PIM kinase inhibitor

Abstract

Disclosed in the present invention are a PIM kinase inhibitor as shown in general formula II, a pharmaceutical composition thereof, a preparation method therefor and the use thereof in the preparation of a drug for preventing and / or treating indications related to a PIM signaling pathway. The compound of the present invention is an ideal PIM kinase inhibitor with a high activity, which can be used for treating and / or preventing diseases including autoimmune diseases and tumors, e.g., inflammatory bowel disease, hematologic malignancies such as acute myeloid leukemia, myelofibrosis and chronic lymphocytic leukemia, and solid tumors such as gastric cancer and prostate cancer.

Description

A PIM kinase inhibitor TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and relates to a PIM kinase inhibitor, a pharmaceutical composition thereof, a preparation method thereof, and use of the PIM kinase inhibitor in preparation of a drug for treating a PIM signaling pathway-related indication. BACKGROUND

[0002] The proviral integration site of murine leukemia virus (PIM) kinase is a serine / threonine protein kinase, which is composed of three subtypes, PIM1, PIM2 and PIM3. PIM1 and PIM2 are highly expressed in hematological tumors and solid tumors, and PIM3 is highly expressed in hepatocellular carcinoma, pancreatic cancer and colon cancer.

[0003] PIM kinase is a downstream molecule of the JAK / STAT pathway, and the JAK pathway plays an important role in autoimmune diseases. Literature research shows that PIM-1 inhibitors are effective in a mouse inflammatory bowel disease model, suggesting that PIM kinase inhibitors can be used in autoimmune diseases.

[0004] In addition, PIM kinase can regulate cell proliferation, growth and invasiveness by phosphorylating a series of downstream signaling molecules such as p53, BAD and MYC, and plays an important role in the occurrence and development of tumors. Preclinical studies have found that PIM inhibitors are effective in treating hematological tumors such as acute myeloid leukemia, myelofibrosis and chronic lymphocytic leukemia, and solid tumors such as gastric cancer and prostate cancer, suggesting that PIM inhibitors can be used in tumor treatment.

[0005] PIM inhibitors can also be combined. Studies have found that the combination of PIM inhibitors and JAK inhibitors such as ruxolitinib is effective in treating myelodysplastic syndrome in mice. Patent WO2016161248 reports the use of PIM inhibitors combined with BTK inhibitors such as ibrutinib in the treatment of B-cell lymphoma.

[0006] Patent CN202210112402.5 discloses a PIM inhibitor with higher activity, but there is still a problem of poor pharmacokinetic effect.

[0007] There is an urgent need to provide a PIM inhibitor with good kinase inhibition effect and better pharmacokinetic properties. SUMMARY

[0008] The present application provides a novel PIM kinase inhibitor, a pharmaceutical composition thereof, a preparation method thereof, and use of the PIM kinase inhibitor in preparation of a drug for treating a PIM signaling pathway-related indication.

[0009] To address the shortcomings of existing technologies, this invention provides, in one aspect, a compound having the structure shown in general formula (I), its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt:

[0010] in,

[0011] L1 is a chemical bond or an ether bond;

[0012] Ring A is a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S; ring A is preferred.

[0013] R1 is selected from cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The alkyl halogen is preferably cyano, methyl, trifluoromethyl, difluoromethyl, methoxy, or trifluoromethoxy.

[0014] L2 represents chemical bonds, -NH-, -SO2-, -NH-SO2-, -SO2-NH-, -O-, and -CH2-.

[0015] R2 is -Z-L3-R3;

[0016] Z is any one of 1-3 R's. a Substituted 4-6 membered cycloalkyl groups, optionally with 1-3 R groups a The substituted 4-11 members contain 1-3 heterocyclic groups selected from N, O, and S heteroatoms; preferably...

[0017] R a Selected from oxo, halogen, hydroxyl, C 1-6 Alkoxy groups, preferably oxo, halogen, or hydroxyl groups;

[0018] L3 is a chemical bond, C 1-3 Alkylene, -SO2-, -(C=O)-;

[0019] R3 is selected from H and C. 1-3 Alkyl, hydroxyl, amino, hydroxy-C 1-3 Alkylene, C 1-3 Alkyl-imino, optionally surrounded by 1-3 R b Substituted 4-6 membered cycloalkyl groups, optionally with 1-3 R groups b The substituted 4-11 members contain 1-3 heterocyclic groups selected from N, O, and S heteroatoms;

[0020] R b Selected from oxo, halogen, hydroxyl, cyano, C1-3 alkyl, hydroxy-C 1-3 alkylene, cyano-C 1-3 alkylene, C 1-3 alkyl-C(=O)-, NH2-C(=O)-, carboxyl, C 1-3 alkyl-O-C 1-3 alkylene.

[0021] As preferred:

[0022] Z is selected from the group consisting of: a consisting of: Preferred

[0023] As preferred:

[0024] R3is selected from the group consisting of: H, methyl, hydroxy, cyano, amino, Preferred H, methyl, hydroxy, cyano, amino,

[0025] Further preferred: L1is a bond; ring A is

[0026] In certain preferred embodiments, the compounds have the structure according to general formula (II):

[0027] R1is selected from the group consisting of cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, preferably cyano, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy;

[0028] L2is selected from the group consisting of a bond, -NH-, -SO2-NH-, -SO2-, -O-, -CH2-;

[0029] R2is -Z-L3-R3;

[0030] Z is selected from the group consisting of: a substituted 5-6 membered cycloalkyl, optionally substituted 4-11 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; preferably a substituted 5-6 membered cycloalkyl, optionally substituted 4-11 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; preferably

[0031] R aselected from oxo, halogen, hydroxy, cyano, C 1-6 alkyl, hydroxy-C

[0032] L3is a bond, C 1-3 alkylene, -SO2-, -(C=0)-;

[0033] R3is selected from H, C 1-3 alkyl, hydroxy, amino, hydroxy-C 1-3 alkylene, C 1-3 alkyl-imino, optionally substituted with 1-3 R b substituted 4-6 membered cycloalkyl, optionally substituted with 1-3 R b substituted 4-11 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S;

[0034] R b selected from oxo, halogen, hydroxy, cyano, C 1-3 alkyl, hydroxy-C 1-3 alkylene, cyano-C 1-3 alkylene, C 1-3 alkyl-C(=0)-, NH2-C(=0)-, carboxy, C 1-3 alkyl-O-C 1-3 alkylene.

[0035] As preferred:

[0036] L2is selected from -NH-, -SO2-, -0-, -CH2-;

[0037] R2is -Z-L3-R3;

[0038] Z is optionally substituted 5-6 membered cycloalkyl, optionally substituted with 1-3 R a substituted 4-8 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; preferably a substituted 4-8 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; preferably

[0039] R a selected from oxo, halogen, hydroxy, cyano, C 1-3 alkyl, hydroxy-C

[0040] preferably Z and R a consist of the following groups:

[0041] more preferably

[0042] As preferred:

[0043] R3is selected from H, C 1-3 alkyl, hydroxy, amino, hydroxy-C 1-3 alkylene, C 1-3 alkyl-imino, optionally substituted with 1-3 R b substituted with 1-3 R

[0044] R b selected from oxo, halogen, hydroxy, cyano, C 1-3 alkyl, hydroxy-C 1-3 alkylene, cyano-C 1-3 alkylene, C 1-3 alkyl-C(=O)-, NH2-C(=O)-, carboxy, C 1-3 alkyl-O-C 1-3 alkylene; preferably oxo, F, hydroxy, cyano, methyl,

[0045] Preferably, R3is selected from H, methyl, hydroxy, cyano, amino, Preferably H, methyl, hydroxy, cyano, amino,

[0046] As preferred:

[0047] L2is selected from a bond;

[0048] Z is a 9-11 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S, optionally substituted with 1-3 R a substituted with 1-3 R

[0049] R a selected from oxo, halogen, hydroxy, C 1-3 alkoxy, preferably oxo, halogen, hydroxy;

[0050] Preferably Z and R a consist of the following groups:

[0051] As preferred:

[0052] R3is selected from H, C 1-3 alkyl, hydroxy, amino, hydroxy-C 1-3 alkylene, C 1-3 alkyl-imino, optionally substituted with 1-3 R b substituted with 1-3 R

[0053] Rb selected from oxo, halogen, hydroxyl, cyano, C 1-3 alkyl, hydroxyl-C 1-3 alkylene, cyano-C 1-3 alkylene, C 1-3 alkyl-C(=O)-, NH2-C(=O)-, carboxyl, C 1-3 alkyl-O-C 1-3 alkylene; preferably oxo, F, hydroxyl, cyano, methyl,

[0054] Preferably, R3is selected from H, methyl, hydroxyl, cyano, amino, preferably H, methyl, hydroxyl, cyano, amino,

[0055] In some preferred embodiments, the compound has the structure shown in general formula (III):

[0056] R3is selected from

[0057] R a selected from hydroxyl or C 1-3 alkoxy;

[0058] R b selected from H, cyano or C 1-3 alkyl.

[0059] The present application also provides the following compounds, including:

[0060] In another aspect, the present application also provides a pharmaceutical composition containing the above-mentioned compound, its deuterated compound, stereoisomer or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier thereof.

[0061] In another aspect, the present application also provides a use of the above-mentioned compound, its deuterated compound, stereoisomer or pharmaceutically acceptable salt or pharmaceutical composition in the preparation of a medicament for treating and / or preventing a PIM-related disease.

[0062] As a preference, the PIM-related disease includes autoimmune diseases, tumors.

[0063] As a preference, the PIM-related disease includes inflammatory bowel disease, hematological neoplasms and solid tumors.

[0064] In some cases, the drug is used alone or in combination with other therapeutic agents for the treatment of the above-mentioned related diseases.

[0065] The compound provided by the present application has strong drug efficacy, good pharmacokinetic properties, and low toxicity and side effects, and is an ideal PIM inhibitor. In particular, compared with existing PIM inhibitors, the compound has better pharmacokinetic properties, including but not limited to the increase of C max , AUC and bioavailability. The increase of bioavailability means that the oral dose required to reach the same blood concentration is significantly reduced, and the gastrointestinal toxicity of the compound of the present application is also significantly reduced. The compound provided by the present application has better PIM inhibitory activity. The compound of the present application can be used as a selective PIM1 inhibitor and has better selective inhibitory activity on PIM1. The compound of the present application is an ideal high-activity PIM inhibitor, and can be used for the treatment and / or prevention of clinical diseases including acute myeloid leukemia, myelofibrosis, chronic lymphocytic leukemia and other hematological tumors, and gastric cancer, prostate cancer and other solid tumors.

[0066] Definitions

[0067] As used herein, numerical ranges include endpoints and any number that falls within the range. For example, "0-3" can include 0, 1, 2, or 3, and "1-3" can include 1, 2, or 3.

[0068] As used herein, "C 1-n " includes C 1-2 , C 1-3 ,... C 1-n . For example, a "C 1-6 " group refers to a moiety having 1-6 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Thus, for example, a "C 1-4 alkyl" group refers to an alkyl group having 1-4 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Numerical ranges as used herein, such as "1-6", are used to indicate each integer within the specified range.

[0069] As used herein, "n-m membered" refers to the number of ring atoms in a ring group. For example, a "3-8 membered" group refers to a moiety having 3-8 ring atoms, i.e., the group contains 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, or 8 ring atoms. Thus, for example, a "3-8 membered cycloalkyl" group refers to a saturated cyclic hydrocarbon group having 3-8 carbon atoms, i.e., the alkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0070] The term "hydrocarbyl" as used herein alone or in combination refers to a radical composed exclusively of carbon and hydrogen elements, including saturated, unsaturated, or aromatic carbon and hydrogen groups, such as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl. When not specified, "hydrocarbyl" can be linear, branched, or cyclic.

[0071] The term "alkyl" as used herein alone or in combination refers to an optionally substituted straight chain or optionally substituted branched chain saturated aliphatic hydrocarbon. The "alkyl" groups herein preferably can have 1 to 6 carbon atoms, for example, 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl- 1-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l-butyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, t-pentyl, hexyl, and the like. When a numerical range, for example, "C1-C6 alkyl" appears in the definition of a group as defined herein, for example, alkyl, this means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. The alkyl groups herein also include cases where no numerical range is specified. The alkyl group can be optionally substituted or unsubstituted.

[0072] "Alkyl" as used in combination herein refers to an alkyl group attached to another group, for example, the alkyl group in an alkoxy group, which is defined the same as when used alone.

[0073] The term "alkylene" as used herein alone or in combination refers to a saturated aliphatic divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a straight chain or branched chain saturated aliphatic hydrocarbon group. The "alkylene" groups herein preferably can have 1 to 6 carbon atoms, for example, 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Non-limiting examples of alkylene groups include -CH2- (i.e., methylene), -CH2-CH2- (i.e., ethylene), -CH2-CH2-CH2-, -CH(CH3)CH2-, -C(CH3)2-, -CH2-C(CH3)-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-CH2-, and the like. The alkylene group can be optionally substituted or unsubstituted.

[0074] The term "alkenyl," used alone or in combination, refers to an optionally substituted straight-chain or optionally substituted unsaturated aliphatic hydrocarbon having one or more carbon-carbon double bonds. Preferably, "alkenyl" herein can have 1 to 6 carbon atoms, for example, 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, 1 -butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3- butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and 1,4-hexadienyl groups / moieties. Unless otherwise indicated, the term "alkenyl" does not include "cycloalkenyl."

[0075] The term "alkoxy" or "-O-alkyl," used alone or in combination, means "alkyl-O-." Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, s-butyloxy, t-butyloxy, and the like. Alkoxy groups can be optionally substituted or unsubstituted.

