Inhibitors of stk33, ret, clk and / or related kinases and methods of use thereof

Abstract

In one aspect, the present disclosure provides compounds that inhibit STK33, RET, CLK family kinases, and / or related kinases.

Description

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 598,802, filed November 14, 2023, pursuant to 35 USC § 119(e) (which is incorporated herein by reference in its entirety).

[0002] sequence list An XML file named “046641-7059WO1 - Sequence Listing.xml”, created on November 13, 2024, contains 7.2 kilobytes and is incorporated into this article in its entirety by reference. Background Technology

[0003] Although women have opted for small-molecule contraceptives for over 50 years, there are still no effective non-hormonal oral contraceptives for men. Therefore, there is a need to identify and validate contraceptives that target novel proteins and structures without relying on endocrine intervention.

[0004] The population of our planet is increasing at an alarming rate. In the past 60 years, the world's population has increased more than 2.6 times, from 3 billion in 1960 to 8 billion in 2022, and is projected to reach 9 billion by 2037. With such a high population growth rate, it is unclear whether every child born in the near future will have enough food, water, and education. Contraception is a crucial strategy for family planning and can help curb the continued population explosion and human impact on the environment. However, since the introduction of birth control pills for women, breakthroughs in contraception have been limited in recent decades. Despite a clear need for more affordable, long-acting, reversible, and therefore safe oral contraceptives, there are currently no effective oral contraceptives available for men.

[0005] Despite the creation of over 800 knockouts of testicular-enriched genes, with approximately 250 revealing male fertility phenotypes, small-molecule inhibitors of these validated targets have yet to be developed, and very few have demonstrated non-hormonal contraceptive efficacy in preclinical models. This disclosure addresses these needs. Summary of the Invention

[0006] The following exemplary implementations are provided, but these implementations do not limit the scope of the disclosure illustrated herein.

[0007] This disclosure provides, in one aspect, a compound of formula (I): (I), Where L 1 X, Y, Z 1 Z 2 Z 3 Ra and R b Defined elsewhere in this article.

[0008] This disclosure provides, in one aspect, pharmaceutical compositions comprising any compound of this disclosure and a pharmaceutically acceptable carrier.

[0009] This disclosure provides, in one aspect, a method for sterilizing a male object, the method comprising administering to the male object a therapeutically effective amount of at least one compound and / or pharmaceutical composition of this disclosure. In some embodiments, the sterilization is temporary.

[0010] This disclosure provides, in one aspect, a method for promoting male contraception and / or infertility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of at least one compound and / or pharmaceutical composition of this disclosure. In some embodiments, the infertility is temporary.

[0011] In one aspect, this disclosure provides a method for minimizing and / or reducing sperm count and / or motility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of at least one compound and / or pharmaceutical composition of this disclosure.

[0012] In one aspect, this disclosure provides a method for inhibiting RET in mammals, the method comprising administering an effective amount of at least one compound and / or pharmaceutical composition of this disclosure to the mammal.

[0013] This disclosure provides, in one aspect, a method for treating, improving, and / or preventing diseases or disorders caused by RET overexpression or high RET activity, the method comprising administering to the mammal a therapeutically effective amount of at least one compound and / or pharmaceutical composition of this disclosure.

[0014] In one aspect, this disclosure provides a method for inhibiting at least one of CL1, CLK2, CLK3, and CLK4 in a mammal, the method comprising administering an effective amount of at least one compound and / or pharmaceutical composition of this disclosure to the mammal.

[0015] This disclosure provides, in one aspect, a method for treating, improving, and / or preventing diseases or disorders caused by CLK overexpression or CLK hyperactivity, the method comprising administering to the mammal a therapeutically effective amount of at least one compound and / or pharmaceutical composition of this disclosure. Attached Figure Description

[0016] The following detailed description of exemplary embodiments of the present disclosure will be better understood when read in conjunction with the accompanying drawings. Non-limiting embodiments are shown in the drawings for illustrative purposes. However, it should be understood that the present disclosure is not limited to the precise arrangement and means of the embodiments shown in the drawings.

[0017] Figure 1 DEC-Tec selection is depicted. The enrichment profile of the BCM DNA-encoded chemical library (DECL) qDOS28_1 for STK33 at 0.1 μM (x-axis, z-score) is compared to a target-free control (y-axis, z-score). A series of hit compounds were identified, sharing similar building blocks 1 (BB1, shown in blue; attached to DNA), BB2 (BB2, shown in red), and BB3 (BB3, shown in black). The enrichment of each trisynthetic at 0.1 μM is shown in the boxes as sequencing count / z-score.

[0018] Figures 2A-2D Examples of STK33-hit compounds, analogues, and biological properties are described. Figure 2A The chemical structure of CDD-2110 (i.e., the hit compound with short linkers enriched in STK33 selection). The blue, red, and black portions correspond to BB1, BB2, and BB3, respectively. Figure 2B The chemical structures of CDD-2211, CDD-2212, and CDD-2807 (i.e., analogues of CDD-2110). Figure 2C Chemical properties, biochemical activities, cellular activity, and metabolic data of CDD-2110, CDD-2211, CDD-2212, and CDD-2807. Dissociation constant (K). d ) value and inhibition constant (K i The values ​​were calculated using LanthaScreen assay and Z'-LYTE assay, respectively; the half-maximum inhibitory concentration (IC50) was calculated. 50 The values ​​were calculated using NanoBRET assays. Half-life (t) was measured using a mouse liver microsomal (MLM) or human liver microsomal (HLM) stability assay. 1 / 2 Data measured >60 min are extrapolated estimates and are included in the relative determination of half-life. Figure 2D The summary of fractional occupancy values ​​of CDD-2807 for kinases with an occupancy rate >30% (red: 30-49.9%; yellow: 50-79.9%; green: 80-100%) is derived from NanoBRET target engagement (TE) K192 assays performed at 1 µM.

[0019] Figures 3A-3E The crystal structure of the STK33 / CDD-2211 complex was depicted. Figure 3A The overall structure of the STK33 / CDD-2211 dimer complex. Chain A is shown as the surface, while chain B is shown as a cartoon. The N-terminus and C-terminus are labeled. The bound CDD-2211 is shown as bars, with carbon atoms shown in yellow, oxygen atoms in red, and nitrogen atoms in blue. The active ring is colored red. Figure 3B When contour lines are drawn with 1σ, the CDD-2211 in the STK33 / CDD-2211 complex has a 2σ value. Fo - Fc density.( Figure 3C An electrostatic surface containing active sites of CDD-2211. Figure 3D The LIGPLOT plot shows the interaction between STK33 and CDD-2211. Figure 3E Detailed interaction between STK33 and CDD-2211. Hinge residues forming hydrogen bonds with the ligands are shown as spheres. Key interacting residues are shown as bars.

[0020] Figures 4A-4H The effects of CDD-2807 treatment on inducing reversible contraception were described. Figure 4A , Figure 4B The average litter size from a two-month fertility assessment showed that in scheme 1 ( Figure 4A (n = 6) and Scheme 2 ( Figure 4B In mice with n = 7, fertility was significantly reduced (*P < 0.0001) in both the first and second months after CDD-2807 treatment. Fertility recovered to the same level as the control group after discontinuing CDD-2807 treatment in protocol 1. Figure 4C In mice of scheme 2, there was no significant difference in testes from control and CDD-2807-treated mice at day 63. Figure 4D-Figure 4G Compared with control mice (n = 3), the sperm count of CDD-2807-treated mice (n = 3) from protocol 2 at day 63 was significantly lower. Figure 4D ),vitality( Figure 4E Forward-moving sperm ( Figure 4F ) and super-activated sperm ( Figure 4G The reduction was statistically significant (*P<0.005). Figure 4H SEM analysis showed that, compared with only 10.9 ± 2.7% of abnormal sperm in the control group (n = 3), 94.7 ± 2.7% of sperm in the CDD-2807-treated mice (n = 3) in Protocol 2 had morphological defects at day 63, including the head and tail defects shown.

[0021] Figures 5A-5B The DEC-Tec selectivity and potent hit compounds were described. Figure 5A BCM DECL qDOS28_1 enrichment profile of STK33 (x-axis, z-score) at 0.5 μM, compared with the target-free control (y-axis, z-score). Figure 5B The enrichment profile of STK33 (x-axis, z-score) at 0.5 μM using BCMDECL qDOS28_1 was compared with the selection of STK33 (y-axis, z-score) at 0.5 μM in the presence of asteroidin. No most hit compounds were observed in the presence of asteroidin, indicating competitive binding.

[0022] Figure 6 Provides a superposition of the two chains of the STK33 / CDD-2211 dimer complex. The magnified image on the right shows the bound CDD-2211 molecule and the residues within 5 Å of CDD-2211. Chain A is colored brown, while chain B is colored magenta. The two chains are nearly identical, showing an RMSD of 0.61 Å between the shared 252 CA atoms. Chains A and B are colored magenta and brown, respectively. Only CA atoms were used for chain alignment.

[0023] Figure 7 Provides structure-based sequence alignments for STK33, RET, and CLK4. Contact residues E199 and M245 of CDD-2211 are specific to STK33 and are marked with arrows.

[0024] Figure 8 A model of CDD-2807 that connects to the active site of human STK33 is provided. (Used with...) Figure 3E Same color theme.

[0025] Figure 9 Provides sequence alignment between human and mouse STK33 proteins. Sequence alignment was performed using the CLUSTAL W program and plotted using the ENDscript program. Identified amino acids using the default ESPript parameters (Risler, global score 0.7) are highlighted in white against a red background, while similar residues are highlighted in red. The secondary structure of the human STK33 kinase domain is indicated above the sequence. CDD-2211 contact residues in the human STK33 / CDD-2211 complex are marked with arrows.

[0026] Figure 10 Provides an evaluation of the pharmacokinetics of CDD-2807 in mice.

[0027] Figure 11 shows the timeline of the study protocol for mouse reproduction and reversibility.

[0028] Figures 12A-12D Data are provided showing no change in body weight in mice treated with CDD-2807 long-term. Body weight change during treatment regimen 1 ( Figure 12A (n = 3-6 mice) and the body weight of the mice in scheme 1 that were sacrificed on day 45 in scheme 1 ( Figure 12C (n = 2-3 mice). Changes in body weight during treatment scheme 2 ( Figure 12B (n = 4-7 mice) and the body weight of the mice in scheme 2 that were sacrificed on day 63 ( Figure 12D (n = 3 mice).

[0029] Figures 13A-13F Data are provided showing that CDD-2807 altered sperm parameters in mice by crossing the BTB, but did not change testicular weight. Figure 13A The levels of CDD-2807 in the testes and brains of mice in Protocol 1 (n = 3) on day 45 and in mice in Protocol 2 (n = 3) on day 63 were measured; CDD-2807 was not observed in tissues of control mice. Figure 13B Although CDD-2807 has a contraceptive effect, the testicular size of CDD-2807-treated mice in both Protocol 1 (n = 2) and Protocol 2 (n = 3) groups remained unchanged on day 45 and day 63, respectively. Figure 13C The mediator control mice (n = 2) in scheme 1 unexpectedly had low sperm counts. Figures 13D-13F Compared with the mediator control mice (n = 2), the sperm motility of CDD-2807-treated mice (n = 3) was significantly lower. Figure 13D Forward-moving sperm ( Figure 13E ) and super-activated sperm ( Figure 13F () was reduced.

[0030] Figures 14A-14B Provided from control mice of Protocol 1 and male mice treated with CDD-2807 ( Figure 14A ) testicular segment and ( Figure 14B Histological analysis of the epididymal segments (head and body). Testes and epididymis were fixed in Bouin's solution and stained with PAS-hematoxylin in 4 μm longitudinal sections. All 12 stages of spermatogenesis were present in both control and CDD-2807-treated mice, showing normal histological morphology and acrosome development. The epididymis from control and CDD-2807-treated mice were histologically similar. Scale bars are included for reference. Detailed Implementation

[0031] On one hand, this disclosure provides a method for altering cellular signaling (such as kinase signaling) in a subject. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the method includes administering a therapeutically effective amount of the disclosed compound to the subject. In some embodiments, the disclosed compound is administered orally to the subject. In some embodiments, the disclosed compound is administered to the male subject at the dosage and timing necessary to provide a contraceptive effect in the male subject.

[0032] In some embodiments, this document provides a method for altering cell signaling in a subject. In some embodiments, this document provides a method for altering kinase function in a subject. In some embodiments, this document provides a method for altering STK signaling in a subject. In some embodiments, this document provides a method for altering RET signaling in a subject. In some embodiments, this document provides a method for altering CLK signaling in a subject. In some embodiments, the method includes administering an effective amount of a compound of the present disclosure, such as, but not limited to, compounds of formula (I), (II), (III), (IV), (V), (VI), and / or (VII).

[0033] In some embodiments, this document provides methods for treating, improving, and / or preventing kinase-mediated diseases and / or disorders (such as, but not limited to, cancer), methods comprising administering compounds of the present disclosure, such as, but not limited to, compounds of formula (I), (II), (III), (IV), (V), (VI), and / or (VII).

[0034] Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are partially illustrated in the accompanying drawings. Although the disclosed subject matter will be described in conjunction with the enumerated claims, it should be understood that the exemplary subject matter is not intended to limit the claims to the disclosed subject matter.

[0035] Throughout this document, values ​​expressed in range format should be interpreted flexibly, including not only the numerical values ​​explicitly stated as range boundaries, but also all individual numerical values ​​or subranges contained within that range, as if each numerical value and subrange were explicitly stated. For example, the range “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted as including not only about 0.1% to about 5%, but also the individual values ​​within the indicated range (e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). Unless otherwise indicated, the statement “about X to Y” has the same meaning as “about X to about Y”. Similarly, unless otherwise indicated, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z”.

[0036] In the method described herein, actions can be performed in any order unless the timing or sequence of operations is explicitly stated. Furthermore, the specified actions can be performed simultaneously unless the explicit wording of the claims states that they are performed separately. For example, the claimed action of doing X and the claimed action of doing Y can be performed simultaneously in a single operation, and the resulting process falls within the literal scope of the claimed method.

[0037] definition As used herein, the term “about” may allow for a degree of variability in a value or range, for example, within 10%, 5%, or 1% of the limits of the stated value or range, and includes the exact stated value or range.

[0038] In this document, unless the context clearly specifies otherwise, the terms “a,” “an,” or “the,” are used to include one or more. Unless otherwise indicated, the term “or” is used to refer to a non-exclusive “or.” The statements “at least one of A and B” or “at least one of A or B” have the same meaning as “A, B, or A and B.” Furthermore, it should be understood that, unless otherwise defined, the wording or terminology used herein is for descriptive purposes only and not for limiting purposes. The use of any section headings is to aid reading of this document and should not be construed as limiting; information relating to a section heading may appear within or outside that particular section. All publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety as if they were individually incorporated.

[0039] As used herein, the term "acyl" refers to a group containing a carbonyl moiety, wherein the group is bonded via a carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen atom forming a "formyl" group or to another carbon atom, which may be part of an alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclic, heterocyclic alkyl, heteroaryl, heteroaryl, or similar group. An acyl group may include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group may include double or triple bonds as understood herein. An example of an acyl group is an acyl group. An acyl group may also include heteroatoms as understood herein. An example of an acyl group as understood herein is a nicotinyl (pyridyl-3-carbonyl). Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acyl. When a group containing a carbon atom bonded to a carbonyl carbon atom contains a halogen, the group is called a "haloacyl" group. An example is a trifluoroacetyl group.

[0040] As used herein, the term "alkyl" refers to straight-chain and branched alkyl and cycloalkyl groups having 1 to 40 carbon atoms, 1 to 20 carbon atoms, 1 to 12 carbon atoms, or, in some embodiments, 1 to 8 carbon atoms. Examples of straight-chain alkyl groups include those having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl. As used herein, the term "alkyl" encompasses n-alkyl, isoalkyl, and trans-isoalkyl groups, as well as other branched forms of alkyl. Representative substituted alkyl groups may be substituted once or multiple times with any of the groups listed herein, such as amino, hydroxyl, cyano, carboxyl, nitro, thio, alkoxy, and halogen groups.

[0041] As used herein, the term "alkenyl" refers to straight-chain and branched, as well as cyclic alkyl groups, as defined herein, differing in that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have 2 to 40 carbon atoms, or 2 to approximately 20 carbon atoms, or 2 to 12 carbon atoms, or 2 to 8 carbon atoms in various embodiments. Examples include, but are not limited to, vinyl, -CH=C=CCH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl, etc.

[0042] As used herein, the term "alkoxy" refers to an oxygen atom bonded to an alkyl group (including cycloalkyl groups) as defined herein. Examples of straight-chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, etc. Examples of branched-chain alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, etc. Examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc. An alkoxy group may include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to an oxygen atom, and may further include double or triple bonds, and may also include heteroatoms. For example, allyloxy or methoxyethoxy are also alkoxy groups in the sense of this document, as are methylenedioxy groups where two adjacent atoms in a structure are substituted with them.

[0043] As used herein, the term "alkynyl" refers to straight-chain and branched alkyl groups, distinguished by the presence of at least one triple bond between two carbon atoms. Therefore, an alkynyl group has 2 to 40 carbon atoms, 2 to approximately 20 carbon atoms, or 2 to 12 carbon atoms, or in some embodiments 2 to 8 carbon atoms. Examples include, but are not limited to, -C. CH, -C C(CH3), -C C(CH2CH3), CH2C CH, CH2C C(CH3) and CH2C C(CH2CH3), etc.

[0044] As used herein, the term "amine" refers to primary, secondary, and tertiary amines having, for example, the formula N(group)3, wherein each group may be independently H or non-H, such as alkyl, aryl, etc. Amines include, but are not limited to, R-NH2, such as alkylamines, arylamines, alkylarylamines; R2NH, wherein each R is independently chosen, such as dialkylamines, diarylamines, arylalkylamines, heterocyclic amines, etc.; and R3N, wherein each R is independently chosen, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, etc. The term "amine" also includes ammonium ions as used herein.

[0045] As used in this article, the term "amino" refers to -NH2, -NHR, -NR2, and -NR3. + Substituents of the form, wherein each R is independently chosen, and each has a protonated form, except for the non-protonable -NR3. + Therefore, any compound substituted with an amino group can be considered an amine. In this context, "amino" can refer to a primary, secondary, tertiary, or quaternary amino group. "Alkylamino" includes monoalkylamino, dialkylamino, and trialkylamino groups.

[0046] As used herein, the term "aminoalkyl" refers to an amine linked to an alkyl group as defined herein. The amino group may appear at any suitable position within the alkyl chain, such as at the end of the alkyl chain or anywhere within the alkyl chain.

[0047] As used herein, the term "aralkyl" refers to an alkyl group as defined herein, wherein the hydrogen or carbon bonds of the alkyl group are replaced by bonds of the aryl group as defined herein. Representative aralkyl groups include benzyl and phenethyl, as well as fused (cycloalkylaryl)alkyl groups, such as 4-ethyl-indenyl. Arylene is an alkenyl group as defined herein, wherein the hydrogen or carbon bonds of the alkyl group are replaced by bonds of the aryl group as defined herein.

[0048] As used herein, the term "aryl" refers to a cyclic aromatic hydrocarbon group that does not contain heteroatoms in its ring. Therefore, aryl groups include, but are not limited to, phenyl, azulel, heptenyl, biphenyl, indacenyl, fluorenyl, phenanthrene, triphenylene, pyrene, tetraphenyl, phenyl, biphenylene, anthracene, and naphthyl. In some embodiments, the aryl group contains about 6 to about 14 carbons in the cyclic portion of the group. As defined herein, aryl groups can be unsubstituted or substituted. Representative substituted aryl groups can be monosubstituted or substituted more than once, such as, but not limited to, phenyl groups substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the benzene ring, or naphthyl groups substituted at any one or more of the 2- to 8-positions of the benzene ring.

[0049] As used in this article, the term "C" 6-10 - C 6-10 "Lianfang (Ji)" means to bind with another C via a single bond. 6-10 C-terminal covalent bond of aryl group 6-10 Aryl moiety. C 6-10 The aryl moiety can be any suitable aryl group as described in this article. C 6-10 - C 6-10 Non-limiting examples of biaryl groups include biphenyl(l) and binatyl(l).

[0050] As used herein, the terms "composition" or "pharmaceutical composition" refer to a mixture of at least one compound described herein with a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of the compound to a patient or subject. Various techniques for administering compounds exist in the art, including but not limited to intravenous, oral, aerosol, parenteral, intraocular, pulmonary, and topical administration.

[0051] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group may have 3 to about 8-12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups, such as, but not limited to, norbornel, adamantyl, bornel, camphenyl, isocamphenyl, and carenyl groups, as well as fused rings, such as, but not limited to, decahydronaphthyl. Cycloalkyl groups also include rings substituted with straight-chain or branched alkyl groups as defined herein. Representative substituted cycloalkyl groups can be monosubstituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups or mono-, di-, or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxyl, cyano, carboxyl, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl" used alone or in combination refers to a cyclic alkenyl group.

[0052] "Disease" refers to the health condition of an animal in which the animal is unable to maintain homeostasis, and in which the animal's health will continue to deteriorate if the disease is not treated.

[0053] In contrast, an "obstacle" in animals is a state of health in which the animal is able to maintain homeostasis, but the animal's health is not as favorable as it would be without the obstacle. Without treatment, the obstacle does not necessarily lead to a further decline in the animal's health.

[0054] The disease or disorder is "reduced" if the severity of the symptoms, the frequency with which the patient experiences the symptoms, or both decrease.

[0055] As used herein, the terms “effective amount,” “pharmaceutical effective amount,” and “therapeutic effective amount” refer to an agent that is nontoxic but provides an adequate amount of the desired biological outcome. This outcome may be a reduction and / or alleviation of the signs, symptoms, or cause of a disease, or any other desired change in a biological system. The appropriate therapeutic amount in any case can be determined by a person skilled in the art using routine laboratory methods.

[0056] Unless otherwise stated, the terms “halogen”, “halogen” or “halide” as used herein refer to a fluorine, chlorine, bromine or iodine atom, either on its own or as part of another substituent.

[0057] As used herein, the term "haloalkyl" includes monohaloalkyl, polyhaloalkyl in which all halogen atoms may be the same or different, and perhaloalkyl in which all hydrogen atoms are replaced by halogen atoms (such as fluorine). Examples of haloalkyl groups include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, etc.

[0058] As used herein, the term "heteroaryl" refers to an aromatic ring compound containing five or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, and S; for example, a heteroaryl ring can have from 5 to approximately 8-12 ring members. A heteroaryl is a type of heterocyclic group possessing an aromatic electronic structure. A heteroaryl named C2-heteroaryl can be a 5-ring containing two carbon atoms and three heteroatoms, a 6-ring containing two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so on. The sum of the number of carbon atoms and the number of heteroatoms equals the total number of ring atoms. Heteroaryls include, but are not limited to, groups such as pyrrole, pyrazolyl, triazolyl, tetrazolyl, etc. azole group, iso Azolyl, thiazolyl, pyridyl, thiophene, benzothiophene, benzofuranyl, indole, azaindole, indazole, benzimidazole, azabenzimidazole, benzo[] Azolyl, benzothiazolyl, benzothiadiazole, imidazopyridyl, iso The heteroaryl groups include azopyridyl, thianaphthalenyl, purine, xanthine, adenine, guanine, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. The heteroaryl groups can be unsubstituted or substituted with groups as discussed herein. Representative substituted heteroaryl groups can be substituted once or multiple times with the groups listed herein.

[0059] Other examples of aryl and heteroaryl groups include, but are not limited to, phenyl, biphenyl, indene, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazole, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracene (1-anthrayl, 2-anthrayl, 3-anthrayl), thiophene (2-thiophene, 3-thiophene), furanyl (2-furanyl, 3-furanyl), indole, diazole group, iso Azolyl, quinazolinyl, fluorenyl, xanthyl, isoninyl, diphenylmethyl, acridineyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazoleyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl) azole (2- azole group, 4- azole, 5- (Azolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolinyl (2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl), isoquinolinyl (1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-quinolinyl) -Isoquinolinyl, 8-isoquinolinyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl) -benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophene (2-benzo[b]thiophene, 3-benzo[b]thiophene, 4-benzo[b]thiophene, 5-benzo[b]thiophene, 6-benzo[b]thiophene, 7-benzo[b]thiophene), 2,3-dihydro-benzo[b]thiophene (2-(2,3-dihydro-benzo[b]thiophene), 3-(2,3-dihydro-benzo[b]thiophene), 4-(2,3-dihydro-benzo[b]thiophene), 5-(2,3-dihydro-benzo[b]thiophene) (b)thienyl), 6-(2,3-dihydro-benzo[b]thienyl), 7-(2,3-dihydro-benzo[b]thienyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazole, 3-indazole, 4-indazole, 5-indazole, 6-indazole, 7-indazole), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzo[b]thienyl azole (1-benzo) azole, 2-benzo (Azolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazole (1-carbazole, 2-carbazole, 3-carbazole, 4-carbazole), 5H-dibenzo[b,f]acoxane (5H-dibenzo[b,f]acoxane-1-yl, 5H-dibenzo[b,f]acoxane-2-yl, 5H-dibenzo[b,f]acoxane-3-yl, 5H-dibenzo[b,f]acoxane-4 ...3-yl, 5H-dibenzo[b,f]acoxane-4-yl, 5H-dibenzo[b,f]acoxane-3-yl, 5H-dibenzo[b,f]acoxane-4-yl, 5H-dibenzo[b,f]acoxane-3-yl, 5H-dibenzo[b,f]acoxane-4-yl, 5H-dibenzo[b,f]acoxane-3-yl, 5H-dibenzo[b,f]acoxane-4-yl, 5H-dibenzo[b,f]acoxane-3-yl, 5H-dibenzo[b,f]acoxane-4-yl, 5H-dibenzo[b,f]acox [b,f]acoxane-5-yl), 10,11-dihydro-5H-dibenzo[b,f]acoxane (10,11-dihydro-5H-dibenzo[b,f]acoxane-1-yl, 10,11-dihydro-5H-dibenzo[b,f]acoxane-2-yl, 10,11-dihydro-5H-dibenzo[b,f]acoxane-3-yl, 10,11-dihydro-5H-dibenzo[b,f]acoxane-4-yl, 10,11-dihydro-5H-dibenzo[b,f]acoxane-5-yl), etc.

[0060] As used herein, the term “heteroaryl” means an alkyl group as defined herein, wherein the hydrogen or carbon bonds of the alkyl group are replaced by bonds of the heteroaryl group as defined herein.

[0061] As used in this article, the term "C" 6-10 "-5-6-membered heteroaryl" means that C is covalently bonded to a 5- or 6-membered heteroaryl moiety via a single bond. 6-10 Aryl moiety. C 6-10 The aryl moiety and the 5-6 membered heteroaryl moiety can be any suitable aryl and heteroaryl moiety as described herein. C 6-10 Non-limiting examples of -5-6 grade heterocyclic aromatics include: and When C 6-10 When -5-6-membered heteroaryl(yl) groups are listed as substituents (e.g., "R" groups), C 6-10 -5-6-yuan heterocyclic aromatic (base) via C 6-10 Part of it binds to the rest of the molecule.

[0062] As used in this article, the term "5-6 yuan C" 6-10 "Hybrid Aroma (Base)" and C 6-10 -5-6-membered heterocyclic aromatics are the same, the difference being that when 5-6-membered C 6-10 When heteroaryl groups are listed as substituents (e.g., "R" groups), the 5-6 member carbon is... 6-10 Heteroarylene groups are bound to the rest of the molecule through a 5-6 member heteroarylene moiety.

[0063] As used herein, the term "heterocyclyl" refers to an aromatic and non-aromatic compound containing three or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, and S. Therefore, a heterocyclyl group can be a cycloheteroalkyl or heteroaryl group, or, if polycyclic, any combination thereof. In some embodiments, a heterocyclyl group comprises 3 to about 20 ring members, while other such groups have 3 to about 15 ring members. A heterocyclyl group named C2-heterocyclyl can be a 5-ring having two carbon atoms and three heteroatoms, a 6-ring having two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heterocyclyl group can be a 5-ring having one heteroatom, a 6-ring having two heteroatoms, and so on. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. The heterocyclyl ring may also include one or more double bonds. A heteroaryl ring is one embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused rings, including those containing fused aromatic and non-aromatic groups. For example, dioxolane and benzodioxolane ring systems (methylenedioxophenyl ring systems) are heterocyclyl groups within the meaning of this document. The phrase also includes polycyclic ring systems containing heteroatoms, such as, but not limited to, quinoline groups. Heterocyclyl groups can be unsubstituted or substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazineyl, morpholinyl, pyrrolidinyl, pyrazolyl, triazolyl, tetrazolyl, etc. azole group, iso Azolyl, thiazolyl, pyridyl, phenylthio, benzo[benzyl]thio, benzo[furan], dihydrobenzo[furan], indole, dihydroindole, aza-indole, indazole, benzimidazole, aza-benzimidazole, benzo[[benzyl]] Azolyl, benzothiazolyl, benzothiadiazole, imidazopyridyl, iso Zolopyridyl, thianaphthyl, purine, xanthine, adenine, guanine, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. Representative substituted heterocyclic groups can be monosubstituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl, which are 2-, 3-, 4-, 5-, or 6-substituted or disubstituted by those groups listed herein.

[0064] As used herein, the term "heterocyclic alkyl" means an alkyl group as defined herein, wherein the hydrogen or carbon bonds of the alkyl group as defined herein are replaced by the bonds of the heterocyclic group as defined herein. Representative heterocyclic alkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl.

[0065] Unless the context clearly indicates otherwise, the term "independently selected" as used herein refers to the same, different, or mixed groups of references. Therefore, under this definition, the phrase "X" 1 X 2 and X 3 "Independently selected from rare gases" will include, for example, X 1 X 2 and X 3 They are all the same, among which X 1 X 2 and X 3 They are all different, among which X 1 and X 2 Same but X 3 Different situations and other similar arrangements.

[0066] As used herein, the term "monovalent" refers to a substituent that is attached to the substituted molecule via a single bond. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it substituted by a single bond.

[0067] As used herein, the term "organic group" refers to any carbon-containing functional group. Examples may include: oxygen-containing groups, such as alkoxy, aryloxy, arylalkoxy, and oxo (carbonyl) groups; carboxyl groups, including carboxylic acids, carboxyl groups, and carboxylic esters; sulfur-containing groups, such as alkyl and aryl thioether groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0-2 N(R)C(O)R、(CH2) 0-2 N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N (R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R and substituted or unsubstituted (C1-C 100 R can be a hydrocarbon group, where R can be hydrogen (in examples that include other carbon atoms) or a carbonyl moiety, and the carbonyl moiety can be substituted or unsubstituted.

[0068] The terms “patient,” “subject,” or “individual” are used interchangeably herein and refer to any animal or its cells, whether in vitro or in situ, as described herein. In a non-limiting embodiment, the patient, subject, or individual is a human being.

[0069] As used herein, the term "pharmaceutically acceptable" means a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of a compound and is relatively non-toxic, so that the material can be applied to an individual without causing undesirable biological effects or interacting in a harmful manner with any component of the composition containing it.

[0070] As used herein, “pharmaceutically acceptable salt” refers to a salt of an applied compound prepared from a pharmaceutically acceptable, non-toxic acid or base, including inorganic acids or bases, organic acids or bases, solvates, hydrates or inclusion complexes thereof.

[0071] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid (including sulfates and hydrogen sulfates), and phosphoric acid (including hydrogen phosphates and dihydrogen phosphates). Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic, and sulfonic acid organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, malonic acid, saccharin, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthraquinone, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylsulfamic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactopyric acid, and galacturonic acid.

[0072] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts and metal salts—including alkali metal, alkaline earth metal, and transition metal salts, such as, for example, calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), and procaine. All these salts can be prepared from the corresponding compounds by reacting them with, for example, a suitable acid or base.

[0073] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" mean a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that participates in the delivery or transport of the compound described herein to or to a patient so that it can perform its intended function. Typically, such compounds are delivered or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of compatibility with other components of the formulation, including one or more of the compounds described herein, and must not cause harm to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered astragalus gum; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and compatible substances used in pharmaceutical preparations. As used herein, "pharmaceuticalally acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delay agents that are compatible with the activity of one or more of the compounds described herein and are physiologically acceptable to patients. Additional active compounds may also be incorporated into the composition. "Pharmaceuticalally acceptable carrier" may further include pharmaceutically acceptable salts of one or more of the compounds described herein. Other additional ingredients known in the art and described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA) (which is incorporated herein by reference), may be included in pharmaceutical compositions used with the methods or compounds described herein.

[0074] As used herein, the term "solvent" refers to a liquid that can dissolve solids, liquids, or gases. Non-limiting examples of solvents include silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0075] As used herein, the term “substantially” means the majority or most, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more or 100%. As used herein, the term “substantially free” can mean not having or having trace amounts of material such that the amount of material present does not affect the material properties of the composition comprising the material, such that the material of the composition is about 0 wt% to about 5 wt%, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term "substantially free" may mean having trace amounts of the material of the composition, such that the composition is about 0 wt% to about 5 wt%, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01 or about 0.001 wt% or less, or about 0 wt%.

[0076] As used herein with the term "substituted" in conjunction with a molecule or organic group as defined herein, it refers to a state in which one or more hydrogen atoms contained herein are replaced by one or more non-hydrogen atoms. As used herein, the terms "functional group" or "substituent" refer to a group that can be substituted or is substituted onto a molecule or organic group. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl, alkoxy, aryloxy, arylalkoxy, oxo (carbonyl) groups, and carboxyl groups (including carboxylic acids, carboxyl groups, and carboxylic esters); sulfur atoms in groups such as thiols, alkyl and aryl sulfides, sulfoxides, sulfones, sulfonyl groups, and sulfonamides; nitrogen atoms in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazines, azides, and enamines; and other heteroatoms in a variety of other groups. Non-limiting examples of substituents that can bind to the substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azide, CF3, OCF3, R, O (oxo), S (thiocarbonyl), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0-2 N(R)C(O)R、(CH2) 0-2 N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, where R can be a hydrogen or carbon-based moiety; for example, R can be hydrogen, (C1-C 100 ) hydrocarbon group, alkyl group, acyl group, cycloalkyl group, aryl group, aralkyl group, heterocyclic group, heteroaryl group or heteroarylalkyl group; or wherein two R groups bonded to a nitrogen atom or to an adjacent nitrogen atom may together with one or more nitrogen atoms to form a heterocyclic group.

[0077] "Therapeutic" treatment is treatment applied to individuals exhibiting pathological signs with the aim of reducing or eliminating those signs.

[0078] As used herein, the term "thioalkyl" refers to a sulfur atom attached to an alkyl group as defined herein. The alkyl group in a thioalkyl group can be straight-chain or branched. Examples of straight-chain thioalkyl groups include, but are not limited to, thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, and thiohexyl. Examples of branched alkoxy groups include, but are not limited to, isothiopropyl, secondary thiobutyl, tertiary thiobutyl, isothiopentyl, and isothiohexyl. The sulfur atom can appear at any suitable position in the alkyl chain, such as at the end of the alkyl chain or anywhere within the alkyl chain.

[0079] As used herein, the terms “treat,” “treating,” and “treatment” mean reducing the frequency or severity of symptoms of a disease or condition experienced by a subject by administering an agent or compound to the subject.

[0080] Throughout this disclosure, all aspects of this disclosure can be presented in range form. It should be understood that descriptions in range format are merely for convenience and brevity and should not be construed as a rigid limitation on the scope of this disclosure. Therefore, a range description should be considered as having specifically disclosed all possible subranges and individual values ​​within that range. For example, a description of a range such as 1 to 6 should be considered as having specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual values ​​within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the range width.

[0081] compound On one hand, this disclosure relates to inhibitors of STK33. In some embodiments, the STK33 inhibitor selectively targets STK33 relative to one or more members of the relevant kinases. In some embodiments, this disclosure relates to inhibitors of RET. In some embodiments, the RET inhibitor selectively targets RET relative to one or more members of the relevant kinases. In some embodiments, this disclosure relates to inhibitors of CLK. In some embodiments, CLK is CLK1. In some embodiments, CLK is CLK2. In some embodiments, CLK is CLK3. In some embodiments, CLK is CLK4. In some embodiments, the CLK inhibitor selectively targets CLK relative to one or more members of the relevant kinases.

[0082] In some embodiments, selectivity is to make the compound target a specific kinase (STK33, RET, and / or one or more CLKs) via pIC. 50The values ​​are approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, or compared to the pIC of the compounds against the other kinases discussed. 50 higher.

[0083] In some embodiments, this document provides a compound of formula (I), or a salt, solvate, stereoisomer, tautomer or geometric isomer thereof.

[0084] In some embodiments, the compound of formula (I) is: (I), or its salts, solvates, stereoisomers, tautomers, or geometric isomers. in: L 1 Selected from -C≡C-, -CH=CH-, -CH2- and bonds; X is selected from -C(=O)-, -C(CH3)2-, -CF2-, -CHF-, -CH(CH3)- and -CH2; Z 1 Z 2 or Z 3 Independently, it is CH or N, where Z 1 Z 2 and Z 3 One of the 0s or 1s is N; R a and R b Independently selected from hydrogen, optionally substituted C1-C8 alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted phenyl groups, and optionally substituted 3- to 8-membered heterocyclic groups. Or R a and R b They can combine with the nitrogen atoms to which they are bonded to form optionally substituted 3- to 8-membered heterocyclic groups; and Y is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C3-C 10 heteroaryl or CN

[0085] In some embodiments, the compound of formula (I) is the compound of formula (Ia): (Ia).

[0086] In some embodiments, X is -C(=O)-. In some embodiments, X is -C(CH3)2-. In some embodiments, X is -CF2-. In some embodiments, X is -CHF-. In some embodiments, X is -CH(CH3)-. In some embodiments, X is -CH2-.

[0087] In some implementations, Z 1 Z 2 and Z 3 It is CH. In some implementations, Z 1 and Z 2 It is CH, and Z 3 It is N. In some implementations, Z 1 and Z 3 It is CH, and Z 2 It is N. In some implementations, Z 2 and Z 3 It is CH, and Z 1 It is N.

[0088] In some embodiments, Y is an optionally substituted phenyl group. In some embodiments, Y is an optionally substituted naphthyl group. In some embodiments, Y is an optionally substituted isoquinolinyl group. In some embodiments, Y is an optionally substituted quinolinyl group. In some embodiments, Y is an optionally substituted 2-pyridyl group. In some embodiments, Y is an optionally substituted 3-pyridyl group. In some embodiments, Y is an optionally substituted 4-pyridyl group. In some embodiments, Y is an optionally substituted pyrimidinyl group. In some embodiments, Y is an optionally substituted pyrazinyl group. In some embodiments, Y is an optionally substituted triazineyl group.

