 254nm & 214nm

[0123] Run time: 1.5 mL / min / 3.5 min

[0124] HPLC used Waters W2489 Instrument type instrument.

[0125] Column: Xbridge C18, 4.6*50mm

[0126] Mobile phase: A: 0.1% Ammonia in water; B: Acetonitrile

[0127] Detection wavelength: 254nm & 214nm

[0128] Run time: 9.0 min

[0129] Supercritical fluid chromatography (SFC) used Waters SFC 150 type instrument.

[0130] Column: DAICEL OJ-10 or DAICEL AD-10

[0131] Mobile phase: A: Supercritical CO2; B: 0.05% Ammonia in Methanol

[0132] Detection wavelength: 254nm & 214nm

[0133] The following compounds are prepared as salts, and the structural formulae represent only the class of salt produced, without limitation as to the number of acid or base molecules. For example, the structural formula of Int-1 represents only that Int-1 is a hydrochloride salt, without limitation as to the number of HCl molecules.

[0134] The following compounds are prepared as salts, and the structural formulae represent only the class of salt produced, without limitation as to the number of acid or base molecules. For example, the structural formula of Int-1

[0135] Intermediate 1

[0136] Intermediate 1 is prepared by the following steps:

[0137] Step A: 2-(Tri-tert-butylphosphonio)acetonitrile (10.0 g, 41.43 mmol) and Int- la (4.5 g, 20.72 mmol) were dissolved in dry tetrahydrofuran (150 mL) and stirred at 80 °C for 3 hours. TLC showed the reaction was complete. The reaction was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound Int- lb (10.4 g, crude), which was used directly in the next step. LC / MS (ESI + m / z: 239.2 [M+H] + .

[0138] Step B: To a solution of compound Int- lb (10.4 g, crude from the previous step) in methanol (150 mL) was added 10% palladium on carbon (1.0 g). The system was replaced with hydrogen gas and stirred at room temperature under hydrogen balloon pressure overnight. LC / MS showed the reaction was complete. The reaction was filtered and the filtrate was concentrated to give compound Int- lc (9.5 g) as a mixture of cis and trans. LC / MS (ESI + m / z: 241.3 [M+H] + .

[0139] Step C: To a solution of compound Int- lc (9.5 g, 39.53 mmol) in dichloromethane (100 mL) was added hydrochloric acid (4.0 N in dioxane) (50 mL). The mixture was stirred at room temperature for 3 hours. TLC showed the reaction was complete. To the mixture was added methyl tert-butyl ether and filtered. The filter cake was dried to give compound Int- 1 (5.5 g, yield 99%) as a mixture of cis and trans. LC / MS (ESI + m / z: 141.3 [M+H] + .

[0140] In the process of hydrogenation reduction of the double bond from Int-1b to Int-1c, according to the reaction mechanism, the reaction result is mainly cis product, that is, in the generated Int-1, the amount of cis product is more than that of trans product, so in the subsequent reaction with Int-1 as the intermediate, the relatively large amount of product is also cis product, and the relatively small amount of product is trans product.

[0141] The synthesis method of the compound of the embodiment in the application is as follows:

[0142] Example 1

[0143] 2-((2R,5S)-5-(2-methyl-1H-imidazo[4,5-d]pyrrolo[1,2-b]pyridazin-1-yl)tetrahydro-2H-pyran-2-yl)acetonitrile

[0144] Example 1 is prepared by the following steps:

[0145] Step A: A mixture of compound 1a (5.3 g) and compound 1b (16.7 g) was stirred at 125°C for 1 hour, the mixture was diluted with diphenyl ether (15 mL), and then heated to 180°C and stirred for 6 hours. LC / MS showed that the reaction was complete. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 97 / 3) to obtain compound 1c (10.0 g, yield: 75%). LC / MS (ESI + m / z: 207.1 [M+H] + .

[0146] Step B: To a solution of compound 1c (6.0 g) in phosphorus oxychloride (89.2 g) was slowly added triethylamine (5.9 g) at 0°C, and the reaction mixture was warmed to 110°C and stirred for 16 hours. The reaction liquid was concentrated, and the residue was added to ice water and extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. Filtration and concentration obtained compound 1d (6 g), which was directly used in the next step. LC / MS (ESI + m / z: 225.0 [M+H] + .

[0147] Step C: Lithium hydroxide (2.56 g) was slowly added to a mixture of compound Id (6.0 g) in tetrahydrofuran (30 mL) and water (5 mL) at room temperature, then stirred at 60 °C for 1 h. The reaction was diluted with water, adjusted to pH 5-6 with 1 N hydrochloric acid solution, and extracted with ethyl acetate. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give compound 1e (5.0 g, yield: 95%). LC / MS (ESI + m / z: 197.1 [M+H] + .

[0148] Step D: Compound 1e (3.0 g), azidodiphenyl phosphate (6.3 g), and triethylamine (4.6 g) were dissolved in dry tert-butanol (20 mL) and stirred at 90 °C for 16 h. The reaction was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give compound 1f (4.0 g, yield: 97%). LC / MS (ESI + m / z: 268.0 [M+H] + .

[0149] Step E: Compound 1f (1.0 g), Int-1 (1.05 g), tris(dibenzylideneacetone)dipalladium (684 mg), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (697 mg), and cesium carbonate (4.8 g) were dispersed in 1,4-dioxane (40 mL), and the reaction system was stirred at 100 °C for 2 h under a nitrogen atmosphere after being replaced with nitrogen. The reaction was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give trans isomer 1g (150 mg, yield: 10%); the polarity was increased (dichloromethane / methanol = 9 / 1) to give the cis isomer. LC / MS (ESI + m / z: 372.2 [M+H] + .

[0150] Step F: Compound 1g (150 mg) and trifluoroacetic acid (1 mL) were added to dichloromethane (3 mL), and the reaction was stirred at room temperature for 0.5 h, and LC / MS showed that the reaction was complete. The reaction was concentrated, and the pH was adjusted to 8 with triethylamine, and then purified by reverse-phase prep-HPLC to give compound 1h (40 mg, yield: 36%). LC / MS (ESI + m / z: 272.2 [M+H] + .

[0151] Step G: Compound 1h (150 mg), pyridine hydrochloride (64 mg) and trimethyl orthoacetate (2 mL) were added to a mixture of 1,2-dichloroethane (1 mL) and tetrahydrofuran (1 mL). The reaction mixture was stirred at 80 °C for 16 h. The reaction was concentrated and the residue was purified by reverse phase prep-HPLC to give compound 1 (12.6 mg, yield: 7.7%). LC / MS (ESI + m / z: 296.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.83 (dd, J = 2.8 and 1.6 Hz, 1H), 6.83 - 6.76 (m, 2H), 4.61 (br s, 1H), 4.10 (d, J = 8.4 Hz, 2H), 4.04 (br s, 1H), 2.95 - 2.86 (m, 1H), 2.83 - 2.76 (m, 1H), 2.65 (s, 3H), 2.18 - 2.12 (m, 1H), 2.03 - 1.97 (m, 1H), 1.78 - 1.66 (m, 1H), 1.26 - 1.20 (m, 1H).

[0152] Example 2

[0153] 2-((2R,5S)-5-(2-ethyl-lH-imidazo[4,5-d]pyrrolo[l,2-b]pyridazin-l-yl)tetrahydro- 2H-pyran-2-yl)acetonitrile

[0154] Example 2 was prepared from the following steps:

[0155] Step A: Compound 1h (30 mg), pyridine hydrochloride (12 mg) and trimethyl ortho-propionate (2 mL) were added to a mixture of 1,2-dichloroethane (1 mL) and anhydrous tetrahydrofuran (1 mL). The reaction mixture was stirred at 80 °C for 16 h. The reaction was concentrated and the residue was purified by reverse phase prep-HPLC to give compound 2 (0.9 mg, yield: 2.6%). LC / MS (ESI + m / z: 310.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.83 (t, J = 2.2 Hz, 1H), 6.84-6.78 (m, 2H), 4.62 (br s, 1H), 4.18-4.02 (m, 3H), 3.28-3.25 (m, 1H), 3.02 (q, J = 7.2 Hz, 2H), 2.94-2.75 (m, 2H), 2.16-2.06 (m, 1H), 2.03-1.97 (m, 1H), 1.76-1.66 (m, 1H), 1.34 (t, J = 7.4 Hz, 3H).

[0156] Example 3

[0157] 2-((2R,5S)-5-(2-((R)-1-hydroxyethyl)-1H-imidazo[4,5-d]pyrrolo[1,2-b]pyridazin-1-yl)tetrahydro-2H-pyran-2-yl)acetonitrile

[0158] Example 3 was prepared from the following steps:

[0159] Step A: (R)-(+)-lactamide (49 mg) was added to a solution of triethyloxonium tetrafluoroborate (105 mg) in THF (2 mL) at 0 °C, stirred for 10 min, then added dropwise to a solution of compound 1h (30 mg) in ethanol (2 mL) at 90 °C, the reaction mixture was stirred at 90 °C for 10 min. The reaction was concentrated, the residue was purified by reverse phase prep-HPLC to give compound 3 (4.2 mg, yield: 11%). LC / MS (ESI + )m / z: 326.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.87-7.84 (m, 1H), 6.86-6.81 (m, 2H), 5.83 (br s, 1H), 5.16-5.10 (m, 1H), 5.00 (br s, 1H), 4.20-4.02 (m, 3H), 2.96-2.78 (m, 2H), 2.13 (s, 1H), 2.16-1.98 (m, 2H), 1.73-1.58 (m, 5H).

[0160] Example 4

[0161] 2-((2R,5S)-5-(8-fluoro-2-methyl-1H-imidazo[4,5-d]pyrrolo[1,2-b]pyridazin-1-yl)tetrahydro-2H-pyran-2-yl)acetonitrile

[0162] Example 4 was prepared from the following steps:

[0163] Step A: Compound 4a (5.0 g, 34.94 mmol), diphenylphosphoryl hydroxylamine (12.2 g, 52.41 mmol) and cesium carbonate (22.7 g, 69.87 mmol) were added into N,N-dimethylformamide (60 mL) sequentially, stirred at room temperature for 1 h. LC / MS showed the reaction was completed. The reaction was quenched by water, extracted with ethyl acetate, the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated by filtration. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 4b (4.0 g, yield: 81%). LC / MS (ESI + m / z: 159.2 [M+H] + .

[0164] Step B: Compound 4b (6.8 g, 43.00 mmol), p-toluenesulfonic acid (370 mg, 2.15 mmol) and compound 4c (9.30 g, 64.50 mmol, 9.38 mL) were dissolved in ethanol (60 mL), stirred at 100 °C overnight. LC / MS showed the reaction was completed. The reaction was concentrated, the residue was purified by silica gel column chromatography (dichloromethane / petroleum ether = 1 / 10) to give compound 4d (6.0 g, yield: 62%). LC / MS (ESI + m / z: 257.4 [M+H] + .

[0165] Step C: Compound 4d (6.0 g, 23.42 mmol) and sodium tert-butoxide (4.50 g, 46.83 mmol) were dissolved in ethanol (45.61 mL), stirred at 100 °C overnight. LC / MS showed the reaction was completed. The reaction was concentrated, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 4e (3.1 g, yield: 59%). LC / MS (ESI + m / z: 225.3 [M+H] + .