[0076] The term "cycloalkyl," used alone or in combination, refers to saturated monocyclic, bicyclic, fused, bridged, spiro, and the like carbocyclic rings. Preferably, cycloalkyl herein is C3-C 12 cycloalkyl, more preferably C3-C 10 cycloalkyl, more preferably C3-C

[0077] The term "cycloalkyl," used alone or in combination, refers to saturated monocyclic, bicyclic, fused, bridged, spiro, and the like carbocyclic rings. Preferably, cycloalkyl herein is C3-C

[0078] "spiro" in the definition of "cycloalkyl" refers to a polycarbocyclic group having two or more cyclic structures with a single ring sharing one carbon atom with each other (referred to as a spiro atom). Preferably, the spiro group is 6- to 12-membered, more preferably 8- to 9-membered. According to the number of spiro atoms shared between the rings, the spiro group can be a mono-, bi- or polyspirocycloalkyl group, preferably a mono- and bi- spirocycloalkyl group, preferably a 4- to 5-, 4- to 6-, 5- to 5-, or 5- to 6- spirocycloalkyl group.

[0079] "bridged" in the definition of "cycloalkyl" refers to a polycyclic ring group having two or more cyclic structures sharing two or more atoms. A "fused" or "annulated" ring is a special type of bridged ring having two or more cyclic structures sharing a pair of atoms. Preferably, the bridged ring is 7- to 15-membered, more preferably 8- to 9-membered. According to the number of rings, the bridged ring can be a bicyclic, tricyclic, tetracyclic or polycyclic ring group, preferably a bicyclic or tricyclic ring group, more preferably a 5- to 5-, 5- to 6-, or 6- to 6- bicyclic ring group. Non-limiting examples include, but are not limited to, bicyclo[2.2.2]octane, spiro[3.4]octane.

[0080] Unless otherwise specified, spiro and bridged rings can also be applied to the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl groups discussed below, including spiroalkyl, spiroalkenyl, spiroheterocycloalkyl, spiroheterocycloalkenyl, bridgedalkyl, bridgedalkenyl, bridgedheterocycloalkyl, bridgedheterocycloalkenyl. Fused rings include fusedalkyl, fusedalkenyl, fusedheterocycloalkyl, fusedheterocycloalkenyl, fusedaryl, fusedheteroaryl. The above terms are defined similarly to spiro, bridged, annulated or fused rings.

[0081] The term "cycloalkyl" as used herein alone or in combination refers to a saturated monocyclic, bicyclic or polycyclic carbocyclic ring, which can be spiro or bridged. Preferably, the cycloalkyl group is a 3- to 12-membered ring, more preferably a 3- to 10-membered ring, most preferably a 3- to 8-membered ring. Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, which can be optionally substituted or unsubstituted.

[0082] "spiro" in the definition of "cycloalkyl" refers to a polycarbocyclic group having two or more cyclic structures with a single ring sharing one carbon atom with each other (referred to as a spiro atom). Preferably, the spiro group is 6- to 12-membered, more preferably 8- to 9-membered. According to the number of spiro atoms shared between the rings, the spiro group can be a mono-, bi- or polyspirocycloalkyl group, preferably a mono- and bi- spirocycloalkyl group, preferably a 4- to 5-, 4- to 6-, 5- to 5-, or 5- to 6- spirocycloalkyl group.

[0083] "Ring" in the definition of "cycloalkyl" means a fully carbon monocyclic ring group. Preferred herein is a 3- to 12-membered ring, more preferably a 3- to 10-membered ring, and most preferably a 3- to 8-membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl, which can be optionally substituted or unsubstituted.

[0084] "Bridged" in the definition of "cycloalkyl" means a fully carbon polycyclic group containing two or more cyclic structures that share two non-adjacent carbon atoms with each other. Preferred herein is a 6- to 12-membered ring, more preferably a 8- to 9-membered ring. Bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, with bicyclic or tricyclic being preferred.

[0085] The term "cycloalkenyl," used alone or in combination, refers to a monocyclic, bicyclic, or polycyclic carbocyclic ring having one or more carbon-carbon double bonds that is not aromatic, which can be spiro or bridged. Preferred herein is a 3- to 12-membered cycloalkenyl, more preferably a 3- to 10-membered cycloalkenyl, and most preferably a 3- to 8-membered cycloalkenyl. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopent-l-en-l-yl, cyclohex-l-en-l-yl, and cyclohex-l,3-dien-l-yl, which can be optionally substituted or unsubstituted.

[0086] The term "aryl," used alone or in combination, refers to an aromatic hydrocarbon ring. The term "aryl" includes both monocyclic aromatic hydrocarbons and polycyclic fused ring aromatic hydrocarbons, wherein all of the fused ring systems (excluding any ring systems that are part of or formed by an optional substituent) are aromatic. Examples of aryl groups / moieties include phenyl, naphthyl, anthryl, and phenanthryl. Unless otherwise indicated, the term "aryl" does not include "heteroaryl."

[0087] The term "heterocyclyl," used alone or in combination, includes aliphatic heterocyclyl and aromatic heterocyclyl groups, wherein one or more (such as one, two, three, or four) ring atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, and the like, including monocyclic, fused, bridged, and spirocyclic. Examples of heterocyclyl groups include heterocycloalkyl, heterocycloalkenyl, and heteroaryl groups, as discussed below. Preferred herein is a 3- to 10-membered monocyclic, bicyclic, or tricyclic heterocyclyl group, which can contain 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and / or sulfur. Non-limiting examples of "heterocyclyl" include azetidinyl, azetidin-2-yl, oxetanyl, thietanyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, 2-oxo-piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, piperazin-2-one, dioxanyl, morpholinyl, and thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, and the like. Heterocyclyl groups can be optionally substituted or unsubstituted.

[0088] "Spiro" in the definition of "heterocyclyl" refers to a polycyclic ring group containing two or more ring structures and sharing a single atom between the rings, the rings containing several unsaturated linkages, but none of the rings having a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) n wherein n is selected from 0, 1, or 2, and the remaining ring atoms are carbon. Preferred herein are 6-12 membered, more preferred 8-9 membered. Spiroheterocyclyl groups can be classified as spiroheterocyclyl, bispiroheterocyclyl, or polyspiroheterocyclyl based on the number of rings sharing a spiro atom between the rings, preferred are spiroheterocyclyl and bispiroheterocyclyl, more preferred are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered spiroheterocyclyl. Non-limiting examples include, but are not limited to, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2-azaspiro[3.4]octane.

[0089] "Bridge" in the definition of "heterocyclyl" refers to a polycyclic ring group containing two or more ring structures and sharing two or more atoms between the rings, one or more of the rings can contain several unsaturated linkages, but none of the rings having a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) n wherein n is selected from 0, 1, or 2, and the remaining ring atoms are carbon. Preferred herein are 6-12 membered, more preferred 8-9 membered. Bridgeheterocyclyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic based on the number of rings, preferred are bicyclic or tricyclic.

[0090] "Fused" in the definition of "heterocyclyl" refers to a polycyclic ring group containing two or more ring structures and sharing a pair of atoms between the rings, one or more of the rings can contain several unsaturated linkages, while at least one of the rings has a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) n wherein n is selected from 0, 1, or 2, and the remaining ring atoms are carbon. Preferred herein are 6-12 membered, more preferred 8-9 membered. Fusedheterocyclyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic based on the number of rings, preferred are bicyclic or tricyclic, more preferred are 5-membered / 5-membered or 5-membered / 6-membered bicyclic fusedheterocyclyl.

[0091] The term "heterocycloalkyl" as used herein alone or in combination refers to a saturated heterocyclyl group having one or more (such as one, two, three, or four) ring atoms that are heteroatoms, which can be spiro or bridged, in a monocyclic, bicyclic, or polycyclic ring system. Preferred herein is a 3-12 membered cycloalkyl, more preferred is a 3-10 membered cycloalkyl, and most preferred is a 3-8 membered cycloalkyl. Non-limiting examples of monocyclic heterocycloalkyl groups include, but are not limited to, propylene oxide, thiirane, aziridine, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, oxazolidine, thiazolidine, imidazolidine, tetrahydropyran, piperidine, dioxane, azepane.

[0092] The term "heterocycloalkenyl" as used herein alone or in combination refers to a monocyclic, bicyclic, or polycyclic ring system having one or more unsaturated double bonds, which is not aromatic, having one or more (such as one, two, three, or four) ring atoms that are heteroatoms, which can be spiro or bridged. Preferred herein is a 3-12 membered heterocycloalkenyl, more preferred is a 3-10 membered heterocycloalkenyl, and most preferred is a 3-8 membered heterocycloalkenyl. Non-limiting examples of heterocycloalkenyl groups include, but are not limited to, azacyclopropene, oxacyclopropene, thiacyclopropene, oxacyclobutene, pyran.

[0093] The term "heteroaryl" as used herein alone or in combination refers to a 5-12 membered (preferably 5-10 membered, more preferably 5-6 membered) monocyclic, bicyclic, or tricyclic ring system, wherein at least one ring is aromatic, and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, and wherein the heteroaryl group has one or more points of attachment to the rest of the molecule. In a "heteroaryl" group that is a bicyclic or tricyclic ring system, the "heteroaryl" group can contain a saturated or unsaturated heterocycloalkyl or "heteroaryl" group. Non-limiting examples of "heteroaryl" groups include furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, thiazolyl, and the like; bicyclic, but not limited to, the following: benzoimidazolyl, benzofuranyl, benzothiophenyl, indolyl, oxoindolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, 1,8-naphthyridinyl, benzo[d]isoxazolyl, benzo[d]thiazolyl, pyrrolo[3,2-b]pyridinyl, furano[3,2-b]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyrimidinyl, thiazolo[4,5-c]pyridinyl, thieno[3,2-b]pyridinyl, pyrrolo[1,2-b]pyridazinyl, 2,3-dihydrobenzofuranyl, benzo[c][1,2,5]oxadiazolyl, 1,3-dihydro-2H-benzo[d]imidazol-2-one, benzo[d]oxazol-2(3H)-one, and the like. The heteroaryl group can be optionally substituted or unsubstituted.

[0094] The term "halogen" as used herein alone or in combination refers to fluorine, chlorine, bromine or iodine.

[0095] The term "hydroxyl" as used herein alone or in combination refers to -OH.

[0096] The term "cyano" as used herein alone or in combination refers to -CN.

[0097] The term "methanesulfonyl" as used herein alone or in combination refers to -S(O)2-CH3.

[0098] The term "substituted" or "substitution" as used herein refers to replacement of one or more hydrogens on a specified atom with the indicated group(s) such as halogen, alkyl, etc. provided that the indicated atom's normal valency is not exceeded and that the resulting compound is stable.

[0099] The term "pharmaceutically acceptable salt" as used herein is art-recognized and refers to salts of the compounds of the present application that are relatively non-toxic to the subject to which they are administered in doses.

[0100] The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not interfere with the biological activity or properties of the compounds of the present application and is relatively non-toxic, i.e., the substance can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0101] The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally in admixture with at least one pharmaceutically acceptable chemical ingredient including, but not limited to, a carrier, a stabilizer, a diluent, a dispersing agent, a suspending agent, a thickening agent, and / or an excipient.

[0102] The term "carrier" as used herein refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of a compound into a cell or tissue.

[0103] The term "stereoisomer" as used herein includes, but is not limited to, enantiomers, cis-trans isomers, and the like.

[0104] The term "enantiomer" as used herein refers to the phenomenon of isomerism in which two compounds having the same molecular formula exist as mirror images of each other and are not superimposable. The term "cis-trans isomer" as used herein refers to the phenomenon of stereoisomerism in which the spatial arrangement of groups in a molecule is different due to the presence of a restriction factor for free rotation. Organic molecules such as alkenes, azo compounds, alicyclic hydrocarbons, etc. are considered to be cis-trans isomers. In the present application, cis-trans isomerism is mainly embodied in the form of alicyclic hydrocarbons. For example, in cyclohexane, cis-trans isomerism occurs when the cyclohexane is substituted with two substituents. When the two substituents are on the same side of the ring, it is a "cis" isomer, and when they are on different sides, it is a "trans" isomer.

[0105] The compounds of the present application can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present application, including but not limited to, diastereomeric, enantiomeric, atropisomeric, and geometric (conformational) isomeric forms, and mixtures thereof such as racemates, be within the scope of the present application.

[0106] Unless otherwise indicated, structures depicted throughout this application are also meant to include all isomeric forms (e.g., diastereomeric, enantiomeric, cis-trans (or E-Z), atropisomeric, and geometric (conformational) isomeric forms) and mixtures thereof of the structures. For example, the R and S configurations of each asymmetric center, the (Z) and (E) double bond isomers, the cis- and trans- isomers of alicyclic hydrocarbons, the atropisomers of biaryls (see, Xinggai et al., p104-105 in Basic Organic Chemistry (2nd Edition), Volume 1), the (Z) and (E) conformers are meant to be included within the scope of the present application. Thus, single stereoisomers, as well as enantiomeric, diastereomeric, atropisomeric, and geometric (or conformational) mixtures are within the scope of the present application. DETAILED DESCRIPTION

[0107] The present application is further described in detail by reference to the following specific examples. The present application is not limited in scope by the examples, which are intended as illustrations of single aspects of the application only.

[0108] The compound (I) can be theoretically synthesized by the following route (each group is consistent with the definition above).

[0109] First step: synthesis of compound SM2

[0110] Method 1:

[0111] To a solution of SM1A (1.0 eq) in toluene (10-20 vol) at 20 °C under nitrogen protection, add A-L1-X-R1 (X represents halogen, 1.0-1.2 eq), potassium carbonate (2.0 eq) and triphenylphosphine or tricyclohexylphosphine (0.2 eq) successively, then replace the system with nitrogen for 3 times. After replacing nitrogen, add palladium acetate (0.1 eq) to the reaction system under nitrogen protection. After completing the addition, warm the reaction liquid to 120 °C and stir at 120 °C for 10-16 hours. TLC or LCMS shows that the reaction is complete. After the reaction liquid is cooled to room temperature, filter. Dilute the filtrate with water (20-30 vol) and extract with ethyl acetate. Dry the combined organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain the crude product. Purify the obtained crude product by column chromatography (petroleum ether / ethyl acetate = 100 / 1-0 / 1) to obtain compound SM2.