[0089] In some embodiments, Y is independently substituted with at least one of the following substituents: hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkoxy, -C(=O)NR e1 R e2 -NR e1 C(=O)R e2 Optionally substituted phenyl groups, optionally substituted naphthyl groups, optionally substituted 3- to 8-membered heterocyclic groups, and optionally substituted C3-C groups. 10 Heteroaryl; or two adjacent substituents may combine with the atoms to which they are bonded to form an optionally substituted phenyl, optionally substituted C4-C8 heterocyclic or optionally substituted C4-C8 heteroaryl.

[0090] In some implementations, R e1 and Re2 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, optionally substituted 3- to 8-membered heterocyclic groups, or optionally substituted C3-C... 10 Mixed aromatics; In some implementations, R a or R b One of them is hydrogen or methyl. In some embodiments, R a and R b The nitrogen atoms they combine with form optionally substituted 5, 6, or 7-membered heterocyclic groups. In some embodiments, R a and R b The nitrogen atoms they combine with form optionally substituted pyrrolidinyl groups.

[0091] In some implementations, Y is , where R c1 R c2 R c3 R c4 and R c5 Independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkoxy, -C(=O)NR e1 R e2 -NR e1 C(=O)R e2 Optionally substituted phenyl groups, optionally substituted naphthyl groups, optionally substituted 3- to 8-membered heterocyclic groups, and optionally substituted C3-C groups. 10 Mixed aromatics; or Selected from R c1 R c2 R c3 R c4 and R c5 The two adjacent substituents can combine with the carbon atoms to which they are bonded to form an optionally substituted phenyl, an optionally substituted C4-C8 heterocyclic group, or an optionally substituted C4-C8 heteroaryl group; Where R e1 and R e2 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, optionally substituted 3- to 8-membered heterocyclic groups, or optionally substituted C3-C... 10 Mixed aromatic compounds.

[0092] In some embodiments, the compound of formula (I) is a compound of formula (II), (III), (IV), or (V): (II) (III) (IV) or (V), in: R c1 R c2 R c3 R c4 and R c5 Independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkoxy, -C(=O)NR e1 R e2 -NR e1 C(=O)R e2 Optionally substituted phenyl groups, optionally substituted naphthyl groups, optionally substituted 3- to 8-membered heterocyclic groups, and optionally substituted C3-C groups. 10 Mixed aromatics; Or selected from R c1 R c2 R c3 R c4 and R c5 The two adjacent substituents can combine with the carbon atoms they are bonded to form an optionally substituted phenyl group, an optionally substituted C4-C8 heterocyclic group, or an optionally substituted C4-C8 heteroaryl group. R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 R d10 R d11 and R d12 If present, it is independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, optionally naphthyl, optionally 3- to 8-membered heterocyclic and optionally substituted 5- to 8-membered heteroaryl, optionally wherein R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 R d10 R d11 and R d12If any two of them are present, they can combine to form an alkylene or heteroalkylene (e.g., a spiro or fused bicyclic ring system) with 2 to 7 atoms that are optionally substituted. X 1 It is C(R) d3 (R) d4 ), O or NR f , where R f Selected from optionally substituted C1-C8 alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted C6-C... 10 Aryl, optionally substituted C3-C8 heterocyclic alkyl, optionally substituted C2-C8 heteroaryl, and optionally substituted C1-C8 acyl; and X 2 It is C(R) d5 (R) d6 ), O or NR f , where R f Selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 Aryl, optionally substituted C3-C8 heterocyclic alkyl, optionally substituted C2-C8 heteroaryl, and optionally substituted C1-C8 acyl.

[0093] In some implementations, NR a R b Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, NR a R b yes In some implementations, NR a R b yes In some implementations, NR a R b yes In some implementations, NR a R b yes In some implementations, NR a R b yes In some implementations, NR a R b Yes. In some implementations, NR a R b yes In some implementations, NR a R b yes In some implementations, NR a R b yes In some implementations, NRa R b yes In some implementations, NR a R b yes .

[0094] In some implementations... The radical group is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, R c5 It is an optionally substituted phenyl group. In some embodiments, yes In some implementations, yes In some implementations, yes In some implementations, yes In some implementations, yes In some implementations, yes In some implementations, yes In some implementations, yes In some implementations, yes In some implementations, yes In some implementations, yes In some implementations, yes In some implementations, yes .

[0095] In some embodiments, compounds of formula (VI) are provided herein: (VI).

[0096] In some embodiments, compounds of formula (VII) are provided herein: (VII)

[0097] In some embodiments, compound (I) is compound (II). In some embodiments, compound (I) is compound (III). In some embodiments, compound (I) is compound (IV). In some embodiments, compound (I) is compound (V). In some embodiments, compound (I) is compound (VI). In some embodiments, compound (I) is compound (VII).

[0098] In some embodiments, compounds are provided herein selected from: 3-([1,1'-biphenyl]-2-ylethynyl)-N-(4-methoxyphenyl)-1H-indazole-5-carboxamide, (S)-3-([1,1'-biphenyl]-2-ylethynyl)-N-(2-(dimethylamino)-2-oxo-1-phenylethyl)-1H-indazole-5-carboxamide, (R)-3-([1,1'-biphenyl]-2-ylethynyl)-N-(2-(dimethylamino)-2-oxo-1-phenylethyl)-1H-indazole-5-carboxamide, 3-([1,1'-biphenyl]-2-ylethynyl)-N-(2-(dimethylamino)-2-oxo-1-phenylethyl)-1H-indazole-5-carboxamide, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(pyrrolidine-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-hydroxypyrrolidine-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-hydroxypyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-hydroxypyrrolidine-1-yl)methyl ketone, 1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-one, 1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-N-methylpiperidine-4-carboxamide, (R)-1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-N-methylpiperidine-4-carboxamide, (S)-1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-N-methylpiperidine-4-carboxamide, 1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-N,N-dimethylpiperidine-4-carboxamide, (R)-1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-N,N-dimethylpiperidine-4-carboxamide, (S)-1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-N,N-dimethylpiperidine-4-carboxamide, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,5-diazabicyclo[2.2.2]octane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3,8-diazabicyclo[3.2.1]octane-3-yl) methyl ketone, 4-(2-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-2,6-diazaspiro[3.5]nonane-6-carbonyl)-N-methylcyclohexane-1-carboxamide, (R)-4-(2-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-2,6-diazaspiro[3.5]nonane-6-carbonyl)-N-methylcyclohexane-1-carboxamide, (S)-4-(2-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-2,6-diazaspiro[3.5]nonane-6-carbonyl)-N-methylcyclohexane-1-carboxamide, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (3-(phenylethynyl)-1H-indazol-5-yl)(pyrrolid-1-yl)methyl ketone, 3-([1,1'-biphenyl]-2-ylethynyl)-N-(2-(dimethylamino)ethyl)-N-methyl-1H-indazole-5-carboxamide, 3-([1,1'-biphenyl]-2-ylethynyl)-N-(2-(dimethylamino)ethyl)-1H-indazole-5-carboxamide, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)(3-(dimethylamino)pyrrolidine-1-yl) methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-(methylamino)pyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-(methylamino)pyrrolidone-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-(methylamino)pyrrolidone-1-yl)methyl ketone, 3-([1,1'-biphenyl]-2-ylethynyl)-N,N-dimethyl-1H-indazole-5-carboxamide, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-(phenylethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-(phenylethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-(phenylethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-((2,6-dichlorophenyl)ethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (S)-(3-((2,6-dichlorophenyl)ethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (3-((2,6-dichlorophenyl)ethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (R)-(3-((2-chlorophenyl)ethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (S)-(3-((2-chlorophenyl)ethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (3-((2-chlorophenyl)ethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-fluorophenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-fluorophenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-((2-fluorophenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-morpholinylphenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-morpholinylphenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-((2-morpholinylphenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-3-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-3-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, ((3-([1,1'-biphenyl]-3-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-4-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-4-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (3-([1,1'-biphenyl]-4-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-(isoquinoline-5-ylethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-(isoquinoline-5-ylethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-(isoquinoline-5-ylethynyl)-1H-indazol-5-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(piperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3,6-diazabicyclo[3.1.1]heptane-3-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,5-diazabicyclo[2.2.2]octane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3,8-diazabicyclo[3.2.1]octane-3-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(8-oxa-3-azabicyclo[3.2.1]octane-3-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-phenylpiperazin-1-yl)methyl ketone, (R)-3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-phenylpiperazin-1-yl)methyl ketone, (S)-3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-phenylpiperazin-1-yl)methyl ketone, 4-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)piperazin-2-one, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-aminopyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-aminopyrrolidine-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-aminopyrrolidine-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(1,4-diazacycloheptane-1-yl)methyl ketone (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(4,7-diazaspiro[2.5]octane-4-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(4,7-diazaspiro[2.5]octane-7-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(5,8-diazaspiro[3.5]nonane-8-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-methyl-2,7-diazaspiro[3.5]nonane-7-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl) methyl ketone, (7-Methyl-2,7-diazaspiro[3.5]nonane-2-yl)(3-((2-(pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-4-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(5-methyl-2,7-diazaspiro[3.5]nonane-2-yl) methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(5-methyl-2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(5-methyl-2,7-diazaspiro[3.5]nonane-2-yl) methyl ketone, (S)-4-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-3-phenylpiperazin-2-one, (R)-4-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-3-phenylpiperazin-2-one, 4-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-3-phenylpiperazin-2-one, 7-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-2,7-diazaspiro[3.5]nonane-1-one, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,8-diazaspiro[4.5]decane-2-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-6-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl) methyl ketone, (2,8-diazaspiro[4.5]decane-2-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(5,8-diazaspiro[3.5]nonane-5-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(6,9-diazaspiro[4.5]decane-6-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-phenylpiperazin-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-phenylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-phenylpiperazin-1-yl)methyl ketone, (S)-(2-phenylpiperazin-1-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(2-phenylpiperazin-1-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (2-Phenylopirabin-1-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-(4-chlorophenyl)piperazin-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-(4-chlorophenyl)piperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-(4-chlorophenyl)piperazin-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-phenylpiperazin-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-phenylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-phenylpiperazin-1-yl)methyl ketone, (S)-(2-phenylpiperazin-1-yl)(3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(2-phenylpiperazin-1-yl)(3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (2-Phenylopirabin-1-yl)(3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-benzylpiperazin-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-benzylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-benzylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)((2S,6S)-2,6-dimethylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)((2R,6S)-2,6-dimethylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)((2R,6R)-2,6-dimethylpiperazin-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-benzylpiperazin-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-benzylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-benzylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-isopropylpiperazin-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-isopropylpiperazin-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-isopropylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,9-diazaspiro[5.5]undecane-2-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[4.5]decane-2-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,7-diazaspiro[4.5]decane-2-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(1,8-diazaspiro[4.5]decane-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(8-oxa-1-azaspiro[4.5]decane-1-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,8-diazaspiro[4.5]decane-8-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-oxa-6-azaspiro[3.4]octane-6-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(8-oxa-2-azaspiro[4.5]decane-2-yl) methyl ketone, 3-([1,1'-biphenyl]-2-ylethynyl)-N-(7-azaspiro[3.5]nonane-2-yl)-1H-indazole-5-carboxamide, (3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(6-methyl-2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(5-methyl-2,5-diazaspiro[3,5]nonane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(5-methyl-2,5-diazaspiro[3,5]nonane-2-yl) methyl ketone, (3-((2-(pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-methyl-2,5-diazaspiro[3,5]nonane-5-yl) methyl ketone, (3-((2-(pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((4-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methylbenzamide, (S)-2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methylbenzamide, 2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methylbenzamide, (R)-N-(2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)phenyl)acetamide, (S)-N-(2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)phenyl)acetamide, N-(2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)phenyl)acetamide, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((3'-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,5-diazaspiro[3.5]nonane-2-yl)methyl ketone, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((2'-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-((2-(naphthyl-2-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methyl-[1,1'-biphenyl]-2-carboxamide, 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methyl-[1,1'-biphenyl]-3-carboxamide, N-(2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-[1,1'-biphenyl]-2-yl)acetamide, 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide, (3-((2-(6-amino-4-methylpyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)(7-oxa-2-azaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(2-aminopyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((3'-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((2'-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-((2-(2-aminopyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(2-(pyrrolidin-1-yl)pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(2-(piperazin-1-yl)pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(2-aminopyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (R)-2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)-N-phenylbenzamide, (S)-2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)-N-phenylbenzamide, 2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)-N-phenylbenzamide, (3-((2-(2-aminopyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(6-amino-4-methylpyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (R)-7-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)indololin-2-one, (S)-7-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)indololin-2-one, 7-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)indoline-2-one, (3-((2-(2-(pyrrolidin-1-yl)pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(2-(piperazin-1-yl)pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(4-methylpiperazin-1-carbonyl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(4-methylpiperazin-1-carbonyl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(4-methylpiperazin-1-carbonyl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, N-(2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-[1,1'-biphenyl]-2-yl)acetamide, 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methyl-[1,1'-biphenyl]-3-carboxamide, 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide, (3-((2-(2-(4-methylpiperazin-1-yl)pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (S)-1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-N-methylpyrrolidine-2-carboxamide, (R)-1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-N-methylpyrrolidine-2-carboxamide, 1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-N-methylpyrrolidine-2-carboxamide, N-(2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-[1,1'-biphenyl]-2-yl)neopentamide, 5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazole-3-nitrile, (R)-5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazole-3-nitrile, (S)-5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazole-3-nitrile, (3-([1,1'-biphenyl]-2-yl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl) methyl ketone, (R)-(3-([1,1'-biphenyl]-2-yl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-yl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylmethyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl) ketone, (R)-(3-([1,1'-biphenyl]-2-ylmethyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylmethyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (E)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (R,E)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (S,E)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (Z)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (R,Z)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (S,Z)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(7-oxa-2-azaspiro[3.5]nonane-2-yl)methyl ketone, (E)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(7-oxa-2-azaspiro[3.5]nonane-2-yl)methyl ketone, (Z)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(7-oxa-2-azaspiro[3.5]nonane-2-yl)methyl ketone, (3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl) methyl ketone, (E)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl) methyl ketone, (Z)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone, 1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-3-phenylurea, (R)-1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-3-phenylurea, (S)-1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-3-phenylurea, 3-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-3,4-quinazolin-2(1H)-one, (R)-3-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-carbonyl)pyrrolidine-3-yl)-3,4-quinazolin-2(1H)-one, (S)-3-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-carbonyl)pyrrolidine-3-yl)-3,4-quinazolin-2(1H)-one, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-((4,6-dimethylpyrimidin-2-yl)amino)pyrrolidine-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-((4,6-dimethylpyrimidin-2-yl)amino)pyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-((4,6-dimethylpyrimidin-2-yl)amino)pyrrolidine-1-yl)methyl ketone, N-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-2,3-dihydrobenzo[b][1,4]di Indo-6-formamide, (R)-N-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-2,3-dihydrobenzo[b][1,4]di Indo-6-formamide, (S)-N-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-2,3-dihydrobenzo[b][1,4]di Indo-6-formamide, N-(2-((1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)benzamide, (R)-N-(2-((1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)benzamide, (S)-N-(2-((1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)benzamide, (3-([1,1'-biphenyl]-3-yl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-4-yl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone, (3-((2'-morpholino-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, 7-(2-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)phenyl)isoindoline-1-one, 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide, (3-((2'-(pyrrolidone-1-ylmethyl)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2'-(morpholinylmethyl)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(6-(vinylsulfonyl)-2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(6-(ethylsulfonyl)-2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone, (3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-phenylpyridin-3-yl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((3-phenylpyridin-4-yl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((4-phenylpyridin-3-yl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((3-phenylpyridin-2-yl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone.

[0099] In some respects, this article provides compounds selected from those listed in Table A: Table A The compounds described herein may have one or more stereocenters, and each stereocenter may be ( R )or( SThe configuration exists independently. In some embodiments, the compounds described herein exist in optical or racemic forms. It should be understood that the compounds described herein encompass racemic, optical, regioisomeric, and stereoisomeric forms, or combinations thereof, having the therapeutically useful properties described herein. Preparation of the optical form is achieved in any suitable manner, including, as a non-limiting example, resolution of the racemic form by recrystallization, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In some embodiments, a mixture of one or more isomers is used as the therapeutic compound described herein. In other embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis, and / or separation of mixtures of enantiomers and / or diastereomers. Resolution of the compounds and their isomers is achieved by any means, including, as a non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0100] The methods and formulations described herein include N-oxides (if appropriate), crystalline forms (also called polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any one or more of the compounds described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ethers (e.g., tetrahydrofuran, methyl tert-butyl ether), or alcohols (e.g., ethanol) solvates, acetates, etc. In some embodiments, the compounds described herein are present in a solvated form using pharmaceutically acceptable solvents such as water and ethanol. In other embodiments, the compounds described herein are present in a non-solvated form.

[0101] In some embodiments, one or more of the compounds described herein may be present as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0102] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" is an agent that is converted into a parent drug in vivo. In some embodiments, after administration in vivo, the prodrug is chemically converted into a biologically, pharmaceutically, or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized into a biologically, pharmaceutically, or therapeutically active form of the compound through one or more steps or processes.

[0103] In some embodiments, sites on the aromatic ring moiety of compounds (one or more) described herein are susceptible to various metabolic reactions. Incorporating appropriate substituents into the aromatic ring structure can reduce, minimize, or eliminate such metabolic pathways. In some embodiments, by way of example only, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are deuterium, halogens, or alkyl groups.

[0104] The compounds described herein also include isotopically labeled compounds, wherein one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from those normally found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include, but are not limited to, atoms with the same atomic number but with a different atomic mass or mass number than those found in nature. 2 H, 3 H, 11 C 13 C 14 C 36 Cl、 18 F, 123 I, 125 I, 13 N、 15 N、 15 O、 17 O、 18 O、 32 P and 35 S. In some embodiments, the isotope-labeled compound is used in drug and / or substrate tissue distribution studies. In other embodiments, substitution with a heavier isotope, such as deuterium, provides greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In still other embodiments, positron-emitting isotopes, such as... 11 C 18 F, 15 O and 13 Nitrogen substitution is used to examine substrate acceptor occupancy in positron emission tomography (PET) studies. Isotope-labeled compounds are prepared by any suitable method or by using a suitable isotope-labeled reagent instead of an unlabeled reagent.

[0105] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling.

[0106] The compounds described herein, as well as other related compounds with different substituents, are described herein and, for example, in Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1–17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1–40 (John Wiley and Sons, 1991); Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th The compounds described herein are synthesized using techniques and materials described in Ed. (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001); and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed. (Wiley 1999) (all of which are incorporated herein by reference for such disclosure). The general methods for preparing the compounds described herein are modified by using appropriate reagents and conditions to incorporate the various parts present in the formulas provided herein.

[0107] The compounds described herein can be synthesized from commercially available compounds using any suitable procedure, or prepared using the procedures described herein.

[0108] In some embodiments, reactive functional groups such as hydroxyl, amino, imino, thio, or carboxyl groups are protected to prevent them from unnecessarily participating in the reaction. Protecting groups are used to block some or all of the reaction sites and prevent such groups from participating in the chemical reaction until the protecting groups are removed. In other embodiments, each protecting group can be removed by different means. Protecting groups that cleave under completely different reaction conditions satisfy the requirement of differential removal.

[0109] In some embodiments, protecting groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidizing conditions. Groups such as triphenyl, dimethoxytriphenyl, acetal, and tert-butyldimethylsilyl are acid-labile, but are used to protect the carboxyl and hydroxyl reactive moieties in the presence of an amino group protected by a Cbz group (which can be removed by hydrogenolysis) and a base-labile Fmoc group. The carboxylic acid and hydroxyl reactive moieties are blocked by base-labile groups (such as, but not limited to, methyl, ethyl, and acetyl groups) in the presence of an amine blocked by an acid-labile group such as tert-butyl carbamate, or by an amine blocked by a carbamate that is stable in both acids and bases but can be removed by hydrolysis.

[0110] In some embodiments, the carboxylic acid and hydroxyl reaction moiety is blocked by a hydrolyzable protecting group such as a benzyl group, while the amino group capable of hydrogen bonding with an acid is blocked by a base-instable group such as Fmoc. The carboxylic acid reaction moiety is protected by conversion to a simple ester compound (including conversion to an alkyl ester) as exemplified herein, or by an oxidatively removable protecting group such as a 2,4-dimethoxybenzyl group, while the coexisting amino group is blocked by a fluorinated, unstable silyl carbamate.

[0111] Allyl-blocked groups are useful in the presence of both acid- and base-protecting groups, as the former is stable and can be subsequently removed by metal or π-acid catalysts. For example, allyl-blocked carboxylic acids are deprotected via palladium-catalyzed reactions in the presence of acid-instable tert-butyl carbamate or base-instable amine acetate protecting groups. Another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue adheres to the resin, the functional group remains blocked and does not react. Once released from the resin, the functional group becomes reactive.

[0112] Typical blocking / protecting groups can be selected from: Other protecting groups and techniques applicable to their creation and removal are described in detail in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994 (which are incorporated herein by reference for such disclosure).

[0113] Composition On the one hand, this disclosure provides pharmaceutical compositions comprising at least one compound of this disclosure and at least one pharmaceutically acceptable carrier.

[0114] Compositions containing one or more of the compounds described herein include pharmaceutical compositions comprising at least one compound as described herein and at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises Kolliphor EL and an aqueous buffer, or a combination thereof. In some embodiments, the aqueous buffer comprises phosphate-buffered saline (PBS). In some embodiments, the aqueous buffer comprises 1x PBS. In some embodiments, the pharmaceutical composition comprises about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% Kolliphor EL. In some embodiments, the pharmaceutical composition comprises about 20% Kolliphor EL in 1x PBS.

[0115] In some embodiments, the composition is formulated for administration via routes such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, sublingual, urethral, ​​vaginal (e.g., vaginal and perivasal), nasal (internal) and rectal (internal), bladder, lung, duodenum, stomach, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, bronchial, inhalation, and topical application. In some embodiments, the composition is formulated as pills, tablets, gelcapsule, or capsules for oral administration.

[0116] Treatment, improvement and / or prevention methods In one aspect, this disclosure relates to methods for promoting male contraception in male subjects. In another aspect, this disclosure relates to methods for promoting male sterilization in male subjects. In yet another aspect, this disclosure relates to methods for minimizing and / or reducing sperm count and / or motility in male subjects. In yet another aspect, this disclosure relates to methods for reducing testicular size in male subjects. In yet another aspect, this disclosure relates to methods for regulating the function and / or activity of RET, STK33, and / or CLK kinases in subjects.

[0117] In some embodiments, the method includes administering a therapeutically effective amount of the compound disclosed herein to a subject.

[0118] In some embodiments, the method includes administering a therapeutically effective amount of the compound disclosed herein to a male subject.

[0119] In some embodiments, the method includes administering a therapeutically effective amount of a compound of formula (I) to a subject. In some embodiments, the method includes administering a therapeutically effective amount of a compound from Table A to a male subject.

[0120] In some embodiments, this document provides a method for inhibiting STK33 in mammals, the method comprising administering to the mammal an effective amount of the compound disclosed herein and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for inhibiting STK33 in mammals, the method comprising administering to the mammal an effective amount of a compound of formula (I) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for inhibiting STK33 in mammals, the method comprising administering to the mammal an effective amount of a compound of formula (II) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for inhibiting STK33 in mammals, the method comprising administering to the mammal an effective amount of a compound of formula (IV) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for inhibiting STK33 in mammals, the method comprising administering to the mammal an effective amount of a compound of formula (V) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for inhibiting STK33 in mammals, the method comprising administering to the mammal an effective amount of a compound of formula (VI) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for inhibiting STK33 in mammals, the method comprising administering to a mammal an effective amount of a compound of formula (VII) and / or a pharmaceutical composition thereof.

[0121] In some embodiments, this document provides a method for sterilizing a male partner, the method comprising administering to the male partner a therapeutically effective amount of at least one of the compounds disclosed herein and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for sterilizing a male partner, the method comprising administering to the male partner a therapeutically effective amount of a compound of formula (I) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for sterilizing a male partner, the method comprising administering to the male partner a therapeutically effective amount of a compound of formula (II) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for sterilizing a male partner, the method comprising administering to the male partner a therapeutically effective amount of a compound of formula (III) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for sterilizing a male partner, the method comprising administering to the male partner a therapeutically effective amount of a compound of formula (IV) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for sterilizing a male partner, the method comprising administering to the male partner a therapeutically effective amount of a compound of formula (V) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for sterilizing a male partner, the method comprising administering to the male partner a therapeutically effective amount of a compound of formula (VI) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for sterilizing a male object, the method comprising administering to the male object a therapeutically effective amount of a compound of formula (VII) and / or a pharmaceutical composition thereof.

[0122] In some embodiments, this document provides a method for promoting male contraception and / or infertility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of at least one of the compounds disclosed herein and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for promoting male contraception and / or infertility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of a compound of formula (I) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for promoting male contraception and / or infertility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of a compound of formula (III) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for promoting male contraception and / or infertility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of a compound of formula (IV) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for promoting male contraception and / or infertility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of a compound of formula (V) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for promoting male contraception and / or infertility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of a compound of formula (VI) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for promoting male contraception and / or infertility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of a compound of formula (VII) and / or a pharmaceutical composition thereof. In some embodiments, the method provides a contraceptive effect in the male subject. In some embodiments, the compound is administered orally to the male subject.

[0123] In some embodiments, this document provides a method for minimizing and / or reducing sperm count and / or motility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of the disclosed compound and / or pharmaceutical composition thereof. In some embodiments, this document provides a method for minimizing and / or reducing sperm count and / or motility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of the compound of formula (I) and / or pharmaceutical composition thereof. In some embodiments, this document provides a method for minimizing and / or reducing sperm count and / or motility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of the compound of formula (II) and / or pharmaceutical composition thereof. In some embodiments, this document provides a method for minimizing and / or reducing sperm count and / or motility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of the compound of formula (III) and / or pharmaceutical composition thereof. In some embodiments, this document provides a method for minimizing and / or reducing sperm count and / or motility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of the compound of formula (IV) and / or pharmaceutical composition thereof. In some embodiments, this document provides a method for minimizing and / or reducing sperm count and / or motility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of a compound of formula (V) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for minimizing and / or reducing sperm count and / or motility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of a compound of formula (VI) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for minimizing and / or reducing sperm count and / or motility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of a compound of formula (VII) and / or a pharmaceutical composition thereof. In some embodiments, the method provides a contraceptive effect in the male subject. In some embodiments, the compound is administered orally to the male subject.

[0124] In some embodiments, this document provides a method for inhibiting RET in mammals, the method comprising administering to the mammal an effective amount of the compound disclosed herein and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for inhibiting RET in mammals, the method comprising administering to the mammal an effective amount of a compound of formula (I) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for inhibiting RET in mammals, the method comprising administering to the mammal an effective amount of a compound of formula (II) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for inhibiting RET in mammals, the method comprising administering to the mammal an effective amount of a compound of formula (IV) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for inhibiting RET in mammals, the method comprising administering to the mammal an effective amount of a compound of formula (V) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for inhibiting RET in mammals, the method comprising administering to the mammal an effective amount of a compound of formula (VI) and / or a pharmaceutical composition thereof. In some embodiments, this document provides a method for inhibiting RET in mammals, the method comprising administering to the mammal an effective amount of a compound of formula (VII) and / or a pharmaceutical composition thereof.

[0125] RET inhibitors can be used to treat, improve, and / or prevent cancers, including but not limited to medullary thyroid carcinoma, non-small cell lung cancer, and / or multiple endocrine neoplasia type 2A (MEN2A). In some embodiments, this document provides methods for treating, improving, and / or preventing diseases or disorders caused by RET overexpression or high RET activity, methods comprising administering a therapeutically effective amount of at least one of the compounds disclosed herein and / or pharmaceutical compositions thereof to a mammal. In some embodiments, methods comprise treating RET-mediated cancers. In some embodiments, RET-mediated cancers include medullary thyroid carcinoma, non-small cell lung cancer, and / or multiple endocrine neoplasia type 2A (MEN2A). In some embodiments, diseases or disorders include Herschprom disease, central hypoventilation syndrome, or renal agenesis.

[0126] In some embodiments, this document provides methods for treating, improving, and / or preventing diseases or disorders caused by RET overexpression or RET hyperactivity, the methods comprising administering to a mammal a therapeutically effective amount of a compound of formula (I) and / or a pharmaceutical composition thereof. In some embodiments, this document provides methods for treating, improving, and / or preventing diseases or disorders caused by RET overexpression or RET hyperactivity, the methods comprising administering to a mammal a therapeutically effective amount of a compound of formula (II) and / or a pharmaceutical composition thereof. In some embodiments, this document provides methods for treating, improving, and / or preventing diseases or disorders caused by RET overexpression or RET hyperactivity, the methods comprising administering to a mammal a therapeutically effective amount of a compound of formula (III) and / or a pharmaceutical composition thereof. In some embodiments, this document provides methods for treating, improving, and / or preventing diseases or disorders caused by RET overexpression or RET hyperactivity, the methods comprising administering to a mammal a therapeutically effective amount of a compound of formula (IV) and / or a pharmaceutical composition thereof. In some embodiments, this document provides methods for treating, improving, and / or preventing diseases or disorders caused by RET overexpression or RET hyperactivity, the methods comprising administering to a mammal a therapeutically effective amount of a compound of formula (V) and / or a pharmaceutical composition thereof. In some embodiments, this document provides methods for treating, improving, and / or preventing diseases or disorders caused by RET overexpression or high RET activity, methods comprising administering to a mammal a therapeutically effective amount of a compound of formula (VI) and / or a pharmaceutical composition thereof. In some embodiments, this document provides methods for treating, improving, and / or preventing diseases or disorders caused by RET overexpression or high RET activity, methods comprising administering to a mammal a therapeutically effective amount of a compound of formula (VII) and / or a pharmaceutical composition thereof.

[0127] The CLK family comprises four homologous proteins: CLK1, CLK2, CLK3, and CLK4. They contribute to cell cycle progression, cell growth, and disease development through the regulation of splicing. Furthermore, human CLK2 plays a role in fatty liver disease by participating in fatty acid oxidation and ketosis. CLKs act as important regulators and perform crucial functions—they are essential in catalyzing splicing and regulating phosphorylation, which is critical in many diseases, such as Duchenne muscular dystrophy, Alzheimer's disease, HIV-1, influenza virus, and cancers (kidney cancer, breast cancer, melanoma).

[0128] On the one hand, this document provides methods for regulating at least one CLK family protein such as CLK1, CLK2, CLK3, and / or CLK4. On the other hand, this document provides methods for inhibiting at least one of CLK1, CLK2, CLK3, or CLK4 in mammals, the methods comprising administering to the mammal an effective amount of at least one compound disclosed herein and / or a pharmaceutical composition thereof. Furthermore, this document provides methods for treating, improving, and / or preventing diseases or disorders caused by CLK overexpression or CLK hyperactivity, the methods comprising administering to the mammal a therapeutically effective amount of at least one compound disclosed herein and / or a pharmaceutical composition thereof. In some embodiments, diseases or disorders include Duchenne muscular dystrophy, Alzheimer's disease, HIV-1, influenza virus, and kidney cancer, breast cancer, or melanoma.

[0129] In some embodiments, the compound of formula (I) is a compound of formula (II). Exemplary compounds of formula (II) are described elsewhere herein. In other embodiments, the compound of formula (I) is a compound of formula (III). Exemplary compounds of formula (III) are described elsewhere herein. In still other embodiments, the compound of formula (I) is a compound of formula (IV). Exemplary compounds of formula (IV) are described elsewhere herein. In still other embodiments, the compound of formula (I) is a compound of formula (V). Exemplary compounds of formula (V) are described elsewhere herein. In still other embodiments, the compound of formula (I) is a compound of formula (VI). Exemplary compounds of formula (VI) are described elsewhere herein. In still other embodiments, the compound of formula (I) is a compound of formula (VII). Exemplary compounds of formula (VII) are described elsewhere herein.

[0130] The methods described herein comprise administering to a subject a therapeutically effective amount of at least one of the compounds described herein, optionally formulated in a pharmaceutical composition. In various embodiments, the at least one of the compounds described herein present in a therapeutically effective amount in the pharmaceutical composition is the only therapeutically active compound in the pharmaceutical composition. In some embodiments, the method further comprises administering to the subject an additional agent for treating, improving, and / or preventing the condition of concern.

[0131] The compounds of this disclosure may be administered to a subject using any administration route known to those skilled in the art. Exemplary administration routes are described elsewhere herein. In some embodiments, compositions comprising the compounds of this disclosure are administered orally to a subject. In some embodiments, pills, tablets, soft capsules, or capsules comprising the compounds of this disclosure are administered orally to a subject.

[0132] The compounds of this disclosure can be administered to a subject in any amount necessary to inhibit STK, at any timing of administration, or in combination thereof, and provide the desired therapeutic effect. In some embodiments, the compounds of this disclosure are administered to male subjects to provide a contraceptive effect. While not wishing to be limited by theory, it is believed that inhibition of STK33 function in spermatocytes and spermatids leads to a reduction in sperm count and motility.

[0133] In some implementations, the object is a mammal. In other implementations, the mammal is a human.

[0134] Application / Dosage / Formulation The administration regimen may affect the composition of the effective dose. The therapeutic agent may be administered to the subject before or after the onset of the disease or disorder. Furthermore, several separate doses, as well as alternating doses, may be administered daily or sequentially, or the dose may be administered via continuous infusion or bolus injection. Additionally, the dosage of the therapeutic agent may be increased or decreased proportionally according to indications of the urgency of the treatment or prevention situation.

[0135] The compositions described herein can be administered to patients using known procedures, dosages, and time periods for effective treatment of the disease or disorder. The effective amount of the therapeutic compound necessary to achieve a therapeutic effect can vary depending on factors such as the patient's disease or disorder status; the patient's age, sex, and weight; and the ability of the therapeutic compound to treat the patient's disease or disorder. Dosing regimens can be adjusted to provide an optimal therapeutic response. For example, as indicated by an emergency situation in the treatment condition, several separate doses may be administered daily, or the dose may be proportionally reduced. A non-limiting example of the effective dose range of the therapeutic compounds described herein is from about 1 mg / kg to 5,000 mg / kg body weight / day. Those skilled in the art will be able to investigate the relevant factors and determine the effective amount of the therapeutic compound without excessive experimentation.

[0136] The actual dosage level of the active ingredient in the pharmaceutical composition described herein can be altered to obtain an amount of active ingredient that effectively achieves the desired therapeutic response for a particular patient, composition, and administration method, while remaining non-toxic to the patient.

[0137] Specifically, the selected dosage level depends on a variety of factors, including the activity of the specific compound used, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health status and medical history of the patient being treated, and similar factors known in the medical field.

[0138] A physician (e.g., a doctor or veterinarian) with ordinary skills in the art can readily determine and prescribe the required effective amount of the pharmaceutical composition. For example, a physician or veterinarian can begin using a dose of the compound described herein in the pharmaceutical composition at a level below what is required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0139] In specific implementations, formulating compounds in dosage units is particularly advantageous for ease of administration and uniformity of dosage. As used herein, dosage units refer to physically discrete units suitable as a unit dosage for a patient to be treated; each unit contains a predetermined amount of the therapeutic compound, which is calculated to combine with the desired pharmaceutical agent to produce the desired therapeutic effect. The dosage unit form of one or more compounds described herein is determined by and directly depends on: (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the field of compounding / formulating such therapeutic compounds.

[0140] In some embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In some embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the compound described herein and a pharmaceutically acceptable carrier.

[0141] The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., C3-C7 aliphatic or aryl n-hydroxy compounds, where n is 1 to 10, such as glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. The desired particle size can be maintained in the dispersed state, for example, by using coatings such as lecithin, and suitable flowability can be maintained by using surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.). In many cases, it is preferable to include isotonic agents in the composition, such as sugars, sodium chloride, or polyols such as mannitol and sorbitol. The absorption of the composition can be prolonged by including agents that delay absorption, such as aluminum monostearate or gelatin, in the injectable composition.

[0142] In some embodiments, the compositions described herein are administered to the patient at a dosage ranging from 1 to 5 or more times daily. In other embodiments, the compositions described herein are administered to the patient at dosages including, but not limited to, once daily, once every two days, once every three days, once weekly, and once every two weeks. It will be apparent to those skilled in the art that the frequency of administration of the various combinations described herein varies from person to person and depends on many factors, including but not limited to age, the disease or disorder to be treated, sex, overall health condition, and other factors. Therefore, the administration of the compounds and compositions described herein should not be construed as being limited to any particular dosage regimen, and the precise dosage and composition to be administered to any patient shall be determined by the attending physician taking into account all other factors of the patient.

[0143] In some embodiments, the composition as described herein is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of the compound described herein, either alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat or reduce one or more symptoms of a patient’s disease or disorder.

[0144] The formulation may be used in combination with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carriers suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable route of administration known in the art. The pharmaceutical formulation may be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure buffers, colorants, fragrances, and / or aromatic substances. It may also be combined with other active agents (e.g., other analgesics) if necessary.

[0145] Routes of administration for any of the compositions described herein include oral, nasal, rectal, vaginal, parenteral, sublingual, sublingual, or topical. The compounds used in the compositions described herein may be formulated for administration via any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, sublingual, urethral, ​​vaginal (e.g., vaginal and perivallary), nasal (internal) and rectal, intrabladder, intrapulmonary, intraduodenal, intragastric, intrathecal, intrasheathal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical application.

[0146] Suitable compositions and dosage forms include, for example, tablets, capsules, pouches, pills, soft capsules, troches, dispersants, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, emulsions, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or nebulized formulations for inhalation, and compositions and formulations for intravesical administration. It should be understood that the formulations and compositions described herein are not limited to the specific formulations and compositions described herein.

[0147] Oral administration For oral administration, tablets, dragees, liquids, drops, suppositories, capsules, pouches, and soft capsules are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions may contain one or more agents selected from inert, pharmaceutically non-toxic excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or they may be coated using known techniques to improve appearance or delay the release of the active ingredient. Oral formulations may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0148] For oral administration, the compounds described herein (one or more) may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., polyvinylpyrrolidone, hydroxypropyl cellulose, or hydroxypropyl methylcellulose); fillers (e.g., corn starch, lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., sodium glycolate starch); or wetting agents (e.g., sodium dodecyl sulfate). If desired, tablets may be coated using suitable methods and coating materials such as the OPADRY™ film coating system available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY, OYC, organic enteric OY-P, aqueous enteric OY-A, OY-PM, and OPADRY™ White, 32K18400). Liquid formulations for oral administration may be in the form of solutions, syrups, or suspensions. Liquid formulations can be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous mediators (e.g., almond oil, oily esters, or ethanol); and preservatives (e.g., methylparaben, propylparaben, or sorbic acid).