[0166] Step D: Compound 4e (2.0 g, 8.92 mmol) was dissolved in phosphorus oxychloride (25 mL), N,N-diisopropylethylamine (11.5 g, 89.21 mmol, 15.5 mL) was added at 0 °C. The reaction mixture was warmed to 120 °C and stirred for 2 hours. LC / MS showed the reaction was completed. The reaction was quenched by slowly dropping into ice water. The reaction was extracted by ethyl acetate, the organic phase was combined, washed by saturated sodium chloride solution, dried over anhydrous sodium sulfate. It was concentrated by filtration, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 4f (800 mg, yield: 36%). LC / MS (ESI + m / z: 243.1 [M+H] + .

[0167] Step E: Compound 4f (800 mg, 3.30 mmol) and lithium hydroxide (276 mg, 6.59 mmol) were dissolved in a mixture solution of tetrahydrofuran (5 mL) and water (5 mL), stirred at room temperature for 2 hours. LC / MS showed the reaction was completed. Water and 1 N hydrochloric acid were added to adjust the pH to 5-6, extracted by ethyl acetate, the organic phase was combined, washed by saturated sodium chloride solution, dried over anhydrous sodium sulfate. It was concentrated by filtration to give compound 4g (600 mg, yield: 84%). LC / MS (ESI + m / z: 215.2 [M+H] + .

[0168] Step F: Compound 4g (600 mg, 2.80 mmol), diphenyl phosphorazide (1.15 g, 4.19 mmol, 903 μί) and triethylamine (565 mg, 5.59 mmol) were dissolved in tert-butanol (10 mL), stirred at 90 °C for 3 hours. LC / MS showed the reaction was completed. The reaction was concentrated, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 4h (700 mg, yield: 87%). LC / MS (ESI + m / z: 286.6 [M+H] + .

[0169] Step G: Compound 4h (200 mg, 700 μmol), Int-1 (147 mg, 1.05 mmol), cesium carbonate (684 mg, 2.10 mmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'- biphenyl (65 mg, 140 μmol) and tris(dibenzylideneacetone)dipalladium (64 mg, 70 μmol) were dispersed in 1,4-dioxane (10 mL), the reaction system was replaced by nitrogen, and stirred at 110 °C for 5 hours under nitrogen atmosphere. LC / MS showed that the reaction was completed. The reaction solution was concentrated, and the residue was purified by reverse phase C18 column chromatography (acetonitrile / water = 1 / 1) to obtain compound 4i (130 mg, yield: 47%). LC / MS (ESI + m / z: 390.7 [M+H] + .

[0170] Step H: Compound 4i (130 mg, 333 μmol) and trifluoroacetic acid (2 mL) were added to dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. LC / MS showed that the reaction was completed. Sodium bicarbonate solution was added to quench the reaction, extracted with ethyl acetate, combined organic phase, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration and concentration gave compound 4j (90 mg, yield: 93%). LC / MS (ESI + m / z: 290.5 [M+H] + .

[0171] Step I: Compound 4j (20 mg, 69 μmol) was dissolved in a mixed solution of 1,2-dichloroethane (1 mL) and ethanol (1 mL), and trimethyl orthoacetate (33 mg, 276 μmol) was slowly added dropwise. The reaction solution was warmed to 100 °C and stirred for 16 hours. LC / MS showed that about 50% of the product was generated and 40% of the cis-unringed intermediate state. The reaction solution was directly purified by reverse phase prep-HPLC to obtain compound 4 (2.8 mg, yield: 12%). LC / MS (ESI + m / z: 314.8 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.90 (t, J = 2.3 Hz, 1H), 6.73 (s, 1H), 4.59 (br s, 1H), 4.12-4.00 (m, 3H), 2.94-2.77 (m, 2H), 2.66 (s, 3H), 2.48-2.40 (m, 1H), 2.18-2.11 (m, 1H), 2.02-1.95 (m, 1H), 1.78-1.68 (m, 1H).

[0172] Example 5

[0173] 2-((2R,5S)-5-(9-fluoro-2-methyl-1H-imidazo[4,5-d]pyrrolo[1,2-b]pyridazin-1-yl)tetrahydro- 2H-pyran-2-yl)acetonitrile

[0174] Example 5 was prepared from the following steps:

[0175] Step A: Compound 5a (10 g), diphenylphosphoryl hydroxylamine (22.2 g) and cesium carbonate (41.5 g) were added into N,N-dimethylformamide (200 mL) sequentially, and reacted at room temperature for 1 hour. LC / MS showed the reaction was complete. The reaction was poured into water and extracted with ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 5b (10.7 g, yield: 97%). LC / MS (ESI + m / z: 172.9 [M+H] + .

[0176] Step B: Compound 5b (10.7 g), compound 4c (13.4 g) and p-toluenesulfonic acid (535 mg) were dissolved in ethanol (110 mL). The reaction was carried out at 100 °C for 16 hours, and LC / MS showed the reaction was complete. The reaction was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / dichloromethane = 1 / 1) to give compound 5c (8.5 g, crude), which was used directly in the next step. LC / MS (ESI + m / z: 271.1 [M+H] + .

[0177] Step C: Compound 5c (8.5 g, from the previous step) and sodium tert-butoxide (6.05 g) were dissolved in ethanol (80 mL) and reacted at 100 °C for 16 hours, and LC / MS showed the reaction was complete. The reaction was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give compound 5d (2.3 g, crude), which was used directly in the next step. LC / MS (ESI + m / z: 225.5 [M+H] + .

[0178] Step D: Compound 5d (1.0 g) and N,N-diisopropylethylamine (5.76 g) were added to phosphorus oxychloride (15 mL) and reacted at 120 °C for 2 h. TLC showed the reaction was complete. The system was slowly dropped into ice water, extracted with ethyl acetate, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give compound 5e (425 mg). 1 H NMR (400 MHz, Chloroform-d) δ 8.31 (s, 1H), 7.51 (dd, J = 4.4 and 3.2 Hz, 1H), 6.57 (d, J = 3.2 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H).

[0179] Step E: Compound 5e (720 mg) and lithium hydroxide (355.3 mg) were added to tetrahydrofuran (8 mL) and water (8 mL). The reaction was carried out at room temperature for 2 h. LC / MS showed the reaction was complete. The reaction was poured into water (100 mL), the pH was adjusted to 4-5 with hydrochloric acid, extracted with ethyl acetate, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 5f (573 mg, yield: 90%). LC / MS (ESI + m / z: 212.9 [M+H] + .

[0180] Step F: Compound 5f (690 mg), diphenyl phosphorazide (1.3 g) and triethylamine (650.8 mg) were added to tert-butanol (20 mL). The reaction was carried out at 90 °C for 2 h under nitrogen protection. LC / MS showed the reaction was complete. The reaction was concentrated, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give compound 5g (650 mg, yield: 65%). LC / MS (ESI + m / z: 285.9 [M+H] + .

[0181] Step G: Compound 5g (790 mg), Int-1 (581 mg), 2-dicyclohexylphospho-2',6'- diisopropoxy-1,1'-biphenyl (258 mg), tris(dibenzylideneacetone)dipalladium (253 mg) and cesium carbonate (2.7 g) were dispersed in 1,4-dioxane (15 mL). The reaction system was replaced with nitrogen and reacted at 110 °C for 4 h under nitrogen atmosphere. LC / MS showed the reaction was complete. The reaction was concentrated, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 5h (590 mg, yield: 54%). LC / MS (ESI +m / z: 390.0 [M+H] + .

[0182] Step H: Compound 5h (270 mg) and trifluoroacetic acid (3 mL) were added to dichloromethane (9 mL). The reaction was stirred at room temperature for 1 h, LC / MS showed the reaction was complete. The reaction was concentrated to give trifluoroacetate salt of compound 5i (420 mg), which was used directly for the next step. LC / MS (ESI + m / z: 290.1 [M+H] + .

[0183] Step I: Compound 5i (420 mg, from previous step), pyridine hydrochloride (83.9 mg) were added to trimethyl orthoacetate (6 mL) and 1,4-dioxane (6 mL). The reaction was stirred at 140 °C for 16 h in a sealed tube, LC / MS showed the reaction was complete. The reaction was concentrated under reduced pressure, the residue was purified by reverse C18 column (water / acetonitrile = 3 / 2) to give 88 mg of crude. Further purification by SFC gave compound 5 (33.3 mg) and 5’ (17.5 mg). The absolute configuration of compound 5 and 5’ were determined by NMR analysis.

[0184] Compound 5: LC / MS (ESI + m / z: 314.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.70 (t, J = 4.0 Hz, 1H), 6.76 (d, J = 3.2 Hz, 1H), 4.81 (br s, 1H), 4.18 - 4.00 (m, 2H), 3.88 - 3.80 (m, 1H), 2.93 - 2.74 (m, 2H), 2.65 (s, 3H), 2.41 - 2.31 (m, 1H), 2.20 - 2.08 (m, 1H), 2.00 - 1.93 (m, 1H), 1.62 - 1.50 (m, 1H).

[0185] Compound 5’: LC / MS (ESI + m / z: 314.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.68 (dd, J = 4.4, 3.2 Hz, 1H), 6.74 (d, J = 3.2 Hz, 1H), 4.89 (br s, 1H), 4.43-4.36 (m, 1H), 4.10-3.96 (m, 2H), 3.07-2.86 (m, 2H), 2.77 (s, 3H), 2.25-2.10 (m, 2H), 1.82-1.71 (m, 1H), 1.63-1.50 (m, 1H).

[0186] Example 6

[0187] 2-((2R,5S)-5-(8-fluoro-2-((R)-1-hydroxyethyl)-1H-imidazo[4,5-d]pyrrolo[1,2-b]pyridazin-1- yl)tetrahydro-2H-pyran-2-yl)acetonitrile

[0188] Example 6 was prepared from the following steps:

[0189] Step A: Triethyl oxonium tetrafluoroborate (591 mg), (R)-(+)-lactamide (277 mg) was added to anhydrous tetrahydrofuran (2 mL) at 0 °C and stirred for 10 min, then it was added dropwise to a solution of compound 4j (90 mg) in anhydrous ethanol (2 mL) at 90 °C, the stirring was continued for 10 min after which the reaction was completed. The reaction was concentrated, the residue was purified by reverse phase Prep-HPLC to give compound 6 (1.5 mg, yield: 1.4 %). LC / MS (ESI + m / z: 344.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.94 (s, 1H), 6.80 (s, 1H), 5.87 (d, J = 7.2 Hz, 1H), 5.14 (t, J = 6.8 Hz, 1H), 4.99 (br s, 1H), 4.15 (br s, 1H), 4.07 (d, J = 8.4 Hz, 2H), 3.00-2.85 (m, 2H), 2.15-1.99 (m, 2H), 1.61 (d, J = 6.4 Hz, 3H), 1.30-1.20 (m, 2H).

[0190] Example 7

[0191] N-(((1R,4r)-4-(2-((R)-1-hydroxyethyl)-1H-imidazo[4,5-d]pyrrolo[1,2-b]pyridazin-1-yl)cyclohexyl)methyl)methanesulfonamide

[0192] Example 7 was prepared from the following steps:

[0193] Step A: Compound 7a (200 mg, 875 pmol) and triethylamine (106 mg, 1.05 mmol, 146 pL) were dissolved in N,N-dimethylformamide (3 mL), to the solution was added methanesulfonyl chloride (120 mg, 1.05 mmol, 81 pL) at 0 °C, stirred at room temperature overnight. LC / MS showed the reaction was completed. The reaction was quenched with water, extracted with ethyl acetate, combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound 7b (220 mg, yield: 81%). LC / MS (ESI+) m / z: 307.3 [M+H] + .

