Deuterated hedgehog pathway SMO receptor inhibitor

Abstract

The present invention relates to a deuterated Hedgehog pathway SMO receptor inhibitor, particularly to a deuterated 4-fluoro-N-methyl-N-[1-[4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl] piperidin-4-yl]-2-(trifluoromethyl)benzamide compound, a pharmaceutical composition containing the compound and the use of the compound in the treatment of diseases, particularly cancer and idiopathic pulmonary fibrosis, which can be treated or prevented by means of inhibiting SMO.

Description

Deuterated hedgehog pathway smo receptor inhibitors Field of the invention

[0001] The present invention relates to a deuterated Hedgehog pathway SMO receptor inhibitor, in particular to a deuterated 4-fluoro-N-methyl-N-[1-[4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl]piperidin-4-yl]-2-(trifluoromethyl)benzamide compound, pharmaceutical compositions comprising said compound and the use of said compound in the treatment of diseases which can be treated or prevented by inhibition of SMO, in particular cancer and idiopathic pulmonary fibrosis. BACKGROUND

[0002] The Hedgehog (HH) signaling pathway is a conserved pathway involved in cell growth and tissue patterning. It is responsible for regulating tissue homeostasis and stem cell behavior, in adult tissues; its abnormal signaling can be found in cancers such as skin cancer, brain cancer, liver cancer, prostate cancer, breast cancer, etc. and malignant hematopathy, involved in regulating cell growth, migration, invasion.

[0003] The signal transduction of HH pathway is mainly completed by three proteins - the secreted protein HH, the HH receptor Patched1 (PTCH1) and the G protein-coupled receptor Smoothened (SM).

[0004] The HH signaling pathway includes typical and atypical pathways. The typical HH pathway acts through the main HH molecules such as HH ligand, PTCH, SMO and GLI proteins, while the atypical HH pathway involves the activation of SMO or GLI through other pathways.

[0005] In the atypical HH signaling pathway, SMO can be activated by Rho, Rac, Src and PI3K / phospholipase C gamma (PLC gamma), as well as calcium and other secondary messengers, allowing target gene expression. SMO is a G protein-coupled receptor (GPCR) with a structure including an N-terminal cysteine-rich domain (CRD), an extracellular loop, 7 transmembrane domains and an intracellular C-terminal, with 3 phosphorylation sites for PKA at the C-terminal of SMO. PI3K can activate the signaling pathway by AKT, mTOR, turning on gene expression. At the same time, PI3K can interact with RhoA and Rac to affect the cytoskeleton. PLC gamma can act on Ca 2+ fluctuations. Therefore, the atypical HH signaling pathway can regulate the cytoskeleton, cell migration, angiogenesis and Ca 2+ oscillations.

[0006] SMO expression is related to tumor size, invasiveness, metastasis and recurrence, and is an important target for cancer treatment. SMO inhibitors can inhibit cancer formation, reduce cancer cell proliferation, trigger apoptosis and inhibit cancer stem cell activity.

[0007] Idiopathic pulmonary fibrosis (IPF) is currently considered a chronic, progressive and irreversible disease. Its characteristics are the transformation of pathogenic fibroblasts into myofibroblasts, the increased plasticity of alveolar epithelial cells, the aggregation of fibroblasts, the cell-matrix interaction and the activation of the immune system in the alveolar wall (Bagnato, G, et al. Cellular interactions in the pathogenesis of interstitial lung diseases. Eur. Respir. Rev. 2015, 24, 102-114). The global incidence and prevalence of IPF is reported to be about 0.09-1.30 and 0.33-4.51 (per 10,000 people), but according to epidemiological estimates, IPF is still a rare disease (Toby M. Maher, et al. Global incidence and prevalence of idiopathic pulmonary fibrosis. Respir Res. 2021 Jul 7;22(1):197).

[0008] The pathogenesis of IPF is still unclear. Early studies suggest that persistent chronic inflammation in the lungs remodels lung tissue cells, leading to fibrosis; but recent studies have found that fibrosis can occur in the lungs without inflammation; therefore, current studies suggest that any abnormality in signaling pathways involved in inflammation or wound repair can induce IPF.

[0009] With the in-depth research on fibrosis, the importance of Sonic Hedgehog (Shh) signaling pathway in the pathogenesis of IPF has been gradually explored by researchers. Shh pathway plays a very important role in the development of individual embryos and after birth (Galperin I, et al. Inhibiting hedgehog: an update on pharmacological compounds and targeting strategies. J Med Chem. 2019; 62: 8392-8411). The entire signaling pathway is mainly composed of Shh ligand, 12 transmembrane receptor PTCH1, seven transmembrane G protein-coupled receptor SMO, fusion inhibitor (SUFU) and zinc finger transcription regulator GLIs (GLI1-3). The activation of Shh pathway begins with the binding of Shh ligand to PTCH1, further activating downstream SMO, thereby inhibiting SUFU activity, releasing GLI protein to initiate downstream gene transcription. Although Shh pathway plays an important role in individual development, Shh pathway is usually inhibited in adult individuals, only maintaining stem cell proliferation and wound repair (Bagnato, G, et al., supra).

[0010] Reactivation and deregulation of the Shh pathway and its interaction with tumor growth factor beta (TGF-b) induce myofibroblast differentiation, epithelial mesenchymal transition (EMT), and excessive secretion of extracellular matrix (ECM) play an important role in the pathogenesis of IPF (Selman, M, et al. Age-driven developmental drift in the pathogenesis of idiopathic pulmonary fibrosis. Eur. Respir. J. 2016, 48, 538-552). Abnormal activation of Shh signaling leads to the formation of various tumors such as pancreatic cancer, medulloblastoma, basal cell carcinoma, small cell lung cancer, and prostate cancer. In addition, it has been reported that inhibition of the Shh pathway by upregulating SUFU protein can prevent pulmonary fibrosis in a mouse IPF model and a significant increase in Shh pathway-related proteins was observed in patient lung tissue (Tan, S, et al. Mechanism of Tripchlorolide Inhibiting Hedgehog Signaling Pathway to Delay Lung Fibrosis. J. Biomater. Tissue Eng. 2020, 10, 992-998; and Jia, G, et al. CXCL14 is a candidate biomarker for Hedgehog signalling in idiopathic pulmonary fibrosis. Thorax 2017, 72, 780-787). All the above results suggest that the Shh pathway is closely related to the occurrence and development of IPF, and it can be an excellent object for IPF drug development.

[0011] Current inhibitors developed for Shh pathway involve SMO and GLI1 targets, but most of them are focused on cancer-related indications. For example, SMO inhibitors for treating cancer are disclosed in WO2009002469A1 (Amgen Inc) and WO2023108140A1 (Endeavor Biomedicines, Inc). The SMO inhibitor Vismodegib for basal cell carcinoma marketed by Roche was terminated due to safety in IPF clinical Ib (Prasse, A, et al. A Phase 1b Study of Vismodegib with Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis. Pulm. Ther. 2019, 5, 151-163), but the SMO inhibitor Taladegib developed by Endeavor has achieved good therapeutic effect in clinical Ib test, and according to its clinical data, SMO inhibitors are likely to play a role in reversing fibrosis, which is unmatched by the currently marketed drugs for IPF, nintedanib and pirfenidone.

[0012] Taladegib (CAS: 1258861-20-9) has the structure shown in the following formula:

[0013] Therefore, more and more attention has been paid to the development of inhibitors for Shh pathway for the treatment of IPF. For example, SMO receptor inhibitor compounds for treating fibrotic diseases are disclosed in WO2018082587A1 (Shanghai Yingpai Pharmaceutical Co., Ltd.).

[0014] There is still a need to develop new SMO receptor inhibitors with better SMO receptor inhibitor activity and / or better metabolic properties. SUMMARY

[0015] The present application provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer and solvate thereof,

[0016] wherein:

[0017] R1and R2are independently selected from CH3and CD3;

[0018] R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 and R 12 are independently selected from H and deuterium;

[0019] provided that when R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , and R 12 are each H, R1and R2are not both CH3.

[0020] In one embodiment, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, and solvate thereof, wherein R1is CD3.

[0021] In one embodiment, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, and solvate thereof, wherein R2is CD3.

[0022] In one embodiment, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, and solvate thereof, wherein R1and R2are each CD3.

[0023] In one embodiment, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, and solvate thereof, wherein R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , and R 12 are each H.

[0024] In one embodiment, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, and solvate thereof, wherein at least one of R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , and R 12 is deuterium. In one embodiment, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, and solvate thereof, wherein two or more of R3, R4, R5, R6, R7, R8, R9, and R 10 are deuterium.

[0025] In one embodiment, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, and solvate thereof, wherein at least one of R 11 and R 12 is deuterium.