[0149] External application For parenteral administration, the compounds described herein may be formulated for injection or infusion, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or for pellet-dose administration and / or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous media may be used, optionally containing other formulations (such as suspending agents, stabilizers, and / or dispersants).

[0150] The sterile injectable form of the compositions described herein can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable mediators and solvents, water, Ringer's solution, and isotonic sodium chloride solution are commonly used. Sterile fixed oils are conventionally used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diesters of glycerol. Fatty acids such as oleic acid and its glycerol ester derivatives are used in the preparation of injectable formulations, as are natural, pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylene forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0151] Other forms of application Additional dosage forms suitable for use with one or more of the compounds and compositions described herein include those described in U.S. Patent Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Further dosage forms suitable for use with one or more of the compounds and compositions described herein include those described in U.S. Patent Application Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with one or more of the compounds and compositions described herein include those described in PCT applications WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757.

[0152] Dosage The therapeutically effective amount or dosage of the compounds described herein depends on the patient's age, sex, weight, current medical condition, and the progression of the disease or disorder being treated. A skilled technician can determine the appropriate dosage based on these and other factors.

[0153] Suitable doses of the compounds described herein can range from about 0.01 mg to about 5,000 mg per day, such as about 0.1 mg to about 1,000 mg per day, such as about 1 mg to about 500 mg per day, such as about 5 mg to about 250 mg per day. Dosage can be administered as a single dose or multiple doses, such as one to four or more times per day. When multiple doses are used, the amounts of each dose can be the same or can be different. For example, a 1 mg daily dose can be administered as two 0.5 mg doses, with an interval of about 12 hours between doses.

[0154] It should be understood that, in non-limiting examples, the amount of compound administered daily may be given once daily, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, when administered every other day, a daily dose of 5 mg may begin on Monday, followed by the first subsequent daily dose of 5 mg on Wednesday, the second subsequent daily dose of 5 mg on Friday, and so on.

[0155] If the patient's condition does improve, the physician may optionally continue administration of one or more of the compounds described herein; alternatively, the dosage of the administered medication may be temporarily reduced or suspended for a period of time (i.e., a "medication holiday"). The length of the medication holiday may optionally vary between 2 days and 1 year, and by way of example only, includes 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dosage reductions during a drug holiday range from 10% to 100%, and are for illustrative purposes only, including 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0156] Once the patient's condition improves, a maintenance dose may be administered if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced to maintain the level of improved disease. In some implementations, long-term intermittent treatment may be required when there is any recurrence of symptoms and / or infection.

[0157] The compounds described herein can be formulated into unit dosage forms. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for a patient receiving treatment, wherein each unit contains a predetermined amount of active material calculated to produce the desired therapeutic effect, optionally associated with a suitable drug carrier. Unit dosage forms can be used for a single daily dose or for multiple daily doses (e.g., about 1 to 4 or more times per day). When using multiple daily doses, the unit dosage forms for each dose may be the same or may be different.

[0158] Optionally, the toxicity and therapeutic efficacy of such treatment regimens may be determined in cell cultures or laboratory animals, including but not limited to determining the LD50. 50 (The dose that is lethal to 50% of the population) and ED 50 (The dose effective for 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, expressed as LD50. 50 With ED 50 The ratio between them. Data obtained from cell culture assays and animal studies are optionally used to determine the dosage range for human use. The dosage of such compounds is preferably within the circulating concentration range, which includes the least toxic ED. 50 The dosage may vary within this range, depending on the dosage form and route of administration.

[0159] Those skilled in the art will recognize or be able to determine many equivalents of the specific procedures, implementations, claims, and examples described herein using only conventional experiments. Such equivalents are considered to be within the scope of this disclosure and are covered by the appended claims. For example, it should be understood that modifications to reaction conditions, including but not limited to reaction time, reaction scale / volume, and experimental reagents such as solvents, catalysts, pressure, atmospheric conditions (e.g., nitrogen atmosphere), and reducing / oxidizing agents, using alternatives known in the art and employing only conventional experiments, are within the scope of this application.

[0160] It should be understood that throughout all sections of this document that provide values ​​and ranges, all values ​​and ranges covered by these values ​​and ranges are meant to be covered within the scope of this disclosure. Furthermore, this application also considers all values ​​falling within these ranges, as well as the upper or lower limits of the ranges of values.

[0161] The following examples further illustrate various aspects of this disclosure. However, they are by no means intended to teach or limit the scope of this disclosure as set forth herein.

[0162] Experimental Examples This disclosure is further described in detail with reference to the following experimental embodiments. These embodiments are provided for illustrative purposes only and are not intended to be limiting unless otherwise specified. Therefore, this disclosure should in no way be construed as limited to the following embodiments, but should be construed as covering any and all variations that become apparent from the teachings provided herein.

[0163] Without further description, it is believed that those skilled in the art can use the foregoing description and the following illustrative examples to prepare and utilize the compounds of this disclosure and to carry out the claimed methods. Therefore, the following working examples specifically point to preferred embodiments of this disclosure and should not be construed as limiting the remainder of this disclosure in any way.

[0164] Materials and Methods Reagents and solvents purchased from the commercial supplier were used as is upon receipt. All reactions involving air-sensitive reagents were carried out in anhydrous solvents under a nitrogen atmosphere. Detection was performed using UV light (254 nm and 365 nm) at BAKER-FLEX. ® The reaction was monitored by thin-layer chromatography (TLC) on silica gel plates (IB2-F) or by liquid chromatography / mass spectrometry (LC-MS). Column chromatography was performed using a Teledyne ISCO CombiFlash system equipped with a silica or C-18 column. The reaction was conducted at room temperature using a Bruker Avance III HD 600 MHz spectrometer (600 MHz). 1 H NMR and at 150 MHz 13 C NMR) or Bruker Avance 800 MHz spectrometer (800 MHz) 1 H NMR and at 200 MHz 13 (C NMR) records the NMR spectrum. Reference solvent signal [ 1 H-NMR: CDCl3 (7.26 ppm), CD3OD (3.31 ppm) and DMSO- d 6 (2.50 ppm); 13 C-NMR: CDCl3 (77.00 ppm), CD3OD (49.15 ppm) and DMSO- d 6(39.51 ppm)], chemical shift (δ) is reported in parts per million (ppm). Signal modes are reported as s (singlet), d (doublet), t (triplet), q (quartet), h (heptet), m (multiplet), and br (broad). Coupling constant ( J (Indicated in Hz.) High-resolution mass spectrometry (HRMS) was recorded using ESI (electrospray ionization) on a ThermoFisher Scientific Q Exactive hybrid quadrupole Orbitrap mass spectrometer. General synthesis procedure (a) General procedures for THP protection: Indazole (5.0 mmol, 1.0 equivalent), DHP (7.5 mmol, 1.5 equivalent), and... were stirred at room temperature under nitrogen atmosphere. p A mixture of -TsOH monohydrate (1.0 mmol, 0.2 equivalents) in anhydrous CH2Cl2 (10 mL) for 16 h was quenched by adding saturated aqueous NaHCO3 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (EtOAc / hexane, 0:100 to 40:60) to give the desired product.

[0165] (b) General procedure for Sonogashira coupling: Microwave vials equipped with magnetic stir bars and dried in an oven were filled with halides (0.5 mmol, 1.0 equivalent), substituted alkynes (0.6 mmol, 1.2 equivalent), CuI (0.05 mmol, 0.1 equivalent), and PdCl2(PPh3)2 (0.05 mmol, 0.1 equivalent). The vials were sealed with microwave caps, purged, and refilled with nitrogen. Anhydrous DMF (1 mL) and TEA (1 mL) were then added via syringe. The mixture was purged under vacuum and refilled with nitrogen three times, followed by heating in a microwave reactor at 80 °C for 1 h (or at the indicated temperature for the indicated time period). After the reaction was complete (monitored by TLC and LC-MS), the reaction mixture was filtered through a Celite pad, and the filtrate was extracted between EtOAc and 1N HCl aqueous solution. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid chromatography using a gradient elution with EtOAc / hexane or CH3OH / CH2Cl2 to obtain the desired product.

[0166] (c) General procedure for hydrolysis of amines without THP protection: Methyl ester (0.5 mmol, 1.0 equivalent) was added to THF / water (2 mL, 1:1). v / v KOH (5.0 mmol, 10.0 equivalent) was added to the solution, and the mixture was vigorously stirred at 40 °C for 48 h or until the starting material disappeared (monitored by TLC and LC-MS). The reaction mixture was neutralized to pH 7 with 4N HCl aqueous solution and concentrated under vacuum. The crude carboxylic acid was used directly in the next step.

[0167] (d) General procedure for amine hydrolysis with THP protection: Methyl ester (0.5 mmol, 1.0 equivalent) was added to THF / water (2 mL, 1:1). v / v LiOH monohydrate (1 mmol, 2.0 equivalent) was added to the solution, and the mixture was vigorously stirred for 1 h at room temperature. After the reaction was complete (monitored by TLC and LC-MS), the reaction mixture was neutralized to pH 7 with 4N HCl aqueous solution and concentrated under vacuum. The residue was purified by C-18 reversed-phase column chromatography (CH3OH / water, 5:95 to 100:0) to obtain the desired product.

[0168] (e) General procedure for amide coupling: Under nitrogen atmosphere, DIEA (0.15 mmol, 1.5 equivalent) was added to a solution of carboxylic acid (0.1 mmol, 1.0 equivalent), substituted amine (0.12 mmol, 1.2 equivalent), and HATU (0.12 mmol, 1.2 equivalent) in anhydrous DMF (0.5 mL). The reaction mixture was stirred for 16 h at room temperature. The mixture was quenched by adding water and extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residues were purified by silica gel rapid chromatography (CH3OH / CH2Cl2, 0:100 to 10:90) or C-18 reversed-phase column chromatography (CH3OH / water, 5:95 to 100:0) to obtain the desired product.

[0169] (f) General procedure for removing THP and / or Boc protecting groups: At room temperature, THP and / or Boc-protected amines (0.1 mmol) were reacted with 4N HCl solution in 1,4-dioxanone. The mixture in alkane (0.5 mL) was stirred for 1 h. After the reaction was complete (monitored by TLC and LC-MS), the resulting mixture was neutralized to pH 7 with 4 M NaOH aqueous solution and concentrated under vacuum. The residue was purified by C-18 reversed-phase column chromatography (CH3OH / water, 5:95 to 100:0) to obtain the desired product.

[0170] Biological and characterization data of synthetic compounds Based on the modification of the scaffold, all compounds were categorized into three series: A, B, and C. The compounds were prepared via synthetic route 1, synthetic route 2, or as described in the synthetic description. Biochemical activity of IC against STK33 was assessed. 50 Value and corresponding K d The value was calculated using Lanthascreen binding assay, while the IC50 value for cell viability against STK33 was... 50 The value is calculated from the NanoBRET target binding intracellular kinase assay. ND means that the following compounds were not measured: compounds that failed the kinase assay for STK33 at 500 nM, or compounds that did not pass the IC50 assay for STK33 in the NanoBRET assay. 50 Compounds with a molecular weight greater than 300 nM.

[0171] Example 1: Discovery of potent STK33 inhibitors from DNA-encoded chemical library screening and compound optimization To identify small molecule binders of the STK33 kinase domain (KD), DNA-encoded chemistry (DEC-Tec) was used to discover potent and selective kinase inhibitors. Using 0.1 μM or 0.5 μM of full-length, His-tagged STK33 protein (with or without astrocytocin—a broad-spectrum ATP-competitive kinase inhibitor), 36 or 45 unique libraries, each containing 3.9 billion unique DNA-encoded molecules, were selected.

[0172] The dissociation constant (Ki) of kinase inhibitors bound to the ATP pocket was calculated using LanthaScreen data. d )value.

[0173] Dynafit was used to fit the complex equilibrium of tracer displacement by a series of dilutions of kinase inhibitors. This method depends on the concentration of the inhibitor, as well as the concentrations of the kinase and tracer, and the K+ of the tracer. d The last three parameters were tabulated by ThermoFisher for each kinase in the LanthaScreen assay panel.

[0174] The inhibition constant (K) of the kinase inhibitor was calculated from the inhibition data of Z'-LYTE and Adapta. i )value.

[0175] In [ATP] = K m app In the case of competitive inhibition, K is obtained using the Morrison equation (Graphpad Prism7 software). i Value. Because K d Value and K i The values ​​are defined in the same way, i.e., K d = [E] [I] / [EI] = K i Therefore, K can be compared. d Value and K i value.

[0176] NanoBRET™ Target Binding Intracellular Kinase Assay HEK293T cells were cultured in DMEM (Gibco11965-092) containing 10% FBS and 1% Pen-Strep (Gibco 15140-122) at 5% CO2 and 37°C. The cell line was validated using short tandem repeats (STRs) at the Cytogenetics and Cell Authentication Core (CCAC) platform at MD Anderson Cancer Center. NanoBRET™ TE intracellular kinase assay, K-10 assay (Cat. # N2641), K-9 assay (Cat. # N2631), FuGENE® HD transfection reagent (Cat. # E2311), DNA transfection carrier (Cat. # E4881), NanoLuc®-STK33 fusion vector (Cat. # NV2111), NanoLuc®-RET fusion vector (Cat. # NV1951), NanoLuc®-CLK1 fusion vector (Cat. # NV1131), NanoLuc®-CLK2 fusion vector (Cat. # NV1141), and NanoLuc®-CLK4 fusion vector (Cat. # NV1151) were purchased from Promega. The binding of the test compounds to cellular target proteins was measured in 384-well configurations according to the manufacturer's instructions. HEK293 cells were transiently transfected with NanoLuc® (STK33, RET, CLK1, CLK2, and CLK4) fusion vectors. Thirty-six hours after transfection, cells were treated with a fixed concentration of tracer (recommended by Promega) followed by 2 hours of incubation with the compound (inhibitor). To determine the affinity of the test compound, cells were titrated with different concentrations of the test compound ranging from 40 μM to 0.4 nM at fixed tracer concentrations. Astrococcal spp. were measured in parallel as a positive control. Subsequently, bioluminescence resonance energy transfer (BRET) was initiated by adding freshly prepared NanoBRET Nano-Glo substrate and an extracellular NanoLuc inhibitor, and measurements were performed using a CLARIOstar Plus BMGLABTECH plate reader. Data analysis was performed by measuring the ratio of acceptor to donor emission (BRET ratio) and normalized by subtracting the background from the tracer-free control.

[0177] NanoBRET target binding to K192 assay. HEK293 cells (ATCC) were cultured in DMEM (Gibco) + 10% FBS (Seradigm) and incubated in a humidified 37°C / 5% CO2 incubator. The NanoBRET target binding to K192 kinase selective system (Promega) contains 192 unique transfection-ready NanoLuc / kinase fusions, pre-diluted in transfection carrier DNA or related cyclin DNA. These NanoLuc / kinase fusion constructs were transfected into HEK293 cells using Fugene HD (Promega) according to the manufacturer's protocol. Briefly, 10 μL of 20 μg / mL DNA solution was added to a white, TC-treated 96-well assay plate (Corning), followed by 30 μL of diluted Fugene HD solution (20 µL Fugene / 1 mL Opti-MEM). After transfection complex formation, HEK293 cells were cultured at 3.3 × 10⁻⁶ cells / well. 5 Cells were resuspended at c / mL in Opti-MEM + 1% FBS and added at a volume of 60 µL / well to obtain approximately 20,000 cells / well. Cells were incubated for 20 hours in a humidified 37°C / 5% CO2 incubator. Tracer K-10 (Promega) was prepared at a concentration of 100× in DMSO (Sigma) and diluted to a working concentration of 10× (Promega) in tracer dilution buffer (12.5 mM HEPES, 31.25% PEG400, pH 7.5). The test compound was prepared as a concentrated stock solution in DMSO and diluted in Opti-MEM to prepare a 10× working stock solution. Cells were equilibrated with the test compound and tracer K-10 for 2 hours prior to BRET measurements. For target binding analysis, tracer K-10 was added to cells at one of four different concentrations (ranging from 25 nM to 1 μM) based on target affinity, according to the manufacturer's protocol. To measure BRET, NanoBRET NanoGlo substrate and the extracellular NanoLuc inhibitor (Promega) were added according to the manufacturer's protocol, and the filtered luminescence was measured using a GloMax Discover photometer equipped with a 450 nm BP filter (donor) and a 600 nm LP filter (acceptor) with an integration time of 0.5 s. Milli-BRET units were calculated by multiplying the original BRET units by 1000. For fractional occupancy determination, the following equation was used: Market share % = [1-(XZ) / (YZ)]×100 Where X = BRET with both the test compound and tracer K10 present, Y = BRET with only tracer K10 present, and Z = complete occupancy, or BRET without both the test compound and tracer K10 present. In this case, the complete occupancy control is the unlabeled NanoLuc construct (Promega).

[0178] DEC-Tec Affinity Selection For these studies, full-length recombinant human STK33 protein (Eurofins #14-671) with an N-terminal His6 tag was used to perform two independent DEC-Tec selections on our in-house libraries. In Experiment 1, 45 libraries (3.94 billion compounds) were selected with 0.5 μM STK33 protein in the presence or absence of astrococcus (10 μM). In Experiment 2, 36 libraries (3.936 billion compounds) were selected with 0.1 μM STK33 protein. The selection methods and informatics were as described previously.

[0179] STK33 KD protein expression and crystallographic purification This allows the product to contain tobacco plaque virus (TEV) cleavage sites and cGFP-Strep-tag. ®Human STK33 KD (GenBank accession number CAC29064.1, residue 99-383) was expressed in insect SF9 cells (Invitrogen). SF9 cells were cultured in SF900III medium (Gibco) and infected with STK33 KD baculovirus at the optimal virus / insect cell ratio. Cells were harvested 48 h post-infection; the pellet was held at -80°C. For purification, the frozen cell pellet was resuspended in lysis buffer (25 mM Tris, pH 8.0, 150 mM NaCl, and 1 mM TCEP) and lysed using a homogenizer (Avestin). After centrifugation at 48,000 g for 1 h, the soluble fraction was loaded onto pre-equilibrated Strep-Tactin Superflow resin (IBA Lifesciences GmbH) and eluted with elution buffer (25 mM Tris, pH 8.0, 150 mM NaCl, 1 mM TCEP, and 2 mM dethiobiotin). The fraction containing the protein was treated with TEV protease (1:60 by weight, overnight) to remove the GFP tag, and the mixture was subjected to a Superdex™ 75 Increase 10 / 300 GL gel filter (Cytiva) equilibrated with the above lysis buffer. The peaks corresponding to the estimated molecular weight of approximately 70 kDa were combined and used for co-crystallization.

[0180] From the library qDOS28_1 in two selection experiments, several enriched hit compounds were found that share the same building blocks 2 (BB2) and 3 (BB3), as well as similar / identical building blocks 1 (BB1) that differ only in their linkers. Figure 1 and Figures 5A-5B The absence of these hit compounds in the selection process in the presence of astrocytocin indicates competitive binding by the hit compounds. The hit compound with the short linker (i.e., CDD-2110) Figure 2A The characteristic of the long linker-targeting compound (i.e., CDD-3348 (Table B)) is that it is synthesized off-DNA and, in a Thermo Fisher LanthaScreen binding assay (K, respectively), K d = 0.1 nM and 0.06 nM; Figure 2C (and Table B) and the Promega cell-based NanoBRET assay performed in our laboratory (in-house) (respectively, IC50, 10 ... 50 = 38 nM and 169 nM; Figure 2CAs shown in Table B), it is a potent STK33 binder. Compared to the two STK33 inhibitors, namely compound 1 (K... d = 1.7 nM and IC 50 = 748 nM; Table B) and ML281 (K d = 39.6 nM and IC 50 = 7707 nM; Table B), CDD-2110 and CDD-3348 both showed significant efficacy against STK33 in both biochemical and cellular assays.

[0181] Table B. Chemical properties, biochemical activities, cellular activity, and metabolic data of the hit compound with a long linker (CDD-3348) and two STK33 inhibitors (compound 1 and ML281). d Value and K i The values ​​were calculated by LanthaScreen assay and Z'-LYTE assay, respectively, as described in the Methods section; IC 50 The values ​​were calculated using the NanoBRET assay; t was measured using a mouse liver microsomal or human liver microsomal stability assay. 1 / 2 Report IC of Compound 1 and ML281 50 The values ​​were 7 nM and 14 nM, respectively. ND means not determined. Although CDD-2110 and CDD-3348 exhibit potent activity, both molecules exist in a racemic form, have large molecular weights (>500 Da), and are metabolically unstable when incubated in mouse liver microsomes (MLM) and human liver microsomes (HLM), respectively. Figure 2C And Table B). To potentially overcome these drawbacks, two truncated enantiomers, namely CDD-2211 (and Table B), were subsequently synthesized and determined. R -isomer) and CDD-2212 ( S -Isomer) Figure 2B ), where when compared with the enantiomer CDD-2212 (K d =1.9 nM and IC 50 = 999 nM) and compared to the original hit compounds CDD-2110 and CDD-3348, CDD-2211 in LanthaScreen (K d = 0.02 nM) and NanoBRET (IC 50 The assay showed excellent inhibitory activity against STK33 (= 5 nM). Figure 2CDespite CDD-2211's strong binding to STK33, its half-life remains short in MLM and HLM metabolic stability assays related to contraception in mice and men (t). 1 / 2 ≤10 min; Figure 2C ).

[0182] Example 2: Chemical Synthesis of STK33 Inhibitors Further medicinal chemistry studies focused on improving the metabolic stability of this series of hit compounds. Tables C, D, E, and F summarize the obtained data, showing the structure-activity relationship (SAR). Based on scaffold modifications, all synthesized compounds were grouped into three series. The compounds were prepared via synthetic route 1, synthetic route 2, or as described in the synthetic description. The synthetic routes and characterizations are further shown below.

[0183] (1) Synthetic route 1: (2) Synthetic route 2: 1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -indazole-5-carbonyl)pyrrolidine-3-yl)- N 4-Methylpiperidine-4-carboxamide (A1, CDD-2110) Applicable synthetic route 1. In step 1, 3-bromo-1-dimethylbenzene is used in the general procedure for coupling with sage. H methyl indazole-5-carboxylate and 2-ethynyl-1,1'-biphenyl yield 3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indole-5-carboxylic acid methyl ester (52%) - is a pale yellow solid; 1 H NMR (600 MHz, CD3OD) δ 8.19 (s,1H), 8.02 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.58–7.38 (m, 7H), 3.99 (s, 3H). In step 2, the cross-coupled intermediate is subjected to a general THP-free amine hydrolysis procedure to give 3-([1,1'-biphenyl]-2-ylethynyl)-1 H-Indazole-5-carboxylic acid. In step 3, the obtained acid and... N -Methyl-1-(pyrrolidone-3-yl)piperidine-4-carboxamide, yielding the title compound (49%, via two steps) – a pale yellow oil; 1 H NMR (600 MHz, DMSO -d 6 (a mixture of diastereomers and rotational isomers) δ 7.78 (d, J = 7.6 Hz, 1H), 7.74–7.58 (m, 4H), 7.56–7.45 (m, 6H), 7.45–7.34 (m, 2H), 3.89–3.77 (m, 0.5H), 3.75–3.66 (m, 0.5H), 3.56–3.46 (m, 1H), 3.34–3.14 (m, 3H), 3.01–2.81 (m, 2H), 2.79–2.68 (m,0.5H), 2.54 (dd, J = 27.7, 4.4 Hz, 3H), 2.23–2.14 (m, 0.5H), 2.12–1.72 (m,4H), 1.71–1.44 (m, 4H); 13 C NMR (150 MHz, DMSO -d 6 (a mixture of diastereomers and rotational isomers) δ 174.8, 174.7, 168.4, 168.3, 143.4, 140.2, 140.0, 132.8, 130.4, 130.0, 129.7, 129.4, 129.1 (2 ×), 128.6, 128.3 (2 ×), 127.8, 127.7, 126.2, 126.1, 123.5, 120.2, 118.7, 110.8, 92.7, 84.0, 64.2, 62.9, 52.8, 51.7, 51.6, 50.8, 50.7, 49.9, 48.1, 44.9, 42.0, 41.9, 40.5, 29.9, 28.5, 28.1, 25.4; HRMS(ESI) C 33 H 34 N5O2 [M + H] + m / z Calculated value: 532.2713; Measured value: 532.2700.

[0184] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(pyrrolidone-1-yl)methyl ketone (A2, CDD-2134) Applicable synthetic route 1. Following the same procedure as the synthesis in A1 (CDD-2110), pyrrolidine is used in the amide coupling reaction to give the title compound (58%, after two steps) – a pale yellow oil; 1 H NMR (600 MHz, DMSO - d 6 ) δ 7.79 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.5 Hz, 2H), 7.60 (d, J = 8.6Hz, 1H), 7.57–7.45 (m, 6H), 7.42–7.36 (m, 2H), 3.58–3.53 (m, 2H), 3.28–3.22(m, 2H), 1.97–1.90 (m, 2H), 1.85–1.77 (m, 2H); 13 C NMR (150 MHz, DMSO -d 6 ) δ168.2, 143.3, 140.1, 140.0, 132.8, 130.6, 129.6, 129.4, 129.1 (2 ×), 128.6,128.2 (2 ×), 127.6, 127.6, 126.2, 123.4, 120.1, 118.5, 110.7, 92.7, 83.9,49.1, 46.0, 26.0, 24.0; HRMS (ESI) C 26 H 22 N3O [M + H] + m / z Calculated value: 392.1763, measured value: 392.1753.

[0185] ( R )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone (A3, CDD-2211) Applicable synthetic route 1. Following the same procedure as the synthesis in A1 (CDD-2110), use ( ) in the amide coupling reaction. R )- N , N -Dimethyl-3-pyrrolidineamine (( R )- N , N -dimethyl-3-pyrrolidinamine), yielding the title compound (77%, after two steps) – a colorless oil; 1 H NMR (600 MHz, DMSO -d 6 (Two rotational isomers) δ 7.78 (dd, J = 7.7, 1.4 Hz, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 8.6 Hz,1H), 7.55–7.44 (m, 6H), 7.43–7.37 (m, 2H), 3.81–3.77 (m, 0.5H), 3.73–3.67 (m,0.5H), 3.56–3.50 (m, 0.5H), 3.43–3.28 (m, 2H), 3.21–3.12 (m, 0.5H), 2.81–2.68(m, 0.5H), 2.68–2.58 (m, 0.5H), 2.22 (s, 3H), 2.14–1.98 (m, 4H), 1.85–1.75(m, 0.5H), 1.75–1.63 (m, 0.5H); 13 C NMR (150 MHz, DMSO -d 6 (Two rotational isomers) δ168.4, 143.2, 140.6, 140.0, 132.7, 130.1, 129.6, 129.3, 129.0 (2 ×), 128.4, 128.2 (2 ×), 127.6 (2 ×), 125.9, 125.7, 123.6, 120.3, 118.6, 111.0, 92.6, 84.3, 65.1, 63.9, 53.0, 50.2, 48.2, 45.0, 43.9, 43.6, 30.5, 28.4; HRMS (ESI)C 28 H 27 N4O [M + H] + m / zCalculated value: 435.2185; Measured value: 435.2174.

[0186] ( S )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone (A4, CDD-2212) Applicable synthetic route 1. Following the same procedure as the synthesis in A1 (CDD-2110), use ( ) in the amide coupling reaction. S )- N , N -Dimethyl-3-pyrrolidineamine, yielding the title compound (19%, via two steps) – a colorless oil; 1 ¹H NMR (600 MHz, CD3OD, two rotational isomers) δ 7.73 (dd, J = 7.7, 1.4 Hz, 1H), 7.66 (d, J = 7.0 Hz, 2H), 7.59 (dd, J = 8.6, 6.0 Hz, 1H), 7.54 (dd, J = 8.6, 1.5 Hz, 1H), 7.51–7.44 (m, 4H), 7.44–7.38 (m, 2H), 7.30 (d, J = 14.4 Hz, 1H), 3.98 (dd, J = 12.1, 7.3 Hz, 0.5H), 3.94–3.85 (m, 0.5H), 3.76–3.64 (m, 0.5H). 3.56–3.36 (m, 2H), 3.26–3.20 (m, 0.5H), 2.99–2.92 (m, 0.5H), 2.84–2.77 (m, 0.5H), 2.38 (s, 3H), 2.35–2.12 (m, 4H), 2.00–1.91 (m, 0.5H), 1.87–1.77 (m, 0.5H); 13 CNMR (150 MHz, DMSO -d 6(Two rotational isomers) δ 168.3, 143.3, 140.3, 140.0, 132.8, 130.3, 129.9, 129.6, 129.4, 129.1 (2 ×), 128.6, 128.2 (2 ×), 127.7, 127.7, 126.2, 126.0, 123.5, 120.2, 118.7, 110.9, 92.7, 84.0, 65.2, 64.0, 53.0, 50.3, 48.2, 45.0, 43.9, 43.7, 30.5, 28.5; HRMS (ESI) C 28 H 27 N4O [M + H] + m / z Calculated value: 435.2185; Measured value: 435.2172.

[0187] 3-([1,1'-biphenyl]-2-ylethynyl)- N -(2-(dimethylamino)ethyl)- N -Methyl-1 H -Indazole-5-carboxamide (A5, CDD-2277) Applicable synthetic route 1. Follow the same procedure as the synthesis in A1 (CDD-2110), using the amide coupling reaction. N 1 , N 1 , N 2 -Trimethylethane-1,2-diamine, yielding the title compound (28%, via two steps) – a colorless oil; 1 HNMR (600 MHz, DMSO -d 6 ) δ 7.80–7.75 (m, 1H), 7.75–7.70 (m, 1H), 7.67 (d, J =7.5 Hz, 1H), 7.64–7.25 (m, 9H), 3.23 (d, J = 13.0 Hz, 3H), 3.10–2.81 (m, 2H), 2.67–2.50 (m, 2H), 2.37–2.14 (m, 3H), 2.15–1.58 (m, 3H); HRMS (ESI) C 27 H 27 N4O[M + H] + m / z Calculated value: 423.2185; Measured value: 423.2172.

[0188] 3-([1,1'-biphenyl]-2-ylethynyl)- N -(2-(dimethylamino)ethyl)-1 H -Indazole-5-carboxamide (A6, CDD-2278) Applicable synthetic route 1. Follow the same procedure as the synthesis in A1 (CDD-2110), using the amide coupling reaction. N 1 , N 1 -Dimethylethane-1,2-diamine, yielding the title compound (63%, via two steps) – a colorless oil; 1 H NMR (600 MHz, DMSO) -d 6 ) δ 8.46 (t, J = 5.7 Hz, 1H), 8.21–8.14 (m, 1H), 7.87 (dd, J = 8.8, 1.6 Hz, 1H), 7.81 (dd, J = 7.7, 1.3 Hz, 1H), 7.77–7.71 (m, 2H), 7.62(d, J = 8.7 Hz, 1H), 7.59–7.51 (m, 4H), 7.48 (td, J = 7.4, 1.6 Hz, 1H), 7.43–7.36 (m, 1H), 3.45–3.37 (m, 2H), 2.45 (t, J = 6.9 Hz, 2H), 2.20 (s, 6H); 13 CNMR (150 MHz, DMSO -d 6 ) δ 166.2, 143.2, 140.9, 139.6, 133.2, 129.7, 129.5,129.0 (2 ×), 128.9, 128.4, 128.3 (2 ×), 127.8, 127.6, 126.0, 123.7, 120.0,119.4, 110.6, 92.4, 83.9, 58.3, 45.3 (2 ×), 37.6; HRMS (ESI) C 26 H25 N4O [M + H] + m / z Calculated value: 409.2028; Measured value: 409.2015.

[0189] 3-([1,1'-biphenyl]-2-ylethynyl)- N , N -Dimethyl-1 H -Indazole-5-carboxamide (A7, CDD-2481) Applicable synthetic route 1. Following the same procedure as the synthesis of A1 (CDD-2110), dimethylamine is used in the amide coupling reaction to give the title compound (19%, after two steps) – a pale yellow solid; 1 H NMR (600 MHz, DMSO - d 6 ) δ 7.79–7.21 (m, 12H), 3.07 (s, 3H), 2.87 (s, 3H); 13 C NMR (150 MHz, DMSO - d 6 ) δ 170.1, 143.4, 140.0, 139.9, 132.7, 129.6, 129.3, 129.1, 128.9, 128.3,128.2, 127.6, 127.6, 126.1, 123.5, 120.2, 118.4, 110.9, 92.7, 83.9; HRMS(ESI) C 24 H 20 N3O [M + H] + m / z Calculated value: 366.1606, measured value: 366.1595.

[0190] ( R )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(3-(methylamino)pyrrolidone-1-yl)methyl ketone (A8, CDD-2535) Applicable synthetic route 2. In step 1, 3-iodine-1 is used in the general procedure for amide coupling. H -Indazole-5-carboxylic acid and ( R2-Methyl(pyrrolidone-3-yl)carbamate tert-butyl ester. In step 2, the general procedure of sage coupling is used, employing 2-ethynyl-1,1'-biphenyl. In step 3, the cross-coupled intermediate is subjected to the general procedure of Boc protecting group removal to obtain the title compound (41%, after three steps) – a pale yellow oil; 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ 7.78 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.64–7.34 (m, 9H), 3.70–3.48 (m, 1H), 3.46–3.34 (m, 2H), 3.29–3.20 (m, 1H), 3.10–3.02 (m, 1H), 2.33 (s, 1.5H), 2.15 (s, 1.5H), 2.09–2.00 (m, 0.5H), 1.97–1.86 (m, 0.5H), 1.85–1.74 (m, 0.5H), 1.74–1.64 (m, 0.5H); 13 C NMR (150 MHz, DMSO -d 6 (Two rotational isomers) δ 168.5, 143.4, 140.5, 140.0, 132.7, 130.4, 130.3, 129.6, 129.3, 129.1 (2 ×), 128.5, 128.3 (2 ×), 127.7, 127.7, 126.0, 123.6, 120.3, 118.6, 118.5, 111.0, 92.7, 92.6, 84.2, 59.4, 57.9, 54.5, 51.7, 47.6, 44.6, 34.4, 34.2, 31.5, 29.7; HRMS (ESI) C 27 H 25 N4O [M + H] + m / z Calculated value: 421.2028; Measured value: 421.2016.

[0191] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(piperazin-1-yl)methyl ketone (A9, CDD-2577) Applicable synthetic route 2. Following the same procedure as the synthesis in A8 (CDD-2535), using piperazine-1-carboxylic acid tert-butyl ester in the amide coupling reaction, yielding the title compound (56%) – a white solid; 1 H NMR (600 MHz, DMSO- d 6 δ8.99 (s, 1H), 7.79 (dd, J = 7.6, 1.3 Hz, 1H), 7.70–7.67 (m, 2H), 7.66 (d, J =8.6 Hz, 1H), 7.56 (td, J = 7.5, 1.4 Hz, 1H), 7.52–7.47 (m, 5H), 7.44–7.39 (m,2H), 3.6 (br s, 4H), 3.16 (br s, 4H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 169.5,143.5, 140.1, 133.0, 129.8, 129.6, 129.2, 128.4, 128.2, 127.8, 126.2, 123.7,120.2, 119.1, 111.3, 92.9, 83.9, 42.9; HRMS (ESI) C 26 H 23 N4O [M + H] + m / z Calculated value: 407.1872; Measured value: 407.1860.

[0192] 4-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H (-Indazole-5-carbonyl)piperazin-2-one (A10, CDD-2578) Applicable synthetic route 2. Following the same procedure as the synthesis in A8 (CDD-2535), piperazine-2-one was used in the amide coupling reaction to give the title compound (55%) – a white foam; 1 H NMR (600 MHz, DMSO- d 6 ) 13.68 (s,1H), 8.20 (s, 1H), 7.79 (dd, J = 7.6, 1.3 Hz, 1H), 7.66 (t, J= 8.6 Hz, 3H), 7.55 (td, J = 7.5, 1.4 Hz, 1H), 7.51–7.44 (m, 5H), 7.38 (t, J = 7.5 Hz, 1H),7.33 (s, 1H), 4.48–3.55 (m, 4H), 3.33–3.06 (m, 2H); 13 C NMR (150 MHz, DMSO- d 6 )δ 169.7, 143.9, 140.5, 140.4, 133.2, 130.1, 129.9, 129.5, 129.1, 128.7,128.1, 128.1, 126.4, 124.0, 120.5, 119.2, 111.6, 93.3, 84.2, 39.4; HRMS (ESI)C 26 H 21 N4O [M + H] + m / z Calculated value: 421.1665; Measured value: 421.1653.

[0193] ( R )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(3-aminopyrrolidone-1-yl)methyl ketone (A11, CDD-2579) Applicable synthetic route 2. Following the same procedure as the synthesis in A8 (CDD-2535), use ( ) in the amide coupling reaction. R )-pyrrolidine-3-ylcarbamate tert-butyl ester, yielding the title compound (52%) – a white foam; 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) 8.27 (br s, 1H), 8.11 (br s, 1H), 7.78 (d, J = 7.7Hz, 1H), 7.67 (d, J = 7.5 Hz, 2H), 7.64 (d, J= 8.6 Hz, 1H), 7.57–7.53 (m,2H), 7.51–7.38 (m, 6H), 3.97–3.75 (m, 2H), 3.72–3.60 (m, 2H), 3.42-3.28 (m,1H), 2.38–2.15 (m, 1H), 2.13–1.91 (m, 1H); 13 C NMR (150 MHz, DMSO- d 6 (Two rotational isomers) δ 168.7, 158.5, 143.5, 140.3, 140.0, 133.0, 129.8, 129.7, 129.2 (2×), 128.8, 128.4 (2×), 127.9, 127.8, 126.3, 123.5, 120.2, 119.0, 111.1, 92.8, 83.9, 52.4, 50.0, 49.7, 48.7, 46.8, 44.0, 30.2, 28.2; HRMS (ESI)C 26 H 23 N4O [M + H] + m / z Calculated value: 407.1872; Measured value: 407.1861.