[0194] Step B: Compound 7b (220 mg, 717 pmol) was dissolved in dichloromethane (5 mL), to the solution was added trifluoroacetic acid (2 mL). Stirred at room temperature for 2 hours. LC / MS showed the reaction was completed. The reaction was concentrated to give trifluoroacetate salt of compound 7c (290 mg), which was used directly in the next step. LC / MS (ESI+) m / z: 207.6 [M+H] + .

[0195] Step C: Compound If (250 mg, 933 pmol), compound 7c (231 mg, from previous step), cesium carbonate (912 mg, 2.80 mmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'- biphenyl (174 mg, 373 pmol), tris(dibenzylideneacetone)dipalladium (171 mg, 186 pmol) were dissolved in dioxane (20 mL). The reaction system was replaced with nitrogen, stirred at 110 °C for 5 hours under nitrogen atmosphere. LC / MS showed the reaction was completed. The reaction was concentrated, the residue was purified by reverse phase C18 column (acetonitrile / water = 1 / 1) to give compound 7d (135 mg, yield: 33%). LC / MS (ESI + )m / z: 438.9 [M+H] + .

[0196] Step D: Compound 7d (135 mg, 308 pmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added slowly, the reaction was stirred at room temperature for 1 hour. LC / MS showed the reaction was completed. The reaction was concentrated to give trifluoroacetate salt of compound 7e (170 mg), which was used directly in the next step. LC / MS (ESI + )m / z: 338.2 [M+H] + .

[0197] Step E: Triethyl oxonium tetrafluoroborate (957 mg, 5.04 mmol, 720 μL) and (R)-(+)-lactamide (448 mg, 5.04 mmol) were added to tetrahydrofuran (1 mL) and stirred at room temperature until clear. The mixture was added dropwise to a solution of compound 7e (170 mg, 503 μmol) in ethanol (2 mL) at 90 °C and the mixture was stirred at 90 °C for 20 minutes. LC / MS showed the reaction was complete. The reaction was concentrated and the residue was purified by reverse phase prep-HPLC to give compound 7 (5.6 mg, yield: 2.8%). LC / MS (ESI + )m / z: 392.7 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.83 (dd, J = 2.7 and 1.2 Hz, 1H), 7.05 (t, J = 6.0 Hz, 1H), 6.84 - 6.80 (m, 1H), 6.66 (t, J = 3.6 Hz, 1H), 5.72 (br s, 1H), 5.14 - 5.06 (m, 1H), 4.84 (br s, 1H), 2.95 - 2.87 (m, 5H), 2.32 - 2.20 (m, 2H), 2.00 - 1.90 (m, 4H), 1.78 (br s, 1H), 1.61 (d, J = 6.4 Hz, 3H), 1.26 - 1.20 (m, 2H).

[0198] Example 8

[0199] N-(((1R,4r)-4-(2-((R)-1-hydroxyethyl)-1H-imidazo[4,5-d]pyrrolo[1,2-b]pyridazin-1- yl)cyclohexyl)methyl)acetamide

[0200] Example 8 was prepared from the following steps:

[0201] Step A: Compound 8a (300 mg) and triethylamine (159 mg) were added to N,N- dimethylformamide (10 mL). After dropwise addition of acetic anhydride (161 mg) at 0 °C, the reaction was continued at room temperature for 1 hour. TLC showed the reaction was complete. The mixture was poured into water and extracted with ethyl acetate three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 8b (310 mg), which was used directly for the next step. LC / MS (ESI + )m / z: 271.3 [M+H] + .

[0202] Step B: Compound 8b (310 mg, from previous step) and trifluoroacetic acid (4 mL) were added to dichloromethane (12 mL) and the reaction was stirred at room temperature for 1 h. TLC showed the reaction was complete. The reaction was concentrated to give trifluoroacetate salt of compound 8c (420 mg) which was used directly in the next step. LC / MS (ESI + m / z: 171.3 [M+H] + .

[0203] Step C: Compound 8c (420 mg, from previous step), compound If (255 mg), 2- dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (89 mg), tris(dibenzylideneacetone)dipalladium (87 mg) and cesium carbonate (933 mg) were dissolved in 1,4-dioxane (10 mL). The reaction was stirred at 110 °C under nitrogen atmosphere for 2 h. LC / MS showed the reaction was complete. The reaction was concentrated and the residue was purified by reverse phase C18 column (water / acetonitrile = 3 / 2) to give compound 8d (80 mg, 15% over 3 steps). LC / MS (ESI + m / z: 402.3 [M+H] + .

[0204] Step D: Compound 8d (80 mg) and trifluoroacetic acid (2 mL) were added to dichloromethane (6 mL) and the reaction was stirred at room temperature for 1 h. LC / MS showed the reaction was complete. The reaction was concentrated to give trifluoroacetate salt of compound 8e (140 mg) which was used directly in the next step. LC / MS (ESI + m / z: 302.1 [M+H] + .

[0205] Step E: Triethylsilyl trifluoromethanesulfonate (220.6 mg) and (R)-(+)-lactamide (103.5 mg) were added to tetrahydrofuran (1.5 mL) and stirred at room temperature until clear. The mixture was added dropwise to a solution of compound 8e (70 mg) in ethanol (1.5 mL) at 90 °C. The reaction was stirred at 90 °C for 30 min. LC / MS showed the reaction was complete. The reaction was concentrated and the residue was purified by silica gel column (dichloromethane / methanol = 15 / 1) to give 25 mg of crude product which was further purified by reverse phase Prep-HPLC to give compound 8 (8.4 mg, 10.2% yield). LC / MS (ESI + m / z: 356.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.90-7.80 (m, 2H), 6.82 (dd, J = 4.4 and 2.8 Hz, 1H), 6.64 (d, J = 4.4 Hz, 1H), 5.70 (br s, 1H), 5.15-5.05 (m, 1H), 4.90-4.76 (m, 1H), 3.05-2.95 (m, 2H), 2.31-2.20 (m, 2H), 2.00-1.90 (m, 4H), 1.84 (s, 3H), 1.77-1.70 (m, H), 1.61 (d, J = 6.4 Hz, 3H), 1.26-1.12 (m, 2H).

[0206] Example 9

[0207] 3-((1R,4r)-4-(2-((R)-1-hydroxyethyl)-1H-imidazo[4,5-d]pyrrolo[1,2-b]pyridazin-1- yl)cyclohexyl)propanenitrile

[0208] Example 9 was prepared from the following steps:

[0209] Step A: To a suspension of potassium tert-butoxide (1.18 g, 10.56 mmol) in dry tetrahydrofuran (20 mL) was added diethyl cyanomethylphosphonate (1.87 g, 10.56 mmol) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, then a solution of compound 9a (2 g, 8.80 mmol) in tetrahydrofuran (40 mL) was added slowly to the reaction, and the mixture was stirred at room temperature for 1 h. TLC showed the reaction was complete. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound 9b (2.6 g), which was used directly for the next step. LC / MS (ESI + m / z: 251.3 [M+H] + .

[0210] Step B: To a solution of compound 9b (2.6 g, from the previous step) in ethanol (40 mL) was added 10% Pd / C (500 mg). After the reaction system was replaced with hydrogen gas, it was stirred at 40 °C under hydrogen atmosphere (balloon) for 16 h. TLC showed the reaction was complete, and the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give compound 9c (1.8 g, two-step yield: 81%). LC / MS (ESI + m / z: 253.2 [M+H] + .

[0211] Step C: Compound 9c (1.1 g, 4.36 mmol) was dissolved in dichloromethane (15 mL), to the solution was added trifluoroacetic acid (15 mL). It was stirred at room temperature for 0.5 h. TLC showed the reaction was complete. The reaction was concentrated, the solid was washed with diethyl ether and dried under vacuum to give trifluoroacetate salt of compound 9d (1.0 g), which was used directly in the next step. LC / MS (ESI + m / z: 153.2 [M+H] + .

[0212] Step D: Compound If (500 mg, 1.87 mmol), compound 9d (568 mg, from previous step), tris(dibenzylideneacetone)dipalladium (342 mg, 373 μmol), cesium carbonate (3.04 g, 9.34 mmol) and 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (348 mg, 747 μmol) were dispersed in anhydrous 1,4-dioxane (20 mL), the reaction system was replaced by nitrogen, then stirred at 100 °C under nitrogen atmosphere for 2.5 h. LC / MS showed the reaction was complete. The reaction was concentrated, the residue was purified by silica gel column chromatography (ethyl acetate / cyclohexane = 1 / 2) to give compound 9e (400 mg, yield: 55%). LC / MS (ESI + m / z: 384.3 [M+H] + .

[0213] Step E: Compound 9e (160 mg, 417 μmol) was dissolved in dichloromethane (9 mL), trifluoroacetic acid (3 mL) was added slowly, the reaction was stirred at room temperature for 1 h. LC / MS showed the reaction was complete. The reaction was concentrated to give trifluoroacetate salt of compound 9f (160 mg), which was used directly in the next step. LC / MS (ESI + m / z: 283.9 [M+H] + .

[0214] Step F: Triethylsilyl trifluoromethanesulfonate (1.07 g, 5.65 mmol) and (R)-(+)-lactamide (503 mg, 5.65 mol) were added to anhydrous tetrahydrofuran (2 mL), stirred at room temperature until clear, at 90 °C, the mixture was added dropwise to compound 9f (160 mg, from previous step) in anhydrous ethanol (2 mL), the mixture was stirred at 90 °C for 20 min. LC / MS showed the reaction was complete. The reaction was concentrated, the residue was purified by prep-HPLC to give compound 9 (8.4 mg, yield: 4.4%). LC / MS (ESI + m / z: 338.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.83 (dd, J = 2.8 and 1.6 Hz, 1H), 6.81 (dd, J = 4.4 and 2.8 Hz, 1H), 6.67 (dd, J = 4.4 and 1.6 Hz, 1H), 5.71 (br s, 1H), 5.14-5.05 (m, 1H), 4.83 (br s, 1H), 2.60 (t, J = 7.2 Hz, 2H), 2.40-2.28 (m, 2H), 2.03-1.90 (m, 4H), 1.85-1.48 (m, 6H), 1.30-1.16 (m, 2H).

[0215] Example 10

[0216] N-(((1r,4r)-4-(2-methyl-1H-imidazo[4,5-d]pyrrolo[1,2-b]pyridazin-1-yl)cyclohexyl)methyl)acetamide

[0217] Example 10 was prepared from the following steps:

[0218] Step A: To a mixture solution of compound 8e (300 mg) in THF (1 mL) and 1,2-dichloroethane (1 mL) was added pyridine hydrochloride (57 mg) and trimethyl orthoacetate (1 mL), then stirred at 90 °C for 19 h. LC / MS showed complete. The reaction was concentrated, the residue was purified by prep-HPLC to give compound 10 (2.5 mg, yield: 0.77 %). LC / MS (ESI + m / z: 326.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.83 (dd, J = 2.8 and 1.6 Hz, 1H), 6.81 (dd, J = 4.4 and 2.8 Hz, 1H), 6.67 (dd, J = 4.4 and 1.6 Hz, 1H), 5.71 (br s, 1H), 5.14-5.05 (m, 1H), 4.83 (br s, 1H), 2.60 (t, J = 7.2 Hz, 2H), 2.40-2.28 (m, 2H), 2.03-1.90 (m, 4H), 1.85-1.48 (m, 6H), 1.30-1.16 (m, 2H).