[0112] Method 2:

[0113] To a solution of SM1B (1 eq) in toluene or dioxane and water (10 / 1-5 / 1, 10-20 vol) at 20 °C under nitrogen protection, add R1-A-L1-B(OH)2 (or borate, 1.2-1.5 eq), potassium carbonate or sodium carbonate (2-3 eq) successively, then replace the system with nitrogen for 3 times. After replacing nitrogen, add 1,1-bis(diphenylphosphino)ferrocene palladium chloride or palladium tetraphenylphosphine (0.03-0.1 eq) to the reaction system under nitrogen protection. After completing the addition, warm the reaction liquid to 80-110 °C and stir at 80-110 °C for 12-16 hours. TLC shows that the starting material is completely consumed. After the reaction liquid is cooled to room temperature, filter, pour the filtrate into water, then extract with ethyl acetate. Wash the combined organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain the crude product. Purify the obtained crude product by column chromatography (petroleum ether / ethyl acetate = 100 / 1-0 / 1) to obtain compound SM2.

[0114] Second step: synthesis of compound (I)

[0115] Method 3:

[0116] To a solution of compound SM2 (1 eq) in dimethylsulfoxide (5-20 vol) at 20 °C, R1-L2-H (1.0-1.4 eq) and a base were added successively. After the addition was completed, the system was warmed to 100-140 °C and stirred at 100-140 °C for 10-16 h. TLC (petroleum ether / ethyl acetate = 0 / 1) showed that the reaction was complete and LCMS showed that the product was generated. After the reaction solution was cooled to room temperature, it was poured into water and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then the filtrate was concentrated to dryness to give a crude product. The obtained crude product was purified by Prep-HPLC or Prep-TLC or column chromatography to give compound (I). The base mainly includes: 1. cesium fluoride (2.0 eq) and N,N-diisopropylethylamine (2.0-5.0 eq); 2. cesium fluoride (2.0 eq) or potassium fluoride (2.0-5.0 eq); 3. potassium fluoride (2.0-5.0 eq) and N,N-diisopropylethylamine (2.0-5.0 eq); 4. without any base, direct high-temperature substitution.

[0117] Method 4:

[0118] To a solution of compound SM2 (1 eq) in toluene or dioxane (5-15 vol) at 20 °C under nitrogen protection, R1-L2-H (1.2-1.8 eq), sodium tert-butoxide (1.2-1.5 eq) and (±)-2,2-bis(diphenylphosphino)-1,1'-binaphthyl (0.1-0.15 eq) were added successively, and then the system was replaced with nitrogen for 3 times. Tris(dibenzylideneacetone)dipalladium (0.05-0.1 eq) was added to the reaction system under nitrogen protection. After the addition was completed, the system was warmed to 80-110 °C and stirred at 80-110 °C for 10-20 h. LCMS showed that the reaction was complete and the product was generated. After the reaction solution was cooled to room temperature, it was filtered, poured into water, and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then the filtrate was concentrated to dryness to give a crude product. The obtained crude product was purified by Prep-HPLC or Prep-TLC or column chromatography to give compound (I).

[0119] The partial preparation conditions used in the examples are as follows:

[0120] Prep-HPLC conditions: Instrument: GILSON-GX281; Wavelength: 220nm & 254nm; Column type: Waters X-bridge (30x100mm, 10pm) or Luna C18 (30x75mm, 3pm) or Luna C18 (30x75mm, 3pm); Mobile phase: A: 10mM ammonium bicarbonate or H20 (0.1% formic acid) or H20 (0.1% trifluoroacetic acid), B: acetonitrile; Run time: 15min; Flow rate: 25mL / min.

[0121] The reverse phase column purification used C18 reverse phase silica gel column (Spherical C18, 40-60pm, 40g-120g) with water / acetonitrile (95 / 5~30 / 70) as mobile phase.

[0122] The synthesis steps of some intermediates in the present application are as follows:

[0123] Intermediate 1: 6-chloro-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazine

[0124] To a solution of 6-chloroimidazo[l,2-b]pyridazine (1.0 g, 6.51 mmol) in toluene (10 mL) was added 2-bromo-5-(trifluoromethyl)thiophene (1.81 g, 7.81 mmol), potassium carbonate (1.80 g, 13.02 mmol) and triphenylphosphine (341.59 mg, 1.30 mmol) successively at 20 °C, and then the system was replaced with nitrogen for 3 times. After the nitrogen replacement, palladium acetate (146.19 mg, 651.17 umol) was added to the reaction system under nitrogen protection. After the addition was completed, the reaction liquid was warmed to 120 °C and stirred for 12 hours. After the reaction liquid was cooled to room temperature, it was poured into water, and then extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness to obtain a crude product. 6-chloro-3-[5-(trifluoromethyl)-2-thienyl]imidazo[l,2-b]pyridazine (1.8 g, crude) was obtained as a yellow solid. MS (ESI): m / z 303.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.59 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.96 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.53 (d, J = 9.6 Hz, 1H).

[0125] Intermediate 2: N-(piperidin-4-yl)-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazine-6-amine

[0126] (1) 4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)piperidine-l -carboxylate

[0127] Intermediate 1 (300 mg, 1 mmol) and tert-butyl 4-aminopiperidine-l-carboxylate (200 mg, 1 mmol) were dissolved in dimethyl sulfoxide (10 mL) at room temperature, and cesium fluoride (456 mg, 3 mmol) and N,N-diisopropylethylamine (387 mg, 3 mmol) were added, and the reaction solution was heated to 120 °C and stirred for 4 hours. The reaction solution was added to water (40 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with a saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 98 / 2) to obtain the title compound (160 mg, yellow solid) at a yield of 34%. MS (ESI): m / z 467.9 [M+H] + .

[0128] (2) N-(piperidin-4-yl)-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- amine

[0129] Tert-butyl 4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)piperidine-l-carboxylate (160 mg, 0.34 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added, and stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain the title compound (125 mg, yellow solid) at a yield of 99%. MS (ESI): m / z 367.9 [M+H] + .

[0130] Example 1

[0131] 2-((2S,5R)-5-((3-(5-methyl-lH-pyrazol-3-yl)imidazo[l,2-b]pyridazin-6-yl)amino)tetrahydro- 2H-pyran-2-yl)propan-2-ol

[0132] (1) Methyl (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate

[0133] (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid (1 g, 4 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (2.1 g, 18 mmol) was added at 0 °C. After the addition was completed, it was stirred at room temperature for 2 hours. Methanol (10 mL) was further added, and it was stirred at room temperature for 0.5 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 40) to obtain the title compound (800 mg, white solid) at a yield of 75%. MS (ESI): m / z 203.8 [M+H-56] + .

[0134] (2) tert-Butyl (3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-ylcarbamate

[0135] Methyl (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate (800 mg, 3 mmol) was dissolved in tetrahydrofuran (8 mL), and 3M methylmagnesium bromide in methyltetrahydrofuran (5 mL, 15 mmol) was added dropwise under nitrogen protection at 0 °C. After the addition was completed, it was stirred at room temperature for 3 hours. The reaction solution was quenched by adding saturated sodium bicarbonate solution (50 mL), and extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to obtain the title compound (400 mg, white solid) at a yield of 50%. MS (ESI): m / z 281.8 [M+Na] + .

[0136] (3) 2-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)propan-2-ol hydrochloride

[0137] Tert-butyl (3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-ylcarbamate (400 mg, 1.5 mmol) was dissolved in 4M hydrochloric acid / 1,4-dioxane solution (10 mL), and it was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the title compound (245 mg, white solid) at a yield of 100%. MS (ESI): m / z 160.0 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ8.20(s,2H),8.05-7.87(m,1H),4.09-4.03(m,1H),3.26-3.20(m,1H),3.06-2.93(m ,2H),2.13-2.08(m,1H),1.81-1.77(m,1H),1.53-1.47(m,1H),1.35-1.32(m,1H),1.07(s,3H),1.01(s,3H).

[0138] (4) 6-Chloro-3-(5-methyl-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine

[0139] 3-Bromo-6-chloroimidazolo[1,2-b]pyridazine (100 mg, 0.43 mmol) was dissolved in 1,4-dioxane / water (10 mL / 2 mL), followed by (5-methyl-1H-pyrazol-3-yl)boric acid (54 mg, 0.43 mmol), potassium carbonate (118 mg, 0.86 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (35 mg, 0.043 mmol). The reaction mixture was heated to 100 °C and stirred overnight under nitrogen protection. The reaction mixture was directly filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (35 mg, yellow solid), yield: 35%. MS (ESI): m / z 234.1 [M+H] + .

[0140] (5)2-((2S,5R)-5-((3-(5-methyl-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-yl)amino)tetrahydro-2H-pyran-2-yl)prop-2-ol

[0141] 6-Chloro-3-(5-methyl-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine (35 mg, 0.15 mmol) and 2-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)prop-2-ol hydrochloride (35 mg, 0.18 mmol) were dissolved in dimethyl sulfoxide (5 mL), and cesium fluoride (68 mg, 0.45 mmol) and N,N-diisopropylethylamine (58 mg, 0.45 mmol) were added. The mixture was heated to 120 °C and stirred overnight. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give a crude product, which was then purified by Prep-HPLC to give the title compound (1.6 mg, white solid), yield: 3%. MS(ESI): m / z 357.1 [M+H] +. 1 H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 7.74-7.72 (m, 2H), 6.93-6.84 (m, 2H), 6.63 (d, J = 8.0 Hz, 1H), 4.27-4.23 (m, 2H), 3.82-3.78 (m, 1H), 3.10-3.05 (m, 2H), 2.27-2.21 (m, 4H), 1.87-1.85 (m, 1H), 1.48-1.43 (m, 2H), 1.14 (s, 3H), 1.08 (s, 3H).

[0142] Example 2

[0143] N-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)piperidine-4- sulfonamide

[0144] (1) 4-(N-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)sulfamoyl)piperidine- 1 -carboxylic acid tert-butyl ester

[0145] Intermediate 1 (200 mg, 0.66 mmol) and 4-sulfamoylpiperidine- 1 -carboxylic acid tert-butyl ester (209 mg, 0.79 mmol) were dissolved in dimethyl sulfoxide (5 mL), cesium fluoride (300 mg, 1.98 mmol) and N,N-diisopropylethylamine (255 mg, 1.98 mmol) were added, the mixture was heated to 120 °C and stirred overnight. Water (20 mL) was added to the reaction, extracted with ethyl acetate (20 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (160 mg, yellow solid) in 46% yield. MS (ESI): m / z 531.8 [M+H] + .

[0146] (2) N-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)piperidine-4- sulfonamide

[0147] 4-(N-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)sulfamoyl)piperidine- 1 -carboxylic acid tert-butyl ester (60 mg, 0.11 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and stirred at room temperature for 1 hour. The reaction was concentrated, and the residue was purified by Prep-HPLC to give the title compound (15.3 mg, white solid) in 64% yield. MS (ESI): m / z 432.0 [M+H]+ . 1 HNMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.07 (s, 1H), 7.78-7.77 (m, 1H), 7.71-7.70 (m, 1H), 7.67 (d, J = 9.2 Hz, 1H), 6.63 (d, J = 9.6 Hz, 1H), 3.93-3.87 (m, 1H), 3.37-3.33 (m, 2H), 2.83-2.76 (m, 2H), 2.14-2.11 (m, 2H), 1.95-1.85 (m, 2H).

[0148] Example 3

[0149] N-(1-(Oxetan-3-yl)piperidin-4-yl)-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2- b]pyridazin-6-amine

[0150] Intermediate 1 (60 mg, 0.2 mmol) and 1-(oxetan-3-yl)piperidin-4-amine hydrochloride (46 mg, 0.2 mmol) were dissolved in dimethyl sulfoxide (5 mL), then cesium fluoride (91 mg, 0.6 mmol) and N,N-diisopropyl ethylamine (77 mg, 0.6 mmol) were added, and the mixture was heated to 120 °C and stirred for 16 hours. The reaction solution was added to water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 92 / 8) to obtain the title compound (40.7 mg, white solid), yield: 32%. MS (ESI): m / z 424.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.82-7.75 (m, 2H), 7.36 (d, J = 6.8 Hz, 1H), 6.75 (d, J = 9.6 Hz, 1H), 4.56 (t, J = 6.4 Hz, 2H), 4.45 (t, J = 6.4 Hz, 2H), 3.78-3.70 (m, 1H), 3.41-3.36 (m, 1H), 2.79 (d, J = 11.2 Hz, 2H), 2.16 (d, J = 12.0 Hz, 2H), 1.97-1.90 (m, 2H), 1.57-1.48 (m, 2H).

[0151] Example 4

[0152] 4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)amino)piperidine- 1 -sulfonamide

[0153] (1) tert-Butyl (4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)piperidin-l-yl)sulfamate

[0154] To a solution of intermediate 2 (30 mg, 0.08 mmol) and triethylamine (24 mg, 0.24 mmol) in dry dichloromethane (2 mL) was added dropwise a solution of chlorosulfonyl isocyanate (11 mg, 0.08 mmol) in dry dichloromethane (3 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 1 h. The reaction mixture was added to water (40 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (10 mg, yellow solid) in 22% yield. MS (ESI): m / z 546.9 [M+H] + .

[0155] (2) 4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)amino)piperidine- 1 -sulfonamide

[0156] To a solution of tert-butyl ((4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)piperidin-l-yl)sulfonyl)carbamate (10 mg, 0.02 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was added to saturated sodium bicarbonate solution (30 mL) and extracted with dichloromethane (15 mL x 3). The organic phase was combined and concentrated. The crude product was diluted with N,N-dimethylformamide and purified by Prep-HPLC to give the title compound (3.3 mg, white solid) in 40% yield. MS (ESI): m / z 447.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.98 (d, J = 9.6 Hz, 1H), 7.83 (d, J = 4.0 Hz, 1H), 7.79 (d, J = 4.0 Hz, 1H), 7.33 (d, J = 10.0 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.56 (s, 2H), 4.20-4.15 (m, 2H), 3.45-3.41 (m, 1H), 3.25-3.18 (m, 2H), 2.03-2.00 (m, 2H), 1.60-1.54 (m, 2H).