[0194] ( R )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(3-hydroxypyrrolidone-1-yl)methyl ketone (A12, CDD-2594) Applicable synthetic route 2. Following the same procedure as the synthesis in A8 (CDD-2535), use ( ) in the amide coupling reaction. R )-pyrrolidine-3-ol, yielding the title compound (43%) – a white foam; 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ 7.79–7.75 (m, 1H), 7.65 (t, J = 7.3 Hz, 2H), 7.62–7.59 (m, 2H), 7.56–7.52 (m, 2H), 7.50–7.45 (m, 4H), 7.44–7.38 (m, 1H), 7.36 (d, J= 3.7 Hz,1H), 4.40 (br s, 0.5H), 4.23 (br s, 0.5H), 3.68–3.62 (m, 2H), 3.43–3.41 (m,1H), 3.29–3.23 (m, 0.5H), 3.11–3.07 (m, 0.5H), 2.04–1.98 (m, 0.5H), 1.94–1.83(m, 1H), 1.84–1.75 (m, 0.5H); 13 C NMR (150 MHz, DMSO- d 6 (Two rotational isomers) δ 169.0, 143.9, 143.9, 140.5, 140.4, 133.2, 133.1, 132.5, 131.9, 131.9, 130.9, 130.1, 129.9, 129.5, 129.4, 129.2, 129.2, 128.7, 128.2, 128.2, 128.1, 126.7, 123.9, 120.5, 119.1, 118.9, 111.2, 93.3, 84.3, 69.8, 68.6, 57.7, 54.9, 47.6, 44.6 34.8, 32.7; HRMS (ESI) C 26 H 22 N3O2 [M + H] + m / z Calculated value: 408.1712; Measured value: 408.1700.

[0195] ( S )-1-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -indazole-5-carbonyl)- N 2-Methylpyrrolidine-2-carboxamide (A13, CDD-2595) Applicable synthetic route 2. Following the same procedure as the synthesis in A8 (CDD-2535), use ( ) in the amide coupling reaction. S )- N -Methylpyrrolidine-2-carboxamide, yielding the title compound (48%) – a white foam; 1 H NMR (600 MHz, CD3OD) δ 7.75 (d, J = 7.6 Hz, 1H), 7.70–7.63 (m, 5H), 7.58 (d,J = 23.8 Hz,2H), 7.52–7.46 (m, 5H), 7.43 (t, J = 7.4 Hz, 3H), 4.59 (t, J = 7.1 Hz, 1H), 3.85 (t, J = 7.0 Hz, 1H), 3.62 (q, J = 7.5 Hz, 1H), 3.47 (d, J = 10.9 Hz,1H), 2.83 (s, 3H), 2.37 (d, J = 8.8 Hz, 2H), 2.05 (s, 2H); HRMS (ESI)C 28 H 25 N4O2 [M + H] + m / z Calculated value: 449.1978; Measured value: 449.1965.

[0196] 1-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H (-Indazole-5-carbonyl)pyrrolidine-3-one (A14, CDD-2596) Applicable synthetic route 2. Following the same procedure as the synthesis in A8 (CDD-2535), using pyrrolidone-3-one in the amide coupling reaction, to give the title compound (55%) – a white solid; 1 H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 7.0 Hz, 1H), 7.67 (d, J = 7.5 Hz, 2H), 7.61 (s, 1H), 7.52–7.38 (m, 6H), 7.37–7.34 (m, 1H), 7.31 (t, J = 7.4 Hz, 1H), 4.33–4.00 (m, 2H), 3.74 (s, 2H), 2.63 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 207.8, 168.3, 142.2, 138.8, 138.7,131.2, 128.8, 127.8, 127.6, 127.6, 127.4, 126.2, 125.5, 125.4, 125.2, 122.1,118.6, 118.4, 114.4, 109.1, 92.8, 80.7, 44.0, 42.0; HRMS (ESI) C 26 H 20 N3O2 [M +H] + m / z Calculated value: 406.1556; Measured value: 406.1542.

[0197] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(2-oxa-6-azaspiro[3.4]octane-6-yl)methyl ketone (A15, CDD-2597) Applicable synthetic route 2. Following the same procedure as the synthesis in A8 (CDD-2535), 2-oxa-6-azaspiro[3,4]octane was used in the amide coupling reaction to give the title compound (52%) – a white foam; 1 ¹H NMR (600 MHz, CDCl₃)δ 7.74 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.5 Hz, 2H), 7.56 (d, J = 8.2 Hz,1H), 7.49–7.41 (m, 4H), 7.40 (t, J = 7.5 Hz, 2H), 7.38–7.34 (m, 1H), 7.31 (t, J = 7.4 Hz, 1H), 4.84 (d, J = 5.9 Hz, 1H), 4.66 (d, J = 6.1 Hz, 1H), 4.59 (d, J = 6.3 Hz, 1H), 4.55–4.45 (m, 1H), 3.96 (s, 1H), 3.76 (d, J= 7.5 Hz, 1H), 3.53 (s, 1H), 3.35 (s, 1H), 2.31 (d, J = 7.5 Hz, 1H), 2.20 (d, J = 6.9 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 169.8, 144.0, 133.1, 129.6, 129.4, 129.1,128.1, 127.4, 127.2, 120.7, 120.1, 80.7, 80.0, 58.3, 57.0, 54.9, 48.4, 45.0,44.3, 36.2, 34.1; HRMS (ESI) C 28 H 24 N3O2 [M + H] + m / z Calculated value: 434.1869; Measured value: 434.1856.

[0198] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(1,4-diazacycloheptane-1-yl)methyl ketone (A16, CDD-2598) Applicable synthetic route 2. Following the same procedure as the synthesis in A8 (CDD-2535), tert-butyl 1,4-diazacycloheptan-1-carboxylic acid was used in the amide coupling reaction to give the title compound (42%) – a white foam; 1 H NMR (600 MHz, CD3OD) δ 7.74–7.70 (m, 1H), 7.67 – 7.63 (m, 2H), 7.62 (d, J = 8.7 Hz, 1H), 7.53 (dd, J = 8.7, 1.5 Hz, 1H), 7.50–7.42 (m, 4H), 7.40 (td, J = 7.5, 1.5 Hz,2H), 7.35 (s, 1H), 4.07 (s, 1H), 3.97 (s, 1H), 3.63–3.47 (m, 3H), 3.34 (d, J = 6.1 Hz, 2H), 2.25 (s, 1H), 2.05 (s, 2H); 13C NMR (150 MHz, CD3OD) δ 172.6,144.2, 140.7, 140.5, 132.5, 129.8, 129.3, 129.0, 129.0, 128.4, 127.9, 127.3,127.1, 125.9, 123.7, 120.5, 119.4, 110.8, 93.3, 82.7, 53.4, 48.3, 48.2, 45.5,44.5, 42.0, 25.7; HRMS (ESI) C 27 H 25 N4O [M + H] + m / z Calculated value: 421.2028; Measured value: 421.2018.

[0199] 3-([1,1'-biphenyl]-2-ylethynyl)- N -(4-Methoxyphenyl)-1 H -Indazole-5-carboxamide (A17, CDD-2606) Applicable synthetic route 2. Following the same procedure as the synthesis in A8 (CDD-2535), 4-methoxyaniline was used in the amide coupling reaction to give the title compound (42%) – a white solid; 1 H NMR (600 MHz, CDCl3) δ 7.99 (s,1H), 7.75–7.55 (m, 7H), 7.46–7.38 (m, 6H), 7.20 (d, J = 7.5 Hz, 1H), 6.98 (s, 2H), 3.86 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 129.5, 128.1, 127.7, 122.6,114.3, 93.2, 82.5, 55.5; HRMS (ESI) C 29 H 22 N3O2 [M + H] + m / z Calculated value: 444.1712; Measured value: 444.1700.

[0200] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(4,7-diazaspiro[2.5]octane-4-yl)methyl ketone (A18, CDD-2607) Applicable synthetic route 1. In step 1, 3-iodine-1-(tetrahydro-2-iodine) is used in the general procedure for coupling with sage. H -pyran-2-yl)-1 H 5-Indazole-5-carboxylic acid methyl ester (which is derived from 3-iodine-1 via the THP protection general procedure) H 3-Indazole-5-carboxylic acid methyl ester) and 2-ethynyl-1,1'-biphenyl. In step 2, the cross-coupled intermediate is subjected to a general THP-protected amine hydrolysis procedure to give 3-([1,1'-biphenyl]-2-ylethynyl)-1-(tetrahydro ... H -pyran-3-yl)-1 H -Indazole-5-carboxylic acid (75%, after two steps) - is a pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 13.06 (s, 1H), 8.15 (s, 1H), 8.01 (dd, J = 8.8, 1.5 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.81 (dd,J = 7.7, 1.3 Hz, 1H), 7.76–7.65 (m, 2H), 7.60–7.51 (m, 4H), 7.48 (td, J =7.5, 1.5 Hz, 1H), 7.46–7.40 (m, 1H), 5.93 (dd, J = 9.5, 2.5 Hz, 1H), 3.91–3.83 (m, 1H), 3.80–3.70 (m, 1H), 2.40–2.27 (m, 1H), 2.08–1.89 (m, 2H), 1.80–1.66 (m, 1H), 1.65–1.52 (m, 2H). In step 3, the acid and 4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester were used in the general procedure for amide coupling. In step 4, the general procedure was performed using THP and Boc protecting groups to obtain the title compound (35%, after two steps) – a yellow oil; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.77(d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.59 (d, J= 8.6 Hz, 1H),7.56–7.35 (m, 8H), 3.37 (s, 2H), 2.92–2.53 (m, 4H), 1.17–0.22 (m, 4H); 13 C NMR (150 MHz, DMSO-) d 6 ) δ 143.2, 140.7, 139.9, 132.9, 129.7, 129.4, 129.1, 128.4,128.2, 127.7, 125.9, 123.7, 120.3, 118.7, 110.9, 92.5, 84.3, 13.8; HRMS (ESI)C 28 H 25 N4O [M + H] + m / z Calculated value: 433.2028; Measured value: 433.2016.

[0201] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(4,7-diazaspiro[2.5]octane-7-yl)methyl ketone (A19, CDD-2608) Applicable synthetic route 1. Following the same procedure as the synthesis of A18 (CDD-2607), tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylic acid was used in the amide coupling reaction to give the title compound (78%, after two steps) – a pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.77 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 7.5Hz, 2H), 7.60 (d, J = 8.6 Hz, 1H), 7.56–7.17 (m, 8H), 3.12 (s, 2H), 2.98–2.54(m, 4H), 0.77–0.01 (m, 4H); 13 C NMR (150 MHz, DMSO- d 6) δ 143.4, 140.1, 140.0,132.7, 129.7, 129.4, 129.1, 128.4, 128.3, 127.7, 127.7, 125.9, 123.7, 120.2,118.4, 111.1, 92.7, 84.1, 11.7; HRMS (ESI) C 28 H 25 N4O [M + H] + m / z Calculated value: 433.2028; Measured value: 433.2015.

[0202] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(5,8-diazaspiro[3.5]nonane-8-yl)methyl ketone (A20, CDD-2609) Applicable synthetic route 1. Following the same procedure as the synthesis of A18 (CDD-2607), tert-butyl 5,8-diazaspiro[3.5]nonane-5-carboxylic acid was used in the amide coupling reaction to give the title compound (72%, after two steps) – a yellow oil; 1 H NMR (600 MHz, DMSO- d 6 δ 7.76 (s, 1H), 7.68 (d, J = 6.9 Hz, 2H), 7.62(d, J = 7.4 Hz, 1H), 7.5–7.42 (m, 5H), 7.38 (t, J = 7.6 Hz, 1H), 7.35–7.26(m, 2H), 3.21 (s, 4H), 2.88–2.52 (m, 2H), 2.16–0.94 (m, 6H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 169.6, 143.2, 141.1, 140.1, 132.7, 129.6, 129.2, 129.1, 128.2,128.1, 127.7, 127.6, 125.2, 123.9, 120.5, 118.4, 111.6, 92.5, 84.8, 56.5,31.1, 12.9; HRMS (ESI) C 29 H 27N4O [M + H] + m / z Calculated value: 447.2185; Measured value: 447.2171.

[0203] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(3,6-diazabicyclo[3.1.1]heptane-3-yl)methyl ketone (A21, CDD-2610) Applicable to synthetic route 1; yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.82–7.74 (m,1H), 7.71–7.58 (m, 3H), 7.58–7.32 (m, 8H), 4.02–3.77 (m, 2H), 3.73–3.62 (m,4H), 2.13–1.67 (m, 1H), 1.56–1.39 (m, 1H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 171.4,143.4, 140.0, 139.9, 132.8, 131.5, 131.5, 130.6, 129.7, 129.4, 129.1, 129.1,128.8, 128.7, 128.4, 128.3, 127.7, 127.7, 125.7, 123.6, 120.2, 118.0, 111.0,92.6, 84.1, 54.8, 54.3, 52.6, 48.7, 30.2; HRMS (ESI) C 27 H 23 N4O [M + H] + m / z Calculated value: 419.1872; Measured value: 419.1861.

[0204] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(2,5-diazabicyclo[2.2.2]octane-2-yl)methyl ketone (A22, CDD-2611) Applicable to synthetic route 1; yellow oily substance; 1 H NMR (600 MHz, DMSO- d6 ) δ 7.77 (d, J = 7.5Hz, 1H), 7.71–7.57 (m, 3H), 7.57–7.25 (m, 8H), 3.27–2.79 (m, 6H), 2.10–1.46(m, 4H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 169.1, 143.3, 140.3, 140.0, 132.8,132.1, 131.5, 131.5, 130.0, 129.7, 129.4, 129.1, 129.0, 128.8, 128.7, 128.4,128.3, 128.3, 127.8, 127.7, 127.7, 126.0, 125.1, 123.9, 120.3, 117.9, 111.3,111.1, 92.7, 84.2, 50.8, 47.9, 43.9, 26.2, 25.9, 24.7; HRMS (ESI) C 28 H 25 N4O [M+ H] + m / z Calculated value: 433.2028; Measured value: 433.2015.

[0205] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(3,8-diazabicyclo[3.2.1]octane-3-yl)methyl ketone (A23, CDD-2612) Applicable to synthetic route 1; yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.77 (d, J = 7.6Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 8.5 Hz, 1H), 7.55–7.43 (m,5H), 7.40 (t, J = 7.4 Hz, 1H), 7.32 (d, J= 8.5 Hz, 1H), 7.24 (s, 1H), 4.41–4.27 (m, 1H), 3.31–3.12 (m, 4H), 3.02–2.90 (m, 1H), 1.79–1.31 (m, 4H); 13 C NMR (150 MHz, DMSO-) d 6 ) δ 170.4, 143.3, 140.5, 140.1, 132.7, 129.6, 129.6, 129.3,129.1, 128.2, 127.7, 125.4, 123.8, 120.4, 118.3, 111.3, 92.6, 84.4, 53.6,28.0; HRMS (ESI) C 28 H 25 N4O [M + H] + m / z Calculated value: 433.2028; Measured value: 433.2016.

[0206] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)methyl ketone (A24, CDD-2613) Applicable to synthetic route 1; yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.77 (d, J = 7.6Hz, 1H), 7.68 (d, J = 7.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.55–7.43 (m,5H), 7.43–7.34 (m, 2H), 7.31 (s, 1H), 4.62–4.08 (m, 4H), 3.41–3.00 (m, 2H),2.06–1.31 (m, 4H); 13 C NMR (150 MHz, DMSO- d 6) δ 170.5, 143.2, 140.7, 140.1,132.7, 129.7, 129.3, 129.1, 128.9, 128.3, 128.2, 127.7, 127.7, 125.5, 123.9,120.3, 118.6, 111.4, 92.6, 84.4, 73.2, 27.1; HRMS (ESI) C 28 H 24 N3O2 [M + H] + m / z Calculated value: 434.1869; Measured value: 434.1854.

[0207] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(3-phenylpiperazin-1-yl)methyl ketone (A25,CDD-2614) Applicable to synthetic route 1; yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.79 (d, J = 6.5Hz, 1H), 7.72–7.58 (m, 3H), 7.58–7.07 (m, 13H), 4.52 (s, 1H), 3.19–2.63 (m,6H); 13 C NMR (150 MHz, DMSO- d 6 ) 169.0, 143.4, 140.1, 140.0, 132.8, 129.7,129.4, 129.3, 129.1, 128.5, 128.3, 128.3, 127.8, 127.7, 127.5, 126.9, 126.0,123.7, 120.2, 118.5, 111.2, 92.8, 84.0; HRMS (ESI) C 32 H 27 N4O [M + H] + m / z Calculated value: 483.2185; Measured value: 483.2171.

[0208] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H-Indazol-5-yl)(2,8-diazaspiro[4.5]decane-2-yl)methyl ketone (A26, CDD-2674) Applicable to synthetic route 1; colorless oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.81–7.76 (m,1H), 7.71–7.66 (m, 2H), 7.63–7.57 (m, 1H), 7.57–7.44 (m, 7H), 7.43–7.32 (m,2H), 3.65–3.59 (m, 2H), 3.09 (s, 2H), 2.79–2.65 (m, 2H), 2.61 (s, 1H), 2.45(s, 1H), 1.87–1.78 (m, 1H), 1.78–1.65 (m, 1H), 1.60–1.42 (m, 2H), 1.39–1.22(m, 2H); HRMS (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2327.

[0209] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(2,9-diazaspiro[5.5]undecane-2-yl)methyl ketone (A27, CDD-2675) Applicable to synthetic route 1; colorless oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.78 (d, J = 7.6Hz, 1H), 7.68 (d, J = 7.5 Hz, 2H), 7.62 (d, J= 8.6 Hz, 1H), 7.58–7.52 (m,1H), 7.52–7.45 (m, 4H), 7.42–7.35 (m, 2H), 7.29 (s, 1H), 3.70–3.59 (m, 2H), 2.92 (s, 4H), 2.14 (s, 1H), 1.67–1.33 (m, 7H), 1.30–1.03 (m, 2H); HRMS (ESI)C 31 H 31 N4O [M + H] + m / z Calculated value: 475.2498; Measured value: 475.2484.

[0210] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(5,8-diazaspiro[3.5]nonane-5-yl)methyl ketone (A28, CDD-2676) Applicable to synthetic route 1; colorless oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.77 (d, J = 7.6Hz, 1H), 7.71 (d, J = 7.7 Hz, 2H), 7.59 (d, J = 8.5 Hz, 1H), 7.56–7.33 (m,8H), 3.16 (s, 2H), 2.92 (s, 2H), 2.49–2.35 (m, 2H), 2.27–2.09 (m, 4H), 1.84–1.60 (m, 2H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 170.7, 143.0, 141.5, 140.0, 132.7,130.0, 129.6, 129.2, 129.1, 128.2, 128.1, 127.7, 127.6, 125.6, 123.9, 120.5,119.0, 111.5, 92.3, 84.9, 60.0, 50.3, 46.6, 45.9, 30.7, 14.5; HRMS (ESI)C 29 H 27 N4O [M + H]+ m / z Calculated value: 447.2185; Measured value: 447.2171.

[0211] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(6,9-diazaspiro[4.5]decane-6-yl)methyl ketone (A29, CDD-2677) Applicable to synthetic route 1; colorless oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.77 (d, J = 7.6Hz, 1H), 7.70 (d, J = 7.7 Hz, 2H), 7.59 (d, J = 8.6 Hz, 1H), 7.56–7.43 (m,5H), 7.43–7.29 (m, 3H), 3.19–3.14 (m, 2H), 2.69 (s, 2H), 2.68–2.61 (m, 2H), 2.20–2.06 (m, 2H), 2.00–1.84 (m, 4H), 1.62–1.50 (m, 2H); HRMS (ESI) C 30 H 29 N4O[M + H] + m / z Calculated value: 461.2341; Measured value: 461.2328.

[0212] ( S )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(2-Phenylopirabin-1-yl)methyl ketone (A30, CDD-2678) Applicable to synthetic route 1; colorless oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.74 (d, J = 7.6Hz, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.62 (d, J= 8.8 Hz, 1H), 7.56–7.23 (m,13H), 3.15–2.59 (m, 7H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 143.1, 140.7, 140.0,139.6, 132.8, 129.6, 129.3, 129.0, 128.5, 128.2, 128.1, 127.7, 127.7, 127.2,126.6, 124.9, 123.8, 120.4, 118.2, 111.5, 92.5, 84.5, 45.8; HRMS (ESI)C 32 H 27 N4O [M + H] + m / z Calculated value: 483.2185; Measured value: 483.2171.

[0213] ( R )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(2-(4-chlorophenyl)piperazin-1-yl)methyl ketone (A31, CDD-2679) Applicable to synthetic route 1; colorless oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.75 (d, J = 7.6Hz, 1H), 7.67 (d, J = 7.5 Hz, 2H), 7.62 (d, J = 8.6 Hz, 1H), 7.58–7.23 (m,12H), 3.15–2.58 (m, 7H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 143.2, 140.5, 140.0,138.8, 132.8, 131.4, 129.6, 129.4, 129.3, 129.2, 129.1, 128.3, 128.2, 128.2,127.7, 125.1, 123.8, 120.3, 118.3, 111.4, 92.5, 84.3, 45.8; HRMS (ESI)C 32H 26 ClN4O [M + H] + m / z Calculated value: 517.1795; Measured value: 517.1784.

[0214] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[4.5]decane-2-yl)methyl ketone (A32, CDD-2765) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.76 (d, J =7.6 Hz, 1H), 7.68 (d, J = 7.5 Hz, 2H), 7.57 (t, J = 7.0 Hz, 1H), 7.54–7.36(m, 8H), 3.67–3.51 (m, 2H), 3.22–3.13 (m, 2H), 2.75 (s, 1H), 2.63 (s, 1H),2.01–1.85 (m, 1H), 1.82–1.67 (m, 1H), 1.62–1.55 (m, 1H), 1.53–1.47 (m, 1H), 1.45–1.17 (m, 4H); HRMS (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2328.

[0215] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(2,7-diazaspiro[4.5]decane-2-yl)methyl ketone (A33, CDD-2766) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.84–7.64 (m,3H), 7.57 (d, J= 8.5 Hz, 1H), 7.53–7.33 (m, 8H), 3.63–3.55 (m, 2H), 3.11–2.96 (m, 2H), 2.46–2.33 (m, 2H), 2.04–1.85 (m, 1H), 1.83–1.68 (m, 1H), 1.59(s, 1H), 1.52–1.29 (m, 4H), 1.15 (s, 1H); HRMS (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2329.

[0216] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(1,8-diazaspiro[4.5]decane-1-yl)methyl ketone (A34, CDD-2767) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.78 (d, J =7.6 Hz, 1H), 7.70 (d, J = 7.5 Hz, 2H), 7.60 (d, J = 8.6 Hz, 1H), 7.57–7.39(m, 7H), 7.34 (s, 1H), 3.30 (t, J = 6.7 Hz, 5H), 3.26–3.17 (m, 2H), 3.08–2.97(m, 2H), 2.11 (t, J = 6.8 Hz, 2H), 1.82–1.73 (m, 2H), 1.73–1.65 (m, 2H); HRMS(ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2327.

[0217] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H-Indazol-5-yl)(8-oxa-1-azaspiro[4.5]decane-1-yl)methyl ketone (A35, CDD-2768) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.78 (d, J =7.6 Hz, 1H), 7.69 (d, J = 7.5 Hz, 2H), 7.58 (d, J = 8.6 Hz, 1H), 7.56–7.45(m, 5H), 7.43–7.37 (m, 2H), 7.32 (s, 1H), 3.90 (dd, J = 11.4, 5.0 Hz, 2H), 3.46 (t, J = 12.2 Hz, 2H), 3.27 (t, J = 6.6 Hz, 3H), 3.15–3.03 (m, 2H), 2.09(t, J = 6.8 Hz, 2H), 1.78–1.69 (m, 2H), 1.39 (d, J = 12.4 Hz, 2H); HRMS (ESI)C 30 H 28 N3O2 [M + H] + m / z Calculated value: 462.2182; Measured value: 462.2365.

[0218] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(2,8-diazaspiro[4.5]decane-8-yl)methyl ketone (A36, CDD-2769) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.76 (d, J =7.7 Hz, 1H), 7.69 (d, J = 7.5 Hz, 2H), 7.58 (t, J= 9.2 Hz, 1H), 7.53–7.25(m, 8H), 3.63–3.56 (m, 2H), 3.17–3.05 (m, 2H), 2.48–2.36 (m, 2H), 1.78–1.32(m, 6H), 1.23 (s, 2H); (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2328.

[0219] 3-([1,1'-biphenyl]-2-ylethynyl)- N -(7-azaspiro[3.5]nonane-2-yl)-1 H -Indazole-5-carboxamide (A37, CDD-2770) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.76 (d, J =7.7 Hz, 1H), 7.69 (d, J = 7.5 Hz, 2H), 7.58 (t, J = 9.2 Hz, 1H), 7.53–7.25(m, 8H), 3.63–3.56 (m, 2H), 3.17–3.05 (m, 3H), 2.48–2.36 (m, 2H), 1.78–1.32(m, 6H), 1.23 (s, 1H); HRMS (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2327.

[0220] ( S )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(2-isopropylpiperazin-1-yl)methyl ketone (A38, CDD-2771) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d6 ) δ 7.79 (d, J =7.6 Hz, 1H), 7.70 (d, J = 7.5 Hz, 2H), 7.65 (d, J = 8.6 Hz, 1H), 7.58–7.35(m, 8H), 4.71–4.26 (m, 1H), 3.55 (s, 2H), 3.27–2.89 (m, 4H), 2.35 (s, 1H),1.16–0.66 (m, 6H); HRMS (ESI) C 29 H 29 N4O [M + H] + m / z Calculated value: 449.2341; Measured value: 449.2326.

[0221] ( R )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(2-isopropylpiperazin-1-yl)methyl ketone (A39, CDD-2772) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.79 (d, J =7.6 Hz, 1H), 7.70 (d, J = 7.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.58–7.44(m, 7H), 7.41 (t, J = 7.4 Hz, 1H), 4.48 (s, 1H), 3.56 (s, 2H), 3.25–2.89 (m,4H), 2.35 (s, 1H), 1.13–0.59 (m, 6H); HRMS (ESI) C 29 H 29 N4O [M + H] + m / z Calculated value: 449.2341; Measured value: 449.2328.

[0222] ( S )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H-Indazole-5-yl)(2-benzylpiperazin-1-yl)methyl ketone (A40, CDD-2773) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.81 (d, J =7.9 Hz, 1H), 7.73–7.67 (m, 2H), 7.60–7.44 (m, 6H), 7.41 (t, J = 7.5 Hz, 1H),7.14 (br s, 7H), 3.32–2.99 (m, 9H); HRMS (ESI) C 33 H 29 N4O [M + H] + m / z Calculated value: 497.2341; Measured value: 497.2326.

[0223] ( R )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(2-benzylpiperazin-1-yl)methyl ketone (A41, CDD-2774) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.82 (d, J =7.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.60–7.43 (m, 6H), 7.41 (t, J = 7.4Hz, 1H), 7.15 (br s, 7H), 3.35–2.94 (m, 9H); HRMS (ESI) C 33 H 29 N4O [M + H] + m / z Calculated value: 497.2341; Measured value: 497.2329.

[0224] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -indazole-5-yl)((2 S 6 S2,6-Dimethylpiperazin-1-yl)methyl ketone (A42, CDD-2775) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.79 (d, J =7.6 Hz, 1H), 7.71 (d, J = 7.5 Hz, 2H), 7.65 (d, J = 8.6 Hz, 1H), 7.58–7.46(m, 7H), 7.41 (t, J = 7.4 Hz, 1H), 4.12–4.02 (m, 2H), 3.40–3.36 (m, 2H), 3.19–3.10 (m, 2H), 1.31 (s, 3H), 1.30 (s, 3H); HRMS (ESI) C 28 H 27 N4O [M + H] + m / z Calculated value: 435.2185; Measured value: 435.2170.

[0225] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone (A43, CDD-2806) Applicable to synthetic route 1; colorless oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.79 (d, J = 7.7Hz, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.69 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.58–7.50 (m, 4H), 7.48 (td, J = 7.4, 1.7 Hz, 1H), 7.43 (t, J= 7.4 Hz, 1H), 3.85 (s, 2H), 3.79 (s, 2H), 2.68–2.52 (m, 4H), 1.62(t, J = 5.4 Hz, 4H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 169.2, 143.2, 140.8, 139.8,133.0, 129.7, 129.5, 129.0 (2 x), 128.8, 128.3 (2 x), 127.8, 127.7, 126.7,126.4, 123.6, 120.1, 119.7, 110.9, 92.6, 84.0, 63.4, 59.0, 42.8 (2x), 36.1(2x), 34.3; HRMS (ESI) C 29 H 27 N4O [M + H] + m / z Calculated value: 447.2185; Measured value: 447.2173.

[0226] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (A44, CDD-2807) Applicable synthetic route 1. Following the same procedure as the synthesis of A18 (CDD-2607), tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylic acid was used in the amide coupling reaction to give the title compound (31%, after two steps) – a white solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 7.80 (dd, J = 7.7, 1.3 Hz, 1H), 7.72 (dd, J =8.2, 1.3 Hz, 2H), 7.69–7.64 (m, 2H), 7.61 (dd, J = 8.6, 0.9 Hz, 1H), 7.58–7.50 (m, 4H), 7.48 (td, J = 7.4, 1.6 Hz, 1H), 7.46–7.42 (m, 1H), 3.84 (d,J =8.4 Hz, 1H), 3.81–3.74 (m, 2H), 3.70 (d, J = 9.7 Hz, 1H), 2.79–2.65 (m, 2H), 2.59–2.51 (m, 2H), 1.68 (br s, 2H), 1.46–1.23 (m, 2H); 13 C NMR (150 MHz, DMSO - d 6 ) δ 169.4, 143.1, 141.3, 139.8, 132.9, 129.7, 129.4, 129.0 (2 ×), 128.6,128.3 (2 ×), 127.8, 127.6, 126.5, 126.0, 123.7, 120.2, 119.6, 111.2, 92.5,84.4, 62.2, 57.7, 54.6, 45.3, 34.7, 34.1, 23.2; HRMS (ESI) C 29 H 27 N4O [M + H] + m / z Calculated value: 447.2185; Measured value: 447.2173.

[0227] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(2,5-diazaspiro[3.5]nonane-2-yl)methyl ketone (A45, CDD-2808) Applicable to synthetic route 1; white solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.79 (d, J = 7.6Hz, 1H), 7.74–7.69 (m, 3H), 7.67 (d, J = 8.8 Hz, 1H), 7.62 (d, J= 8.6 Hz,1H), 7.58–7.50 (m, 4H), 7.50–7.42 (m, 2H), 3.98–3.92 (m, 1H), 3.92–3.84 (m,2H), 3.82–3.77 (m, 1H), 2.68–2.62 (m, 1H), 2.61–2.54 (m, 1H), 1.67–1.58 (m,2H), 1.55–1.48 (m, 1H), 1.48–1.40 (m, 1H), 1.38–1.31 (m, 2H); 13 C NMR (150MHz, DMSO- d 6 ) δ 169.4, 143.3, 140.7, 139.8, 133.1, 129.7, 129.6, 129.0 (2×), 128.9, 128.3 (2×), 127.9, 127.7, 127.0, 126.5, 123.6, 120.1, 119.8,110.9, 92.7, 83.9, 64.3, 60.1, 53.3, 42.3, 34.5, 24.9, 21.3; HRMS (ESI)C 29 H 27 N4O [M + H] + m / z Calculated value: 447.2185; Measured value: 447.2171.

[0228] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(7-oxa-2-azaspiro[3.5]nonane-2-yl)methyl ketone (A46, CDD-2809) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.77 (d, J =7.7 Hz, 1H), 7.72 (d, J = 7.5 Hz, 2H), 7.69 (s, 1H), 7.59 (s, 2H), 7.55–7.49(m, 4H), 7.49–7.40 (m, 2H), 3.92 (s, 2H), 3.85 (s, 2H), 2.50 (br s, 4H), 1.72(t,J = 5.3 Hz, 4H); HRMS (ESI) C 29 H 26 N3O2 [M + H] + m / z Calculated value: 448.2025; Measured value: 448.2012.

[0229] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(8-oxa-2-azaspiro[4.5]decane-2-yl)methyl ketone (A47, CDD-2810) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.76 (s, 1H),7.69 (s, 2H), 7.58 (d, J = 8.7 Hz, 1H), 7.54–7.41 (m, 7H), 7.38 (s, 1H), 3.63(s, 6H), 3.18–3.12 (m, 2H), 1.91 (t, J = 7.3 Hz, 1H), 1.78 (s, 1H), 1.68–1.50(m, 2H), 1.41 (s, 2H); HRMS (ESI) C 30 H 28 N3O2 [M + H] + m / z Calculated value: 462.2182; Measured value: 462.2166.

[0230] ( R )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(2-Phenylopirabin-1-yl)methyl ketone (A48, CDD-2811) Applicable to synthetic route 1; colorless oily substance; 1 H NMR (600 MHz, DMSO- d 6) δ 7.76–7.71 (m,1H), 7.71–7.65 (m, 2H), 7.63–7.56 (m, 1H), 7.53–7.38 (m, 9H), 7.37–7.18 (m,4H), 3.17–2.94 (m, 5H), 2.81 (s, 1H), 2.68 (s, 1H); HRMS (ESI) C 32 H 27 N4O [M +H] + m / z Calculated value: 483.2185; Measured value: 483.2172.

[0231] ( R )-or( S ) - (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[4.5]decane-2-yl)methyl ketone (A49 and A50, CDD-2830 and CDD-2831) A49 (CDD-2830) and A50 (CDD-2831) are undetermined fractions separated from A32 (CDD-2765) by chiral separation. R -enantiomers and S -Enantiomer.

[0232] A49: Pale yellow oily substance; HRMS (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2331.

[0233] A50: Pale yellow oily substance; HRMS (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2325.

[0234] 7-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-carbonyl)-2,7-diazaspiro[3.5]nonane-1-one (A51, CDD-2921) Applicable to synthetic route 1; colorless oily substance; 1H NMR (600 MHz, DMSO- d 6 ) δ 7.76 (dd, J =7.6, 1.4 Hz, 1H), 7.70–7.65 (m, 2H), 7.59 (dd, J = 8.5, 0.9 Hz, 1H), 7.54–7.43 (m, 5H), 7.40–7.35 (m, 1H), 7.34–7.30 (m, 1H), 7.28 (t, J = 1.2 Hz, 1H),3.69–3.64 (m, 4H), 3.15–3.03 (m, 4H), 2.69 (s, 2H); HRMS (ESI) C 29 H 22 N4O2 [M +H] + m / z Calculated value: 458.1743; Measured value: 458.1726.

[0235] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(2-Methyl-2,7-diazaspiro[3.5]nonane-7-yl)methyl ketone (A52, CDD-2922) Applicable to synthetic route 1; colorless oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.73 (d, J = 7.4Hz, 1H), 7.71–7.67 (m, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.50–7.43 (m, 5H), 7.39–7.33 (m, 1H), 7.28 (d, J = 1.4 Hz, 1H), 7.19 (dd, J = 8.5, 1.5 Hz, 1H),3.24–3.12 (m, 4H), 2.96 (s, 4H), 2.22 (s, 3H), 1.80–1.47 (m, 4H); HRMS (ESI)C 30 H 29 N4O [M + H] + m / zCalculated value: 461.2341; Measured value: 461.2328.

[0236] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone (A53, CDD-2923) Applicable to synthetic route 1; colorless oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.79 (dd, J =7.8, 1.3 Hz, 1H), 7.74–7.67 (m, 3H), 7.65 (dd, J = 8.7, 1.6 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.57–7.49 (m, 4H), 7.48 (td, J = 7.3, 1.7 Hz, 1H), 7.45–7.40(m, 1H), 3.86 (s, 2H), 3.79 (s, 2H), 2.23 (br s, 4H), 2.10 (s, 3H), 1.71 (t, J = 5.4 Hz, 4H); HRMS (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2329.

[0237] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(5-methyl-2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone (A54, CDD-2924) Applicable to synthetic route 1; colorless oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.78 (d, J = 7.6Hz, 1H), 7.72 (d, J= 7.9 Hz, 3H), 7.66–7.58 (m, 2H), 7.56–7.38 (m, 6H), 3.96–3.91 (m, 2H), 3.86–3.59 (m, 2H), 2.74–2.50 (m, 3H), 2.33–2.12 (m, 1H),1.88–1.73 (m, 1H), 1.62 (s, 1H), 1.56–1.45 (m, 1H), 0.89 (dd, J = 19.0, 6.8Hz, 3H); HRMS (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2329.

[0238] ( S )-4-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H (-Indazole-5-carbonyl)-3-phenylpiperazin-2-one (A55, CDD-2925) Applicable to synthetic route 1; white solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.37 (d, J = 3.3Hz, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 7.5 Hz, 2H), 7.61–7.54 (m,1H), 7.52–7.10 (m, 13H), 3.22–3.06 (m, 5H); HRMS (ESI) C 32 H 25 N4O2 [M + H] + m / z Calculated value: 497.1978; Measured value: 497.1965.

[0239] ( S )-3-([1,1'-biphenyl]-2-ylethynyl)- N -(2-(dimethylamino)-2-oxo-1-phenylethyl)-1 H -Indazole-5-carboxamide (A56, CDD-2926) Applicable to synthetic route 1; white solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.85–7.78 (m, 1H),7.75 (dt, J = 7.7, 1.7 Hz, 1H), 7.73–7.66 (m, 2H), 7.60–7.25 (m, 13H), 3.68(s, 1H), 2.99 (s, 3H), 2.90 (s, 3H); HRMS (ESI) C 32 H 27 N4O2 [M + H] + m / z Calculated value: 499.2134; Measured value: 499.2120.

[0240] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(6-methyl-2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (A57, CDD-3009) Applicable to synthetic route 1; white solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.76 (d, J = 7.5Hz, 1H), 7.72 (d, J = 7.5 Hz, 2H), 7.67 (s, 1H), 7.58–7.48 (m, 6H), 7.48–7.41(m, 2H), 3.85–3.73 (m, 4H), 2.47–2.17 (m, 4H), 2.16 (s, 3H), 1.64–1.38 (m,4H; HRMS (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2328.

[0241] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(5-methyl-2,5-diazaspiro[3.5]nonane-2-yl)methyl ketone (A58, CDD-3010) Applicable to synthetic route 1; colorless oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.76 (d, J = 7.6Hz, 1H), 7.75–7.71 (m, 3H), 7.59–7.50 (m, 6H), 7.49–7.44 (m, 1H), 7.44–7.39(m, 1H), 4.21 (dd, J = 35.4, 9.7 Hz, 2H), 3.72 (dd, J = 48.7, 9.7 Hz, 2H),2.45–2.33 (m, 2H), 2.29 (s, 3H), 1.72 (d, J = 10.0 Hz, 2H), 1.53–1.33 (m,4H); HRMS (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2328.