[0026] In one embodiment, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, and solvate thereof, wherein R1and R2are each CD3.

[0027] or a pharmaceutically acceptable salt, stereoisomer, and solvate thereof.

[0028] In one embodiment, the stereoisomer is a atropisomer, including individual atropisomers and mixtures of any ratio of each individual atropisomer.

[0029] In one embodiment, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer and solvate thereof, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

[0030] In one embodiment, the present application provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and solvate thereof of the present application and a pharmaceutically acceptable carrier and excipient.

[0031] In one embodiment, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and solvate thereof of the present application in the manufacture of a medicament for the treatment of a disease which can be treated or prevented by the inhibition of SMO.

[0032] In one embodiment, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and solvate thereof of the present application in the manufacture of a medicament for the treatment or prevention of cancer in a subject in need thereof.

[0033] In one embodiment, the cancer is selected from brain cancer, basal cell carcinoma, esophageal cancer, gastric cancer, pancreatic cancer, biliary tract cancer, prostate cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, B-cell lymphoma, multiple myeloma, ovarian cancer, colorectal cancer, liver cancer, renal cancer, melanoma, head and neck cancer, mesothelioma, soft tissue sarcoma, osteosarcoma, leukemia and testicular cancer.

[0034] In one embodiment, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and solvate thereof of the present application in the manufacture of a medicament for the treatment or prevention of a fibrotic disease, in particular idiopathic pulmonary fibrosis, in a subject in need thereof.

[0035] Advantages of the invention

[0036] Many drugs suffer from poor absorption, distribution, metabolism, and / or excretion (ADME) properties, which hinder their widespread use or limit their use in certain indications. Poor ADME properties are also a major cause of failure of drug candidates in clinical trials. While formulation techniques and prodrug strategies can be used in some cases to improve certain ADME properties, these approaches often do not address the underlying ADME problems that many drugs and drug candidates suffer from. One such problem is rapid metabolism, which causes many drugs that could otherwise be highly effective in treating diseases to be rapidly cleared from the body. A possible solution to rapid drug clearance is to dose frequently or in large amounts to achieve sufficiently high drug plasma levels. However, this introduces many potential therapeutic problems, such as poor patient compliance with the dosing regimen, more acute side effects at higher doses, and increased cost of treatment. Drugs that are rapidly metabolized can also expose patients to undesirable toxic or reactive metabolites.

[0037] One strategy that has potential appeal for improving drug metabolic properties is deuterium modification. In this approach, one attempts to slow CYP-mediated drug metabolism or reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms a stronger bond with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, leading to the potential for improved drug efficacy, safety, and / or tolerability. At the same time, because the size and shape of deuterium are essentially the same as those of hydrogen, replacing hydrogen with deuterium is not expected to affect the biochemical potency and selectivity of a drug compared to the original chemical entity containing only hydrogen.

[0038] However, the impact of deuterium modification on drug metabolic properties is not predictable, even in cases where the deuterium atoms are incorporated at known sites of metabolism. One can only determine whether and how the rate of metabolism changes relative to the non-deuterated form of the drug by actually making and testing the deuterated drug. (See, e.g., Fukuto et al., J. Med. Chem., 1991, 34, 2871-76).

[0039] It has been reported in the literature that the results of numerous studies to determine the effect of deuterium substitution on overall metabolic stability are variable and unpredictable. For some compounds, deuteration results in a decrease in the rate of metabolic clearance in vivo. For other compounds, there is no change in metabolism. Still other compounds exhibit an increase in the rate of metabolic clearance. The variability of deuterium isotope effects has also led technologists to question or abandon deuterium modification as a viable drug design strategy to inhibit unfavorable metabolism (see, e.g., Foster, AB, Adv. Drug Res., 1985, 14: 1-40; Fisher, MB, et al., Curr. Opin. Drug Discov. Devel., 2006, 9: 101-09).

[0040] The compound of formula (I) of the present application is deuterated form of 4-fluoro-N-methyl-N-[1-[4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl]piperidin-4-yl]-2- (trifluoromethyl)benzamide (i.e., Taladegib). As demonstrated by the biological tests of the present application, the compound of the present application has good SMO receptor inhibitory activity, and the compound of the present application has more favorable pharmacokinetic properties, including significantly improved metabolic stability and / or pharmacokinetic properties, compared to the non-deuterated form of the compound Taladegib.

[0041] Definitions

[0042] Herein, "D" and "d" both refer to deuterium. For example, "CD3" refers to a deuterated methyl group.

[0043] In the compounds of the present application, any atom not specifically designated as a particular isotope is meant to denote any stable isotope of that atom. Unless otherwise indicated, when a position is designated specifically as "H" or "hydrogen," that position is to be understood to have hydrogen in its natural abundance isotope composition. Likewise, unless otherwise indicated, when a position is designated specifically as "D" or "deuterium," that position is to be understood to have deuterium in an abundance of at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). For example, the compounds of the present application have an isotopic enrichment factor of at least 3500 for each designated deuterium atom (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0044] The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance of a particular isotope and the natural abundance.

[0045] It will be recognized that depending on the source of the chemical materials used in the synthesis, there are some variations in the natural isotopic abundance in the synthesized compounds. Thus, the compound Taladegib will inherently contain small amounts of isotopologues that are deuterated. Despite this variation, the concentration of stable hydrogen isotopes of natural abundance is very low and insignificant compared to the degree of stable isotope substitution of the compounds of the present application (see, e.g., Wada, E, et al., Seikagaku, 1994, 66: 15; Gannes, LZ, et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119: 725).

[0046] Likewise, it will be apparent to those skilled in the art that a compound of the present application represented by a particular chemical structure containing designated deuterium atoms also contains minor amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions of the structure. The relative amounts of such isotopologues in a compound of the present application will depend on a variety of factors, including the isotopic purity of the deuterated reagents used to make the compound and the efficiency of deuterium incorporation in each of the synthetic steps used to prepare the compound. However, as noted above, the overall relative amount of such isotopologues will be less than 49.9% of the compound. In other embodiments, the overall relative amount of such isotopologues will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0047] The term "isotopologue" as used herein refers to a substance in which the chemical structure differs from a particular compound of the present application only in its isotopic composition.

[0048] It will be apparent to those skilled in the art that a compound of the present application can contain one or more chiral centers and thus exist in two or more stereoisomers, due to, for example, deuterium substitution or other reasons (e.g., hindered rotation of a chemical bond, such as an amide bond in a compound of the present application, due to steric effects). The phenomenon of stereochemical isomerism due to hindered rotation of a chemical bond is known as "atropisomerism" and the resulting resolvable enantiomeric isomers are known as "atropisomers". It will be understood by those skilled in the art that the present application includes all individual stereoisomers (e.g., enantiomers, including atropisomers) of compounds of Formula (I), a racemic mixture or any mixture thereof in any proportion.

[0049] Thus, the compounds of the present application can exist as individual enantiomers or as mixtures of enantiomers. In addition, the compounds of the present application can also exist as racemic mixtures or as non-racemic mixtures, or as the corresponding individual stereoisomers substantially free of other possible stereoisomers. The term "substantially free of other stereoisomers" as used herein means that less than 25% of the other stereoisomers are present, preferably less than 10% of the other stereoisomers are present, more preferably less than 5% of the other stereoisomers are present, and most preferably less than 2% of the other stereoisomers are present.

[0050] The term "pharmaceutically acceptable" as used herein means within the scope of sound medical judgment a component that is suitable for use in contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response, and the like, and commensurate with a reasonable benefit / risk ratio.

[0051] The term "pharmaceutically acceptable salt" as used herein means a salt of a compound of formula (I) of the present application that is non-toxic, biologically tolerable, and otherwise suitable for administration to individuals in need of treatment or prevention of the diseases described herein. For example, the pharmaceutically acceptable salt is an acid addition salt including, for example, salts derived from inorganic and organic acids such as hydrochloride.

[0052] The term "solvate" as used herein means a solvent addition form of a compound that is a stoichiometric or non-stoichiometric complex. Some compounds have a propensity for the inclusion of solvent molecules in their solid state, for example, as hydrates, alcoholates, and the like.

[0053] The term "treatment" as used herein means reducing, inhibiting, alleviating, abrogating, or stabilizing the development or progression of a disease (e.g., a disease outlined herein such as idiopathic pulmonary fibrosis), reducing the severity of the disease, or ameliorating symptoms associated with the disease.

[0054] The term "individual" as used herein includes, but is not limited to, humans; non-human primates, such as chimpanzees and other apes and monkey species; farm animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In some embodiments, the individual is a human.

[0055] Pharmaceutical compositions and uses

[0056] The compounds of the present application are useful as inhibitors of SMO. In some embodiments, the compounds of the present application can be used to treat diseases that can be treated or prevented by inhibiting SMO, for example, cancer, fibrotic diseases, particularly idiopathic pulmonary fibrosis.