[0157] Example 5

[0158] 1 -Methyl- N-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[ 1,2-b]pyridazin-6- yl)piperidine-4-sulfonamide

[0159] N-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)piperidine-4- sulfonamide (16 mg, 0.037 mmol, Example 2, step 2), 40% aqueous formaldehyde solution (8 mg, 0.11 mmol) were dissolved in methanol (5 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (7 mg, 0.11 mmol) was added and stirred at room temperature overnight. The reaction was concentrated and the residue was purified by Prep-HPLC to give the title compound (2.1 mg, white solid) in 15% yield. MS (ESI): m / z 446.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.88-7.74 (m, 3H), 6.75-6.71 (m, 1H), 3.92-3.84 (m, 1H), 3.18-3.16 (m, 2H), 2.61-2.58 (m, 2H), 2.44-2.40 (m, 3H), 2.14-2.11 (m, 2H), 1.93-1.88 (m, 2H).

[0160] Example 6

[0161] 2-((2S,5R)-5-((3-(5-(trifluoromethyl)-lH-pyrazol-3-yl)imidazo[l,2-b]pyridazin-6- yl)amino)tetrahydro-2H-pyrazin-2-yl)propan-2-ol

[0162] (1)2-((2S,5R)-5-((3-bromoimidazolo[1,2-b]pyridazin-6-yl)amino)tetrahydro-2H-pyran-2-yl)prop-2-ol

[0163] 2-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)prop-2-ol hydrochloride (137 mg, 0.86 mmol, Step 3 of Example 1) and 3-bromo-6-chloroimidazolo[1,2-b]pyridazine (200 mg, 0.86 mmol) were dissolved in dimethyl sulfoxide (5 mL), and cesium fluoride (392 mg, 2.58 mmol) and N,N-diisopropylethylamine (333 mg, 2.58 mmol) were added. The reaction mixture was heated to 120 °C and stirred for 4 hours. The reaction mixture was added to water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 92 / 8) to give the title compound (90 mg, brown oil), yield: 30%. MS (ESI): m / z 354.8 [M+H] + .

[0164] (2)2-((2S,5R)-5-((3-(5-(trifluoromethyl)-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-yl)amino)tetrahydro-2H-pyrazin-2-yl)prop-2-ol

[0165] 2-((2S,5R)-5-((3-bromoimidazolo[1,2-b]pyridazin-6-yl)amino)tetrahydro-2H-pyran-2-yl)prop-2-ol (83 mg, 0.23 mmol) and (5-(trifluoromethyl)-1H-pyrazol-3-yl)boronic acid (83 mg, 0.46 mmol) were dissolved in a 1,4-dioxane / water mixture (5 mL / 1 mL). Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (17 mg, 0.023 mmol) and cesium carbonate (150 mg, 0.46 mmol) were added. The mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol = 97 / 3) to obtain the title compound (7 mg, white solid), which was then purified by Prep-HPLC in 7% yield. MS(ESI): m / z411.1[M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 13.45 (s, 1H), 7.98 (s, 1H), 7.81 (d, J = 10.0 Hz, 1H), 7.38 (s, 1H), 7.14 (d, J = 6.8 Hz, 1H), 6.74 (d, J = 9.6 Hz, 1H), 4.26-4.21 (m, 2H), 3.81-3.77 (m, 1H), 3.11-3.05 (m, 2H), 2.25-2.22 (m, 1H), 1.88-1.85 (m, 1H), 1.47-1.40 (m, 2H), 1.13 (s, 3H), 1.06 (s, 3H).

[0166] Example 7

[0167] 4-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)-l-oxa-4,9- diazaspiro[5.5]undecane

[0168] (1) 4-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)-l-oxa-4,9- diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester

[0169] Intermediate 1 (200 mg, 0.66 mmol) and tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate (186 mg, 0.73 mmol) were dissolved in dimethyl sulfoxide (5 mL), cesium fluoride (300 mg, 1.98 mmol) and N,N-diisopropylethylamine (255 mg, 1.98 mmol) were added, the mixture was heated to 120 °C and stirred overnight. Water (20 mL) was added to the reaction, extracted with ethyl acetate (20 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (200 mg, yellow solid) with a yield of 58%. MS (ESI): m / z 523.9 [M+H] + .

[0170] (2) 4-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)-l-oxa-4,9- diazaspiro[5.5]undecane

[0171] tert-Butyl 4-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)- 1 -oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (100 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and stirred at room temperature for 1 hour. The reaction was concentrated, and the residue was purified by Prep-HPLC to give the title compound (50.7 mg, white solid) in 63% yield. MS (ESI): m / z 424.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.00 (d, J = 10.0 Hz, 1H), 7.84-7.78 (m, 2H), 7.33 (d, J = 10.0 Hz, 1H), 3.84-3.82 (m, 2H), 3.63-3.58 (m, 4H), 3.17 (s, 1H), 2.79-2.68 (m, 4H), 1.70-1.54 (m, 4H).

[0172] Example 8

[0173] 9-(oxetan-3-yl)-4-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)- 1 -oxa-4,9-diazaspiro[5.5]undecane

[0174] tert-Butyl 4-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)- 1 -oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (100 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and stirred at room temperature for 1 hour. The reaction was concentrated, and the residue was purified by Prep-HPLC to give the title compound (50.7 mg, white solid) in 63% yield. MS (ESI): m / z 424.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.01 (d, J = 10.0 Hz, 1H), 7.84-7.79 (m, 2H), 7.32 (d, J = 10.0 Hz, 1H), 4.50 (t, J = 6.4 Hz, 2H), 4.40 (t, J = 6.0 Hz, 2H), 3.83-3.81 (m, 2H), 3.63-3.59 (m, 4H), 3.38 (t, J = 6.4 Hz, 1H), 2.29-2.20 (m, 4H), 1.80-1.68 (m, 4H).

[0175] Example 9

[0176] (1-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)sulfonyl)piperidin-4-yl)methanol

[0177] (1) 6-((4-methoxybenzyl)thio)-3-(5-(trifluoromethyl)thiophen-2- yl)imidazo[l,2-b]pyridazine

[0178] To a suspension of 6-((4-methoxybenzyl)thio)-3-(5-(trifluoromethyl)thiophen-2- yl)imidazo[l,2-b]pyridazine (240 mg, 0.47 mmol) in a mixed solvent (20 mL, acetonitrile / water / acetic acid = 40 / 1 / 1.5) at 0 °C, dichloroisocyanuric acid (224 mg, 1.14 mmol) was added portionwise, the suspension turned into a clear yellow solution rapidly, the temperature was kept for 2 h. The reaction was used directly for the next step. MS (ESI): m / z 368.0 [M+H] + .

[0179] (2) 3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazine-6-sulfonyl chloride

[0180] To a suspension of 6-((4-methoxybenzyl)thio)-3-(5-(trifluoromethyl)thiophen-2- yl)imidazo[l,2-b]pyridazine (240 mg, 0.47 mmol) in a mixed solvent (20 mL, acetonitrile / water / acetic acid = 40 / 1 / 1.5) at 0 °C, dichloroisocyanuric acid (224 mg, 1.14 mmol) was added portionwise, the suspension turned into a clear yellow solution rapidly, the temperature was kept for 2 h. The reaction was used directly for the next step. MS (ESI): m / z 368.0 [M+H] + .

[0181] (3)(1-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2-b]pyridazin-6-yl)sulfonyl)piperidin-4-yl)methanol

[0182] To the solution from previous step (15 mL, 100 mg, 0.27 mmol) was added piperidin-4-ylmethanol (63 mg, 0.54 mmol) and triethylamine (55 mg, 0.54 mmol) and the reaction was stirred at room temperature for 1 h. The reaction was filtered and concentrated. The residue was purified by Prep-HPLC to give the title compound (55.9 mg, yellow solid) in 45.7% yield. MS (ESI): m / z 447.0 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.55 (d, J = 9.6 Hz, 1H), 8.02 (dd, J = 3.6, 1.2 Hz, 1H), 7.90 (dd, J = 4.0, 1.2 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H), 4.47 (s, 1H), 3.84 (d, J = 7.6 Hz, 2H), 3.23-3.20 (m, 2H), 2.90-2.83 (m, 2H), 1.76-1.71 (m, 2H), 1.46-1.38 (m, 1H), 1.24-1.13 (m, 2H).

[0183] Example 10

[0184] N-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2-b]pyridazin-6-amine

[0185] Intermediate 2 (40 mg, 0.11 mmol) and dihydrofuran-3(2H)-one (9 mg, 0.11 mmol) were dissolved in dichloroethane (5 mL) and heated to 65 °C and stirred for 1 h. Sodium cyanoborohydride (25 mg, 0.39 mmol) was added and the reaction was stirred at 65 °C for another 2 h. The reaction was added to saturated sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC to give the title compound (11.6 mg, light yellow solid) in 24% yield. MS (ESI): m / z 438.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.95 (d, J = 10.0 Hz, 1H), 7.82-7.78 (m, 2H), 7.31 (d, J = 10.0 Hz, 1H), 4.18 (d, J = 12.8 Hz, 2H), 3.77-3.74 (m, 2H), 3.67-3.61 (m, 2H), 3.46-3.44 (m, 1H), 3.20-3.11 (m, 2H), 2.78-2.71 (m, 1H), 1.99-1.95 (m, 2H), 1.67-1.55 (m, 2H), 1.38-1.33 (m, 2H).

[0186] Example 11

[0187] N-methyl-4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)piperidine- 1 -carboxamide

[0188] Intermediate 2 (20 mg, 0.05 mmol), methylcarbamoyl chloride (10 mg, 0.11 mmol) and N,N-diisopropylethylamine (42 mg, 0.33 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 16 hours. The reaction was concentrated and the residue was purified by Prep-HPLC to give the title compound (13.6 mg, white solid) in 59% yield. MS (ESI): m / z 425.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.97 (d, J = 10.0 Hz, 1H), 7.83-7.78 (m, 2H), 7.32 (d, J = 10.0 Hz, 1H), 5.92 (d, J = 7.6 Hz, 1H), 5.62-5.60 (m, 1H), 4.16-4.13 (m, 2H), 3.73-3.70 (m, 1H), 3.24 (t, J = 11.2 Hz, 2H), 2.54 (d, J = 4.4 Hz, 3H), 1.91-1.87 (m, 2H), 1.51-1.42 (m, 2H).

[0189] Example 12

[0190] 6-((l-(oxetan-3-yl)piperidin-4-yl)oxy)-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2- b]pyridazine

[0191] (1) 4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)oxy)piperidine- 1 -carboxylic acid tert-butyl ester

[0192] tert-Butyl 4-hydroxypiperidine-l-carboxylate (133 mg, 0.66 mmol) was dissolved in tetrahydrofuran (5 mL), sodium hydride (40 mg, 0.99 mmol) was added at room temperature and the reaction was stirred for 30 minutes. Intermediate 1 (100 mg, 0.33 mmol) was added and the mixture was heated to 65 °C and stirred for 4 hours. The reaction was quenched by adding methanol (20 mL) and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (130 mg, light yellow oil) in 84% yield. MS (ESI): m / z 469.0 [M+H] + .

[0193] (2) 6-(Piperidin-4-yloxy)-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazine

[0194] tert-Butyl 4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)oxy)piperidine- 1 -carboxylate (75 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated to give the title compound (59 mg, light yellow oil) in 100% yield. MS (ESI): m / z 368.8 [M+H] + .

[0195] (3) 6-((l-(Oxetan-3-yl)piperidin-4-yl)oxy)-3-(5-(trifluoromethyl)thiophen-2- yl)imidazo[l,2-b]pyridazine

[0196] 6-(Piperidin-4-yloxy)-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazine (59 mg, 0.16 mmol) and oxetan-3-one (23 mg, 0.32 mmol) were dissolved in dichloroethane (5 mL) and the reaction was stirred at 65 °C for 1 hour. Sodium cyanoborohydride (35 mg, 0.56 mmol) was added and the reaction was stirred at 65 °C for 2 hours. The reaction was quenched by adding saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC to give the title compound (3.5 mg, white solid) in 5% yield. MS (ESI): m / z 425.0 [M+H] + .1 HNMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.16 (d, J = 10.0 Hz, 1H), 7.88 (dd, J = 4.0, 0.8 Hz, 1H), 7.82 (dd, J = 3.6, 0.8 Hz, 1H), 7.01 (d, J = 9.6 Hz, 1H), 5.14-5.04 (m, 1H), 4.56 (t, J = 6.4 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 3.45-3.42 (m, 1H), 2.74-2.71 (m, 2H), 2.26-2.24 (m, 2H), 2.13-2.07 (m, 2H), 1.86-1.78 (m, 2H).

[0197] Example 13

[0198] N-(1-(methylsulfonyl)piperidin-4-yl)-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2- b]pyridazin-6-amine

[0199] Intermediate 2 (20 mg, 0.05 mmol) and triethylamine (25 mg, 0.22 mmol) were dissolved in dichloromethane (5 mL), methylsulfonyl chloride (25 mg, 0.22 mmol) was added at -20 °C, and the reaction was continued to stir for 2 hours at -20 °C. The reaction was concentrated, and the residue was purified by Prep-HPLC to obtain the title compound (5 mg, white solid) with a yield of 21%. MS (ESI): m / z 446.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.27-8.26 (m, 1H), 8.01-7.97 (m, 1H), 7.84-7.79 (m, 2H), 7.35-7.31 (m, 1H), 7.14-7.13 (m, 1H), 4.21-4.18 (m, 2H), 3.55-3.49 (m, 1H), 3.24-3.20 (m, 2H), 2.98-2.97 (m, 3H), 2.00-1.98 (m, 2H), 1.59-1.56 (m, 2H).