[0219] Example 11

[0220] (R)-1-(1-((1r,4R)-4-(2-(methylsulfonyl)ethyl)cyclohexyl)-1H-imidazo[4,5- d]pyrrolo[1,2-b]pyridazin-2-yl)ethan-1-ol

[0221] Example 11 was prepared from the following steps:

[0222] Step A: To a solution of 1-[ethoxy(methylsulfonylmethyl)phosphoryl]oxoethane (1.00 g, 4.35 mmol) in anhydrous tetrahydrofuran (20 mL) was added sodium hydride (60%) (181 mg, 4.53 mmol) slowly at 0 °C. After the resulting mixture was stirred at room temperature for 1 h, compound 9a (1.09 g, 4.77 mmol) was added slowly to the reaction, which was stirred at room temperature for 2 h. LC / MS showed the reaction was complete. The reaction was quenched with water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by silica gel column chromatography to give compound 11a (1.3 g, yield: 89%) LC / MS (ESI + m / z: 304.1 [M+H] + .

[0223] Step B: To a solution of compound 11a (1.3 g, 4.28 mmol) in methanol (40 mL) was added 10% Pd / C (500 mg), the reaction system was replaced with hydrogen gas and stirred at 40 °C under hydrogen gas (balloon) for 16 h. TLC showed the reaction was complete. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure to give compound 11b (1.3 g, yield: 99%). LC / MS (ESI + m / z: 306.1 [M+H] + .

[0224] Step C: Compound 11b (1.3 g, 4.26 mmol) was dissolved in dichloromethane (10 mL), to the solution was added trifluoroacetic acid (4 mL). It was stirred at room temperature for 1 h. TLC showed the reaction was complete. The reaction was concentrated to give the trifluoroacetate salt of compound 11c (1.3 g), which was used directly in the next step. LC / MS (ESI + m / z: 206.1 [M+H] + .

[0225] Step D: Compound If (500 mg, 1.87 mmol), compound lie (575 mg, from previous step), tris(dibenzylideneacetone)dipalladium (342 mg, 373 pmol), cesium carbonate (2.43 g, 7.47 mmol) and 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (348 mg, 747 pmol) were dispersed in anhydrous 1,4-dioxane (20 mL), the reaction system was replaced by nitrogen, and the reaction was stirred at 100 °C for 3 hours under nitrogen atmosphere. LC / MS showed that the reaction was completed. The reaction was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3 / 2) to obtain compound lid (340 mg, yield: 41%). LC / MS (ESI + )m / z: 437.2 [M+H] + .

[0226] Step E: Compound lid (150 mg, 343 pmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (5 mL) was slowly added. The reaction was stirred at room temperature for 1 hour. LC / MS showed that the reaction was completed. The reaction was concentrated to obtain the trifluoroacetate salt of compound lie (150 mg), which was directly used in the next step. LC / MS (ESI + )m / z: 336.8 [M+H] + .

[0227] Step F: Triethylsilyl trifluoromethanesulfonate (745 mg, 3.92 mmol) and (R)-(+)-lactamide (349 mg, 3.92 mmol) were added to anhydrous tetrahydrofuran (2 mL), stirred at room temperature until clear, and the mixture was added dropwise to compound lie (120 mg, from previous step) in anhydrous ethanol (2 mL) at 90 °C. The mixture was stirred at 90 °C for 20 minutes. LC / MS showed that the reaction was completed. The reaction was concentrated, and the residue was purified by prep-HPLC to obtain compound 11 (21.1 mg, yield: 15%). LC / MS (ESI + )m / z: 391.5 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.83 (dd, J = 2.9 and 1.6 Hz, 1H), 6.80 (dd, J = 4.4 and 2.8 Hz, 1H), 6.69 (dd, J = 4.4 and 1.6 Hz, 1H), 5.71 (br s, 1H), 5.09 (d, J = 6.8 Hz, 1H), 4.83 (br s, 1H), 3.26-3.19 (m, 2H), 2.99 (s, 3H), 2.37-2.23 (m, 2H), 2.03-1.94 (m, 4H), 1.77-1.66 (m, 3H), 1.61 (d, J = 6.4 Hz, 3H), 1.28-1.20 (m, 2H).

[0228] Example 12

[0229] N-(((1R,4r)-4-(2-((R)-1-hydroxyethyl)-1H-imidazo[4,5-d]pyrrolo[1,2-b]pyridazin-1- yl)cyclohexyl)methyl)-N-methylmethanesulfonamide

[0230] Example 12 was prepared from the following steps:

[0231] Step A: To a solution of tert-butyl N-(trans-4-formylcyclohexyl)carbamate (1.8 g, 7.92 mmol) in methanol (30 mL) was added methylamine hydrochloride (588 mg, 8.71 mmol). The mixture was stirred at room temperature for 30 minutes, then cooled to 5 °C, and sodium triacetoxyborohydride (2.52 g, 11.88 mmol) was added, and stirred at 5 °C for 1 hour. Then carefully quenched with 1 M aqueous sodium bicarbonate and 2 M sodium hydroxide. Filtered and washed with methanol, and concentrated the filtrate. Extracted with ethyl acetate (2 x 30 mL) and 1 M aqueous sodium bicarbonate. The organic phase was washed with brine and dried over anhydrous sodium sulfate. Purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to give compound 12a (580 mg, yield: 30%). LC / MS (ESI + m / z: 243.2 [M+H] + .

[0232] Step B: Compound 12a (580 mg, 2.39 mmol) and triethylamine (290 mg, 2.87 mmol) were dissolved in a solution of anhydrous N,N-dimethylformamide (20 mL) at 0 °C, and methanesulfonyl chloride (328 mg, 2.87 mmol) was added slowly. The mixture was stirred at room temperature overnight. LC / MS showed the reaction was complete. Ethyl acetate (20 mL) and water (40 mL) were added to the reaction, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2), and the combined organic phase was washed with water and brine (20 mL each), dried over sodium sulfate, filtered, and concentrated under vacuum to give compound 12b (695 mg, yield: 90.63%). LC / MS (ESI + )m / z: 321.1 [M+H] + .

[0233] Step C: Compound 12b (695 mg, 2.17 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (5 mL) was added, and stirred at room temperature for 1.5 hours. TLC showed the reaction was complete. The reaction was concentrated to give the trifluoroacetate salt of compound 12c (660 mg), which was used directly in the next step. LC / MS (ESI + )m / z: 221.1 [M+H] + .

[0234] Step D: Compound If (300 mg, 1.12 mmol), compound 12c (320 mg, 1.46 mmol), tris(dibenzylideneacetone)dipalladium (205 mg, 224 μmol), cesium carbonate (1.46 g, 4.48 mmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (209 mg, 448 μmol) were dispersed in anhydrous 1,4-dioxane (20 mL), and the reaction system was replaced with nitrogen, and stirred at 100 °C for 2.5 hours under a nitrogen atmosphere. LC / MS showed the reaction was complete. The mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / cyclohexane = 1 / 2) to give compound 12d (100 mg, yield: 19%). LC / MS (ESI + )m / z: 452.1 [M+H] + .

[0235] Step E: Compound 12d (70 mg, 155 μmol) was dissolved in dichloromethane (9 mL), and trifluoroacetic acid (3 mL) was added slowly, and the reaction was stirred at room temperature for 1 hour. LC / MS showed the reaction was complete. The reaction was concentrated to give the trifluoroacetate salt of compound 12e (70 mg), which was used directly in the next step. LC / MS (ESI + )m / z: 352.3 [M+H] + .

[0236] Step F: Triethyl oxonium tetrafluoroborate (378 mg, 1.99 mmol) and (R)-(+)-lactamide (177 mg, 1.99 mmol) were added to anhydrous tetrahydrofuran (2 mL) and stirred at room temperature until clear. The mixture was added dropwise to compound 12e (70 mg, from previous step) in anhydrous ethanol (2 mL) at 90 °C and the mixture was stirred at 90 °C for 20 minutes. LC / MS showed the reaction was complete. The reaction was concentrated and the residue was purified by prep-HPLC to give compound 12 (28.6 mg, yield: 35%). LC / MS (ESI + m / z: 406.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.85-7.80 (m, 1H), 6.81 (dd, J = 4.3 and 2.9 Hz, 1H), 6.78-6.72 (m, 1H), 5.72 (br s, 1H), 5.10 (br s, 1H), 4.82 (br s, 1H), 3.00-2.94 (m, 2H), 2.90-2.79 (m, 6H), 2.37-2.22 (m, 2H), 2.00-1.75 (m, 5H), 1.61 (d, J = 6.4 Hz, 3H), 1.25-1.15 (m, 2H).

[0237] Example 13

[0238] N-(((1R,4r)-4-(2-((R)-1-hydroxyethyl)-1H-imidazo[4,5-d]pyrrolo[1,2-b]pyridazin-1-yl)cyclohexyl)methyl)ethanesulfonamide

[0239] Example 13 was prepared from the following steps:

[0240] Step A: Compound 7a (900 mg, 3.94 mmol) was dissolved in dichloromethane (9 mL) and triethylamine (1.2 g, 11.82 mmol, 1.65 mL) and ethylsulfonyl chloride (760 mg, 5.91 mmol, 0.56 mL) were added sequentially to the solution at 0 °C and then stirred at room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction was quenched with water and extracted with dichloromethane, the organic phase was washed with saturated ammonium chloride and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 13a (989 mg, yield: 78%). LC / MS (ESI + m / z: 321.3 [M+H] + .

[0241] Step B: Compound 13a (989 mg, 3.09 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added to the solution. Stirring at room temperature for 0.5 h. LC / MS showed the reaction was completed. The reaction was concentrated to give compound 13b (1.3 g) containing trifluoroacetic acid, and was used directly for the next step. LC / MS (ESI + m / z: 221.4 [M+H] + .

[0242] Step C: Compound If (801 mg, 2.99 mmol), compound 13b (1.3 g, from the previous step), cesium carbonate (8.13 g, 24.96 mmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'- biphenyl (465 mg, 998 μmol), tris(dibenzylideneacetone)dipalladium (457 mg, 499 μmol) were dissolved in dioxane (80 mL), the reaction system was replaced by nitrogen, and stirred at 110 °C under nitrogen atmosphere for 2 h. LC / MS showed the reaction was completed. The reaction was concentrated, and the residue was purified by reverse phase C18 column chromatography (acetonitrile / water = 1 / 1) to give compound 13c (320 mg, yield: 14%). LC / MS (ESI + m / z: 452.5 [M+H] + .

[0243] Step D: Compound 13c (290 mg, 642 μmol) was dissolved in dichloromethane (9 mL), trifluoroacetic acid (3 mL) was added slowly, and the reaction was stirred at room temperature for 1 h. LC / MS showed the reaction was completed. The reaction was concentrated to give compound 13d (376 mg) containing trifluoroacetic acid, and was used directly for the next step. LC / MS (ESI + m / z: 352.2 [M+H] + .

[0244] Step E: Triethylsilyl trifluoromethanesulfonate (1.22 g, 6.40 mmol, 915 μL) and (R)-(+)-lactamide (570 mg, 6.40 mmol) were dissolved in tetrahydrofuran (3 mL), and the mixture was stirred at a temperature below 10 °C until it became clear, then added dropwise to a 90 °C preheated ethanol solution (3 mL) of compound 13d (376 mg), and stirred at 90 °C for 15 min. LC / MS showed the reaction was completed. The reaction was concentrated, and the residue was purified by reverse phase prep-HPLC to give compound 13 (25.0 mg, yield: 9.6%). LC / MS (ESI + m / z: 406.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.83 (t, J = 2.0 Hz, 1H), 7.07 (s, 1H), 6.82 (t, J = 3.6 Hz, 1H), 6.66 (s, 1H), 5.71 (d, J = 6.0 Hz, 1H), 5.10 (t, J = 6.4 Hz, 1H), 4.83 (s, 1H), 3.31 - 3.27 (m, 2H), 3.03 (q, J = 7.2 Hz, 2H), 2.88 (t, J = 6.4 Hz, 2H), 2.36 - 2.23 (m, 2H), 2.02 - 1.95 (m, 4H), 1.78 - 1.73 (m, 1H), 1.61 (d, J = 6.4 Hz, 3H), 1.22 (t, J = 7.3 Hz, 3H).