[0057] The compounds of the present application (e.g., any of the example compounds herein) can be formulated into pharmaceutical compositions either alone or in combination with one or more additional therapeutic agents, which include an effective amount of a compound of the present application, a pharmaceutically acceptable carrier and / or excipient; and, optionally, one or more additional therapeutic agents.

[0058] Pharmaceutical compositions comprising a compound of the present application can be administered in a variety of known ways, e.g., orally, topically, rectally, parenterally, by inhalation, or by implantation. The term "parenterally" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion.

[0059] The pharmaceutical compositions described herein can be prepared in the form of tablets, capsules, sachets, dragees, powders, granules, pastilles, suppositories, liquid formulations, or stacks. In some embodiments, the pharmaceutical compositions comprising a compound of the present application can be formulated for intravenous infusion, topical administration, or oral administration.

[0060] In the pharmaceutical compositions of the present application, the compounds of the present application are present in an effective amount. The term "effective amount" as used herein means an amount that is generally sufficient to treat or prevent the targeted disorder, e.g., cancer or a fibrotic disease, particularly idiopathic pulmonary fibrosis. The effective amount or dosage of the active ingredients in the present application can be determined by routine methods, such as modeling, dose escalation studies or clinical trials, in conjunction with routine factors, such as the mode or route of administration, the pharmacokinetics of the pharmaceutical ingredients, the severity and course of the disease or disorder, the subject's previous or ongoing therapy, the subject's health status and response to the drugs, and the judgment of the treating physician. Examples

[0061] To further illustrate the present application, the compounds of the present application, their preparation and use are exemplified in detail below in conjunction with the examples. It is to be understood that the examples below are illustrative of the present application and are not meant to limit the application in any way. The data given (e.g., amounts, temperatures, etc.) are intended to be examples and the artisan will appreciate that there can be some experimental error and variation. Unless otherwise indicated, all temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure.

[0062] In any of the structural formulae in this application, if there is a spare valence on any atom, the spare valence is actually a hydrogen atom that is not specifically depicted for simplicity.

[0063] In this application, where reference is made to a compound by name and structural formula, the reference is to the compound having the structural formula, unless the context indicates otherwise, even if the name of the compound is incorrect.

[0064] The following abbreviations or terms have the indicated meanings: HATU means N,N,N',N'-tetramethyl-0-(7-azabenzotriazol-l-yl)urea hexafluorophosphate; DIPEA means N,N-diisopropylethylamine; DCM means dichloromethane; MeCN means acetonitrile; THF means tetrahydrofuran; NMP means N-methylpyrrolidinone; DMAc means N,N-dimethylacetamide; n-BuLi means butyllithium; Pd(PPh3)4 means tetrakis(triphenylphosphine)palladium; Tol. means toluene; EtOH means ethanol; TLC means thin layer chromatography.

[0065] Preparation Example 1: Preparation of N-(l-(4-chlorophthalazin-l-yl)piperidin-4-yl)-4-fluoro-N-methyl-2-(trifluoromethyl)benzamide

[0066] Step 1: Preparation of tert-butyl 4-(4-fluoro-N-methyl-2-(trifluoromethyl)benzamido)piperidine-l-carboxylate

[0067] To a solution of 4-fluoro-2-(trifluoromethyl)benzoic acid (2.0 g), N,N,N',N'-tetramethyl-0-(7-azabenzotriazol-l-yl)urea hexafluorophosphate (4.38 g) and N,N-diisopropylethylamine (2.48 g) in dichloromethane (20 mL) was stirred at room temperature for 0.5 h. Then tert-butyl 4-(methylamino)piperidine-l-carboxylate (2.47 g) was added and the reaction was continued for 1 h. LCMS showed the starting material was consumed completely. The reaction mixture was washed with water (15 mL) for three times and saturated sodium chloride solution for once. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give the title compound 3.8 g.

[0068] MS (ESI) m / z (M+H) + = 405.1.

[0069] Step 2: Preparation of 4-fluoro-N-methyl-N-(piperidin-4-yl)-2-(trifluoromethyl)benzamide hydrochloride

[0070] Dissolve 4-(4-fluoro-N-methyl-2-(trifluoromethyl)benzamido)piperidine- 1 -carboxylic acid tert-butyl ester (3.8 g) in dichloromethane (10 mL), add hydrogen chloride / dioxane (4 M, 30 mL) solution, and stir for 2 hours. LCMS shows the starting material is consumed. Concentrate the system, and a large amount of solid is formed. Filter to give the crude title compound 3.1 g.

[0071] MS (ESI) m / z (M+H) + = 305.1.

[0072] Step 3: Preparation of N-(l-(4-chlorophthalazin-l-yl)piperidin-4-yl)-4-fluoro-N- methyl-2-(trifluoromethyl)benzamide

[0073] Dissolve the crude 4-fluoro-N-methyl-N-(piperidin-4-yl)-2- (trifluoromethyl)benzamide hydrochloride (3.1 g) from the previous step, 1,4- dichlorophthalazine (1.99 g), and potassium carbonate (3.77 g) in anhydrous acetonitrile (30 mL), and stir at 90 °C overnight. Stop the reaction, filter, collect the filtrate, and concentrate. Purify the crude product by column chromatography to give the title compound 3.5 g.

[0074] MS (ESI) m / z (M+H) + = 467.1.

[0075] Preparation Example 2: Preparation of N-(l-(4-chlorophthalazin-l-yl)piperidin-4-yl)-4-fluoro-N-(methyl-d3)-2-(trifluoromethyl)benzamide

[0076] Step 1: Preparation of tert-butyl (l-(4-chlorophthalazin-l-yl)piperidin-4- yl)carbamate

[0077] Dissolve 1,4-dichlorophthalazine (5.0 g), 4-tert-butoxycarbonylaminopiperidine (5.28 g), and potassium carbonate (6.93 g) in N-methylpyrrolidinone (80 mL) under nitrogen atmosphere, and stir at 80 °C for 4 hours. After the reaction is completed, add the system dropwise into water (400 mL). A large amount of solid is precipitated. Filter, wash the filter cake with water several times, collect the solid, and dry under reduced pressure to give the title compound 8.7 g.

[0078] MS (ESI) m / z (M+H) + = 363.1.

[0079] Step 2: Preparation of l-(4-chlorophthalazin-l-yl)piperidin-4-amine hydrochloride

[0080] Dissolve tert-butyl (1 -(4-chlorophthalazin-1 -yl)piperidin-4-yl)carbamate (5.0 g) in dichloromethane (50 mL), drop in hydrogen chloride / 1,4-dioxane solution (4.0 M, 14 mL), react at room temperature for 3 hours. After the reaction is completed, a large amount of solid is precipitated. Concentrate to remove the solvent, slurry with ethyl acetate (50 mL), suction filter, collect the solid, and dry under vacuum to obtain the crude product 4.7 g. Without purification, directly use in the next step.

[0081] MS (ESI) m / z (M+H) + = 263.1.

[0082] Step 3: Preparation of N-(1 -(4-chlorophthalazin-1 -yl)piperidin-4-yl)-4-fluoro-2- (trifluoromethyl)benzamide

[0083] Dissolve 4-fluoro-2-(trifluoromethyl)benzoic acid (3.0 g) in tetrahydrofuran (50 mL), add benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.75 g) and N,N-diisopropyl ethylamine (7.43 g), and react at room temperature for 0.5 hours. Add the crude product of 1 -(4-chlorophthalazin-1 -yl)piperidin-4-amine hydrochloride (4.7 g), and continue to react at room temperature for 1.5 hours. After the reaction is completed, quench the reaction by adding an appropriate amount of water, extract with ethyl acetate for 3 times, dry the combined organic phase over anhydrous sodium sulfate, filter, concentrate, slurry the crude product with ethyl acetate (30 mL), suction filter, collect the solid, and dry under vacuum to obtain the title compound 4.3 g.

[0084] MS (ESI) m / z (M+H) + = 453.1.

[0085] Step 4: Preparation of N-(1 -(4-chlorophthalazin-1 -yl)piperidin-4-yl)-4-fluoro-N- (methyl-d3)-2-(trifluoromethyl)benzamide

[0086] Under an atmosphere of nitrogen, dissolve N-(1 -(4-chlorophthalazin-1 -yl)piperidin-4- yl)-4-fluoro-2-(trifluoromethyl)benzamide (2.3 g) in N,N-dimethylacetamide (30 mL), and add sodium hydride (407 mg) in portions, and react for 10 minutes. Add deuterated methyl iodide (959 mg), and move to room temperature to react for 1.5 hours. After the reaction is completed, quench the system by dropwise adding water (300 mL) to quench the reaction, a large amount of solid is precipitated, suction filter to remove the solvent, wash the filter cake with water, dry the filter cake under vacuum, collect the solid, slurry with ethyl acetate (30 mL), suction filter to remove the solvent, and dry under vacuum to obtain the title compound 2.0 g.