[0200] Example 14

[0201] 2-(trans-4-((3-(3-(trifluoromethyl)phenoxy)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol

[0202] (1) 2-(trans-4-((3-bromo-[l,2,4]triazolo[4,3-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol

[0203] To a solution of 3-bromo-6-chloro-[l,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.52 mmol) and 2-(trans-4-aminocyclohexyl)propan-2-ol (82 mg, 0.52 mmol) in N,N- dimethylformamide (5 mL) was added triethylamine (158 mg, 1.56 mmol) and the mixture was heated to 80 °C and stirred overnight. Water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (20 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (100% ethyl acetate) to give the title compound (110 mg, yellow solid) in a yield of 60%. MS (ESI): m / z 354.2 [M+H] + .

[0204] (2) 2-(trans-4-((3-(3-(trifluoromethyl)phenoxy)-[l,2,4]triazolo[4,3-b]pyridazin-6- yl)amino)cyclohexyl)propan-2-ol

[0205] To a solution of 2-(trans-4-((3-bromo-[l,2,4]triazolo[4,3-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol (100 mg, 0.28 mmol) and 3-(trifluoromethyl)phenol (45 mg, 0.28 mmol) in 1,4-dioxane (10 mL) was added 2-dicylohexylphosphino-2',4',6'-triisopropylbiphenyl (13.3 mg, 0.028 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.022 mmol) and cesium carbonate (183 mg, 0.56 mmol) and the reaction mixture was heated to 100 °C under nitrogen and stirred overnight. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give a crude product, which was further purified by Prep-HPLC to give the title compound (12.2 mg, white solid) in a yield of 10%. MS (ESI): m / z 436.1 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 10.0 Hz, 1H), 7.66-7.58 (m, 3H), 7.44 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 10.0 Hz, 1H), 4.00 (s, 1H), 3.28-3.20 (m, 1H), 1.89 (d, J = 10.4 Hz, 2H), 1.73 (d, J = 12.0 Hz, 2H), 1.17-1.08 (m, 1H), 1.05-1.01 (m, 8H), 0.94-0.85 (m, 2H).

[0206] Example 15

[0207] 4-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)-l-oxa-4,9- diazaspiro[5.5]undecan-3-one

[0208] (1) 3-oxo-4-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)-l-oxa- 4,9-diazaspiro[5.5]undecan-9-carboxylic acid tert-butyl ester

[0209] Intermediate 1 (20 mg, 0.066 mmol), 3-oxo-l-oxo-4,9-diazaspiro[5.5]undecan-9- carboxylic acid tert-butyl ester (21 mg, 0.079 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (8 mg, 0.013 mmol), tris(dibenzylideneacetone)dipalladium (6 mg, 0.07 mmol) and cesium carbonate (54 mg, 0.165 mmol) were dissolved in ethylene glycol dimethyl ether (5 mL), replaced with nitrogen, stirred under the protection of nitrogen at 90 °C for 2 hours under microwave conditions. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 90) to obtain the title compound (25 mg, yellow solid), yield: 71%. MS (ESI): m / z 538.0 [M+H] + .

[0210] (2) 4-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)-l-oxa-4,9- diazaspiro[5.5]undecan-3-one

[0211] tert-Butyl 3-oxo-4-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)- 1-oxo-4,9-diazaspiro[5.5]undecane-9-carboxylate (25 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 1 h. The reaction was concentrated, diluted with N,N-dimethylformamide and purified by Prep-HPLC to give the title compound (15.5 mg, light yellow solid) in 76% yield. MS (ESI): m / z 438.0 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.30 (d, J = 9.6 Hz, 1H), 7.98 (d, J = 10.0 Hz, 1H), 7.95-7.94 (m, 1H), 7.86-7.85 (m, 1H), 4.37 (s, 2H), 4.09 (s, 2H), 2.84-2.75 (m, 2H), 2.73-2.66 (m, 2H), 1.83-1.72 (m, 2H), 1.69-1.62 (m, 2H).

[0212] Example 16

[0213] 9-(oxetan-3-yl)-4-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)- 1-oxa-4,9-diazaspiro[5.5]undecan-3-one

[0214] tert-Butyl 3-oxo-4-(3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)- 1-oxo-4,9-diazaspiro[5.5]undecane-9-carboxylate (25 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 1 h. The reaction was concentrated, diluted with N,N-dimethylformamide and purified by Prep-HPLC to give the title compound (15.5 mg, light yellow solid) in 76% yield. MS (ESI): m / z 438.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.92-8.90 (m, 1H), 8.56-8.51 (m, 1H), 8.48-8.43 (m, 1H), 8.15-8.14 (m, 1H), 7.95-7.94 (m, 1H), 4.54-4.50 (m, 2H), 4.44-4.41 (m, 4H), 4.11-4.10 (m, 2H), 3.41-3.39 (m, 1H), 2.36-2.31 (m, 2H), 2.27-2.22 (m, 2H), 1.95-1.92 (m, 2H), 1.79-1.75 (m, 2H).

[0215] Example 17

[0216] 2-hydroxy-1-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2-b]pyridazin-6- yl)amino)piperidin-1-yl)ethan-1-one

[0217] (1) 2-chloro-1-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2-b]pyridazin-6- yl)amino)piperidin-1-yl)ethan-1-one

[0218] Intermediate 2 (47 mg, 0.13 mmol) and potassium carbonate (53 mg, 0.38 mmol) were dissolved in tetrahydrofuran (5 mL), 2-chloroacetyl chloride (16 mg, 0.14 mmol) was added at 0 °C, then the reaction was stirred at room temperature for 12 hours. The reaction was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 92 / 8) to obtain the title compound (20 mg, yellow solid), yield: 35%. MS (ESI): m / z 443.8 [M+H] + .

[0219] (2) 2-hydroxy-1-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2-b]pyridazin-6- yl)amino)piperidin-1-yl)ethan-1-one

[0220] To a solution of 2-chloro-l-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2- b]pyridazin-6-yl)amino)piperidin-l-yl)ethan-l-one (20 mg, 0.045 mmol), sodium acetate (7.4 mg, 0.09 mmol) in N,N-dimethylformamide (1 mL) was stirred at 80 °C for 1 h. Then cooled to room temperature, sodium hydroxide (3.6 mg, 0.09 mmol) and methanol / water (5 mL / 1 mL) was added to the reaction mixture, stirred at room temperature for 1 h. The reaction mixture was concentrated, the residue was purified by Prep-HPLC to give the title compound (5 mg, white solid) in 26% yield. MS (ESI): m / z 426.0 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.99 (d, J = 10.0 Hz, 1H), 7.84 (d, J = 2.8 Hz, 1H), 7.79 (d, J = 3.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 10.0 Hz, 1H), 5.42-5.40 (m, 1H), 4.26 (d, J = 13.2 Hz, 2H), 4.00-3.98 (m, 1H), 3.80 (s, 2H), 3.20 (t, J = 12.0 Hz, 2H), 1.84-1.81 (m, 2H), 1.71-1.65 (m, 2H).

[0221] Example 18

[0222] 2-hydroxy-l-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)piperidin-l-yl)ethan-l-one

[0223] To a solution of 3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazine-6-sulfonyl chloride (35 mg, 0.1 mmol, Example 9, step 2) in acetonitrile (10 mL) was added l-(oxetan-3-yl)piperazine (28 mg, 0.2 mmol) and triethylamine (50 mg, 0.5 mmol) and stirred at room temperature for 1 h. The reaction mixture was filtered, the filtrate was concentrated, the residue was purified by Prep-HPLC to give the title compound (21.7 mg, yellow solid) in 42% yield. MS (ESI): m / z 474.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.57 (d, J = 9.2 Hz, 1H), 8.03 (dd, J = 4.0, 1.2 Hz, 1H), 7.90 (dd, J = 4.0, 0.8 Hz, 1H), 7.72 (d, J = 9.6 Hz, 1H), 4.49 (t, J = 6.4 Hz, 2H), 4.32 (t, J = 6.0 Hz, 2H), 3.44-3.41 (m, 1H), 3.38-3.36 (m, 4H), 2.37-2.35 (m, 4H).

[0224] Example 19

[0225] N-(1 -methylpiperidin-4-yl)-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2- b]pyridazine-6-sulfonamide

[0226] N-(1 -methylpiperidin-4-yl)-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2- b]pyridazine-6-sulfonamide + . 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.57 (d, J = 9.2 Hz, 1H), 8.03 (dd, J = 4.0, 1.2 Hz, 1H), 7.90 (dd, J = 4.0, 0.8 Hz, 1H), 7.72 (d, J = 9.6 Hz, 1H), 4.49 (t, J = 6.4 Hz, 2H), 4.32 (t, J = 6.0 Hz, 2H), 3.44-3.41 (m, 1H), 3.38-3.36 (m, 4H), 2.37-2.35 (m, 4H).

[0227] Example 20

[0228] 2-(1 -((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2-b]pyridazin-6- yl)sulfonyl)piperidin-4-yl)propan-2-ol

[0229] To a solution of 3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazine-6- sulfonyl chloride (35 mg, 0.1 mmol, Example 9, step 2) in acetonitrile (10 mL) was added 2-(piperidin-4-yl)propan-2-ol (28 mg, 0.2 mmol) and triethylamine (50 mg, 0.5 mmol) and the reaction was stirred at room temperature for 1 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC to give the title compound (13.1 mg, yellow solid) in 29% yield. MS (ESI): m / z 475.0 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.56 (d, J = 9.2 Hz, 1H), 8.03-8.02 (m, 1H), 7.91-7.90 (m, 1H), 7.72 (d, J = 9.2 Hz, 1H), 4.17 (s, 1H), 3.90 (d, J = 12.0 Hz, 2H), 2.82 (t, J = 12.0 Hz, 2H), 1.77 (d, J = 10.0 Hz, 2H), 1.29-1.23 (m, 3H), 0.97 (s, 6H).

[0230] Example 21

[0231] N-(l-(3-methyloxetan-3-yl)piperidin-4-yl)-3-(5-(trifluoromethyl)thiophen-2- yl)imidazo[l,2-b]pyridazin-6-amine

[0232] (l) 3-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)piperidin-l-yl)oxetan-3-one

[0233] To a solution of intermediate 2 (250 mg, 0.68 mmol) and potassium acetate (100 mg, 1.02 mmol) in 1,2-dichloroethane (20 mL) was stirred at room temperature for 10 min. Oxetan-3-one (59 mg, 0.82 mmol) was added and the reaction was stirred at 50 °C for 1 h. Then trimethylsilyl cyanide (101 mg, 1.02 mmol) was added and the reaction was stirred at 50 °C for 12 h. The reaction was concentrated. Water (50 mL) and dichloromethane (50 mL) were added. The organic phase was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 90 / 10) to give the title compound (220 mg, white solid) in 72% yield. MS (ESI): m / z 449.0 [M+H] + .

[0234] (2) N-(l-(3-methyloxetan-3-yl)piperidin-4-yl)-3-(5-(trifluoromethyl)thiophen-2- yl)imidazo[l,2-b]pyridazin-6-amine

[0235] To a solution of 3-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)piperidin-l-yl)oxetan-3-amine (220 mg, 0.49 mmol) in anhydrous tetrahydrofuran (10 mL) was added 1 M methylmagnesium bromide in 2-methyltetrahydrofuran (2.2 mL, 2.2 mmol) dropwise at 0 °C. The reaction was then warmed to 50 °C and stirred for 16 h. The reaction was concentrated and the crude product was diluted with anhydrous methanol and purified by Prep-HPLC to give the title compound (23.8 mg, white solid) in 11% yield. MS (ESI): m / z 438.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.78-7.76 (m, 2H), 7.38 (d, J = 6.4 Hz, 1H), 6.75 (d, J = 9.6 Hz, 1H), 4.41 (d, J = 4.8 Hz, 2H), 4.13 (d, J = 4.8 Hz, 2H), 3.80-3.67 (m, 1H), 2.61 (d, J = 10.0 Hz, 2H), 2.24-2.16 (m, 4H), 1.54-1.46 (m, 2H), 1.30 (s, 3H).

[0236] Example 22

[0237] 1 -(3-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[ 1,2-b]pyridazin-6-yl)amino)piperidin- 1 -yl)oxetan-3-yl)ethan- 1 -one

[0238] Example 21 Step 2 reaction also gave another product, the title compound (11.8 mg, white solid) in 5% yield. MS (ESI): m / z 466.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.82 (d, J = 9.6 Hz, 1H), 7.78-7.45 (m, 2H), 7.37 (d, J = 6.0 Hz, 1H), 6.75 (d, J = 9.6 Hz, 1H), 4.63-4.60 (m, 4H), 3.83-3.72 (m, 1H), 2.90-2.87 (m, 2H), 2.41-2.35 (m, 2H), 2.21-2.19 (m, 5H), 1.57-1.49 (m, 2H).

[0239] Example 23

[0240] N-(8-(oxetan-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2-b]pyridazine-6-amine

[0241] (1) 3-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0242] Intermediate 1 (134 mg, 0.44 mmol) and 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100 mg, 0.44 mmol) were dissolved in dimethyl sulfoxide (5 mL), cesium fluoride (198 mg, 1.3 mmol) and N,N-diisopropyl ethylamine (168 mg, 1.3 mmol) were added, and the reaction was stirred at 120 °C for 3 hours. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane / methanol = 20 / 1) gave the title compound (200 mg, yellow solid) with a yield of 92%. MS (ESI): m / z 494.1 [M+H] + .

[0243] (2) N-(8-azabicyclo[3.2.1]octan-3-yl)-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2-b]pyridazine-6-amine

[0244] tert-Butyl 3-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.1 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain the title compound (40 mg, yellow oil). MS (ESI): m / z 394.2 [M+H] + .

