CN115667246A

CN115667246A - Crystal form of pyridazine derivative free base and preparation method and application thereof

Info

Publication number: CN115667246A
Application number: CN202180035717.8A
Authority: CN
Inventors: 杜俊锋; 呙临松
Original assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Current assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Priority date: 2020-07-24
Filing date: 2021-07-23
Publication date: 2023-01-31
Also published as: CA3186000A1; WO2022017494A1; TW202214603A; JP2023534492A; KR20230043887A

Abstract

Relates to aA crystal form of pyridazine derivative free alkali, a preparation method and application thereof. In particular to a compound shown in a general formula (I), a crystal form and a preparation method thereof, a pharmaceutical composition containing a therapeutically effective amount of the compound or the crystal form and application thereof in preparing TYK2 inhibitor drugs.

Description

Crystal form of pyridazine derivative free base and preparation method and application thereof

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a pyridazine derivative free base crystal form and a preparation method and application thereof.

Background

Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates the signaling and activation of various cytokines. The JAK kinase family is divided into four subtypes of JAK1, JAK2, JAK3 and TYK2, each subtype mediates different types of cytokine signal pathways, JAK-1, JAK-2 and TYK-2 are expressed in various histiocytes of a human body, and JAK-3 is mainly expressed in various hematopoietic histiocytes. A common feature of cytokine receptors is that the receptor itself has no kinase activity, but the intracellular segment of the receptor has a binding site for the tyrosine kinase JAK. After the cell factor receptor is combined with a ligand thereof, JAKs coupled with the receptor are activated, so that the receptor is phosphorylated, a phosphorylated tyrosine site can be combined with STAT protein containing an SH2 structural domain, STAT is recruited to the receptor and is phosphorylated through JAKs, then phosphotyrosine mediates STAT dimerization, the activated STAT dimer is transferred to a cell nucleus and activates target gene transcription of the STAT dimer, and thus, multiple functions of growth, activation, differentiation and the like of multiple cells are regulated and controlled.

TYK2 is an early found subtype of JAK family, mediates the functions of cytokines such as IFN-alpha, IL-6, IL-10, IL-12, IL-23 and the like, and researches show that the deletion mutation of TYK2 can effectively inhibit the generation of immunological diseases such as allergy, autoimmunity and inflammation and the like. IL-23 plays a crucial role in the development process of psoriasis, and the latest research shows that the pathogenesis of psoriasis is that endogenous unknown antigen-activated antigen presenting cells APC secrete IL-23, IL-23 activates Th17 cells and secrete cytokines such as IL-17, the differentiation and the secretion of IL-23 of keratinocytes are induced, and inflammation and the proliferation of keratinocytes are further stimulated to generate psoriasis. TYK2 and JAK2 jointly mediate a downstream signal pathway of IL-23, and inhibition of JAK2 can cause anemia and other blood-related side effects, so that targeting TYK2 is a good strategy for inhibiting the IL-23 signal pathway to treat psoriasis.

Early TYK2 inhibitors such as Tofacitinib and the like belong to JAK non-selective inhibitors, are the first oral JAK inhibitors and have obvious inhibitory activity on JAK1, 2 and 3 subtypes. The activity inhibition of other subtypes such as JAK1, JAK2 and JAK3 increases the curative effect of tofacitinib, but also brings more serious side effects, and adverse reactions comprise infection, tuberculosis, tumor, anemia, liver injury, cholesterol increase and the like. Because the JAK2 activity is related to erythroid cell differentiation and lipid metabolism processes, part of adverse reactions such as anemia are considered to be related to the insufficient selectivity of Tofacitinib on JAK-2, and are caused by the nonselective inhibition of the medicine. At present, no TYK2 selective inhibitor is on the market, and the early JAK inhibitor mainly plays a role by competing the combination of a kinase domain and ATP, so that the problem of low selectivity exists generally.

The compound is intermediate between the good curative effect of the JAK non-selective inhibitor and the relevant serious side effect of various targets, and the development of a TYK2 selective inhibitor drug with higher safety has huge clinical application potential for treating inflammatory diseases such as psoriasis and the like. In the subsequent research and development, in order to enable products to be easy to process, filter and dry, convenient to store, stable for a long time, high in bioavailability and the like, the invention comprehensively researches free alkali of the substances and aims to obtain the most suitable crystal form.

Disclosure of Invention

All matters referred to in PCT/CN2020/073152 are hereby incorporated by reference.

The invention aims to provide a crystal form of a compound shown as a general formula (I),

wherein:

R ₁ selected from hydrogen, deuterium, halogen, amino, mercapto, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy or haloalkoxy;

R ₂ one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, mercapto, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl or heterocyclyl, said amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl and heterocyclyl optionally being further substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl and heterocyclyl; and is provided with

x is an integer of 0 to 3.

In a preferred embodiment of the invention, the crystal form shown in the general formula (I) is shown in the specification, wherein R is ₁ Selected from hydrogen, deuterium, halogen, amino, mercapto, nitro, hydroxy, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 A haloalkoxy group;preferably hydrogen, deuterium, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy or cyano; more preferably hydrogen, deuterium, fluorine, chlorine or bromine, most preferably hydrogen or fluorine.

In a preferred embodiment of the invention, the crystal form shown in the general formula (I) is shown in the specification, wherein R is ₂ Selected from hydrogen, deuterium, halogen, amino, mercapto, nitro, hydroxy, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl and 3-8 membered heterocyclyl, optionally further substituted by halogen, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl;

preferably, R ₂ Selected from hydrogen, deuterium, halogen, cyano, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl, said amino, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 HalogenatedAlkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl and 3-6 membered heterocyclyl, optionally further substituted by halogen, nitro, cyano, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl;

more preferably, R ₂ Selected from methyl, ethyl, propyl, cyclopropyl, said methyl, ethyl, propyl and cyclopropyl, optionally may be further substituted with one or more substituents of halogen, nitro, cyano or ethynyl.

In a preferable embodiment of the invention, when R is the crystal form shown in the general formula (I) ₂ When selected from methyl or ethyl, R ₁ Is not hydrogen.

In a more preferred embodiment of the present invention, the crystalline form represented by the general formula (I) has the following structure:

in a more preferred embodiment of the present invention, there is provided the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d ₃ ) Crystalline forms of pyridazine-3-carboxamide.

In a more preferred embodiment of the invention, there is provided a crystalline form of the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide.

In a more preferred embodiment of the invention, there is provided a crystalline form of the compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide.

In the inventionIn a preferred embodiment of step (b), there is provided the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d ₃ ) Crystalline forms A-C of pyridazine-3-carboxamide (example 1).

The X-ray powder diffraction pattern of the crystal form A has a diffraction peak at the 2 theta of 23.7 +/-0.2 degrees; or a diffraction peak at 6.4 ± 0.2 °; or a diffraction peak at 19.4 ± 0.2 °; or a diffraction peak at 21.2 ± 0.2 °; or a diffraction peak at 23.0 ± 0.2 °; or a diffraction peak at 14.8 ± 0.2 °; or a diffraction peak at 11.3 ± 0.2 °; or a diffraction peak at 28.5 ± 0.2 °; or a diffraction peak at 13.0 ± 0.2 °; or a diffraction peak at 11.8 ± 0.2 °; preferably comprises any of 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the diffraction peaks; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the crystal form B has a diffraction peak at a2 theta position of 21.5 +/-0.2 degrees; or a diffraction peak at 15.0 ± 0.2 °; or a diffraction peak at 19.6 ± 0.2 °; or a diffraction peak at 23.0 ± 0.2 °; or a diffraction peak at 23.2 ± 0.2 °; or a diffraction peak at 14.5 ± 0.2 °; or a diffraction peak at 20.8 ± 0.2 °; or a diffraction peak at 13.3 ± 0.2 °; or a diffraction peak at 10.5 ± 0.2 °; or a diffraction peak at 11.8 ± 0.2 °; preferably, any 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, and more preferably any 6, 7, or 8 of the diffraction peaks are included.

The X-ray powder diffraction pattern of the crystal form C has a diffraction peak at the 2 theta of 26.1 +/-0.2 degrees; or a diffraction peak at 24.7 ± 0.2 °; or a diffraction peak at 8.3 ± 0.2 °; or a diffraction peak at 9.9 ± 0.2 °; or a diffraction peak at 12.8 ± 0.2 °; or a diffraction peak at 18.9 ± 0.2 °; or a diffraction peak at 26.7 ± 0.2 °; or a diffraction peak at 17.3 ± 0.2 °; or a diffraction peak at 10.4 ± 0.2 °; or a diffraction peak at 11.0 ± 0.2 °; preferably comprises any of 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the diffraction peaks; more preferably any 6, 7 or 8 thereof.

In a further preferred embodiment of the invention, there is provided the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d ₃ ) Crystalline forms A-C of pyridazine-3-carboxamide (example 1).

The X-ray powder diffraction pattern of the crystal form A at least comprises one or more diffraction peaks with the 2 theta of 23.7 +/-0.2 degrees, 6.4 +/-0.2 degrees and 19.4 +/-0.2 degrees, preferably comprises 2, and more preferably comprises 3; optionally, the composition further comprises at least one position with 2 theta of 21.2 +/-0.2 degrees, 23.0 +/-0.2 degrees, 14.8 +/-0.2 degrees, 11.3 +/-0.2 degrees or 28.5 +/-0.2 degrees, preferably comprises 2,3, 4 or 5 positions;

for example:

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、28.5±0.2；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、11.3±0.2°、28.5±0.2；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2；

23.7±0.2°、6.4±0.2°、19.4±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2；

23.7±0.2°、6.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2；

23.7±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2；

6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、11.3±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、28.5±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、14.8±0.2°、11.3±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、14.8±0.2°、28.5±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、11.3±0.2°、28.5±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、23.0±0.2°、14.8±0.2°、28.5±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、23.0±0.2°、11.3±0.2°、28.5±0.2°；

23.7±0.2°、6.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°；

23.7±0.2°、6.4±0.2°、21.2±0.2°、22.0±0.2°、11.3±0.2°；

23.7±0.2°、6.4±0.2°、21.2±0.2°、23.0±0.2°、28.5±0.2°；

23.7±0.2°、6.4±0.2°、21.2±0.2°、28.5±0.2°、14.8±0.2°；

23.7±0.2°、6.4±0.2°、21.2±0.2°、28.5±0.2°、11.3±0.2°；

23.7±0.2°、6.4±0.2°、21.2±0.2°、28.5±0.2°、28.5±0.2°；

the X-ray powder diffraction pattern of the crystal form B at least comprises one or more diffraction peaks with 2 theta of 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees and 19.6 +/-0.2 degrees, preferably comprises two positions, and more preferably comprises three positions; optionally, at least one of 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees and 13.3 +/-0.2 degrees can be further contained; preferably 2,3, 4 or 5 thereof;

for example:

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、 13.3±0.2°；

15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°；

19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°；

15.0±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

15.0±0.2°、19.6±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

15.0±0.2°、19.6±0.2°、23.0±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、20.8±0.2°、13.3±0.2°；

15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、13.3±0.2°；

15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°；

21.5±0.2°、19.6±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、19.6±0.2°、23.0±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°；

21.5±0.2°、15.0±0.2°、23.0±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.2±0.2°、14.5±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、14.5±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、14.5±0.2°、20.8±0.2°；

23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

19.6±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

19.6±0.2°、23.0±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

19.6±0.2°、23.0±0.2°、23.2±0.2°、20.8±0.2°、13.3±0.2°；

19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°；

15.0±0.2°、23.0±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

15.0±0.2°、23.0±0.2°、23.2±0.2°、20.8±0.2°、13.3±0.2°；

15.0±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、13.3±0.2°；

15.0±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°；

21.5±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°。

the X-ray powder diffraction pattern of the crystal form C at least comprises one or more diffraction peaks with the 2 theta of 26.1 +/-0.2 degrees, 24.7 +/-0.2 degrees and 8.3 +/-0.2 degrees, preferably comprises 2, and more preferably comprises 3; optionally, the composition can further comprise at least one position with 2 theta of 9.9 +/-0.2 degrees, 12.8 +/-0.2 degrees, 18.9 +/-0.2 degrees, 26.7 +/-0.2 degrees or 17.3 +/-0.2 degrees, preferably comprises 2,3, 4 or 5 positions; for example:

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、26.7±0.2°、17.3±0.2；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、26.7±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、17.3±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、17.3±0.2°、26.7±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、26.7±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、17.3±0.2°；

26.1±0.2°、24.7±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°；

26.1±0.2°、24.7±0.2°、9.9±0.2°、12.8±0.2°、26.7±0.2°；

26.1±0.2°、24.7±0.2°、9.9±0.2°、12.8±0.2°、17.3±0.2°；

26.1±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°；

26.1±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、26.7±0.2°；

26.1±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、17.3±0.2°。

further, the X-ray powder diffraction pattern of form a optionally further comprises one or more diffraction peaks at 13.0 ± 0.2 °, 11.8 ± 0.2 °, 22.7 ± 0.2 °, 16.3 ± 0.2 °, 29.4 ± 0.2 °, 14.2 ± 0.2 ° or 25.3 ± 0.2 ° 2 Θ; preferably at least any 2 to 3, or 4 to 5, or 6 to 7 thereof; further preferably, any of 2,3, 4,5, 6, 7;

for example:

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、28.5±0.2、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、11.3±0.2°、28.5±0.2、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2、13.0±0.2°、11.8±0.2°；

23.7±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2、13.0±0.2°、11.8±0.2°；

6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、11.3±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、28.5±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、14.8±0.2°、11.3±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、14.8±0.2°、28.5±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、11.3±0.2°、28.5±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、23.0±0.2°、14.8±0.2°、28.5±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、23.0±0.2°、11.3±0.2°、28.50±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、21.2±0.2°、23.0±0.2°、11.3±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、21.2±0.2°、23.0±0.2°、28.5±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、21.2±0.2°、28.5±0.2°、14.8±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、21.2±0.2°、28.5±0.2°、11.3±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、21.2±0.2°、11.3±0.2°、28.5±0.2°、13.0±0.2°、11.8±0.2°。

the X-ray powder diffraction pattern of form B optionally further comprises X-ray diffraction patterns at 2 Θ of 10.5 ± 0.2 °, 11.8 ± 0.2 °, 18.3 ± 0.2 °, 16.7 ± 0.2 °, 16.3 ± 0.2 °, 24.2 ± 0.2 °, 29.1 ± 0.2 °; one or more diffraction peaks; preferably at least any 2 to 3, or 4 to 5, or 6 to 7 thereof; further preferably, any 2,3, 4,5, 6, 7 thereof;

for example:

21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.3 +/-0.2 degrees, 11.8 +/-0.2 degrees and 10.5 +/-0.2 degrees; or,

21.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.3 +/-0.2 degrees, 11.8 +/-0.2 degrees and 10.5 +/-0.2 degrees; or,

21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 23.0 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees, 11.8 +/-0.2 degrees and 10.5 +/-0.2 degrees; or,

21.5±0.2°、15.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°、11.8±0.2°、10.5±0.2°；

21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees and 10.5 +/-0.2 degrees; or,

21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees, 10.5 +/-0.2 degrees and 11.8 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees and 10.5 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees, 10.5 +/-0.2 degrees and 11.8 +/-0.2 degrees; or,

21.5 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees and 10.5 +/-0.2 degrees; or,

21.5 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees, 10.5 +/-0.2 degrees and 11.8 +/-0.2 degrees; or,

21.5 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees and 10.5 +/-0.2 degrees; or,

21.5 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees, 10.5 +/-0.2 degrees and 18.3 +/-0.2 degrees; or,

21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees and 10.5 +/-0.2 degrees; or,

21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees, 10.5 +/-0.2 degrees and 16.3 +/-0.2 degrees; or,

21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 13.3 +/-0.2 degrees and 10.5 +/-0.2 degrees; or,

21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 13.3 +/-0.2 degrees, 10.5 +/-0.2 degrees and 11.8 +/-0.2 degrees; or,

21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees and 10.5 +/-0.2 degrees; or,

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、10.5±0.2°、11.8±0.2°。

the X-ray powder diffraction pattern of form B optionally further comprises diffraction peaks at one or more of 5.2 ± 0.2 °,10.5 ± 0.2 °, 11.8 ± 0.2 °, 12.6 ± 0.2 °, 16.7 ± 0.2 °, 17.5 ± 0.2 °, 18.3 ± 0.2 °; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any of 2,3, 4,5, 6, 7; for example:

21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees and 5.2 +/-0.2 degrees; or,

21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 5.2 +/-0.2 degrees and 12.6 +/-0.2 degrees; or,

21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 5.2 +/-0.2 degrees, 12.6 +/-0.2 degrees and 17.5 +/-0.2 degrees; or alternatively

21.5 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.8 +/-0.2 degrees, 18.3 +/-0.2 degrees, 14.5 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees and 12.6 +/-0.2 degrees; or,

21.5 +/-0.2 °,15.0 +/-0.2 °,19.6 +/-0.2 °, 23.0 +/-0.2 °,23.2 +/-0.2 °, 14.5 +/-0.2 °, 20.8 +/-0.2 °,13.3 +/-0.2 °,10.5 +/-0.2 °, 11.8 +/-0.2 °, 5.2 +/-0.2 ° and 17.5 +/-0.2 °; or,

21.5 +/-0.2 °,15.0 +/-0.2 °,19.6 +/-0.2 °, 23.0 +/-0.2 °,23.2 +/-0.2 °, 14.5 +/-0.2 °, 20.8 +/-0.2 °,13.3 +/-0.2 °,10.5 +/-0.2 °, 11.8 +/-0.2 °, 5.2 +/-0.2 ° and 12.6 +/-0.2 °; or,

21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 17.5 +/-0.2 degrees and 18.3 +/-0.2 degrees; or,

21.5 +/-0.2 °,15.0 +/-0.2 °,19.6 +/-0.2 °, 23.0 +/-0.2 °,23.2 +/-0.2 °, 14.5 +/-0.2 °, 20.8 +/-0.2 °, 5.2 +/-0.2 °,10.5 +/-0.2 °, 11.8 +/-0.2 °, 17.5 +/-0.2 ° and 18.3 +/-0.2 °; or,

21.5 +/-0.2 °,15.0 +/-0.2 °,19.6 +/-0.2 °, 23.0 +/-0.2 °,23.2 +/-0.2 °, 14.5 +/-0.2 °, 20.8 +/-0.2 °,13.3 +/-0.2 °, 5.2 +/-0.2 °,10.5 +/-0.2 °, 11.8 +/-0.2 °, 12.6 +/-0.2 °, 16.7 +/-0.2 °, 17.5 +/-0.2 ° and 18.3 +/-0.2 °; or,

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5.0±0.2°、20.8±0.2°、13.3±0.2°、10.5±0.2°、11.8±0.2°、5.2±0.2°、12.6±0.2°、16.7±0.2°、17.5±0.2°、18.3±0.2°。

the X-ray powder diffraction pattern of the crystal form B comprises diffraction peaks at one or more of 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5.0 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.3 +/-0.2 degrees, 16.7 +/-0.2 degrees, 16.3 +/-0.2 degrees, 24.2 +/-0.2 degrees, 29.1 +/-0.2 degrees, 5.2 +/-0.2 degrees, 12.6 +/-0.2 degrees and 17.5 +/-0.2 degrees; preferably at least 2-3, or 4-5, or 7-8, or 10-12, or 15-18 thereof; further preferably, any of 2,3, 4,5, 6, 8, 10, 12, 16, 18 are included.

The X-ray powder diffraction pattern of the crystal form B comprises diffraction peaks at one or more positions of 15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.3 +/-0.2 degrees, 16.7 +/-0.2 degrees, 24.2 +/-0.2 degrees and 29.1 +/-0.2 degrees of 2 theta; preferably, the compound comprises diffraction peaks at3, 4,5, 6, 7, 8 and 10;

for example, the X-ray powder diffraction pattern of the form B has diffraction peaks at the following positions 2 θ:

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees and 14.5 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 14.5 +/-0.2 degrees and 20.8 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees and 20.8 +/-0.2 degrees; or,

at 23.2 + -0.2 deg., 14.5 + -0.2 deg. and 20.8 + -0.2 deg.; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees and 20.8 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 10.5 +/-0.2 degrees and 11.8 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees and 11.8 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 11.8 +/-0.2 degrees and 18.3 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 24.2 +/-0.2 degrees and 29.1 +/-0.2 degrees; or,

23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 18.3 +/-0.2 degrees and 16.7 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 18.3 +/-0.2 degrees and 16.7 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.3 +/-0.2 degrees and 16.7 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.3 +/-0.2 degrees and 16.7 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.3 +/-0.2 degrees and 24.2 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.3 +/-0.2 degrees and 29.1 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 16.7 +/-0.2 degrees and 24.2 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 16.7 +/-0.2 degrees, 24.2 +/-0.2 degrees and 29.1 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 18.3 +/-0.2 degrees, 16.7 +/-0.2 degrees, 24.2 +/-0.2 degrees and 29.1 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.3 +/-0.2 degrees, 16.7 +/-0.2 degrees and 29.1 +/-0.2 degrees; or,

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.3 +/-0.2 degrees, 16.7 +/-0.2 degrees, 24.2 +/-0.2 degrees and 29.1 +/-0.2 degrees.