[0087] MS (ESI) m / z (M+H) + = 470.1.

[0088] Preparation Example 3: Preparation of l-(methyl-d3)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole

[0089] Step 1: Preparation of l-(methyl-d3)-lH-pyrazole.

[0090] Under ice water bath condition, pyrazole (750 mg) was dissolved in tetrahydrofuran (8 mL), sodium hydride (528 mg) was added portionwise, the reaction was allowed to proceed for 10 minutes. Deuterated iodomethane (1.9 g) was added, the reaction was allowed to proceed for 1.5 hours at room temperature. LCMS showed the reaction was complete. The reaction was slowly added to saturated aqueous ammonium chloride solution (20 mL), the aqueous solution was extracted with ethyl acetate for three times, the organic phase was combined, washed with saturated sodium chloride solution once, dried over anhydrous sodium sulfate, filtered, concentrated to give 800 mg of crude product, which was used in the next step without purification. MS (ESI) m / z (M+H) + = 86.1.

[0091] Step 2: Preparation of l-(methyl-d3)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole

[0092] Under nitrogen atmosphere, l-(methyl-d3)-lH-pyrazole (800.0 mg) was dissolved in tetrahydrofuran (8 mL), butyllithium (2.5 M, 4.5 mL) was added slowly dropwise, the reaction was allowed to proceed for 30 minutes. Isopropyl alcohol pinacol borate (2.1 g) was added slowly dropwise, the reaction was allowed to proceed for 1.5 hours. LCMS showed the reaction was complete. The system was allowed to return to room temperature, saturated aqueous ammonium chloride solution (0.5 mL) was added to quench the reaction, water (30 mL) was added, ethyl acetate was used to extract twice, the aqueous phase was collected, diluted hydrochloric acid (2 M) was used to adjust the pH of the aqueous phase to about 2-4, ethyl acetate was used to extract three times, the organic phase was combined, washed with saturated sodium chloride solution once, dried over anhydrous sodium sulfate, filtered, concentrated to give 1.1 g of crude product, which was used in the next step without purification.

[0093] MS (ESI) m / z (M+H) + = 212.1.

[0094] Preparation Example 4: Preparation of N-(l-(4-chlorophthalazin-l-yl-5-d)piperidin-4-yl)-4- fluoro-N-methyl-2-(trifluoromethyl)benzamide

[0095] Step 1: Preparation of 5-bromo-2,3-dihydrophthalazine-1,4-dione

[0096] Dissolve 4-bromoisobenzo furan-1,3-dione (5 g) in acetic acid (50 mL), slowly drop hydrazine hydrate (2 mL) into the solution, react at 110 °C for 4 hours. LCMS shows no starting material left, product formed. Remove most of the acetic acid by rotary evaporation, add ethyl acetate (50 mL), stir for 0.5 hour, filter, collect the filter cake, wash with appropriate amount of ethyl acetate and petroleum ether, dry to get the title compound 4.5 g. MS (ESI) m / z (M+H) + = 240.9.

[0097] Step 2: Preparation of 5-bromo-1,4-dichlorophthalazine

[0098] Dissolve 5-bromo-2,3-dihydrophthalazine-1,4-dione (4.5 g) in phosphorus oxychloride (25 mL), react at 110 °C for 2 hours. LCMS shows no starting material left, product formed. Remove most of the solvent by rotary evaporation, slowly drop the remaining reaction solution into ice water, stir for 0.5 hour, filter, collect the filter cake, wash with water (50 mL), dry to get the crude title compound 4.0 g. It is used directly in the next step without purification.

[0099] MS (ESI) m / z (M+H) + = 276.8.

[0100] Step 3: Preparation of tert-butyl (1-(8-bromo-4-chlorophthalazin-1-yl)piperidin-4- yl)carbamate and tert-butyl (1-(5-bromo-4-chlorophthalazin-1-yl)piperidin-4-yl)carbamate

[0101] Dissolve the crude 5-bromo-1,4-dichlorophthalazine (4.0 g) obtained in step 2 in N- methylpyrrolidone (50 mL), add tert-butyl piperidin-4-ylcarbamate (3.5 g) and potassium carbonate (4.0 g), react at 80 °C for 4 hours. LCMS shows no starting material left, product formed. Cool the system to room temperature, add water (50 mL), extract with ethyl acetate (100 mL*3), wash the combined organic phase with saturated brine five times, dry over anhydrous sodium sulfate, filter, concentrate, purify the crude by column chromatography to get tert-butyl (1-(8-bromo-4-chlorophthalazin-1-yl)piperidin-4-yl)carbamate 2.0 g and tert-butyl (1-(5-bromo-4-chlorophthalazin-1-yl)piperidin-4-yl)carbamate 1.6 g.

[0102] MS (ESI) m / z (M+H) + = 441.0.

[0103] Step 4: Preparation of tert-butyl (l-(5-bromo-4-chlorophthalazin-l- yl)piperidin-4-yl)(methyl)carbamate

[0104] Under nitrogen atmosphere, tert-butyl (l-(5-bromo-4-chlorophthalazin-l- yl)piperidin-4-yl)carbamate (1.6 g) was dissolved in N,N-dimethylacetamide (30 mL), sodium hydride (218 mg) was added in portions, the reaction was allowed to proceed for 10 minutes. Iodomethane (761 mg) was added, the reaction was allowed to proceed for 1.5 hours at room temperature. After the reaction was completed, the reaction was quenched with water (50 mL), a large amount of solid was precipitated, the solvent was removed by suction filtration, the filter cake was collected, washed with water, and dried under vacuum. The solid was slurried with ethyl acetate (30 mL), the solvent was removed by suction filtration, and dried under vacuum to give the title compound 1.3 g.

[0105] MS (ESI) m / z (M+H) + = 455.0.

[0106] Step 5: Preparation of tert-butyl l-(4-chlorophthalazin-l-yl-5-d)piperidin-4- yl)(methyl)carbamate

[0107] Under nitrogen atmosphere, tert-butyl (l-(5-bromo-4-chlorophthalazin-l- yl)piperidin-4-yl)(methyl)carbamate (400 mg), palladium acetate (25.0 mg), potassium phosphate (382.0 mg), and n-butyl bis(l-adamantyl)phosphine (36.0 mg) were dissolved in toluene (5 mL) and deuterated methanol (2 mL), and the reaction was allowed to proceed for 6 hours at 80 °C. LCMS showed that the starting material was not left and the product was generated. The system was moved to room temperature, water (5 mL) was added, and ethyl acetate (15 mL*3) was extracted. The combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give the title compound 110 mg.

[0108] MS (ESI) m / z (M+H) + = 378.1.

[0109] Step 6: Preparation of l-(4-chlorophthalazin-l-yl-5-d)-N-methylpiperidin-4- amine hydrochloride

[0110] Tert-butyl l-(4-chlorophthalazin-l-yl-5-d)piperidin-4-yl)(methyl)carbamate (110 mg) was dissolved in a hydrochloric acid-1,4-dioxane (2 mL, 4N) solution, and the reaction was allowed to proceed for two hours at room temperature. LCMS showed that the starting material was not left and the product was generated. The reaction was concentrated under reduced pressure to give the crude product 130 mg.

[0111] MS (ESI) m / z (M+H) + = 278.1.

[0112] Step 7: Preparation of N-(l-(4-chlorophthalazin-l-yl-5-d)piperidin-4-yl)-4-fluoro-N- methyl-2-(trifluoromethyl)benzamide

[0113] Under ice water bath condition, 1-(4-chlorophthalazin-l-yl-5-d)-N-methylpiperidin-4-amine hydrochloride (130 mg) was dissolved in dichloromethane (2 mL), triethylamine (92.0 mg) was added, stirred for 5 minutes. 4-fluoro-2-(trifluoromethyl)benzoyl chloride (103 mg) was added slowly dropwise into the reaction system, moved to room temperature and stirred for 1 hour. LCMS showed that there was no remaining raw material and product was generated. Water (5 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 95 mg of the title compound.

[0114] MS (ESI) m / z (M+H) + = 468.1.

[0115] Preparation Example 5: Preparation of N-(l-(4-chlorophthalazin-l-yl-8-d)piperidin-4-yl)-4-fluoro-N-methyl-2-(trifluoromethyl)benzamide

[0116] Using the corresponding general commercially available reagents and the aforementioned preparation example intermediates as raw materials, using the similar preparation method as in Preparation Example 4, the title compound was prepared.

[0117] MS (ESI) m / z (M+H) + = 468.1.