[0242] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(2-Methyl-2,5-diazaspiro[3.5]nonane-5-yl)methyl ketone (A59, CDD-3011) Applicable to synthetic route 1; colorless oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.77 (d, J = 7.5Hz, 1H), 7.74–7.69 (m, 2H), 7.60 (d, J = 8.5 Hz, 1H), 7.56–7.42 (m, 7H), 7.38(dd, J = 8.5, 1.5 Hz, 1H), 3.59–3.54 (m, 2H), 3.17–3.13 (m, 2H), 2.90 (d, J =7.4 Hz, 2H), 2.30 (s, 3H), 1.98 (t, J= 6.0 Hz, 2H), 1.76–1.65 (m, 2H), 1.25–1.13 (m, 2H); HRMS (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2326.

[0243] 1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -indazole-5-carbonyl)pyrrolidine-3-yl)- N , N -Dimethylpiperidine-4-carboxamide (A60, CDD-3347) Suitable for synthetic route 1; pale yellow oil; 1H NMR (800 MHz, CD3OD) δ 7.74 (dd, J =7.6, 0.6 Hz, 1H), 7.66 (t, J = 8.5 Hz, 2H), 7.60 (dd, J = 11.6, 6.5 Hz, 1H), 7.54 (t, J = 9.2 Hz, 1H), 7.51–7.48 (m, 3H), 7.47 (d, J = 6.9 Hz, 1H), 7.42(dd, J = 14.9, 7.6 Hz, 2H), 7.31 (t, J = 12.5 Hz, 1H), 4.07–3.84 (m, 1H), 3.70–3.48 (m, 2H), 3.46–3.34 (m, 1H), 3.29–3.11 (m, 3H), 3.11–2.92 (m, 5H), 2.90–2.57 (m, 3H), 2.36–2.25 (m, 1H), 2.25–2.13 (m, 1H), 2.12–2.00 (m, 1H),1.98–1.58 (m, 4H); HRMS (ESI) C 34 H 36 N5O2 [M + H] + m / z Calculated value: 546.2869; Measured value: 546.2857.

[0244] 3-(1-(1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-carbonyl)pyrrolidine-3-yl)piperidine-4-carbonyl)piperidine-4-yl)- N -Methylpropionamide (A61, CDD-3348) Applicable synthetic route 1. Following the same procedure as the synthesis in A18 (CDD-2607), using the amide coupling reaction... N -Methyl-3-(1-(1-(pyrrolidin-3-yl)piperidin-4-carbonyl)piperidin-4-yl)propionamide (which is derived via amide coupling and subsequent removal of the Boc protecting group from) N 1-Methyl-3-(piperidin-4-yl)acrylamide and 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)piperidin-4-carboxylic acid) yield the title compound (71%, via two steps) – a pale yellow solid; 1 H NMR (800 MHz, CD3OD, mixture of diastereomers and rotational isomers) δ 7.73 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.5 Hz, 2H), 7.59 (t, J = 8.2 Hz, 1H), 7.53 (t, J = 7.7 Hz,1H), 7.44–7.50 (m, 4H), 7.42 (t, J = 7.3 Hz, 2H), 7.30 (d, J = 7.4 Hz, 1H), 4.49 (dd, J = 48.1, 13.4 Hz, 1H), 4.08–3.96 (m, 1H), 3.90 (dd, J 2.07 (dq, J = 49.8, 11.6, 11.0, 11.0 Hz, 1H), 1.98–1.44 (m, 10H), 1.19–0.72 (m, 2H); 13C NMR (200 MHz, CD3OD, mixture of diastereomers and rotational isomers) δ 176.6, 175.2, 171.9, 171.8, 145.8, 145.7, 145.5, 142.2, 142.2, 142.0 (br), 141.6, 134.3, 133.8, 131.3 (br), 131.1, 130.8, 130.7, 130.6, 130.5, 130.4, 130.4, 130.2, 129.5, 129.5, 129.4, 129.4, 129.1, 128.8, 128.8, 128.5, 128.4, 127.4, 127.3, 125.4, 125.1, 125.1, 122.0, 122.0, 120.7,120.7, 120.5, 112.0 (br), 94.8, 94.7, 84.2, 78.2, 65.8, 64.8, 56.3, 54.3,54.2, 53.2, 52.9, 52.4, 52.1, 51.1, 49.8, 46.9, 46.8, 46.4, 43.4, 43.3, 39.2,39.2, 36.9, 36.9, 34.2, 34.1, 34.0, 33.4, 33.3, 32.9, 32.8, 31.1, 29.6, 29.5,29.3, 29.3, 26.3, 26.3; HRMS (ESI) C 41 H 47 N6O3 [M + H] + m / z Calculated value: 671.3710; Measured value: 671.3694.

[0245] 3-(4-(2-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-carbonyl)-2,6-diazaspiro[3.5]nonane-6-carbonyl)phenyl)- N -Methylpropionamide (A62, CDD-3408) Applicable to synthetic route 1; white solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.79 (d, J= 7.6Hz, 1H), 7.76–7.69 (m, 3H), 7.65–7.40 (m, 8H), 7.27 (d, J = 7.9 Hz, 2H), 7.23(d, J = 7.8 Hz, 2H), 4.04–3.44 (m, 8H), 2.82 (t, J = 7.9 Hz, 2H), 2.54 (d, J = 4.6 Hz, 3H), 2.35 (t, J = 7.8 Hz, 2H), 1.85 (s, 2H), 1.50 (s, 2H); HRMS(ESI) C 40 H 38 N5O3 [M + H] + m / z Calculated value: 636.2975; Measured value: 636.2956.

[0246] 3-(4-(2-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)phenyl)- N -Methylpropionamide (A63, CDD-3410) Applicable to synthetic route 1; white solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.80 (d, J = 7.6Hz, 1H), 7.78–7.74 (m, 1H), 7.74–7.71 (m, 2H), 7.70–7.65 (m, 2H), 7.62 (d, J = 8.7 Hz, 1H), 7.57–7.50 (m, 4H), 7.50–7.42 (m, 2H), 7.28–7.23 (m, 4H), 4.02–3.79 (m, 4H), 3.70–3.40 (m, 4H), 2.83 (t, J = 7.8 Hz, 2H), 2.55 (d, J = 4.6Hz, 3H), 2.37 (t, J= 7.8 Hz, 2H), 1.91–1.62 (m, 4H); HRMS (ESI) C 40 H 38 N5O3 [M+ H] + m / z Calculated value: 636.2975; Measured value: 636.2958.

[0247] 4-(2-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -indazole-5-carbonyl)-2,6-diazaspiro[3.5]nonane-6-carbonyl)- N 1-Methylcyclohexane-1-carboxamide (A64, CDD-3459) Applicable to synthetic route 1; white solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.80 (d, J = 7.7Hz, 1H), 7.72 (d, J = 7.7 Hz, 2H), 7.68–7.59 (m, 3H), 7.59–7.39 (m, 6H), 4.07–3.44 (m, 8H), 2.84–2.60 (m, 1H), 2.55 (dd, J = 9.9, 4.5 Hz, 3H), 2.29–2.14 (m, 1H), 2.09–1.14 (m, 12H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 174.6, 140.8,139.8, 133.0, 129.7, 129.5, 129.0, 128.3, 127.9, 127.7, 126.6, 126.3, 123.6,120.1, 83.9, 56.7, 43.4, 34.9, 33.4, 26.1, 25.9, 25.6, 25.4; HRMS (ESI)C 38 H 40 N5O3 [M + H] + m / z Calculated value: 614.3131; Measured value: 614.3113.

[0248] 4-(2-(3-([1,1'-biphenyl]-2-ylethynyl)-1H -indazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)- N 1-Methylcyclohexane-1-carboxamide (A65, CDD-3460) Applicable to synthetic route 1; white solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.79 (dd, J = 7.8, 3.5 Hz, 1H), 7.69 (dd, J = 7.8, 3.8 Hz, 2H), 7.60 (d, J = 8.6 Hz, 1H), 7.57–7.45 (m, 7H), 7.41–7.37 (m, 1H), 3.68–3.45 (m, 6H), 3.15 (s, 2H), 2.72–2.61(m, 1H), 2.59–2.52 (m, 3H), 2.32–2.13 (m, 1H), 1.97–1.84 (m, 2H), 1.81–1.25(m, 12H); HRMS (ESI) C 39 H 42 N5O3 [M + H] + m / z Calculated value: 628.3288; Measured value: 628.3270.

[0249] 3-(4-(8-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-2-carbonyl)phenyl)- N -Methylpropionamide (A66, CDD-3461) Applicable to synthetic route 1; white solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.83–7.71 (m, 2H),7.71–7.58 (m, 3H), 7.56–7.23 (m, 11H), 3.81–3.48 (m, 4H), 3.08 (d, J = 6.2Hz, 1H), 2.83 (dt, J= 25.7, 7.9 Hz, 2H), 2.55 (d, J = 4.7 Hz, 3H), 2.42–2.28(m, 2H), 2.11–1.18 (m, 7H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 171.5, 171.5, 143.3,140.0, 132.8, 129.7, 129.4, 129.1, 128.2, 128.2, 127.7, 127.2, 126.8, 120.2,110.8, 92.7, 84.0, 41.3, 36.6, 32.7, 30.8, 25.4; HRMS (ESI) C 41 H 40 N5O3 [M + H] + m / z Calculated value: 650.3131; Measured value: 650.3115.

[0250] 3-(4-(2-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)phenyl)- N -Methylpropionamide (A67, CDD-3462) Applicable to synthetic route 1; yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.83–7.72 (m, 2H),7.71–7.64 (m, 2H), 7.60 (dd, J = 8.7, 6.0 Hz, 1H), 7.56–7.35 (m, 8H), 7.34–7.25 (m, 2H), 7.24–7.15 (m, 2H), 3.89–3.46 (m, 4H), 3.17 (s, 2H), 2.82 (dt, J = 26.8, 7.8 Hz, 2H), 2.59–2.52 (m, 3H), 2.36 (dt, J = 24.4, 7.8 Hz, 2H), 1.92(t, J= 7.6 Hz, 1H), 1.80 (s, 1H), 1.71–1.28 (m, 4H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 171.6, 169.0, 168.6, 143.3, 142.9, 142.8, 140.2, 140.0, 133.9, 132.9,132.8, 130.4, 129.7, 129.5, 129.1, 128.6, 128.3, 128.2, 128.1, 127.7, 126.9,126.7, 126.1, 123.6, 123.5, 120.1, 118.8, 92.8, 84.0, 59.0, 55.6, 47.3, 44.2,41.3, 36.6, 33.0, 30.8, 25.4; HRMS (ESI) C 41 H 40 N5O3 [M + H] + m / z Calculated value: 650.3131; Measured value: 650.3111.

[0251] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-5-yl)(2,7-diazaspiro[3.5]nonane-7-yl)methyl ketone (A68, CDD-3463) Applicable to synthetic route 1; white solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.78 (dd, J = 7.7,1.3 Hz, 1H), 7.69–7.64 (m, 2H), 7.62 (d, J = 8.5 Hz, 1H), 7.56–7.50 (m, 1H), 7.50–7.42 (m, 4H), 7.40–7.33 (m, 2H), 7.28 (s, 1H), 3.45–3.07 (m, 8H), 1.95–1.46 (m, 4H); 13 C NMR (150 MHz, DMSO- d 6) δ 169.1, 143.3, 140.0, 140.0, 132.8,129.7, 129.6, 129.4, 129.1, 128.4, 128.3, 127.7, 125.8, 123.6, 120.2, 118.2,111.1, 92.7, 84.0, 55.1; HRMS (ESI) C 29 H 27 N4O [M + H] + m / z Calculated value: 447.2185; Measured value: 447.2173.

[0252] 3-(4-(7-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-carbonyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)phenyl)- N -Methylpropionamide (A69, CDD-3464) Applicable synthetic route 1; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.81–7.73 (m,2H), 7.70–7.65 (m, 2H), 7.61 (d, J = 8.6 Hz, 1H), 7.58–7.55 (m, 2H), 7.53(dd, J = 7.5, 1.4 Hz, 1H), 7.51–7.43 (m, 4H), 7.40–7.35 (m, 2H), 7.31–7.24(m, 3H), 4.09 (s, 2H), 3.83 (br s, 6H), 2.84 (t, J = 7.7 Hz, 2H), 2.55 (d, J = 4.6 Hz, 3H), 2.41–2.31 (m, 2H), 2.06–1.45 (m, 4H); 13 C NMR (150 MHz, DMSO- d 6) δ 171.5, 169.2, 169.0, 144.6, 143.3, 140.1, 140.0, 132.8, 130.9, 129.7,129.5, 129.4, 129.1, 128.3, 128.2, 127.9, 127.7, 125.7, 123.7, 120.2, 118.2,111.1, 92.7, 84.0, 62.4, 58.1, 36.5, 34.0, 30.8, 25.4; HRMS (ESI) C 40 H 38 N5O3 [M+ H] + m / z Calculated value: 636.2975; Measured value: 636.2957.

[0253] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(4-(4-aminophenoxy)piperidin-1-yl)methyl ketone (A70, CDD-3465) Applicable to synthetic route 1; yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) 13 C NMR (150 MHz, DMSO- d 6 ) δ 7.79 (dd, J = 7.7, 1.3 Hz, 1H), 7.71–7.65 (m, 2H), 7.62 (dd, J =8.6, 0.8 Hz, 1H), 7.57–7.52 (m, 1H), 7.52–7.45 (m, 4H), 7.45–7.39 (m, 2H), 7.33–7.28 (m, 1H), 6.76–6.68 (m, 2H), 6.53–6.48 (m, 2H), 4.65 (s, 2H), 4.46–4.30 (m, 1H), 4.23–3.53 (m, 2H), 2.12–1.38 (m, 4H); HRMS (ESI) C 33 H 29 N4O2 [M +H] + m / z Calculated value: 513.2291; Measured value: 513.2276.

[0254] N 1 -(4-((1-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -indazole-5-carbonyl)piperidin-4-yl)oxy)phenyl)- N 4 1,4-Methylcyclohexane-1,4-dicarboxamide (A71, CDD-3466) Applicable to synthetic route 1; yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) 9.79–9.50 (m, 1H),7.78 (d, J = 7.6 Hz, 1H), 7.71–7.38 (m, 13H), 7.31 (s, 1H), 7.00–6.90 (m, 2H), 4.66–4.56 (m, 1H), 4.07 (br s, 2H), 3.26–3.20 (m, 2H), 2.62–2.51 (m,3H), 2.45–2.35 (m, 1H), 2.30–2.19 (m, 1H), 2.14–1.18 (m, 12H); 13 C NMR (150MHz, DMSO- d 6 ) δ 175.3, 174.7, 173.6, 173.5, 169.2, 152.4, 143.4, 140.1,140.0, 133.1, 133.0, 132.8, 129.7, 129.5, 129.4, 129.1, 128.4, 128.3, 127.7,125.8, 123.7, 120.8, 120.7, 120.6, 120.2, 118.3, 116.4, 116.2, 116.2, 111.1,92.7, 84.0, 72.1, 44.1, 43.3, 41.8, 40.3, 28.4, 26.2, 26.2, 25.6, 25.4; HRMS(ESI) C 42 H 42 N5O4 [M + H] + m / z Calculated value: 680.3237; Measured value: 680.3220.

[0255] N-(4-((1-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-carbonyl)piperidin-4-yl)oxy)phenyl)-4-(3-(methylamino)-3-oxopropyl)benzamide (A72, CDD-3467) Applicable to synthetic route 1; yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.06 (s, 1H),7.87–7.82 (m, 2H), 7.79 (dd, J = 7.7, 1.5 Hz, 2H), 7.71–7.64 (m, 4H), 7.64–7.59 (m, 1H), 7.57–7.39 (m, 8H), 7.36–7.28 (m, 3H), 7.06–6.93 (m, 2H), 4.75–4.55 (m, 1H), 4.08 (s, 2H), 3.23 (d, J = 6.3 Hz, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.55 (d, J = 4.6 Hz, 3H), 2.39 (t, J = 7.7 Hz, 2H), 2.23–1.38 (m, 4H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 171.5, 169.2, 165.0, 153.0, 145.2, 143.4, 140.1,140.1, 132.8, 132.7, 132.6, 129.7, 129.5, 129.4, 129.1, 128.4, 128.3, 128.2,127.7, 127.7, 127.6, 125.8, 123.7, 122.0, 120.7, 120.2, 118.3, 116.4, 116.1,111.1, 92.7, 84.1, 72.1, 36.6, 30.9, 25.5; HRMS (ESI) C 44 H 40 N5O4 [M + H] + m / z Calculated value: 702.3080; Measured value: 702.3061.

[0256] N 1 -(6-(4-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -indazole-5-carbonyl)piperazin-1-yl)pyridin-3-yl)- N 4 1,4-Methylcyclohexane-1,4-dicarboxamide （ A73, CDD-3468) Applicable synthetic route 1; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.79–9.58 (m,1H), 8.33 (dd, J = 6.4, 2.6 Hz, 1H), 7.82 (dt, J = 9.2, 2.0 Hz, 1H), 7.78(dd, J = 7.7, 1.3 Hz, 1H), 7.73–7.57 (m, 4H), 7.56–7.28 (m, 8H), 6.85 (d, J =9.1 Hz, 1H), 3.78 (s, 2H), 2.59–2.52 (m, 3H), 2.45–2.40 (m, 1H), 2.31–2.21(m, 1H), 2.12–2.04 (m, 1H), 1.93–1.72 (m, 4H), 1.59–1.32 (m, 4H); 13 C NMR (150MHz, DMSO- d 6 ) δ 175.3, 174.8, 173.8, 173.7, 169.3, 155.3, 155.3, 143.3,140.3, 140.0, 139.1, 139.0, 132.8, 130.0, 129.7, 129.4, 129.1, 129.1, 128.5,128.2, 127.7, 127.6, 127.5, 126.0, 123.7, 120.2, 118.6, 111.2, 107.3, 92.7,84.1, 44.0, 43.3, 41.6, 40.4, 28.4, 26.2, 26.2, 25.6, 25.4; HRMS (ESI)C 40H 40 N7O3 [M + H] + m / z Calculated value: 666.3193; Measured value: 666.3174.

[0257] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(4-(6-aminopyridin-3-yl)piperazin-1-yl)methyl ketone (A74, CDD-3469) Applicable synthetic route 1; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.78 (dd, J =7.6, 1.4 Hz, 1H), 7.70–7.59 (m, 4H), 7.57–7.40 (m, 6H), 7.40–7.30 (m, 2H), 7.20 (dd, J = 8.8, 3.0 Hz, 1H), 6.42 (d, J = 8.9 Hz, 1H), 5.46 (s, 2H), 3.81(br s, 4H), 3.07–2.80 (m, 4H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 169.1, 154.8,143.3, 140.2, 140.0, 138.6, 136.8, 132.8, 129.7, 129.4, 129.2, 129.1, 128.8,128.5, 128.3, 127.7, 127.7, 125.9, 123.7, 120.2, 118.6, 111.2, 108.4, 92.8,84.1, 50.7; HRMS (ESI) C 31 H 27 N6O [M + H] + m / z Calculated value: 499.2246; Measured value: 499.2234.

[0258] N -(5-(4-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H-Indazole-5-carbonyl)piperazin-1-yl)pyridin-2-yl)-4-(3-(methylamino)-3-oxopropyl)benzamide (A75, CDD-3470) Applicable synthetic route 1; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.51 (s, 1H), 8.13 (d, J = 3.0 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.97–7.92 (m, 2H), 7.82–7.76 (m, 2H), 7.71–7.62 (m, 3H), 7.58–7.43 (m, 7H), 7.40–7.34 (m, 2H), 7.32(d, J = 8.2 Hz, 2H), 3.86 (br s, 4H), 3.24 (br s, 4H), 2.93–2.82 (m, 2H), 2.56 (d, J = 4.6 Hz, 3H), 2.41 (t, J = 7.7 Hz, 2H); 13 C NMR (150 MHz, DMSO- d 6 )δ 171.5, 169.2, 165.2, 145.5, 144.9, 143.6, 143.3, 140.2, 140.0, 135.7,132.8, 131.9, 129.7, 129.4, 129.1, 129.1, 128.3, 128.2, 127.9, 127.7, 127.7,126.0, 125.4, 123.7, 120.2, 118.6, 115.2, 111.2, 92.8, 84.0, 48.6, 36.5,30.9, 25.5; HRMS (ESI) C 42 H 38 N7O3 [M + H] + m / z Calculated value: 688.3036; Measured value: 688.3018.

[0259] ( R )-1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H(-Indazole-5-carbonyl)pyrrolidine-3-yl)-3-phenylurea (A76, CDD-3525) Applicable to synthetic route 1; light yellow solid. 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ8.87–8.61 (m, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.72–7.63 (m, 2H), 7.59 (d, J =8.6 Hz, 1H), 7.54–7.30 (m, 10H), 7.28–7.10 (m, 2H), 7.00–6.77 (m, 2H), 4.41–4.04 (m, 1H), 3.86–3.52 (m, 2H), 3.52–3.41 (m, 1H), 3.41–3.34 (m, 0.5H), 3.28–3.11 (m, 0.5H), 2.30–2.05 (m, 1H), 2.03–1.78 (m, 1H); HRMS (ESI)C 33 H 28 N5O2 [M + H] + m / z Calculated value: 526.2243; Measured value: 526.2233.

[0260] ( R )-3-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-carbonyl)pyrrolidine-3-yl)-3,4-quinazolin-2(1 H )-Ketone (A77, CDD-3526) Applicable synthetic route 1; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ 9.45–9.25 (m, 1H), 7.77 (d, J= 7.6 Hz, 1H), 7.73–7.64 (m, 2H), 7.63–7.55 (m,1H), 7.53–7.40 (m, 8H), 7.21–7.04 (m, 2H), 6.95–6.68 (m, 2H), 5.14–4.71 HRMS (ESI) C 34 H 28 N5O2 [M + H] + m / z Calculated value: 538.2243; Measured value: 538.2235.

[0261] ( R )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(3-((4,6-dimethylpyrimidin-2-yl)amino)pyrrolidine-1-yl)methyl ketone (A78, CDD-3527) Applicable synthetic route 1; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ7.77 (dd, J = 10.8, 7.5 Hz, 1H), 7.67 (dd, J = 20.1, 7.6 Hz, 2H), 7.62–7.27(m, 10H), 6.42 (s, 0.5H), 6.28 (s, 0.5H), 4.59–4.49 (m, 0.5H), 4.40–4.29 (m,0.5H), 3.91–3.74 (m, 1H), 3.67–3.57 (m, 1H), 3.53–3.43 (m, 1H), 3.40–3.33 (m,0.5H), 3.22–3.16 (m, 0.5H), 2.24 (s, 3H), 2.21–2.18 (m, 0.5H), 2.15–2.11 (m,0.5H), 2.10 (s, 3H), 2.06–2.00 (m, 0.5H), 1.91–1.84 (m, 0.5H); HRMS (ESI)C 32 H29 N6O [M + H] + m / z Calculated value: 513.2403; Measured value: 513.2393.

[0262] ( R )- N -(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -indazole-5-carbonyl)pyrrolidine-3-yl)-2,3-dihydrobenzo[ b [1,4] II Indo-6-formamide (A79, CDD-3585) Applicable synthetic route 1; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ8.51–8.34 (m, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.72–7.64 (m, 2H), 7.62–7.54 (m,1H), 7.53–7.29 (m, 10H), 6.97–6.81 (m, 1H), 4.61–4.49 (m, 0.5H), 4.37–4.31(m, 0.5H), 4.31–4.18 (m, 4H), 3.87–3.75 (m, 1H), 3.67–3.62 (m, 1H), 3.58–3.49(m, 1H), 3.36–3.21 (m, 1H), 2.31–2.19 (m, 0.5H), 2.18–2.01 (m, 1H), 2.00–1.89(m, 0.5H); HRMS (ESI) C 35 H 29 N4O4 [M + H] + 569.2189 m / z Calculated value, measured value 569.2180.

[0263] ( R )- N -(2-((1-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-carbonyl)pyrrolidine-3-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)benzamide (A80, CDD-3586) Applicable synthetic route 1; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ9.10–8.88 (m, 1H), 8.38–8.08 (m, 3H), 7.96–7.88 (m, 1H), 7.79 (d, J = 7.6 Hz,1H), 7.77–7.65 (m, 3H), 7.63–7.58 (m, 1H), 7.56–7.38 (m, 8H), 4.47–4.36 (m,0.5H), 4.25–4.15 (m, 0.5H), 3.98–3.69 (m, 3H), 3.67–3.59 (m, 0.5H), 3.58–3.52(m, 0.5H), 3.46–3.42 (m, 1H), 3.19–3.07 (m, 1H), 2.26–2.16 (m, 0.5H), 2.12–2.03 (m, 0.5H), 2.00–1.91 (m, 0.5H), 1.87–1.76 (m, 0.5H); HRMS (ESI)C 36 H 29 F3N5O3 [M + H] + m / z Calculated value: 636.2222; Measured value: 636.2214.

[0264] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(6-(vinylsulfonyl)-2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (A81, CDD-3880) Applicable synthetic route 1; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.80 (dd, J =7.7, 1.3 Hz, 1H), 7.71 (d, J = 6.8 Hz, 2H), 7.69–7.65 (m, 2H), 7.65–7.61 (m,1H), 7.59–7.50 (m, 4H), 7.48 (td, J = 7.4, 1.6 Hz, 1H), 7.44 (t, J= 7.4 Hz, 1H), 6.79 (dd, J = 16.5, 10.0 Hz, 1H), 6.16 (d, J = 10.0 Hz, 1H), 6.12 (d, J = 16.5 Hz, 1H), 3.94–3.74 (m, 4H), 3.21–3.08 (m, 2H), 3.02–2.90 (m, 2H), 1.79–1.64 (m, 2H), 1.64–1.48 (m, 2H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 169.4,143.3, 140.7, 139.8, 133.0, 132.9, 129.7, 129.6, 129.1, 129.1 (2 ×), 129.0,128.3 (2 ×), 127.8, 127.7, 126.6, 126.5, 123.6, 120.1, 119.8, 110.9, 92.8,83.8, 61.2, 56.9, 52.9, 45.1, 34.4, 32.2, 21.7; HRMS (ESI) C 31 H 29 N4O3S [M + H] + m / z Calculated value: 537.1960; Measured value: 537.1953.

[0265] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole-5-yl)(6-(ethylsulfonyl)-2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (A82, CDD-3881) Applicable synthetic route 1; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.80 (dd, J =7.7, 1.3 Hz, 1H), 7.72–7.65 (m, 4H), 7.63 (dd, J = 8.6, 0.9 Hz, 1H), 7.57–7.50 (m, 4H), 7.48 (td, J= 7.4, 1.6 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 3.94–3.73 (m, 4H), 3.31–3.26 (m, 2H), 3.15–3.07 (m, 2H), 3.05 (q, J = 7.4 Hz, 2H),1.81–1.69 (m, 2H), 1.62–1.45 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H); 13 C NMR (150MHz, DMSO- d 6 ) δ 169.4, 143.3, 140.7, 139.8, 133.1, 129.7, 129.6, 129.1 (2×), 129.0, 128.3 (2×), 127.9, 127.7, 126.6, 126.5, 123.6, 120.1, 119.8,110.9, 92.8, 83.8, 61.2, 56.8, 52.9, 45.1, 43.0, 34.5, 32.5, 22.1, 7.6; HRMS(ESI) C 31 H 31 N4O3S [M + H] + m / z Calculated value: 539.2117; Measured value: 539.2108.

[0266] ( R )-(3-([1,1'-biphenyl]-2-ylethynyl)-1-methyl-1 H -Indazole-5-yl)(3-dimethylamino)pyrrolidone-1-yl)methyl ketone (B1, CDD-2533) Applicable synthetic route 2. The general procedure for amide coupling is employed, using 3-iodo-1-methyl-1- H -Indazole-5-carboxylic acid and ( R )- N , N -Dimethyl-3-pyrrolidineamine. The resulting amide was partially purified and subjected to a general procedure of styrax coupling using 2-ethynyl-1,1'-biphenyl to give the title compound (16%, after two steps) – a pale yellow oil; 1 H NMR (600 MHz, DMSO) -d 6(Two rotational isomers) δ 7.77 (dd, J = 7.7, 1.4 Hz, 1H), 7.72(dd, J = 8.6, 2.9 Hz, 1H), 7.66 (d, J = 7.5 Hz, 2H), 7.59–7.51 (m, 2H), 7.51–7.44 (m, 4H), 7.43–7.37 (m, 2H), 4.07 (s, 3H), 3.84–3.76 (m, 0.5H), 3.75–3.65(m, 0.5H), 3.59–3.48 (m, 0.5H), 3.36–3.27 (m, 2H), 3.22–3.12 (m, 0.5H), 2.80–2.69 (m, 0.5H), 2.67–2.59 (m, 0.5H), 2.21 (s, 3H), 2.16–1.96 (m, 4H), 1.84–1.78 (m, 0.5H), 1.74–1.64 (m, 0.5H); 13 C NMR (150 MHz, DMSO -d 6 (Two rotational isomers) δ 168.3, 168.2, 143.3, 140.0, 139.9, 132.8, 130.5, 130.1, 129.6, 129.4, 129.1, 129.0, 128.3, 127.7, 127.7, 127.4, 126.2, 126.0, 124.2, 124.1, 120.1, 118.8, 118.8, 110.4, 93.1, 83.5, 65.2, 63.9, 53.0, 50.3, 48.2, 45.0, 43.9, 43.7, 36.0, 30.5, 28.5; HRMS (ESI) C 29 H 29 N4O [M + H] + m / z Calculated value: 449.2341; Measured value: 449.2328.

[0267] ( R )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -pyrazolo[3,4-b]pyridin-5-yl)(3-(dimethylamino)pyrrolidine-1-yl) methyl ketone (B2, CDD-2534) Applicable synthetic route 2. Following the same procedure as the synthesis in B1 (CDD-2533), 3-bromo-1-methyl-2 ... H methyl pyrazolo[3,4-b]pyridine-5-carboxylate; pale yellow oil; 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ 8.72–8.66 (m, 1H), 7.82 (td, J = 9.6, 1.7 Hz, 2H), 7.67 (d, J =7.6 Hz, 2H), 7.64–7.44 (m, 6H), 7.44–7.38 (m, 1H), 3.85–3.75 (m, 0.5H), 3.75–3.68 (m, 0.5H), 3.58–3.47 (m, 1H), 3.32–3.21 (m, 2H), 2.80–2.73 (m, 0.5H), 2.70–2.61 (m, 0.5H), 2.22 (s, 3H), 2.17–2.12 (m, 0.5H), 2.08 (s, 3H), 2.05–1.98 (m, 0.5H), 1.88–1.78 (m, 0.5H), 1.78–1.66 (m, 0.5H); 13 C NMR (150 MHz, DMSO- d 6 (Two rotational isomers) δ 166.4, 166.3, 151.3, 148.9, 148.8, 143.6, 139.9, 132.9, 132.0, 132.0, 131.5, 131.4, 129.7, 129.7, 129.1, 129.1, 128.8, 128.7, 128.3, 128.2, 127.9, 127.8, 127.7, 126.9, 126.5, 119.8, 115.0, 114.9, 93.0, 83.3, 65.2, 63.9, 52.9, 50.4, 48.1, 45.2, 43.9, 43.7, 30.5, 28.5; HRMS (ESI)C 27 H 26 N5O [M + H] + m / z Calculated value: 436.2137; Measured value: 436.2126.

[0268] 3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazole (B3, CDD-2536) The general procedure for coupling with sage heads was followed, using 3-iodine-1 H -Indazole and 2-ethynyl-1,1'-biphenyl yield the title compound (78%) – a pale yellow oil; 1 H NMR (600 MHz, DMSO- d 6 ) δ 13.44 (s, 1H), 7.77 (dd, J = 7.7, 1.4 Hz, 1H), 7.71–7.66 (m, 2H), 7.59–7.43 (m, 7H), 7.40 (ddd, J = 8.2, 6.8, 1.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.16 (ddd, J = 7.9, 6.8, 0.9 Hz, 1H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 143.3, 140.0, 139.9, 132.8, 129.6,129.3, 129.1, 128.3, 127.8, 127.7, 127.6, 126.8, 124.2, 121.4, 120.3, 119.4,110.8, 92.1, 84.5; HRMS (ESI) C 21 H 14 N2 [M + H] + m / z Calculated value: 295.1235; Measured value: 295.1224.

[0269] ( R )-1-((3-([1,1'-biphenyl]-2-ylethynyl)-1 H -indazole-5-yl)methyl)- N , N -Dimethylpyrrolidine-3-amine (B4, CDD-2761) In addition to reducing amination—using 3-iodine-1 H -Indazole-5-formaldehyde (3-iodo-1 H-indazole-5-carboxaldehyde) and ( R )- N , N -Dimethylpyrrolidine-3-amine—Except for the amide coupling reaction, all follow synthetic route 2; pale yellow oil; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.76 (d, J = 7.6 Hz, 1H), 7.70(d, J = 7.6 Hz, 2H), 7.58–7.42 (m, 7H), 7.39–7.32 (m, 1H), 7.21 (s, 1H), 3.66(d, J = 12.6 Hz, 1H), 3.56 (d, J = 12.7 Hz, 1H), 2.75–2.63 (m, 2H), 2.62–2.54(m, 1H), 2.47–2.39 (m, 1H), 2.30–2.21 (m, 1H), 2.07 (s, 6H), 1.91–1.79 (m,1H), 1.67–1.56 (m, 1H); HRMS (ESI) C 28 H 29 N4 [M + H] + m / z Calculated value: 421.2392; Measured value: 421.2379.

[0270] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -pyrazolo[3,4-b]pyridin-5-yl)(2,8-diazaspiro[4.5]decane-2-yl)methyl ketone (B5, CDD-2803) Applicable synthetic route 1. Following the same procedure as the synthesis in A26 (CDD-2674), 3-bromo-1-methyl-2 ... H methyl pyrazolo[3,4-b]pyridine-5-carboxylate; pale yellow oil; 1 H NMR (600 MHz, DMSO- d 6) δ8.71–8.61 (m, 1H), 7.95–7.74 (m, 2H), 7.70–7.66 (m, 2H), 7.58–7.53 (m, 1H), 7.51–7.46 (m, 4H), 7.42–7.35 (m, 1H), 3.62 (t, J = 7.2 Hz, 2H), 3.19 (s, 2H), 2.83–2.51 (m, 4H), 1.84 (t, J = 7.3 Hz, 1H), 1.74 (t, J = 6.8 Hz, 1H), 1.60–1.44 (m, 2H), 1.43–1.31 (m, 2H); HRMS (ESI) C 29 H 28 N5O [M + H] + 462.2294 m / z Calculated value, measured value 462.2280.

[0271] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -pyrazolo[3,4-b]pyridin-5-yl)(2,6-diazaspiro[4.5]decane-2-yl) methyl ketone (B6, CDD-2805) Applicable synthetic route 1. Following the same procedure as the synthesis in B5 (CDD-2803), 2,6-diazaspiro[4.5]decane-6-carboxylic acid tert-butyl ester is used in the amide coupling reaction; pale yellow oil; 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.71–8.63 (m, 1H), 7.91–7.73 (m, 2H), 7.67 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.6Hz, 1H), 7.52–7.39 (m, 5H), 3.71–3.65 (m, 1H), 3.61–3.56 (m, 2H), 3.26–3.23(m, 1H), 2.80–2.71 (m, 1H), 2.68–2.51 (m, 1H), 2.04–1.87 (m, 1H), 1.85–1.66(m, 1H), 1.64–1.19 (m, 6H); HRMS (ESI) C 29 H28 N5O [M + H] + m / z Calculated value: 462.2294; Measured value: 462.2281.

[0272] ( S )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Pyrazolo[3,4-b]pyridin-5-yl)(2-phenylpiperazin-1-yl)methyl ketone (B7, CDD-2846) Applicable synthetic route 1. Following the same procedure as the synthesis in B5 (CDD-2803), use ( ) in the amide coupling reaction. S 3-Phenylopiramycin-1-carboxylic acid tert-butyl ester; pale yellow oil; 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.40–8.26 (m,1H), 7.72–7.63 (m, 4H), 7.48–7.38 (m, 9H), 7.28 (t, J = 7.3 Hz, 2H), 3.59–3.55 (m, 1H), 3.11–2.97 (m, 3H), 2.89–2.65 (m, 3H); HRMS (ESI) C 31 H 26 N5O [M +H] + m / z Calculated value: 484.2137; Measured value: 484.2121.

[0273] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -pyrazolo[3,4-b]pyridin-5-yl)(7-oxa-2-azaspiro[3.5]nonane-2-yl) methyl ketone (B8, CDD-2870) Applicable synthetic route 1. Following the same procedure as the synthesis in B5 (CDD-2803), 7-oxa-2-azaspiro[3.5]nonane is used in the amide coupling reaction; pale yellow oil; 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.43 (d, J = 2.2Hz, 1H), 7.84 (d, J= 2.2 Hz, 1H), 7.77–7.72 (m, 2H), 7.70–7.63 (m, 1H), 7.51(t, J = 7.7 Hz, 2H), 7.47–7.37 (m, 4H), 3.96 (s, 2H), 3.90–3.73 (m, 2H), 3.55–3.48 (m, 4H), 1.73 (t, J = 5.3 Hz, 4H); HRMS (ESI) C 28 H 25 N4O2 [M + H] + m / z Calculated value: 449.1978; Measured value: 449.1965.

[0274] ( R )-(3-([1,1'-biphenyl]-2-ylethynyl)-1 H -pyrazolo[4,3-b]pyridin-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone (B9, CDD-2933) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ8.07 (dd, J = 8.7, 4.1 Hz, 1H), 7.80–7.63 (m, 4H), 7.56–7.49 (m, 2H), 7.48–7.40 (m, 3H), 7.40–7.33 (m, 1H), 4.01 (dd, J = 11.3, 6.7 Hz, 0.5H), 3.87–3.60(m, 2.5H), 3.26 (dd, J HRMS (ESI) C 27 H 26 N5O [M +H] + m / z Calculated value: 436.2137; Measured value: 436.2126.