The X-ray powder diffraction pattern of form C optionally further comprises one or more diffraction peaks at 10.4 ± 0.2 °, 11.0 ± 0.2 °, 19.2 ± 0.2 °, 12.1 ± 0.2 °, 20.0 ± 0.2 °, 25.5 ± 0.2 °, or 13.7 ± 0.2 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2,3, 4,5, 6, 7 thereof; for example, 26.1 + -0.2 deg., 24.7 + -0.2 deg., 8.3 + -0.2 deg., 9.9 + -0.2 deg., 12.8 + -0.2 deg., 18.9 + -0.2 deg., 26.7 + -0.2 deg., 17.3 + -0.2 deg., 10.4 + -0.2 deg., 11.0 + -0.2 deg.;

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、26.7±0.2°、10.4±0.2°、11.0±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、17.3±0.2°、10.4±0.2°、11.0±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、17.3±0.2°、26.7±0.2°、10.4±0.2°、11.0±0.2°

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、10.4±0.2°、11.0±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、26.7±0.2°、10.4±0.2°、11.0±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、17.3±0.2°、10.4±0.2°、11.0±0.2°；

26.1±0.2°、24.7±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、10.4±0.2°、11.0±0.2°；

26.1±0.2°、24.7±0.2°、9.9±0.2°、12.8±0.2°、26.7±0.2°、10.4±0.2°、11.0±0.2°；

26.1±0.2°、24.7±0.2°、9.9±0.2°、12.8±0.2°、17.3±0.2°、10.4±0.2°、11.0±0.2°；

26.1±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、10.4±0.2°、11.0±0.2°；

26.1±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、26.7±0.2°、10.4±0.2°、11.0±0.2°；

26.1±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、17.3±0.2°、10.4±0.2°、11.0±0.2°。

in a further preferred embodiment of the present invention, there is provided the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d ₃ ) Form A-C of pyridazine-3-carboxamide (example 1) having an X-ray powder diffraction pattern comprising one or more diffraction peaks at 23.7 + -0.2 °, 6.4 + -0.2 °, 19.4 + -0.2 °, 21.2 + -0.2 °, 23.0 + -0.2 °, 14.8 + -0.2 °,11.3 + -0.2 °, 28.5 + -0.2, 13.0 + -0.2 °, 11.8 + -0.2 °, 22.7 + -0.2 ° or 16.3 + -0.2 ° 2 θ; preferably, the compound comprises diffraction peaks at 4,5, 6, 8 or 10 optionally; for example:

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、23.0±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、14.8±0.2°；

23.7±0.2°、6.4±0.2°、23.0±0.2°、21.2±0.2°；

23.7±0.2°、6.4±0.2°、14.8±0.2°、21.2±0.2°；

23.7±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°；

23.7±0.2°、19.4±0.2°、21.2±0.2°、14.8±0.2°；

6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°；

6.4±0.2°、19.4±0.2°、21.2±0.2°、14.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、13.0±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、13.0±0.2°、11.3±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、13.0±0.2°、28.5±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、14.8±0.2°、13.0±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、13.0±0.2°、14.8±0.2°、28.5±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、13.0±0.2°、11.3±0.2°、28.5±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、23.0±0.2°、13.0±0.2°、11.3±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、23.0±0.2°、14.8±0.2°、13.0±0.2°；

23.7±0.2°、6.4±0.2°、13.0±0.2°、23.0±0.2°、11.3±0.2°、28.5±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、13.0±0.2；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、11.8±0.2；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、28.5±0.2°、13.0±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、28.5±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、11.3±0.2°、28.5±0.2°、13.0±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、11.3±0.2°、28.5±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2°、13.0±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2°、13.0±0.2°、22.7±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2°、13.0±0.2°、16.3±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、 28.5±0.2°、22.7±0.2°、16.3±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2°、22.7±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、28.5±0.2°、16.3±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、22.7±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、11.3±0.2°、16.3±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、22.7±0.2°、28.5±0.2°、13.0±0.2°、11.8±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、14.8±0.2°、16.3±0.2°、28.5±0.2°、13.0±0.2°、11.8±0.2°；

the X-ray powder diffraction pattern of the crystal form B comprises one or more diffraction peaks positioned in 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.3 +/-0.2 degrees, 16.7 +/-0.2 degrees, 16.3 +/-0.2 degrees, 24.2 +/-0.2 degrees and 29.1 +/-0.2 degrees of 2 degrees,

preferably, the compound comprises diffraction peaks at 4,5, 6, 8 or 10 optionally; for example, the X-ray powder diffraction pattern of form B has diffraction peaks at the following positions 2 θ:

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.2±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、14.5±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、20.8±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、10.5±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、11.8±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、18.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、16.7±0.2°；

15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°；

15.0±0.2°、19.6±0.2°、23.0±0.2°、14.5±0.2°；

15.0±0.2°、19.6±0.2°、23.0±0.2°、20.8±0.2°；

15.0±0.2°、19.6±0.2°、23.0±0.2°、13.3±0.2°；

15.0±0.2°、19.6±0.2°、23.0±0.2°、10.5±0.2°；

15.0±0.2°、19.6±0.2°、23.0±0.2°、11.8±0.2°；

15.0±0.2°、19.6±0.2°、23.0±0.2°、18.3±0.2°；

15.0±0.2°、19.6±0.2°、23.0±0.2°、16.7±0.2°；

19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°；

19.6±0.2°、23.0±0.2°、23.2±0.2°、20.8±0.2°；

19.6±0.2°、23.0±0.2°、23.2±0.2°、13.3±0.2°；

19.6±0.2°、23.0±0.2°、23.2±0.2°、10.5±0.2°；

19.6±0.2°、23.0±0.2°、23.2±0.2°、11.8±0.2°；

19.6±0.2°、23.0±0.2°、23.2±0.2°、18.3±0.2°；

19.6±0.2°、23.0±0.2°、23.2±0.2°、16.7±0.2°；

21.5±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°；

21.5±0.2°、19.6±0.2°、23.0±0.2°、14.5±0.2°；

21.5±0.2°、19.6±0.2°、23.0±0.2°、20.8±0.2°；

21.5±0.2°、19.6±0.2°、23.0±0.2°、13.3±0.2°；

21.5±0.2°、19.6±0.2°、23.0±0.2°、10.5±0.2°；

21.5±0.2°、19.6±0.2°、23.0±0.2°、11.8±0.2°；

21.5±0.2°、19.6±0.2°、23.0±0.2°、18.3±0.2°；

21.5±0.2°、19.6±0.2°、23.0±0.2°、16.7±0.2°；

21.5±0.2°、15.0±0.2°、23.0±0.2°、23.2±0.2°；

21.5±0.2°、15.0±0.2°、23.0±0.2°、14.5±0.2°；

21.5±0.2°、15.0±0.2°、23.0±0.2°、20.8±0.2°；

21.5±0.2°、15.0±0.2°、23.0±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、23.0±0.2°、10.5±0.2°；

21.5±0.2°、15.0±0.2°、23.0±0.2°、11.8±0.2°；

21.5±0.2°、15.0±0.2°、23.0±0.2°、18.3±0.2°；

21.5±0.2°、15.0±0.2°、23.0±0.2°、16.7±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、20.8±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.2±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、23.0±0.2°、23.2±0.2°、20.8±0.2°、13.3±0.2°；

21.5±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、13.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、10.5±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、11.8±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、18.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、16.7±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、13.3±0.2°、10.5±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、13.3±0.2°、11.8±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、10.5±0.2°、11.8±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、20.8±0.2°、13.3±0.2°、10.5±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、20.8±0.2°、13.3±0.2°、11.8±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°、10.5±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°、11.8±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、20.8±0.2°、13.3±0.2°、10.5±0.2°、 11.8±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、14.5±0.2°、13.3±0.2°、10.5±0.2°、11.8±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°、10.5±0.2°、11.8±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°、11.8±0.2°、18.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°、11.8±0.2°、16.7±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、13.3±0.2°、18.3±0.2°、16.7±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、10.5±0.2°、11.8±0.2°、18.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、10.5±0.2°、11.8±0.2°、16.7±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、20.8±0.2°、10.5±0.2°、18.3±0.2°、16.7±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、13.3±0.2°、10.5±0.2°、11.8±0.2°、18.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、13.3±0.2°、10.5±0.2°、11.8±0.2°、16.7±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、14.5±0.2°、10.5±0.2°、11.8±0.2°、18.3±0.2°、16.7±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、20.8±0.2°、13.3±0.2°、10.5±0.2°、11.8±0.2°、18.3±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、20.8±0.2°、13.3±0.2°、10.5±0.2°、18.3±0.2°、16.7±0.2°；

21.5±0.2°、15.0±0.2°、19.6±0.2°、23.0±0.2°、23.2±0.2°、13.3±0.2°、10.5±0.2°、11.8±0.2°、18.3±0.2°、16.7±0.2°；

the X-ray powder diffraction pattern of the crystal form C comprises one or more diffraction peaks positioned in 26.1 +/-0.2 degrees, 24.7 +/-0.2 degrees, 8.3 +/-0.2 degrees, 9.9 +/-0.2 degrees, 12.8 +/-0.2 degrees, 18.9 +/-0.2 degrees, 26.7 +/-0.2 degrees, 17.3 +/-0.2 degrees, 10.4 +/-0.2 degrees, 11.0 +/-0.2 degrees, 19.2 +/-0.2 degrees or 12.1 +/-0.2 degrees of 2 theta; preferably, the compound comprises diffraction peaks at 4,5, 6, 8 or 10;

for example: 26.1 +/-0.2 degrees, 24.7 +/-0.2 degrees, 8.3 +/-0.2 degrees and 9.9 +/-0.2 degrees;

26.1±0.2°、24.7±0.2°、8.3±0.2°、12.8±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、18.8±0.2°；

26.1±0.2°、24.7±0.2°、9.9±0.2°、12.8±0.2°；

26.1±0.2°、24.7±0.2°、9.9±0.2°、18.9±0.2°；

26.1±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°；

26.1±0.2°、8.3±0.2°、9.9±0.2°、18.9±0.2°；

24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°；

24.7±0.2°、8.3±0.2°、9.9±0.2°、18.9±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、23.0±0.2°、10.4±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、10.4±0.2°、11.3±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、10.4±0.2°、23.0±0.2°、28.5±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、14.8±0.2°、10.4±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、21.2±0.2°、10.4±0.2°、28.5±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、10.4±0.2°、11.3±0.2°、28.5±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、23.0±0.2°、10.4±0.2°、11.3±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、23.0±0.2°、10.4±0.2°、28.5±0.2°；

23.7±0.2°、6.4±0.2°、19.4±0.2°、23.0±0.2°、11.3±0.2°、10.4±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、26.7±0.2°、10.4±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、26.7±0.2°、11.0±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、17.3±0.2°、10.4±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、17.3±0.2°、11.0±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、26.7±0.2°、17.3±0.2°、10.4±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、26.7±0.2°、17.3±0.2°、11.0±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、18.9±0.2°、26.7±0.2°、17.3±0.2°、10.4±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、18.9±0.2°、26.7±0.2°、17.3±0.2°、11.0±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、12.8±0.2°、18.9±0.2°、26.7±0.2°、17.3±0.2°、10.4±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、12.8±0.2°、18.9±0.2°、26.7±0.2°、17.3±0.2°、11.0±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、26.7±0.2°、17.3±0.2、10.4±0.2°、11.0±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、26.7±0.2°、17.3±0.2、10.4±0.2°、19.2±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、26.7±0.2°、17.3±0.2、10.4±0.2°、12.1±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、26.7±0.2°、10.4±0.2、17.3±0.2、19.2±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、26.7±0.2°、10.4±0.2、17.3±0.2、12.1±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、26.7±0.2°、10.4±0.2、11.0±0.2°、19.2±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、26.7±0.2°、10.4±0.2、11.0±0.2°、12.1±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、17.3±0.2、10.4±0.2°、11.0±0.2°、19.2±0.2°；

26.1±0.2°、24.7±0.2°、8.3±0.2°、9.9±0.2°、12.8±0.2°、18.9±0.2°、17.3±0.2、10.4±0.2°、11.0±0.2°、12.1±0.2°。

as a specific example, the XRPD pattern of form B comprises one or more peaks at the following diffraction angles (2 Θ): 21.5 +/-0.2 °,15.0 +/-0.2 °,19.6 +/-0.2 °, 23.0 +/-0.2 °,23.2 +/-0.2 °, 14.5 +/-0.2 °, 20.8 +/-0.2 °,13.3 +/-0.2 °,10.5 +/-0.2 °, 11.8 +/-0.2 °, 18.3 +/-0.2 °, 16.7 +/-0.2 °, 16.3 +/-0.2 °, 24.2 +/-0.2 °, 29.1 +/-0.2 °,26.1 +/-0.2 °, 16.0 +/-0.2 °, 23.8 +/-0.2 °, 27.7 +/-0.2 °, 15.7 +/-0.2 °, 17.5 +/-0.2 °, 24.8 +/-0.2 °, 5.2 +/-0.2 °; preferably, the XRPD pattern of form B comprises at least the four, or six, or eight peaks described above.

Most preferably, in a further preferred embodiment of the present invention, said crystalline form a of compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide, shown in example 1, has characteristic X-ray diffraction peaks expressed in terms of 2 theta angles and interplanar spacings d as shown in table 1 using Cu-ka radiation.

TABLE 1

The compound shown in example 1 of the invention has a crystal form A of 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide, and the X-ray powder diffraction pattern of the crystal form A is basically shown in figure 1; the DSC pattern is basically shown in figure 2; the TGA profile is substantially as shown in figure 3.

In a further preferred embodiment of the present invention, said compound of example 1, 6- (cyclopropylcarboxamide) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide, form B, most preferably, the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacings d using Cu-ka radiation, are shown in table 2.

TABLE 2

The compound shown in example 1 of the invention has a crystal form B of 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide, and the X-ray powder diffraction pattern of the crystal form B is basically shown in figure 4; the DSC pattern is basically shown in figure 5; the TGA profile is substantially as shown in figure 6.

In a further preferred embodiment of the present invention, the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d, shown in example 1 ₃ ) Form C of pyridazine-3-carboxamide, most preferably, using Cu-K.alpha.radiation, characteristic X-ray diffraction peaks expressed in terms of 2 theta angles and interplanar spacings d are shown in Table 3.

TABLE 3

The compound shown in example 1 in the invention has a crystal form C of 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide, and the X-ray powder diffraction pattern of the crystal form C is substantially shown in figure 7; the DSC pattern is basically shown in figure 8; the TGA profile is substantially as shown in figure 9.

In a further preferred embodiment of the present invention, the crystalline form of the compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide shown in example 6 comprises crystalline forms a-C, wherein:

the X-ray powder diffraction pattern of the crystal form A has a diffraction peak at the 2 theta of 24.5 +/-0.2 degrees; or a diffraction peak at 19.0 ± 0.2 °; or a diffraction peak at 13.1 ± 0.2 °; or a diffraction peak at 15.8 ± 0.2 °; or a diffraction peak at 13.4 ± 0.2 °; or a diffraction peak at 23.8 ± 0.2 °; or a diffraction peak at 7.9 ± 0.2 °; or a diffraction peak at 14.7 ± 0.2 °; or a diffraction peak at 15.0 ± 0.2 °; or a diffraction peak at 27.1 ± 0.2 °; preferably comprises any of 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the diffraction peaks; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the crystal form B has a diffraction peak at the 2 theta of 7.1 +/-0.2 degrees; or a diffraction peak at 23.5 ± 0.2 °; or a diffraction peak at 22.6 ± 0.2 °; or a diffraction peak at 25.7 ± 0.2 °; or a diffraction peak at 17.3 ± 0.2 °; or a diffraction peak at 23.2 ± 0.2 °; or a diffraction peak at 21.9 ± 0.2 °; or a diffraction peak at 8.2 ± 0.2 °; or a diffraction peak at 13.9 ± 0.2 °; or a diffraction peak at 17.9 ± 0.2 °; preferably comprises any of 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the diffraction peaks; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the crystal form C has a diffraction peak at 24.5 +/-0.2 degrees of 2 theta; or a diffraction peak at 13.3 ± 0.2 °; or a diffraction peak at 15.9 ± 0.2 °; or a diffraction peak at 14.6 ± 0.2 °; or a diffraction peak at 19.0 ± 0.2 °; or a diffraction peak at 7.9 ± 0.2 °; or a diffraction peak at 15.0 ± 0.2 °; or a diffraction peak at 20.1 ± 0.2 °; or a diffraction peak at 13.9 ± 0.2 °; or a diffraction peak at 13.1 ± 0.2 °; preferably comprises any of 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the diffraction peaks; more preferably any 6, 7 or 8 thereof.

Still further, the X-ray powder diffraction pattern of form a comprises at least one or more diffraction peaks, preferably 2, more preferably 3, located at 2 θ of 24.5 ± 0.2 °, 19.0 ± 0.2 °, 13.1 ± 0.2 °; optionally, the composition can further comprise at least one position with 2 theta of 15.8 +/-0.2 degrees, 13.4 +/-0.2 degrees, 23.8 +/-0.2 degrees, 7.9 +/-0.2 degrees or 14.7 +/-0.2 degrees, preferably comprises 2 positions, 3 positions, 4 positions or 5 positions;

for example:

24.5±0.2°、19.0±0.2°、13.1±0.2°、15.8±0.2°；

24.5±0.2°、19.0±0.2°、13.1±0.2°、15.8±0.2°、13.4±0.2°、23.8±0.2°；

24.5±0.2°、19.0±0.2°、13.1±0.2°、15.8±0.2°、13.4±0.2°、23.8±0.2°、7.9±0.2°、14.7±0.2；

the X-ray powder diffraction pattern of the crystal form B at least comprises one or more diffraction peaks with 2 theta of 7.1 +/-0.2 degrees, 23.5 +/-0.2 degrees and 22.6 +/-0.2 degrees, preferably comprises 2, more preferably comprises 3; optionally, the composition can further comprise at least one position with 2 theta of 25.7 +/-0.2 degrees, 17.3 +/-0.2 degrees, 23.2 +/-0.2 degrees, 21.9 +/-0.2 degrees or 8.2 +/-0.2 degrees, preferably comprises 2 positions, 3 positions, 4 positions or 5 positions;

for example:

7.1±0.2°、23.5±0.2°、22.6±0.2°、25.7±0.2°；

7.1±0.2°、23.5±0.2°、22.6±0.2°、25.7±0.2°、17.3±0.2°、23.2±0.2°；

7.1±0.2°、23.5±0.2°、22.6±0.2°、25.7±0.2°、17.3±0.2°、23.2±0.2°、21.9±0.2°、8.2±0.2；

the X-ray powder diffraction pattern of the crystal form C at least comprises one or more diffraction peaks with the 2 theta of 24.5 +/-0.2 degrees, 13.3 +/-0.2 degrees and 15.9 +/-0.2 degrees, preferably comprises 2, and more preferably comprises 3; optionally, the composition can further comprise at least one position with 2 theta of 14.6 +/-0.2 degrees, 19.0 +/-0.2 degrees, 7.9 +/-0.2 degrees, 15.0 +/-0.2 degrees or 20.1 +/-0.2 degrees, preferably comprises 2 positions, 3 positions, 4 positions or 5 positions;

for example:

24.5±0.2°、13.3±0.2°、15.9±0.2°、14.6±0.2°；

24.5±0.2°、13.3±0.2°、15.9±0.2°、14.6±0.2°、19.0±0.2°、7.9±0.2°；

24.5±0.2°、13.3±0.2°、15.9±0.2°、14.6±0.2°、19.0±0.2°、7.9±0.2°、15.0±0.2、20.1±0.2°。

as a specific example, further, the X-ray powder diffraction pattern of form a optionally further comprises one or more diffraction peaks at 15.0 ± 0.2 °, 27.1 ± 0.2 °, 14.0 ± 0.2 °, 20.1 ± 0.2 °, 22.3 ± 0.2 °, 28.2 ± 0.2 ° or 18.4 ± 0.2 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2,3, 4,5, 6, 7 thereof;

for example:

24.5±0.2°、19.0±0.2°、13.1±0.2°、15.8±0.2°、15.0±0.2°；

24.5±0.2°、19.0±0.2°、13.1±0.2°、15.8±0.2°、13.4±0.2°、23.8±0.2°、15.0±0.2°；

24.5±0.2°、19.0±0.2°、13.1±0.2°、15.8±0.2°、13.4±0.2°、23.8±0.2°、7.9±0.2°、14.7±0.2、15.0±0.2°；

the X-ray powder diffraction pattern of form B optionally further comprises one or more diffraction peaks at 13.9 ± 0.2 °, 17.9 ± 0.2 °, 25.3 ± 0.2 °,5.4 ± 0.2 °, 8.6 ± 0.2 °, 14.3 ± 0.2 °, or 27.5 ± 0.2 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2,3, 4,5, 6, 7 thereof;

for example:

7.1±0.2°、23.5±0.2°、22.6±0.2°、25.7±0.2°、13.9±0.2°；

7.1±0.2°、23.5±0.2°、22.6±0.2°、25.7±0.2°、17.3±0.2°、23.2±0.2°、13.9±0.2°；

7.1±0.2°、23.5±0.2°、22.6±0.2°、25.7±0.2°、17.3±0.2°、23.2±0.2°、21.9±0.2°、8.2±0.2、13.9±0.2°；

the X-ray powder diffraction pattern of form C optionally further comprises one or more diffraction peaks at 13.9 ± 0.2 °, 13.1 ± 0.2 °, 23.8 ± 0.2 °, 27.0 ± 0.2 °, 22.3 ± 0.2 °, 18.4 ± 0.2 °, or 29.9 ± 0.2 ° 2 Θ; preferably at least any 2 to 3, or 4 to 5, or 6 to 7 thereof; further preferably, any 2,3, 4,5, 6, 7 thereof;

for example:

24.5±0.2°、13.3±0.2°、15.9±0.2°、14.6±0.2°、13.94±0.2°；

24.5±0.2°、13.3±0.2°、15.9±0.2°、14.6±0.2°、19.0±0.2°、7.9±0.2°、13.9±0.2°；

24.5±0.2°、13.3±0.2°、15.9±0.2°、14.6±0.2°、19.0±0.2°、7.9±0.2°、15.0±0.2、20.1±0.2°、13.9±0.2°。

in a further preferred embodiment of the invention, the crystalline form of the compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide shown in example 6 comprises form a-C, wherein the X-ray powder diffraction pattern of form a comprises diffraction peaks at one or more of 2 Θ at 24.5 ± 0.2 °, 19.0 ± 0.2 °, 13.1 ± 0.2 °, 15.8 ± 0.2 °, 13.4 ± 0.2 °, 23.8 ± 0.2 °, 7.9 ± 0.2 °, 14.7 ± 0.2, 15.0 ± 0.2 °, 27.1 ± 0.2 °, 14.0 ± 0.2 ° or 20.1 ± 0.2 °; preferably, the compound comprises diffraction peaks at 4,5, 6, 8 or 10;

for example, the X-ray powder diffraction pattern of the form a has diffraction peaks at the following positions 2 θ:

19.0±0.2°、13.1±0.2°、15.8±0.2°、13.4±0.2°；

24.5±0.2°、19.0±0.2°、13.1±0.2°、15.8±0.2°、13.4±0.2°、23.8±0.2°、7.9±0.2°、 14.7±0.2；

24.5±0.2°、19.0±0.2°、13.1±0.2°、15.8±0.2°、13.4±0.2°、23.8±0.2°、7.9±0.2°、14.7±0.2、15.0±0.2°、27.1±0.2°；

the X-ray powder diffraction pattern of the crystal form B comprises one or more diffraction peaks located at 7.1 +/-0.2 degrees, 23.5 +/-0.2 degrees, 22.6 +/-0.2 degrees, 25.7 +/-0.2 degrees, 17.3 +/-0.2 degrees, 23.2 +/-0.2 degrees, 21.9 +/-0.2 degrees, 8.2 +/-0.2 degrees, 13.9 +/-0.2 degrees, 17.9 +/-0.2 degrees, 25.3 +/-0.2 degrees or 5.4 +/-0.2 degrees of 2 theta; preferably, the compound comprises diffraction peaks at 4,5, 6, 8 or 10;

for example, the X-ray powder diffraction pattern of form B has diffraction peaks at the following positions 2 θ:

23.5±0.2°、22.6±0.2°、25.7±0.2°、17.3±0.2°；

7.1±0.2°、23.5±0.2°、22.6±0.2°、25.7±0.2°、17.3±0.2°、23.2±0.2°、21.9±0.2°、13.9±0.2°；

the X-ray powder diffraction pattern of the crystal form C comprises one or more diffraction peaks positioned at 24.5 +/-0.2 degrees, 13.3 +/-0.2 degrees, 15.9 +/-0.2 degrees, 14.6 +/-0.2 degrees, 19.0 +/-0.2 degrees, 7.9 +/-0.2 degrees, 15.0 +/-0.2 degrees, 20.1 +/-0.2 degrees, 13.9 +/-0.2 degrees, 13.1 +/-0.2 degrees, 23.8 +/-0.2 degrees or 27.0 +/-0.2 degrees of 2 theta; preferably, the compound comprises diffraction peaks at 4,5, 6, 8 or 10 optionally; for example, the form C has an X-ray powder diffraction pattern with diffraction peaks at the following positions 2 θ:

13.3±0.2°、15.9±0.2°、14.6±0.2°、19.0±0.2°；

13.3±0.2°、15.9±0.2°、14.6±0.2°、19.0±0.2°、7.9±0.2°、15.0±0.2；

24.5±0.2°、13.3±0.2°、15.9±0.2°、14.6±0.2°、19.0±0.2°、7.9±0.2°、15.0±0.2、27.0±0.2°；

24.5±0.2°、13.3±0.2°、15.9±0.2°、14.6±0.2°、19.0±0.2°、7.9±0.2°、15.0±0.2、20.1±0.2°、13.9±0.2°、27.0±0.2°。

in a further preferred embodiment of the present invention, said compound of example 6, 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide, crystalline form a, more preferably, the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacings d using Cu-ka radiation, are shown in table 4.

TABLE 4

The compound shown in example 6 in the invention has a crystal form A of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide, and an X-ray powder diffraction pattern of the crystal form A is basically shown in a figure 10; the DSC pattern is basically shown in figure 11; the TGA profile is substantially as shown in figure 12.

In a further preferred embodiment of the present invention, said compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide of example 6 shows crystalline form B, more preferably the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacings d using Cu-ka radiation as shown in table 5.

TABLE 5

The compound shown in example 6 of the invention, namely 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide, has the crystal form B, and the X-ray powder diffraction pattern is basically shown in figure 13; the DSC pattern is basically as shown in figure 14; the TGA profile is substantially as shown in figure 15.

In a further preferred embodiment of the present invention, said compound of example 6, 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide, form C, most preferably, the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacings d using Cu-ka radiation, are shown in table 6.

TABLE 6

The compound shown in example 6 of the invention, namely 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide, has a crystal form C, and an X-ray powder diffraction pattern of the crystal form C is basically shown in figure 16; the DSC spectrum is basically shown in figure 17.

The 2 theta error between the diffraction peak position with the first ten-strong relative peak intensity in the X-ray powder diffraction pattern and the diffraction peak position corresponding to the corresponding figure is +/-0.2-0.5 degrees, preferably +/-0.2-0.3 degrees and most preferably +/-0.2 degrees.

In the present invention, the X-ray powder diffraction pattern is substantially as shown in FIG. 4, wherein "substantially" means that there may be some error, for example, the 2 θ error of the diffraction peak may be ± 0.2 ° to ± 0.5 °, and the like, and the other parts have the same or similar meanings.

In a preferred embodiment of the invention, the compound of formula (I) is in a crystalline form, with or without a solvent, wherein the solvent is selected from one or more of water, methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, N-butanol, isobutanol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, N-propanol, tert-butanol, 2-butanone, 3-pentanone, N-heptane, ethyl formate, isopropyl acetate, cyclohexane, methyl tert-butyl ether or isopropyl ether.

In a preferred embodiment of the invention, the number of solvents in the crystalline form of any one of the compounds of formula (I) is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1,2 or 3.

In a preferred embodiment of the present invention, the crystalline form of the compound of formula (I) is a non-solvent crystalline form, preferably an anhydrous crystalline form.

In a preferred embodiment of the invention, the crystalline form of the compound of formula (I) is a hydrate crystalline form, the number of water is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1,2 or 3.

In a more preferred embodiment of the invention, the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d ₃ ) The crystalline form of pyridazine-3-carboxamide is a non-solvent compound, preferably an anhydrate or hydrate.

In a more preferred embodiment of the invention, the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d ₃ ) The number of water in the hydrate crystal form of pyridazine-3-carboxamide is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1,2 or 3.

In a more preferred embodiment of the invention, the crystalline form of the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide is a non-solvated compound, preferably an anhydrate or hydrate.

In a more preferred embodiment of the invention, the number of water in the hydrate crystalline form of the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide is between 0.2 and 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1,2 or 3.

In a more preferred embodiment of the invention, the crystalline form of the compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide is a non-solvated compound, preferably an anhydrate or hydrate.

In a more preferred embodiment of the invention, the number of water in the hydrate crystalline form of the compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1,2 or 3.

It is well known to those skilled in the art that XRPD can produce certain displacements and intensity deviations due to the detection method, conditions and instrumentation. As a specific example of the crystal form of the present invention, XRPD is shown as pattern X, but the ordinary skilled person understands that when the deviation of key characteristic peak shift 2 theta is about + -0.5, especially + -0.2, all can be identified as the same crystal form; for example, the 2 theta error of the diffraction peak of the invention plus or minus 0.2 degree can be replaced by other reasonable errors of plus or minus 0.3 degree, plus or minus 0.5 degree and the like.

In another aspect, the present invention also relates to a process for preparing a crystalline form of the compound of formula (I), comprising the steps of:

1) Weighing a proper amount of free alkali, and suspending with a poor solvent; the suspension density is preferably 50-200 mg/mL;

2) Shaking or pulping the obtained suspension for a certain time at a certain temperature; the temperature is preferably 0 to 50 ℃; the time is 1 to 10 days; preferably 1-5 days;

3) Optionally further centrifuging the suspension, removing the supernatant, and drying to obtain a target product; drying, preferably drying in a vacuum drying oven at 40 ℃ to constant weight;

the poor solvent is one or more selected from 88% acetone, isopropanol, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, ethyl acetate, N-hexane, N-heptane, acetonitrile, ethanol, dichloromethane, 1,4-dioxane, benzene, toluene, N-butanol, isobutanol, N-dimethylformamide, N-dimethylacetamide, N-propanol, t-butanol, 2-butanone, or 3-pentanone; preferably one or more of 3-pentanone, acetonitrile, dichloromethane or 1, 4-dioxane.

The invention also relates to a method for preparing the crystal form of the compound shown in the general formula (I), which comprises the following steps:

a) Weighing a proper amount of free alkali, and dissolving the free alkali in a good solvent;

b) Dropwise adding an anti-solvent into the solution obtained in the step a), and naturally cooling or stirring until a solid is separated out to obtain a suspension;

c) Optionally, further centrifuging the suspension obtained in the step b), removing supernatant, and drying to obtain a target product; drying preferably in a vacuum drying oven at 40-50 deg.C to constant weight;

the good solvent is selected from one or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, N-butanol, isobutanol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, N-propanol, tert-butanol, 2-butanone, 3-pentanone or dimethyl sulfoxide; preferably one or more of N-methylpyrrolidone, N-dimethylformamide or acetonitrile;

the antisolvent is selected from one or more of heptane, isopropyl ether, ethyl acetate, acetonitrile, ethanol, toluene, isopropanol, isopropyl acetate, water, methyl tert-butyl ether or cyclohexane; preferably one or more of isopropyl ether, n-heptane or water.

The invention also relates to a method for preparing the crystal form A of the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide, which specifically comprises the following steps:

1) Weighing a proper amount of free alkali, and dissolving the free alkali in a good solvent under a heating condition;

2) Dropwise adding an anti-solvent, stirring, naturally cooling to room temperature, and separating out a large amount of solids;

3) Filtering the obtained suspension, removing supernatant, and drying to obtain a target product; drying, preferably placing the mixture into a vacuum drying oven at 50 ℃ to dry the mixture to constant weight; or

1) Adding free alkali into a reaction bottle, adding N-methyl pyrrolidone, heating to 95 ℃, and enabling a reaction solution to be in a brown clear state; the milliliter number of the N-methylpyrrolidone is preferably 3 times of the weight gram number of the free alkali, namely 3V;

2) Dropwise adding isopropanol, keeping the temperature and stirring for 1 hour after the dropwise adding is finished, then closing the heating, naturally cooling to room temperature, and precipitating a large amount of solids; the milliliter number of the isopropanol is preferably 6 times of the weight gram number of the free alkali, namely 6V;

3) Cooled in ice bath, stirred for 1 hour, filtered, and the solid obtained is washed with isopropanol and dried to obtain a yellow solid. To obtain free base crystal form a. The isopropanol is preferably used in ml in the same amount as the free base in grams by weight.

The poor solvent is selected from one or more of 88% acetone, isopropanol, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, ethyl acetate, acetonitrile, ethanol, dichloromethane, 1,4-dioxane, benzene, toluene, N-butanol, isobutanol, N-dimethylformamide, N-dimethylacetamide, N-propanol, tert-butanol, 2-butanone or 3-pentanone; preferably one or more of 3-pentanone, acetonitrile, dichloromethane or 1, 4-dioxane.

The invention also relates to a method for preparing the crystal form B of the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide, which specifically comprises the following steps:

1) Adding free alkali into a reaction bottle, adding ethyl acetate and n-heptane, stirring and pulping for 24 hours at room temperature; the milliliter number of the ethyl acetate is preferably 1.25 times of the weight gram number of the free alkali, namely 1.25V; the milliliter number of the used n-heptane is preferably 12.5 times of the weight gram number of the free base, namely 12.5V;

2) Filtering, washing the obtained solid with n-heptane, and drying to obtain yellow solid. To obtain free base crystal form B. The milliliter value of the used amount of the n-heptane is preferably half of the weight and gram value of the free alkali; or

1) Adding free alkali and dimethyl sulfoxide into a reaction bottle, dissolving under heating, and filtering while hot;

2) Dripping isopropanol, cooling and stirring;

3) Filtering, washing with isopropanol, and drying to obtain free base crystal form B.

The invention also relates to a method for preparing the crystal form C of the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide, which specifically comprises the following steps:

1) Weighing 20mg of free alkali into a 2ml glass bottle, adding 700 mu l of dichloromethane, and dissolving and clearing at room temperature;

2) Slowly adding 800 mu l of isopropyl ether at 37 ℃, and separating out solids in the process of adding the isopropyl ether;

3) Stirring for 2h at 37 ℃, centrifuging, removing supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain free base crystal form C.

The invention also relates to a method for preparing the compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide in the form of crystal form a, which comprises the following steps:

1) Weighing 10mg of free alkali into a 2ml glass bottle, adding 100 mu L of toluene, and stirring at 50 ℃ for 5 days;

2) Centrifuging, removing supernatant, and drying the residual solid in a vacuum drying oven at 50 deg.C to constant weight to obtain free base crystal form A.

The invention also relates to a method for preparing the compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide in crystal form B, which comprises the following steps:

1) Weighing 10mg of free alkali into a 2ml glass bottle, adding 100 mu L of acetone, and stirring at 50 ℃ for 5 days;

2) Centrifuging, removing supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain free base crystal form B.

The invention also relates to a method for preparing the compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide in crystal form C, which specifically comprises the following steps:

1) Weighing 10mg of free alkali into a 2ml glass bottle, adding 100 mu L of acetonitrile, and stirring at 50 ℃ for 5 days;

3) Centrifuging, removing supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain free base crystal form C.

The invention also aims to provide a pharmaceutical composition which contains a therapeutically effective amount of the crystal form of the compound shown in the general formula (I) and one or more pharmaceutically acceptable carriers, diluents or excipients.

The invention also aims to provide the crystal form of the compound shown in the general formula (I) and application of the pharmaceutical composition in preparation of TYK2 inhibitor drugs.

The invention also aims to provide a crystal form of the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide shown in the general formula (I) and application of a pharmaceutical composition in preparation of TYK2 inhibitor drugs.

The invention also aims to provide a crystal form of the compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide shown in the general formula (I) and application of a pharmaceutical composition in preparation of TYK2 inhibitor drugs.

The invention aims to provide the crystal form of the compound shown in the general formula (I) and the application of the pharmaceutical composition in treating inflammatory diseases and autoimmune diseases; wherein the inflammatory and autoimmune diseases are selected from rheumatoid arthritis, dermatitis, psoriasis or inflammatory bowel disease.

Detailed description of the invention

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms. <xnotran> , , , , , , , , ,1,1- ,1,2- ,2,2- ,1- ,2- ,3- , ,1- -2- ,1,1,2- ,1,1- ,1,2- ,2,2- ,1,3- ,2- ,2- ,3- ,4- ,2,3- , ,2- ,3- ,4- ,5- ,2,3- ,2,4- ,2,2- ,3,3- ,2- ,3- , ,2,3- ,2,4- ,2,5- ,2,2- ,3,3- ,4,4- ,2- ,3- ,4- ,2- -2- ,2- -3- , ,2- -2- ,2- -3- ,2,2- , ,3,3- ,2,2- , </xnotran> And various branched chain isomers thereof, and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, most preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) _m (wherein m is an integer of 0 to 2) but does not include a cyclic moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; optimization ofOptionally containing 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, thietanyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetanyl, pyrrolidinonyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.

The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.

"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

"alkenyl" refers to alkenyl, also known as alkenylene, wherein the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"alkynyl" refers to (CH ≡ C-), wherein said alkynyl may be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

"hydroxy" refers to an-OH group.

"halogen" means fluorine, chlorine, bromine or iodine.

"amino" refers to-NH ₂ 。

"cyano" means-CN.

"Nitro" means-NO ₂ 。

"carboxy" means-C (O) OH.

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N, N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetonitrile.

"DMA" refers to N, N-dimethylacetamide.

“Et ₂ O "means diethyl ether.

"DCE" refers to 1, 2-dichloroethane.

"DIPEA" refers to N, N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

“Pd ₂ (dba) ₃ "refers to tris (dibenzylideneacetone) dipalladium.

"Dppf" refers to 1,1' -bisdiphenylphosphinoferrocene.

"HATU" refers to 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilyl amide.

"MeLi" refers to methyllithium.

"n-BuLi" refers to n-butyllithium.

“NaBH(OAc) ₃ "refers to sodium triacetoxyborohydride.

"DMAP" refers to 4-dimethylaminopyridine.

"SEM-Cl" refers to chloromethyl trimethylsilylethyl ether.

"Xantphos" refers to 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene.

"DCM" refers to dichloromethane.

Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B and C.

All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the heterocyclic group is not substituted with an alkyl group.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

Drawings

FIG. 1 is a scheme of 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d ₃ ) XRPD pattern of pyridazine-3-carboxamide form a.

FIG. 2 shows 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d ₃ ) DSC representation of crystalline form A of pyridazine-3-carboxamide.

FIG. 3 is a scheme showing 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d ₃ ) TGA schematic representation of pyridazine-3-carboxamide form A.

FIG. 4 is a schematic representation of 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d) ₃ ) XRPD representation of pyridazine-3-carboxamide form B.

FIG. 5 is a schematic representation of 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d) ₃ ) DSC representation of crystalline form B of pyridazine-3-carboxamide.

FIG. 6 is a schematic representation of 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d) ₃ ) TGA representation of pyridazine-3-carboxamide form B.

FIG. 7 is a drawing of a schematic representation of 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d) ₃ ) XRPD pattern of pyridazine-3-carboxamide form C.

FIG. 8 is 6- (cyclopropyl)Carboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d ₃ ) DSC representation of form C of pyridazine-3-carboxamide.

FIG. 9 is a scheme showing 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d ₃ ) TGA representation of pyridazine-3-carboxamide form C.

Figure 10 is an XRPD representation of crystalline form a of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide.

Figure 11 is a DSC representation of crystalline form a of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide.

Figure 12 is a TGA schematic representation of crystalline form a of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide.

Figure 13 is a schematic representation of the XRPD of crystalline form B of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide.

Figure 14 is a DSC representation of crystalline form B of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide.

Figure 15 is a TGA schematic representation of crystalline form B of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide.

Figure 16 is a schematic representation of the XRPD of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide form C.

Figure 17 is a DSC representation of crystalline form C of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide.