[0118] Preparation Example 6: Preparation of l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-4-d

[0119] Step 1: Preparation of l-methyl-lH-pyrazol-4-d

[0120] To a solution of 4-bromo-l-methyl-lH-pyrazole (5 g) in tetrahydrofuran (50 mL) at -40 °C, isopropylmagnesium chloride-lithium chloride (37.5 mL, 1.3 M) was added slowly dropwise and stirred for one hour. Deuterated methanol (5 mL) was added and stirring was continued for 2 hours. LCMS showed no remaining starting material and product formation. The system was moved to room temperature, 50 mL saturated aqueous ammonium chloride and 50 mL water were added, and the mixture was extracted with ethyl acetate three times. The organic phase was combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude title compound 3.2 g. It was used directly in the next step without purification.

[0121] MS (ESI) m / z (M+H) + = 84.1.

[0122] The subsequent steps were prepared using the similar preparation method as described in Preparation Example 3, Step 2, starting from the corresponding commercially available reagents.

[0123] MS (ESI) m / z (M+H) + = 210.1.

[0124] Preparation Example 7: Preparation of l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-3-d

[0125] The title compound was prepared using the similar preparation method as described in Preparation Example 6, starting from the corresponding commercially available reagents.

[0126] MS (ESI) m / z (M+H) + = 210.1.

[0127] Preparation Example 8: Preparation of N-(l-(4-chlorophthalazin-l-yl)piperidin-4-yl-2,2-d2)-4-fluoro-N-methyl-2-(trifluoromethyl)benzamide

[0128] Step 1: Preparation of piperidin-2,2-d4-ol

[0129] In a nitrogen atmosphere, 4-hydroxypiperidin-2-one (5.0 g) was dissolved in tetrahydrofuran (80 mL), lithium aluminum deuteride (3.65 g) was added portionwise, and the reaction was allowed to proceed for 4 hours. The system was transferred to an ice water bath, and water (3.65 mL) was added dropwise, with a large amount of gas bubbling out. After stirring for 10 minutes, 15% sodium hydroxide (3.65 mL) was added, followed by water (11.0 mL). The system was stirred for 10 minutes, and anhydrous sodium sulfate was added to remove the water. The solid was removed by suction filtration, and the filter cake was washed with methanol several times. The filtrate was collected and concentrated under reduced pressure to give the crude product 3.7 g.

[0130] MS (ESI) m / z (M+H) + = 104.1.

[0131] Step 2: Preparation of 4-hydroxypiperidine-l-carboxylic acid benzyl ester-2,2-d2

[0132] The crude 4-hydroxypiperidine-l-carboxylic acid benzyl ester-2,2-d2 (1.64 g) was dissolved in 1,2-dichloroethane (20 mL), 4-dimethylaminopyridine (19 mg) and N,N-diisopropylethylamine (3.72 g) were added, and finally methylsulfonic anhydride (1.39 g) was added. The system was warmed to 40 °C and allowed to react for 3 hours. The reaction was monitored by LCMS, and the system was transferred to room temperature. Water was added to quench the reaction, and the organic phase was extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 1.86 g.

[0133] MS (ESI) m / z (M+H) + = 104.1.

[0134] Step 3: Preparation of 4-(methylsulfonyl)oxy)piperidine-l-carboxylic acid benzyl ester-2,2-d2

[0135] The crude 4-hydroxypiperidine-l-carboxylic acid benzyl ester-2,2-d2 (1.64 g) was dissolved in 1,2-dichloroethane (20 mL), 4-dimethylaminopyridine (19 mg) and N,N-diisopropylethylamine (3.72 g) were added, and finally methylsulfonic anhydride (1.39 g) was added. The system was warmed to 40 °C and allowed to react for 3 hours. The reaction was monitored by LCMS, and the system was transferred to room temperature. Water was added to quench the reaction, and the organic phase was extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 1.86 g. + = 104.1.

[0136] Step 4: Preparation of 4-azidopiperidine-l-carboxylic acid benzyl ester-2,2-d2

[0137] Benzyl 4-(methylsulfonyl)oxy)piperidine-l-carboxylate-2,2-d2 (1.86 g) was dissolved in N,N-dimethylacetamide (30 mL) under nitrogen atmosphere, sodium azide (585 mg) was added, the system was heated to 70 °C for 6 hours. After the reaction was completed, the system was moved to room temperature, quenched with water, extracted with ethyl acetate, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.5 g of a crude product.

[0138] MS (ESI) m / z (M+H) + = 263.1.

[0139] Step 5: Preparation of benzyl 4-aminopiperidine-l-carboxylate-2,2-d2

[0140] Benzyl 4-azidopiperidine-l-carboxylate-2,2-d2 crude product (1.5 g) and triphenylphosphine (1.57 g) were dissolved in tetrahydrofuran (15 mL) and water (5 mL) under nitrogen atmosphere, the system was heated to 70 °C overnight. After the reaction was completed, the system was moved to room temperature, quenched with water, extracted with ethyl acetate (30 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was purified by high-pressure preparative liquid chromatography to obtain 670 mg of the title compound.

[0141] MS (ESI) m / z (M+H) + = 237.1.

[0142] Step 6: Preparation of benzyl 4-(4-fluoro-2-(trifluoromethyl)benzamido)piperidine-l- carboxylate-2,2-d2

[0143] Benzyl 4-aminopiperidine-l-carboxylate-2,2-d2 (670 mg) was dissolved in dichloromethane (10 mL), N,N-diisopropylethylamine (732 mg) and 4-fluoro-2- (trifluoromethyl)benzoyl chloride (770 mg) were added in sequence, and the system was reacted at room temperature for 1 hour. After the reaction was completed, the system was quenched with water, extracted with ethyl acetate, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain 1.1 g of the title compound.

[0144] MS (ESI) m / z (M+H) + = 427.1.

[0145] Step 7: Preparation of benzyl 4-(4-fluoro-N-methyl-2-(trifluoromethyl)benzamido)piperidine- l-carboxylate-2,2-d2

[0146] Benzyl 4-(4-fluoro-2-(trifluoromethyl)benzamido)piperidine-l-carboxylate-2,2-d2 (200 mg) was dissolved in N,N-dimethylformamide (5 mL) under ice water bath, sodium hydride (38 mg) was added and stirred for 5 minutes. Iodomethane (71 mg) was added and the reaction was continued for 1 hour. The reaction was monitored by LCMS and was complete. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 190 mg.

[0147] MS (ESI) m / z (M+H) + = 441.1.

[0148] Step 8: Preparation of 4-fluoro-N-methyl-N-(piperidin-4-yl-2,2-d2)-2- (trifluoromethyl)benzamide

[0149] Benzyl 4-(4-fluoro-N-methyl-2-(trifluoromethyl)benzamido)piperidine-l- carboxylate-2,2-d2 (190 mg) was dissolved in ethanol (10 mL) under hydrogen atmosphere, 10% palladium on carbon (60 mg) was added and the reaction was continued at 60 °C for 1 hour. The reaction was monitored by LCMS and was complete. The system was allowed to reach room temperature and the solid was removed by suction filtration. The filter cake was washed with methanol several times. The filtrate was collected and concentrated under reduced pressure to give the crude product 200 mg.

[0150] MS (ESI) m / z (M+H) + = 307.1.

[0151] Step 9: Preparation of N-(l-(4-chlorophthalazin-l-yl)piperidin-4-yl-2,2-d2)-4- fluoro-N-methyl-2-(trifluoromethyl)benzamide

[0152] l,4-Dichlorophthalazine (103 mg), 4-fluoro-N-methyl-N-(piperidin-4-yl-2,2-d2)-2- (trifluoromethyl)benzamide crude (200 mg) and potassium carbonate (148 mg) were dissolved in N-methyl pyrrolidine (3 mL) under nitrogen atmosphere and the reaction was continued at 80 °C for 4 hours. After the reaction was complete, the system was quenched with water and extracted with ethyl acetate (30 mL). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by high pressure preparative liquid chromatography to give the title compound.

[0153] MS (ESI) m / z (M+H) + = 469.1.

[0154] Preparation Example 9: Preparation of N-(l-(4-chlorophthalazin-l-yl)piperidin-4-yl- 2,2-d2)-4-fluoro-N-(methyl-d3)-2-(trifluoromethyl)benzamide

[0155] Using the corresponding commercially available reagents and the product of Step 6 of Preparation Example 8 above, the title compound was prepared using a similar procedure as described in Preparation Example 8 above.

[0156] MS (ESI) m / z (M+H) + = 472.1.