[0275] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Pyrazolo[4,3-b]pyridin-5-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone (B10, CDD-2934) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.95 (d, J =8.6 Hz, 1H), 7.79–7.74 (m, 2H), 7.69 (dd, J = 8.2, 1.7 Hz, 2H), 7.52–7.44 (m,4H), 7.42 (td, J = 7.4, 1.7 Hz, 1H), 7.40–7.36 (m, 1H), 4.42 (s, 2H), 3.75(s, 2H), 2.46–1.93 (m, 7H), 1.80–1.65 (m, 4H); HRMS (ESI) C 29 H 28 N5O [M + H] + m / z Calculated value: 462.2294; Measured value: 462.2280.

[0276] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-4-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone (B11, CDD-3006) Applicable synthesis route 1; white foam; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.75–7.68 (m, 3H),7.63 (d, J = 8.3 Hz, 1H), 7.51–7.44 (m, 5H), 7.42–7.35 (m, 1H), 7.27–7.20 (m,1H), 7.02 (d, J= 6.8 Hz, 1H), 3.64 (s, 2H), 2.41–1.64 (m, 7H), 1.54–1.42 (m,4H); (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2328.

[0277] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-6-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone (B12, CDD-3007) Applicable synthesis route 1; white foam; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.81 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 7.3 Hz, 2H), 7.53–7.42 (m, 6H), 7.33 (d, J = 8.2 Hz, 1H), 7.30–7.26 (m, 1H), 4.00 (s, 2H), 3.73 (s, 2H), 2.49–1.99 (m,6H), 1.70 (s, 4H); HRMS (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2329.

[0278] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -Indazol-7-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone (B13, CDD-3008) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.79 (dd, J=7.6, 1.3 Hz, 1H), 7.71–7.66 (m, 2H), 7.64 (d, J = 7.2 Hz, 1H), 7.57–7.43 (m,7H), 7.21 (t, J = 7.6 Hz, 1H), 4.05 (s, 2H), 3.81 (s, 2H), 2.45–1.83 (m, 7H), 1.76–1.67 (m, 4H); HRMS (ESI) C 30 H 29 N4O [M + H] + m / z Calculated value: 461.2341; Measured value: 461.2327.

[0279] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -pyrazolo[4,3-b]pyridin-5-yl)(2,7-diazaspiro[3,5]nonane-2-yl) methyl ketone (B14, CDD-3034) Applicable to synthetic route 1; yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.15 (d, J = 8.8Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.77–7.75 (m, 1H), 7.75–7.71 (m, 2H), 7.59–7.52 (m, 2H), 7.51–7.44 (m, 3H), 7.43–7.36 (m, 1H), 4.39 (s, 2H), 3.78(s, 2H), 2.75–2.55 (m, 4H), 1.75–1.53 (m, 4H); HRMS (ESI) C 28 H 26 N5O [M + H] + m / z Calculated value: 448.2137; Measured value: 448.2126.

[0280] (3-([1,1'-biphenyl]-2-ylethynyl)-1 H -pyrazolo[4,3-b]pyridin-5-yl)(2,6-diazaspiro[3,5]nonane-2-yl) methyl ketone (B15, CDD-3882) Applicable to synthetic route 1; yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.86 (dd, J = 8.8,2.3 Hz, 1H), 7.81–7.77 (m, 2H), 7.68 (d, J = 7.5 Hz, 1H), 7.56–7.52 (m, 1H), 7.48–7.36 (m, 6H), 4.40–4.32 (m, 2H), 3.74 (d, J = 9.7 Hz, 1H), 3.66 (d, J =9.7 Hz, 1H), 2.78–2.51 (m, 4H), 1.73–1.60 (m, 2H), 1.45–1.32 (m, 2H); HRMS(ESI) C 28 H 26 N5O [M + H] + m / z Calculated value: 448.2137; Measured value: 448.2130.

[0281] ( R )-(3-(dimethylamino)pyrrolidine-1-yl)(3-(phenylethynyl)-1 H (-Indazole-5-yl)methyl ketone (C1,CDD-2530) Applicable synthetic route 2. The general procedure for amide coupling is followed, using 3-iodine-1... H -Indazole-5-carboxylic acid and ( R )- N , N -Dimethyl-3-pyrrolidineamine. The resulting amide was partially purified and subjected to a general procedure of styrax coupling using phenylacetylene to give the title compound (8%, after two steps) – a pale yellow oil; 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ 7.99 (s, 1H), 7.72–7.67 (m, 2H), 7.65 (d, J = 8.6 Hz, 1H), 7.58 (t, J= 8.5 Hz, 1H), 7.50–7.44 (m, 3H), 3.76–3.71 (m, 0.5H), 3.67–3.62(m, 0.5H), 3.59–3.52 (m, 1H), 3.52–3.45 (m, 1H), 3.27–3.22 (m, 1H), 2.77–2.69(m, 0.5H), 2.68–2.60 (m, 0.5H), 2.18 (s, 3H), 2.13–1.97 (m, 4H), 1.82–1.73(m, 0.5H), 1.73–1.62 (m, 0.5H); 13 C NMR (150 MHz, DMSO- d 6 (Two rotational isomers) δ 168.3, 140.3, 131.5, 129.1, 128.8, 128.6, 126.1, 121.8, 118.9, 110.8, 92.8, 81.1, 65.2, 63.9, 53.0, 50.2, 48.2, 45.0, 43.9, 43.6, 30.4, 28.3; HRMS (ESI)C 22 H 23 N4O [M + H] + m / z Calculated value: 359.1872, measured value: 359.1860.

[0282] ( R )-(3-((2,6-dichlorophenyl)ethynyl)-1 H -Indazole-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone (C2, CDD-2531) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, 1,3-dichloro-2-ethynylbenzene was used in the co-linking reaction of the scallion to give the title compound (20%, after two steps) – a pale yellow oil; 1 H NMR (600 MHz, DMSO-) d 6 (Two rotational isomers) δ 7.96 (d, J= 10.0 Hz, 1H), 7.71–7.47 (m,5H), 3.76–3.51 (m, 3H), 3.28–3.25 (m, 1H), 2.83–2.57 (m, 1H), 2.18 (s, 3H), 2.12–1.95 (m, 4H), 1.83–1.62 (m, 1H); 13 C NMR (150 MHz, DMSO- d 6 (Two rotational isomers) δ 168.0, 140.4, 135.8, 131.0, 129.0, 128.3, 128.3, 127.8, 126.7, 123.8, 121.5, 118.7, 111.1, 91.5, 86.8, 65.2, 63.8, 53.2, 50.3, 48.3, 45.2, 43.8, 43.7, 30.4, 28.3; HRMS (ESI) C 22 H 21 Cl2N4O [M + H] + m / z Calculated value: 427.1092; Measured value: 427.1080.

[0283] ( R )-(3-([1,1'-biphenyl]-3-ylethynyl)-1 H -Indazole-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone (C3, CDD-2532) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, 3-ethynyl-1,1'-biphenyl was used in the coupling reaction of the sage to give the title compound (26%, after two steps) – a pale yellow oil; 1 H NMR (600MHz, DMSO -d 6 (Two rotational isomers) δ 8.06 (d, J = 4.8 Hz, 1H), 7.97 (s, 1H), 7.77–7.72 (m, 3H), 7.71–7.64 (m, 2H), 7.61–7.54 (m, 2H), 7.49 (t, J = 7.7 Hz, 2H), 7.40 (t, J= 7.2 Hz, 1H), 3.76–3.71 (m, 0.5H), 3.66–3.62 (m, 0.5H), 3.58–3.51(m, 0.5H), 3.51–3.44 (m, 0.5H), 3.36–3.34 (m, 1H), 3.27–3.22 (m, 1H), 2.75–2.66 (m, 0.5H), 2.66–2.58 (m, 0.5H), 2.17 (s, 3H), 2.10–1.95 (m, 4H), 1.81–1.72 (m, 0.5H), 1.72–1.62 (m, 0.5H); 13 C NMR (150 MHz, DMSO -d 6 (Two rotational isomers) δ 168.4, 140.8, 140.3, 139.1, 130.5, 130.2, 129.6, 129.5, 129.0 (2 ×), 128.6, 128.3, 127.9, 127.5, 126.9 (2 ×), 126.3, 126.2, 123.5, 122.5, 119.0, 110.8, 92.8, 81.4, 65.1, 63.9, 53.0, 50.3, 48.2, 45.1, 43.8, 43.6, 30.4, 28.3; HRMS (ESI) C 28 H 27 N4O [M + H] + m / z Calculated value: 435.2185; Measured value: 435.2172.

[0284] ( R )-(3-([1,1'-biphenyl]-4-ylethynyl)-1 H -Indazole-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone (C4, CDD-2563) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, using 4-ethynyl-1,1'-biphenyl in the sage coupling reaction, the title compound (8%, after two steps) is given as a pale yellow oil. 1 H NMR (600MHz, DMSO -d 6 (Two rotational isomers) δ 8.03 (s, 1H), 7.78 (s, 4H), 7.74 (d,J = 7.2Hz, 2H), 7.66 (d, J = 8.6 Hz, 1H), 7.59 (t, J = 8.8 Hz, 1H), 7.50 (t, J = 7.6Hz, 2H), 7.41 (t, J = 7.3 Hz, 1H), 3.80–3.71 (m, 0.5H), 3.69–3.61 (m, 0.5H), 3.60–3.46 (m, 2H), 3.29–3.22 (m, 1H), 2.79–2.69 (m, 0.5H), 2.69–2.60 (m,0.5H), 2.19 (s, 3H), 2.13–1.96 (m, 4H), 1.83–1.63 (m, 1H); 13 C NMR (150 MHz, DMSO) -d 6 (Two rotational isomers) δ 168.3, 140.6, 140.3, 139.1, 132.1 (2 ×), 130.5, 130.1, 129.0 (2 ×), 128.6, 128.0, 126.9 (2 ×), 126.7 (2 ×), 126.3, 123.5, 120.8, 118.9, 110.8, 92.8, 81.8, 65.2, 63.9, 53.1, 50.3, 48.2, 45.0, 43.9, 43.6, 30.4, 28.3; HRMS (ESI) C 28 H 27 N4O [M + H] + m / z Calculated value: 435.2185; Measured value: 435.2173.

[0285] ( R )-(3-(dimethylamino)pyrrolidine-1-yl)(3-(isoquinoline-5-ylethynyl)-1 H (-Indazole-5-yl)methyl ketone (C5, CDD-2564) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, using 5-ethynylisoquinoline in the coagulation reaction of the sage, we obtain the title compound (18%, after two steps) – a white solid; 1 H NMR (600 MHz, DMSO) -d6 (Two rotational isomers) δ 13.90 (s, 1H), 9.46 (s, 1H), 8.73 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.25–8.17 (m, 2H), 8.11 (d, J = 7.0 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.71 (dd, J = 8.6, 2.7 Hz, 1H), 7.64 (dd, J = 13.3, 8.5 Hz,1H), 3.81–3.46 (m, 3H), 3.42–3.39 (m, 1H),2.80–2.61 (m, 1H), 2.20 (s, 3H),2.09 (s, 3H), 2.02 (q, J = 6.2 Hz, 1H), 1.75 (dt, J = 43.4, 10.4 Hz, 1H); 13 CNMR (150 MHz, DMSO -d 6 (Two rotational isomers) δ 168.2, 153.0, 144.4, 140.4, 134.8, 134.8, 129.0, 128.3, 127.3, 126.4, 123.4, 119.0, 118.4, 117.9, 111.0, 89.3, 87.0, 65.2, 63.8, 53.2, 50.2, 48.2, 45.1, 43.8, 43.7, 30.4, 28.3; HRMS (ESI)C 25 H 24 N5O [M + H] + m / z Calculated value: 410.1980; Measured value: 410.1971.

[0286] ( R )-(3-(dimethylamino)pyrrolidine-1-yl)(3-(pyrimidin-5-ylethynyl)-1 H -Indazole-5-yl)methyl ketone (C6, CDD-2568) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, using 5-ethynylpyrimidine in the coagulation reaction of the sage, we obtain the title compound (29%, after two steps) – a white solid; 1 ¹H NMR (600 MHz, CDCl₃, two rotational isomers) δ 12.47 (s, ¹H), 9.20 (s, ¹H), 8.94 (s, ²H), 8.06 (d, ¹H) J = 12.1 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 4.06–3.89 (m, 1H), 3.76–3.42 (m, 3H), 2.91–2.70 (m, 1H), 2.36 (s, 3H), 2.25 (s,3H), 2.13 (dt, J = 13.7, 6.6 Hz, 1H), 1.92 (q, J = 11.2 Hz, 1H); 13 C10 NMR (150MHz, CDCl3, two rotational isomers) δ 169.9, 158.8, 157.0, 140.7, 130.3, 129.4, 126.4, 124.0, 119.8, 119.3, 110.8, 87.7, 86.4, 65.7, 64.5, 54.2, 50.7, 48.9, 45.7, 44.2, 31.1, 29.1; HRMS (ESI) C10 20 H 21 N6O [M + H] + m / z Calculated value: 361.1776; Measured value: 361.1765.

[0287] ( R )-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-fluorophenyl)ethynyl)-1 H -Indazole-5-yl)methyl ketone (C7, CDD-2569) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, using 1-ethynyl-2-fluorobenzene in the sage coupling reaction, we obtain the title compound (27%, after two steps) – a white solid; 1¹H NMR (600 MHz, CDCl₃, two rotational isomers) δ 12.69 (s, ¹H), 8.10 (d, J = 17.6 Hz, 1H), 7.59 (dd, J = 20.3, 8.2 Hz, 3H), 7.37 (tdd, J = 7.4, 5.2, 1.7 Hz, 1H), 7.20–7.12 (m,2H), 3.97 (ddd, J = 68.6, 12.7, 8.4 Hz, 1H), 3.81–3.42 (m, 3H), 2.90–2.69 (m,1H), 2.35 (s, 3H), 2.25 (s, 4H), 1.91 (dt, J = 26.6, 10.7 Hz, 1H); 13 C10 NMR (150 MHz, CDCl3, two rotational isomers) δ 169.9, 163.6, 161.9, 140.8, 133.6, 130.6, 130.6, 130.2, 129.9, 126.6, 124.1, 124.1, 120.0, 119.9, 115.7, 115.6, 111.3, 111.2, 110.8, 87.3, 85.6, 65.8, 64.5, 54.1, 50.7, 48.9, 45.7, 44.2, 44.2, 31.1, 29.2; HRMS (ESI) C10 22 H 22 FN4O [M + H] + m / z Calculated value: 377.1777; Measured value: 377.1767.

[0288] ( R )-5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1 H -Indazole-3-nitrile (C8, CDD-2572) Applicable synthetic route 2. To ( R )-(3-(dimethylamino)pyrrolidone-1-yl)(3-iodine-1 H(-Indazole-5-yl)methyl ketone (0.1 mmol) was reacted in anhydrous DMA (0.5 mL) with Zn(CN)₂ (0.17 mmol), Zn (0.06 mmol), CuI (0.1 mmol), and Pd(dppf)Cl₂ (0.015 mmol). The reaction was carried out by microwave heating at 120 °C for 1 h. The solution was then filtered through a Celite pad. The filtrate was concentrated and purified by rapid chromatography to give the title compound (55%). 1 ¹H NMR (600MHz, CDCl₃, two rotational isomers) δ 8.00 (d, J = 8.3 Hz, 1H), 7.61 (dd, J = 8.8, 5.7 Hz, 1H), 7.50 (t, J = 9.3 Hz, 1H), 4.04–3.98 (m, 0.5H), 3.94 (t, J = 10.8Hz, 0.5H), 3.75–3.67 (m, 0.5H), 3.67–3.54 (m, 2H), 3.43 (t, J HRMS (ESI) C 15 H 18 N5O [M + H] + m / z Calculated value: 284.1511; Measured value: 284.1503.

[0289] ( R )-(3-([1,1'-biphenyl]-2-yl)-1 H -Indazole-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone (C9, CDD-2573) Applicable synthetic route 2. The general procedure for amide coupling is employed, using 3-iodo-1-(tetrahydro-2-) H -pyran-2-yl)-1 H -Indazole-5-carboxylic acid and ( R )- N , N-Dimethyl-3-pyrrolidone. The resulting amide was partially purified by rapid chromatography and used in the next step. Oven-dried microwave-safe vials equipped with magnetic stirrers were filled with the amide (0.05 mmol, 1.0 equivalent), [1,1'-biphenyl]-2-ylboronic acid (0.1 mmol, 2.0 equivalent), Pd(PPh3)4 (0.005 mmol, 0.1 equivalent), and K2CO3 (0.1 mmol, 2.0 equivalent). The vials were sealed with microwave caps, purged, and refilled with nitrogen. Anhydrous DMF (0.3 mL) and water (0.1 mL, purged with nitrogen) were then added via syringe. The mixture was purged under vacuum and refilled with nitrogen three times, followed by heating in a microwave reactor at 100 °C for 1 h. After the reaction was complete (monitored by TLC and LC-MS), the reaction mixture was filtered through a Celite pad. The filtrate was concentrated and partially purified by rapid chromatography to obtain (3-([1,1'-biphenyl]-2-yl)-1-(tetrahydro-2-yl) H -pyran-2-yl)-1 H -indazole-5-yl)(( R )-3-(dimethylamino)pyrrolidone-1-yl)methyl ketone. Following a standard THP removal procedure, the title compound (45%, after three steps) was obtained as a yellow oil. 1 ¹H NMR (600 MHz, CDCl₃, two rotational isomers) δ 7.65 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 6.1Hz, 2H), 7.50–7.32 (m, 4H), 7.21 (br s, 2H), 7.12 (d, J = 7.4 Hz, 3H), 3.94–3.84 (m, 0.5H), 3.84–3.72 (m, 0.5H), 3.69–3.54 (m, 0.5H), 3.46–3.34 (m, 1H), 3.26–3.11 (m, 1.5H), 2.85–2.58 (m, 1H), 2.33 (s, 3H), 2.25–1.99 (m, 4H),1.88–1.54 (m, 1H); HRMS (ESI) C 26 H 27 N4O [M + H] + m / z Calculated value: 411.2185; Measured value: 411.2176.

[0290] ( R)-2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1 H -indazole-3-yl)ethynyl)- N -Phenylenamide (C10, CDD-2580) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, using 2-ethynyl- in the stalk coupling reaction. N -Phenylenamide, yielding the title compound (8%, via two steps) – a pale yellow oil; 1 H NMR (600 MHz, DMSO-) d 6 (Two rotational isomers) δ 7.94–7.49 (m, 9H), 7.36–6.91 (m, 3H), 3.81–3.62 (m, 1H), 3.55–3.42 (m, 2H), 3.30–3.25 (m, 1H), 2.78–2.58 (m, 1H), 2.28–2.15 (m, 3H), 2.11–1.84 (m, 4H), 1.84–1.52 (m, 1H); HRMS (ESI) C 29 H 28 N5O2[M + H] + m / z Calculated value: 478.2243; Measured value: 478.2228.

[0291] ( R )-(3-(dimethylamino)pyrrolidine-1-yl)(3-((2-(4-methylpiperazin-1-carbonyl)phenyl)ethynyl)-1 H (-Indazole-5-yl)methyl ketone (C11, CDD-2581) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, (2-ethynylphenyl)(4-methylpiperazin-1-yl) methyl ketone was used in the coagulation reaction of the sage to give the title compound (14%, after two steps) – a pale yellow oil; 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ 7.93 (s, 1H), 7.78–7.71 (m, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.59 (d, J= 8.7 Hz, 1H), 7.55–7.48 (m, 2H), 7.43–7.36 (m, 1H), 3.78–3.72 (m, 1H), 3.66–3.55 (m, 2H), 3.54–3.46 (m, 2H), 3.30–3.26 (m, 1H), 3.23–3.14 (m, 2H), 2.84–2.58 (m, 1H), 2.42–2.23 (m, 4H), 2.20 (s, 3H), 2.08 (s, 3H), 2.06–1.98 (m, 4H), 1.86–1.61 (m, 1H); 13 C NMR (150MHz, DMSO- d 6 (Two rotational isomers) δ 167.3, 140.2, 139.4, 131.8, 129.4, 129.0, 128.4, 126.5, 126.4, 123.7, 118.9, 118.7, 110.9, 90.9, 84.3, 65.2, 63.9, 54.5, 54.0, 52.9, 50.3, 48.2, 46.4, 45.5, 45.0, 43.8, 43.6, 41.0, 30.4, 28.2; HRMS (ESI) C 28 H 33 N6O2 [M + H] + m / z Calculated value: 485.2665; Measured value: 485.2654.

[0292] ( R )-(3-(cyclopropylethynyl)-1 H -Indazole-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone (C12, CDD-2589) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, using ethynylcyclopropane in the stalk coupling reaction, we obtain the title compound (32%, after two steps) – a white solid; 1 ¹H NMR (600 MHz, CDCl₃, two rotational isomers) δ 11.68 (s, ¹H), 7.98 (d, ¹H) J = 8.7 Hz, 1H), 7.58–7.45(m, 2H), 4.04–3.82 (m, 1H), 3.75–3.39 (m, 3H), 2.74 (ddt,J = 74.9, 16.0, 7.5Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 2.10 (dd, J = 12.4, 6.3 Hz, 1H), 1.88(dq, J = 20.3, 10.4 Hz, 1H), 1.56 (tt, J = 8.1, 5.2 Hz, 1H), 0.97–0.89 (m,4H); 13 C10 NMR (150 MHz, CDCl3, two rotational isomers) δ 170.0, 140.6, 131.3, 129.8, 126.4, 124.1, 120.2, 110.4, 98.4, 66.7, 65.8, 64.6, 54.3, 50.6, 48.8, 45.6, 44.3, 31.2, 29.3, 8.9, 0.3; HRMS (ESI) C10 19 H 23 N4O [M + H] + m / z Calculated value: 323.1871, measured value: 323.1862.

[0293] ( R )-6-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1 H -indazole-3-yl)ethynyl)pyridine-2(1 H )-Ketone (C13, CDD-2590) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, 6-ethynylpyridine-2(1) is used in the coupling reaction of the stalk. H )-ketone, yielding the title compound (20%, via two steps) – a white solid; 1 H NMR (600MHz, DMSO -d 6 (Two rotational isomers) δ 13.87 (s, 1H), 12.14 (s, 1H), 8.20 (d, J =4.0 Hz, 1H), 7.68 (dd, J = 8.7, 2.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.50 (dd, J= 9.2, 6.8 Hz, 1H), 6.70 (d, J = 6.8 Hz, 1H), 6.48 (d, J = 9.1 Hz,1H), 3.82–3.63 (m, 1H), 3.59–3.46 (m, 2H), 3.27 (dd, J = 11.8, 8.4 Hz, 1H), 2.69 (dq, J = 52.1, 7.4 Hz, 1H), 2.20 (s, 3H), 2.08 (s, 4H), 1.84–1.67 (m,1H); 13 C NMR (150 MHz, DMSO -d 6 (Two rotational isomers) δ 168.4, 162.4, 140.3, 140.2, 130.8, 130.5, 127.4, 126.4, 126.3, 123.9, 119.2, 111.4, 110.9, 87.0, 84.6, 65.1, 63.9, 53.1, 50.2, 48.2, 45.0, 43.9, 43.7, 30.4, 28.4; HRMS (ESI)C 21 H 25 N5O2 [M + H] + m / z Calculated value: 376.1773; Measured value: 376.1764.

[0294] ( R )-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1 H (-Indazole-5-yl)methyl ketone (C14, CDD-2591) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, 1-ethynyl-2-(trifluoromethoxy)benzene was used in the sage coupling reaction to give the title compound (24%, after two steps) – a white solid; 1 ¹H NMR (600 MHz, CDCl₃, two rotational isomers) δ 12.44 (s, ¹H), 8.06 (d, ¹H) J = 9.6 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.58 (t, J= 8.2 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.33 (q, J = 6.3 Hz, 2H), 4.08–3.88 (m, 1H), 3.75–3.41 (m, 3H), 2.80 (dp, J = 59.1, 7.9 Hz, 1H), 2.36 (s, 3H), 2.24 (s, 3H), 2.13 (dd, J = 12.0, 6.3 Hz, 1H), 1.91 (dt, J = 22.4, 11.0 Hz, 1H); 13 C10 NMR (150 MHz, CDCl3, two rotational isomers) δ 169.9, 149.3, 140.8, 133.8, 130.2, 130.0, 126.9, 126.6, 124.2, 124.1, 121.5, 121.2, 119.8, 119.7, 118.1, 117.3, 110.8, 87.8, 85.8, 65.7, 64.5, 53.9, 50.7, 48.8, 45.6, 44.2, 44.1, 31.1, 29.1; HRMS (ESI) C10 23 H 22 F3N4O2 [M + H] + m / z Calculated value: 443.1694; Measured value: 443.1682.

[0295] ( R )-(3-((2-chlorophenyl)ethynyl)-1 H -Indazole-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone (C15, CDD-2593) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, 1-chloro-2-ethynylbenzene was used in the sage coupling reaction to give the title compound (24%, after two steps) – a white solid; 1 ¹H NMR (600 MHz, CDCl₃, two rotational isomers) δ 12.36 (s, ¹H), 8.10 (d, J = 14.2 Hz, 1H), 7.62 (d,J = 7.5 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.50 (dd, J = 8.7, 4.8 Hz, 1H), 7.44(dd, J = 8.1, 4.2 Hz, 1H), 7.32–7.23 (m, 2H), 3.95 (ddd, J = 67.3, 12.7, 8.5Hz, 1H), 3.76–3.40 (m, 3H), 2.88–2.66 (m, 1H), 2.22 (s, 3H), 2.20–2.06 (m,1H), 1.88 (dp, J = 30.6, 10.1 Hz, 1H); 13 C NMR (150 MHz, CDCl3, two rotational isomers) δ 169.86, 140.81, 135.94, 133.41, 130.39, 130.16, 129.90, 129.81, 129.38, 126.78, 126.72, 126.62, 124.30, 124.26, 122.55, 120.11, 120.03, 110.77, 90.54, 85.60, 65.76, 64.50, 54.11, 50.70, 48.91, 45.67, 44.25, 44.21, 31.16, 29.17; HRMS (ESI) C 22 H 22 ClN4O [M + H] + m / z Calculated value: 393.1482, measured value: 393.1473.

[0296] ( R )-2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1 H -indazole-3-yl)ethynyl)- N -Methylbenzamide (C16, CDD-2599) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, using 2-ethynyl- in the stalk coupling reaction. N -Methylbenzamide, yielding the title compound (36%, after two steps) – a white solid; 1¹H NMR (600 MHz, CDCl₃, two rotational isomers) δ 8.61 (s, ¹H), 7.87 (d, ¹H) J = 7.8 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.59–7.53 (m, 4H), 6.64 (s, 1H), 3.98–3.87 (m, 1H), 3.63 (br s, 2H), 3.47 (s, 3H), 3.41 (br s, 1H), 2.80–2.69 (m, 1H), 2.33 (s,3H), 2.21 (s, 3H), 2.08 (br s, 1H), 1.88 (br s, 1H); HRMS (ESI) C 24 H 26 N5O2 [M +H] + m / z Calculated value: 416.2087; Measured value: 416.2077.

[0297] ( R )-7-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1 H -Indazole-3-yl)ethynyl)indoline-2-one methylbenzamide (C17, CDD-2603) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, using 7-ethynylindol-2-one in the coagulation reaction of the sage, we obtain the title compound (39%, after two steps) – a white solid; 1 ¹H NMR (600 MHz, CDCl₃, two rotational isomers) δ 8.00 (br, 1H), 7.66 (br, 1H), 7.57 (br, 2H), 7.47 (br, 1H), 7.07 (br, 1H), 3.93–3.80 (m, 1H), 3.64–3.57 (m, 2H), 3.37 (br s, 1H), 2.74 (br s, 1H), 2.65 (br s, 1H), 2.26 (s, 3H), 2.21 (br s, 2H), 2.16 (s, 3H), 2.02 (br s, 1H), 1.82 (br s, 1H); HRMS (ESI) C 24 H 24 N5O2 [M + H] + m / z Calculated value: 414.1930; Measured value: 414.1923.

[0298] ( R )-(3-(dimethylamino)pyrrolidine-1-yl)(3-(pyridazin-3-ylethynyl)-1 H -Indazole-5-yl)methyl ketone (C18, CDD-2604) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, 3-ethynylpyridazine was used in the coupling reaction of sage to give the title compound (22%, after two steps) – a white solid; 1 H NMR (600 MHz, CDCl3, two rotational isomers) δ 9.15 (t, J = 3.7 Hz, 1H), 8.07 (d, J = 14.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.63–7.48 (m, 3H), 4.04–3.83 (m, 1H), 3.73–3.38 (m,3H), 2.85–2.67 (m, 1H), 2.31 (s, 3H), 2.21 (s, 3H), 2.08 (dt, J = 13.0, 6.2Hz, 1H), 1.87 (dp, J = 30.7, 10.3 Hz, 1H); 13 C10 NMR (150 MHz, CDCl3, two rotational isomers) δ 170.0, 149.5, 148.0, 140.9, 130.6, 130.2, 130.0, 128.8, 126.7, 126.4, 126.0, 124.3, 124.2, 119.7, 119.6, 111.2, 89.5, 85.7, 65.7, 64.5, 54.0, 50.7, 48.9, 45.6, 44.3, 44.1, 31.1, 29.1; HRMS (ESI) C10 20 H 21 N6O [M + H] + m / z Calculated value: 361.1776; Measured value: 361.1768.

[0299] ( R)-(3-(dimethylamino)pyrrolidine-1-yl)(3-(piperidin-4-ylethynyl)-1 H -Indazole-5-yl)methyl ketone (C19, CDD-2605) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, using 4-ethynylpiperidin-1-carboxylic acid tert-butyl ester in the coagulation reaction, we obtain the title compound (18%, after two steps) – a white solid; 1 ¹H NMR (600 MHz, CDCl₃, two rotational isomers) δ 7.98 (d, J = 16.6 Hz, 1H), 7.53 (t, J =7.8 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 4.04–3.80 (m, 1H), 3.74–3.38 (m, 3H), 3.17 (dt, J = 10.9, 4.5 Hz, 2H), 2.91–2.64 (m, 4H), 2.34 (s, 3H), 2.23 (s,3H), 2.10 (dt, J = 12.8, 6.5 Hz, 1H), 2.03–1.95 (m, 2H), 1.92–1.83 (m, 1H); 13 C10 NMR (150 MHz, CDCl3, two rotational isomers) δ 170.0, 140.7, 130.9, 129.6, 129.4, 126.2, 124.0, 120.2, 120.0, 110.4, 97.6, 77.2, 65.7, 64.5, 54.2, 50.6, 48.8, 45.6, 44.9, 44.2, 32.5, 31.1, 29.2, 28.2; HRMS (ESI) C10 21 H 28 N5O [M + H] + m / z Calculated value: 366.2294; Measured value: 366.2285.

[0300] ( R )-(3-([1,1'-biphenyl]-2-ylmethyl)-1 H -Indazole-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone (C20, CDD-2647) Preparation of potassium trifluoroborate ([1,1'-biphenyl]-2-ylmethyl)trifluoroborate: Under nitrogen atmosphere, xanthracene (0.05 mmol, 0.05 equivalent) and CuCl (0.05 mmol, 0.05 equivalent) were added to a solution of 2-(bromomethyl)-1,1'-biphenyl (1.0 mmol, 1.0 equivalent) and bis(pinacol)diborane (1.25 mmol, 1.25 equivalent) in anhydrous THF (2 mL). The reaction mixture was stirred for 16 h at room temperature and filtered through a Celite pad. The filtrate was concentrated and purified by rapid chromatography to give 2-([1,1'-biphenyl]-2-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (70%) – a white solid; 1 ¹H NMR (600 MHz, CDCl₃) δ 7.42 (m, 4H), 7.35 (m, 1H), 7.31 (m, 2H), 7.26 (m, 2H), 2.34 (s, 2H), 1.20 (s, 12H). KHF₂ (0.2 mL, 4.5 M in water) was added dropwise to a solution of 2-([1,1'-biphenyl]-2-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (0.3 mmol) in CH₃OH (2 mL). The solution was stirred for 1 h at room temperature and concentrated to give potassium ([1,1'-biphenyl]-2-ylmethyl)trifluoroborate. This product was then used in the next step without any purification.

[0301] Applicable synthetic route 2. The general procedure for amide coupling is employed, using 3-iodo-1-(tetrahydro-2-) H -pyran-2-yl)-1 H -Indazole-5-carboxylic acid and ( R )- N , N-Dimethyl-3-pyrrolidone. The resulting amide was partially purified by rapid chromatography and used in the next step. Oven-dried microwave-safe vials equipped with magnetic stirrers were filled with the amide (0.1 mmol, 1.0 equivalent), potassium ([1,1'-biphenyl]-2-ylmethyl)trifluoroborate (0.25 mmol, 2.5 equivalent), Pd(OAc)₂ (0.01 mmol, 0.1 equivalent), RuPhos (0.02 mmol, 0.2 equivalent), and Cs₂CO₃ (0.3 mmol, 3.0 equivalent). The vials were sealed with microwave caps, purged, and refilled with nitrogen. Anhydrous toluene (3 mL) and water (0.3 mL, purged with nitrogen) were then added via syringe. The mixture was purged under vacuum and refilled with nitrogen three times, followed by heating in a microwave reactor at 120 °C for 1 h. After the reaction was complete (monitored by TLC and LC-MS), the reaction mixture was filtered through a Celite pad. The filtrate was concentrated and partially purified by rapid chromatography to obtain (3-([1,1'-biphenyl]-2-ylmethyl)-1-(tetrahydro ... H -pyran-2-yl)-1 H -indazole-5-yl)(( R )-3-(dimethylamino)pyrrolidone-1-yl)methyl ketone. Following a standard THP removal procedure, the title compound (29%, after three steps) was obtained as a yellow oil. 1 ¹H NMR (600 MHz, CDCl₃, two rotational isomers) δ 7.52 (dd, J = 8.6, 1.5 Hz, 1H), 7.38–7.26 (m, 10H), 7.21–7.13 (m, 1H), 4.37–4.26 (m, 2H), 4.00–3.90 (m, 0.5H), 3.87–3.76 (m, 0.5H), 3.70–3.59 (m,0.5H), 3.53–3.37 (m, 1.5H), 3.34–3.14 (m, 1H), 2.85–2.72 (m, 0.5H), 2.71–2.56(m, 0.5H), 2.34 (s, 3H), 2.26–1.98 (m, 4H), 1.90–1.64 (m, 1H); HRMS (ESI)C 27 H 29 N4O [M + H] + m / z Calculated value: 425.2341; Measured value: 425.2331.

[0302] ( R)-(3-(dimethylamino)pyrrolidine-1-yl)(3-((2-morpholinylphenyl)ethynyl)-1 H -Indazole-5-yl)methyl ketone (C21, CDD-2648) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, using 4-(2-ethynylphenyl)morpholine in the sarsaparilla coupling reaction, we obtain the title compound (41%, after two steps) – a white solid; 1 ¹H NMR (600MHz, CDCl₃, two rotational isomers) δ 8.06 (d, J = 9.6 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.34 (m, 1H), 7.16 (m, 1H), 7.02 (t, J = 6.6Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.00 (m, 0.5H), 3.89 (t, 4.8 Hz, 4.5H), 3.72–3.62 (m, 1.5H), 3.58–3.48 (m, 1H), 3.42 (m, 0.5H), 3.27 (t, J = 4.2Hz,4H), 2.81–2.72 (m, 1H), 2.33 (s, 3H), 2.22 (s, 3H), 2.09 (br s, 0.5H), 1.91(m, 1.5H); HRMS (ESI) C 26 H 30 N5O2 [M + H] + m / z Calculated value: 444.2400; Measured value: 444.2389.

[0303] ( R , E )-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1 H -Indazole-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone (C22, CDD-2649) Applicable synthetic route 2. To ( R )-(3-(dimethylamino)pyrrolidone-1-yl)(3-iodine-1H 0.1 mmol of 5-indazole-5-yl)methyl ketone was prepared in anhydrous THF (0.5 mL) with the addition of Pd(OAc)₂ (0.01 mmol), PPh₃ (0.02 mmol), and 2-vinyl-1,1'-biphenyl (0.15 mmol). The reaction solution was microwave-heated at 80 °C. After 2 h, the solution was filtered through a Celite pad and the filtrate was concentrated. The crude product was purified to give the title compound (65%) as a yellow oil. 1 ¹H NMR (600 MHz, CDCl₃, two rotational isomers) δ 7.85 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 9.0Hz, 1H), 7.56 (m, 2H), 7.46–7.37 (m, 9H), 7.16 (m, 1H), 3.99–3.88 (m, 1H), 3.68 (m, 0.5H), 3.50–3.42 (m, 1.5H), 3.20 (br s, 1H), 2.81–2.68 (m, 1H), 2.37(s, 3H), 2.20 (s, 3H), 2.04–1.82 (m, 2H); HRMS (ESI) C 28 H 29 N4O [M + H] + m / z Calculated value: 437.2341; Measured value: 437.2331.

[0304] ( R )- N -(2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1 H -Indazole-3-yl)ethynyl)phenyl)acetamide (C23, CDD-2651) Applicable synthetic route 2. Following the same procedure as the C1 (CDD-2530) synthesis, using the coagulation reaction of the scallion. N -(2-ethynylphenyl)acetamide, yielding the title compound (14%, via two steps) – a pale yellow oil; 1 HNMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ 8.37 (dd, J = 8.6, 2.7 Hz, 1H), 8.16(s, 1H), 7.83 (t, J= 9.6 Hz, 1H), 7.66–7.53 (m, 1H), 7.42 (d, J = 7.7 Hz,1H), 7.22–7.15 (m, 1H), 6.84–6.74 (m, 1H), 6.65–6.54 (m, 1H), 3.79–3.70 (m,1H), 3.70–3.62 (m, 1H), 3.52–3.46 (m, 2H), 3.28–3.23 (m, 1H), 2.76 (s, 3H), 2.73–2.62 (m, 1H), 2.19 (s, 3H), 2.09–2.07 (m, 3H), 2.07–1.98 (m, 1H), 1.81–1.66 (m, 1H); HRMS (ESI) C 24 H 26 N5O2 [M + H] + m / z Calculated value: 416.2087; Measured value: 416.2075.

[0305] (3,6-diazabicyclo[3.1.1]heptane-3-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1 H -Indazole-5-yl)methyl ketone (C24, CDD-2762) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.90–7.85 (m,2H), 7.75 (d, J = 8.6 Hz, 1H), 7.62 (t, J HRMS (ESI) C 22 H 18 F3N4O2 [M + H] + m / z Calculated value: 427.1382; Measured value: 427.1371.