Figure 18 is the results of PASI scoring in imiquimod-induced mouse psoriasis model at different doses of compound.

Detailed Description

The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.

1. Preparation of the Compounds

Examples

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated methanol (CD) ₃ OD) and deuterated chloroform (CDCl) ₃ ) Internal standard is Tetramethylsilane (TMS).

LC-MS was measured using an Agilent 1200 Infinity Series Mass spectrometer. The HPLC measurements were carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18X 4.6mm column).

The thin layer chromatography silica gel plate adopts a cigarette platform yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by a thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh Titai Huanghai silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available, or can be synthesized according to methods known in the art.

All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.

Example 1

6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d ₃ ) Preparation of pyridazine-3-carboxamides

First step preparation of 2-methoxy-3-nitrobenzamide

Methyl 2-methoxy-3-nitrobenzoate (5g, 23.7mmol) was dissolved in methanolic ammonia (100mL, 7M) at room temperature, ammonia (28 wt%,50 mL) was added, the mixture was stirred overnight at room temperature, diluted with ethyl acetate (300 mL) and the organic phase was then successively diluted with saturated NaHCO ₃ Aqueous solution (300 mL. Times.2) and brine. The organic phase was separated and dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure and then subjected to column chromatography to give the title compound, 2-methoxy-3-nitrobenzamide (4.3g, 92%).

MS m/z(ESI):197.1[M+H] ⁺ .

Second step preparation of 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole

2-methoxy-3-nitrobenzamide (4.2g, 21.4 mmol) was dissolved in DMF-DMA (28.6 mL), heated to 95 ℃ for 1 hour, concentrated under reduced pressure to give the crude DMF-DMA adduct, which was dissolved in ethanol (20 mL) for use. After 5 minutes of stirring in ethanol (70 mL), acetic acid (21 mL), hydrazine hydrate (80 wt.%,10.5 mL) was slowly added dropwise and stirring was continued for 15 minutes under ice-bath, then the above ethanol solution of the crude DMF-DMA addition product was added dropwise, slowly warmed to room temperature, and stirring was continued for 4 hours at room temperature. The reaction was concentrated under reduced pressure, diluted with ethyl acetate (300 mL) and the organic phase was successively diluted with saturated NaHCO ₃ Washing with aqueous solution (300 mL × 2) and saturated saline, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography to obtainThe title compound, 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (4.5g, 95%).

MS m/z(ESI):221.1[M+H] ⁺ .

The third step is the preparation of 1-cyclopropyl-3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole

3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (200mg, 0.91mmol), copper acetate (198mg, 1.1 mmol), 2' -bipyridine (170mg, 1.1 mmol), sodium carbonate (192mg, 1.8mmol) were mixed with 1, 2-dichloroethane (5 mL), cyclopropylboronic acid (234mg, 2.72mmol) was added at room temperature, and the mixture was heated to 85 ℃ and stirred overnight. After the reaction solution was cooled to room temperature, it was diluted with a large amount of ethyl acetate. The organic phase was washed with saturated brine several times, then the separated organic phase was dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure and column chromatography was performed to separate the title compound, 1-cyclopropyl-3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (125mg, 53%).

¹ H NMR(400MHz,CDCl ₃ )δ1.15-1.21(m,2H),1.24-1.29(m,2H),3.70-3.79(m,1H),3.94(s,3H),7.23-7.31(m,1H),7.78-7.81(m,1H),8.20-8.23(m,1H),8.36(s,1H)；

MS m/z(ESI):261.1[M+H] ⁺ .

The fourth step of preparation of 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyaniline

To a solution of 1-cyclopropyl-3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (120mg, 0.46mmol) in methanol (5 mL) was added palladium on carbon (30 mg), and the mixture was reacted under a hydrogen atmosphere at ordinary temperature and pressure for 12 hours, followed by filtering off the catalyst with celite. The filtrate was concentrated under reduced pressure to give the title compound, 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyaniline (102 mg), which was used directly in the next reaction.

MS m/z(ESI):231.1[M+H] ⁺ .

Fifth step preparation of lithium 4, 6-dichloropyridazine-3-carboxylate

Methyl 4, 6-dichloropyridazine-3-carboxylate (2.07g, 10mmol), lithium bromide (2.6g, 30mmol) were dissolved in acetonitrile (20 mL) and water (2 mL), cooled to 0 ℃, DIPEA (5.2mL, 30mmol) was added dropwise, the mixture was allowed to naturally rise to room temperature and reacted for 1 hour, the reaction solution was filtered, the filter cake was washed with acetonitrile (2 mL. Times.4), the filter cake was collected, and dried to obtain the title compound, lithium 4, 6-dichloropyridazine-3-carboxylate (1.73g, 87%).

MS m/z(ESI):191.1[M-Li] ^- .

Sixth step preparation of Zinc 6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylate

3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyaniline (100mg, 0.4 mmol), lithium 4, 6-dichloropyridazine-3-carboxylate (103.7 mg,0.5 mmol) and zinc acetate (95.6 mg,0.5 mmol) were mixed with isopropanol (0.5 mL) and water (3.5 mL), and the mixture was heated to 80 ℃ for reaction overnight. The reaction was cooled to room temperature, water (3 mL) was added, stirring was carried out for 1H, the reaction was filtered, the filter cake was washed with water (3 mL. Times.2) and THF (2 mL), and the filter cake was collected and dried to give the title compound, zinc 6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylate (130mg, 78%).

MS m/z(ESI):387.1[M+H] ⁺ .

Seventh step preparation of Zinc 6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylate

6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylic acid zinc (130mg, 0.31mmol), cyclopropylamide (86mg, 1.0mmol), DBU (61mg, 0.4mmol), potassium carbonate (110mg, 0.8mmol) were mixed in toluene (1.2 mL) and acetonitrile (0.6 mL), and palladium acetate (4.5mg, 0.02mmol) and (R) - (-) -1- [ (S) -2- (dicyclohexylphosphine) ferrocene were added]Ethyl di-tert-butylphosphine (22mg, 0.04mmol), the reaction system was replaced with nitrogen three times, and the reaction was heated to 75 ℃ for overnight reaction. The reaction was cooled to room temperature, water (4 mL) and acetic acid (2 mL) were added, washing was with petroleum ether (6 mL. Times.2), the aqueous phase was separated, and water (2 mL), CH, was added to the aqueous phase ₂ Cl ₂ (5 mL. Times.3) and the organic phases were combined, washed with saturated aqueous NaCl solution, the separated organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to give the title compound, zinc 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylate (109mg, 75%).

MS m/z(ESI):436.1[M+H] ⁺ .

Eighth step preparation of 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylic acid zinc (90mg, 0.19mmol), deuterated methylamine hydrochloride (71mg, 1.0mmol), DIPEA (258mg, 2.0mmol) were mixed in DMF (1 mL), HATU (380mg, 1.0mmol) was added, and the mixture was reacted at 50 ℃ overnight. The reaction was cooled to room temperature and saturated aqueous sodium bicarbonate solution was used with CH ₂ Cl ₂ Separating, washing the organic phase with saturated NaCl aqueous solution, drying with anhydrous sodium sulfate, and concentrating the organic solution under reduced pressurePost-dose column chromatography gave the title compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (35mg, 38%).

¹ H NMR(400MHz,CDCl ₃ )δ0.86-0.99(m,2H),1.07-1.18(m,4H),1.22-1.26(m,2H),1.73-1.82(m,1H),3.65-3.72(m,1H),3.81(s,3H),7.27-7.29(m,1H),7.48-7.52(m,1H),7.81-7.84(m,1H),7.96(s,1H),8.17-8.24(m,2H),9.87(s,1H),11.27(s,1H)；

MS m/z(ESI):452.2[M+H] ⁺ .

Example 2

6- (Cyclopropanecarboxamido) -4- ((5-fluoro-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d ₃ ) Pyridazine-3-carboxamides

6- (Cyclopropanecarboxamido) -4- ((5-fluoro-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d ₃ ) Pyridazine-3-carboxamide may be prepared by following the procedure of example 1.

¹ H NMR(400MHz，CDCl ₃ )δ0.89-0.94(m,2H),1.11-1.15(m,2H),1.78-1.84(m,1H),3.81(s,3H),4.01(s,3H),7.23-7.26(m,1H),7.53-7.56(m,1H),8.04(s,1H),8.11(s,1H),8.30(s,1H),9.73(s,1H),11.17(s,1H)；

MS m/z(ESI):444.2[M+H] ⁺ .

Example 3

6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

First step preparation of 3- (5-fluoro-2-methoxyphenyl) -1H-1,2, 4-triazole

5-fluoro-2-methoxybenzamide (3.5g, 20.7mmol) was dissolved in DMF-DMA (25 mL) and heated to 95 ℃ for 1 hour, after concentration under reduced pressure, the crude DMF-DMA addition product was obtained and dissolved in ethanol (20 mL) for use. After 5 minutes of stirring in ethanol (56 mL), acetic acid (17 mL), hydrazine hydrate (80 wt.%,8.4 mL) was added dropwise and stirring was continued for 15 minutes under ice-bath, then the above ethanol solution of the crude DMF-DMA addition product was added dropwise, slowly warmed to room temperature, and stirring was continued for 4 hours at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (300 mL) and saturated NaHCO ₃ The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound, 3- (5-fluoro-2-methoxyphenyl) -1H-1,2, 4-triazole (3.1g, 77%).

MS m/z(ESI):194.2[M+H] ⁺ .

Second step preparation of 3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole

3- (5-fluoro-2-methoxyphenyl) -1H-1,2, 4-triazole (1.1 g, 5.69mmol) was dissolved in concentrated sulfuric acid (10 mL), and after dropwise addition, nitric acid (68 wt.%,1.05g, 11.39mmol) was added dropwise in ice bath, and after dropwise addition, stirring was continued for 2 hours in ice bath. The reaction mixture was poured into ice water, aqueous ammonia was slowly added dropwise to adjust the pH to about 9, extracted with ethyl acetate, the organic phase was separated and dried, and the organic solvent was concentrated under reduced pressure to give the title compound, crude 3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (1.26 g), which was used directly in the next reaction.

MS m/z(ESI):239.2[M+H] ⁺ .

The third step is the preparation of 1-cyclopropyl-3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole

3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (600mg, 2.52mmol), copper acetate (688mg, 3.8mmol), 2' -bipyridine (590mg, 3.8mmol), sodium carbonate (534mg, 5.0 mmol) were mixed with 1, 2-dichloroethane (5 mL), cyclopropylboronic acid (865mg, 10.0 mmol) was added at room temperature, and the mixture was stirred overnight at 85 ℃. After the reaction solution was cooled to room temperature, it was diluted with a large amount of ethyl acetate. The organic phase was washed with saturated brine several times, then the separated organic phase was dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure and column chromatography was performed to separate the title compound, 1-cyclopropyl-3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (260mg, 38%).

¹ H NMR(400MHz,CDCl ₃ )δ1.16-1.20(m,2H),1.24-1.27(m,2H),3.64-3.73(m,1H),3.94(s,3H),7.52-7.54(m,1H),7.98-8.01(m,1H),8.23(s,1H)；

MS m/z(ESI):279.0[M+H] ⁺ .

The fourth step of preparation of 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyaniline

To a solution of 1-cyclopropyl-3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (260mg, 0.93mmol) in methanol (5 mL) was added palladium/carbon (60 mg), and the mixture was reacted under a hydrogen atmosphere at ordinary temperature and pressure for 8 hours, followed by filtering off the catalyst with celite. The filtrate was concentrated under reduced pressure to give the title compound, 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyaniline (230 mg), which was used directly in the next reaction.

MS m/z(ESI):249.2[M+H] ⁺ .

Fifth step preparation of 6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

To a solution of 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyaniline (230mg, 0.93mmol) and 4, 6-dichloro-N- (methyl-d 3) pyridazine-3-carboxamide (194mg, 0.93mmol) in tetrahydrofuran (8 mL) at room temperature was added dropwise a solution of LiHMDS (1M, 2.78mL, 2.78mmol) in tetrahydrofuran, and the reaction mixture was stirred at room temperature for 2 hours and then quenched with a saturated aqueous ammonium chloride solution. The reaction solution was diluted with methylene chloride, the organic phase was washed with saturated brine for several times, then the organic phase was separated and dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure and then subjected to column chromatography to obtain the title compound 6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazole-3-)

Yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (290mg, 74%).

MS m/z(ESI):421.2[M+H] ⁺ .

Sixth step preparation of 6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (155mg, 0.37mmol), cyclopropylamide (62mg, 0.74mmol), cesium carbonate (360mg, 1.1mmol) were mixed in dioxane (5 mL), tris (dibenzylideneacetone) dipalladium (101mg, 0.11mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (127mg, 0.22mmol) were added, nitrogen was deoxygenated for 5 minutes, and microwave was reacted at 145 ℃ for 2 hours. The reaction solution was diluted with methylene chloride, and the organic phase was washed with saturated brine several times, then the organic phase was separated, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure and column chromatography was performed to give the title compound, 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (116mg, 67%).

¹ H NMR(400MHz,CDCl ₃ )δ0.90-0.95(m,2H),1.11-1.16(m,4H),1.21-1.26(m,2H),1.74-1.80(m,1H),3.65-3.71(m,1H),3.80(s,3H),7.22-7.25(m,1H),7.51-7.54(m,1H),8.03(s,1H),8.19(s,1H),8.29(s,1H),9.59(s,1H),11.21(s,1H)；

MS m/z(ESI):470.2[M+H] ⁺ .

Example 4

6- (Cyclopropanecarboxamido) -4- ((2-methoxy-5-methyl-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

Preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-5-methyl-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.

MS m/z(ESI):440.2[M+H] ⁺ .

Example 5

4- ((3- (1-allyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide

First step preparation of 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole

To a solution of 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (1.00g, 4.54mmol), DMAP (55.0mg, 0.454mmol) and DIPEA (1.05mL, 6.36mmol) in methylene chloride (20 mL) at-20 ℃ was slowly added dropwise a solution of SEM-Cl (0.964mL, 5.45mmol) in methylene chloride (10 mL). After the addition was complete, the temperature was slowly raised to-10 ℃ and stirred at this temperature overnight. The reaction solution was washed with saturated brine, the organic phase was separated and dried, and the organic solvent was concentrated under reduced pressure after filtration to give crude 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole which was used directly in the next reaction.

MS m/z(ESI):351.2[M+H] ⁺ .

Second step preparation of 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline

The above crude product was dissolved in a mixture of ethanol (30 mL) and water (5 mL), followed by addition of ammonium chloride solid (1.60g, 30.0 mmol) and reduced iron powder (1.67g, 30.0 mmol) in this order, stirring at 50 ℃ for 2 hours, cooling the reaction system, filtering off insoluble matter with celite, concentrating the filtrate, dissolving the residue with dichloromethane, washing with saturated brine, separating the organic phase, drying with a drying agent, filtering, concentrating the organic solvent under reduced pressure, and separating by column chromatography to give the title compound, 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline (650 mg, two-step yield: 45%).

MS m/z(ESI):321.2[M+H] ⁺ .

Third step preparation of 6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

To a solution of 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline (640mg, 2.00mmol), 4, 6-dichloro-N- (methyl-d 3) pyridazine-3-carboxamide (417mg, 2.00mmol) in THF (20 mL) at 0 deg.C was added LiHMDS (1M in THF, 5.00mL) dropwise, and after dropwise addition, the mixture was slowly warmed to room temperature and stirred at room temperature for 2 hours. Quenched by addition of saturated brine, extracted twice with DCM, and the organic phases were combined, dried, concentrated under reduced pressure and subjected to column chromatography to give the title compound 6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (780mg, 79%).

MS m/z(ESI):493.2[M+H] ⁺ .

Fourth step preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (850mg, 1.73mmol), cyclopropylamide (372mg, 4.38mmol) and cesium carbonate (2.14g, 6.57mmol) were mixed in 1,4-dioxane (20 mL), the reaction solution was deoxygenated with nitrogen for 5 minutes, and Pd was added successively ₂ (dba) ₃ (400mg, 0.438mmol) and Xantphos (506mg, 0.876mmol). The reaction was heated at 130 ℃ for 90 minutes under nitrogen by microwave, cooled to room temperature, and the organic solvent was concentrated under reduced pressure and then subjected to column chromatography to give the title compound, 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (680mg, 73%).

MS m/z(ESI):542.3[M+H] ⁺ .

Fifth step preparation of 6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

To a solution of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (630mg, 1.16mmol) in DCM at 0 ℃ was added TFA (6.0 mL) and the mixture was stirred at room temperature overnight. The organic solvent was concentrated under reduced pressure the next day, the residue was dissolved in DCM, washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, the organic phase was dried and concentrated under reduced pressure, and column chromatography was performed to isolate the title compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (270mg, 57%).

1H NMR(400MHz,CDCl ₃ )δ0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88(m,1H),3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H)；

MS m/z(ESI):412.2[M+H] ⁺ .

Sixth step preparation of 4- ((3- (1-allyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide

6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (30mg, 0.073mmol), allyl bromide (8.7mg, 0.073mmol) and potassium carbonate (20mg, 0.15mmol) were mixed in MeCN (3 mL) and stirred at 0 ℃ for 2 days. The reaction solution was concentrated under reduced pressure, and column chromatography was performed to isolate the title compound, 4- ((3- (1-allyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylcarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide (12mg, 39%).

¹ H NMR(400MHz,CDCl ₃ )δ0.88-0.92(m,2H),1.10-1.12(m,2H),1.80-1.85(m,1H),3.80(s,3H),4.86-4.88(m,2H),5.35-5.38(m,2H),6.03-6.11(m,1H),7.27-7.31(m,1H),7.52(d,J＝8.0Hz,1H),7.80(d,J＝8.0Hz,1H),8.03(s,1H),8.15(s,1H),8.24(s,1H),9.88(br s,1H),11.05(s,1H)；

MS m/z(ESI):452.2[M+H] ⁺ .

Example 6

6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

MS m/z(ESI):351.2[M+H] ⁺ .

MS m/z(ESI):321.2[M+H] ⁺ .

MS m/z(ESI):493.2[M+H] ⁺ .

6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (850mg, 1.73mmol), cyclopropylamide (372mg, 4.38mmol) and cesium carbonate (2.14g, 6.57mmol) were mixed in 1,4-dioxane (20 mL), the reaction solution was deoxygenated with nitrogen for 5 minutes, and Pd was added successively ₂ (dba) ₃ (400mg, 0.438mmol) and Xantphos (506mg, 0.876mmol). The reaction was heated at 130 ℃ for 90 minutes under a nitrogen atmosphere by a microwave, cooled to room temperature, concentrated under reduced pressure and then subjected to column chromatography to give the title compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (680mg, 73%).

MS m/z(ESI):542.3[M+H] ⁺ .

To a solution of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (630mg, 1.16mmol) in DCM (20 mL) was added TFA (6.0 mL) at 0 ℃ and the mixture was stirred at room temperature overnight. The organic solvent was concentrated under reduced pressure the next day, the residue was dissolved in DCM, washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, the organic phase was dried and concentrated under reduced pressure, and column chromatography was performed to isolate the title compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (270mg, 57%).

¹ H NMR(400MHz,CDCl ₃ )δ0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88(m,1H),3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H)；

MS m/z(ESI):412.2[M+H] ⁺ .

Sixth step preparation of 6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (30mg, 0.073mmol), bromopropyne (8.7mg, 0.073mmol) and potassium carbonate (20mg, 0.15mmol) were mixed in MeCN (3 mL) and stirred at 0 ℃ for 2 days. The reaction mixture was concentrated under reduced pressure, and column chromatography was performed to isolate the title compound, 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (10mg, 31%).

¹ H NMR(400MHz,CDCl ₃ )δ0.88-0.93(m,2H),1.10-1.14(m,2H),1.75-1.82(m,1H),2.62(s,1H),3.81(s,3H),5.07(s,2H),7.26-7.30(m,1H),7.52(d,J＝8.0Hz,1H),7.82(d,J＝8.0Hz,1H),8.00(s,1H),8.23(s,1H),8.38(s,1H),9.88(br s,1H),11.13(s,1H)；

MS m/z(ESI):450.2[M+H] ⁺ .

Example 7

6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (3-methyloxetan-3-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

Preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (3-methyloxetan-3-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.

¹ H NMR(400MHz,CDCl ₃ )δ0.91-0.93(m,2H),1.08-1.13(m,2H),1.72-1.75(m,1H),2.07(s,3H),3.86(s,3H),4.71(d,J＝6.6Hz,2H),5.25(d,J＝6.4Hz,2H),7.28-7.30(m,1H),7.52-7.55(m,1H),7.82-7.85(m,1H)8.05(s,1H),8.23-8.25(m,2H),9.31(s,1H),11.16(s,1H)；

MS m/z(ESI):482.2[M+H] ⁺ .