[0157] Example 1: Preparation of 4-fluoro-N-methyl-N-(l-(4-(l-(methyl-d3)-lH-pyrazol-5- yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide

[0158] N-(l-(4-chlorophthalazin-l-yl)piperidin-4-yl)-4-fluoro-N-methyl-2- (trifluoromethyl)benzamide (100 mg), tetrakis(triphenylphosphine)palladium (30 mg) and potassium carbonate (59.2 mg) were dissolved in a mixture of toluene (0.9 mL), ethanol (0.3 mL) and water (0.3 mL) under nitrogen atmosphere, and the mixture was heated to about 74 °C. 1-(methyl-d3)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (90.6 mg) was added dropwise slowly, and the reaction was continued for 1 hour. LCMS showed that the starting material was consumed completely. The system was allowed to cool to room temperature, and the reaction was quenched with water. The organic phase was extracted with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography and high performance liquid chromatography to give 70 mg of the title compound.

[0159] MS (ESI) m / z (M+H) + = 516.2.

[0160] 1 H NMR (400 MHz, DMSO-d6) δ 8.25 - 8.15 (m, 1H), 8.05 - 7.88 (m, 3H), 7.85 - 7.74 (m, 1H), 7.71 - 7.54 (m, 3H), 6.68 (dd, J = 8.2, 1.9 Hz, 1H), [4.73 - 4.60 (m, 0.6H), 3.46 - 3.36 (m, 0.4H)], 4.00 (dd, J = 59.4, 12.9 Hz, 2H), 3.22 (t, J = 12.8 Hz, 1H), 3.00 (s, 1H), 2.94 - 3.78 (m, 1H), 2.71 (s, 2H), 2.34 - 2.06 (m, 2H), 2.05 - 1.73 (m, 2H).

[0161] Example 2: Preparation of 4-fluoro-N-(methyl-d3)-N-(l-(4-(l-methyl-lH-pyrazol-5- yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide

[0162] N-(l-(4-chlorophthalazin-l-yl)piperidin-4-yl)-4-fluoro-N-(methyl-d3)-2- (trifluoromethyl)benzamide (70 mg), l-methyl-lH-pyrazole-5-boronic acid pinacol ester (46 mg) and sodium carbonate (32 mg) were dissolved in toluene (0.6 mL), ethanol (0.2 mL) and water (0.2 mL) under nitrogen atmosphere, and tetrakis triphenylphosphine palladium (35 mg) was added, and the reaction was carried out at about 74 °C for 2 hours. After the reaction was completed, the system was cooled to room temperature, quenched with an appropriate amount of water, extracted with ethyl acetate (30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative TLC and high pressure liquid chromatography to give 38 mg of the title compound.

[0163] MS (ESI) m / z (M+H) + = 516.2.

[0164] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 - 8.14 (m, 1H), 8.05 - 7.88 (m, 3H), 7.83 - 7.76 (m, 1H), 7.70 - 7.57 (m, 3H), 6.68 (dd, J = 8.3, 1.9 Hz, 1H), [4.71 - 4.65 (m, 0.67H), 3.47 - 3.38 (m, 0.33H)], 4.00 (dd, J = 59.4, 13.0 Hz, 2H), 3.87 (s, 2H), 3.84 (s, 1H), [3.22 (t, J = 12.7 Hz, 1.34H), 2.91 - 2.82 (m, 0.66H)], 2.30 - 2.10 (m, 2H), 1.97 - 1.61 (m, 2H).

[0165] Example 3: Preparation of 4-fluoro-N-(methyl-d3)-N-(l-(4-(l-(methyl-d3-)-lH-pyrazol-5- yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide

[0166] Using the corresponding commercially available reagents and the products in the aforementioned Preparation Examples as starting materials, the title compound was prepared by the similar method as described in Example 2.

[0167] MS (ESI) m / z (M+H) + = 519.2.

[0168] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 - 8.14 (m, 1H), 8.05 - 7.88 (m, 3H), 7.83 - 7.76 (m, 1H), 7.70 - 7.57 (m, 3H), 6.68 (dd, J = 8.3, 1.9 Hz, 1H), [4.71 - 4.65 (m, 0.67H), 3.47 - 3.38 (m, 0.33H)], 4.00 (dd, J = 59.4, 13.0 Hz, 2H), [3.22 (t, J = 12.7 Hz, 1.34H), 2.91-2.82 (m, 0.66H)], 2.30 - 2.10 (m, 2H), 1.97 - 1.61 (m, 2H).

[0169] Example 4: Preparation of 4-fluoro-N-(methyl-d3)-N-(l-(4-(l-(methyl-d3)-lH- pyrazol-5-yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide hydrochloride

[0170] To 4-fluoro-N-(methyl-d3)-N-(l-(4-(l-(methyl-d3)-lH-pyrazol-5-yl)phthalazin-l- yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide (80 mg) in dichloromethane (1 mL) was added dropwise hydrogen chloride / 1,4-dioxane solution (1.0 M, 0.34 mL) and stirred for half an hour. The system was concentrated under reduced pressure and the solvent was removed to give the title compound 80 mg.

[0171] MS (ESI) m / z (M+H) + = 519.2.

[0172] 1 H NMR (400 MHz, DMSO-d6) δ 8.48 - 8.32 (m, 1H), 8.18 - 8.07 (m, 2H), 8.04 - 7.97 (m, 1H), 7.83 - 7.76 (m, 1H), 7.73 - 7.58 (m, 3H), 6.78 (dd, J = 9.0, 2.0 Hz, 1H), 4.84 - 4.70 (m, 0.67H), 4.36 - 4.12 (m, 2H), 3.62 - 3.54 (m, 1.67H), 3.34 - 3.19 (m, 0.66H), 2.33 - 2.13 (m, 2H), 2.01 - 1.79 (m, 1.67H), 1.70 - 1.64 (m, 0.33H).

[0173] Example 5: Preparation of 4-fluoro-N-(methyl-d3)-N-(1-(4-(1-methyl-1H- pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide hydrochloride

[0174] Using the corresponding commercially available reagents and the product in the previous Example 2 as starting material, the title compound was prepared by the similar procedure described in Example 4.

[0175] MS (ESI) m / z (M+H) + = 516.2.

[0176] 1 H NMR (400 MHz, DMSO-d6) δ 8.47 - 8.29 (m, 1H), 8.17 - 8.07 (m, 2H), 8.03 - 7.95 (m, 1H), 7.84 - 7.77 (m, 1H), 7.74 - 7.59 (m, 3H), 6.77 (dd, J = 9.0, 2.0 Hz, 1H), 4.82 - 4.70 (m, 0.67H), 4.34 - 4.09 (m, 2H), 3.88 (d, J = 10.6 Hz, 3H), 3.57 - 3.48 (m, 1.66H), 3.29 - 3.14 (m, 0.67H), 2.32 - 2.14 (m, 2H), 2.04 - 1.78 (m, 1.67H), 1.70 - 1.62 (m, 0.33H).

[0177] Example 6: Preparation of 4-fluoro-N-methyl-N-(1-(4-(1-(methyl-d3)-1H-pyrazol-5- yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide hydrochloride

[0178] Using the corresponding commercially available reagents and the product in the previous Example 1 as starting material, the title compound was prepared by the similar procedure described in Example 4.

[0179] MS (ESI) m / z (M+H) + = 516.2.

[0180] 1H NMR (400 MHz, DMSO-d6) δ 8.41 - 8.23 (m, 1H), 8.17 - 8.02 (m, 2H), 8.02 - 7.92 (m, 1H), 7.85 - 7.75 (m, 1H), 7.74 - 7.65 (m, 2H), 7.61 - 7.50 (m, 1H), 6.74 (dd, J = 9.3, 2.0 Hz, 1H), [4.80 - 4.66 (m, 0.6H), 3.60 - 3.50 (m, 0.4H)], 4.21 (d, J = 12.9 Hz, 2H), 3.46 - 3.40 (m, 1H), 3.20 - 3.03 (m, 1H), 2.99 (s, 1H), 2.70 (s, 2H), 2.35 - 2.11 (m, 2H), 2.05 - 1.61 (m, 2H).

[0181] Example 7: Preparation of 4-fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl) phthalazin-1-yl-5-d)piperidin-4-yl)-2-(trifluoromethyl)benzamide

[0182] The title compound was prepared by using the similar preparation method described in Example 2 above, starting from the corresponding commercially available reagents and the product in Preparation Example 4.

[0183] MS (ESI) m / z (M+H) + = 514.1.

[0184] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 - 8.14 (m, 1H), 8.06 - 7.92 (m, 2H), 7.83 - 7.74 (m, 1H), 7.72 - 7.56 (m, 3H), 6.68 (dd, J = 8.3, 1.9 Hz, 1H), [4.74 - 4.60 (m, 0.6H), 3.46 - 3.35 (m, 0.4H)], 4.14 - 3.90 (m, 2H), 3.89 - 3.78 (m, 3H), 3.22 (t, J = 12.8 Hz, 1H), 3.00 (s, 1H), 2.95 - 2.79 (m, 1H), 2.71 (s, 2H), 2.33 - 2.05 (m, 2H), 2.04 - 1.74 (m, 2H).