[0306] (2,8-diazaspiro[4.5]decane-2-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1 H -Indazole-5-yl)methyl ketone (C25, CDD-2763) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.98–7.84 (m,2H), 7.72–7.66 (m, 1H), 7.66–7.49 (m, 4H), 3.64–3.58 (m, 2H), 3.56–3.53 (m,2H), 3.13 (s, 2H), 3.07–2.95 (m, 2H), 1.92–1.85 (m, 1H), 1.84–1.76 (m, 2H), 1.74–1.68 (m, 1H), 1.65–1.54 (m, 2H); HRMS (ESI) C 25 H 24 F3N4O2 [M + H] + m / z Calculated value: 469.1851; Measured value: 469.1838.

[0307] ( S )-(2-phenylpiperazin-1-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1 H -Indazole-5-yl)methyl ketone (C26, CDD-2764) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.83 (d, J =7.8 Hz, 1H), 7.77 (s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.64–7.50 (m, 3H), 7.50–7.33 (m, 5H), 7.26 (t, J = 7.3 Hz, 1H), 3.62–3.52 (m, 2H), 3.10–2.92 (m, 3H), 2.85–2.75 (m, 1H), 2.66 (dt, J= 11.5, 6.3 Hz, 1H); HRMS (ESI) C 27 H 22 F3N4O2 [M+ H] + m / z Calculated value: 491.1695; Measured value: 491.2679.

[0308] ( R )-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone (C27, CDD-2871) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ8.70–8.66 (m, 2H), 7.82 (dt, J = 7.1, 1.3 Hz, 1H), 7.74–7.70 (m, 2H), 7.61–7.50 (m, 5H), 7.45 (d, J = 8.6 Hz, 1H), 3.78–3.75 (m, 1H), 3.70–3.64 (m, 1H), 3.23–3.20 (m, 1H), 2.78 (s, 1H), 2.66 (s, 1H), 2.21 (s, 3H), 2.17–1.97 (m,4H), 1.90–1.62 (m, 1H); HRMS (ESI) C 27 H 26 N5O [M + H] + m / z Calculated value: 436.2137; Measured value: 436.2126.

[0309] (3-((2-(pyridin-4-yl)phenyl)ethynyl)-1 H -Indazol-5-yl)(2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone (C28, CDD-2872) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 8.72 (d, J= 5.7Hz, 2H), 7.82 (d, J = 7.3 Hz, 1H), 7.76 (d, J = 6.1 Hz, 3H), 7.63–7.50 (m,5H), 3.87 (s, 2H), 3.76 (s, 2H), 2.68–2.53 (m, 4H), 1.72–1.53 (m, 4H); HRMS(ESI) C 28 H 26 N5O [M + H] + m / z Calculated value: 448.2137; Measured value: 448.2126.

[0310] (3-((2-(pyridin-4-yl)phenyl)ethynyl)-1 H -Indazol-5-yl)(7-oxa-2-azaspiro[3.5]nonane-2-yl)methyl ketone (C29, CDD-2873) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.74–8.69 (m,2H), 7.84 (d, J = 7.4 Hz, 1H), 7.79–7.73 (m, 3H), 7.70–7.53 (m, 5H), 3.95 (s,2H), 3.84 (s, 2H), 3.55–3.52 (m, 2H), 3.50–3.48 (m, 2H), 1.80–1.67 (m, 4H);HRMS (ESI) C 28 H 25 N4O2 [M + H] + m / z Calculated value: 449.1978; Measured value: 449.1966.

[0311] ( S )-(2-phenylpiperazin-1-yl)(3-((2-(pyridin-4-yl)phenyl)ethynyl)-1 H -Indazole-5-yl)methyl ketone (C30, CDD-2884) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d6 ) δ 8.71–8.64 (m,2H), 7.82 (d, J = 7.5 Hz, 1H), 7.74–7.68 (m, 2H), 7.66–7.38 (m, 10H), 7.26(t, J = 7.3 Hz, 1H), 3.61–3.49 (m, 2H), 3.15–2.94 (m, 3H), 2.84–2.66 (m, 2H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 149.6, 147.2, 140.4, 140.1, 139.4, 133.2, 129.8,129.7, 129.5, 128.9, 128.5, 128.1, 127.1, 126.6, 125.5, 123.9, 123.7, 120.0,118.1, 111.3, 91.7, 84.7, 45.7; HRMS (ESI) C 31 H 26 N5O [M + H] + m / z Calculated value: 484.2137; Measured value: 484.2125.

[0312] ( R )-(3-(dimethylamino)pyrrolidine-1-yl)(3-((2-(pyridin-3-yl)phenyl)ethynyl)-1 H -Indazole-5-yl)methyl ketone (C31, CDD-2885) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ8.90 (d, J = 2.3 Hz, 1H), 8.61 (dt, J = 4.6, 2.5 Hz, 1H), 8.11 (dt, J = 7.8,2.0 Hz, 1H), 7.86–7.81 (m, 1H), 7.63–7.51 (m, 6H), 7.45 (d, J = 13.9 Hz, 1H), 3.80 (dd, J= 11.8, 7.1 Hz, 0.5H), 3.70 (t, J = 11.1 Hz, 0.5H), 3.57–3.51 (m,0.5H), 3.48–3.43 (m, 2H), 3.27–3.25 (m, 0.5H), 2.84–2.74 (m, 0.5H), 2.70–2.60(m, 0.5H), 2.22 (s, 3H), 2.17–2.11 (m, 0.5H), 2.07 (s, 3H), 2.05–1.98 (m,0.5H), 1.89–1.65 (m, 1H); HRMS (ESI) C 27 H 26 N5O [M + H] + m / z Calculated value: 436.2137; Measured value: 436.2126.

[0313] ( R )-(3-(cyclohexylethynyl)-1 H -Indazole-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone (C32, CDD-2886) Applicable to synthetic route 2; pale yellow oily substance; 1 H NMR (600 MHz, DMSO- d 6 (Two rotational isomers) δ7.78 (d, J = 3.6 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.51 (t, J = 9.8 Hz, 1H),3.75–3.67 (m, 2H), 3.65–3.59 (m, 2H), 2.84–2.57 (m, 3H), 2.18 (s, 3H), 2.08(s, 4H), 1.93–1.84 (m, 2H), 1.79–1.65 (m, 3H), 1.61–1.45 (m, 3H), 1.43–1.32(m, 3H); HRMS (ESI) C 22 H 29 N4O [M + H] + m / z Calculated value: 365.2341; Measured value: 365.2329.

[0314] ( E)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1 H -Indazol-5-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone (C33, CDD-2942) Applicable synthetic route 1. To 3-iodine-1 H Methyl indazole-5-carboxylate (0.1 mmol) was reacted with Pd(OAc)₂ (0.01 mmol), PPh₃ (0.02 mmol), and 2-vinyl-1,1'-biphenyl (0.15 mmol) in anhydrous THF (0.5 mL). The reaction solution was microwave-heated at 80 °C. After 2 h, the solution was filtered through a Celite pad and the filtrate was concentrated. The crude product was dissolved in THF / MeOH / H₂O (4:1:1, 0.1 M) and 2 M LiOH (5 equivalents) was added to the solution. After overnight reaction, the solution was acidified to pH = 2 with 1 N HCl. The solution was extracted with CH₂Cl₂, and the combined organic layers were concentrated and purified by rapid chromatography to give ( E )-3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1 H -Indazole-5-carboxylic acid; 1 H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.49–7.44 (m,3H), 7.40–7.32 (m, 6H), 6.75 (q, 1H), 5.75 (d, J = 17.4 Hz, 1H), 5.23 (d, J =17.4 Hz, 1H). Using the general procedure for amide coupling, the resulting acid and 7-methyl-2,7-diazaspiro[3.5]nonane were used to give the title compound (80%) – a white solid; 1 H NMR (600 MHz, CDCl3) δ 7.97 (s, 1H),7.87 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.58 (d, J= 16.8 Hz,1H), 7.50–7.40 (m, 10H), 3.94 (s, 2H), 3.74 (s, 2H), 2.35 (s, 5H), 1.88 (s,6H); HRMS (ESI) C 30 H 31 N4O [M + H] + m / z Calculated value: 463.2498; Measured value: 463.2488.

[0315] ( E )-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1 H -Indazole-5-yl)(7-oxa-2-azaspiro[3.5]nonane-2-yl)methyl ketone (C34, CDD-2953) Applicable synthetic route 1. Following the same procedure as the C33 (CDD-2942) synthesis, 7-oxa-2-azaspiro[3.5]nonane was used in the amide coupling reaction to give the title compound (78%) – a white solid; 1 H NMR (600 MHz, CDCl3) δ 7.99 (s, 1H), 7.87 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 6.0 Hz, 1H), 7.61 (d, J = 16.8 Hz, 1H), 7.52–7.40 (m, 10H), 4.00 (s, 2H), 3.79 (s, 2H), 3.63 (s, 4H), 1.80 (s, 4H); HRMS (ESI) C 29 H 28 N3O2 [M + H] + m / z Calculated value: 450.2182; Measured value: 450.2170.

[0316] (7-Methyl-2,7-diazaspiro[3.5]nonane-2-yl)(3-((2-(pyridin-3-yl)phenyl)ethynyl)-1 H -Indazole-5-yl)methyl ketone (C35, CDD-2986) Applicable to synthetic route 1; pale yellow oily substance; 1H NMR (600 MHz, CD3OD) δ 8.92–8.88 (m,1H), 8.64 (dd, J = 4.9, 1.6 Hz, 1H), 8.21 (dt, J = 7.9, 1.9 Hz, 1H), 7.86–7.76 (m, 1H), 7.75–7.71 (m, 2H), 7.65–7.51 (m, 5H), 4.05 (s, 2H), 3.97 (s,2H), 2.51–2.38 (m, 4H), 2.27 (s, 3H), 1.91 (br s, 4H); HRMS (ESI) C 29 H 28 N5O [M+ H] + m / z Calculated value: 462.2294; Measured value: 462.2285.

[0317] (7-Methyl-2,7-diazaspiro[3.5]nonane-2-yl)(3-((3-phenylpyridin-2-yl)ethynyl)-1 H -Indazole-5-yl)methyl ketone (C36, CDD-2987) Applicable to synthetic route 1; pale yellow oily substance; 1 H NMR (600 MHz, CD3OD) δ 8.63 (dd, J =4.8, 1.6 Hz, 1H), 7.99 (dd, J = 7.9, 1.7 Hz, 1H), 7.79–7.74 (m, 3H), 7.73(dd, J = 8.7, 1.6 Hz, 1H), 7.64 (dd, J = 8.7, 0.9 Hz, 1H), 7.61–7.55 (m, 3H),7.55–7.49 (m, 1H), 4.00 (s, 2H), 3.97 (s, 2H), 2.53 (br s, 4H), 2.28 (s, 3H),1.90 (br s, 4H); HRMS (ESI) C 29 H 28 N5O [M + H] + m / z Calculated value: 462.2294; Measured value: 462.2285.

[0318] (3-((2-(pyridin-3-yl)phenyl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C37, CDD-3094) Applicable synthetic route 1; pale yellow solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 8.91 (d, J = 2.3Hz, 1H), 8.65 (dd, J = 4.8, 1.6 Hz, 1H), 8.15 (dt, J = 7.9, 2.0 Hz, 1H), 7.83(d, J = 7.6 Hz, 1H), 7.65–7.59 (m, 4H), 7.59–7.50 (m, 4H), 3.90 (d, J = 8.5Hz, 1H), 3.85 (d, J = 8.4 Hz, 1H), 3.77 (d, J = 9.7 Hz, 1H), 3.70 (d, J = 9.7Hz, 1H), 2.85–2.68 (m, 2H), 2.62–2.52 (m, 2H), 1.77–1.60 (m, 2H), 1.45–1.27(m, 2H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 169.0, 148.9, 148.3, 141.7, 139.1,136.1, 135.1, 132.5, 129.3, 129.0, 128.0, 127.7, 125.8, 125.2, 123.3, 122.9,120.4, 118.9, 111.2, 91.3, 84.9, 61.8, 57.2, 54.2, 44.9, 34.2, 33.7, 22.8;HRMS (ESI) C 28 H 26 N5O [M + H] + m / z Calculated value: 448.2137; Measured value: 448.2133.

[0319] (2,6-diazaspiro[3.5]nonane-2-yl)(3-((4-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)ethynyl)-1 H -Indazole-5-yl)methyl ketone (C38, CDD-3134) Applicable to synthetic route 2; pale yellow solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 7.83 (d, J = 2.6Hz, 1H), 7.75–7.69 (m, 3H), 7.67 (dd, J = 8.7, 1.5 Hz, 1H), 7.66–7.61 (m,2H), 7.59–7.52 (m, 3H), 7.49–7.45 (m, 1H), 3.85 (d, J = 8.5 Hz, 1H), 3.83–3.76 (m, 2H), 3.71 (d, J = 9.7 Hz, 1H), 2.73 (d, J = 5.1 Hz, 2H), 2.57–2.54(m, 1H), 2.49–2.44 (m, 1H), 1.68 (s, 2H), 1.45–1.31 (m, 2H); HRMS (ESI)C 30 H 26 F3N4O2 [M + H] + m / z Calculated value: 531.2008; Measured value: 531.1990.

[0320] (3-((2-(naphthyl-2-yl)phenyl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C39, CDD-3135) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 8.23 ​​(s, 1H), 8.09 (d, J = 8.7 Hz, 1H), 8.02–7.93 (m, 3H), 7.81 (dd, J= 7.6, 1.4 Hz, 1H), 7.69–7.61 (m, 2H), 7.59–7.46 (m, 6H), 3.73–3.69 (m, 2H), 3.66–3.59 (m, 2H), 2.64(s, 2H), 2.55–2.51 (m, 2H), 1.61–1.56 (m, 2H), 1.40–1.23 (m, 2H); HRMS (ESI)C 33 H 29 N4O [M + H] + m / z Calculated value: 497.2341; Measured value: 497.2327.

[0321] (2,6-diazaspiro[3.5]nonane-2-yl)(3-((5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)ethynyl)-1 H -Indazole-5-yl)methyl ketone (C40, CDD-3136) Applicable to synthetic route 2; pale yellow solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 8.03 (d, J = 7.9Hz, 1H), 7.86–7.82 (m, 2H), 7.82–7.75 (m, 2H), 7.70–7.65 (m, 2H), 7.64 (dd, J = 8.5, 1.0 Hz, 1H), 7.57 (dd, J = 8.4, 6.9 Hz, 2H), 7.53–7.47 (m, 1H), 3.84(d, J = 8.5 Hz, 1H), 3.81–3.76 (m, 2H), 3.71 (d, J = 9.7 Hz, 1H), 2.73 (d, J = 6.2 Hz, 2H), 2.57–2.52 (m, 2H), 1.68 (s, 2H), 1.47–1.28 (m, 2H); HRMS (ESI)C 30 H 26 F3N4O [M + H] + m / z Calculated value: 515.2059; Measured value: 515.2042.

[0322] (3-((4'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C41, CDD-3137) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 7.95 (d, J = 8.0Hz, 1H), 7.78 (dd, J = 8.0, 1.8 Hz, 1H), 7.76 (s, 1H), 7.67 (d, J = 7.8 Hz,2H), 7.63 (s, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.52 (dd, J = 8.6, 1.5 Hz, 1H), 7.37 (d, J = 7.8 Hz, 2H), 3.83 (d, J = 8.4 Hz, 1H), 3.80–3.73 (m, 2H), 3.68(d, J = 9.8 Hz, 1H), 2.78–2.65 (m, 2H), 2.56–2.51 (m, 2H), 2.39 (s, 3H), 1.67(s, 2H), 1.42–1.28 (m, 2H); HRMS (ESI) C 31 H 28 F3N4O [M + H] + m / z Calculated value: 529.2215; Measured value: 529.2199.

[0323] (2,6-diazaspiro[3.5]nonane-2-yl)(3-((3'-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)ethynyl)-1 H -Indazole-5-yl)methyl ketone (C42, CDD-3153) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO -d 6) δ 7.84 (d, J = 7.6Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.70–7.51 (m, 8H), 7.42 (dd, J = 8.4, 2.3Hz, 1H), 3.86 (d, J = 8.4 Hz, 1H), 3.80 (d, J = 8.4 Hz, 1H), 3.76 (d, J = 9.8Hz, 1H), 3.68 (d, J = 9.7 Hz, 1H), 2.72 (s, 2H), 2.54 (t, J = 5.1 Hz, 2H),1.72–1.57 (m, 2H), 1.46–1.28 (m, 2H); HRMS (ESI) C 30 H 26 F3N4O2 [M + H] + m / z Calculated value: 531.2008; Measured value: 531.1992.

[0324] (2,6-diazaspiro[3.5]nonane-2-yl)(3-((2'-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)ethynyl)-1 H -Indazole-5-yl)methyl ketone (C43, CDD-3154) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 7.80 (dd, J = 7.5,1.6 Hz, 1H), 7.66–7.50 (m, 8H), 7.46 (s, 1H), 7.44 (dd, J = 7.4, 1.5 Hz, 1H), 3.84 (d, J = 8.5 Hz, 1H), 3.79 (d, J = 9.8 Hz, 2H), 3.72 (d, J= 9.8 Hz, 1H),2.74 (s, 2H), 2.58–2.51 (m, 2H), 1.68 (s, 2H), 1.46–1.32 (m, 2H); HRMS (ESI)C 30 H 26 F3N4O2 [M + H] + m / z Calculated value: 531.2008; Measured value: 531.1993.

[0325] 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1 H -indazole-3-yl)ethynyl)- N 2-Methyl-[1,1'-biphenyl]-2-carboxamide (C44, CDD-3155) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 8.05–7.99 (m, 1H),7.72 (dd, J = 7.1, 1.9 Hz, 1H), 7.63 (dd, J = 8.7, 1.5 Hz, 1H), 7.58 (d, J =8.7 Hz, 1H), 7.57–7.53 (m, 2H), 7.51 (td, J = 7.5, 1.4 Hz, 1H), 7.48 (s, 1H), 7.46–7.40 (m, 3H), 7.33 (dd, J = 7.2, 1.8 Hz, 1H), 3.86–3.76 (m, 3H), 3.70(d, J = 9.7 Hz, 1H), 2.72 (s, 2H), 2.57 (d, J = 4.6 Hz, 3H), 2.57–2.51 (m,2H), 1.75–1.61 (m, 2H), 1.42–1.32 (m, 2H); HRMS (ESI) C 31 H 30 N5O2 [M + H] + m / z Calculated value: 504.2400; Measured value: 504.2388.

[0326] 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1 H -indazole-3-yl)ethynyl)- N 3-Methyl-[1,1'-biphenyl]-3-carboxamide (C45, CDD-3156) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 8.54–8.49 (m, 1H),8.12 (s, 1H), 7.91 (dd, J = 8.0, 4.3 Hz, 2H), 7.83 (d, J = 7.7 Hz, 1H), 7.67–7.64 (m, 2H), 7.64–7.56 (m, 4H), 7.52 (s, 1H), 3.89 (d, J = 8.5 Hz, 1H), 3.82(t, J = 9.6 Hz, 2H), 3.72 (d, J = 9.8 Hz, 1H), 2.85 (s, 2H), 2.74 (d, J = 4.5Hz, 3H), 2.64 (t, J = 5.5 Hz, 2H), 1.77–1.64 (m, 2H), 1.51–1.38 (m, 2H); HRMS(ESI) C 31 H 30 N5O2 [M + H] + m / z Calculated value: 504.2400; Measured value: 504.2388.

[0327] 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1 H -indazole-3-yl)ethynyl)- N 1,1'-Biphenyl]-4-carboxamide (C46, CDD-3157) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO -d 6) δ 8.57–8.52 (m, 1H), 8.02–7.98 (m, 2H), 7.85–7.76 (m, 4H), 7.69 (dd, J = 8.8, 1.5 Hz, 1H), 7.62(d, J = 8.7 Hz, 1H), 7.59–7.55 (m, 2H), 7.55–7.48 (m, 1H), 3.89 (d, J = 8.4Hz, 1H), 3.83 (d, J = 8.4 Hz, 1H), 3.79 (d, J = 9.7 Hz, 1H), 3.70 (d, J = 9.7Hz, 1H), 2.82 (d, J = 4.5 Hz, 3H), 2.80–2.70 (m, 2H), 2.59–2.52 (m, 2H), 1.78–1.57 (m, 2H), 1.44–1.31 (m, 2H); HRMS (ESI) C 31 H 30 N5O2 [M + H] + m / z Calculated value: 504.2400; Measured value: 504.2388.

[0328] (3-((2-(6-amino-4-methylpyridin-3-yl)phenyl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C47, CDD-3197) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 7.81 (s, 1H), 7.75–7.67 (m, 2H), 7.62–7.55 (m, 2H), 7.50–7.40 (m, 2H), 7.34 (d, J= 7.5 Hz, 1H), 6.42 (s, 1H), 5.80 (s, 2H), 3.98–3.87 (m, 2H), 3.73–3.69 (m, 2H), 2.85–2.67(m, 2H), 2.63–2.50 (m, 2H), 2.10 (s, 3H), 1.78–1.59 (m, 2H), 1.36 (s, 2H);HRMS (ESI) C 29 H 29 N6O [M + H] + m / z Calculated value: 477.2403; Measured value: 477.2391.

[0329] (3-((2-(2-aminopyridin-4-yl)phenyl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C48, CDD-3198) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO -d 6 8.05 (d, J = 5.2 Hz,1H), 7.87 (s, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.69 (dd, J = 8.8, 1.4 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.59–7.45 (m, 3H), 6.85 (dd, J = 5.2, 1.5 Hz, 1H), 6.70 (s, 1H), 5.99 (s, 2H), 3.89 (d, J = 8.4 Hz, 1H), 3.84 (d, J = 8.4 Hz, 1H), 3.76 (d, J = 9.8 Hz, 1H), 3.70 (d, J = 9.7 Hz, 1H), 2.78 (d, J = 11.7Hz, 1H), 2.72 (d, J= 11.9 Hz, 1H), 2.57–2.51 (m, 2H), 1.72 (s, 1H), 1.66 (s,1H), 1.42–1.36 (m, 1H), 1.36–1.31 (m, 1H); 13 C NMR (150 MHz, DMSO -d 6 ) δ 169.1,159.9, 148.2, 147.7, 141.6, 140.8, 133.3, 129.6, 129.1, 128.8, 128.4, 126.9,126.6, 123.5, 119.8, 119.7, 112.4, 110.9, 107.8, 92.0, 84.5, 62.2, 57.7,54.5, 45.3, 34.7, 34.0, 23.2; HRMS (ESI) C 28 H 27 N6O [M + H] + m / z Calculated value: 463.2246; Measured value: 463.2236.

[0330] (3-((2-(2-aminopyridin-3-yl)phenyl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C49, CDD-3232) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 8.01 (d, J = 5.0Hz, 1H), 7.74 (dd, J = 7.3, 1.7 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.51–7.34(m, 6H), 6.76–6.51 (m, 1H), 5.69 (br s, 1H), 5.44 (s, 1H), 3.97–3.79 (m, 2H), 3.76–3.67 (m, 2H), 2.92–2.68 (m, 2H), 2.66–2.51 (m, 2H), 1.82–1.51 (m, 2H),1.45–1.30 (m, 2H); HRMS (ESI) C 28 H27 N6O [M + H] + m / z Calculated value: 463.2246; Measured value: 463.2236.

[0331] (3-((2-(2-(pyrrolid-1-yl)pyridin-3-yl)phenyl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C50, CDD-3233) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 8.16 (d, J = 4.9Hz, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.53–7.47 (m,2H), 7.47–7.34 (m, 4H), 6.80–6.73 (m, 1H), 3.92–3.73 (m, 2H), 3.73–3.63 (m,2H), 3.11–2.93 (m, 4H), 2.74 (s, 2H), 2.62–2.51 (m, 2H), 1.73–1.60 (m, 6H),1.44–1.29 (m, 2H); HRMS (ESI) C 32 H 33 N6O [M + H] + m / z Calculated value: 517.2716; Measured value: 517.2704.

[0332] (3-((2-(2-(piperazin-1-yl)pyridin-3-yl)phenyl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C51, CDD-3234) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 8.27 (dd, J = 4.8, 1.9 Hz, 1H), 7.75 (d, J= 7.6 Hz, 1H), 7.68 (dd, J = 7.3, 1.9 Hz, 1H), 7.62–7.38 (m, 6H), 7.12–6.95 (m, 1H), 3.88–3.74 (m, 2H), 3.74–3.65 (m, 2H), 3.24(s, 4H), 2.90 (s, 4H), 2.75 (s, 2H), 2.60–2.52 (m, 2H), 1.80–1.62 (m, 2H),1.45–1.30 (m, 2H); HRMS (ESI) C 32 H 34 N7O [M + H] + m / z Calculated value: 532.2825; Measured value: 532.2814.

[0333] N -(2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1 H -Indazole-3-yl)ethynyl)-[1,1'-biphenyl]-2-yl)acetamide (C52, CDD-3235) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 9.13 (s, 1H), 7.78–7.70 (m, 1H), 7.66 – 7.59 (m, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.51–7.41 (m,4H), 7.40–7.33 (m, 2H), 7.32–7.21 (m, 2H), 3.81–3.71 (m, 2H), 3.71–3.64 (m,2H), 2.72 (s, 2H), 2.61–2.51 (m, 2H), 1.85 (s, 3H), 1.68 (s, 2H), 1.45–1.29(m, 2H); HRMS (ESI) C 31 H 30 N5O2 [M + H] + m / z Calculated value: 504.2400; Measured value: 504.2387.

[0334] N-(2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1 H -Indazol-3-yl)ethynyl)-[1,1'-biphenyl]-2-yl)neopentamide (C53, CDD-3236) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO -d 6 ) δ 8.58–8.45 (m, 1H),7.77–7.70 (m, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.58–7.48 (m, 2H), 7.48–7.37 (m,5H), 7.37–7.27 (m, 2H), HRMS (ESI)C 34 H 36 N5O2 [M + H] + m / z Calculated value: 546.2869; Measured value: 546.2856.

[0335] (3-((2-(2-(4-methylpiperazin-1-yl)pyridin-3-yl)phenyl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C54, CDD-3353) Applicable to synthetic route 2; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.31–8.24 (m,1H), 7.76 (d, J = 7.7 Hz, 1H), 7.69 (dd, J= 7.4, 1.9 Hz, 1H), 7.62–7.55 (m,1H), 7.55–7.47 (m, 3H), 7.47–7.40 (m, 2H), 7.13–6.99 (m, 1H), 3.86–3.74 (m,4H), 3.73–3.66 (m, 2H), 3.01–2.94 (m, 4H), 2.74 (s, 1H), 2.58–2.52 (m, 1H), 2.18–2.08 (m, 4H), 2.06 (s, 3H), 1.70 (s, 2H), 1.45–1.26 (m, 2H); HRMS(ESI)C 33 H 36 N7O [M + H] + m / z Calculated value: 546.2981; Measured value: 546.2968.

[0336] (3-([1,1'-biphenyl]-3-yl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C55, CDD-3808) Applicable to synthetic route 2; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.50 (s, 1H),7.35 (s, 1H), 7.14 (d, J = 7.7 Hz, 1H), 6.94–6.90 (m, 2H), 6.89–6.85 (m, 2H), 6.83–6.78 (m, 2H), 6.68 (t, J = 7.7 Hz, 2H), 6.58 (t, J = 7.3 Hz, 1H), 3.21(d, J = 8.5 Hz, 1H), 3.17 (d, J = 8.1 Hz, 1H), 2.90 (d, J = 9.7 Hz, 1H), 2.83(d, J = 9.7 Hz, 1H), 1.96–1.81 (m, 2H), 1.74–1.67 (m, 2H), 0.90–0.74 (m, 2H),0.60–0.44 (m, 2H); HRMS (ESI) C27 H 27 N4O [M + H] + m / z Calculated value: 423.2185; Measured value: 423.2176.

[0337] (3-([1,1'-biphenyl]-4-yl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C56, CDD-3809) Applicable to synthetic route 2; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.35 (s, 1H), 8.09 (d, J = 8.3 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.79–7.74 (m, 2H), 7.70(dd, J = 8.7, 1.4 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 4.03 (d, J = 8.4 Hz, 1H), 3.98 (d, J = 8.4 Hz, 1H), 3.75 (d, J = 9.7 Hz, 1H), 3.68 (d, J = 9.8 Hz, 1H), 2.78–2.67 (m, 2H), 2.58–2.51 (m, 2H), 1.74–1.60 (m, 2H), 1.42–1.31 (m, 2H); HRMS (ESI) C 27 H 27 N4O[M + H] + m / z Calculated value: 423.2185; Measured value: 423.2175.

[0338] (3-((2'-morpholino-[1,1'-biphenyl]-2-yl)ethynyl)-1 H-Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C57, CDD-3810) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.73 (dd, J = 7.6,1.3 Hz, 1H), 7.59–7.53 (m, 1H), 7.53–7.44 (m, 3H), 7.43–7.31 (m, 4H), 7.21–7.09 (m, 2H), 3.82–3.74 (m, 2H), 3.74–3.66 HRMS(ESI) C 33 H 34 N5O2 [M + H] + m / z Calculated value: 532.2713; Measured value: 532.2710.

[0339] 7-(2-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1 H -Indazol-3-yl)ethynyl)phenyl)isoindoline-1-one (C58, CDD-3811) Applicable to synthetic route 2; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.74–7.34 (m,10H), 7.27 (s, 1H), 4.37 (s, 2H), 3.86–3.75 (m, 2H), 3.74–3.69 (m, 2H), 2.81–2.64 (m, 2H), 2.61–2.51 (m, 2H), 1.75–1.56 (m, 2H), 1.47–1.25 (m, 2H); HRMS(ESI) C 31 H 28 N5O2 [M + H] + m / zCalculated value: 502.2243; Measured value: 502.2235.

[0340] 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1 H -indazole-3-yl)ethynyl)- N , N -Dimethyl-[1,1'-biphenyl]-2-carboxamide (C59, CDD-3812) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.79–7.71 (m, 1H),7.66–7.40 (m, 9H), 7.31–7.25 (m, 1H), 3.79–3.73 (m, 2H), 3.72–3.67 (m, 2H),2.80–2.50 (m, 10H), 1.75–1.59 (m, 2H), 1.47–1.27 (m, 2H); HRMS (ESI) C 32 H 32 N5O2[M + H] + m / z Calculated value: 518.2556; Measured value: 518.2549.

[0341] (3-((2'-(pyrrolidone-1-ylmethyl)-[1,1'-biphenyl]-2-yl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C60, CDD-3813) Applicable to synthetic route 2; pale yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.73–7.67 (m,1H), 7.59 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.48–7.37 (m, 4H), 7.36–7.30 (m, 2H), 7.27 (dd, J= 7.5, 1.5 Hz, 1H), 7.21 (s, 1H), 3.89–3.60(m, 6H), 2.79–2.67 (m, 2H), 2.60–2.52 (m, 2H), 2.26 (s, 4H), 1.75–1.65 (m, 2H), 1.54 (s, 4H), 1.44–1.30 (m, 2H); HRMS (ESI) C 34 H 36 N5O [M + H] + m / z Calculated value: 530.2920; Measured value: 530.2919.

[0342] (3-((2'-(morpholinylmethyl)-[1,1'-biphenyl]-2-yl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C61, CDD-3814) Applicable to synthetic route 2; white solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.73 (dd, J = 7.2,1.8 Hz, 1H), 7.58–7.34 (m, 8H), 7.30 (dd, J = 7.3, 1.6 Hz, 1H), 7.27–7.22 (m,1H), 3.84–3.64 (m, 4H), 3.42–3.27 (m, 6H), 2.79–2.67 (m, 2H), 2.61–2.53 (m,2H), 2.14 (s, 4H), 1.76–1.64 (m, 2H), 1.45–1.33 (m, 2H); HRMS (ESI) C 34 H 36 N5O2[M + H] + m / z Calculated value: 546.2869; Measured value: 546.2869.

[0343] (3-((2-(pyridin-4-yl)phenyl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C62, CDD-3883) Applicable to synthetic route 2; yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.76–8.67 (m, 2H),7.84 (d, J = 7.2 Hz, 1H), 7.79–7.69 (m, 3H), 7.64–7.53 (m, 5H), 3.86 (d, J =8.4 Hz, 1H), 3.81 (d, J = 8.4 Hz, 1H), 3.76 (d, J = 9.8 Hz, 1H), 3.68 (d, J =9.8 Hz, 1H), 2.81–2.68 (m, 2H), 2.58–2.51 (m, 2H), 1.76–1.62 (m, 2H), 1.42–1.31 (m, 2H); HRMS (ESI) C 28 H 26 N5O [M + H] + m / z Calculated value: 448.2137; Measured value: 448.2133.

[0344] (3-((2-phenylpyridin-3-yl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C63, CDD-3884) Applicable to synthetic route 2; yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.64 (dd, J = 4.7,1.7 Hz, 1H), 8.15–8.06 (m, 3H), 7.77 (d, J = 3.9 Hz, 1H), 7.60–7.48 (m, 4H), 7.45 (dd, J = 7.8, 4.7 Hz, 1H), 7.40 (dd, J= 8.6, 1.6 Hz, 1H), 3.87–3.83 (m,1H), 3.80–3.77 (m, 1H), 3.69–3.61 (m, 2H), 2.80–2.62 (m, 2H), 2.57–2.50 (m,2H), 1.71–1.63 (m, 2H), 1.43–1.26 (m, 2H); HRMS (ESI) C 28 H 26 N5O [M + H] + m / z Calculated value: 448.2137; Measured value: 448.2135.

[0345] (3-((3-phenylpyridin-4-yl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C64, CDD-3885) Applicable to synthetic route 2; yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.69 (s, 1H), 8.60 (d, J = 5.1 Hz, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.71–7.65 (m, 2H), 7.63–7.56(m, 3H), 7.55–7.50 (m, 1H), 7.48 (d, J = 8.8 Hz, 1H), 3.85–3.74 (m, 2H), 3.71–3.66 (m, 2H), 2.82–2.63 (m, 2H), 2.61–2.50 (m, 2H), 1.74–1.63 (m, 2H), 1.43–1.29 (m, 2H); HRMS (ESI) C 28 H 26 N5O [M + H] + m / z Calculated value: 448.2137; Measured value: 448.2134.

[0346] (3-((4-phenylpyridin-3-yl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C65, CDD-3886) Applicable to synthetic route 2; yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.92 (s, 1H), 8.63 (d, J = 5.1 Hz, 1H), 7.87–7.81 (m, 2H), 7.78–7.72 (m, 1H), 7.65–7.49 (m, 6H), 3.88–3.83 (m, 1H), 3.81–3.79 (m, 1H), 3.71–3.66 (m, 2H), 2.81–2.64 (m, 2H),2.61–2.50 (m, 2H), 1.72–1.63 (m, 2H), 1.42–1.30 (m, 2H); HRMS (ESI) C 28 H 26 N5O[M + H] + m / z Calculated value: 448.2137; Measured value: 448.2134.

[0347] (3-((3-phenylpyridin-2-yl)ethynyl)-1 H -Indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone (C66, CDD-3887) Applicable to synthetic route 2; yellow solid; 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.61 (dd, J = 4.8, 1.6 Hz, 1H), 7.87 (dd, J = 7.8, 1.6 Hz, 1H), 7.79–7.75 (m, 2H), 7.59–7.47 (m,5H), 7.44 (dd, J = 7.8, 4.7 Hz, 1H), 7.34–7.28 (m, 1H), 3.86–3.60 (m, 4H), 2.81–2.63 (m, 2H), 2.59–2.51 (m, 2H), 1.71–1.63 (m, 2H), 1.41–1.28 (m, 2H);HRMS (ESI) C 28 H 26 N5O [M + H] + m / zCalculated value: 448.2137; Measured value: 448.2134.

[0348] Table C. Validation of the STK33 / CDD-2211 interaction through structure-activity-relationship (SAR) studies of CDD-2211 analogs. The hinge binding of indazole (CDD-2211 vs. CDD-2533), the ortho orientation of biphenyl (CDD-2211 vs. CDD-2532 and CDD-2563), and the two-carbon distance between indazole and biphenyl (CDD-2211 vs. CDD-2573 and CDD-2647) contribute to the activity against STK33. ND means compounds not assayed: compounds that did not pass the kinase assay against STK33 at 500 nM. Table D. Structure-activity relationship of substituted amines on indazole molecular scaffolds. Table E. Structure-activity relationship of N-substituted and methyleneamine-substituted compounds. Table F. Structure-activity relationships of N-substituted and methyleneamine-substituted compounds with alkyl, alkenyl, alkynyl, and aryl groups. Example 3: Metabolism, toxicity, and distribution studies of STK33 inhibitors Determination of metabolic stability in liver microsomes.

[0349] As previously reported, the stability of CDD-2110, CDD-2211, CDD-2212, CDD-2807, and CDD-3348 in liver microsomes was investigated, and their half-lives were calculated. Briefly, each CDD compound (2.0 μM) was incubated in mouse or human liver microsomes (0.5 mg protein / mL) at 37 °C in 1× PBS enhanced with NADPH (1.0 mM). Samples were collected at specific time points (i.e., 0, 30, and 60 min), repeated twice. The reaction was terminated by adding an equal volume of ice-cold CH3OH and vortexing. After centrifugation at 15000 g for 10 min, 3.0 μL of the supernatant was analyzed using a UHPLC-Q Exactive Orbitrap MS equipped with a 50 mm × 4.6 mm column (XDB C-18, Agilent Technologies, USA). The column temperature was maintained at 40 °C. Q Exactive MS was performed using electrospray ionization in positive ion mode. MS data were acquired from 100 to 800 Da in in-profile mode. During acquisition, the ion with m / z 371.1012 (positive ion mode) was used as the reference mass.

[0350] Pharmacokinetics of CDD-2807 in mice.