[0245] (3) N-(8-(oxetan-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-(5-(trifluoromethyl)thiophen-2- yl)imidazo[l,2-b]pyridazin-6-amine

[0246] N-(8-azabicyclo[3.2.1]octan-3-yl)-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2- b]pyridazin-6-amine (40 mg, 0.1 mmol), 3-oxetanone (14 mg, 0.2 mmol), and potassium acetate (19.6 mg, 0.2 mmol) were dissolved in methanol (5 mL), and stirred at room temperature for 1 hour. Sodium cyanoborohydride (18.9 mg, 0.3 mmol) was further added, and stirred at room temperature overnight. The reaction solution was concentrated, and purified by Prep-HPLC to obtain the title compound (9.5 mg, white solid) at a yield of 21%. MS (ESI): m / z 450.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.81-7.75 (m, 3H), 7.18 (d, J = 7.6 Hz, 1H), 6.70 (d, J = 9.6 Hz, 1H), 4.57 (t, J = 6.4 Hz, 2H), 4.34 (t, J = 5.6 Hz, 2H), 4.23-4.18 (m, 1H), 3.69 (t, J = 5.6 Hz, 1H), 3.15 (s, 2H), 2.04-2.00 (m, 2H), 1.92-1.89 (m, 2H), 1.82-1.77 (m, 2H), 1.58-1.53 (m, 2H).

[0247] Example 24

[0248] N-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-3-(5-(trifluoromethyl)thiophen-2- yl)imidazo[l,2-b]pyridazin-6-amine

[0249] Intermediate 1 (100 mg, 0.33 mmol) and 1-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (61 mg, 0.33 mmol) were dissolved in dimethyl sulfoxide (5 mL) at room temperature, then cesium fluoride (150 mg, 0.99 mmol) and N,N-diisopropylethylamine (128 mg, 0.99 mmol) were added, and the mixture was heated to 120 °C and stirred for 4 hours. The reaction was added to water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to give the title compound (55 mg, white solid) in a yield of 37%. MS (ESI): m / z 452.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.77-7.74 (m, 2H), 7.33 (d, J = 6.8 Hz, 1H), 6.74 (d, J = 10.0 Hz, 1H), 3.90 (dd, J = 10.8, 3.6 Hz, 2H), 3.73-3.64 (m, 1H), 3.28 (t, J = 10.8 Hz, 2H), 2.95 (d, J = 10.8 Hz, 2H), 2.48-2.43 (m, 1H), 2.31 (t, J = 10.8 Hz, 2H), 2.16 (d, J = 10.4 Hz, 2H), 1.66 (d, J = 10.8 Hz, 2H), 1.51-1.41 (m, 4H).

[0250] Example 25

[0251] 2-(3-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)piperidin-l-yl)oxetan-3-yl)acetonitrile

[0252] Intermediate 2 (100 mg, 0.27 mmol) and 2-(oxetan-3-ylidene)acetonitrile (26 mg, 0.27 mmol) were dissolved in methanol (5 mL) at room temperature, and the reaction was heated to 50 °C and stirred for 24 hours. The reaction was concentrated, and the residue was purified by Prep-HPLC to give the title compound (45 mg, white solid) in a yield of 36%. MS (ESI): m / z 463.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.79-7.75 (m, 2H), 7.35 (d, J = 6.8 Hz, 1H), 6.76 (d, J = 10.0 Hz, 1H), 4.50 (d, J = 6.4 Hz, 2H), 4.40 (d, J = 6.4 Hz, 2H), 3.81-3.72 (m, 1H), 2.97 (s, 2H), 2.75-2.72 (m, 2H), 2.30 (t, J = 10.8 Hz, 2H), 2.16 (d, J = 10.0 Hz, 2H), 1.57-1.49 (m, 2H).

[0253] Example 26

[0254] (3R,4R)-1-(oxetan-3-yl)-4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2- b]pyridazin-6-yl)amino)piperidin-3-ol

[0255] (1) tert-butyl (3R,4R)-3-hydroxy-4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2- b]pyridazin-6-yl)amino)piperidine-1-carboxylate

[0256] In a 20 mL sealed tube was placed intermediate 1 (150 mg, 0.5 mmol) and tert-butyl (3R,4R)-4-amino-3-hydroxypiperidine-1-carboxylate (214 mg, 1 mmol), cesium fluoride (150 mg, 1 mmol), N,N-diisopropylethylamine (192 mg, 1.5 mmol) and dimethyl sulfoxide (5 mL). The mixture was heated to 120 °C for 16 hours under nitrogen protection. The reaction was poured into saturated brine (50 mL) and extracted with ethyl acetate (3 x 25 mL). The organic phase was combined, washed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to give the title compound (60 mg, yellow solid) in 25% yield. MS (ESI): m / z 484.1 [M+H] + .

[0257] (2) (3R,4R)-4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2-b]pyridazin-6- yl)amino)piperidin-3-ol hydrochloride

[0258] (3R,4R)-3-hydroxy-4-((3-(5-(trifluoromethyl)thiophene-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.124 mmol) was dissolved in dichloromethane (5 mL), and a 4M hydrochloric acid solution of dioxane (2 mL) was added. The reaction was carried out at room temperature for 3 hours. The reaction solution was concentrated to obtain a pale yellow solid, which was used directly in the next step. MS (ESI): m / z 384.0 [M+H] + .

[0259] (3)(3R,4R)-1-(oxetane-3-yl)-4-((3-(5-(trifluoromethyl)thiophene-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)piperidin-3-ol

[0260] (3R,4R)-4-((3-(5-(trifluoromethyl)thiophene-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)piperidin-3-ol hydrochloride (50 mg, 0.10 mmol) was dissolved in methanol (4 mL), and oxetane-3-one (26 mg, 0.36 mmol), potassium acetate (35 mg, 0.36 mmol), and sodium cyanoborohydride (23 mg, 0.36 mmol) were added. The mixture was heated to 50 °C and reacted overnight. The reaction solution was filtered and concentrated, and the crude product was purified by Prep-HPLC to give the title compound (17.5 mg, white solid), yield: 33%. MS (ESI): m / z 440.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.14 (s, 1H), 7.82 (d, J = 10.0Hz, 1H), 1.79-7.75 (m, 2H), 7. 38(d,J=5.2Hz,1H),6.82(d,J=9.6Hz,1H),4.93(s,1H),4.62-4.53(m,2H),4.49-4 .42(m,2H),3.67-3.58(m,2H),3.45-3.40(m,1H),2.94-2.90(m,1H),2.80-2.74(m ,1H),2.43-2.37(m,1H),1.92-1.87(m,1H),1.78-1.73(m,1H),1.41-1.31(m,1H).

[0261] Example 27

[0262] (3S,4S)-1-(oxetane-3-yl)-4-((3-(5-(trifluoromethyl)thiophene-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)piperidin-3-ol

[0263] The title compound (6.7 mg, white solid) was obtained in reference to the synthetic method of Example 26, Step 1 using intermediate 1 and (3S,4S)-4-amino-3-hydroxypiperidine-1- carboxylate tert-butyl ester as starting material, by an analogous procedure. MS (ESI): m / z 440.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.78-7.76 (m, 2H), 7.39 (d, J = 4.0 Hz, 1H), 6.83 (d, J = 9.6 Hz, 1H), 4.94 (s, 1H), 4.60-4.55 (m, 2H), 4.47-4.40 (m, 2H), 3.69-3.54 (m, 2H), 3.48-3.40 (m, 1H), 2.97-2.89 (m, 1H), 2.79-2.74 (m, 1H), 2.43-2.41 (m, 1H), 1.93-1.87 (m, 1H), 1.77-1.72 (m, 1H), 1.40-1.31 (m, 1H).

[0264] Example 28

[0265] 3-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)piperidin-1- yl)thietan-1,1-dioxide

[0266] Intermediate 2 (20 mg, 0.05 mmol), 3-bromothietan-1,1-dioxide (15 mg, 0.08 mmol) were dissolved in acetonitrile (5 mL), then cesium carbonate (35 mg, 0.11 mmol) was added, and the reaction was stirred at 70 °C for 12 h. The reaction was concentrated, diluted with anhydrous methanol, filtered, and purified by Prep-HPLC to give the title compound (7.0 mg, white solid) in 27% yield. MS (ESI): m / z 472.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.82 (d, J = 9.6 Hz, 1H), 7.79-7.75 (m, 2H), 7.33 (d, J = 6.8 Hz, 1H), 6.75 (d, J = 10.0 Hz, 1H), 4.30-4.25 (m, 2H), 4.14-4.09 (m, 2H), 3.80-3.70 (m, 1H), 3.20-3.12 (m, 1H), 2.93-2.90 (m, 2H), 2.18-2.06 (m, 4H), 1.58-1.49 (m, 2H).

[0267] Example 29

[0268] 1-(3-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)amino)piperidin-l- yl)oxetan-3-yl)methanol

[0269] l-(3-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)amino)piperidin-l- yl)oxetan-3-yl)methanol (20 mg, 0.04 mmol, Example 22) and sodium borohydride (6.51 mg, 0.17 mmol) were dissolved in methanol (5 mL) and reacted at room temperature for 10 minutes. The reaction was detected to be completed by LCMS, the reaction solution was concentrated, and the residue was purified by Prep-HPLC to obtain the title compound (16.4 mg, white solid), yield: 82%. MS (ESI): m / z 468.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.82 (d, J = 9.6 Hz, 1H), 7.77-7.76 (m, 2H), 7.35 (d, J = 6.4 Hz, 1H), 6.75 (d, J = 9.6 Hz, 1H), 4.81 (d, J = 5.2 Hz, 1H), 4.46-4.45 (m, 1H), 4.41-4.35 (m, 3H), 3.99 (t, J = 5.6 Hz, 1H), 3.77-3.72 (m, 1H), 2.99-2.96 (m, 1H), 2.83-2.80 (m, 1H), 2.65-2.59 (m, 2H), 2.19-2.12 (m, 2H), 1.47-1.42 (m, 2H), 1.18 (d, J = 6.4 Hz, 3H).

[0270] Example 30

[0271] 3-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)amino)piperidin-l- yl)oxetane-3-carboxamide

[0272] To a solution of 3-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)amino)piperidin-l- yl)oxetane-3-carbonitrile (20 mg, 0.04 mmol, Example 21, step 1) and 4 M sodium hydroxide solution (0.5 mL) in ethanol (3 mL) was stirred at 85 °C for 4 h. The reaction was monitored by LCMS and the reaction mixture was concentrated. The residue was purified by Prep-HPLC to give the title compound (5.5 mg, white solid) in 26% yield. MS (ESI): m / z 467.0 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.82 (d, J = 9.6 Hz, 1H), 7.78-7.74 (m, 2H), 7.34 (d, J = 6.4 Hz, 1H), 7.32-7.31 (m, 2H), 6.77 (d, J = 9.6 Hz, 1H), 4.61 (d, J = 6.8 Hz, 2H), 4.47 (d, J = 6.8 Hz, 2H), 3.78-3.68 (m, 1H), 2.84-2.81 (m, 2H), 2.32-2.26 (m, 2H), 2.19-2.16 (m, 2H), 1.59-1.51 (m, 2H).

[0273] Example 31

[0274] 2-methyl-l-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)amino)-lH- pyrazol-l-yl)propan-2-ol

[0275] Intermediate 1 (50 mg, 0.16 mmol) was dissolved in 1,4-dioxane (8 mL), 1-(4-amino-1H- pyrazol-1-yl)-2-methylpropan-2-ol (77 mg, 0.5 mmol), tris[dibenzylideneacetone]dipalladium (11 mg, 0.012 mmol), S-(-)-1,1'-binaphthalene-2,2'-diphenylphosphine (15 mg, 0.023 mmol) and cesium carbonate (161 mg, 0.5 mmol) were added, and the reaction was heated to 90 °C for 16 h under nitrogen protection. The reaction was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give the crude product, which was further purified by Prep-HPLC to give the title compound (67 mg, white solid) in a yield of 67%. MS (ESI): m / z 423.0 [M+H] + .1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.15 (s, 1H), 8.14 (s, 1H), 7.02 (d, J = 9.6 Hz, 1H), 7.80-7.78 (m, 2H), 7.60 (s, 1H), 6.90 (d, J = 9.6 Hz, 1H), 4.68 (s, 1H), 4.00 (s, 2H), 1.08 (s, 6H).

[0276] Example 32

[0277] 5-(6-((1-(oxetan-3-yl)piperidin-4-yl)amino)imidazo[1,2-b]pyridazin-3-yl)thiophene-2- carbonitrile

[0278] (1) 5-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thiophene-2-carbonitrile

[0279] A 20 mL sealed tube was charged with 6-chloro-3-iodoimidazo[1,2-b]pyridazine (250 mg, 0.9 mmol), (5-cyanothiophen-2-yl)boronic acid (164 mg, 1.07 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (66 mg, 0.09 mmol), potassium carbonate (309 mg, 2.2 mmol), copper(I) iodide (5 mL), 1,4-dioxane (5 mL), and water (1 mL), and the reaction was heated to 100 °C for 16 h under nitrogen protection. The reaction was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (47 mg, yellow solid) in a yield of 20%. MS (ESI): m / z 261.0 [M+H] + .

[0280] (2) 5-(6-((1-(oxetan-3-yl)piperidin-4-yl)amino)imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carbonitrile

[0281] To a solution of 5-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thiophene-2-carbonitrile (40 mg, 0.15 mmol) in dimethyl sulfoxide (2 mL) was added 1-(oxetan-3-yl)piperidin-4-amine dihydrochloride (42 mg, 0.18 mmol), N,N-diisopropylethylamine (99 mg, 0.77 mmol) and cesium fluoride (47 mg, 0.3 mmol), the mixture was heated to 120 °C and stirred for 48 h. The reaction was filtered and concentrated, the residue was purified by Prep-HPLC to give the title compound (13.2 mg, white solid) in 22% yield. MS (ESI): m / z 381.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.00 (d, J = 4.0 Hz, 1H), 7.85-7.82 (m, 2H), 7.38 (d, J = 6.8 Hz, 1H), 6.79 (d, J = 10.0 Hz, 1H), 4.56 (t, J = 6.4 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 3.80-3.73 (m, 1H), 3.46-3.40 (m, 1H), 2.79-2.76 (m, 2H), 2.16-2.14 (m, 2H), 2.03-1.98 (m, 2H), 1.59-1.50 (m, 2H).