[0245] Example 14

[0246] N-(((1R,4r)-4-(2-((R)-1-hydroxyethyl)-1H-imidazo[4,5-d]pyrrolo[1,2-b]pyridazin-1- yl)cyclohexyl)methyl)cyclopropanesulfonamide

[0247] Example 14 was prepared from the following steps:

[0248] Step A: Compound 7a (1.0 g, 4.38 mmol) was dissolved in dichloromethane (10 mL), to the solution was added triethylamine (1.3 g, 13.14 mmol, 1.8 mL) and cyclopropylsulfonyl chloride (738 mg, 5.26 mmol, 0.54 mL) sequentially at 0 °C, then the solution was stirred at room temperature for 2 hours. LC / MS showed the reaction was completed. The reaction was quenched by water, extracted by dichloromethane, the organic phase was washed by saturated ammonium chloride and saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered and concentrated to give compound 14a (1.4 g, yield: 96%). LC / MS (ESI + m / z: 333.7 [M+H] + .

[0249] Step B: Compound 14a (220 mg, 717.97 umol) was dissolved in dichloromethane (15 mL), to the solution was added hydrochloric acid dioxane solution (4 M, 4 mL), stirred at room temperature for 2 hours. LC / MS showed the reaction was completed. The reaction was concentrated to give compound 14b hydrochloride salt ((978 mg), which was used directly for the next step. LC / MS (ESI + m / z: 233.6 [M+H] + .

[0250] Step C: Compound If (558 mg, 2.09 mmol), compound 14b (489 mg, from previous step), cesium carbonate (2.7 g, 8.35 mmol), 2-dicyclohexylphospho-2',6'- diisopropoxy-1,1'-biphenyl (389 mg, 834 pmol), tris(dibenzylideneacetone)dipalladium (382 mg, 417 pmol) were dispersed in dioxane (20 mL), the reaction system was replaced by nitrogen, and stirred at 90 °C under nitrogen atmosphere for 16 hours. LC / MS showed that the reaction was completed. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7 / 3) to obtain compound 14c (190 mg, yield: 19%). LC / MS (ESI + m / z: 464.2 [M+H] + .

[0251] Step D: Compound 14c (170 mg, 366 pmol) was dissolved in dichloromethane (5.1 mL), and trifluoroacetic acid (1.7 mL) was slowly added. The reaction was stirred at room temperature for 1 hour. LC / MS showed that the reaction was completed. The reaction solution was concentrated to obtain compound 14d (268 mg) containing trifluoroacetic acid, which was directly used in the next step. LC / MS (ESI + m / z: 364.1 [M+H] + .

[0252] Step E: Triethylsilyl trifluoromethanesulfonate (695 mg, 3.66 mmol) and (R)-(+)- lactamide (326 mg, 3.66 mmol) were dissolved in tetrahydrofuran (3 mL), and the reaction mixture was stirred at a temperature below 10 °C until it was clear, then added dropwise to a 90 °C preheated ethanol (3 mL) solution of compound 14d (268 mg), and stirred at 90 °C for 20 minutes. LC / MS showed that the reaction was completed. The reaction solution was concentrated, and the residue was purified by reverse phase Prep-HPLC to obtain compound 14 (24.4 mg, yield: 15%). LC / MS (ESI + m / z: 418.5 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.90-7.80 (m, 1H), 7.11 (t, J = 6.0 Hz, 1H), 6.82 (t, J = 3.6 Hz, 1H), 6.66 (d, J = 4.3 Hz, 1H), 5.72 (br s, 1H), 5.10 (br s, 1H), 4.83 (br s, 1H), 2.95 (t, J = 6.4 Hz, 2H), 2.63-2.55 (m, 1H), 2.37-2.19 (m, 2H), 2.10-1.90 (m, 5H), 1.82-1.74 (m, 2H), 1.61 (d, J = 6.4 Hz, 3H), 1.28-1.18 (m, 3H), 1.05-0.84 (m, 4H).

[0253] Example 15

[0254] N-(((1r,4r)-4-(9-fluoro-2-methyl-1H-imidazo[4,5-d]pyrrolo[1,2-b]pyridazin-1-yl)cyclohexyl)methyl)methanesulfonamide

[0255] Example 15 was prepared from the following steps:

[0256] Step A: Compound 5g (850 mg, 2.98 mmol), compound 7c (920 mg, 4.46 mmol), dicyclohexyl-[2-(2.6-diisopropoxyphenyl)phenyl]phosphine (277 mg, 595 μmol), cesium carbonate (2.91 g, 8.93 mmol) and tris(dibenzylideneacetone)dipalladium (272 mg, 297 μmol) were dissolved in a solution of dioxane (20 mL). The reaction system was replaced by nitrogen and the reaction was stirred at 120 °C under nitrogen atmosphere for 16 hours. LC / MS showed the reaction was completed. The reaction solution was concentrated and the residue was purified by C18 reverse phase column (acetonitrile / water = 1 / 1) to give compound 15a (590 mg, yield: 43%). LC / MS (ESI + m / z: 456.4 [M+H] + .

[0257] Step B: Compound 15a (250 mg, 548 μmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added dropwise slowly. The reaction solution was stirred at room temperature for 1 hour. LC / MS showed the reaction was completed. The reaction solution was concentrated to give compound 15b (400 mg) containing trifluoroacetic acid, which was used directly for the next step. LC / MS (ESI + m / z: 356.3 [M+H] + .

[0258] Step C: Compound 15b (270 mg, from previous step), trimethyl orthoacetate (2 mL) and pyridine hydrochloride (43 mg, 379 pmol) were dissolved in dioxane (2 mL). The reaction was stirred at 120 °C overnight. LC / MS showed the reaction was complete. The reaction was concentrated and the residue was purified by reverse phase Prep-HPLC to give compound 15 (30 mg). LC / MS (ESI + m / z: 380.4 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) d 8.39 (s, 1H), 7.72 - 7.65 (m, 1H), 7.08 (t, J = 6.4 Hz, 1H), 6.73 (s, 1H), 4.80 - 4.70 (m, 1H), 2.90 (s, 3H), 2.86 (t, J = 6.4 Hz, 2H), 2.62 (s, 3H), 2.30 - 1.80 (m, 5H), 1.68 - 1.58 (m, 1H), 1.25 - 1.05 (m, 2H).

[0259] Example 16

[0260] 2-((1r,4r)-4-(9-Fluoro-2-methyl-1H-imidazo[4,5-d]pyrrolo[1,2-b]pyridazin-1-yl)cyclohexyl)acetonitrile

[0261] Example 16 was prepared from the following steps:

[0262] Step A: Compound 5g (400 mg, 1.40 mmol), compound 16a (251 mg), cesium carbonate (1.82 g), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (261 mg), tris(dibenzylideneacetone)dipalladium (256 mg) were dissolved in anhydrous dioxane (20 mL), the reaction system was replaced by nitrogen, and stirred at 100 °C under nitrogen atmosphere for 2.5 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 16b (240 mg, yield: 44%). LC / MS (ESI + m / z: 388.1 [M+H] + .

[0263] Step B: Compound 16b (145 mg) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour, LC / MS showed the reaction was on demand. The reaction was concentrated under reduced pressure to give compound 16c (trifluoroacetate, 210 mg), which was used directly for the next step. LC / MS (ESI + m / z: 288.1 [M+H] + .

[0264] Step C: Compound 16c (210 mg) was dissolved in 1,4-dioxane (3 mL), then pyridine hydrochloride (22 mg) and trimethyl orthoacetate (2 mL) were added. The reaction was carried out at 140 °C for 16 hours in a closed condition, LC / MS showed the reaction was on demand. The reaction was concentrated under reduced pressure, the residue was purified by reverse phase C18 column to give 60 mg of crude. Further purified by reverse phase prep-HPLC to give compound 16 (18.4 mg, yield: 11.3%). LC / MS (ESI + m / z: 312.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.68 (t, J = 3.6 Hz, 1H), 6.74 (d, J = 3.6 Hz, 1H), 2.63 (s, 3H), 2.56 (d, J = 6.4 Hz, 2H), 2.20 - 1.80 (m, 8H), 1.40 - 1.26 (m, 2H).

[0265] Example 17

[0266] 2-((2R,5S)-5-(2-methyl-lH-imidazo[4,5-c]thieno[2,3-e]pyridazin-l-yl)tetrahydro- 2H-pyran-2-yl)acetonitrile

[0267] Example 17 was prepared from the following steps:

[0268] Step A: To a solution of compound 17a (10 g) in super dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexane, 60 mL) slowly dropwise at -30 °C. The reaction was stirred at -10 °C for 30 min, then cooled to -45 °C. To the reaction was added N-methoxy-N-methylacetamide (12.9 g), and slowly warmed to room temperature in 40 min, and kept for 16 h. TLC showed the reaction was complete. The reaction was quenched by the addition of brine (80 mL), and extracted with ethyl acetate (60 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 97 / 3) to give compound 17b (11.0 g, yield: 90%). LC / MS (ESI+) m / z: 242.1 [M+H] + . + .

[0269] Step B: Compound 17b (11.0 g) was added to 4 M hydrochloric acid in 1,4-dioxane (30 mL) and stirred at room temperature for 5 h. LC / MS showed the reaction was complete. The reaction was concentrated to give compound 17c (6.5 g), which was used directly in the next step. LC / MS (ESI+) m / z: 142.1 [M+H] + . + .

[0270] Step C: Compound 17c (10.0 g) was dispersed in a mixture solution of acetic acid (8 mL), concentrated hydrochloric acid (13 mL) and water (28 mL) at 0 °C. After stirring for 15 min, sodium nitrite (5.86 g) in water (19 mL) was added slowly. Stirring was continued at 0 °C for another hour, then urea (468 mg) was added portionwise in 10 min. Stirring was continued for 1 h, LC / MS showed the reaction was complete. The reaction was extracted with ethyl acetate, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase (C18 column, 0.1% formic acid-acetonitrile) to give compound 17d (5.0 g, yield: 46%). LC / MS (ESI+) m / z: 152.8 [M+H] + .

[0271] Step D: Compound 17d (5.0 g) was dissolved in propionic acid (24.3 g) at room temperature, and fuming nitric acid (15.9 g) was added. The reaction was heated to 130 °C and stirred for 5 h. LC / MS showed about 60% product was formed. The reaction was cooled to room temperature, and methyl tert-butyl ether was added, and a solid precipitated. Filtration gave compound 17e (940 mg, yield: 14%). LC / MS (ESI+) m / z: 198.0 [M+H] + . + .

[0272] Step E: Compound 17e (940 mg) was dissolved in dry DMF (30 mL) under nitrogen protection, the solution was cooled to 0 °C, to which was added dropwise phosphorus oxychloride (4.39 g) and DIEA (1.23 g). The reaction was stirred at room temperature for 16 hours. The reaction was cooled to 0 °C, then the reaction was slowly added to ice-cold saturated sodium bicarbonate solution (50 mL). The reaction mixture was extracted with ethyl acetate, the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 17f (800 mg, yield: 77%). LC / MS (ESI + m / z: 215.8 [M+H] + .