[0351] Pharmacokinetic studies of CDD-2807 50The administration was performed in two doses. CDD-2807 was dissolved in 10% Captisol containing 5% DMSO to prepare 0.5 mg / mL and 2.5 mg / mL solutions. Six male mice (strain: C57BL / 6NJ, 8–12 weeks old) were equally and randomly divided into two groups (n = 3 per dose). One group of mice was administered 5 mg / kg CDD-2807 (ip, 10 µL of 0.5 mg / mL solution per g), and the second group was administered 25 mg / kg CDD-2807 (ip, 10 µL of 2.5 mg / mL solution per g). Approximately 20 µL of blood was collected from the tail vein and anticoagulated with heparin at 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-administration. Blood samples were centrifuged at 2000 g for 3 min at 4 °C, and plasma samples were transferred to tubes and stored at -80 °C for later analysis. All samples were analyzed by Thermo TSQQuantis MS coupled with Thermo Vanquish UHPLC (San Jose, CA). CDD-2807 was separated by a Luna C18 column (1 mm × 50 mm, 1.6 µm, Phenomenex, Torrance, CA) and separated by a water-acetonitrile mobile phase system (both containing 0.1% formic acid). v / v Elution was performed at a flow rate of 0.15 mL / min. CDD-2807 was monitored using a positive electrospray ionization (ESI) source in selected reaction monitoring (SRM) mode. For CDD-2807, the SRM ion pair was 447→321. The ion spray voltage was set to 3500 V. High-purity nitrogen (35 units of arbitrary value) was used as the sheath gas, 7 units of arbitrary value as the auxiliary gas, and high-purity argon as the collision gas. The temperatures of the ion transfer tube and vaporizer were set to 300 °C and 275 °C, respectively. The concentration of CDD-2807 in plasma was quantified using a separate calibration curve. The calibration curve used 1 / x 2 Regression using weights yields high linearity (r). 2 >0.99). The half-life (t) was calculated using non-compartmental analysis with WinNonlin software (Certara, Princeton, NJ). 1 / 2 ), Area under the plasma concentration-time curve (AUC) during the observation period 0–t The area under the plasma concentration-time curve (AUC) from zero to infinity. 0–∞PK parameters, including clearance rate normalized to bioavailability (CL / F), volume of distribution normalized to bioavailability (Vd / F), and mean residence time (MRT), were calculated. Plasma concentration-time curves were plotted in Prism 9 (GraphPad, San Diego, CA) and expressed as mean ± SD.

[0352] CDD-2807 concentration in the testes and brain.

[0353] Testes and brains harvested on day 45 of Protocol 1 and day 63 of Protocol 2 were weighed and flash-frozen in liquid nitrogen. Samples were stored at -80°C for later analysis. 25 mg of testicular or brain tissue was homogenized in 150 μL of 50% methanol, and 50 μL of the homogenate was added to 200 μL of ice-cold CH3OH containing 0.1 μM agomelatine (internal standard). The mixture was vortexed and centrifuged at 15000 g for 15 min, and the supernatant was transferred to sample vials for analysis. CDD-2807 was analyzed using the same LC-MS / MS method used in pharmacokinetic studies. The concentrations of CDD-2807 in the testes and brain were determined using separate calibration curves established with corresponding tissue homogenates from untreated mice. Calibration curves were performed using 1 / x... 2 Regression using weights yields high linearity (r). 2 >0.99).

[0354] Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured.

[0355] On day 45 of Protocol 1 and day 63 of Protocol 2, three mice in each protocol were euthanized, and blood was collected via cardiac puncture. Serum was separated by centrifuging whole blood samples at 1500 g for 10 min and then kept on wet ice for later analysis. ALT and AST levels were determined using assay kits (StanBio, Boerne, TX) according to the manufacturer's instructions, repeated twice. ALT and AST levels were determined using NADH oxidation rate—which was quantified by measuring absorbance at 340 nm using a CLARIOstar plate reader (BMG Labtech, Cary, NC).

[0356] CDD-2807 ( Figure 2B It is revealed to be a potent STK33 ligand (K d = 0.02 nM), not only maintaining high potency against STK33 in NanoBRET cell assay (IC50, 0.02 nM), but also maintaining high efficacy against STK33 (IC50, 0.02 nM). 50 = 9.2 nM), and it also exhibits excellent metabolic stability with a half-life >60 min in both MLM and HLM. Figure 2CTo determine kinome-wide selectivity, CDD-2807 was subjected to a NanoBRET target binding assay (Promega) against 192 full-length protein kinases in HEK293 cells at a dose of 1 μM. In this assay, STK33 was the most potent kinase bound (95.9% occupancy), but CDD-2807 also bound other kinases. Figure 2D The potency of CDD-2807 against off-target kinases with >80% occupancy was evaluated using the ThermoFisher dose-response assay and the NanoBRET cell assay. These kinases included CDC-like kinase 4 (CLK4) (94.7% occupancy), CLK2 (89.7% occupancy), RET (85.8% occupancy), and CLK1 (83.5% occupancy). In both assays, compared to its effect on CLK4 (K... d = 0.9 nM and IC 50 = 85 nM), CLK2 (K i = 1.3 nM and IC 50 =101 nM), RET(K) i = 0.3 nM and IC 50 = 363 nM) and CLK1 (K i = 3.1 nM and IC 50 The interaction of CDD-2807 (116 nM) with STK33 makes CDD-2807 the most potent ligand for STK33. Figure 2C In summary, CDD-2807 is a potent, stable, and relatively selective STK33 inhibitor, exhibiting >9-fold selectivity compared to other kinases. Figure 2C ).

[0357] For the extratarget kinases CLK1, CLK2, CLK4, and RET, the original hit compounds CDD-2110 and CDD-3348, along with the truncated enantiomers CDD-2211 and CDD-2212, were also determined. Figure 2C (and Table C). All compounds (except CDD-2212) exhibited >10-fold selectivity for STK33 extratarget kinases in control cells. CDD-2211 ( R -Isomer) and CDD-2212 ( S Significant differences in biochemical and cellular activity between the two isomers (e.g., in the NanoBRET assay, CDD-2211 was 16-fold more selective for STK33 than for RET, compared to 1.1-fold more selective for CDD-2212). Figure 2CThis indicates that chirality plays a crucial role in selectivity. Compared to CDD-3348, CDD-2110 exhibits increased selectivity (e.g., in biochemical assays, CDD-2110 shows a 96-fold selectivity for STK33 compared to CLK4, compared to 437-fold for CDD-3348; while in NanoBRET assays, CDD-2110 shows a 14-fold selectivity for STK33 compared to CLK4, compared to 23-fold for CDD-3348). Figure 2C Table B also shows that selectivity for STK33 can be improved by modifying the linker at BB1. Data related to other molecular scaffolds are summarized in Table B. Pharmacokinetic (PK) parameters are summarized in Table G.

[0358] Table G. Non-compartmental PK parameters of CDD-2807 (intraperitoneal injection, n = 3, mean ± SD). Example 4: Production of X-ray eutectic structure of STK33 One obstacle to better understanding the molecular basis of the high affinity of our STK33 inhibitor is the lack of available STK33 structures. To address this challenge, the crystal structure of the human STK33 kinase domain in the complex with CDD-2211 was determined at 2.7 Å resolution (Figure 3 and Table H).

[0359] STK33 KD protein expression and crystallographic purification.

[0360] This allows the product to contain tobacco plaque virus (TEV) cleavage sites and cGFP-Strep-tag. ®Human STK33 KD (GenBank accession number CAC29064.1, residue 99-383) was expressed in insect SF9 cells (Invitrogen). SF9 cells were cultured in SF900III medium (Gibco) and infected with STK33 KD baculovirus at the optimal virus / insect cell ratio. Cells were harvested 48 h post-infection; the pellet was held at -80°C. For purification, the frozen cell pellet was resuspended in lysis buffer (25 mM Tris, pH 8.0, 150 mM NaCl, and 1 mM TCEP) and lysed using a homogenizer (Avestin). After centrifugation at 48,000 g for 1 h, the soluble fraction was loaded onto pre-equilibrated Strep-Tactin Superflow resin (IBA Lifesciences GmbH) and eluted with elution buffer (25 mM Tris, pH 8.0, 150 mM NaCl, 1 mM TCEP, and 2 mM dethiobiotin). The fraction containing the protein was treated with TEV protease (1:60 by weight, overnight) to remove the GFP tag, and the mixture was subjected to a Superdex™ 75 Increase 10 / 300 GL gel filter (Cytiva) equilibrated with the above lysis buffer. Peaks corresponding to estimated molecular weights of approximately 70 kDa were combined and used for co-crystallization.

[0361] Crystallization, data acquisition, and structure solution. STK33 KD and CDD-2211 were co-crystallized using a hanging drop vapor diffusion method. For crystallization, 1.8 mg / mL of purified STK33 was mixed with a 6-molar excess of CDD-2211. The protein-inhibitor mixture was concentrated to 14 mg / mL using an Amicon Ultra-15 centrifuge filter (Millipore Sigma). Equal volumes of protein and reservoir (250 nl each) were dispensed into 96-well crystallization plates (SPT Labtech 96-well transparent polystyrene microplates) using a Mosquito (SPT Labtech) with 70 μL of reservoir buffer. Crystals were observed after 2 days of dropwise addition under JCSGplus-A12 conditions (0.2 M potassium nitrate, 20% w / v polyethylene glycol 3350). Diffraction data at wavelength (λ) = 1.0000 Å were acquired at the Advanced Light Source (ALS), Beam Line 5.0.2 (UC Berkeley, USA) using a Decrispilotus 6M detector. The data were integrated and scaled using iMosflm and SCALA, respectively. The crystal structure of the STK33 / CDD-2211 complex was determined by molecular substitution using a monomer model of STK33 KD (residues 99-383) generated by Alphafold as the search model. CDD-2211 was tracked using COOT and manually fitted to electron density. The final model underwent several rounds of refinement using phenix.refine. 46 Then use COOT to manually build the model ( 47 For all structural analysis and graph preparation, the visualization program PyMOL was used. 48 This section displays a summary of the collected data.

[0362] Table H. Data collection and refinement statistics. a The highest resolution shell is shown in parentheses.

[0363] b 5% of the observation intensity was excluded from refinement and used for cross-validation.

[0364] c Rms It means the root mean square.

[0365] STK33:CDD-2211 eutectic. Each asymmetric unit contains a dimer, and each monomer shows a clear density of bound CDD-2211. Figure 3B The two STK33 kinase domain monomers are very similar, showing a root mean square deviation (RMSD) of approximately 0.5 Å between about 240 shared CA atoms. Figure 6 For CDD-2211 bound in the ATP pocket ( Figure 3B Each individual exhibits almost identical posture ( Figure 6 Except for the activated ring segment (residues 273-283 in chain A and residues 274-284 in chain B are disordered), all residues in the construct are ordered. The STK33 dimer consists of an activated ring segment and a double-turn helix containing an APE motif from one monomer coupled to another monomer. E-helix and The surface formed between G-helices forms ( Figure 3A ).

[0366] CDD-2211 binds to the active site formed between the leaflets and the macrophages. Figures 3A-3E and Figure 6 Biphenyl (BB3) binds to the outer lip of the active site near the hinge. Figure 3C It interacts with L122 and G123 above and G198, E199 and M245 below through van der Waals interactions. Figure 3D and Figure 3E Indazole (BB2) binds to the ribosome pocket near the hinge region. It forms hydrogen bonds with the backbone at E193 and C195 at the hinge. Figure 3E ). Pyrrolidine (BB1) containing dimethylamine contacting Mg 2+ Positioning ring, glycine-rich ring, and activating ring. Dimethylamine is typically associated with Mg. 2+ Interacting D265 hydrogen bonds. BB1 is masked by F127 (top) at the Gly-rich ring and E242 and N243 (bottom) at the catalytic ring, and it interacts with these residues through van der Waals interactions.

[0367] This eutectic structure is consistent with a group of CDD-2211 analogs studied using structure-activity (SAR) analysis (Table B). The -NH group at the indazole (BB2) is... NThe -methyl substitution resulted in complete loss of STK33 activity at 500 μM, confirming that hydrogen bonding interactions at the hinge are crucial for STK33 efficacy. At biphenyl (BB3), ortho substitution proved to be the optimal orientation, as STK33 efficacy gradually decreased as the phenyl substituent moved from the ortho to the meta and para positions. Furthermore, no STK33 activity was observed at 500 μM for analogs with shorter linkers between indazole and biphenyl. Therefore, the interaction involving the indazole fragment at the hinge region, the ortho orientation of the biphenyl, and the specific distance maintained by the two-carbon acetylene linker between the indazole and biphenyl components within the CDD-2211 scaffold synergistically contribute to its enhanced anti-STK33 efficacy.

[0368] Based on the crystal structure of the STK33 / CDD-2211 complex, a computational model for the binding of STK33 and CDD-2807 was generated. Figure 8 The model indicates that the nitrogen of the piperidine moiety at BB1 will interact with the side chain of E199 via hydrogen bonds, while its interactions with the active site at BB2 and BB3 will be similar to those in the STK33 / CDD-2211 complex.

[0369] CDD-2211, similar to CDD-2807, shows some (albeit low) inhibition of extratarget kinases CLK1, CLK2, CLK4, and RET. Figure 2C As shown. To understand their cross-activity, the crystal structures of RET and CLK4 were compared, using the STK33 / CDD-2211 complex as an example, and the binding site residues were compared. Structural comparison showed that most of the CDD-2211 contact residues of STK33 are conserved in both RET and CLK4, except for E199 of the linker (immediately following the hinge) and 7 M245 ( Figure 7 In RET and CLK4, E199 was replaced by serine (S811 in RET and S247 in CLK4), and M245 was replaced by leucine (L881 in RET and L295 in CLK4), suggesting that it is possible to increase selectivity for STK33 by modifying the BB1 ​​or BB3 portion of CDD-2211 near E199.

[0370] Example 5: Study on contraceptive effect in mice Based on molecular modeling, mouse and human STK33 share the same ATP-binding pocket, consistent with the evolutionary conservation and function of STK33. The amino acids in human STK33 exposed to CDD-2211 are identical in mouse STK33. Figure 9This indicates that CDD-2807 inhibits STK33 equally in mice and humans. To determine the consequences of STK33 inhibition in vivo, male reproductive outcomes were evaluated in mice administered the potent and stable compound CDD-2807.

[0371] Fertility analysis Sexually mature male C57 / 129 hybrid mice were randomly assigned to either the causative control group or the CDD-2807 treatment group. Drug formulation and injection were as follows: Mice receiving 15 mg / kg CDD-2807 twice daily were administered the compound dissolved in DMSO at a final volume of 5% in 10% Captisol and water. Mice receiving a single daily dose of 50 mg / kg CDD-2807 once daily were administered the compound dissolved in DMSO at a final volume of 5% in 20% Captisol and water. All injections were administered intraperitoneally (IP), and for the 15 mg / kg CDD-2807 and DMSO control mice, injections were delivered in the morning and evening. Mice receiving the 50 mg / kg dose received a single IP injection in the evening. Body weight was collected daily before drug administration and monitored throughout the injection period. Injections were administered for 21 days prior to the introduction of female mice. During the fertility assessment, males were housed with two sexually mature females (C57 / 129) for 45 consecutive days to generate approximately two months of fertility data. During the fertility assessment, the total number of offspring per litter for each male was counted, and the total number of litters and offspring per male throughout the entire trial was calculated. Differences in the average number of offspring per litter were determined using Prism 9 and t-tests, with mean offspring number and SEM analysis.

[0372] Histological analysis In short, the tissue was fixed in Bouin solution, washed with 70% ethanol, embedded in paraffin, sectioned at a thickness of 4 µm, and stained with periodic acid Schiff (PAS)-hematoxylin.

[0373] Computer-assisted sperm analysis (CASA).

[0374] Sperm were extracted by cutting the two segments of the epididymal tail 25 times in 1 mL of Enhance Sperm Wash w / gentamicin (Vitrolife, Sweden) medium with dissecting scissors. All media were maintained at 37°C throughout the procedure. After incubation for 15 minutes, the supernatant was diluted, and 6 µL of the diluted sample was added to a single chamber of a dual-chamber 20 µm deep Leja semen analysis slide (Spectrum Technologies). Sperm parameters were measured using the Hamilton ThorneCEROS II system. A minimum of 200 sperm were measured per sample, typically consisting of recording at least five non-overlapping fields of view. Another measurement was performed after incubation at 37°C for 90 minutes, taking into account sperm capacitation.

[0375] Sperm analysis using scanning electron microscopy (SEM).

[0376] Sperm was extracted by cutting the epididymal tail 30 times in 1 mL of Enhance Sperm Wash w / gentamicin (Vitrolife, Sweden) medium incubated at 37°C using dissecting scissors. The sperm were left in the medium at 37°C for at least 15 minutes to allow them to disperse from the tissue. The medium and sperm were then collected and transferred to separate tubes, where they were vortexed at 300 xg for 5 minutes at room temperature to allow collection at the bottom without any epididymal fragments. The medium was removed and the sperm cells were resuspended in DPBS for washing. After washing, the sperm were vortexed a second time and then resuspended in fresh 2.5% glutaraldehyde / PBS and fixed on a shaker at room temperature for 30 minutes. After fixation, the sperm were dehydrated in increasing concentrations of ethanol (20%, 30%, 50%, 60%, 70%, 90%, and 100% successively). During each dehydration step, the sperm were incubated at room temperature for 15 minutes. Each increase in ethanol percentage alters sperm density and requires a higher velocity for subsequent rotational sedimentation; when sperm is in 100% ethanol, ≥1200 xg is needed for precipitation. Sperm were incubated overnight in 100% ethanol at 4°C, and the samples were separated the following day. They were then rotated at 1500 xg for 5 minutes at room temperature, resuspended in 50% tert-butanol / ethanol, and incubated for 15 minutes. The samples were then imaged on a FEI Nova NanoSEM 230 instrument at the Houston Methodist Research Institute Microscopy SEM / AFM core.

[0377] Due to the plasma t of CDD-2807 during intraperitoneal delivery 1 / 2More than 11 hours, while the maximum concentration (C) max The area under the curve (AUC) and the curve area under the curve (AUC) increased in a dose-dependent manner. Figure 10 And Table G), therefore adult male mice were subjected to two protocols ( Figures 11A-11B In Protocol 1, adult male mice (n=6 per cohort) were treated twice daily with either the mediator control or 15 mg / kg CDD-2807 for 21 days, and were continuously housed with reproductive-age female mice (two females per male). The effects of CDD-2807 on the male reproductive tract were then assessed on day 45 (after the first litter) or the mice were continued to be housed with females until day 66. Figure 11A In Protocol 2, adult male mice (n = 7 per cohort) were treated daily with either the mediator control or 50 mg / kg CDD-2807 for 21 days, and were continuously housed with females (two females per male) before being evaluated at later time points. During CDD-2807 or control parturition, Protocol 1 ( Figure 12A ) or Option 2 ( Figure 12B Neither cohort of mice died, nor did they show significant weight changes, indicating that CDD-2807 is very safe. Although in Month 1, the six control-treated males in Protocol 1 produced an average of 1.83 ± 0.07 litters / male and 6.75 ± 0.19 pups / female / litter, four of the six CDD-2807-treated males produced litters (1 or 2 litters; 1.0 ± 0.37 litters / male) and fewer—0.92 pups / female / litter (…). Figure 4A In the second month, all females housed with the 6 control males gave birth to litters (2.0±0 litters per male; 7.25±0.17 pups per female litter). Figure 4A In contrast, female non-laying litters kept with males receiving CDD-2807 ( Figure 4A For mice in scheme 2, in month 1, all 7 control males resulted in two litters of females (7.29 ± 0.18 pups / litter / female), while the 7 males treated with CDD-2807 (50 mg / kg / day) resulted in only one female becoming pregnant and giving birth to one pup (0.07 ± 0.07 pups / litter / female). Figure 4B In the second month, males treated with CDD-2807 did not produce any litters, although they were capable of mating; while all females housed with control males produced litters (2.71±0.07 litters of males; 9.16±0.09 pups / female / litter). Therefore, CDD-2807 delivery resulted in a contraceptive effect in both programs....

Claims

1. A compound of formula (I), or a salt, solvate, stereoisomer, tautomer or geometric isomer thereof: (I)， in: L 1 Selected from -C≡C-, -CH=CH-, -CH2- and bonds; X is selected from -C(=O)-, -C(CH3)2-, -CF2-, -CHF-, -CH(CH3)- and -CH2; Z 1 Z 2 or Z 3 Independently, it is CH or N, where Z 1 Z 2 and Z 3 One of the 0s or 1s is N; R a and R b Independently selected from hydrogen, optionally substituted C1-C8 alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted phenyl groups, and optionally substituted 3- to 8-membered heterocyclic groups. or R a and R b They can combine with the nitrogen atoms to which they are bonded to form optionally substituted 3- to 8-membered heterocyclic groups; and Y is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C2-C 10 Mixed aryl or CN.

2. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (Ia): (It)。 3. The compound according to claim 1 or 2, wherein X is -C(=O)-.

4. The compound according to any one of claims 1-3, wherein Y is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted isoquinolinyl, optionally substituted quinolinyl, optionally substituted 2-pyridyl, optionally substituted 3-pyridyl, optionally substituted 4-pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted triazineyl.

5. The compound according to any one of claims 1-4, wherein Y is , in R c1 R c2 R c3 R c4 and R c5 Independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkoxy, -C(=O)NR e1 R e2 -NR e1 C(=O)R e2 Optionally substituted phenyl groups, optionally substituted naphthyl groups, optionally substituted 3- to 8-membered heterocyclic groups, and optionally substituted C3-C groups. 10 Mixed aromatics; or Selected from R c1 R c2 R c3 R c4 and R c5 The two adjacent substituents can combine with the carbon atoms to which they are bonded to form an optionally substituted phenyl, an optionally substituted C4-C8 heterocyclic group, or an optionally substituted C4-C8 heteroaryl group; R e1 and R e2 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, optionally substituted 3- to 8-membered heterocyclic groups, or optionally substituted C3-C... 10 Mixed aromatic compounds.

6. The compound according to any one of claims 1-5, wherein R a or R b One of them is hydrogen or methyl.

7. The compound according to any one of claims 1-6, wherein R a and R b The nitrogen atoms they combine with form optionally substituted 5, 6, or 7-membered heterocyclic groups.

8. The compound according to any one of claims 1-7, wherein R a and R b The nitrogen atoms they combine with form optionally substituted pyrrolidinyl groups.

9. The compound according to any one of claims 1-3 and 5-8, wherein it is a compound of formula (II), (III), (IV) or (V): (II) (III) (IV) or (V), in R c1 R c2 R c3 R c4 and R c5 Independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkoxy, -C(=O)NR e1 R e2 -NR e1 C(=O)R e2 Optionally substituted phenyl groups, optionally substituted naphthyl groups, optionally substituted 3- to 8-membered heterocyclic groups, and optionally substituted C3-C groups. 10 Mixed aromatics; Or selected from R c1 R c2 R c3 R c4 and R c5 The two adjacent substituents can combine with the carbon atoms they are bonded to form an optionally substituted phenyl group, an optionally substituted C4-C8 heterocyclic group, or an optionally substituted C4-C8 heteroaryl group. R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 R d10 R d11 and R d12 If present, it is independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, optionally naphthyl, optionally 3- to 8-membered heterocyclic and optionally substituted 5- to 8-membered heteroaryl, optionally wherein R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 R d10 R d11 and R d12 If any two of them are present, they can combine to form an alkylene or heteroalkylene group with 2 to 7 atoms that are optionally substituted (e.g., a spiro or fused bicyclic ring system). X 1 It is C(R) d3 (R) d4 ), O or NR f , where R f Selected from optionally substituted C1-C8 alkyl groups, optionally substituted C3-C8 cycloalkyl groups, optionally substituted C6-C... 10 Aryl, optionally substituted C3-C8 heterocyclic alkyl, optionally substituted C2-C8 heteroaryl, and optionally substituted C1-C8 acyl; and X 2 It is C(R) d5 (R) d6 ), O or NR f , where R f Selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 Aryl, optionally substituted C3-C8 heterocyclic alkyl, optionally substituted C2-C8 heteroaryl, and optionally substituted C1-C8 acyl.

10. The compound according to any one of claims 1-9, wherein NR a R b Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

11. The compound according to any one of claims 5-10, wherein... The radical group is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

12. The compound according to any one of claims 5-10, wherein R c5 It is an optionally substituted phenyl group.

13. The compound according to any one of claims 5-10 and 12, wherein R c1 R c2 R c3 and R c4 Each is hydrogen on its own.

14. The compound according to claim 5, wherein it is a compound of formula (VI): (WE).

15. The compound according to claim 14, wherein it is a compound of formula (VII): (VII)。 16. The compound according to any one of claims 1-15, wherein the compound is selected from: 3-([1,1'-biphenyl]-2-ylethynyl)-N-(4-methoxyphenyl)-1H-indazole-5-carboxamide, (S)-3-([1,1'-biphenyl]-2-ylethynyl)-N-(2-(dimethylamino)-2-oxo-1-phenylethyl)-1H-indazole-5-carboxamide, (R)-3-([1,1'-biphenyl]-2-ylethynyl)-N-(2-(dimethylamino)-2-oxo-1-phenylethyl)-1H-indazole-5-carboxamide, 3-([1,1'-biphenyl]-2-ylethynyl)-N-(2-(dimethylamino)-2-oxo-1-phenylethyl)-1H-indazole-5-carboxamide, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(pyrrolidine-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-hydroxypyrrolidine-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-hydroxypyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-hydroxypyrrolidine-1-yl)methyl ketone, 1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-one, 1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-N-methylpiperidine-4-carboxamide, (R)-1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-N-methylpiperidine-4-carboxamide, (S)-1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-N-methylpiperidine-4-carboxamide, 1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-N,N-dimethylpiperidine-4-carboxamide, (R)-1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-N,N-dimethylpiperidine-4-carboxamide, (S)-1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-N,N-dimethylpiperidine-4-carboxamide, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,5-diazabicyclo[2.2.2]octane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3,8-diazabicyclo[3.2.1]octane-3-yl) methyl ketone, 4-(2-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-2,6-diazaspiro[3.5]nonane-6-carbonyl)-N-methylcyclohexane-1-carboxamide, (R)-4-(2-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-2,6-diazaspiro[3.5]nonane-6-carbonyl)-N-methylcyclohexane-1-carboxamide, (S)-4-(2-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-2,6-diazaspiro[3.5]nonane-6-carbonyl)-N-methylcyclohexane-1-carboxamide, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (3-(phenylethynyl)-1H-indazol-5-yl)(pyrrolid-1-yl)methyl ketone, 3-([1,1'-biphenyl]-2-ylethynyl)-N-(2-(dimethylamino)ethyl)-N-methyl-1H-indazole-5-carboxamide, 3-([1,1'-biphenyl]-2-ylethynyl)-N-(2-(dimethylamino)ethyl)-1H-indazole-5-carboxamide, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)(3-(dimethylamino)pyrrolidine-1-yl) methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-(methylamino)pyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-(methylamino)pyrrolidone-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-(methylamino)pyrrolidone-1-yl)methyl ketone, 3-([1,1'-biphenyl]-2-ylethynyl)-N,N-dimethyl-1H-indazole-5-carboxamide, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-(phenylethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-(phenylethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-(phenylethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-((2,6-dichlorophenyl)ethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (S)-(3-((2,6-dichlorophenyl)ethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (3-((2,6-dichlorophenyl)ethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (R)-(3-((2-chlorophenyl)ethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (S)-(3-((2-chlorophenyl)ethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (3-((2-chlorophenyl)ethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-fluorophenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-fluorophenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-((2-fluorophenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-morpholinylphenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-morpholinylphenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-((2-morpholinylphenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-3-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-3-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, ((3-([1,1'-biphenyl]-3-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-4-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-4-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (3-([1,1'-biphenyl]-4-ylethynyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidine-1-yl)methyl ketone, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-(isoquinoline-5-ylethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-(isoquinoline-5-ylethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-(isoquinoline-5-ylethynyl)-1H-indazol-5-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(piperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3,6-diazabicyclo[3.1.1]heptane-3-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,5-diazabicyclo[2.2.2]octane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3,8-diazabicyclo[3.2.1]octane-3-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(8-oxa-3-azabicyclo[3.2.1]octane-3-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-phenylpiperazin-1-yl)methyl ketone, (R)-3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-phenylpiperazin-1-yl)methyl ketone, (S)-3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-phenylpiperazin-1-yl)methyl ketone, 4-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)piperazin-2-one, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-aminopyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-aminopyrrolidine-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-aminopyrrolidine-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(1,4-diazacycloheptane-1-yl)methyl ketone (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(4,7-diazaspiro[2.5]octane-4-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(4,7-diazaspiro[2.5]octane-7-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(5,8-diazaspiro[3.5]nonane-8-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-methyl-2,7-diazaspiro[3.5]nonane-7-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl) methyl ketone, (7-Methyl-2,7-diazaspiro[3.5]nonane-2-yl)(3-((2-(pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-4-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(5-methyl-2,7-diazaspiro[3.5]nonane-2-yl) methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(5-methyl-2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(5-methyl-2,7-diazaspiro[3.5]nonane-2-yl) methyl ketone, (S)-4-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-3-phenylpiperazin-2-one, (R)-4-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-3-phenylpiperazin-2-one, 4-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-3-phenylpiperazin-2-one, 7-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-2,7-diazaspiro[3.5]nonane-1-one, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,8-diazaspiro[4.5]decane-2-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-6-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl) methyl ketone, (2,8-diazaspiro[4.5]decane-2-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(5,8-diazaspiro[3.5]nonane-5-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(6,9-diazaspiro[4.5]decane-6-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-phenylpiperazin-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-phenylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-phenylpiperazin-1-yl)methyl ketone, (S)-(2-phenylpiperazin-1-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(2-phenylpiperazin-1-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (2-Phenylopirabin-1-yl)(3-((2-(trifluoromethoxy)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-(4-chlorophenyl)piperazin-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-(4-chlorophenyl)piperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-(4-chlorophenyl)piperazin-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-phenylpiperazin-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-phenylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-phenylpiperazin-1-yl)methyl ketone, (S)-(2-phenylpiperazin-1-yl)(3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(2-phenylpiperazin-1-yl)(3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (2-Phenylopirabin-1-yl)(3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-benzylpiperazin-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-benzylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-benzylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)((2S,6S)-2,6-dimethylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)((2R,6S)-2,6-dimethylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)((2R,6R)-2,6-dimethylpiperazin-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-benzylpiperazin-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-benzylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-benzylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-isopropylpiperazin-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-isopropylpiperazin-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-isopropylpiperazin-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,9-diazaspiro[5.5]undecane-2-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[4.5]decane-2-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,7-diazaspiro[4.5]decane-2-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(1,8-diazaspiro[4.5]decane-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(8-oxa-1-azaspiro[4.5]decane-1-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,8-diazaspiro[4.5]decane-8-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-oxa-6-azaspiro[3.4]octane-6-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(8-oxa-2-azaspiro[4.5]decane-2-yl) methyl ketone, 3-([1,1'-biphenyl]-2-ylethynyl)-N-(7-azaspiro[3.5]nonane-2-yl)-1H-indazole-5-carboxamide, (3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(6-methyl-2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(5-methyl-2,5-diazaspiro[3,5]nonane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(5-methyl-2,5-diazaspiro[3,5]nonane-2-yl) methyl ketone, (3-((2-(pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2-methyl-2,5-diazaspiro[3,5]nonane-5-yl) methyl ketone, (3-((2-(pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((4-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (R)-2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methylbenzamide, (S)-2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methylbenzamide, 2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methylbenzamide, (R)-N-(2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)phenyl)acetamide, (S)-N-(2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)phenyl)acetamide, N-(2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)phenyl)acetamide, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((3'-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(2,5-diazaspiro[3.5]nonane-2-yl)methyl ketone, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((2'-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-((2-(naphthyl-2-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methyl-[1,1'-biphenyl]-2-carboxamide, 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methyl-[1,1'-biphenyl]-3-carboxamide, N-(2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-[1,1'-biphenyl]-2-yl)acetamide, 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide, (3-((2-(6-amino-4-methylpyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)(7-oxa-2-azaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(2-aminopyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((3'-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (2,6-diazaspiro[3.5]nonane-2-yl)(3-((2'-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-((2-(2-aminopyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(2-(pyrrolidin-1-yl)pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(2-(piperazin-1-yl)pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(2-aminopyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (R)-2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)-N-phenylbenzamide, (S)-2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)-N-phenylbenzamide, 2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)-N-phenylbenzamide, (3-((2-(2-aminopyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(6-amino-4-methylpyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (R)-7-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)indololin-2-one, (S)-7-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)indololin-2-one, 7-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazol-3-yl)ethynyl)indoline-2-one, (3-((2-(2-(pyrrolidin-1-yl)pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-(2-(piperazin-1-yl)pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (R)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(4-methylpiperazin-1-carbonyl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (S)-(3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(4-methylpiperazin-1-carbonyl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, (3-(dimethylamino)pyrrolidone-1-yl)(3-((2-(4-methylpiperazin-1-carbonyl)phenyl)ethynyl)-1H-indazol-5-yl)methyl ketone, N-(2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-[1,1'-biphenyl]-2-yl)acetamide, 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methyl-[1,1'-biphenyl]-3-carboxamide, 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide, (3-((2-(2-(4-methylpiperazin-1-yl)pyridin-3-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (S)-1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-N-methylpyrrolidine-2-carboxamide, (R)-1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-N-methylpyrrolidine-2-carboxamide, 1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)-N-methylpyrrolidine-2-carboxamide, N-(2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-[1,1'-biphenyl]-2-yl)neopentamide, 5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazole-3-nitrile, (R)-5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazole-3-nitrile, (S)-5-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-indazole-3-nitrile, (3-([1,1'-biphenyl]-2-yl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl) methyl ketone, (R)-(3-([1,1'-biphenyl]-2-yl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-yl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylmethyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl) ketone, (R)-(3-([1,1'-biphenyl]-2-ylmethyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylmethyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (E)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (R,E)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (S,E)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (Z)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (R,Z)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (S,Z)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone, (3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(7-oxa-2-azaspiro[3.5]nonane-2-yl)methyl ketone, (E)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(7-oxa-2-azaspiro[3.5]nonane-2-yl)methyl ketone, (Z)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(7-oxa-2-azaspiro[3.5]nonane-2-yl)methyl ketone, (3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl) methyl ketone, (E)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl) methyl ketone, (Z)-(3-(2-([1,1'-biphenyl]-2-yl)vinyl)-1H-indazol-5-yl)(7-methyl-2,7-diazaspiro[3.5]nonane-2-yl)methyl ketone, 1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-3-phenylurea, (R)-1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-3-phenylurea, (S)-1-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-3-phenylurea, 3-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-3,4-quinazolin-2(1H)-one, (R)-3-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-carbonyl)pyrrolidine-3-yl)-3,4-quinazolin-2(1H)-one, (S)-3-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-carbonyl)pyrrolidine-3-yl)-3,4-quinazolin-2(1H)-one, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-((4,6-dimethylpyrimidin-2-yl)amino)pyrrolidine-1-yl)methyl ketone, (R)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-((4,6-dimethylpyrimidin-2-yl)amino)pyrrolidine-1-yl)methyl ketone, (S)-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(3-((4,6-dimethylpyrimidin-2-yl)amino)pyrrolidine-1-yl)methyl ketone, N-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-2,3-dihydrobenzo[b][1,4]di Indo-6-formamide, (R)-N-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-2,3-dihydrobenzo[b][1,4]di Indo-6-formamide, (S)-N-(1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)-2,3-dihydrobenzo[b][1,4]di Indo-6-formamide, N-(2-((1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)benzamide, (R)-N-(2-((1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)benzamide, (S)-N-(2-((1-(3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazole-5-carbonyl)pyrrolidine-3-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)benzamide, (3-([1,1'-biphenyl]-3-yl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-4-yl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone, (3-((2'-morpholino-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, 7-(2-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)phenyl)isoindoline-1-one, 2'-((5-(2,6-diazaspiro[3.5]nonane-2-carbonyl)-1H-indazol-3-yl)ethynyl)-N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide, (3-((2'-(pyrrolidone-1-ylmethyl)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2'-(morpholinylmethyl)-[1,1'-biphenyl]-2-yl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(6-(vinylsulfonyl)-2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-indazol-5-yl)(6-(ethylsulfonyl)-2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone, (3-([1,1'-biphenyl]-2-ylethynyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone, (3-((2-(pyridin-4-yl)phenyl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((2-phenylpyridin-3-yl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((3-phenylpyridin-4-yl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl)methyl ketone, (3-((4-phenylpyridin-3-yl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone, and (3-((3-phenylpyridin-2-yl)ethynyl)-1H-indazol-5-yl)(2,6-diazaspiro[3.5]nonane-2-yl) methyl ketone.

17. A compound selected from Table A, or its salts, solvates, stereoisomers, tautomers or geometric isomers.

18. A pharmaceutical composition comprising a compound according to any one of claims 1-17 and a pharmaceutically acceptable carrier.

19. A method for sterilizing a male object, the method comprising administering to the male object a therapeutically effective amount of at least one compound according to any one of claims 1-17 and / or a pharmaceutical composition according to claim 18, optionally wherein the sterilization is temporary.

20. A method for promoting male contraception and / or infertility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of at least one compound according to any one of claims 1-17 and / or a pharmaceutical composition according to claim 18, optionally wherein the infertility is temporary.

21. A method for minimizing and / or reducing sperm count and / or motility in a male subject, the method comprising administering to the male subject a therapeutically effective amount of at least one compound according to any one of claims 1-17 and / or a pharmaceutical composition according to claim 18.

22. The method according to any one of claims 19-21, wherein the compound provides a contraceptive effect in the male subject.

23. The method according to any one of claims 19-22, wherein the compound is administered orally to the male subject.

24. A method for inhibiting RET in a mammal, the method comprising administering to the mammal an effective amount of at least one compound according to any one of claims 1-16 and / or a pharmaceutical composition according to claim 18.

25. A method for treating, improving, and / or preventing diseases or disorders caused by RET overexpression or high RET activity, the method comprising administering to the mammal a therapeutically effective amount of at least one compound according to any one of claims 1-17 and / or a pharmaceutical composition according to claim 18.

26. The method of claim 25, wherein the disease or disorder includes RET-mediated cancer.

27. The method of claim 26, wherein the RET-mediated cancer includes medullary thyroid carcinoma, non-small cell lung cancer, and / or multiple endocrine neoplasia type 2A (MEN2A).

28. The method of claim 25, wherein the disease or disorder includes Herschprom disease, central hypoventilation syndrome and / or renal agenesis.

29. A method for inhibiting at least one of CL1, CLK2, CLK3 and CLK4 in a mammal, the method comprising administering to the mammal an effective amount of at least one compound according to any one of claims 1-17 and / or a pharmaceutical composition according to claim 18.

30. A method for treating, improving, and / or preventing diseases or disorders caused by CLK overexpression or CLK hyperactivity, the method comprising administering to the mammal a therapeutically effective amount of at least one compound according to any one of claims 1-17 and / or a pharmaceutical composition according to claim 18.

31. The method of claim 30, wherein the disease or disorder includes Duchenne muscular dystrophy, Alzheimer's disease, HIV-1, influenza virus, and kidney cancer, breast cancer, and / or melanoma.

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