[0282] Example 33

[0283] 3-(4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)piperidin-1-yl)oxetane-3-carbonitrile

[0284] Intermediate 2 (20 mg, 0.05 mmol) and potassium acetate (14.7 mg, 0.15 mmol) were dissolved in 1,2-dichloroethane (5 mL) and reacted at room temperature for 10 minutes. Oxetan-3-one (7.2 mg, 0.10 mmol) was added and the reaction was heated to 50 °C for 1 hour. Finally, trimethylsilyl cyanide (9.9 mg, 0.10 mmol) was added and the reaction was stirred at 50 °C for 12 hours. The reaction was detected to be completed by LCMS and the reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3), washed with saturated sodium chloride solution (15 mL) and dried over anhydrous sodium sulfate. The reaction solution was concentrated and the residue was purified by Prep-HPLC to obtain the title compound (14 mg, white solid) in a yield of 58%. MS (ESI): m / z 449.0 [M+H] + .1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.84 (d, J = 9.6 Hz, 1H), 7.78-7.74 (m, 2H), 7.41 (d, J = 6.4 Hz, 1H), 6.76 (d, J = 10.0 Hz, 1H), 4.76 (d, J = 7.2 Hz, 2H), 4.63 (d, J = 6.8 Hz, 2H), 3.83-3.76 (m, 1H), 2.83-2.80 (m, 2H), 2.26-2.23 (m, 2H), 2.19-2.14 (m, 2H), 1.63-1.55 (m, 2H).

[0285] Example 34

[0286] 6-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2-b]pyridazine

[0287] (1) 3-(5-(trifluoromethyl)thiophen-2-yl)-6-vinylimidazo[1,2-b]pyridazine

[0288] To a stirred solution of 6-chloro-3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2- b]pyridazine (700 mg, 2.3 mmol) in 1,4-dioxane / water (10 mL / 2 mL) was added potassium vinyltrifluoroborate (616 mg, 4.6 mmol), potassium carbonate (635 mg, 4.6 mmol) and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium (168 mg, 0.23 mmol) and the reaction mixture was stirred at 100 °C overnight. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (500 mg, yellow solid) in 73% yield. MS (ESI): m / z 296.0 [M+H] + .

[0289] (2) 3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazine-6-carbaldehyde

[0290] To a stirred solution of 3-(5-(trifluoromethyl)thiophen-2-yl)-6-vinylimidazo[l,2- b]pyridazine (200 mg, 0.68 mmol) and potassium osmate (25 mg, 0.068 mmol) in tetrahydrofuran / water (15 mL / 5 mL) was added sodium periodate (437 mg, 2.04 mmol) at 0 °C and the reaction mixture was stirred at room temperature for half an hour. The reaction mixture was stirred at room temperature overnight. The reaction mixture was added with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (100 mg, yellow solid) in 50% yield. MS (ESI): m / z 298.2 [M+H] + .

[0291] (3) 6-((4-(oxetan-3-yl)piperazin-l-yl)methyl)-3-(5-(trifluoromethyl)thiophen-2- yl)imidazo[l,2-b]pyridazine

[0292] To a stirred solution of 3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazine-6- carbaldehyde (60 mg, 0.2 mmol) and l-(oxetan-3-yl)piperazine (56.8 mg, 0.4 mmol) in methanol (5 mL) was added sodium cyanoborohydride (37.7 mg, 0.6 mmol) at room temperature and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by Pre-HPLC to give the title compound (18.3 mg, white solid) in 21% yield. MS (ESI): m / z 424.1 [M+H] +1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.24 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 3.6 Hz, 1H), 7.82 (d, J = 3.6 Hz, 1H), 7.40 (d, J = 9.6 Hz, 1H), 4.52 (t, J = 6.4 Hz, 2H), 4.41 (t, J = 6.0 Hz, 2H), 3.82 (s, 2H), 4.39 (t, J = 6.4 Hz, 1H), 2.55 (s, 4H), 2.30 (s, 4H).

[0293] Example 35

[0294] 2-(l-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)methyl)piperidin-4-yl)morpholine-4-carboxylic acid

[0295] To a solution of 3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazine-6- carboxaldehyde (100 mg, 0.34 mmol, Example 34, step 2) and 2-(piperidin-4- yl)ethanol (97 mg, 0.68 mmol) in methanol (5 mL) was stirred at room temperature for 1 h. Sodium cyanoborohydride (64.3 mg, 1.02 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was concentrated and the residue was purified by Pre-HPLC to give the title compound (17.5 mg, yellow solid) in 12% yield. MS (ESI): m / z 425.0 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.26 (d, J = 9.6 Hz, 1H), 7.94 (d, J = 3.2 Hz, 1H), 7.83 (d, J = 3.2 Hz, 1H), 7.43 (d, J = 9.6 Hz, 1H), 4.10 (s, 1H), 3.87 - 3.79 (m, 2H), 3.07 - 2.97 (m, 2H), 2.18 - 2.03 (m, 2H), 1.71 - 1.69 (m, 2H), 1.31 - 1.19 (m, 3H), 1.03 (s, 6H).

[0296] Example 36

[0297] 3-(5-(difluoromethyl)thiophen-2-yl)-N-(l-(oxetan-3-yl)piperidin-4-yl)imidazo[l,2- b]pyridazin-6-amine

[0298] (1) 5-(6-chloroimidazo[l,2-b]pyridazin-3-yl)thiophene-2-carbaldehyde

[0299] 6-chloro-3-iodoimidazo[l,2-b]pyridazine (500 mg, 1.8 mmol) and (5-formylthiophen-2-yl)boronic acid (280 mg, 1.8 mmol) were dissolved in dioxane / water (20 mL / 2 mL), then cuprous iodide (34 mg, 0.18 mmol), potassium carbonate (497 mg, 3.6 mmol) and bis(triphenylphosphine)palladium dichloride (126 mg, 0.18 mmol) were added, and the reaction system was stirred at 95 °C under nitrogen protection overnight. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (200 mg, yellow solid), yield: 43%. MS (ESI): m / z 264.0 [M+H] + .

[0300] (2) 6-chloro-3-(5-(difluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazine

[0301] 5-(6-chloroimidazo[l,2-b]pyridazin-3-yl)thiophene-2-carbaldehyde (200 mg, 0.76 mmol) was dissolved in dichloroethane (5 mL), diethylamine sulfide trifluoride (DAST) (367 mg, 2.28 mmol) was added, and the reaction system was stirred at 80 °C for 3 hours. The reaction was quenched with methanol, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (90 mg, yellow solid), yield: 41%. MS (ESI): m / z 285.9 [M+H] + .

[0302] (3) 3-(5-(difluoromethyl)thiophen-2-yl)-N-(l-(oxetan-3-yl)piperidin-4-yl)imidazo[l,2-b]pyridazin-6-amine

[0303] 6-Chloro-3-(5-(difluoromethyl)thiophene-2-yl)imidazo[1,2-b]pyridazine (60 mg, 0.21 mmol) and 1-(oxetane-3-yl)piperidin-4-amine trifluoroacetate (107 mg, 0.42 mmol) were dissolved in dimethyl sulfoxide (5 mL), and cesium fluoride (64 mg, 0.42 mmol) and N,N-diisopropylethylamine (81 mg, 0.63 mmol) were added. The mixture was stirred overnight at 120 °C. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the title compound (5.5 mg, yellow solid), yield: 6%. MS (ESI): m / z 406.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.05 (s, 1H), 7.80 (d, J = 9.6Hz, 1H), 7.69 (s, 1H), 7. 50(s,1H),7.35-7.21(m,2H),6.73(d,J=9.2Hz,1H),4.55(t,J=6.0Hz,2H), 4.46(t,J=5.6Hz,2H),3.77-3.74(m,1H),3.42-3.40(m,1H),2.77(d,J=10. 4Hz,2H),2.16(d,J=11.6Hz,2H),1.97(t,J=11.2Hz,2H),1.56-1.48(m,2H).

[0304] Example 37

[0305] (3S,4R)-1-(oxetane-3-yl)-4-((3-(5-(trifluoromethyl)thiophene-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)piperidin-3-ol

[0306] (1)(3S,4R)-3-hydroxy-4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0307] In a 20 mL sealed tube, intermediate 1 (100 mg, 0.33 mmol), (3S,4R)-4-amino-3- hydroxypiperidine-1-carboxylic acid tert-butyl ester (107 mg, 0.49 mmol), cesium fluoride (100 mg, 0.66 mmol), N,N-diisopropylamine (85 mg, 0.66 mmol) and dimethyl sulfoxide (5 mL) were added. The reaction was stirred at 120 °C for 16 h under nitrogen atmosphere. The reaction was poured into saturated brine (50 mL) and extracted with dichloromethane (3 x 25 mL). The organic phase was washed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (dichloromethane / methanol = 10 / 1) to give the title compound (130 mg, yellow solid) in 81.7% yield. MS (ESI): m / z 484.2 [M+H] + .

[0308] (2) (3S,4R)-4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)piperidin-3-ol hydrochloride

[0309] (3S,4R)-3-hydroxy-4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)piperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.27 mmol) was dissolved in dichloromethane (5 mL), 4M hydrochloric acid / dioxane solution (2 mL) was added and the reaction was stirred at room temperature for 3 h. The reaction was concentrated to give a light yellow solid which was used directly in the next step. MS (ESI): m / z 384.2 [M+H] + .

[0310] (3) (3S,4R)-1-(oxetan-3-yl)-4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)piperidin-3-ol

[0311] (3S,4R)-4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)amino)piperidin-3-ol hydrochloride (110 mg, 0.26 mmol) was dissolved in methanol (5 mL), oxetan-3-one (38 mg, 52 mmol), potassium acetate (77 mg, 0.93 mmol) and sodium cyanoborohydride (50 mg, 0.79 mmol) were added and the reaction was stirred at 50 °C overnight. The reaction was filtered and concentrated. The residue was purified by Prep-HPLC to give the title compound (49.8 mg, white solid) in 43.2% yield. MS (ESI): m / z 440.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.78-7.74 (m, 2H), 7.21 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 10.0 Hz, 1H), 4.80 (d, J = 5.2 Hz, 1H), 4.58-4.54 (m, 2H), 4.50-4.45 (m, 2H), 4.10-4.04 (m, 1H), 3.93-3.84 (m, 1H), 3.46-3.40 (m, 1H), 2.77-2.68 (m, 2H), 2.14-2.12 (m, 1H), 2.04-1.93 (m, 2H), 1.87-1.82 (m, 1H).

[0312] Example 38

[0313] (3R,4S)-1-(oxetan-3-yl)-4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2- b]pyridazin-6-yl)amino)piperidin-3-ol

[0314] The title compound (25.2 mg, white solid) was obtained in accordance with the procedures of Example 37, using Intermediate 1 and (3R,4S)-4-amino-3-hydroxypiperidine-1- carboxylate tert-butyl ester as starting materials. MS (ESI): m / z 440.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.81 (d, J = 10.0 Hz, 1H), 7.78-7.75 (m, 2H), 7.21 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 9.6 Hz, 1H), 4.80 (d, J = 5.6 Hz, 1H), 4.58-4.53 (m, 2H), 4.50-4.44 (m, 2H), 4.10-4.04 (m, 1H), 3.95-3.83 (m, 1H), 3.44-3.39 (m, 1H), 2.76-2.67 (m, 2H), 2.14-2.11 (m, 1H), 2.03-1.95 (m, 2H), 1.87-1.82 (m, 1H).

[0315] Example 39

[0316] 3-((3R,4R)-3-hydroxy-4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[1,2- b]pyridazin-6-yl)amino)piperidin-1-yl)oxetan-3-ol

[0317] (3R,4R)-4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)piperidin-3-ol hydrochloride (40 mg, 0.10 mmol, Example 26, step 2) and potassium acetate (28.06 mg, 0.29 mmol) were added into 1,2-dichloroethane (5 mL) and reacted at room temperature for 10 min. Oxetan-3-one (13.74 mg, 0.19 mmol) was added and the reaction mixture was heated to 50 °C for 1 h. Finally, trimethylsilyl cyanide (18.91 mg, 0.19 mmol) was added and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (15 mL) and dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure and purified by Prep-HPLC to give the title compound (13.4 mg, white solid) in 30% yield. MS (ESI): m / z 465.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.15 (s, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.78-7.74 (m, 2H), 7.43 (d, J = 5.6 Hz, 1H), 6.84 (d, J = 9.6 Hz, 1H), 5.06 (d, J = 5.6 Hz, 1H), 4.77 (dd, J = 10.0, 6.8 Hz, 2H), 4.62 (dd, J = 16.0, 6.8 Hz, 2H), 3.72-3.64 (m, 2H), 2.93-2.91 (m, 1H), 2.79-2.76 (m, 1H), 2.47-2.43 (m, 1H), 2.13-2.10 (m, 1H), 1.98-1.93 (m, 1H), 1.43-1.40 (m, 1H).