[0185] Example 8: Preparation of 4-fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl) phthalazin-1-yl-8-d)piperidin-4-yl)-2-(trifluoromethyl)benzamide

[0186] Using the similar preparation method of Example 2 above, the title compound was prepared from the corresponding commercially available reagents and the product in Preparation Example 5 above.

[0187] MS (ESI) m / z (M+H) + = 514.1.

[0188] 1 H NMR (400 MHz, DMSO-d6) δ 8.05 - 7.89 (m, 3H), 7.83 - 7.75 (m, 1H), 7.72 - 7.55 (m, 3H), 6.69 (dd, J = 8.3, 1.9 Hz, 1H), [4.74 - 4.60 (m, 0.6H), 3.45 - 3.35 (m, 0.4H)], 4.15 - 3.90 (m, 2H), 3.89 - 3.78 (m, 3H), 3.22 (t, J = 12.8 Hz, 1H), 3.00 (s, 1H), 2.96 - 2.79 (m, 1H), 2.71 (s, 2H), 2.32 - 2.06 (m, 2H), 2.04 - 1.74 (m, 2H).

[0189] Example 9: Preparation of 4-fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl-4-d)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide

[0190] Using the similar preparation method of Example 2 above, the title compound was prepared from the corresponding commercially available reagents and the product in Preparation Example 6 above.

[0191] MS (ESI) m / z (M+H) + = 514.1.

[0192] 1 H NMR (400 MHz, DMSO-d6) δ 8.05 - 7.89 (m, 3H), 7.83 - 7.75 (m, 1H), 7.72 - 7.55 (m, 3H), 6.69 (dd, J = 8.3, 1.9 Hz, 1H), [4.74 - 4.60 (m, 0.6H), 3.45 - 3.35 (m, 0.4H)], 4.15 - 3.90 (m, 2H), 3.89 - 3.78 (m, 3H), 3.22 (t, J = 12.8 Hz, 1H), 3.00 (s, 1H), 2.96 - 2.79 (m, 1H), 2.71 (s, 2H), 2.32 - 2.06 (m, 2H), 2.04 - 1.74 (m, 2H).

[0193] Example 10: Preparation of 4-fluoro-N-methyl-N-(l-(4-(l-methyl-lH-pyrazol-5-yl) phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide

[0194] Using the corresponding commercially available reagents and the product in the above Preparation Example 7 as starting materials, the title compound was prepared by the similar procedure described in Example 2.

[0195] MS (ESI) m / z (M+H) + = 514.1.

[0196] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 - 8.14 (m, 1H), 8.06 - 7.88 (m, 3H), 7.83 - 7.74 (m, 1H), 7.71 - 7.55 (m, 2H), 6.68 (dd, J = 8.3, 1.9 Hz, 1H), [4.74 - 4.60 (m, 0.6H), 3.46 - 3.35 (m, 0.4H)], 4.14 - 3.90 (m, 2H), 3.89 - 3.79 (m, 3H), 3.22 (t, J = 12.8 Hz, 1H), 3.00 (s, 1H), 2.94 - 2.79 (m, 1H), 2.71 (s, 2H), 2.34 - 2.06 (m, 2H), 2.05 - 1.74 (m, 2H).

[0197] Example 11: Preparation of 4-fluoro-N-methyl-N-(l-(4-(l-methyl-lH-pyrazol-5-yl) phthalazin-l-yl)piperidin-4-yl-2,2-d2)-2-(trifluoromethyl)benzamide

[0198] Using the corresponding commercially available reagents and the product in the above Preparation Example 8 as starting materials, the title compound was prepared by the similar procedure described in Example 2.

[0199] MS (ESI) m / z (M+H) + = 515.1.

[0200] 1H NMR (400 MHz, DMSO-d6) δ 8.25 - 8.13 (m, 1H), 8.05 - 7.89 (m, 3H), 7.82 - 7.75 (m, 1H), 7.70 - 7.56 (m, 3H), 6.68 (dd, J = 8.3, 1.9 Hz, 1H), 4.76 - 4.60 (m, 0.67H), 4.15 - 4.03 (m, 0.67H), 3.98 - 3.90 (m, 0.33H), 3.86 (d, J = 13.5 Hz, 3H), 3.28 - 3.12 (m, 1H), 3.00 (s, 1H), 2.91 - 2.82 (m, 0.33H), 2.71 (s, 2H), 2.32 - 2.09 (m, 2H), 1.99 - 1.74 (m, 1.67H), 1.66 - 1.60 (m, 0.33H).

[0201] Example 12: Preparation of 4-fluoro-N-(methyl-d3)-N-(1-(4-(1-(methyl-d3)-1H- pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl-2,2-d2)-2-(trifluoromethyl)benzamide

[0202] The title compound was prepared by using the similar preparation method described in Example 2 above, starting from the corresponding commercially available reagents and the product in Preparation 9.

[0203] MS (ESI) m / z (M+H) + = 521.1.

[0204] 1 H NMR (400 MHz, DMSO-d6) δ 8.18 - 8.05 (m, 1H), 7.98 - 7.78 (m, 3H), 7.76 - 7.66 (m, 1H), 7.63 - 7.46 (m, 3H), 6.65 - 6.54 (m, 1H), 4.69 - 4.48 (m, 0.67H), 4.11 - 3.93 (m, 0.67H), 3.91 - 3.79 (m, 0.33H), 3.39 - 3.32 (m, 0.33H), 3.20 - 3.10 (m, 0.67H), 2.86 - 2.73 (m, 0.33H), 2.22 - 2.02 (m, 2H), 1.89 - 1.65 (m, 1.67H), 1.60 - 1.51 (m, 0.33H).

[0205] Biological Example

[0206] Test Example 1: Cell viability test

[0207] 1 Purpose of Experiment

[0208] Determination of the inhibitory activity of the compounds of the present application on SMO receptor.

[0209] 2 Experimental materials

[0210] 2.1 Main reagents / cells

[0211] 3 Experimental method

[0212] 3.1 Luciferase Assay Reagent (LAR): add a whole bottle of Bright-Glo Buffer to a bottle containing freeze-dried substrate (Bright-Glo Substrate), mix, and dissolve the substrate. To avoid repeated freeze-thawing, aliquot the prepared LAR. Before each use, equilibrate the LAR to room temperature.

[0213] 3.2 Transient transfection of GLI luciferase reporter vector in NIH3T3 cells, incubate in a constant temperature incubator for 20-30 h. After incubation, discard the supernatant, digest, centrifuge, resuspend with DMEM medium, count, and add to a white 96-well plate at a density of 2x10 4 cells per well;

[0214] 3.3 Add 10x test compound: prepare a 10x test compound solution with DMED medium, 4-fold serial dilution of 9 gradients. Add 10 μL of test compound at different concentrations to each well, and incubate in an incubator for 1 h.

[0215] 3.4 Add SAG: prepare SAG with fresh DMEM medium, and add the prepared SAG to each well to make the final concentration 100 nM. Set up blank control group (containing only cells) and SAG group (containing cells and SAG) synchronously.

[0216] 3.5 Mix well, and incubate the plate in an incubator for 24 h.

[0217] 3.6 Take out the cell culture plate after incubation, equilibrate at room temperature, add an appropriate amount of LAR to each well, incubate at room temperature, and detect.

[0218] 3.7 Fluorescence detection: after equilibration of the cells at room temperature, add 100 μL of LAR to each well (i.e. add an equal volume of reagent to the volume of medium in the well), and lyse at room temperature for 2-5 min. Use a syringe to suck the lysate into an opaque 96-well white plate (150 ul / well). Use Graph Pad Prism8 to analyze the data and calculate the IC 50 value.

[0219] 4 Data analysis

[0220] Data were analyzed using Graph Pad Prism four-parameter non-linear regression and IC 50 values were calculated.

[0221] The IC 50 values of the compounds of Examples 1, 2 and 3, and 7-12 of the present application determined by the above method were all <100 nM.

[0222] Test Example 2: Liver microsomal stability test

[0223] 1. Purpose of experiment

[0224] The stability of the compounds of the present application in mouse, rat, monkey and human liver microsomes was determined.