Example 8

6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (oxetan-3-ylmethyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

Preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (oxetan-3-ylmethyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 6.

¹ H NMR(400MHz,CDCl ₃ )δ0.91-0.94(m,2H),1.08-1.14(m,2H),3.55-3.62(m,1H),3.81(s,3H),4.54-4.59(m,4H),4.80-4.90(m,2H),7.27-7.29(m,1H),7.50-7.52(m,1H),7.80-7.82(m,1H),8.06(s,1H),8.13(s,1H),8.20(s,1H),9.14(s,1H),11.09(s,1H)；

MS m/z(ESI):482.2[M+H] ⁺ .

Example 9

6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

To a solution of 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (1.00g, 4.54mmol), DMAP (55.0 mg, 0.454mmol) and DIPEA (1.05mL, 6.36mmol) in dichloromethane (20 mL) at-20 ℃ was slowly added dropwise a solution of SEM-Cl (0.964mL, 5.45mmol) in dichloromethane (10 mL). After the addition was complete, the temperature was slowly raised to-10 ℃ and stirred at this temperature overnight. The reaction solution was washed with saturated brine, the organic phase was separated and dried, and the organic solvent was concentrated under reduced pressure after filtration to give crude 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole which was used directly in the next reaction.

MS m/z(ESI):351.2[M+H] ⁺ .

MS m/z(ESI):321.2[M+H] ⁺ .

MS m/z(ESI):493.2[M+H] ⁺ .

6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N-(methyl-d 3) pyridazine-3-carboxamide (850mg, 1.73mmol), cyclopropylamide (372mg, 4.38mmol) and cesium carbonate (2.14g, 6.57mmol) were mixed in 1,4-dioxane (20 mL), the reaction solution was purged with nitrogen for 5 minutes, and Pd was sequentially added thereto ₂ (dba) ₃ (400mg, 0.438mmol) and Xantphos (506mg, 0.876mmol). The reaction was carried out under nitrogen at 130 ℃ for 90 minutes by microwave, cooled to room temperature, and the organic solvent was concentrated under reduced pressure and then subjected to column chromatography to give the title compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (680mg, 73%).

MS m/z(ESI):542.3[M+H] ⁺ .

To a solution of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (630mg, 1.16mmol) in DCM at 0 ℃ was added TFA (6.0 mL) and the mixture was stirred at room temperature overnight. The organic solvent was concentrated under reduced pressure the next day, the residue was dissolved in DCM, washed with saturated aqueous sodium bicarbonate and saturated brine in this order, the organic phase was dried and concentrated under reduced pressure, and column chromatography was performed to give the title compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (270mg, 57%).

MS m/z(ESI):412.2[M+H] ⁺ .

Example 10

6- (Cyclopropanecarboxamido) -4- ((5-fluoro-2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

Preparation of 6- (cyclopropylcarboxamido) -4- ((5-fluoro-2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 6.

¹ H NMR(400MHz,DMSO-d ₆ )δ0.84-0.87(m,2H),1.23-1.34(m,2H),2.09-2.12(m,1H),3.60(s,1H),3.75(s,3H),5.24(s,2H),7.39-7.47(m,2H),8.26(s,1H),8.72(s,1H),9.19(s,1H),11.20(s,1H),11.41(s,1H)；

MS m/z(ESI):468.2[M+H] ⁺ .

Example 11

6- (Cyclopropanecarboxamido) -4- ((3- (1- (cyclopropylmethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

Preparation of 6- (cyclopropylcarboxamido) -4- ((3- (1- (cyclopropylmethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 6.

¹ H NMR(400MHz,CDCl ₃ )δ0.44-0.48(m,2H),0.70-0.76(m,2H),0.86-0.93(m,2H),1.08-1.11(m,2H),1.33-1.40(m,1H),1.82-1.89(m,1H),3.82(s,3H),4.10(d,J＝7.2Hz,2H),7.25-7.30(m,1H),7.50-7.54(m,1H),7.80-7.83(m,1H),8.02(s,1H),8.23-8.25(m,2H),9.98(s,1H),11.04(s,1H)；

MS m/z(ESI):466.2[M+H] ⁺ .

2. Compound biological assay evaluation

The present invention is further described and explained below in connection with test examples, which are not intended to limit the scope of the present invention.

Test example 1 determination of the inhibitory Effect of Compounds of the examples of the present invention on the cellular TYK2 Signal pathway

The purpose of the experiment is as follows: the purpose of this test example was to test the activity of the compounds of the examples on inhibition of the cellular TYK2 signaling pathway.

An experimental instrument:

centrifuge (5702R) was purchased from Eppendorf corporation,

pipettes were purchased from the Eppendorf company,

the microplate reader is purchased from BioTek company of America, and is a SynergyH1 full-function microplate reader.

The experimental method comprises the following steps: this experiment adopts the U266 cell line that expresses TYK2, stimulates activation TYK2 signal path through INF-alpha, detects the inhibitory activity of compound to its low reaches STAT3 phosphorylation to obtain half inhibitory concentration IC of compound to TYK2 signal path activity ₅₀ 。

The specific experimental operation is as follows:

3-12 mu L of U266 fine particles are paved in a 384-well detection plate, the number of cells in each well is 100-300K, 2 mu L of compound solution diluted in a gradient way is added, and the mixture is incubated for 2 hours in a carbon dioxide incubator. After 2 hours, 2. Mu.L of INF-alpha was added thereto, and the final INF-alpha concentration was 1000U/mL, followed by shaking at room temperature for 20min. Add 2-5. Mu.L (5X) of LANCE Ultra Lysis Buffer 2 solution and shake at room temperature for 2h. After 2h 5. Mu.L of LANCE Ultra Eu-labeled Anti-STAT5 (Y694/Y699) Anti body (Perkinelmer) solution at a final concentration of 2nM and LANCE Ultra ULight-labeled Anti-STAT5 Anti body (Perkinelmer) solution at a final concentration of 20nM were added and incubated overnight at room temperature. Measuring 665nm fluorescence signal value of each plate hole by a microplate reader, calculating inhibition rate through the fluorescence signal value, and obtaining IC of the compound through curve fitting according to the inhibition rates of different concentrations ₅₀ 。

The experimental data processing method comprises the following steps:

percent inhibition data {% inhibition =100- [ (assay) for wells treated with compound was calculated by counting the percent inhibition data from positive control wells (DMSO control wells) and negative control wells (no cells) on the plateTest compound value-negative control value)]/(positive control value-negative control value) × 100}. IC was calculated using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula ₅₀ The value is obtained.

The experimental conclusion is that:

the above protocol yields the data for the activity assay of the compounds of the examples of the invention in inhibiting the cellular TYK2 signaling pathway as shown in the following table:

compound numbering	Cell Activity U266 pSTAT3 (nM)
Example 1	1.41
Example 2	2.43
Example 3	0.83
Example 4	4.95
Example 5	0.34
Example 6	0.13
Example 7	0.90
Example 8	1.88
Example 9	4.60
Example 10	2.10
Example 11	3.43

Test example 2 measurement of inhibitory Effect of Compounds according to examples of the present invention on cellular JAK2 Signal pathway

Purpose of the experiment: the purpose of this test example was to test the activity of compounds of the present example on inhibition of the cellular JAK2 signaling pathway.

An experimental instrument:

centrifuge (5702R) was purchased from Eppendorf corporation,

pipettes were purchased from the Eppendorf company,

The experimental method comprises the following steps: the experiment adopts TF-1 cell line, stimulates and activates JAK2 signal channel through IL6, detects the inhibition activity of the compound to the downstream STAT3 phosphorylation, and obtains the half inhibition concentration IC of the compound to the JAK2 signal channel activity ₅₀ 。

The specific experimental operation is as follows:

spreading TF-1 cells 3-12 μ L in each well with cell number of 100-300K in 384-well test plate, adding 2 μ L of compound solution diluted in gradient, and incubating in carbon dioxide incubator for 2 hr. After 2 hours, 2. Mu.L of IL6 was added, with a final IL6 concentration of 30ng/mL, and shaken at room temperature for 20min. Add 2-5. Mu.L (5X) of LANCE Ultra Lysis Buffer 2 solution and shake at 4 ℃ for 2h.2h later 5. Mu.L of Lance Ultra Eu-labeled Anti-STAT3 (Tyr 705) Antibody (PerkinElmer) at a final concentration of 2nM and Lance Ultra high-labeled Anti-STAT3 at a final concentration of 20nMThe Antibody (PerkinElmer) solution was incubated overnight at room temperature. Measuring 665nm fluorescence signal value of each plate hole by a microplate reader, calculating inhibition rate through the fluorescence signal value, and obtaining IC of the compound through curve fitting according to the inhibition rates of different concentrations ₅₀ 。

The experimental data processing method comprises the following steps:

percent inhibition data {% inhibition =100- [ (test compound value-negative control value) for wells treated with compound was calculated by plating positive control wells (DMSO control wells) and negative control wells (no cells) on the plate]V (positive control value-negative control value) × 100}. IC was calculated using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula ₅₀ The value is obtained.

The experimental conclusion is that:

the activity test data of the compounds shown in the examples of the present invention in inhibiting the cellular JAK2 signaling pathway are shown in the following table:

the experimental conclusion is that: as can be seen from the data in the table, the example compounds are more selective for JAK2 cellular activity compared to TYK2 cellular activity.

Test example 3 plasma protein binding Rate test in mice

1. The research purpose is as follows:

the purpose of this experiment was to evaluate the protein binding rate of the compound of example (5. Mu.M) in mouse plasma by equilibrium dialysis.

2. Compounds and experimental materials:

1) Test compounds were formulated as 10mM stock solutions in DMSO and stored at-20 ℃ in a refrigerator for use;

2) Frozen plasma of the desired species, dialysate (100 mM phosphate buffer (Lot # SLBS7904 and Lot # SLBR 3106V), pH 7.4).

3. Laboratory apparatus

The kit comprises a 96-pore plate (Lot # 07917415), a detection membrane device (Lot # SD 2369421), a liquid chromatography combined tandem mass spectrometer (LC-MS/MS) (LC-20AD, API4000), a centrifuge (Eppendorf 5804R/5424R), a VORTEX instrument (IKA VORTEX GENIUS 3), a liquid-transfering gun (Eppendorf 10-100 mu L (PIP-100-002), eppendorf 100-1000 mu L (PIP-1000-002), RAININ 0.5-10 mu L (PIP-10-002)), and a water bath kettle (Shanghai Hengke).

4. Experimental procedure

4.1 preparation of the dialysate

1M of K2HPO4 (AR grade) 4.01mL and 1M of KH2PO4 (AR grade) 0.99mL were diluted with ultrapure water to 50mL to prepare 100mM phosphate buffer (pH = 7.4) as a dialysate.

4.2 preparation of plasma

The frozen plasma was thawed in a water bath at room temperature or 37 ℃, centrifuged at 3500rpm for 5min, and the supernatant was collected.

4.3 preparation of reaction stop solution

Acetonitrile (or other suitable solution) containing the internal standard was used as a stop solution and stored in a refrigerator at 2-8 ℃ and the specific concentration of the internal standard was reported at the end.

4.4 preparation of working solution of Compound

Preparing a working solution of the compound: stock solutions were diluted to a final concentration of 1mM in DMSO.

4.5 preparation of plasma solution

Add 4. Mu.L of compound working solution into 796. Mu.L of blank plasma with a final concentration of 5. Mu.M, shake and mix.

4.6 equilibrium dialysis

1) Preparing a balance dialysis device, and putting the detection membrane device into a balance dialysis 96-well plate;

2) Adding 200 μ L of the prepared plasma solution into the membrane, n =2;

3) Taking another 4 mu L of plasma solution, diluting the plasma solution by 10 times by using 36 mu L of blank plasma of the same species, adding 160 mu L of acetonitrile stop solution containing an internal standard, and storing the solution in a refrigerator at the temperature of 20 ℃ below zero to obtain a T0 (Total) sample;

4) Add 350 μ L dialysate (100 mM phosphate buffer) outside the membrane;

5) Sealing the dialysis plate, and putting the dialysis plate into a water bath kettle at the temperature of 37 ℃ for incubation for 6 hours;

6) After dialysis, 4 μ L of each sample was removed from the intramembrane wells and diluted 10-fold with 36 μ L of blank plasma of the same species; respectively taking out 40 mu L of dialysate from the sample hole outside the membrane, and adding 160 mu L of acetonitrile stop solution with an internal standard to obtain a T6 (Total) sample and an F6 (Total) sample;

7) Centrifuging T0 (Total) and T6 (Total) samples and taking supernate;

8) LC-MS analysis.

5. Results of the experiment

Test example 4 pharmacokinetic assay of Balb/C mice

1. The research aims are as follows:

Balb/C mice were used as test animals to study the pharmacokinetic behavior of compounds of the example compounds administered orally at a dose of 5mg/kg in plasma in mice.

2. Test protocol

2.1 test drugs:

the compound of the embodiment of the invention is prepared by self.

Drug formulation 0.5% CMC-Na (1% Tweenen 80), homemade.

2.2 test animals:

Balb/C Mouse (6/example), male, shanghai Jie Si laboratory animals Ltd, animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).

2.3 administration:

Balb/C mice 18, male; p.o. after fasting overnight, respectively, 0.5% CMC-Na (1% Tween 80) dosage of 5mg/kg, administration volume 10mL/kg.

2.4 sample collection:

before and after administration, at 0, 0.5, 1,2,4, 6, 8 and 24 hours, the mice were bled by orbital bleeding 0.1mL, and placed in EDTA-K ₂ The plasma was separated by centrifugation at 6000rpm for 6min at 4 ℃ in a test tube and stored at-80 ℃.

2.5 sample treatment:

1) Plasma samples 40. Mu.L were precipitated by addition of 160. Mu.L acetonitrile, mixed and centrifuged at 3500 Xg for 5-20 minutes.

2) Taking 100 mu L of the treated supernatant solution for LC/MS/MS analysis to analyze the concentration of the compound to be detected.

2.6 liquid phase analysis

● Liquid phase conditions: shimadzu LC-20AD pump

● Mass spectrum conditions AB Sciex API4000 mass spectrometer

● A chromatographic column: phenomenex Gemiu 5um C18X 4.6mm

● Mobile phase: the solution A is 0.1% formic acid aqueous solution, and the solution B is acetonitrile

● Flow rate: 0.8mL/min

● Elution time: 0-4.0 min, the eluent is as follows:

3. test results and analysis

The main pharmacokinetic parameters were calculated with WinNonlin 6.1, and the results of the mouse pharmacokinetic experiments are shown in the following table:

compound (I)	t _max (h)	C _max (ng/mL)	AUC _0-t (ng/mL*h)	AUC _0-∞ (ng/mL*h)	t _1/2 (h)	MRT _0-∞ (h)
BMS-986165	1.0	696	1987	2038	1.4	2.3
Example 1	0.5	3930	13590	14473	1.9	3.0
Example 2	0.5	2043	6250	6348	1.3	2.3
Example 3	1.0	2190	20991	21001	2.1	5.6
Example 6	1.0	939	2466	2637	2.0	2.8

And (4) experimental conclusion: as can be seen from the data in the table, the AUC of the drug-induced exposure of the example compounds in mice _0-t (ng/mL. Times.h) was superior to reference compound BMS-986165.

Test example 5 Balb/C mice different dose pharmacokinetics

1. The research purpose is as follows:

Balb/C mice were used as test animals to study the pharmacokinetic behavior of plasma in mice administered orally at different doses with the compound example 1 and the reference compound BMS-986165.

2. Test protocol

2.1 test drugs

The compound of the embodiment of the invention is prepared by self.

CMC-Na,Sigma-C9481-500G。

Drug formulation 0.5% CMC-Na (1% Tweenen 80), homemade.

2.2 test animals

Balb/C Mouse, male, shanghai Jitsie laboratory animals Ltd, animal production license number (SCXK (Shanghai) 2013-0006N0.311400001794).

2.3 administration of drugs

Balb/C mice (3 per group), male; p.o. after fasting overnight, respectively, the CMC-Na (1% Tween 80) dosage was 1mg/kg,3mg/kg,10mg/kg, respectively, the administration volume was 10mL/kg, 0.5% of the pharmaceutical formulation.

2.4 sample collection:

mice were bled periorbital and post-dose at 0, 0.5, 1,2,4, 6, 8 and 24 hours0.1mL, placed in EDTA-K ₂ The plasma was separated by centrifugation at 6000rpm for 6min at 4 ℃ in a test tube and stored at-80 ℃.

2.5 sample treatment:

3) Plasma samples 40. Mu.L were precipitated by addition of 160. Mu.L acetonitrile, mixed and centrifuged at 3500 Xg for 5-20 minutes.

4) Taking 100 mu L of the treated supernatant solution for LC/MS/MS analysis to determine the concentration of the compound to be detected.

2.6 liquid phase analysis

● Liquid phase conditions: shimadzu LC-20AD pump

● Mass spectrum condition AB Sciex API4000 mass spectrometer

● A chromatographic column: phenomenex Gemiu 5um C18X 4.6mm

● Mobile phase: the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile

● Flow rate: 0.8mL/min

● Elution time: 0-4.0 min, eluent as follows:

3. test results and analysis

The results of the mouse pharmacokinetic experiments with different doses of example 1 and the reference compound BMS-986165 are shown in the following table:

and (4) experimental conclusion: as can be seen from the data in the table, AUC of the drug-induced exposure amount in mice in example 1 _0-t (ng/mL h) showed dose-dependence, which was superior to the reference compound BMS-986165 at the same dose.

Test example 6 determination of the efficacy of compounds of the present example on imiquimod-induced psoriasis-like model in mice at different doses

1. Purpose of experiment

Compounds were evaluated for efficacy at different doses in an imiquimod-induced psoriasis-like model in mice.

2. Main experimental instrument and reagent

2.1 instruments

Name of instrument and equipment	Model number	Manufacturer of the product
Electronic balance	SQP type SECURA225D-1CN	Sartorius
Electronic balance	MP5002 type	Constant flow of Shunhu Shanghai

2.2 reagents

Name (R)	Batch number	Brand/goods number
Imiquimod Cream	GTH110C	Aldara
CMC-Na	SLBV9664	C9481-500G

3. Experimental procedure

3.1 Molding

Day 0 animals were shaved on the back test sites. Day 1-Day 6 were applied to the test sites on the backs of the animals with 62.5mg of imiquimod once a Day.

3.2 administration of drugs

Day 1-Day 7 were administered to each group of animals according to the protocol, and the experimental design of the imiquimod-induced psoriasis-like model in mice is shown in the following table:

the prescription of the medicine is as follows: 0.5% of CMC-Na (1% of Tween 80)

3.3 dermatitis severity index score

The redness, scaling and thickening of the animal back test sites were scored on a scale of 0-4 for Day 1-Day 7, respectively. 0, no damage; 1, slight; 2, moderate; 3, apparent; 4, very clearly. The total score indicates the severity of the injury

3.4 PASI-time was plotted and the area under the curve AUC was calculated. The change in the PASI score AUC (total profile) was proportional% = (dosing group AUC-model group AUC)/model group AUC × 100%.

4. Test data

4.1 comparison of PASI scores in the imiquimod-induced mouse psoriasis model at different doses of compound the results are given in the following table:

4.2 results of PASI scores in imiquimod-induced mouse psoriasis models at different doses of compound are shown in figure 18, where data points represent the mean of the AUC of the PASI score-time curve in the group, N =8, p <0.001 compared to the Vehicle group using One-way ANOVA.

5. Results of the experiment

From the above results, it can be seen that example 1 of the present invention is effective in improving psoriasis symptoms in an imiquimod-induced psoriasis-like model in mice, with very significant differences compared to the Vehicle group, with P <0.001, and example 1 at a 1mg/kg dose, achieves comparable improvement in psoriasis symptoms as the reference compound BMS-986165 at a 3mg/kg dose.

3. Study of Crystal forms

1. Laboratory apparatus

1.1 some parameters of the physicochemical measuring instrument

2. Preparation of the crystalline form

2.1 preparation of the Compound of example 1 6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide in different crystalline forms

Preparation of form A

6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (10.0 g) was added to a 250ml reaction flask, and N-methylpyrrolidone (3V, 30ml) was added thereto and the reaction mixture was heated to 95 ℃ to be in a brown clear state. Dropwise adding isopropanol (6V, 60ml), keeping the temperature and stirring for 1 hour after the dropwise adding is finished, then closing the heating, naturally cooling to room temperature, and precipitating a large amount of solid. Cooled in an ice bath, stirred for 1 hour, filtered and the solid washed with isopropanol (10 ml) to give, after drying, 8.1g of a yellow solid which, upon detection analysis, has an XRPD pattern as shown in figure 1, a DSC pattern as shown in figure 2 and a TGA pattern as shown in figure 3.