[0273] Step F: Compound 17f (900 mg) and Int-1 (1.17 g) were dissolved in dry 1,4- dioxane (20 mL), DIEA (2.70 g) was added. The reaction was warmed to 60 °C and stirred for 5 hours, LCMS showed the reaction was complete. The reaction was concentrated, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 96 / 4) to give compound 17g (701 mg, yield: 52%). LC / MS (ESI + m / z: 319.8 [M+H] + .

[0274] Step G: Compound 17g (700 mg) was dissolved in ethanol (10 mL), 10% Pd / C (100 mg) was added, the mixture was replaced with hydrogen balloon for 3 times, the mixture was stirred at 40 °C under hydrogen atmosphere for 1 hour. LC / MS showed the reaction was complete. The reaction was filtered, the filtrate was concentrated, the residue was purified by silica gel column chromatography (dichloromethane / methanol 20 / 1) to give the target compound 17h (130 mg, yield: 20%) as the more polar isomer. LC / MS (ESI + m / z: 289.8 [M+H] + .

[0275] Step H: Compound 17h (30 mg) was dissolved in a mixture solution of 1,2- dichloroethane (1 mL) and dry tetrahydrofuran (1 mL), pyridine hydrochloride (11 mg) and trimethylorthoacetate (2 mL) were added. After the mixture was stirred at 90 °C for 16 hours, LCMS showed the reaction was complete. The reaction was concentrated, the residue was purified by reverse phase Prep-HPLC to give compound 17 (4.3 mg, yield: 13%). LC / MS (ESI+) m / z: 314.6 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 5.6 Hz, 1H), 8.01 (d, J = 5.6 Hz, 1H), 4.74 - 4.64 (m, 1H), 4.27 - 4.19 (m, 1H), 4.14 - 4.07 (m, 1H), 3.99 - 3.94 (m, 1H), 3.00 - 2.92 (m, 1H), 2.88 - 2.80 (m, 4H), 2.48 - 2.41 (m, 1H), 2.34 - 2.25 (m, 1H), 2.09 - 2.01 (m, 1H), 1.80 - 1.68 (m, 1H).

[0276] Example 18

[0277] 2-((1R,4r)-4-(2-((R)-1-hydroxyethyl)-1H-imidazo[4,5-c]thieno[2,3- e]pyridazin-1-yl)cyclohexyl)acetonitrile

[0278] Example 18 was prepared from the following steps:

[0279] Step A: Compound 17f (250 mg), compound 16a (241 mg) and DIEA (2.0 g) were added to anhydrous 1,4-dioxane (20 mL), and the reaction was stirred at 80 °C for 2 hours. LC / MS showed the reaction was complete. The reaction was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0% to 5%) to give compound 18a (200 mg, yield: 54%). LC / MS (ESI + m / z: 318.0 [M+H] + .

[0280] Step B: Palladium on carbon (10%, 100 mg) was added to a solution of compound 18a (200 mg) in ethanol (10 mL). The mixture was stirred under hydrogen atmosphere at 40 °C for 1 hour. LC / MS showed the reaction was complete. The reaction was filtered, and the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 18b (160 mg, crude), which was used directly for the next step. LC / MS (ESI + m / z: 288.3 [M+H] + .

[0281] Step C: Triethyl oxonium tetrafluoroborate (70 mg), (R)-(+)-lactamide (33 mg) were added to dry tetrahydrofuran (2 mL) at 0 °C and stirred for 10 min, then added dropwise to a solution of compound 18b in dry ethanol (2 mL) at 90 °C. The reaction was stirred for 10 min and then quenched. The reaction was concentrated and the residue was purified by reverse phase Prep-HPLC to give compound 18 (5 mg, yield: 4.7%). LC / MS (ESI + m / z: 342.2 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 5.6 Hz, 1H), 6.01 (d, J = 7.2 Hz, 1H), 5.29 (t, J = 6.4 Hz, 1H), 4.95 (s, 1H), 3.30 (s, 1H), 2.66-2.60 (m, 2H), 2.35-2.24 (m, 2H), 2.10-1.95 (m, 4H), 1.69 (d, J = 6.6 Hz, 3H), 1.52-1.40 (m, 2H).

[0282] Example 19

[0283] 2-((2R,5S)-5-(2-((R)-1-hydroxyethyl)-1H-imidazo[4,5-c]thieno[2,3- e]pyridazin-1-yl)tetrahydro-2H-pyran-2-yl)acetonitrile

[0284] Example 19 was prepared from the following steps:

[0285] Step A: Triethyl oxonium tetrafluoroborate (1.38 g), (R)-(+)-lactamide (646 mg) were added to dry tetrahydrofuran (5 mL) at 0 °C and stirred for 10 min, then added dropwise to a solution of compound 17h (140 mg) in dry ethanol (5 mL) at 85 °C. The reaction was stirred for 10 min and then quenched. The reaction was concentrated and the residue was purified by reverse phase Prep-HPLC to give compound 19 (3.7 mg, yield: 2.2%). LC / MS (ESI + m / z: 344.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 5.6 Hz, 1H), 8.04 (d, J = 5.6 Hz, 1H), 6.11 (s, 1H), 5.30 (d, J = 7.4 Hz, 1H), 5.16 - 5.08 (m, 1H), 4.27 - 4.13 (m, 2H), 4.03 - 3.93 (m, 1H), 3.02 - 2.93 (m, 1H), 2.89 - 2.82 (m, 1H), 2.28 - 2.21 (m, 1H), 2.11 - 2.04 (m, 1H), 1.75 - 1.65 (m, 5H).

[0286] Example 20

[0287] 2-((2R,5S)-5-(2-((R)-1-hydroxyethyl)-1H-pyrazolo[5,1-b]pyrazin-1-yl)tetrahydro- 2H-pyran-2-yl)acetonitrile

[0288] Example 20 was prepared from the following steps:

[0289] Step A: 4-methoxybenzaldehyde (437 mg), compound Int-1 was dissolved in dry methanol (10 mL), AcOH (1 drop) was added, the reaction was stirred at 70 °C for 3 hours, LC / MS (basic system) showed about 30% of imine formed. The reaction was concentrated, the residue was dissolved in dichloromethane (10 mL), sodium cyanoborohydride (448 mg) was added, stirred at room temperature for 16 hours. After the reaction was quenched with water, the reaction was concentrated, the residue was purified by reverse phase C18 column (0.5% ammonia water to acetonitrile) to give compound 20a (100 mg, yield: 10.7%). LC / MS (ESI + m / z: 261.2 [M+H] + .

[0290] Step B: compound 20a (138 mg), compound 20b (100 mg) and N,N- diisopropylethylamine (286 mg) was dissolved in dry dioxane (10 mL), stirred at 120 °C for 3 hours, LC / MS showed the reaction was complete. The reaction was concentrated, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 50%) to give compound 20c (95 mg, yield: 47%). LC / MS (ESI + m / z: 450.3 [M+H] + .

[0291] Step C: Compound 20c (90 mg), lithium hydroxide (48 mg) were dissolved in a mixture of methanol (0.5 mL), tetrahydrofuran (0.5 mL) and water (1 mL), stirred at room temperature for 16 hours, LC / MS showed the reaction was complete. The reaction was adjusted to pH 5-6 with dilute hydrochloric acid, then extracted with ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 20d (70 mg, yield: 82%). LC / MS (ESI + m / z: 422.3 [M+H] + .

[0292] Step D: Compound 20d (70 mg), diphenyl phosphorazide (68 mg) and triethylamine (33 mg) were dissolved in dry tert-butanol (2 mL), stirred at 90 °C for 6 hours, LC / MS showed the reaction was complete. The reaction was concentrated, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 50%) to give compound 20e (25 mg, yield: 30%). LC / MS (ESI + m / z: 493.3 [M+H] + .

[0293] Step E: To a solution of compound 20e (70 mg) in dichloromethane (2 mL) was added 4M hydrochloric acid in dioxane (2 mL) at 0 °C. The reaction was stirred at room temperature for 3 hours, LC / MS showed the reaction was complete. The reaction was concentrated under reduced pressure at room temperature to give compound 20f (40 mg), which was used directly in the next step. LC / MS (ESI + m / z: 273.0 [M+H] + .

[0294] Step F: Triethyl oxonium tetrafluoroborate (70 mg), ((R)-(+)-lactamide (33 mg) were added to anhydrous tetrahydrofuran (2 mL) at 0 °C, stirred for 10 minutes, then added dropwise to a solution of compound 20f (20 mg) in anhydrous ethanol (2 mL) at 90 °C, the reaction was completed after continuous stirring for 10 minutes. The reaction was concentrated, the residue was purified by reverse phase Prep-HPLC to give compound 20 (2 mg, yield: 8.3%). LC / MS (ESI + m / z: 327.2 [M+H] + ; 1HNMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.33 (s, 1H), 6.87 (s, 1H), 5.96 (d, J = 10.2 Hz, 1H), 5.33 (t, J = 5.6 Hz, 1H), 5.21 (d, J = 7.6 Hz, 1H), 4.73 (s, 1H), 4.11-4.02 (m, 1H), 4.04-3.96 (m, 1H), 2.97-2.89 (m, 1H), 2.85-2.78 (m, 1H), 2.08 (s, 1H), 2.02 (d, J = 7.6 Hz, 1H), 1.66 (d, J = 6.4 Hz, 3H).

[0295] Example 21

[0296] 2-((2R,5S)-5-(2-methyl-1H-d imidazo[1,2-b:4',5'-d]pyridazin-1-yl)tetrahydro-2H-pyran-2-yl)acetonitrile

[0297] Example 21 was prepared from the following steps:

[0298] Step A: Dissolve benzyl alcohol (10.2 g) in tetrahydrofuran (300 mL), slowly add sodium hydride (3.8 g) under ice-bath, after 0.5 h reaction at room temperature, slowly drop compound 21a (20.0 g) under ice-bath. After drop completion, return to room temperature and stir overnight. LC / MS shows the reaction is complete. Add the system to water, and extract with ethyl acetate. Dry the combined organic phase over anhydrous sodium sulfate, filter and concentrate under reduced pressure, the residue is purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 21b (21.0 g, yellow solid, yield: 94.0%). LC / MS (ESI + m / z: 259.9 [M+H] + .

[0299] Step B: Dissolve compound 21b (22.0 g), palladium on carbon (10%, 2.7 g) in methanol (600 mL), after the system is replaced by hydrogen, react under hydrogen balloon pressure at 40 °C for 16 h, LC / MS shows the reaction is complete. Filter the reaction solution, concentrate the filtrate under reduced pressure to give compound 21c crude, which is used directly for the next step. LC / MS (ESI + m / z: 136.0 [M+H] + .

[0300] Step C: Compound 21c (200 mg) from previous step was dissolved in acetic acid (1.1 g), fuming nitric acid (186 mg) was added. The reaction was heated at 130 °C for 5 hours under a closed condition. LC / MS showed the reaction was complete. Methyl tert-butyl ether (100 mL) was added, filtered, and the filter cake was dried under reduced pressure to give compound 21d (30 mg, yellow solid. Yield: 11.3%). LC / MS (ESI + m / z: 180.9 [M+H] + .

[0301] Step D: Compound 21d (575 mg) was dissolved in N,N-dimethylformamide (8.5 mL). Phosphorus oxychloride (4.89 g) was added dropwise at 0 °C. After the addition was complete, the reaction was allowed to warm to room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction was slowly added to ice water, and the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 21e (384 mg, yellow solid, yield: 60%). LC / MS (ESI + m / z: 198.9 [M+H] + .