[0225] 2. Reagents and consumables

[0226] 3. Experimental procedure

[0227] 3.1 Incubation system for test

[0228] 3.2 An appropriate amount of liver microsomal solution was removed into a 1 mL 96-deep well plate, and the test drug solution (or probe substrate solution) was added, and pre-incubated at 37°C in a thermal mixer for 5 min. Two portions of the mixture were removed from the system, and 1xPBS was added instead of NADPH, and the mixture was removed at 0, 60 min, and methanol (containing internal standard) was added to terminate the reaction. NADPH was added to start the reaction in the remaining mixture, and the test group was removed at 0, 5, 15, 30, 45, 60 min, and the control group was removed at 0, 30, 60 min, and methanol (containing internal standard) was added to terminate the reaction. All samples after termination of the reaction were mixed, centrifuged at 3800 rpm for 15 min in a centrifuge, and the supernatant was subjected to LC-MS / MS analysis.

[0229] 3.3 Data analysis

[0230] The peak area was determined from the extracted ion chromatogram. The slope value k was determined by linear regression of the natural logarithm of the percentage of the parent drug remaining versus incubation time. The in vitro half-life (t 1 / 2 ) was calculated from the slope, and the in vitro intrinsic clearance (CL int ) was calculated, expressed in μL / min / mg protein. The calculation formulae are as follows:

[0231] t 1 / 2 = ln2 / k = 0.693 / k; CL int = 0.693 / t 1 / 2 / protein concentration of liver microsomes

[0232] The stability data of the compounds of the present application in mouse, rat, monkey and human liver microsomes are shown in the following table:

[0233] Surprisingly, referring to the human PK clearance level classification in "Pharmacokinetics: From ADME to Safety Optimization of Concepts, Structure Design and Methods", the compound of Example 3 unexpectedly has a particularly "low" clearance classification, which is expected to provide more persistent drug efficacy, more stable blood drug concentration, lower drug dosage or drug frequency, and lower metabolic burden, thereby improving efficacy and reducing side effects.

[0234] Test Example 3: In vivo pharmacokinetic study of SD rats administered with test compounds by intravenous and gavage

[0235] 1. Experimental animals

[0236] Species: SD rats, 200-220 g, male, SPF level, a total of 24. Source: purchased from Sichuan Weitong Lihua Experimental Animal Technology Co., Ltd., Experimental Animal Production License No.: SCXK (Chuan) 2023-0040.

[0237] 2. Preparation of test sample

[0238] 2.1 Accurately weigh an appropriate amount of drug, first add 5% DMSO to the final volume and stir to dissolve, then add 95% 10% HP-β-CD, ultrasonic, vortex and mix to obtain a 0.2 mg / mL drug solution for intravenous administration.

[0239] 2.2 Accurately weigh an appropriate amount of drug, first add 5% DMSO to the final volume and stir to dissolve, then add 95% 10% HP-β-CD, ultrasonic, vortex and mix to obtain a 0.5 mg / mL drug solution for gavage administration.

[0240] 3. Test design

[0241] 4. Blood sampling time points

[0242] 5 min, 15 min, 0.5, 1, 2, 4, 6, 8, 24 h after administration.

[0243] 5. Sample collection and disposal

[0244] Blood samples were collected via jugular vein, about 0.2 mL per sample, anticoagulated with EDTA-K2, and placed on ice after collection. The blood samples were centrifuged (6000g, 5 min, 2-8℃) within 2 hours after collection. The plasma samples were stored at -70℃ before analysis, and the remaining plasma samples were stored at -70℃ after analysis.

[0245] 6. Bioanalysis and data processing

[0246] The plasma concentration of the designated compound was determined by LC-MS / MS method, and the main pharmacokinetic parameters were calculated by Winnolin 8.3 non-compartment model. When calculating the pharmacokinetic parameters, C max BLQ (including "No peak") before was calculated as 0; C max BLQ (including "No peak") after was not involved in the calculation.

[0247] The in vivo pharmacokinetic data of the compound of the present application in SD rats given intravenously and orally are shown in the following table:

[0248] Test Example 4: In vivo pharmacokinetic study of the test compound given intravenously and orally to ICR mice

[0249] 1. Experimental animals

[0250] Species: ICR mice, 20-22 g, male, SPF level, a total of 24. Source: purchased from Sichuan Weitong Lihua Experimental Animal Technology Co., Ltd., Experimental Animal Production License No.: SCXK (Chuan) 2023-0040.

[0251] 2. Preparation of test sample

[0252] 2.1 Accurately weigh an appropriate amount of drug, first add 5% DMSO to the final volume, and stir to dissolve, then add 95% 10% HP-β-CD, ultrasonic, vortex to mix, to get 0.4 mg / mL of drug solution for intravenous injection.

[0253] 2.2 Accurately weigh an appropriate amount of drug, first add 5% DMSO to the final volume, and stir to dissolve, then add 95% 10% HP-β-CD, ultrasonic, vortex to mix, to get 1 mg / mL of drug solution for oral administration.

[0254] 3. Test design

[0255] 4. Blood sampling time points

[0256] 5 min, 15 min, 0.5, 1, 2, 4, 6, 8, 24 h after dosing.

[0257] 5. Sample collection and disposal

[0258] Blood samples were collected from the orbital plexus, approximately 0.04 mL per sample, anti-coagulated with EDTA-K2. Blood samples were placed on ice after collection and centrifuged for plasma separation (centrifugation condition: 6000g, 5 min, 2-8°C) within 2 hours. The collected plasma samples were stored at -70°C before analysis, and the remaining plasma samples were stored at -70°C after analysis.

[0259] 6. Bioanalysis and data processing

[0260] LC-MS / MS method was used to determine the drug concentration of the specified compound in plasma, and Winnolin 8.3 non-compartment model was used to calculate the main pharmacokinetic parameters. When calculating the pharmacokinetic parameters, C max BLQ (including "No peak") before was calculated as 0; C max BLQ (including "No peak") after was not involved in the calculation.

[0261] The in vivo pharmacokinetic data of the compound of the present application in ICR mice by intravenous and gavage are shown in the following table:

Claims

1. A compound of the formula ###0001### or a pharmaceutically acceptable salt, stereoisomer, and solvate thereof, 2. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer and solvate thereof, wherein: R1and R2are independently of each other selected from CH3and CD3; R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , and R 12 are independently of each other selected from H and deuterium; provided that when R3, R4, R5, R6, R7, R8, R 10 , R 11 , and R 12 are all H, R1 and R2 are not both CH3.

3. The compound of claim 2 of formula (I) or a pharmaceutically acceptable salt, stereoisomer and solvate thereof, wherein R1is CD3.

4. The compound of claim 2 of formula (I) or a pharmaceutically acceptable salt, stereoisomer and solvate thereof, wherein R2is CD3.

5. The compound of claim 2 of formula (I) or a pharmaceutically acceptable salt, stereoisomer and solvate thereof, wherein R1and R2are both CD3.

6. The compound of any one of claims 2-5 of formula (I) or pharmaceutically acceptable salts, stereoisomers, and solvates thereof, wherein R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , and R 12 are each H.

7. The compound of any one of claims 2-5 of Formula (I) or pharmaceutically acceptable salts, stereoisomers, and solvates thereof, wherein at least one of R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , and R 12 is deuterium.

8. The compound of any one of claims 2-5 of Formula (I) or pharmaceutically acceptable salts, stereoisomers, and solvates thereof, wherein R3, R4, R5, R6, R7, R8, R9, and R 10 two or more of which are deuterium.

9. The compound of any one of claims 2-5 of Formula (I) or pharmaceutically acceptable salts, stereoisomers, and solvates thereof, wherein R 11 and at least one of R 12 is deuterium.

10. The compound of claim 2 of formula (I) or pharmaceutically acceptable salts, stereoisomers, and solvates thereof, selected from the group consisting of:

11. The compound according to any one of claims 2 to 10 or a pharmaceutically acceptable salt, stereoisomer and solvate thereof, wherein the stereoisomer is a atropisomer, including individual atropisomers and mixtures of any ratio of the individual atropisomers.

12. The compound according to any one of claims 2 to 11 or a pharmaceutically acceptable salt, stereoisomer and solvate thereof, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

13. A pharmaceutical composition comprising a compound, stereoisomer or a pharmaceutically acceptable salt and solvate thereof according to any one of claims 2 to 12 and a pharmaceutically acceptable excipient.

14. Use of a compound according to any one of claims 2 to 12 or a pharmaceutically acceptable salt, stereoisomer and solvate thereof for the manufacture of a medicament for the treatment of a disease which can be treated or prevented by inhibition of SMO, preferably the disease is selected from the group consisting of cancer and fibrotic diseases; more preferably the cancer is selected from the group consisting of brain cancer, basal cell carcinoma, esophageal cancer, gastric cancer, pancreatic cancer, biliary tract cancer, prostate cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, B-cell lymphoma, multiple myeloma, ovarian cancer, colorectal cancer, liver cancer, kidney cancer, melanoma, head and neck cancer, mesothelioma, soft tissue sarcoma, osteosarcoma, leukemia and testicular cancer, and the fibrotic disease is idiopathic pulmonary fibrosis.

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