Preparation of form B

6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (2.0 g) was added to a 100ml reaction flask, ethyl acetate (1.25V, 2.5ml) and N-heptane (12.5V, 25ml) were added, and the mixture was stirred and slurried at room temperature for 24 hours. Filtration and washing of the solid with n-heptane (5 ml) gave, after drying, 1.9g of a yellow solid which, upon detection and analysis, had the XRPD pattern shown in figure 4, the DSC pattern shown in figure 5 and the TGA pattern shown in figure 6.

Preparation of form C

Weighing 20mg of 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide into a 2ml glass bottle, adding 700 mu l of dichloromethane, dissolving at room temperature, slowly adding 800 mu l of isopropyl ether at 37 ℃, separating out solids in the process of adding the isopropyl ether, stirring for 2 hours at 37 ℃, centrifuging, removing supernatant, drying the remaining solids in a 50 ℃ vacuum drying oven to constant weight to obtain crystal form C, and detecting and analyzing the crystal form C to have an XRPD pattern shown in figure 7, a DSC pattern shown in figure 8 and a TGA pattern shown in figure 9.

2.2 example preparation of different crystalline forms of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

Preparation of form A

10mg of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide were weighed into a 2ml glass bottle, and 100. Mu.L of toluene was added and stirred at 50 ℃ for 5 days. Centrifuging, removing a supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain the 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide crystalline form A, which has an XRPD pattern as shown in figure 10, a DSC pattern as shown in figure 11, and a TGA pattern as shown in figure 12.

Preparation of form B

10mg of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide free base was weighed into a 2ml glass vial, and 100. Mu.L of acetone was added and stirred at 50 ℃ for 5 days. Centrifuging, removing the supernatant, and drying the remaining solid in a vacuum drying oven at 50 ℃ to constant weight to obtain 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide free base crystalline form B, which has an XRPD pattern as shown in figure 13, a DSC pattern as shown in figure 14 and a TGA pattern as shown in figure 15.

Preparation of form C

10mg of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide free base was weighed into a 2ml glass vial, and 100. Mu.L of acetonitrile was added and stirred at 50 ℃ for 5 days. Centrifuging, removing the supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide free base crystalline form C with an XRPD pattern as shown in figure 16 and a DSC pattern as shown in figure 17.

3. Solid stability test

3.1 solid stability test of Compound 6- (Cyclopropanecarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

3.1.1 Experimental purposes:

the physicochemical stability of the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide crystal form A and crystal form B under the conditions of high temperature, high humidity, high temperature and high humidity and illumination is investigated, and a basis is provided for crystal form screening and compound storage.

3.1.2 Instrument and conditions for liquid phase analysis

Apparatus and equipment:

name of instrument	Model number
Analytical balance	Sartorius BSA224S-CW
Water purifier	Milli-Q Plus，Millipore

High performance liquid chromatograph	Agilent1260
Pump	Agilent G1311B
Sample injector	G1329B
Column oven	G1316A
Detector	G1315D

Chromatographic conditions are as follows:

a chromatographic column: ZORBAX (SB-C8, 3.5 μm, 4.6X 75mm)

Flow rate: 1mL/min

Column temperature: 30 deg.C

Detection wavelength: 240nm

Sample injection volume: 5.0 μ L

Operating time: 20min

Diluent (b): DMSO (dimethylsulfoxide)

Mobile phase: a: water (0.05% trifluoroacetic acid); b: acetonitrile (0.05% trifluoroacetic acid)

T(min)	A(％)	B(％)
0.00	90	10
17.00	10	90
17.01	90	10
20.00	90	10

3.1.3 protocol:

taking about 2mg of each of the crystal form A and the crystal form B of the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide, 10 days and 20 days were examined in a 60 ℃,95% RH,50 ℃,75% RH and a light box (5000 lx. + -. 500 lx), the content was measured by HPLC, external standard method, and the change of the relevant substance was calculated by using a chromatographic peak area normalization method.

3.1.4 results of the experiment:

3.2 Compound 6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide solid stability experiment

3.2.1 Experimental purposes:

the physicochemical stability of the compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yne-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide crystal form A under the conditions of high temperature, high humidity, high temperature and high humidity and illumination is investigated, and a basis is provided for crystal form screening and compound storage.

3.2.2 Instrument and conditions for liquid phase analysis

Apparatus and equipment:

name of instrument	Type number
Analytical balance	Sartorius BSA224S-CW
Water purifier	Milli-Q Plus，Millipore
High performance liquid chromatograph	Thermo U3000
Pump	LPG-3400SDN
Sample injector	WPS-3000TSL
Column oven	TCC-3000SD
Detector	DAD-3000

Chromatographic conditions are as follows:

a chromatographic column: waters Xbridge C18 (4.6 mm 150mm,3.5 μm)

Flow rate: 1mL/min

Column temperature: 35 deg.C

Detection wavelength: 252nm

Sample injection volume: 10.0 μ L

Operating time: 13min

Diluent (b): ACN-Water (v/v, 1

Mobile phase: a:50mM phosphate buffer (pH 2.0); b: methanol

T(min)	A(％)	B(％)
0.00	85.0	15.0
7.00	30.0	70.0
10.00	30.0	70.0
10.01	85.0	15.0
13.00	85.0	15.0

3.2.3 protocol:

taking 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide crystal form A2 mg, observing for 10 days in a 60 ℃,95% RH,50 ℃ 75% RH and a light box (5000 lx +/-500 lx), determining the content by HPLC, external standard method, and calculating the change of related substances by using a chromatographic peak area normalization method.

3.2.4 results of the experiment:

3.2.5 conclusion of the experiment:

form A is stable at 60 deg.C, 95% RH,50 deg.C, 75% RH, slightly degraded under light (5000 lx + -500 lx), and solved by coating and packaging in dark at later stage, and the stability of form A crystal meets the requirement of later development.

4. Dynamic hygroscopicity test

4.1 hygroscopicity assay of the Compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

4.1.1 Experimental purposes:

and (3) investigating the hygroscopicity of the crystal form A and the crystal form B of the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide under different relative humidity conditions, and providing a basis for screening and storing the crystal form of the compound.

4.1.2 protocol:

putting crystal form A and crystal form B of a compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide into saturated water vapor with different relative humidity, so that the compound and the water vapor reach dynamic equilibrium, and calculating the percentage of hygroscopic weight gain of the compound after equilibrium.

4.1.3 dynamic moisture-leading test results of the crystal form A:

4.1.4 dynamic moisture-wicking test results for form B:

4.1.5 conclusion of the experiment:

the moisture absorption weight gain of the crystal form A and the crystal form B under the condition of RH80 percent is about 0.721 percent and 0.192 percent respectively, and the crystal form A and the crystal form B are slightly hygroscopic.

4.2 test of hygroscopicity of the Compound 6- (Cyclopropanecarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

4.2.1 Experimental purposes:

and (3) investigating the hygroscopicity of the compound crystal form A under different relative humidity conditions, and providing a basis for screening and storing the compound crystal form.

4.2.2 Experimental protocol:

and (3) placing the crystal form A of the compound in saturated water vapor with different relative humidity to enable the compound and the water vapor to reach dynamic balance, and calculating the percentage of moisture absorption weight gain of the compound after the balance.

4.2.3 results of the experiment:

4.2.4 conclusion of the experiment:

the crystal form A has the moisture absorption weight gain of about 0.168 percent under the condition of RH80 percent and is slightly hygroscopic.

5. Solubility experiments in different media

5.1 solubility experiments in different media of the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxybenzyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

5.1.1 Experimental purposes:

the solubility of the crystal form A and the crystal form B of the compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide in media such as water, artificial Simulated Gastric Fluid (SGF), fasted artificial simulated intestinal fluid (FaSSIF) and non-fasted artificial simulated intestinal fluid (FeSSIF) is compared, and a basis is provided for the evaluation of drugability.

5.1.2 Instrument and conditions for liquid phase analysis

Apparatus and equipment:

name of instrument	Type number
Analytical balance	Sartorius BSA224S-CW
Water purifier	Milli-Q Plus，Millipore
High performance liquid chromatograph	Agilent1260
Pump and method of operating the same	Agilent G1311B
Sample injector	G1329B
Column oven	G1316A
Detector	G1315D

Chromatographic conditions are as follows:

a chromatographic column: ZORBAX (SB-C8, 3.5 μm, 4.6X 75mm)

Flow rate: 1mL/min

Column temperature: 30 deg.C

Detection wavelength: 240nm

Sample injection volume: 5.0. Mu.L

Operating time: 20min

Diluent (b): DMSO (dimethylsulfoxide)

T(min)	A(％)	B(％)
0.00	90	10
17.00	10	90
17.01	90	10
20.00	90	10

5.1.3 protocol:

suspending crystal form A and crystal form B of a compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide each 2mg in different media for 24 hours, and determining the thermodynamic solubility of the compound at 37 ℃ by using HPLC (high performance liquid chromatography) and an external standard method.

5.1.4 results of the experiment:

sample name	Solubility of form A (mg/mL)	Solubility of form B (mg/mL)
FaSSIF	0.008	0.006
FeSSIF	0.084	0.076
SGF	0.382	0.469
Water (I)	0.002	0.001

Solubility experiments in different media for the compound 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide

5.2.1 Experimental purposes:

the solubility of the free base crystal form A in media such as water, artificial Simulated Gastric Fluid (SGF), fasting artificial simulated intestinal fluid (FaSSIF), non-fasting artificial simulated intestinal fluid (FeSSIF) and the like is compared, and a basis is provided for evaluation of drugability.

5.2.2 Instrument and conditions for liquid phase analysis

Instruments and equipment:

name of instrument	Model number
Analytical balance	Sartorius BSA224S-CW
Water purifier	Milli-Q Plus，Millipore
High performance liquid chromatograph	Thermo U3000
Pump	LPG-3400SDN
Sample injector	WPS-3000TSL
Column oven	TCC-3000SD
Detector	DAD-3000

Chromatographic conditions are as follows:

a chromatographic column: waters Xbridge C18 (4.6 mm 150mm,3.5 μm)

Flow rate: 1mL/min

Column temperature: 35 deg.C

Detection wavelength: 252nm

Sample introduction volume: 10.0. Mu.L

Operating time: 13min

Diluent agent: ACN-Water (v/v, 1

Mobile phase: a:50mM phosphate buffer (pH 2.0); b: methanol

T(min)	A(％)	B(％)
0.00	85.0	15.0
7.00	30.0	70.0
10.00	30.0	70.0
10.01	85.0	15.0

13.00

85.0

15.0

5.2.3 protocol:

approximately 2mg of compound free base form a was suspended in various media for 24 hours and thermodynamic solubility of compound at 37 ℃ was determined by HPLC, external standard method.

5.2.4 Experimental results:

sample name	Solubility of Crystal form A (mg/mL)
FaSSIF	0.007
FeSSIF	0.030
SGF	0.269
Water (I)	<0.001

6. Thermodynamic stability test

6.1 polycrystal screening and thermodynamically stable crystal form confirmation experiment of compound 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-formamide

6.1.1 Experimental purposes:

obtaining thermodynamically stable crystal form by polycrystalline screening

6.1.2 Experimental protocol:

weighing 10mg of each of the crystal form A and the crystal form B, placing the crystal form A and the crystal form B in a 2ml glass bottle, respectively adding 200 acetonitrile, ethyl acetate, ethanol, isopropanol, methyl tert-butyl ether or toluene, stirring for 7 days at 40 ℃, quickly centrifuging, removing supernatant, drying solid precipitates in a 40 ℃ oven in vacuum, and then performing XRPD characterization.

6.1.3 results of the experiment:

pulping, changing crystallization solvent, crystallizing and the like to obtain three crystal forms, namely a crystal form A, a crystal form B and a crystal form C. The crystal form A can be converted into a crystal form B under the mediated condition of acetonitrile, ethyl acetate, ethanol, isopropanol and toluene serving as solvents.

6.1.4 conclusion of the experiment:

form B is thermodynamically stable compared to form a.

Claims

A crystal form of a compound shown in a general formula (I),

wherein:

R ₁ selected from hydrogen, deuterium, halogen, amino, mercapto, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy or haloalkoxy;

R ₂ selected from hydrogen, deuterium, halogen, amino, mercapto, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl or 3-8 membered heterocyclyl, andthe amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, and 3-8 membered heterocyclyl optionally may be further substituted with one or more substituents selected from halogen, nitro, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, and 3-8 membered heterocyclyl;

x is an integer of 0 to 3;

and when R is ₂ When selected from methyl or ethyl, x is not 0 and R ₁ Is not hydrogen.
A crystalline form of the compound of claim 1, wherein R is ₁ Selected from hydrogen, deuterium, halogen, amino, mercapto, nitro, hydroxy, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 A haloalkoxy group; preferably hydrogen, deuterium, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy or cyano; more preferably hydrogen, deuterium, fluorine, chlorine or bromine, most preferably hydrogen or fluorine.
A crystalline form of a compound according to claim 1, wherein R is ₂ Selected from hydrogen, deuterium, halogen, amino, mercapto, nitro, hydroxy, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl and 3-8 membered heterocyclyl, optionally further substituted by halogen, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl;

preferably, R ₂ Selected from hydrogen, deuterium, halogen, cyano, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl, said amino, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl and 3-6 membered heterocyclyl, optionally further substituted by halogen, nitro, cyano, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl;

more preferably, R ₂ Selected from hydrogen, methyl, ethyl, propyl, cyclopropyl or oxetanyl, optionally further substituted by one or more substituents selected from halogen, nitro, cyano, methyl, ethyl, vinyl, ethynyl, cyclopropyl or oxetanyl.
A crystalline form of a compound according to claim 1, characterized in that the specific compound structure is as follows:
a crystalline form of the compound of claim 1, wherein the compound is 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d ₃ ) Pyridazine-3-carboxamide, the crystal forms are crystal form A, crystal form B, crystal form C, wherein:

the X-ray powder diffraction pattern of the crystal form A has a diffraction peak at the 2 theta of 23.7 +/-0.2 degrees; or a diffraction peak at 6.4 ± 0.2 °; or a diffraction peak at 19.4 ± 0.2 °; or a diffraction peak at 21.2 ± 0.2 °; or a diffraction peak at 23.0 ± 0.2 °; or a diffraction peak at 14.8 ± 0.2 °; or a diffraction peak at 11.3 ± 0.2 °; or a diffraction peak at 28.5 ± 0.2 °; or a diffraction peak at 13.0 ± 0.2 °; or a diffraction peak at 11.8 ± 0.2 °; preferably comprises any of 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the diffraction peaks; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the crystal form B has a diffraction peak at a2 theta position of 21.5 +/-0.2 degrees; or a diffraction peak at 15.0 ± 0.2 °; or a diffraction peak at 19.6 ± 0.2 °; or a diffraction peak at 23.0 ± 0.2 °; or a diffraction peak at 23.2 ± 0.2 °; or a diffraction peak at 14.5 ± 0.2 °; or a diffraction peak at 20.8 ± 0.2 °; or a diffraction peak at 13.3 ± 0.2 °; or a diffraction peak at 10.5 ± 0.2 °; or a diffraction peak at 11.8 ± 0.2 °; preferably comprises any 2-5, or 3-6, or 3-8, or 5-8, or 6-8 of the diffraction peaks, more preferably comprises any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the crystal form C has a diffraction peak at the 2 theta of 26.1 +/-0.2 degrees; or a diffraction peak at 24.7 ± 0.2 °; or a diffraction peak at 8.3 ± 0.2 °; or a diffraction peak at 9.9 ± 0.2 °; or a diffraction peak at 12.8 ± 0.2 °; or a diffraction peak at 18.9 ± 0.2 °; or a diffraction peak at 26.7 ± 0.2 °; or a diffraction peak at 17.3 ± 0.2 °; or a diffraction peak at 10.4 ± 0.2 °; or a diffraction peak at 11.0 ± 0.2 °; preferably comprises any of 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the diffraction peaks; more preferably any 6, 7 or 8 thereof.
A crystalline form according to claim 5, characterized in that form A has an X-ray powder diffraction pattern comprising at least one or more diffraction peaks, preferably 2 thereof, more preferably 3 thereof, located in 2 θ at 23.7 ± 0.2 °, 6.4 ± 0.2 °, 19.4 ± 0.2 °; optionally, the compound can further comprise at least one position with 2 theta of 21.2 +/-0.2 degrees, 23.0 +/-0.2 degrees, 14.7 +/-0.2 degrees, 11.3 +/-0.2 degrees or 28.49 +/-0.2 degrees, preferably comprises 2 positions, 3 positions, 4 positions or 5 positions;

for example:

contains diffraction peaks at 23.7 + -0.2 DEG, 6.4 + -0.2 DEG, 21.2 + -0.2 DEG, 23.0 + -0.2 DEG and 14.8 + -0.2 DEG of 2 theta;

or, diffraction peaks at 23.7 ± 0.2 °, 6.4 ± 0.2 °, 21.2 ± 0.2 °, 23.0 ± 0.2 ° and 11.3 ± 0.2 ° 2 θ are included;

or, diffraction peaks at 23.7 ± 0.2 °, 6.4 ± 0.2 °, 19.4 ± 0.2 °, 21.2 ± 0.2 °, 23.0 ± 0.2 ° and 28.5 ± 0.2 ° 2 θ are included;

or, diffraction peaks at 23.7 ± 0.2 °, 6.4 ± 0.2 °, 19.4 ± 0.2 °, 21.2 ± 0.2 °, 14.8 ± 0.2 ° and 11.3 ± 0.2 ° of 2 θ;

or, diffraction peaks at 23.7 ± 0.2 °, 6.4 ± 0.2 °, 19.4 ± 0.2 °, 21.2 ± 0.2 °, 23.0 ± 0.2 °, 14.8 ± 0.2 °,11.3 ± 0.2 ° and 28.5 ± 0.2 ° in 2 θ;

or, diffraction peaks at 23.7 ± 0.2 °, 6.4 ± 0.2 °, 19.4 ± 0.2 °, 21.2 ± 0.2 °, 23.0 ± 0.2 °, 14.8 ± 0.2 ° and 11.3 ± 0.2 ° of 2 θ are included;

the X-ray powder diffraction pattern of the crystal form B at least comprises one or more diffraction peaks with 2 theta of 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees and 19.6 +/-0.2 degrees, preferably comprises two or more diffraction peaks, and more preferably comprises three diffraction peaks; optionally, at least one of 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees and 13.3 +/-0.2 degrees can be further contained; preferably 2,3, 4 or 5 thereof;

for example:

contains diffraction peaks at 21.5 + -0.2 DEG, 15.0 + -0.2 DEG, 19.6 + -0.2 DEG, 23.0 + -0.2 DEG and 23.2 + -0.2 DEG of 2 theta;

or, diffraction peaks at 21.5 ± 0.2 °,15.0 ± 0.2 °,19.6 ± 0.2 °, 23.0 ± 0.2 ° and 13.3 ± 0.2 ° of 2 θ are included;

or, diffraction peaks at 21.5 + -0.2 °, 23.0 + -0.2 °,23.2 + -0.2 °, 14.5 + -0.2 °, 20.8 + -0.2 °, and 13.3 + -0.2 ° of 2 θ;

or, diffraction peaks at 21.5 ± 0.2 °,15.0 ± 0.2 °,23.2 ± 0.2 °, 14.5 ± 0.2 °, 20.8 ± 0.2 °, and 13.3 ± 0.2 ° 2 θ are included;

or the included angle is 15.0 plus or minus 0.2 degrees, 19.6 plus or minus 0.2 degrees, 23.0 plus or minus 0.2 degrees, 23.2 plus or minus 0.2 degrees, 14.5 plus or minus 0.2 degrees, 20.8 plus or minus 0.2 degrees and 13.3 plus or minus 0.2 degrees at 2 theta;

or, diffraction peaks at 21.5 ± 0.2 °,19.6 ± 0.2 °, 23.0 ± 0.2 °,23.2 ± 0.2 °, 14.5 ± 0.2 °, 20.8 ± 0.2 ° and 13.3 ± 0.2 ° of 2 θ;

or, diffraction peaks at 21.5 ± 0.2 °,15.0 ± 0.2 °,19.6 ± 0.2 °, 23.0 ± 0.2 °,23.2 ± 0.2 °, 14.5 ± 0.2 °, 20.8 ± 0.2 °, and 13.3 ± 0.2 ° of 2 θ are included;