[0318] Example 40

[0319] (3R,4R)-1-(tetrahydro-2H-pyran-4-yl)-4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6-yl)amino)piperidin-3-ol

[0320] (3R,4R)-4-((3-(5-(trifluoromethyl)thiophen-2-yl)imidazo[l,2-b]pyridazin-6- yl)amino)piperidin-3-ol hydrochloride (30 mg, 0.07 mmol, Example 26, Step 2) was dissolved in methanol (4 mL), added tetrahydro-4H-pyran-4-one (14 mg, 0.14 mmol), potassium acetate (21 mg, 0.21 mmol), acetic acid (0.5 mL) and sodium cyanoborohydride (14 mg, 0.21 mmol), and reacted at 50 °C overnight. The reaction was filtered and concentrated, and the residue was purified by Prep-HPLC to give the title compound (16.4 mg, white solid), yield: 48.7%. MS (ESI): m / z 468.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.81 (d, J = 10.0 Hz, 1H), 7.78-7.75 (m, 2H), 7.34 (d, J = 6.0 Hz, 1H), 6.82 (d, J = 9.6 Hz, 1H), 4.85 (d, J = 5.2 Hz, 1H), 3.92-3.89 (m, 2H), 3.63-3.49 (m, 2H), 3.29-3.26 (m, 2H), 3.10-3.07 (m, 1H), 2.91-2.88 (m, 1H), 2.54-2.52 (m, 1H), 2.45-2.41 (m, 1H), 2.31-2.25 (m, 1H), 2.09-2.04 (m, 1H), 1.67-1.64 (m, 2H), 1.51-1.40 (m, 2H), 1.30-1.20 (m, 1H).

[0321] Test Example 1: PIM1 / 2 / 3 kinase activity test

[0322] 1. ADP-Glo method

[0323] 1.1 Experimental method

[0324] The PIM1 / 2 / 3 activity test of the compound was carried out by using the ADP-Glo method, and the specific method was as follows: the test compound was dissolved in DMSO to prepare a 10 mM stock solution. In a 384-well plate, it was diluted by gradient to a solution with a final concentration of 100 times. The initial concentration of the compound test was 10 μM, 4-fold dilution, 10 concentrations.

[0325] In 384-well plates, add 0.05 μL of compound solution, add 2.5 μL of enzyme working solution (PIM1, PIM2, PIM3 three kinases are from Carna company), centrifuge at 1000 rpm for 1 min, incubate at 25°C for 15 min. Add 2.5 μL of substrate working solution (ATP and PIM substrate (from Genscript company)) to start the reaction, centrifuge at 1000 rpm for 1 min, incubate at 25°C for 60 min. Add 4 μL of ADP-Glo reagent, centrifuge at 1000 rpm for 1 min, incubate at 25°C for 40 min. Add 8 μL of ADP-Glo detection reagent, centrifuge at 1000 rpm for 1 min, incubate at 25°C for 40 min. Read the luminescence value with BMG microplate reader.

[0326] 1.2 Result calculation

[0327] The IC50 values of each compound on enzyme activity were obtained by fitting the dose-effect curve with analysis software XLfit 5.5.5. The results of each compound are shown in Table 1, in which A represents <10 nM, B represents 10-100 nM, C represents 100-1000 nM, D represents 1000-10000 nM, and E represents >10000 nM.

[0328] Table 1 Kinase data

[0329] Test example 2: cell inhibition activity test

[0330] The EPOR-JAK2-V617F gene was transferred into Ba / F3 wild type cells through a retrovirus packaging system to obtain a stable cell line Ba / F3-EPOR-JAK2-V617F, which was used to test the cell inhibition activity IC50 of the compound. 50 (reference: Blood. 2010; 115(15): 3109-3117). The specific method is as follows:

[0331] The cells were inoculated in a 96-well plate, treated with the test compound (0.2% final DMSO concentration) from the DMSO stock solution, and after 72 hours of culture at 37°C, 5% CO2, the cell proliferation inhibition activity was detected by CTG (Cell-Titer Glo) method. The initial concentration of the compound test was 10 μM, 3-fold dilution, 9 concentrations. The IC50 value was obtained by fitting the dose-effect curve with Graphpad 7.0 analysis software. 50

[0332] The results showed that the cell inhibition activity of most compounds was stronger or equivalent to that of PIM inhibitor TP-3654. The cell inhibition activity IC50 of some preferred compounds was stronger than that of PIM inhibitor TP-3654. 50 ​Significantly better than PIM inhibitor TP-3654 (significantly better means a difference of one order of magnitude). The results of the partial test compounds are shown in Table 2, wherein ++ means 0-100 nM and + means > 100 nM.

[0333] Table 2 Test results of cell inhibition activity data

[0334] Test Example 3: Rat pharmacokinetic experiment

[0335] 1. Experimental method

[0336] Experimental animals: SD rats, male, body weight: 170-180 g.

[0337] Preparation of test sample: The target compound was prepared into 2 mg / mL (solvent: [20% GELUCIRE 44 / 14]) and used as needed. Administration route: oral. Administration volume and frequency: 10 mL / kg, single administration.

[0338] Sample collection: Blood was collected at the following time points: 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr and 24 hr after administration.

[0339] 2. Sample analysis and results

[0340] Sample analysis: The collected samples were detected using the LC-MS / MS method. The instrument model used was Triple Quad 5500+.

[0341] Pharmacokinetic data analysis: The obtained blood drug concentration data were fitted and calculated according to the non-compartment model method, and some results are summarized in Table 3.

[0342] Comparative compound 1 is compound 20 in patent CN202210112402.5, which is prepared according to the method of Example 10 in patent CN202210112402.5.

[0343] Comparative compound 2 (TP-3654) is prepared according to Example 31 in patent WO2013013188.

[0344] Table 3 Pharmacokinetic parameters of the target compound in rats

[0345] The test results show that the compound of the present application has good pharmacokinetic characteristics, and the oral drug exposure, maximum blood drug concentration and bioavailability of the test compound in rats are significantly higher than those of the comparative compound.

[0346] Test Example 4: Beagle pharmacokinetic experiment

[0347] 1. Experimental Methods

[0348] Experimental Animals: Beagle dogs, male, body weight: 10-12 kg

[0349] (1) Example 26

[0350] Test article preparation: The test compound was prepared into 2 mg / mL (vehicle: [20% GELUCIRE 44 / 14]) and used as needed. Route of administration: oral. Dose volume and frequency: 10 mL / kg, single dose.

[0351] Sample collection: Blood was collected at the following time points: 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, and 24 hr after administration.

[0352] (2) Comparative Compound 1 and Comparative Compound 2 (TP-3654)

[0353] Test article preparation: The test compound was prepared into 10 mg / mL (vehicle: [20% GELUCIRE 44 / 14]) and used as needed. Route of administration: oral. Dose volume and frequency: 5 mL / kg, single dose.

[0354] Sample collection: Blood was collected at the following time points: 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, and 24 hr after administration.

[0355] 2. Sample Analysis and Results

[0356] Sample analysis: The collected samples were detected using the LC-MS / MS method. The instrument model used was Triple Quad 5500+ (Example 26) and Triple Quad 6500 (Comparative Compound 1 and Comparative Compound 2 (TP-3654)).

[0357] Pharmacokinetic data analysis: The obtained blood concentration data were fitted and calculated according to the non-compartment model method, and some of the results are summarized in Table 4.

[0358] Table 4 Pharmacokinetic parameters of the test compound in beagle dogs

[0359] The test results show that the compound of the present application has good pharmacokinetic characteristics, and the oral drug exposure, maximum blood concentration, and bioavailability of the test compound in dogs are significantly higher than those of the comparative compounds.

Claims

1. A compound having the structure shown in general formula (I), its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt: in, L1 is a chemical bond or an ether bond; Ring A is a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S; ring A is preferred. R1 is selected from cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The alkyl halogen is preferably cyano, methyl, trifluoromethyl, difluoromethyl, methoxy, or trifluoromethoxy. L2 represents chemical bonds, -NH-, -SO2-, -NH-SO2-, -SO2-NH-, -O-, and -CH2-. R2 is -Z-L3-R3; Z is any one of 1-3 R's. a Substituted 4-6 membered cycloalkyl groups, optionally with 1-3 R groups a The substituted 4-11 members contain 1-3 heterocyclic groups selected from N, O, and S heteroatoms; preferably... R a Selected from oxo, halogen, hydroxyl, C 1-6 Alkoxy groups, preferably oxo, halogen, or hydroxyl groups; L3 is a chemical bond, C 1-3 Alkylene, -SO2-, -(C=O)-; R3 is selected from H and C. 1-3 Alkyl, hydroxyl, amino, hydroxy-C 1-3 Alkylene, C 1-3 Alkyl-imino, optionally surrounded by 1-3 R b Substituted 4-6 membered cycloalkyl groups, optionally with 1-3 R groups b The substituted 4-11 members contain 1-3 heterocyclic groups selected from N, O, and S heteroatoms; R b Selected from oxo, halogen, hydroxyl, cyano, C 1-3 Alkyl, hydroxy-C 1-3 Alkylene, cyano-C 1-3 Alkylene, C 1-3 Alkyl-C(=O)-, NH2-C(=O)-, carboxyl, C 1-3 Alkyl-OC 1-3 Alkylene.

2. The compound, its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt according to claim 1, characterized in that: Z and R a It consists of the following groups: Preferred 3. The compound, its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt according to claim 1, characterized in that: R3 is selected from: H, methyl, hydroxyl, cyano, amino. Preferred groups include H, methyl, hydroxyl, cyano, and amino.

4. The compound, its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt according to claim 1, characterized in that: L1 is a chemical bond; Ring A is 5. The compound, its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt according to claim 1, characterized in that, It has the structure shown in general formula (II): R1 is selected from cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The alkyl halogen is preferably cyano, methyl, trifluoromethyl, difluoromethyl, methoxy, or trifluoromethoxy. L2 is selected from chemical bonds, -NH-, -SO2-, -SO2-NH-, -O-, and -CH2-. R2 is -Z-L3-R3; Z is any one of 1-3 R's. a Substituted 5-6 membered cycloalkyl groups, optionally with 1-3 R groups a The substituted 4-11 members contain 1-3 heterocyclic groups selected from N, O, and S heteroatoms; preferably... R a Selected from oxo, halogen, hydroxyl, C 1-6 Alkoxy groups, preferably oxo, halogen, or hydroxyl groups; L3 is a chemical bond, C 1-3 Alkylene, -SO2-, -(C=O)-; R3 is selected from H and C. 1-3 Alkyl, hydroxyl, amino, hydroxy-C 1-3 Alkylene, C 1-3 Alkyl-imino, optionally surrounded by 1-3 R b Substituted 4-6 membered cycloalkyl groups, optionally with 1-3 R groups b The substituted 4-11 members contain 1-3 heterocyclic groups selected from N, O, and S heteroatoms; R b Selected from oxo, halogen, hydroxyl, cyano, C 1-3 Alkyl, hydroxy-C 1-3 Alkylene, cyano-C 1-3 Alkylene, C 1-3 Alkyl-C(=O)-, NH2-C(=O)-, carboxyl, C 1-3 Alkyl-OC 1-3 Alkylene.

6. The compound, its deuterated form, stereoisomer, or pharmaceutically acceptable salt according to claim 5, characterized in that: L2 is selected from -NH-, -SO2-, -O-, and -CH2-. R2 is -Z-L3-R3; Z is any one of 1-3 R's. a Substituted 5-6 membered cycloalkyl groups, optionally with 1-3 R groups a The substituted 4-8 member contains 1-3 heterocyclic groups selected from N, O, and S heteroatoms; preferably... R a Selected from oxo, halogen, hydroxyl, C 1-3 Alkoxy groups, preferably oxo, halogen, or hydroxyl groups; Preferred Z and R a It consists of the following groups: More 7. The compound, its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt according to claim 6, characterized in that: R3 is selected from H and C. 1-3 Alkyl, hydroxyl, amino, hydroxy-C 1-3 Alkylene, C 1-3 Alkyl-imino, optionally surrounded by 1-3 R b The following groups are substituted R b Selected from oxo, halogen, hydroxyl, cyano, C 1-3 Alkyl, hydroxy-C 1-3 Alkylene, cyano-C 1-3 Alkylene, C 1-3 Alkyl-C(=O)-, NH2-C(=O)-, carboxyl, C 1-3 Alkyl-OC 1-3 Alkylene; preferably oxo, F, hydroxy, cyano, methyl, Preferably, R3 is selected from H, methyl, hydroxyl, cyano, amino, Preferred groups include H, methyl, hydroxyl, cyano, and amino.

8. The compound, its deuterated form, stereoisomer, or pharmaceutically acceptable salt according to claim 5, characterized in that: L2 is selected from chemical bonds; Z is any one of 1-3 R's. a The substituted 9-11 members contain 1-3 heterocyclic groups selected from N, O, and S heteroatoms; preferably... R a Selected from oxo, halogen, hydroxyl, C 1-3 Alkoxy groups, preferably oxo, halogen, or hydroxyl groups; Preferred Z and R a It consists of the following groups:

9. The compound, its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt according to claim 8, characterized in that: R3 is selected from H and C. 1-3 Alkyl, hydroxyl, amino, hydroxy-C 1-3 Alkylene, C 1-3 Alkyl-imino, optionally surrounded by 1-3 R b The following groups are substituted R b Selected from oxo, halogen, hydroxyl, cyano, C 1-3 Alkyl, hydroxy-C 1-3 Alkylene, cyano-C 1-3 Alkylene, C 1-3 Alkyl-C(=O)-, NH2-C(=O)-, carboxyl, C 1-3 Alkyl-OC 1-3 Alkylene; preferably oxo, F, hydroxy, cyano, methyl, Preferably, R3 is selected from H, methyl, hydroxyl, cyano, amino, Preferred groups include H, methyl, hydroxyl, cyano, and amino.

10. A compound as claimed in claim 1, its deuterated form, stereoisomer, or pharmaceutically acceptable salt, comprising:

11. A pharmaceutical composition comprising the compound of any one of claims 1-10, its deuterated form, stereoisomer, or pharmaceutically acceptable salt thereof, or its pharmaceutically acceptable carrier.

12. Use in the preparation of medicaments for the treatment and / or prevention of PIM-related diseases from any one of the compounds, deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts of the compounds according to any one of claims 1 to 10, or from the pharmaceutical compositions according to claim 11.

13. The use according to claim 12, characterized in that: The diseases associated with PIM include autoimmune diseases and tumors.

14. The use according to claim 13, characterized in that: The diseases associated with PIM include inflammatory bowel disease, hematologic malignancies, and solid tumors.

15. The use according to claim 13, characterized in that: The drug may be used alone or in combination with other therapeutic agents.

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