[0302] Step E: Compound 21e (384 mg), compound Int-1 (542 mg), N,N-diisopropylethylamine (1.25 g) were added to dioxane (15 mL). The reaction was heated at 60 °C for 16 hours. LC / MS showed the reaction was complete. The reaction was dried under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 50 / 1 to 20 / 1) to give compound 21f (375 mg, yellow-green solid, yield: 64%). LC / MS (ESI + m / z: 303.0 [M+H] + .

[0303] Step F: Compound 21f (375 mg), palladium on carbon (10%, 66 mg) were dispersed in ethanol (20 mL). The reaction was hydrogenated at 40 °C for 3 hours under a hydrogen balloon. LC / MS showed the reaction was complete. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give compound 21g (250 mg, crude), which was used directly in the next step. LC / MS (ESI + m / z: 273.2 [M+H] + .

[0304] Step G: Compound 21g (44 mg, from previous step), pyridine hydrochloride (18 mg), were added to a mixture of trimethyl orthoacetate (2 mL), tetrahydrofuran (1 mL) and 1,2-dichloroethane (1 mL). Stirring at 140 °C for 16 hours, LC / MS showed the reaction reached the requirement. The reaction was dried under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 20 / 1) to give 22 mg of crude product, which was further purified by Prep-HPLC to give compound 21 (5.3 mg, yield: 11%) and the cis-isomer 21' (1.7 mg).

[0305] Compound 21: LC / MS (ESI + )m / z: 297.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.26 (s, 1H), 7.69 (s, 1H), 4.67 (d, J = 7.2 Hz, 2H), 4.05 - 3.95 (m, 2H), 3.20 - 3.09 (m, 1H), 2.97 - 2.87 (m, 1H), 2.84 - 2.74 (m, 1H), 2.71 (s, 3H), 2.10 - 2.03 (m, 1H), 2.02 - 1.95 (m, 1H), 1.74 - 1.64 (m, 1H).

[0306] Compound 21': LC / MS (ESI + )m / z: 297.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.28 (s, 1H), 7.73 (s, 1H), 4.70 - 4.50 (m, 2H), 4.36 - 4.29 (m, 1H), 4.22 - 4.11 (m, 1H), 3.86 - 3.80 (m, 1H), 3.25 - 3.17 (m, 1H), 3.06 - 2.97 (m, 1H), 2.71 (s, 3H), 2.13 - 2.03 (m, 1H), 1.94 - 1.78 (m, 2H).

[0307] Example 22

[0308] 2-((2R,5S)-5-(2-methyl-lH-pyrazolo[5,l-b]pyrazin-l-yl)tetrahydro-2H-pyran-2- yl)acetonitrile

[0309] Example 22 was prepared from the following steps:

[0310] Step A: Compound 20f (30 mg), pyridine hydrochloride (6 mg) were added to a mixture of trimethyl orthoacetate (2 mL), tetrahydrofuran (1 mL) and 1,2-dichloroethane (1 mL), and stirred at 90 °C for 16 hours. LC / MS showed the reaction reached the requirement. The reaction was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to give compound 22 (9 mg, yield: 27%). LC / MS (ESI + m / z: 297.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.30 (s, 1H), 6.90-6.77 (m, 1H), 4.61 (br s, 1H), 4.16-4.05 (m, 1H), 4.03-3.91 (m, 1H), 3.01-2.90 (m, 1H), 2.85-2.78 (m, 1H), 2.77 (s, 3H), 2.18-2.12 (m, 1H), 2.02-1.95 (m, 1H), 1.73-1.65 (m, 1H).

[0311] Reference Example 1

[0312] 2-((2R,5S)-5-(2-((R)-1-hydroxyethyl)-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl)tetrahydro- 2H-pyran-2-yl)acetonitrile

[0313] Reference Example 1 was obtained by referring to the synthetic method of Compound 4 described in patent WO2018067422. LC / MS (ESI + m / z: 327.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 5.93 (d, J = 6.4 Hz, 1H), 5.25-5.18 (m, 1H), 5.08-5.00 (m, 1H), 4.20-4.12 (m, 2H), 3.96-3.88 (m, 1H), 3.00-2.92 (m, 1H), 2.88-2.80 (m, 1H), 2.60-2.54 (m, 1H), 2.19-2.13 (m, 1H), 2.06-1.99 (m, 1H), 1.73-1.62 (m, 4H).

[0314] Reference Example 2

[0315] 2-((2R,5S)-5-(2-methyl-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)acetonitrile

[0316] Reference Example 1 was obtained by reference to the synthetic method of Compound 11 described in patent WO2018067422. LC / MS (ESI + m / z: 297.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.38 (s, 1H), 7.28 (s, 1H), 4.68-4.58 (m, 1H), 4.21-4.08 (m, 2H), 3.94-3.86 (m, 1H), 2.99-2.91 (m, 1H), 2.86-2.77 (m, 1H), 2.73 (s, 3H), 2.22-2.15 (m, 1H), 2.05-1.98 (m, 1H), 1.80-1.68 (m, 1H).

[0317] TYK2 inhibitor biological screening and results

[0318] Test Example 1: Inhibition test of the compound of the present application on JAK family kinases (TYK2, JAK1, JAK2, JAK3) JH1 kinase domain

[0319] 1.1 Purpose of the experiment

[0320] The kinase experiment adopts homogeneous time-resolved fluorescence resonance energy transfer technology (HTRF) to detect the inhibition effect of small molecule inhibitors on JAK1 / JAK2 / JAK3 / TYK2 JH1 kinase activity.

[0321] 1.2 Experimental materials

[0322] The JAK1 kinase protein is purchased from Thermo Fisher Company, item number PV4774, molecular weight 60.8 KDa, weight 10 micrograms; the enzyme is divided and then frozen in a-80℃ refrigerator for storage.

[0323] The JAK2 kinase protein is purchased from Thermo Fisher Company, item number PV4210, molecular weight 66.6 KDa, weight 10 micrograms; the enzyme is divided and then frozen in a-80℃ refrigerator for storage.

[0324] The JAK3 kinase protein is purchased from Thermo Fisher Company, item number PV3855, molecular weight 67.4 KDa, weight 10 micrograms; the enzyme is divided and then frozen in a-80℃ refrigerator for storage.

[0325] TYK2 kinase protein was purchased from Carna Biosciences, Cat. No. 08-147-10 ug, with a molecular weight of 63 KDa and a weight of 10 micrograms. The enzyme was aliquoted and stored frozen at -80°C.

[0326] KinEASE TM -TK 20000 tests kit was purchased from Cisbio, Cat. No. 62TK0PEC, aliquoted and stored at -80°C after preparation according to the manufacturer’s instructions.

[0327] ATP solution (100 mM) was purchased from Invitrogen, Cat. No. R0441, aliquoted and stored at -20°C.

[0328] DTT, Sigma-Aldrich, Cat. No. D0632-10G, was prepared as a 1000 mM stock solution in Milli-Q filtered water and aliquoted and stored at -20°C.

[0329] MnCl2, Sigma-Aldrich, Cat. No. M1787-100ML, was stored at room temperature.

[0330] MgCl2, Sigma-Aldrich, Cat. No. M1028-100ML, was stored at room temperature.

[0331] Brij-35 solution, Sigma-Aldrich, Cat. No. B4184-10ML, was stored at room temperature.

[0332] BSA, Sigma-Aldrich, Cat. No. B2064-50G, was stored at room temperature.

[0333] EGTA, Sigma-Aldrich, Cat. No. E3889, was stored at room temperature.

[0334] DMSO, Sigma-Aldrich, Cat. No. D2650-100ML, was stored at room temperature.

[0335] 5X Enzymatic buffer, Revvity, Cat. No. 62EZBFDD, was stored at room temperature.

[0336] 1.3 Preparation of the reaction buffer

[0337] JAK1 JH1 reaction buffer (10 ml)

[0338] JAK2 / 3 JH1 reaction buffer (10 mL)

[0339] TYK2 JH1 reaction buffer (10 mL)

[0340] 1.4 Experimental Methods

[0341] a. Compound and kinase pre-incubation: 2x JAK1 / JAK2 / JAK3 / TYK2 JH1 enzyme solution was prepared using the corresponding reaction buffer (enzyme final concentration was 0.133 ng / μL, 0.0225 ng / μL, 0.224 ng / μL, 0.25 ng / μL, respectively). Compound was dissolved in DMSO to a stock concentration of 10 mM. The 96-well plate was prepared with 100-fold starting concentration of compound, and then 27-fold serial dilution of the starting concentration was performed to obtain different concentration gradients. The 96-well plate was transferred to a 384 compound master plate, and each point was transferred to a 384-well experimental plate using an Echo instrument with 100 nL, 35 nL, and 12.5 nL of compound, respectively. The 100 nL of DMSO was added to the insufficient 100 nL point, and 100 nL of DMSO was used to replace the negative and positive groups. 5 μL of 2x JAK1 / JAK2 / JAK3 / TYK2 JH1 enzyme solution (compound well and positive control well) or reaction buffer (negative control well) was added to each well, centrifuged, mixed, and incubated at 25°C for 15 minutes.

[0342] b. Enzyme reaction: 2x TK-Sub-biotin substrate and ATP mixed solution was prepared using the corresponding reaction buffer (in JAK1, JAK2, JAK3, TYK2 enzyme reaction, the final concentration of TK-Sub-biotin substrate was 5 μM, 2 μM, 0.6 μM, 1 μM, respectively; the final concentration of ATP was 2 μM, 7 μM, 0.85 μM, 0.1 μM, respectively). After step a incubation was completed, 5 μL of 2x TK-Sub-biotin substrate and ATP mixed solution was added to each well of the above 384-well experimental plate, centrifuged, mixed, and reacted at 25°C for 45 minutes (JAK1 / JAK2 JH1) or 60 minutes (JAK3 / TYK2 JH1).

[0343] c. Detection: Detection mix of TK Antibody-Eu and streptavidin-XL665 was prepared using detection buffer (final concentration of TK Antibody-Eu was 0.25x, final concentration of streptavidin-XL665 was 1 / 16 of the final concentration of TK-Sub-biotin substrate). After the incubation of step b was completed, 10 μL of detection mix was added to each well of the above-mentioned 384-well assay plate according to the illustration, and the plate was centrifuged and mixed, and then incubated at 25°C for 60 minutes (JAK1 / JAK2 JH1) or 120 minutes (JAK3 / TYK2 JH1). After the reaction was completed, the plate was incubated overnight at 4°C, and then the fluorescence value was read on an Envision 2104 Multilabel Reader (340 nm excitation, detection of 665 nm and 615 nm emission, 665 nm / 615 nm fluorescence ratio as the raw data of the well reaction signal value).

[0344] 1.5 Data processing and analysis

[0345] The test data were processed and analyzed using XLfit, a software written by IDBS and integrated in the Microsoft Excel environment. First, the average values of the positive control and negative control wells were calculated, respectively, and then the inhibition rate of each compound well was calculated according to the formula "single-well inhibition rate = (1 - (single-well signal value - average value of negative control signal) / (average value of positive control signal - average value of negative control signal)) x 100%". Then, the concentration and corresponding inhibition rate data were imported into the XLfit software, and the Dose Response One Site 205 model in the software was used to fit the four-parameter inhibition rate-concentration curve, and the IC 50 value of the compound was calculated.

[0346] The inhibitory activity of the compounds of the present application on JAK family kinases (TYK1, JAK1-3) JH1 kinases is shown in Table 1.