the X-ray powder diffraction pattern of the crystal form C at least comprises one or more diffraction peaks with the 2 theta of 26.1 +/-0.2 degrees, 24.7 +/-0.2 degrees and 8.3 +/-0.2 degrees, preferably comprises 2 positions and more preferably comprises 3 positions; optionally, the composition can further comprise at least one position with 2 theta of 9.9 +/-0.2 degrees, 12.8 +/-0.2 degrees, 18.9 +/-0.2 degrees, 26.7 +/-0.2 degrees or 17.3 +/-0.2 degrees, preferably comprises 2,3, 4 or 5 positions;

for example:

contains diffraction peaks at 26.1 + -0.2 DEG, 24.7 + -0.2 DEG, 9.9 + -0.2 DEG, 12.8 + -0.2 DEG and 18.9 + -0.2 DEG 2 theta;

or, diffraction peaks at 26.1 ± 0.2 °, 24.7 ± 0.2 °, 8.6 ± 0.2 °, 9.9 ± 0.2 °, 12.8 ± 0.2 °, and 17.3 ± 0.2 ° 2 θ are included;

or, diffraction peaks at 26.1 ± 0.2 °, 24.7 ± 0.2 °, 8.3 ± 0.2 °, 9.9 ± 0.2 °, 12.8 ± 0.2 °, 18.9 ± 0.2 °, and 26.7 ± 0.2 ° 2 θ are included;

alternatively, diffraction peaks at 26.1 ± 0.2 °, 24.7 ± 0.2 °, 8.3 ± 0.2 °, 9.9 ± 0.2 °, 12.8 ± 0.2 °, 18.9 ± 0.2 °, 26.7 ± 0.2 ° and 17.3 ± 0.2 in 2 θ are included.
A crystalline form according to any one of claims 5-6, characterized in that the X-ray powder diffraction pattern of form A optionally further comprises one or more diffraction peaks, in terms of 2 θ, at 13.0 ± 0.2 °, 11.8 ± 0.2 °, 22.7 ± 0.2 °, 16.3 ± 0.2 °, 29.4 ± 0.2 °, 14.2 ± 0.2 ° or 25.3 ± 0.2 °; preferably at least any 2 to 3, or 4 to 5, or 6 to 7 thereof; further preferably, any 2,3, 4,5, 6, 7 thereof;

for example:

contains diffraction peaks at 23.7 + -0.2 DEG, 6.4 + -0.2 DEG, 19.4 + -0.2 DEG, 21.2 + -0.2 DEG, 23.0 + -0.2 DEG, 14.8 + -0.2 DEG, 11.3 + -0.2 DEG, 28.5 + -0.2 DEG, 13.0 + -0.2 DEG and 11.8 + -0.2 DEG of 2 theta;

or diffraction peaks at 23.7 + -0.2 °, 6.4 + -0.2 °, 19.4 + -0.2 °, 21.2 + -0.2 °, 23.0 + -0.2 °, 14.8 + -0.2 °,11.3 + -0.2 °, 13.0 + -0.2 °, 11.8 + -0.2 ° in 2 θ;

or diffraction peaks at 23.7 + -0.2 °, 6.4 + -0.2 °, 19.4 + -0.2 °, 21.2 + -0.2 °, 23.0 + -0.2 °, 14.8 + -0.2 °, 13.0 + -0.2 ° and 11.8 + -0.2 ° of 2 θ;

or, diffraction peaks at 23.7 ± 0.2 °, 6.4 ± 0.2 °, 19.4 ± 0.2 °, 21.2 ± 0.2 °, 23.0 ± 0.2 °,11.3 ± 0.2 °, 13.0 ± 0.2 °, and 11.8 ± 0.2 ° of 2 θ are included;

or, diffraction peaks at 23.7 ± 0.2 °, 6.4 ± 0.2 °, 21.2 ± 0.2 °, 23.0 ± 0.2 °, 14.8 ± 0.2 °, 13.0 ± 0.2 ° and 11.8 ± 0.2 ° of 2 θ are included;

or, diffraction peaks at 23.7 ± 0.2 °, 6.4 ± 0.2 °, 21.2 ± 0.2 °, 23.0 ± 0.2 °,11.3 ± 0.2 °, 13.0 ± 0.2 ° and 11.8 ± 0.2 ° in 2 θ;

the X-ray powder diffraction pattern of form B optionally further comprises one or more diffraction peaks at 10.5 ± 0.2 °, 11.8 ± 0.2 °, 18.3 ± 0.2 °, 16.7 ± 0.2 °, 16.3 ± 0.2 °, 24.2 ± 0.2 °, 29.1 ± 0.2 ° 2 Θ; preferably at least any 2 to 3, or 4 to 5, or 6 to 7 thereof; further preferably, any 2,3, 4,5, 6, 7 thereof;

for example:

contains diffraction peaks at 21.5 + -0.2 DEG, 15.0 + -0.2 DEG, 19.6 + -0.2 DEG, 23.0 + -0.2 DEG, 13.3 + -0.2 DEG and 10.5 + -0.2 DEG 2 theta;

or, diffraction peaks at 21.5 + -0.2 °,15.0 + -0.2 °,19.6 + -0.2 °, 23.0 + -0.2 °,23.2 + -0.2 °, and 10.5 + -0.2 ° of 2 θ;

or, diffraction peaks at 21.5 ± 0.2 °, 23.0 ± 0.2 °,23.2 ± 0.2 °, 14.5 ± 0.2 °, 20.8 ± 0.2 °,13.3 ± 0.2 °, and 10.5 ± 0.2 ° 2 θ are included;

or, diffraction peaks at 21.5 ± 0.2 °,15.0 ± 0.2 °,23.2 ± 0.2 °, 14.5 ± 0.2 °, 20.8 ± 0.2 °,13.3 ± 0.2 ° and 10.5 ± 0.2 ° of 2 θ are included;

or, diffraction peaks at 15.0 ± 0.2 °,19.6 ± 0.2 °, 23.0 ± 0.2 °,23.2 ± 0.2 °, 14.5 ± 0.2 °, 20.8 ± 0.2 °,13.3 ± 0.2 °, and 10.5 ± 0.2 ° of 2 θ are included;

or, diffraction peaks at 21.5 ± 0.2 °,19.6 ± 0.2 °, 23.0 ± 0.2 °,23.2 ± 0.2 °, 14.5 ± 0.2 °, 20.8 ± 0.2 °,13.3 ± 0.2 °, and 10.5 ± 0.2 ° of 2 θ are included;

or diffraction peaks at 21.5 + -0.2 °,15.0 + -0.2 °,19.6 + -0.2 °, 23.0 + -0.2 °,23.2 + -0.2 °, 14.5 + -0.2 °, 20.8 + -0.2 °,13.3 + -0.2 ° and 10.5 + -0.2 ° of 2 θ;

the X-ray powder diffraction pattern of form C optionally further comprises one or more diffraction peaks at 10.4 ± 0.2 °, 11.0 ± 0.2 °, 19.2 ± 0.2 °, 12.1 ± 0.2 °, 20.0 ± 0.2 °, 25.5 ± 0.2 ° or 13.7 ± 0.2 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any of 2,3, 4,5, 6, 7;

for example;

contains diffraction peaks at 2 theta of 26.1 + -0.2 DEG, 24.7 + -0.2 DEG, 9.9 + -0.2 DEG, 12.8 + -0.2 DEG, 18.9 + -0.2 DEG, 10.4 + -0.2 DEG and 11.0 + -0.2 DEG;

or, diffraction peaks at 26.1 ± 0.2 °, 24.7 ± 0.2 °, 9.9 ± 0.2 °, 12.8 ± 0.2 °, 26.7 ± 0.2 °, 10.4 ± 0.2 ° and 11.0 ± 0.2 ° in 2 θ;

or, diffraction peaks at 26.1 ± 0.2 °, 24.7 ± 0.2 °, 8.3 ± 0.2 °, 9.9 ± 0.2 °, 12.8 ± 0.2 °, 18.9 ± 0.2 °, 10.4 ± 0.2 °, and 11.0 ± 0.2 ° of 2 θ are included;

or, diffraction peaks at 26.1 ± 0.2 °, 24.7 ± 0.2 °, 8.3 ± 0.2 °, 9.9 ± 0.2 °, 12.8 ± 0.2 °, 26.7 ± 0.2 °, 10.4 ± 0.2 °, and 11.0 ± 0.2 ° 2 θ are included;

or diffraction peaks at 26.1 + -0.2 °, 24.7 + -0.2 °, 8.3 + -0.2 °, 9.9 + -0.2 °, 12.8 + -0.2 °, 18.9 + -0.2 °, 26.7 + -0.2 °, 10.4 + -0.2 ° and 11.0 + -0.2 ° of 2 θ;

alternatively, diffraction peaks at 26.1 ± 0.2 °, 24.7 ± 0.2 °, 8.3 ± 0.2 °, 9.9 ± 0.2 °, 12.8 ± 0.2 °, 18.9 ± 0.2 °, 26.7 ± 0.2 °, 17.3 ± 0.2, 10.4 ± 0.2 ° and 11.0 ± 0.2 ° in 2 θ are included.
A crystalline form according to claim 5 characterized in that the form A has an X-ray powder diffraction pattern comprising one or more diffraction peaks, in terms of 2 θ, at 23.7 ± 0.2 °, 6.4 ± 0.2 °, 19.4 ± 0.2 °, 21.2 ± 0.2 °, 23.0 ± 0.2 °, 14.8 ± 0.2 °,11.3 ± 0.2 °, 28.5 ± 0.2, 13.0 ± 0.2 °, 11.8 ± 0.2 °, 22.7 ± 0.2 ° or 16.3 ± 0.2 °; preferably, the compound comprises diffraction peaks at 4,5, 6, 8 or 10 optionally;

for example, the form a has an X-ray powder diffraction pattern with diffraction peaks at the following positions 2 θ:

23.7 +/-0.2 degrees, 6.4 +/-0.2 degrees, 19.4 +/-0.2 degrees and 21.2 +/-0.2 degrees;

or at 23.7 + -0.2 deg., 6.4 + -0.2 deg., 19.4 + -0.2 deg. and 23.0 + -0.2 deg.;

or at 23.7 ± 0.2 °, 6.4 ± 0.2 °, 19.4 ± 0.2 °, 21.2 ± 0.2 °, 23.0 ± 0.2 ° and 13.0 ± 0.2 °;

or at 23.7 ± 0.2 °, 6.4 ± 0.2 °, 19.4 ± 0.2 °, 21.2 ± 0.2 °, 13.0 ± 0.2 ° and 11.3 ± 0.2 °;

or, at positions 23.7 ± 0.2 °, 6.4 ± 0.2 °, 19.4 ± 0.2 °, 21.2 ± 0.2 °, 23.0 ± 0.2 °, 14.8 ± 0.2 °,11.3 ± 0.2 ° and 13.0 ± 0.2 °;

or, at positions 23.7 ± 0.2 °, 6.4 ± 0.2 °, 19.4 ± 0.2 °, 21.2 ± 0.2 °, 23.0 ± 0.2 °, 14.8 ± 0.2 °,11.3 ± 0.2 ° and 11.8 ± 0.2 °;

or at 23.7 + -0.2 °, 6.4 + -0.2 °, 19.4 + -0.2 °, 21.2 + -0.2 °, 23.0 + -0.2 °, 14.8 + -0.2 °,11.3 + -0.2 °, 28.5 + -0.2 °, 13.0 + -0.2 ° and 11.8 + -0.2 °;

or at 23.7 ± 0.2 °, 6.4 ± 0.2 °, 19.4 ± 0.2 °, 21.2 ± 0.2 °, 23.0 ± 0.2 °, 14.8 ± 0.2 °,11.3 ± 0.2 °, 28.5 ± 0.2 °, 13.0 ± 0.2 ° and 22.7 ± 0.2 °;

the X-ray powder diffraction pattern of the crystal form B comprises diffraction peaks at one or more of 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.3 +/-0.2 degrees, 16.7 +/-0.2 degrees, 16.3 +/-0.2 degrees, 24.2 +/-0.2 degrees and 29.1 +/-0.2 degrees of 2 theta; preferably, the compound comprises diffraction peaks at 4,5, 6, 8 and 10;

for example, the X-ray powder diffraction pattern of the form B has diffraction peaks at the following positions 2 θ:

21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees and 23.0 +/-0.2 degrees;

or 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees and 23.2 +/-0.2 degrees;

or 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees and 14.5 +/-0.2 degrees;

or 21.5 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees and 23.2 +/-0.2 degrees;

or 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees and 14.5 +/-0.2 degrees;

or 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees and 20.8 +/-0.2 degrees;

or at 15.0 + -0.2 deg., 19.6 + -0.2 deg., 23.0 + -0.2 deg., 23.2 + -0.2 deg., 14.5 + -0.2 deg. and 20.8 + -0.2 deg.;

or 21.5 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees and 20.8 +/-0.2 degrees;

or 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees and 13.3 +/-0.2 degrees;

or 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 10.5 +/-0.2 degrees and 11.8 +/-0.2 degrees;

or 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees, 10.5 +/-0.2 degrees and 11.8 +/-0.2 degrees;

or 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.3 +/-0.2 degrees, 10.5 +/-0.2 degrees and 11.8 +/-0.2 degrees;

or 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees, 10.5 +/-0.2 degrees and 11.8 +/-0.2 degrees;

or 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 13.3 +/-0.2 degrees, 11.8 +/-0.2 degrees and 18.3 +/-0.2 degrees;

or 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 18.3 +/-0.2 degrees and 16.7 +/-0.2 degrees;

or 21.5 +/-0.2 degrees, 15.0 +/-0.2 degrees, 19.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.3 +/-0.2 degrees and 16.7 +/-0.2 degrees;

the X-ray powder diffraction pattern of the crystal form C comprises one or more diffraction peaks positioned in 26.1 +/-0.2 degrees, 24.7 +/-0.2 degrees, 8.3 +/-0.2 degrees, 9.9 +/-0.2 degrees, 12.8 +/-0.2 degrees, 18.9 +/-0.2 degrees, 26.7 +/-0.2 degrees, 17.3 +/-0.2 degrees, 10.4 +/-0.2 degrees, 11.0 +/-0.2 degrees, 19.2 +/-0.2 degrees or 12.1 +/-0.2 degrees of 2 theta; preferably, the compound comprises diffraction peaks at 4,5, 6, 8 or 10;

for example, the form C has an X-ray powder diffraction pattern with diffraction peaks at the following positions 2 θ:

26.1 +/-0.2 degrees, 24.7 +/-0.2 degrees, 8.3 +/-0.2 degrees and 9.9 +/-0.2 degrees;

or 26.1 +/-0.2 degrees, 24.7 +/-0.2 degrees, 8.3 +/-0.2 degrees and 12.8 +/-0.2 degrees;

or at 23.7 ± 0.2 °, 6.4 ± 0.2 °, 19.4 ± 0.2 °, 21.2 ± 0.2 °, 23.0 ± 0.2 ° and 10.4 ± 0.2 °;

or at 23.7 + -0.2 °, 6.4 + -0.2 °, 19.4 + -0.2 °, 21.2 + -0.2 °, 10.4 + -0.2 ° and 11.3 + -0.2 °;

or 26.1 +/-0.2 degrees, 24.7 +/-0.2 degrees, 8.3 +/-0.2 degrees, 9.9 +/-0.2 degrees, 12.8 +/-0.2 degrees, 18.9 +/-0.2 degrees, 26.7 +/-0.2 degrees and 10.4 +/-0.2 degrees;

or 26.1 +/-0.2 degrees, 24.7 +/-0.2 degrees, 8.3 +/-0.2 degrees, 9.9 +/-0.2 degrees, 12.8 +/-0.2 degrees, 18.9 +/-0.2 degrees, 26.7 +/-0.2 degrees and 11.0 +/-0.2 degrees.
A crystalline form according to claim 5 characterized in that the form B has an X-ray powder diffraction pattern comprising diffraction peaks at one or more of 15.0 ± 0.2 °,23.2 ± 0.2 °, 14.5 ± 0.2 °, 20.8 ± 0.2 °,10.5 ± 0.2 °, 11.8 ± 0.2 °, 18.3 ± 0.2 °, 16.7 ± 0.2 °, 24.2 ± 0.2 °, 29.1 ± 0.2 ° 2 θ; preferably, the compound comprises diffraction peaks at3, 4,5, 6, 7, 8 and 10;

for example, the X-ray powder diffraction pattern of form B has diffraction peaks at the following positions 2 θ:

15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees and 14.5 +/-0.2 degrees;

or at 15.0 + -0.2 deg., 14.5 + -0.2 deg. and 20.8 + -0.2 deg.;

or at 15.0 + -0.2 deg., 23.2 + -0.2 deg. and 20.8 + -0.2 deg.;

or at 23.2 + -0.2 deg., 14.5 + -0.2 deg. and 20.8 + -0.2 deg.;

or at 15.0 + -0.2 deg., 23.2 + -0.2 deg., 14.5 + -0.2 deg. and 20.8 + -0.2 deg.;

or at 15.0 + -0.2 deg., 23.2 + -0.2 deg., 14.5 + -0.2 deg., 10.5 + -0.2 deg. and 11.8 + -0.2 deg.;

or 15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees and 11.8 +/-0.2 degrees;

or 15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 11.8 +/-0.2 degrees and 18.3 +/-0.2 degrees;

or at 15.0 + -0.2 deg., 23.2 + -0.2 deg., 14.5 + -0.2 deg., 20.8 + -0.2 deg., 24.2 + -0.2 deg. and 29.1 + -0.2 deg.;

or at 23.2 + -0.2 deg., 14.5 + -0.2 deg., 20.8 + -0.2 deg., 10.5 + -0.2 deg., 18.3 + -0.2 deg. and 16.7 + -0.2 deg.;

or at 15.0 + -0.2 deg., 23.2 + -0.2 deg., 14.5 + -0.2 deg., 20.8 + -0.2 deg., 10.5 + -0.2 deg., 18.3 + -0.2 deg. and 16.7 + -0.2 deg.;

or at 15.0 + -0.2 °,23.2 + -0.2 °, 14.5 + -0.2 °,10.5 + -0.2 °, 11.8 + -0.2 °, 18.3 + -0.2 ° and 16.7 + -0.2 °;

or 15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.3 +/-0.2 degrees and 16.7 +/-0.2 degrees;

or at 15.0 + -0.2 °,23.2 + -0.2 °, 14.5 + -0.2 °, 20.8 + -0.2 °,10.5 + -0.2 °, 11.8 + -0.2 °, 18.3 + -0.2 ° and 24.2 + -0.2 °;

or 15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.3 +/-0.2 degrees and 29.1 +/-0.2 degrees;

or 15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 16.7 +/-0.2 degrees and 24.2 +/-0.2 degrees;

or 15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 16.7 +/-0.2 degrees, 24.2 +/-0.2 degrees and 29.1 +/-0.2 degrees;

or 15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 18.3 +/-0.2 degrees, 16.7 +/-0.2 degrees, 24.2 +/-0.2 degrees and 29.1 +/-0.2 degrees;

or at 15.0 + -0.2 °,23.2 + -0.2 °, 14.5 + -0.2 °, 20.8 + -0.2 °, 11.8 + -0.2 °, 18.3 + -0.2 °, 16.7 + -0.2 ° and 29.1 + -0.2 °;

or 15.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.3 +/-0.2 degrees, 16.7 +/-0.2 degrees, 24.2 +/-0.2 degrees and 29.1 +/-0.2 degrees.
The crystalline form of claim 5, characterized in that the form a has an X-ray powder diffraction pattern as shown in figure 1; the X-ray powder diffraction pattern of the crystal form B is shown in figure 4; the X-ray powder diffraction pattern of the crystal form C is shown in figure 7.
A crystalline form according to claim 5, characterised in that the diffraction peaks at the X-ray powder diffraction patterns of form A, form B and form C, having the first ten-fold strong relative peak intensities, have 2 θ errors of ± 0.2 ° to ± 0.5 °, preferably ± 0.2 ° to ± 0.3 °, most preferably ± 0.2 °, from the diffraction peaks at the corresponding positions in figures 1,4 and 7, respectively.
The crystalline form according to claim 5, characterized in that,

the melting point of form a is about 240 ℃ to 248 ℃;

the form B melting point is about 244 ℃ to 250 ℃;

the crystalline form C has a melting point of about 241 ℃ to 248 ℃.
The crystalline form of claim 5, characterized in that the form A has a DSC profile as shown in figure 2; or a TGA profile as shown in figure 3; the form B has a DSC pattern as shown in figure 5; or a TGA profile as shown in figure 6; the form C has a DSC pattern as shown in figure 8; or a TGA profile as shown in figure 9.
A crystalline form of the compound according to claim 1, wherein the compound is 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide, and wherein the crystalline form is form a, form B or form C, wherein:

the X-ray powder diffraction pattern of the crystal form A has a diffraction peak at the 2 theta of 24.5 +/-0.2 degrees; or a diffraction peak at 19.0 ± 0.2 °; or a diffraction peak at 13.1 ± 0.2 °; or a diffraction peak at 15.8 ± 0.2 °; or a diffraction peak at 13.4 ± 0.2 °; or a diffraction peak at 23.8 ± 0.2 °; or a diffraction peak at 7.9 ± 0.2 °; or a diffraction peak at 14.7 ± 0.2 °; or a diffraction peak at 15.0 ± 0.2 °; or a diffraction peak at 27.1 ± 0.2 °; preferably comprises any of 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the diffraction peaks; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the crystal form B has a diffraction peak at a position with 2 theta of 7.1 +/-0.2 degrees; or a diffraction peak at 23.5 ± 0.2 °; or a diffraction peak at 22.6 ± 0.2 °; or a diffraction peak at 25.7 ± 0.2 °; or a diffraction peak at 17.3 ± 0.2 °; or a diffraction peak at 23.2 ± 0.2 °; or a diffraction peak at 21.9 ± 0.2 °; or a diffraction peak at 8.2 ± 0.2 °; or a diffraction peak at 13.9 ± 0.2 °; or a diffraction peak at 17.9 ± 0.2 °; preferably comprises any of 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the diffraction peaks; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the crystal form C has a diffraction peak at the 2 theta of 24.5 +/-0.2 degrees; or a diffraction peak at 13.3 ± 0.2 °; or a diffraction peak at 15.9 ± 0.2 °; or a diffraction peak at 14.6 ± 0.2 °; or a diffraction peak at 19.0 ± 0.2 °; or a diffraction peak at 7.9 ± 0.2 °; or a diffraction peak at 15.0 ± 0.2 °; or a diffraction peak at 20.1 ± 0.2 °; or a diffraction peak at 13.9 ± 0.2 °; or a diffraction peak at 13.1 ± 0.2 °; preferably comprises any of 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the diffraction peaks; more preferably any 6, 7 or 8 thereof.
A crystalline form according to claim 14, characterized in that the form a has an X-ray powder diffraction pattern comprising at least one or more diffraction peaks, preferably 2, more preferably 3, located in 2 Θ at 24.5 ± 0.2 °, 19.0 ± 0.2 °, 13.1 ± 0.2 °; optionally, the composition can further comprise at least one position with 2 theta of 15.8 +/-0.2 degrees, 13.4 +/-0.2 degrees, 23.8 +/-0.2 degrees, 7.8 +/-0.2 degrees or 14.7 +/-0.2 degrees, preferably comprises 2 positions, 3 positions, 4 positions or 5 positions;

for example:

comprises diffraction peaks at 24.5 + -0.2 DEG, 19.0 + -0.2 DEG, 13.1 + -0.2 DEG and 15.8 + -0.2 DEG of 2 theta;

or, diffraction peaks at 24.5 ± 0.2 °, 19.0 ± 0.2 °, 13.1 ± 0.2 °, 15.8 ± 0.2 °, 13.4 ± 0.2 ° and 23.8 ± 0.2 ° 2 θ are included;

or, diffraction peaks at 24.5 ± 0.2 °, 19.0 ± 0.2 °, 13.1 ± 0.2 °, 15.8 ± 0.2 °, 13.4 ± 0.2 °, 23.8 ± 0.2 °, 7.9 ± 0.2 °, and 14.7 ± 0.2 ° 2 θ are included;

the X-ray powder diffraction pattern of the crystal form B at least comprises one or more diffraction peaks with 2 theta of 7.1 +/-0.2 degrees, 23.5 +/-0.2 degrees and 22.6 +/-0.2 degrees, preferably comprises 2, more preferably comprises 3; optionally, the composition can further comprise at least one position with the 2 theta of 25.7 +/-0.2 degrees, 17.3 +/-0.2 degrees, 23.2 +/-0.2 degrees, 21.9 +/-0.2 degrees or 8.2 +/-0.2 degrees, preferably comprises 2,3, 4 or 5 positions;

for example:

contains diffraction peaks at 2 theta of 7.1 + -0.2 DEG, 23.5 + -0.2 DEG, 22.6 + -0.2 DEG and 25.7 + -0.2 DEG;

or, diffraction peaks at 7.1 ± 0.2 °, 23.5 ± 0.2 °, 22.6 ± 0.2 °, 25.7 ± 0.2 °, 17.3 ± 0.2 ° and 23.2 ± 0.2 ° 2 θ are included;

or, diffraction peaks at 7.1 ± 0.2 °, 23.5 ± 0.2 °, 22.6 ± 0.2 °, 25.7 ± 0.2 °, 17.3 ± 0.2 °,23.2 ± 0.2 °, 21.9 ± 0.2 °, and 8.2 ± 0.2 ° 2 θ are included;

the X-ray powder diffraction pattern of the crystal form C at least comprises one or more diffraction peaks with the 2 theta of 24.5 +/-0.2 degrees, 13.3 +/-0.2 degrees and 15.9 +/-0.2 degrees, preferably comprises 2, and more preferably comprises 3; optionally, the composition can further comprise at least one position with 2 theta of 14.6 +/-0.2 degrees, 19.0 +/-0.2 degrees, 7.9 +/-0.2 degrees, 15.0 +/-0.2 degrees or 20.1 +/-0.2 degrees, preferably comprises 2 positions, 3 positions, 4 positions or 5 positions;

for example:

contains diffraction peaks at 24.5 + -0.2 DEG, 13.3 + -0.2 DEG, 15.9 + -0.2 DEG and 14.6 + -0.2 DEG of 2 theta;

or, diffraction peaks at 24.5 ± 0.2 °,13.3 ± 0.2 °, 15.9 ± 0.2 °, 14.6 ± 0.2 °, 19.0 ± 0.2 ° and 7.9 ± 0.2 ° of 2 θ;

alternatively, diffraction peaks at 24.5. + -. 0.2 °, 13.3. + -. 0.2 °, 15.9. + -. 0.2 °, 14.6. + -. 0.2 °, 19.0. + -. 0.2 °, 7.9. + -. 0.2 °, 15.0. + -. 0.2 and 20.1. + -. 0.2 ° in 2. Theta. Are included.
A crystalline form according to any one of claims 14-15, characterized in that the form a X-ray powder diffraction pattern optionally further comprises one or more diffraction peaks, in terms of 2 Θ, at 14.5 ± 0.2 °, 27.1 ± 0.2 °, 14.0 ± 0.2 °, 20.1 ± 0.2 °, 22.3 ± 0.2 °, 28.2 ± 0.2 ° or 18.4 ± 0.2 °; preferably at least any 2 to 3, or 4 to 5, or 6 to 7 thereof; further preferably, any of 2,3, 4,5, 6, 7;

for example:

contains diffraction peaks at 24.5 + -0.2 DEG, 19.0 + -0.2 DEG, 13.1 + -0.2 DEG, 15.8 + -0.2 DEG and 15.0 + -0.2 DEG of 2 theta;

or, diffraction peaks at 24.5 ± 0.2 °, 19.0 ± 0.2 °, 13.1 ± 0.2 °, 15.8 ± 0.2 °, 13.4 ± 0.2 °, 23.8 ± 0.2 °, and 15.0 ± 0.2 ° 2 θ are included;

or, diffraction peaks at 24.5 ± 0.2 °, 19.0 ± 0.2 °, 13.1 ± 0.2 °, 15.8 ± 0.2 °, 13.4 ± 0.2 °, 23.8 ± 0.2 °, 7.9 ± 0.2 °, 14.7 ± 0.2 and 15.0 ± 0.2 ° 2 θ are included;

the X-ray powder diffraction pattern of form B optionally further comprises one or more diffraction peaks at 13.9 ± 0.2 °, 17.9 ± 0.2 °, 25.3 ± 0.2 °,5.4 ± 0.2 °, 8.6 ± 0.2 °, 14.3 ± 0.2 °, or 27.5 ± 0.2 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any of 2,3, 4,5, 6, 7;

for example:

contains diffraction peaks at 2 theta of 7.1 + -0.2 DEG, 23.5 + -0.2 DEG, 22.6 + -0.2 DEG, 25.7 + -0.2 DEG and 13.9 + -0.2 DEG;

or, diffraction peaks at 7.1 ± 0.2 °, 23.5 ± 0.2 °, 22.6 ± 0.2 °, 25.7 ± 0.2 °, 17.3 ± 0.2 °,23.2 ± 0.2 °, and 13.9 ± 0.2 ° 2 θ are included;

or, diffraction peaks at 7.1 ± 0.2 °, 23.5 ± 0.2 °, 22.6 ± 0.2 °, 25.7 ± 0.2 °, 17.3 ± 0.2 °,23.2 ± 0.2 °, 21.9 ± 0.2 °, 8.2 ± 0.2 and 13.9 ± 0.2 ° 2 θ are included;

the X-ray powder diffraction pattern of form C optionally further comprises one or more diffraction peaks at 13.9 ± 0.2 °, 13.1 ± 0.2 °, 23.8 ± 0.2 °, 27.0 ± 0.2 °, 22.3 ± 0.2 °, 18.4 ± 0.2 °, or 29.9 ± 0.2 ° 2 Θ; preferably at least any 2 to 3, or 4 to 5, or 6 to 7 thereof; further preferably, any 2,3, 4,5, 6, 7 thereof; for example:

contains diffraction peaks at 24.5 + -0.2 DEG, 13.3 + -0.2 DEG, 15.9 + -0.2 DEG, 14.6 + -0.2 DEG and 13.9 + -0.2 DEG 2 theta;

or diffraction peaks at 24.5 + -0.2 DEG, 13.3 + -0.2 DEG, 15.9 + -0.2 DEG, 14.6 + -0.2 DEG, 19.0 + -0.2 DEG, 7.9 + -0.2 DEG and 13.9 + -0.2 DEG in terms of 2 theta;

or diffraction peaks at 24.5 + -0.2 °,13.3 + -0.2 °, 15.9 + -0.2 °, 14.6 + -0.2 °, 19.0 + -0.2 °, 7.9 + -0.2 °,15.0 + -0.2 °, 20.1 + -0.2 °, and 13.9 + -0.2 ° in 2 θ are included.
A crystalline form according to claim 14 characterized in that the form a has an X-ray powder diffraction pattern comprising one or more diffraction peaks, in terms of 2 Θ, at 24.5 ± 0.2 °, 19.0 ± 0.2 °, 13.1 ± 0.2 °, 15.8 ± 0.2 °, 13.4 ± 0.2 °, 23.8 ± 0.2 °, 7.9 ± 0.2 °, 14.7 ± 0.2, 15.0 ± 0.2 °, 27.1 ± 0.2 °, 14.0 ± 0.2 ° or 20.1 ± 0.2 °; preferably, the compound comprises diffraction peaks at 4,5, 6, 8 or 10;

for example, the form a has an X-ray powder diffraction pattern with diffraction peaks at the following positions 2 θ:19.0 +/-0.2 degrees, 13.1 +/-0.2 degrees, 15.8 +/-0.2 degrees and 13.4 +/-0.2 degrees;

or 24.5 +/-0.2 degrees, 19.0 +/-0.2 degrees, 13.1 +/-0.2 degrees, 15.8 +/-0.2 degrees, 13.4 +/-0.2 degrees and 23.8 +/-0.2 degrees;

or 24.5 +/-0.2 degrees, 19.0 +/-0.2 degrees, 13.1 +/-0.2 degrees, 15.8 +/-0.2 degrees, 13.4 +/-0.2 degrees, 23.8 +/-0.2 degrees, 7.9 +/-0.2 degrees and 14.7 +/-0.2 degrees;

or 24.5 +/-0.2 degrees, 19.0 +/-0.2 degrees, 13.1 +/-0.2 degrees, 15.8 +/-0.2 degrees, 13.4 +/-0.2 degrees, 23.8 +/-0.2 degrees, 7.9 +/-0.2 degrees, 14.7 +/-0.2 degrees, 15.0 +/-0.2 degrees and 27.1 +/-0.2 degrees;

the X-ray powder diffraction pattern of the crystal form B comprises one or more diffraction peaks located at 7.1 +/-0.2 degrees, 23.5 +/-0.2 degrees, 22.6 +/-0.2 degrees, 25.7 +/-0.2 degrees, 17.3 +/-0.2 degrees, 23.2 +/-0.2 degrees, 21.9 +/-0.2 degrees, 8.2 +/-0.2 degrees, 13.9 +/-0.2 degrees, 17.9 +/-0.2 degrees, 25.3 +/-0.2 degrees or 5.4 +/-0.2 degrees of 2 theta; preferably, the compound comprises diffraction peaks at 4,5, 6, 8 or 10;

for example, the X-ray powder diffraction pattern of form B has diffraction peaks at the following positions 2 θ:23.5 +/-0.2 degrees, 22.6 +/-0.2 degrees, 25.7 +/-0.2 degrees and 17.3 +/-0.2 degrees;

or at 7.1 + -0.2 °, 23.5 + -0.2 °, 22.6 + -0.2 °, 25.7 + -0.2 °, 17.3 + -0.2 ° and 23.2 + -0.2 °;

or at 7.1 + -0.2 °, 23.5 + -0.2 °, 22.6 + -0.2 °, 25.7 + -0.2 °, 17.3 + -0.2 °,23.2 + -0.2 °, 21.9 + -0.2 ° and 13.9 + -0.2 °;

or at 7.1 + -0.2 °, 23.5 + -0.2 °, 22.6 + -0.2 °, 25.7 + -0.2 °, 17.3 + -0.2 °,23.2 + -0.2 °, 21.9 + -0.2 °, 8.2 + -0.2 ° and 13.9 + -0.2 °;

the X-ray powder diffraction pattern of the crystal form C comprises one or more diffraction peaks located at 24.5 +/-0.2 degrees, 13.3 +/-0.2 degrees, 15.9 +/-0.2 degrees, 14.6 +/-0.2 degrees, 19.0 +/-0.2 degrees, 7.9 +/-0.2 degrees, 15.0 +/-0.2 degrees, 20.1 +/-0.2 degrees, 13.9 +/-0.2 degrees, 13.1 +/-0.2 degrees, 23.8 +/-0.2 degrees or 27.0 +/-0.2 degrees of 2 theta; preferably, the compound comprises diffraction peaks at 4,5, 6, 8 or 10 optionally; for example, the X-ray powder diffraction pattern of form B has diffraction peaks at the following positions 2 θ:

13.3 +/-0.2 degrees, 15.9 +/-0.2 degrees, 14.6 +/-0.2 degrees and 19.0 +/-0.2 degrees;

or 13.3 +/-0.2 degrees, 15.9 +/-0.2 degrees, 14.6 +/-0.2 degrees, 19.0 +/-0.2 degrees, 7.9 +/-0.2 degrees and 15.0 +/-0.2 degrees;

or 24.5 +/-0.2 degrees, 13.3 +/-0.2 degrees, 15.9 +/-0.2 degrees, 14.6 +/-0.2 degrees, 19.0 +/-0.2 degrees, 7.9 +/-0.2 degrees, 15.0 +/-0.2 degrees and 27.0 +/-0.2 degrees;

or 24.5 +/-0.2 degrees, 13.3 +/-0.2 degrees, 15.9 +/-0.2 degrees, 14.6 +/-0.2 degrees, 19.0 +/-0.2 degrees, 7.9 +/-0.2 degrees, 15.0 +/-0.2 degrees, 20.1 +/-0.2 degrees, 13.9 +/-0.2 degrees and 27.0 +/-0.2 degrees.
A crystalline form of claim 14, wherein form a has an X-ray powder diffraction pattern as shown in figure 10; the X-ray powder diffraction pattern of the crystal form B is shown in figure 13; the X-ray powder diffraction pattern of the crystal form C is shown in figure 16.
A crystalline form according to claim 14, characterised in that the diffraction peaks at the X-ray powder diffraction patterns of crystalline form a, crystalline form B and crystalline form C having the first ten times higher relative peak intensities have 2 θ errors of ± 0.2 ° to ± 0.5 °, preferably ± 0.2 ° to ± 0.3 °, most preferably ± 0.2 °, from the diffraction peaks at the positions corresponding to fig. 10, fig. 13 and fig. 16, respectively.
A crystalline form according to claim 14, characterized in that form a has a melting point of about 218 ℃ to 224 ℃;

the form B melting point is about 216 ℃ to 220 ℃;

the crystalline form C has a melting point of about 218 ℃ to 223 ℃.
The crystalline form of claim 14, characterized in that form a has a DSC profile as shown in figure 11; or a TGA profile as shown in figure 12; the form B has a DSC pattern as shown in figure 14; or a TGA profile as shown in figure 15; the form C has a DSC pattern as shown in figure 17.
A crystalline form of a compound according to any one of claims 5 to 21, wherein the diffraction peaks have a2 Θ error of ± 0.3 ° or ± 0.5 °.
A crystalline form of the compound of claim 1, wherein the compound is 6- (cyclopropylcarboxamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d ₃ ) Pyridazine-3-carboxamide, the crystal forms are crystal form A, crystal form B, crystal form C, wherein:

the X-ray powder diffraction pattern of the crystal form A is basically shown in figure 1; the X-ray powder diffraction pattern of the crystal form B is basically shown in figure 4; the form C has an X-ray powder diffraction pattern substantially as shown in figure 7;

or,

the compound is 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide in a crystal form a, a crystal form B or a crystal form C, wherein:

the X-ray powder diffraction pattern of the crystal form A is basically as shown in figure 10; the X-ray powder diffraction pattern of the crystal form B is basically as shown in figure 13; the X-ray powder diffraction pattern of the crystal form C is basically shown in figure 16.
A crystalline form of a compound according to any one of claims 1 to 23, characterised in that it is a solvent-containing or solvent-free form, wherein the solvent is selected from one or more of water, methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, N-butanol, isobutanol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, N-propanol, tert-butanol, 2-butanone, 3-pentanone, N-heptane, ethyl formate, isopropyl acetate, cyclohexane, methyl tert-butyl ether or isopropyl ether.
A crystalline form of a compound according to claim 24, wherein the number of solvents is 0 to 3, preferably 0, 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0, 0.5, 1,2 or 3.
A process for preparing a crystalline form of a compound according to any one of claims 1 to 25, comprising in particular the steps of:

a) Weighing a proper amount of free alkali, and suspending with a poor solvent; the suspension density is preferably 50 to 200mg/mL,

b) Shaking or pulping the obtained suspension for a certain time at a certain temperature; the temperature is preferably 0-50 ℃, and the time is 1-10 days; preferably, the amount of the surfactant is 1 to 5 days,

c) Optionally further centrifuging the suspension, removing the supernatant, and drying to obtain a target product; drying, preferably drying in a vacuum drying oven at 40 deg.C to constant weight,

the poor solvent is selected from one or more of 88% acetone, isopropanol, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, ethyl acetate, N-hexane, N-heptane, acetonitrile, ethanol, dichloromethane, 1,4-dioxane, benzene, toluene, N-butanol, isobutanol, N-dimethylformamide, N-dimethylacetamide, N-propanol, tert-butanol, 2-butanone or 3-pentanone; preferably one or more of 3-pentanone, acetonitrile, dichloromethane or 1, 4-dioxane;

or, the method specifically comprises the following steps:

a) Weighing appropriate amount of free base, dissolving with good solvent, optionally heating,

b) Dripping an anti-solvent into the solution obtained in the step a), naturally cooling or stirring until solid is separated out to obtain suspension,

c) Optionally, further centrifuging the suspension obtained in the step b), removing supernatant, and drying to obtain a target product; drying preferably in a vacuum drying oven at 40-50 deg.C to constant weight,

the good solvent is selected from one or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, N-butanol, isobutanol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, N-propanol, tert-butanol, 2-butanone or 3-pentanone; preferably one or more of N-methylpyrrolidone, N-dimethylformamide or acetonitrile; or, the good solvent can also be dimethyl sulfoxide;

the antisolvent is selected from one or more of heptane, isopropyl ether, ethyl acetate, acetonitrile, ethanol, toluene, isopropanol, isopropyl acetate, water, methyl tert-butyl ether or cyclohexane; preferably one or more of isopropyl ether, n-heptane or water.
A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of a compound of any one of claims 1-25, and one or more pharmaceutically acceptable carriers or excipients.
A crystalline form of a compound according to any one of claims 1-25, and the use of a pharmaceutical composition according to claim 27 for the manufacture of a TYK2 inhibitor medicament.
A crystalline form of a compound according to any one of claims 1-25, and the use of a pharmaceutical composition according to claim 27 in the treatment of an inflammatory disease and an autoimmune disease; wherein the inflammatory and autoimmune diseases are selected from rheumatoid arthritis, dermatitis, psoriasis or inflammatory bowel disease.