[0347] Table 1: Inhibitory activity of the compounds of the present application on TYK2, JAK1-3 JH1 kinases ND: not tested

[0348] According to the activity test results of the present application, for example, 5 and 5', 21 and 21' are two pairs of cis-trans isomers, and the activity of the cis isomer is poorer than that of the trans isomer. Therefore, when a compound has cis-trans isomers, it can be inferred that the trans isomer is relatively more active.

[0349] Test Example 2: Evaluation of the in vitro human liver microsomal enzyme stability of the compounds of the present application

[0350] Two 96-well incubation plates were prepared and named as T60 incubation plate and NCF60 incubation plate, respectively. 445 μL of microsomes working solution (0.56 mg / mL of liver microsomal protein) was added to the T60 incubation plate and NCF60 incubation plate, respectively, and then the incubation plates were pre-incubated in a 37 °C water bath for about 10 minutes. After pre-incubation, 5 μL of test compound or control compound working solution was added to the T60 incubation plate and NCF60 incubation plate, respectively, and mixed well. The reaction was initiated by adding 50 μL of potassium phosphate buffer to each well of the NCF60 incubation plate. The reaction was terminated by adding 180 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) and 6 μL of NADPH regenerating system working solution to each well of the T0 termination plate, and 54 μL of sample from the T60 incubation plate was transferred to the T0 termination plate (T0 sample generation). In the Blank plate, only 54 μL of microsomes working solution, 6 uL of NADPH regenerating system working solution and 180 μL of stop solution were added. The reaction was initiated by adding 44 μL of NADPH regenerating system working solution to each well of the T60 incubation plate. Thus, in the samples of test compound or control compound, the final concentration of compound was 1 μM, the concentration of liver microsomes was 0.5 mg / mL, and the final concentration of DMSO and acetonitrile in the reaction system was 0.01% (v / v) and 0.99% (v / v), respectively.

[0351] After incubation for an appropriate time (e.g., 5, 15, 30, 45 and 60 minutes), 180 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) was added to each well of the termination plate, and then 60 μL of sample from the T60 incubation plate or NCF60 incubation plate was removed to terminate the reaction. All sample plates were shaken well and centrifuged at 3220 x g for 20 minutes, and then 80 μL of supernatant was taken from each well and diluted into 240 μL of pure water for liquid chromatography tandem mass spectrometry analysis.

[0352] The in vitro elimination rate constant ke of the test compound and control compound was obtained by converting the ratio of the peak area of the compound to the internal standard in the following formula to the remaining percentage:

[0353] When

[0354] By k e Calculate the in vitro liver microsomal intrinsic clearance (CLint(mic)) and the liver intrinsic clearance (CLint(liver))

[0355] CLint(mic) = 0.693 / T 1 / 2 / microsome protein content (microsome concentration mg / mL at incubation)

[0356] CLint(liver) = CLint(mic) x microsome protein content in liver (mg / g) x liver weight / body weight ratio

[0357] The in vitro human liver microsomal enzyme stability data for each compound obtained in Test Example 2 is shown in Table 2.

[0358] Table 2: Results of human liver microsomal enzyme stability experiment for compounds of the present application

[0359] Although the specific embodiments of the present application have been described above, it is understood by those skilled in the art that these are merely illustrative and various changes or modifications can be made to these embodiments without departing from the principles and the essence of the present application. Therefore, the scope of protection of the present application is defined by the appended claims.

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, in, R 1 It is a C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic alkyl, or is composed of one or more R 1-1 Substituted C1-C6 alkyl groups; R 1-1 Independently -OH, -CN, or halogen; R 2 For C3-C 12 Cycloalkyl, 4-12 membered heterocyclic alkyl, with one or more R 2-1 Replacement C3-C 12 cycloalkyl or with one or more R 2-2 Substituted 4-12 membered heterocyclic alkyl groups; R 2-1 Independently halogen, -NR b R c or -OC(=O)R e ; R 2-2 Independently halogen, -NR b R c 、 -C(=O)R d or -OC(=O)R e ; R a -CN, -NR a-1 R a-2 -C(=O)R a-4 C1-C6 alkyl, C1-C6 alkoxy, halogen, or containing one or more R a-3 Substituted C1-C6 alkyl groups; R a-1 and R a-2 Each is independently -H, C1-C6 alkyl, -S(=O)2R A-1 -C(=O)R A-2 , by one or more R A-3 Substituted C1-C6 alkyl groups; R A-1 and R A-2 Each of the following is independently C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic alkyl, C1-C6 alkoxy, or -NR B-1 R B- 2 ; R B-1 and R B-2 Each is independently -H or C1-C6 alkyl; R A-3 Halogens are independent of each other; R a-4 For -NR B-1 R B-2 ; R a-3 Independently halogen, -CN, -S(=O)2R A-1 or -C(=O)NR B-1 R B-2 ; R b and R c Each independently of -H, C1-C6 alkyl, -S(=O)2R A-1 -C(=O)R A-2 Or by one or more R b-1 Substituted C1-C6 alkyl groups; R b-1 Halogens are independent of each other; R d It is a C1-C6 alkyl, C1-C6 alkoxy, -NR d-2 R d-3 Or by one or more R d-1 Substituted C1-C6 alkyl groups; R d-1 -CN; R d-2 and R d-3 Each is independently -H or C1-C6 alkyl; R e For -NR e-1 R e-2 ; R e-1 and R e-2 Each is independently -H or C1-C6 alkyl; Or, two R atoms on the same carbon atom 2-1 Together they form C3-C6 cycloalkyl groups, 4-6 membered heterocyclic alkyl groups, and are bonded by one or more R groups. C-1 Substituted C3-C6 cycloalkyl groups or those with one or more R C-2 Substituted 4-6 membered heterocyclic alkyl groups; Or, two R atoms on the same carbon atom 2-2 Together they form C3-C6 cycloalkyl groups, 4-6 membered heterocyclic alkyl groups, and are bonded by one or more R groups. C-1 Substituted C3-C6 cycloalkyl groups or those with one or more R C-2 Substituted 4-6 membered heterocyclic alkyl groups; R C-1 and R C-2 Each independently constitutes a halogen, -NR b R c 、 -C(=O)R d or -OC(=O)R e ; R 3 Independently -H, halogen, -CN or C1-C6 alkyl; n is 0, 1, 2, or 3; Each "4-6 membered heterocyclic alkyl group" is independently a 4-6 membered heterocyclic alkyl group with one, two or three heteroatoms selected from N, O and S. Each "4-12 membered heterocyclic alkyl group" is independently a 4-12 membered heterocyclic alkyl group with one, two or three heteroatoms selected from N, O and S.

2. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) Each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl or isopropyl; (2) Each "C3-C6 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl; (3) Each “4-6 membered heterocyclic alkyl” is independently a 4-6 membered heterocyclic alkyl with N and / or O heteroatoms and one or two heteroatoms, such as oxobutane, azirane, tetrahydropyrrole, tetrahydrofuran, piperidinyl, morpholinyl or piperazine. (4) Each "C3-C" 12 Each "cycloalkyl" is independently a C3-C6 monocyclic cycloalkyl or a C6-C6 monocyclic cycloalkyl. 12 Bicyclic cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or C8 spirocycloalkyl, further such as cyclohexyl or spiro[2.5]octyl, preferably (5) Each "4-12 membered heterocyclic alkyl group" is independently a 4-6 membered heterocyclic alkyl group with one or two heteroatoms selected from N and / or O, or a 6-12 membered bicyclic heterocyclic alkyl group with one, two, or three heteroatoms selected from N and / or O, such as oxobutane, azabutane, tetrahydropyrrole, tetrahydrofuranyl, piperidinyl, morpholinyl, or piperazine, more preferably tetrahydropyranyl or piperidinyl. (6) Each "halogen" is independently F, Cl, Br or I, for example F, Cl or Br; (7) Each "C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy or ethoxy.

3. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, for R 1 It is a C1-C6 alkyl group or is composed of one or more R groups. 1-1 Substituted C1-C6 alkyl groups; R 1-1 Independently -OH; R 2 For one or more R 2-1 Replacement C3-C 12 cycloalkyl or with one or more R 2-2 Substituted 4-12 membered heterocyclic alkyl groups; R 2-1 and R 2-2 Each independently R a -CN, -NR a-1 R a-2 Or by one or more R a-3 Substituted C1-C6 alkyl groups; R a-1 and R a-2 Each is independently -H, C1-C6 alkyl, -S(=O)2R A-1 or -C(=O)R A-2 ; R A-1 and R A-2 Each is independently a C1-C6 alkyl or a C3-C6 cycloalkyl; R a-3 Independently halogen, -CN, -S(=O)2R A-1 or -C(=O)NR B-1 R B-2 ; R B-1 and R B-2 Each is independently -H or C1-C6 alkyl; R 3 Independently -H or halogen; n is 0 or 1; Each "4-12 membered heterocyclic alkyl group" is independently a 4-12 membered heterocyclic alkyl group with one, two or three heteroatoms selected from N, O and S.

4. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 1-1 Independently -OH, -CN, or -F; (2)R a -CN, -NR a-1 R a-2 -C(=O)R a-4 C1-C3 alkoxy, halogen, or by one or more R a-3 Substituted C1-C3 alkyl groups; For example, -CN, -NHS(=O)2R A-1 -NCH3S(=O)2R A-1 -NHC(=O)R A-2 -NCH3C(=O)R A-2 -C(=O)R a-4 C1-C3 alkoxy, halogen, or one or more R a-3 Substituted methyl groups, further for example -CN, (3)R C-1 and R C-2 Each independently as -NR b R c .

5. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 2-1 R 2-2 R C-1 and R C-2 Each independently is -F, Ideally, R C-1 and R C-2 Each independently 6. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 It is a C1-C3 alkyl, C3-C4 cycloalkyl, or composed of one or more R 1-1 Substituted C1-C3 alkyl groups; (2)R 2 Cyclohexyl, a 6-membered heterocyclic alkyl group, and formed by one or more R groups 2-1 Replacement C3-C 12 Cyclohexyl or cyclohexyl group with one or more R groups 2-2 Substituted 6-membered heterocyclic alkyl groups; (3)R 3 Independently -H, -F, -Cl, -Br, -CN, or -CH3; (4) n is 1, 2 or 3.

7. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 Methyl, ethyl, isopropyl, cyclopropyl, Wherein, the carbon atom marked with "*" is in the R configuration, S configuration or a mixture thereof, preferably the R configuration; Ideally, R 1 Methyl, ethyl, isopropyl, cyclopropyl, Preferred (2)R 2 for For example Further examples 8. The compound of formula (I) as claimed in at least one of claims 1-7, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, for Preferred Among them, R 3-1 R 3-2 and R 3-3 The definition is the same as that of R as described in any one of claims 1-7. 3 ; Ideally, R 3-2 For H or F; Ideally, R 3-3 For H.

9. The compound of formula (I) as claimed in at least one of claims 1-7, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (I) is any one of the following compounds:

10. A pharmaceutical composition comprising a compound of formula (I) as claimed in at least one of claims 1-9, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. The use of a compound of formula (I) as claimed in at least one of claims 1-9, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 10 in the preparation of a selective inhibitor of JAK1 and / or TYK2.

12. The use of a compound of formula (I) as claimed in at least one of claims 1-9, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 10 in the preparation of a medicament for the prevention and / or treatment of diseases associated with JAK1 and / or TYK2, preferably, wherein the diseases associated with JAK1 and / or TYK2 are autoimmune diseases.

13. The use of a compound of formula (I) as claimed in at least one of claims 1-9, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 10 in the preparation of a medicament for the prevention and / or treatment of autoimmune diseases.

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